Completed, Recruiting, Terminated, Active, not recruiting, Unknown status, Not yet recruiting, Enrolling by invitation

Principal Investigators

Social determinants such as education, income, marital status, and social networks play a crucial role in cancer outcomes, including breast cancer. One potential influencing factor is diet, and the Mediterranean diet has been shown to benefit both the health and the microbiome. This raises the question: Does adherence to the Mediterranean diet impact the microbiome, quality of life, overall well-being, and outcomes in breast cancer patients undergoing (neo)adjuvant treatment, particularly among those with unfavorable socioeconomic determinants? The Mediterranean diet consists of plant foods such as vegetables, fruits, nuts, seeds, berries, legumes, herbs, and spices. It also features animal proteins like fish, meat, and cheese, along with fat from olive oil. Thus, adherence to the Mediterranean diet is adherence to the official Danish diet recommendations. This phase II clinical trial is an interdisciplinary study combining nutrition, sociology, and health research. Breast cancer patients candidates for (neo)adjuvant treatment at four oncology departments in Region South Denmark will be randomized 2:1 to the Mediterranean diet (with individual dietary guidance from a nutrition therapist aiming at daily consumption of a minimum of 30 grams of dietary fiber and weekly consumption of a minimum of 30 different plant foods; minimizing the amount of ultra-processed food) versus the patient's regular diet, in conjuction with the (neo)adjuvant chemotherapy. The trial's primary endpoint will be changes in gut microbiota composition in feces. The study evaluates how the Mediterranean diet affects the microbiota (evaluated using Oxford Nanopore Technology 16S sequencing on fecal samples); short-chain fatty acids in stool and plasma (assessed by mass spectrometry); immune system (using flow cytometry for immune cell determination in blood and immunohistochemical determination of immune cells in the tumor tissue); and patients' social quality of life, overall well-being, sense of empowerment, and personal feeling of agency (using the WHOQOL-100 questionnaire); taking into account the impact of the distance from the patient residence to the hospital (tracked from GEOTEAM at Statistics Denmark), and socioeconomic factors (using the DREAM database). The evaluation of biological parameters is based on the suggested mechanism of action. A diet rich in various plant foods and dietary fiber will alter the gut microbiota, promoting bacteria producing high amounts of short-chain fatty acids. These fatty acids will activate immune cells, aiding in the destruction of cancer cells. The study will also assess whether the Mediterranean diet will positively impact the patients' social quality of life, overall well-being, sense of empowerment, and personal feeling of agency. The Mediterranean diet may not only lead to improved dietary habits but also serve as a crucial tool for breast cancer patients, particularly among those with unfavorable socioeconomic determinants. Enhanced empowerment and improved coping tools could be an important step in combating cancer-related inequalities.

STUDY PURPOSE The project investigates whether adherence to the Mediterranean diet can influence the microbiome, improve quality of life, overall well-being, sense of empowerment, personal feeling of agency, immune activity, levels of short-chain fatty acids and patient outcomes in breast cancer patients undergoing chemotherapy. Additionally, it examines if these effects are more pronounced in individuals with challenging socioeconomic determinants. BREAST CANCER Among women, breast cancer is the most diagnosed cancer, and is the leading cause of cancer deaths globally in most countries, with 2.3 million new cases recorded in 2022 and approximately 665,000 deaths. In Denmark, there are 5000 new cases, and 1.050 deaths annually, of those 250 in the Region of Southern Denmark. In men, breast cancer is rare with an average of 42 new cases annually in Denmark. ONCOLOGICAL TREATMENT The oncological treatment of early breast cancer encompasses neoadjuvant (pre-surgery) and adjuvant (post-surgery) treatments.Chemotherapy comprising anthracyclines and taxanes is a cornerstone in both neoadjuvant and adjuvant settings for breast cancer treatment. These drugs have been shown to significantly improve patient outcomes as these regimens are particularly effective in shrinking tumors before surgery, reducing the risk of recurrence and improving overall survival. HER2-targeted therapies, such as trastuzumab, are specifically used for HER2-positive breast cancers in conjunction with chemotherapy and have significantly improved outcomes. Recently, checkpoint immunotherapy, pembrolizumab, has been approved in Denmark for triple-negative early breast cancer together with chemotherapy due to increased pathological complete response (pCR). SOCIOECONIC INEQUALITY At the national level, disparities in breast cancer outcomes are commonly observed along socioeconomic and demographic lines in both low-, middle- and, high-income countries. These disparities are evident across all stages of the breast cancer continuum, from exposure to modifiable risk factors to access to palliative care and mortality rates. Consequently, women with lower socioeconomic status are more likely to present with late-stage cancer and experience poorer breast cancer prognoses compared to those with higher socioeconomic status. Cancer inequalities at the individual level are predominantly shaped by systemic social determinants of health. In Denmark an estimated 21% of breast cancer deaths five years after the diagnosis of breast cancer could have been avoided, had patients in all income groups had the same survival rate as the high-income group. Thus, social inequality in cancer survival is a critical problem, and patients with little education, low income, or living alone have poorer survival than better educated cancer patients, with higher income, and living in a relationship. This applies despite women with higher socioeconomic status having significantly higher breast cancer incidence. GUT MICROBIOTA AND MEDITERRANEAN DIET The human gut hosts approximately 38 trillion cells called the microbiota; the human gut microbiome consists of the genes these cells harbor. In the 2022 update of Hallmarks of Cancer, the microbiome was introduced as a new important hallmark of cancer. Importantly, the microbiome modulates four other hallmarks: tumor growth, tumor-promoting inflammation, immune evasions, and genomic instability; additionally, the microbiome modulates therapy resistance. The implication is, therefore, that the microbiome is a critical link in cancer development, progression, and treatment response. The Mediterranean diet is defined as the consumption of fresh fruits, vegetables, nuts, berries, legumes, and non-refined cereals. Olive oil is the principal source of lipids. Moderate intake of alcohol, preferably red wine, with meals; moderate consumption of fish, poultry, eggs, low-fat dairy products, and sweets; monthly consumption of red meat; and regular physical activity. As the Mediterranean diet includes a wide variety of plant foods and proteins from animal sources, it is a flexible option for many patients. It is not restrictive and allows for many different types of food, with the main limitation being processed foods. This flexibility was a key reason why Harvey et al. chose this diet for a randomized clinical trial involving cancer patients. The study aimed to measure fatigue during chemotherapy and included a sub-study to qualitatively assess how patients felt about making dietary changes during their treatment, identifying facilitators and barriers. Importantly, patients reported that the diet gave them a sense of control and empowerment. They enjoyed learning about nutrition, trying new foods, feeling in control, setting goals, doing something constructive to aid their treatment, and having a positive focus. Barriers included chemotherapy side effects (mouth sores, taste changes, and lack of energy) and food preferences. Higher adherence to the Mediterranean diet was associated with a 23% lower risk of all-cause mortality. The Mediterranean diet was feasible and safe for adults with cancer. Mediterranean diet has been associated with a reduced risk of breast cancer development. Its impact on survival outcomes after breast cancer diagnosis remains an area of active investigation. Changes in the microbiome composition were observed already after four weeks of the Mediterranean diet. The Mediterranean diet has several effects, including lipid-lowering and anti-inflammatory actions, reducing chronic inflammation. Moreover, bacteria in the gut ferment dietary fiber to short-chain fatty acids; factors that upregulate immune functions. Short-chain fatty acids are important as an energy source for intestinal epithelial cells, but some enter the bloodstream and act as signaling molecules. They target G-protein-coupled receptors (GPCR) GPCR41, GPCR43, and GPCR109A. Several studies in patients with melanoma, and cancers of the kidney, lung, and bladder have found that bacterial diversity at baseline can predict response to immunotherapy treatment; some types of bacteria are often reported to be found in larger quantities at baseline in responders than in non-responders, especially Akkermansia mucinifila, Ruminococcaceae, Faecalibacterium, and Lachnospiraceae. In patients with primary HER2-positive breast cancer undergoing trastuzumab treatment, a recent study revealed the direct involvement of the gut microbiota in trastuzumab efficacy. To the extend of our knowledge, the association with response to checkpoint immunotherapy in breast cancer patients has not been reported. MICROBIOME AND VITAMIN D Vitamin D has recently been associated with changes in the microbiome and cancer outcomes. Vitamin D is the only vitamin not normally consumed sufficiently even in a well-balanced diet. The main source of vitamin D is solar exposure to the skin. Denmark is situated between the 55th and 57th northern latitudes and therefore UV exposure is insufficient for vitamin D production for large parts of the year. Measurements of vitamin D will be performed at baseline and at Day 1 of cycle 6, and daily supplementation with 50 micrograms of vitamin D is encouraged. POTENTIAL BENEFITS AND RISKS The potential benefits are that the Mediterranean diet will result in greater microbial diversity during (neo)adjuvant therapy, increase the amounts of short-chain fatty acids in serum and stool, activate the immune system, and improve patient outcomes. Moreover, the Mediterranean diet may positively impact the patient's social quality of life, overall well-being, sense of empowerment, and personal feeling of agency. Additionally, these effects may be more pronounced in individuals with challenging socioeconomic determinants. The potential risk of harm is considered minimal since the intervention is food, and the investigated Mediterranean Diet is comparable to the diet recommended by the Danish Health Authorities (foedevarestyrelsen.dk) The study will be carried out according to the principles outlined in the Declaration of Helsinki. With food as the intervention, the study does not need monitoring from the GCP unit, according to Danish rules. INTERVENTION The intervention is the Mediterranean Diet. STUDY POPULATION The study population consists of patients with newly diagnosed early breast cancer, candidates for (neo)adjuvant chemotherapy-based treatment at one of the participating sites in the Region of Southern Denmark. PATIENT INVOLVEMENT A patient panel, comprising four breast cancer survivors and one representative from a cancer patient association, is actively involved in the design and execution of the MEDITERRACARE study helping developping patient information material, review and provide feedback on questionnaires, and offer practical insights for conducting the trial. RELEVANCE OF THE TRIAL Changes in bacterial composition can occur within a few weeks of switching to a diet rich in dietary fiber and various plant foods. A positive correlation between gut microbiota and favorable outcomes to checkpoint immunotherapy has been demonstrated in cancer patients. Gut microbiota is important for HER2 therapy efficacy. Socioeconomic inequalities are critical for breast cancer patients. The study will evaluate whether adherence to the Mediterranean diet can influence the microbiome, and improve quality of life, overall well-being, sense of empowerment, personal feeling of agency, immune activity, amounts of short-chain fatty acids, and patient outcomes in breast cancer patients undergoing chemotherapy. Additionally, it examines if these effects are more pronounced in individuals with challenging socioeconomic determinants. This study addresses a knowledge gap. No study worldwide has assessed the Mediterranean diet in early breast cancer patients during chemotherapy with special emphasis on socioeconomic inequality. HYPOTHESIS The hypothesis is that the Mediterranean diet results in greater microbial diversity during (neo)adjuvant therapy, increases the amounts of short-chain fatty acids in serum and stool, increases the numbers of T- and Natural Killer cells in blood and tumor tissue, reduces inflammation in blood and tumor tissue, and improves patient outcomes. Moreover, the Mediterranean diet will positively impact the patient's social quality of life, overall well-being, sense of empowerment, and personal feeling of agency. Additionally, these effects will be more pronounced in individuals with challenging socioeconomic determinants. STUDY DESIGN The MEDITERRACARE study is designed as a phase II randomized, controlled trial with two arms in a 2:1 allocation ratio evaluating the Mediterranean diet versus regular diet, and a primary endpoint of changes in gut microbiota composition. The study protocol is reported following the CONSORT guidelines. STUDY SETTING AND RECRUITEMENT Enrolment takes place at four Danish oncology outpatient clinics in the Region of Southern Denmark (Odense, Vejle, Sønderborg, Esbjerg). Randomization will be performed as block randomization with 2:1 allocation using a computer-generated table of block sizes of 6 or 9, created and supervised by a data manager at OPEN, Open Patient Data Explorative Network, Odense University Hospital, Region of Southern Denmark. Blinding of patients and health care professionals involved is not intended. DETAILS ON INTERVENTION The patients randomized to the intervention arm, and if possible a partner or other family member, will receive nutritional guidance during the weekly outpatient chemotherapy visits or via online calls or home visits. Initially 1x weekly during the first month and every other week onwards. In addition, patients will get a booklet on how to implement the Mediterranean Diet in daily life, and access to a password-protected website with teaching videos and Mediterranean diet recipes. To ensure compliance regarding sampling of feces and reporting of food intake patients in the control arm will also be called on during visits to the department. Group sessions will be arranged for patients randomized to the Mediterranean diet and a hot-line is open during working hours. DATA COLLECTION Study data will be collected and managed using the REDCap electronic data capture tool (Vanderbilt University, v.12.0.33) hosted at OPEN (Open Patient Data Explorative Network, Odense University Hospital). At the first consultation at the Department of Oncology, a blood test will be drawn for baseline values and kits for stool sampling at home will be provided to the patient. The stool sample should be obtained at home before the chemotherapy starts. TIMING DATA COLLECTION The WHOQOL-100 questionnaire and baseline dietary and lifestyle questionnaire will be provided to the patient's E-boks. Data will be captured in REDCap. Stool samples (1-2 grams per collection) will be collected by patients at home and immediately frozen at -18 C in their home freezer. Patients will bring their samples to the hospital in a cooling bag at the next planned visit and the samples will immediately be transferred to -20 C until DNA extraction. Stool samples will be obtained at baseline, and at Day 1 of cycle 2, 4, 6, or in case of early discontinuation of chemotherapy and stored in a research biobank until completion of primary analyses. Potential left-over stool or Bacterial DNA after the analyses for this study are stored in the OPEN BIOBANK for future, not yet specified, research. Participants will be contacted and asked for consent in case of future research. Microbiome evaluation will use Oxford Nanopore Technology 16S sequencing of fecal samples. Metabolome assessment will detect short-chain fatty acids (SCFAs) in patient stool and plasma samples using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Adhesion to the diet will be measured via food diaries (www.myfood24.org). The software provides feedback to the user about reaching the daily/weekly goals, thereby nudging the participant to reach the target. Patients will also fill out a paper record of different plant foods eaten every week. Quantification of CD4 T-cells, CD8 T-cells, CD19 B cells, and 56 Natural Killer cells will be performed by flow cytometry. Hematology (hemoglobin, white blood cell count, absolute neutrophils, monocytes, lymphocytes, and platelet count) CRP, Vitamin D status will be measured at initiation of the study and at day 1 of chemotherapy cycle 6. GlycA and lipoproteins will be examined using Nuclear Magnetic Resonance (NMR)-technique at Nightingale, Finland, (https://nightingalehealth.com) as an expression of metabolic improvements. Blood samples drawn after a minimum of 6 hours fasting will be treated and stored according to current research ethical practice in Denmark in a research biobank assigned for this trial. Blood samples of a total of 40 ml/time are drawn at four time points: at baseline, and Day 1 of cycle 2, 4, and 6 chemotherapy, or in case of early discontinuation of chemotherapy. Samples are stored as plasma, serum, buffy coat, and whole blood at minus 80 degrees Celsius at the Departments of Biochemistry of participating hospitals and final storage at the OPEN BIOBANK and stored in a research biobank until completion of primary analyses. Potential left-over blood after the analyses for this study are stored in the OPEN BIOBANK for future, not yet specified, research. Participants will be contacted and asked for consent in case of future research. Archived tumor tissue from the primary breast tumor will be sampled, including the diagnostic biopsy and surgery specimens in neoadjuvant-treated patients, and the surgery specimens in adjuvant-treated patients, which are then stored in a research biobank. Primary tumor tissue will be analyzed for tumor-infiltrating immune cells. Pathological samples are stored according to clinical routines at the Departments of Pathology affiliated with the trial sites. Immunohistochemical staining will be performed at the Department of Pathology, Esbjerg Hospital. The following immune cells will be identified within the tumor tissue: CD8 T cells, CD4 T cells, FoxP3 regulatory T Cells, CD20 B Cells, CD57 NK Cells, CD66b Neutrophils granulocytes, CD68 Macrophages, Granzyme B (GZMB) Cells, PD-L1. These immune cells will be quantified using digital image analysis combined with artificial intelligence at the Department of Clinical Medicine, Aarhus University. The median cell density of immune cells per mm2 tumor tissue will be calculated. DATA REGISTRATION Data will be collected in a secure and central REDCap database. Groups and subgroups Participating patients should have newly diagnosed early breast cancer and be considered eligible for initiating either adjuvant or neoadjuvant chemotherapy-based treatment. DURATION OF PARTICIPATION In MEDITERRACARE, patients will be followed from randomization before chemotherapy commencement until the start of treatment cycle 6. If a patient stops chemotherapy before cycle 6, blood and fecal samples are collected and participation in the trial ends. Recruitment is planned to begin uniformly across centers from April 2025. The recruitment period is expected to last 18 months. Data collection is planned to cease latest April 2027, with primary study reporting completed by April, 2028. Follow-up for clinical events, i.e. recurrence, will be conducted through Danish Breast Cancer Cooperative Group(DBCG) database until December 2036. Follow up for for vital status will be followed up via the Central Person Register (CPR) registry until December 2036. STOPPING THE TRIAL The sponsor can stop the trial in case of practical issues such as insufficient inclusion of patients. RANDOMIZATION CODE The randomization code will be stored in the REDCap database. Code breaking is not relevant in the MEDITERRACARE study. CASE REPORT FILES (CRFs) Data to be extracted from the hospital records will be directly typed into the central REDCap database. Questionnaires filled out by the patient electronically at home will directly be stored in the central REDCap database. Questionnaires filled out by the patient on paper (plants consumed per week) will be collected and typed into the REDCap database. Patients can stop participating in the trial at any time point without explanation. EXCLUSION OF GENDER OR AGE GROUPS There are no restrictions on age and gender except for restricting the participation to adults. Breast cancer is extremely rare below the age of 18. As breast cancer is rare in males, we expect only a few males to be recruited. As the oncology department typically handles breast cancer in males, we do not expect males to be underrepresented. SOCIOECONOMIC EQUALITY AND PATIENT QUALITY OF LIFE The driving question in this part of the study is whether the Mediterranean diet will positively impact the patients' social quality of life, overall well-being, sense of empowerment, and personal feeling of agency, using the WHOQOL-100 questionnaire. We will explore both geographic and social inequality, based on our previous extensive research in this area encompassing both geographic and social inequality in health. The distance to the healthcare system is defined as the geographical distance between the patient's place of residence and the hospital. The distance calculation is carried out by GEOTEAM at Statistics Denmark. Co-variables include socio-demographic and socio-economic characteristics, such as age, gender, cohabitation status, employment, income, and education, in addition to disease stage and co-morbidity. These will be obtained from relevant registers in the DREAM database, such as income, education, and employment. In the qualitative study, the focus is on the experience of the intervention, and the benefits or barriers associated with it. The emphasis is on patients' everyday experiences, how the intervention affects their practical lives, and whether they encounter challenges and, if so, what those challenges are. The qualitative interview study is based on semi-structured interviews with 20 patients, of whom 15 have received the Mediterranean diet intervention and 5 have not. First, the register analysis will be performed to establish a foundational understanding of the participants' socio-economic and socio-demographic conditions. Second, responses from utilizing the WHOQOL-100 questionnaire will analyzed. Third, individual interviews will be conducted with the patient group, focusing on uncovering their experiences, practices, and perspectives regarding their life situations and overall well-being. Moreover, data on family/relatives support on dietary changes and support in general for women under critical risk will be extracted. ADHERENCE Adherence to the protocol will be monitored via food registration in the MyFood24 system. Patients are required to report their daily food intake at least 3 days per week. Every week a separate report on weekly intake of different plants should be filled out. Patients are required to fill out the forms, and will be encouraged to fulfill the goals of consuming 30 grams of dietary fiber daily and 30 different plants per week in the intervention group and follow their normal diet in the control group. COMPLIANCE AND MONITORING Compliance will be monitored via MyFood24 and by collection of plant registration forms. SUBSEQUENT TREATMENT If a patient leaves the trial, they will continue their normal medical treatment without the diet intervention. SAFETY EVALUATION Since the MEDITERRACARE study is a clinical trial investigating a diet similar to that recommended by the Danish Health Authorities, there will be no safety issues to assess. STATISTICS Data will be stored in a secure server in OPEN Analysis. Descriptive analyses will be performed to explore exchangeability between the two study arms and presented in a table describing the study population on key characteristics. The WHOQOL-100 questionnaire will be analyzed. A DREAM database analysis will be performed to establish an understanding of participant's socioeconomic and socio-demographic levels. Individual interviews will be conducted to uncover experiences, practices, and perspectives regarding their life situation and general well-being. The analysis will separate participants into three socio-economic groups (low-risk vs. median-risk vs. high-risk). This stratification will be used as the key to interpreting data for gut bacteria composition and immune cell activity For comparison between groups two-sample Student's t-test will be applied for normally distributed numerical data and the Wilcoxon-Mann-Whitney test will be applied for non-normally distributed numerical data while categorical data will be compared by chi-squared test. Correlation analyses of median values (measured at the start of cycle 6) of the six domains in the WHO-100 questionnaire, and median estimates (measured at the start of cycle 6) of blood CRP, monocytes, neutrophils, CD4/CD8/CD19/CD56 cells as well as median values of daily dietary fiber and median weekly plant food intake; concentrations of fecal metabolites including SCFA, and alpha diversity, beta diversity as well as microbial differential abundance will be performed with relevant stats package within the statistical programming language R (v.3.5.1). A recurrence will be defined as any invasive breast cancer recurrence irrespective of localization. Information on overall survival will be retrieved by linkage to the national CPR registry. Invasive disease-free survival among groups will be analyzed in crude analysis using the Kaplan-Meier and distant recurrence-free survival will be analyzed using competing risk analysis with cumulative incidences. Cox regression hazards analysis will be performed allowing for controlling for confounders in multivariable analysis. A 2-sided p-value of 0.05 will be used to determine significance. All statistical data analysis will be carried out using R. SAMPLE SIZE CONSIDERATIONS Assuming a larger heterogeneity in the intervention group of a factor of sqrt(2) (due to compliance and the dietary flexibility for the intervention) and with a distribution of 2:1 between intervention and standard diet, the relative effect size detectable on the change from baseline to the end of intervention should be 0.69 with n 33 in the standard diet group and n 66 in the intervention group to have a study power of 0.8 with a significance level of 0.05. Thus, assuming a 5% drop-off, the study needs 105 patients to be included. There will be stratification for neoadjuvant chemotherapy versus adjuvant chemotherapy. INTERIM ANALYSIS IS NOT PLANNED Missing data will be handled according to the scoring instructions of the instruments or imputations. Deviations from the statistical analysis plan will be reported in the final publications. All analyses will be performed as intention-to-treat analyses.

Microbiome ; Mediterranean Diet ; Inequality in cancer ; Chemotherapy ; Adjuvant ; Neoadjuvant ; Short-chain Fatty Acids

Odense University Hospital,University of Copenhagen,Aalborg University,Aarhus University Hospital,Danish Breast Cancer Cooperative Group,Vejle Hospital,Syddansk Universitet, Denmark,hospital of southern jutland

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This phase II trial studies how well intra-tumor injection of double checkpoint inhibitors work when given alone and in combination with chemotherapy or/and bevacizumab in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as ipilimumab, pembrolizumab or durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Drugs used in interventional radiological chemotherapy, such as idabubicin, can directly kill the cancer cell and release tumor antigens to activate DC function in situ. Giving intra-tumor injection of checkpoints inhibitors with or without chemotherapy and/or bevecizumab may work better than in vein infusion of the drugs in treating patients with non-small cell lung cancer.

Antibodies against CTLA4, PD1 or PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab and PD1 antibody or PDL1 antibody, so called double checkpoint inhibitors combination therapy, as neoadjuvant therapy for NSCLC via intra-tumor admistration. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the double checkpoint inhibitors combination therapy for cancer patients as neoadjuvant treatment via intra-tumor delivery. This phase II clinical trial is designed to assess the safety and survival benefit of ipilimumab and pembrolizumab or durvalumab combination with or without chemodrug and/or bevacizumab as neoaduvant therapy on patients with NSCLC, including safety, pCR, mPR, PFS, ORR, DCR, and median survival time.

NSCLC ; Intra-tumor injection ; Neoadjuvant therapy ; Double immunotherapy ; Interventional radiology ; Bevacizumab

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This trial is designed to investigate the safety, response rates and survival outcomes of patients with hepatocellular carcinoma by infusion of CTLA4, PD1 and PDL1 antibodies combination with chemodrug or/and bevacizumab through intra-tumor (IT).

Antibodies against CTLA4, PD1 and PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab and PD1 antibody or PDL1 antibody, so called double checkpoint inhibitors combination therapy, as first line for hepatocellular carcinoma (HCC) via intra-tumor admistration. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the double checkpoint inhibitors combination therapy for cancer patients as first line via intra-tumor delivery. This phase II clinical trial is designed to assess the safety and survival benefit of ipilimumab and pembrolizumab or durvalumab combination with or without chemodrug or bevacizumab as first line therapy on patients with HCC, including PFS, ORR, DCR, and median survival time.

Hepatocellular Carcinoma ; Intra-tumor injection ; First line ; CTLA4 antibody ; PD1 antibody ; PDL1 antibody ; chemodrug ; anti-angiogenesis

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Timing of Minimally Invasive Local Treatment After First-Line Systemic Therapy in Oligometastatic Esophageal or Gastric Adenocarcinoma

Purpose of the Study: This clinical study investigates whether a shorter or longer duration of systemic therapy before local treatment (surgery or radiation) results in better disease control in patients with esophageal or gastric cancer with a limited number of metastases, also known as oligometastases. Background: In about 25% of patients with advanced esophageal or gastric cancer, the disease spreads to only a few sites (oligometastatic disease). Prior studies suggest that local treatment after systemic therapy may extend survival in this subgroup. However, it is unclear how long systemic therapy should last before initiating local treatment. The OMEC-5 study aims to clarify this and identify potential biomarkers for treatment response. Study Design: Initiated by Amsterdam UMC and UMCU and conducted in multiple hospitals across Europe. Total of 414 patients to be enrolled. Duration: \ 53 months (35 months enrollment 18 months follow-up). Approved by the medical ethics committee at Amsterdam UMC. Procedure: Eligibility screening: Includes physical exam, blood tests (incl. circulating tumor cells), medical history review, and confirmation of oligometastases by an expert panel. Initial treatment: All participants receive 4 months of standard systemic therapy (chemotherapy immunotherapy and/or targeted therapy depending on tumor markers like HER2 or Claudin 18.2). Response assessment (Review 1): Imaging and/or laparoscopic examination. If oligometastases persist and tumors have not progressed, participants are randomized into two groups: Group A (longer systemic therapy): 4 more months of systemic therapy, then local treatment if disease is stable, followed by 4 months of immunotherapy targeted therapy. Group B (shorter systemic therapy): Immediate local treatment followed by 4 months of systemic therapy, then reassessment and potentially 4 months of immunotherapy targeted therapy. Follow-up: Regular scans and quality-of-life questionnaires (5 times), and periodic blood sampling (4 times). Treatments Involved: Chemotherapy: CapOx or FOLFOX Immunotherapy: nivolumab or pembrolizumab Targeted therapy: trastuzumab (HER2-positive) or zolbetuximab (Claudin 18.2-positive) Potential Benefits and Risks: Patients may benefit from better disease control and a personalized treatment strategy. Known side effects relate to the standard treatments used (chemo, immuno, targeted therapies), and no extra medical risk is expected beyond routine care. Possible inconveniences include blood draws, scans, minor surgery (laparoscopy), and time investment. Data and Sample Handling: Personal data and tumor/blood samples are coded and securely stored. Data may be used for future cancer research if the patient consents. Participants can withdraw at any time. Confidentiality and Privacy: Patient data are kept confidential, and participants have rights to access or delete their data. Privacy measures comply with GDPR and Dutch law. Compensation and Insurance: Participation is voluntary, with no financial compensation. Standard treatment costs are covered by healthcare insurance. No extra insurance is required, as the treatment aligns with standard care practices.

Esophageal Cancer ; Gastric (Stomach) Cancer ; Gastric Adenocarcinoma ; Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma ; Esophageal Carcinoma ; Gastric (Cardia, Body) Cancer

Hanneke Van Laarhoven,richard van hillgersberg,Peter Van Rossum

Amsterdam UMC,University of Zurich

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Neoadjuvant Intra-tumor Double Immunotherapy for Hepatocellular Carcinoma.

This trial is designed to investigate the safety, response rates and survival outcomes of patients with hepatocellular carcinoma by delivery of CTLA4 and PD1 or PDL1 antibodies combination through CT-guided intra-tumor (IT) injection.

Antibodies against CTLA4, PD1 or PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab and PD1 antibody or PDL1 antibody, so called double checkpoint inhibitors combination therapy, as neoadjuvant therapy for hepatocellular carcinoma (HCC) via intra-tumor admistration. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the double checkpoint inhibitors combination therapy for cancer patients as neoadjuvant treatment via intra-tumor delivery. This phase II clinical trial is designed to assess the safety and survival benefit of ipilimumab and pembrolizumab or durvalumab combination with or without chemodrug or bevacizumab as neoaduvant therapy on patients with HCC, including safety, pCR, mPR, PFS, ORR, DCR, and median survival time.

Hepatocellular Carcinoma; ; Intra-tumor injection ; Neoadjuvant therapy ; Surgery ; Immunotherapy ; CTLA4 antibody ; PD1 antibody ; PDL1 antibody

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Checkpoint Inhibitor Combinations Therapy as First Line for Inoperable Lung Cancer Via IT

This trial is designed to investigate the safety, response rates and survival outcomes of patients with inoperable lung cancer by infusion of CTLA4, PD1 and PDL1 antibodies combination with chemodrug or/and bevacizumab through intra-tumor (IT).

Antibodies against CTLA4, PD1 and PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab and PD1 antibody or PDL1 antibody, so called double checkpoint inhibitors combination therapy, as first line for inoperable lung cancer via intra-tumor admistration. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the double checkpoint inhibitors combination therapy for cancer patients as first line via intra-tumor delivery. This phase II clinical trial is designed to assess the safety and survival benefit of ipilimumab and pembrolizumab or durvalumab combination with or without chemodrug or bevacizumab as first line therapy on patients with inoperable lung cancer, including PFS, ORR, DCR, and median survival time.

Inoperable lung cancer ; Intra-tumor injection ; Immunotherapy ; First line therapy

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Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma

1. Rational Every year, around 5,000 people in Sweden are diagnosed with malignant skin melanoma. In the early stages of malignant skin melanoma, the chance of cure with surgery is very good. At a later stage, when the melanoma has become thick and/or has spread, the risk of recurrence is greater despite radical surgery. Therefore, in these cases (even in cases of recurrence after radical surgery), additional treatment with immunotherapy is often given, as it has been shown to reduce the risk of recurrence. Immunotherapy is given for one year based on previous research studies, but it has not been investigated whether a shorter treatment period has the same effect. The hypothesis is that six months of treatment is equally effective, which would have several advantages. The main advantage of a shorter treatment period is that the risk of severe side effects is reduced. A shorter treatment period also means fewer hospital visits for patients. In addition, significant drug costs and other healthcare resources could be saved. 2. Aim/objective The aim of the study is to investigate whether 6 months of treatment with immunotherapy, in addition to radical surgery, for malignant skin melanoma at high risk of recurrence, is as effective in preventing recurrence as 12 months of treatment. Secondary objectives: To investigate overall survival after 6 versus 12 months of treatment with immunotherapy. To investigate the health economic effects of a shorter treatment. 3. Primary endpoints The two primary endpoints of the study are relapse-free survival (RFS) and distant metastatic-free survival (DMFS) and they will be analyzed for the first time in the interim analysis conducted after 2/3 of the estimated number of patients have been included in the study. 4. Secondary outcome measures Overall survival will be analyzed for the first time in the interim analysis. Health economic calculations are planned only at the final stage of the study. 5. Study design This is a randomised phase 3 study, with the aim of showing that treatment in the experimental arm (6 months of immunotherapy) is not inferior to the treatment in the standard arm (12 months of immunotherapy). Patients will be followed up to five years. The visits in the study follow clinical routine. 6. Study population Patients aged 18 years undergoing radical surgery for stage IIb-c, III or IV cutaneous malignant melanoma, with a WHO general condition score of 0-1 and deemed tolerable to immunotherapy. 7. Study treatment The study treatment consists of immunotherapy according to clinical routine, currently nivolumab or pembrolizumab given intravenously for either 6 months (experimental treatment) or 12 months (standard treatment). For patients receiving neoadjuvant treatment (additional treatment before surgery), the neoadjuvant treatment time is added to the adjuvant treatment time (additional treatment after surgery) to give a total treatment time of 6 or 12 months. Treatment is followed up according to routine, with imaging (CT or PET-CT) at baseline and after 6 months and at an additional time beyond clinical routine, after 36 months, as well as medical examination at baseline, 6, 12, 18, 24 and 36 months. In case of any signs of relapse, additional examinations are performed as needed. If relapse is detected, the patient is discussed at a local multidisciplinary conference to select the best available treatment for each patient. All study patients are followed for survival status for up to five years. 8. Risk-benefit and ethical issues If this study shows that a shorter treatment period is as effective as the current one-year treatment, it would greatly benefit patients by reducing the risk of side effects and reducing the number of hospital visits. It would also save healthcare resources, which could then be used in other areas. The Swedish Melanoma Patient Association (Melanompatientföreningen) has been consulted and is positive about the study, however they expect that patients may be reluctant to participate for fear of receiving inferior treatment. However, none of the pivotal studies conducted to date have shown that adjuvant systemic treatment of patients with malignant melanoma significantly prolongs overall survival, but its routine use is based on prolonged relapse-free survival. In addition, a recent cohort study indicated no survival benefit after the introduction of immunotherapy. To ensure that the experimental arm is not clearly inferior to the standard arm, an interim analysis will be conducted in this study (see above). It is worth mentioning that similar studies to Grand SLAM have been conducted in breast and colon cancer where additional treatment after surgery has been introduced as it not only reduces the risk of recurrence but also prolongs overall survival. These studies have shown that shorter treatment is equally effective.

A prospective randomized international multicenter study to compare Short versus Long Adjuvant immunotherapy after radical surgery of stage IIb-c, III and IV cutaneous malignant Melanoma, Acronym: Grand SLAM (Study Long Adjuvant Melanoma) Purpose and aims Between 2013 and 2023 the incidence of cutaneous malignant melanoma (CMM) increased from 3400 to 5800 cases/year in Sweden (Swedish Melanoma Registry, SweMR) and the number of cases is expected to multiply during the next decades (www.cancerfonden.se). Since 2017, post-operative treatment with programmed death 1 (PD-1) inhibitors for 12 months is routine in the Western world for stage III melanoma patients. However, a rational for having chosen a 12-month treatment period in the registration studies is lacking. As in other malignancies, adjuvant treatment for CMM is most often given in vain as many patients would not relapse even without adjuvant treatment and a large group of patients relapse despite having received adjuvant treatment. Noteworthy, no randomized study has investigated whether a shorter adjuvant treatment is as effective as 12 months and there is no ongoing study on this subject (www.clinicaltrials.gov). One major disadvantage with a long adjuvant treatment is the increased risk for severe toxicity. In the adjuvant studies the observed grade 3-4 toxicity is 10-15 % (1, 2). Another drawback with adjuvant treatment is the resources required, including costs. The cost for checkpoint inhibitors has been estimated to raise from astonishing 24 billion USD in 2021 to 46 billion USD in 2026 (https://www.researchandmarkets.com/report/checkpoint-inhibitors). A large unknown part of this sum could be referred to adjuvant treatments. In conclusion, since adjuvant studies on malignant melanoma patients usually have been conducted with pharmaceutical companies as sponsors, the important question whether a shorter adjuvant treatment period is as effective as the current one-year schedule has so far not been addressed. A shorter treatment period would clearly be advantageous for patients and lead to a substantial reduction in drug costs and health care resources. The aim is to conduct a prospective randomized international multicenter non-inferiority study with systemic immunotherapy comparing treatment for 6 months (experimental arm) versus treatment for 12 months (standard arm) in patients having undergone radical surgery for stage IIb-c, III and IV CMM. The main research question is whether 6 months of immunotherapy in this patient group with high risk of relapse is as effective as the current 12-month scheme. The primary clinically relevant outcome variables are distant metastatic free survival (DMFS) and relapse free survival (RFS). Substudies, investigating the risk with food supplements (Melanoma Kost, MelKo) and biomarkers, are also planned. Survey of the field The introduction of adjuvant immunotherapy was based on two phase III studies, one for nivolumab (Opdivo ) and the other for pembrolizumab (Keytruda ). Two years ago, results were presented from another randomized phase III study assessing immunotherapy in patients operated for thick CMM without lymph node involvement (stage IIb-c). Treatment with PD-1 inhibitor significantly prolonged RFS compared to placebo. In addition, results from a randomized phase II study in patients with macroscopic stage III and operable stage IV CMM were published last year showing that the event-free survival was significantly better for patients receiving neoadjuvant PD-1 inhibitor compared to standard adjuvant treatment. The ongoing phase III NADINA study aims to confirm the increased benefit of neoadjuvant over adjuvant immunotherapy (NCT04949113). There are ongoing studies assessing new drugs in the adjuvant setting for high risk CMM patients. Two phase III studies investigate the potential benefit of adding a LAG 3 inhibitor to anti PD-1 treatment: In RELATIVITY-098, relatlimab is given together with nivolumab (Opdualag ) (NCT05002569) while fianlimab is tested together with cemiplimab (Libtayo ) in the other study (NCT05608291). Furthermore, whether pembrolizumab in combination with the TIGIT-inhibitor, vibostolimab is more effective than pembrolizumab alone is addressed in another large study (NCT05665595). Yet another potential registration study is KEYNOTE-942 where patients who have undergone surgery for different stages of high risk CMM, receive pembrolizumab combined with injections with a neoantigen mRNA-based vaccine which has shown promising results in a phase 2 study (NCT03897881). Study design Research questions PICO: High risk CMM/Treatment at standard doses with checkpoint inhibitor for 6 months/Standard treatment with checkpoint inhibitor for 12 months/DMFS and RFS. Variables and measures DMFS and RFS at 2 years measured in months from start of treatment. The patient must be randomized and start systemic treatment within 12 weeks after final surgery, i.e. excision sentinel node biopsy, lymph-node dissection or metastasectomy. Study procedures Randomization procedure Randomization is performed after stratification according to tumor stage. Study treatment Adjuvant treatment with current immunotherapy standard drugs (at present nivolumab or pembrolizumab) will be given in both study groups. The standard drugs might change during the study, based on upcoming results from ongoing adjuvant studies (see above). Patients who have undergone neoadjuvant immunotherapy are also eligible for the study providing that a complete pathological response has not been achieved which usually is the case in 20% of the cases (4). Since the neoadjuvant treatment duration is two months, these patients will in the standard arm receive 10 months post-operative treatment and in the experimental arm, four months only. Follow-up visits, blood tests and management of side effects will follow current practice based on national guidelines. Study Follow-up Scheme in brief A baseline visit 1-11 weeks after the final surgery is scheduled for study information, inclusion and randomization. The national routine schedule for follow-up visits will be applied for all patients in the study according to standard practice which normally includes doctor appointments with physical examinations after each scan. These visits are important for ethical reasons; the results of the scans should always be delivered to the patient in person. The imaging scheme follows national guidelines but computor tomography (CT) thorax, abdomen and brain, or i.v. contrast enhanced whole body FluoroDeoxyGlucose-Position Emission Tomography (FDG-PET-CT) (including brain) at baseline, and at 6 and 36 months is mandatory (see flow-chart below). The scan at 36 months is not included in Swedish practice but the minimum scheme is clearly less extensive than currently used in most other countries and in previous adjuvant studies (1, 2). Extra diagnostic evaluation (imaging and laboratory tests) will be allowed for all subjects presenting signs and/or symptoms. Patients in both groups are instructed to contact their study center if they experience any symptoms suspicious of recurrence. Estimated sample size and power The study design is a non-inferiority trial investigating whether short-term adjuvant immunotherapy, is non-inferior to long-term adjuvant immunotherapy (standard of care) with a non-inferiority margin of 4.0% being clinically appropriate in this study population. Assumptions for the sample size calculation: * DMFS at 2 years was 88.1% for stage IIb-c patients (Keynote 716 study) (1) * DMFS at 2 years was 70% for stage III-IV patients (Checkmate 238 trial) (2) * DMFS for the sample size will be based on these two measurements with a conservative estimate of 75.0% at 2 years. * Power 80% Alpha level 5% Non-inferiority Margin 4% * Accrual time 48 months Follow up time 60 months A sample size of 1792 patients (896 in each study arm) will have 80% power with one-sided 95% confidence to declare non-inferiority with a margin of 4.0% based on a 1:1 randomization with a corresponding HR of 1.19. If emerging data demonstrate a higher 3-year DMFS proportion than 75%, the sample size may be either re-estimated or the non-inferiority boundary adjusted or if the number of patients lost to follow-up is of concern. Statistical methods Anders Berglund, PhD is responsible statistician and the efficacy analyses will include all randomized patients. Kaplan-Meier techniques will be used to plot both outcomes. Comparison of outcomes between the study arms will be based on a Cox regression model. The hazard ratio (HR) associated with the study arms will be derived along with the associated 95% confidence interval (CI). The p value for testing the null hypothesis that the HR between the interventions will be greater than or equal to 1.19 will be derived from this model by comparing the log-likelihood of the fitted model with the log-likelihood of a model where the HR between the groups is set to 1.19 by use of a likelihood ratio test. Co-primary endpoints DMFS and RFS at 2 years are co-primary endpoints and to preserve the overall type I error rate, comparisons will be performed according to hierarchical testing: 1. The alternative non-inferiority hypothesis, H11: DMFS short-term treatment is not inferior to long-term treatment (standard of care) for the first co-primary endpoint (DMFS). If H11 is accepted., i.e., non-inferiority is declared in (1), then the following hypothesis will be tested. 2. The alternative non-inferiority hypothesis, H12: DMFS short-term treatment is not inferior to long-term treatment (standard of care) for the second co-primary endpoint (RFS). 5% level of significance will be applied, with comparisons in the sequential testing procedure being conditional on rejection of the null hypothesis of the previous comparison. Interim analysis The interim analysis will be conducted when two-thirds of the total number of planned subjects are enrolled which is the optimal timing when using the O'Brien-Fleming Boundary (5). Organisation The PIs in Sweden have been involved in the TRIM study and the PIs in the other countries are also experienced and active researchers at university centers. The statistician has been responsible for the TRIM study. The study coordinator has been involved in several clinical studies over the years. The monitors from the research unit at Uppsala University Hospital are very experienced. All principal PIs will be GCP trained. There is support for agreements at the research unit at Uppsala University Hospital and that unit is highly competent in GDPR. Study subject information will be handled strictly confidentially and only by authorized personnel. When data is processed, name and personal number will be replaced by a code. Patients will be recruited from centers all over Sweden and university clinics in other European countries. Based on data from the SweMR, the expected incidence of stage IIIb-d according to AJCC8 classification at the time of diagnosis, is 250 patients/year. With a recruitment rate of 60%, 150 patients are estimated to be enrolled/year in Sweden only. In addition, CMM patients diagnosed with stage III at relapse and patients undergoing radical surgery for stage IV CMM are also eligible. We estimate that 50 patients from these subgroups will be included/year, yielding a total recruitment of 200 patients/year. Time plan * 2023: Planning, fund-raising, writing the final protocol. * Spring 2024: Setting up the eCRF and randomization procedure, gaining ethical and radiation protection committees and the Swedish Medical Products Agency approvals. * 2023-2024: Recruitment of centers. * 2024-2028: Inclusion of patients, around 200/year (Sweden), 450/year in total. * Interim analysis in 2027 * 2033: Last patient followed-up for 5 years. Risk mitigation As the study is a non-inferiority study it will require a large number of participants. The Swedish Melanoma Study Group, the Nordic Melanoma Group and the European Melanoma Group are in favor of the study. We will take advantage of the organization for the ongoing TRIM study which has recruited over 1100 patients despite that only Swedish centers participate. More university centers will likely join when the study is up and running. Equipment Need for research infrastructure No equipment is needed for this project. Not applicable for this study.

Skåne University Hospital,Sahlgrenska University Hospital,University Hospital, Linkoeping,gavle hospital,Karolinska University Hospital,Falu Hospital,Karlstad Central Hospital,Västmanland County Council, Sweden,Norrlands University Hospital,Region Örebro County

Uppsala University Hospital

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This is a single arm, open-label, multicenter, phase II study of pembrolizumab (pembro), gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) in patients with relapsed or refractory classic Hodgkin lymphoma (cHL) with response-adapted consolidation. This study will investigate using circulating tumor DNA (ctDNA) at pre-determined time points using Foresight CLARITY LDT, an ultra-sensitive liquid biopsy platform that detects Minimal residual disease (MRD) in patients with B-cell lymphomas using the phased variant enrichment and sequencing technology (PhasEDq) to determine response to study interventions.

PRIMARY OBJECTIVE: I. To determine the ctDNA/MRD-negative, PET-negative complete response rate for cHL patients undergoing treatment with pembro GVD. SECONDARY OBJECTIVES: I. To determine progression-free survival (PFS) overall survival (OS) at 2 years among patients receiving non-transplant consolidation. II. To determine PFS and OS at 2 years for the overall cohort. III. To determine the proportion of patients treated with pembro GVD and non-transplant consolidation who ultimately undergo Autologous Stem Cell Transplant (ASCT) within 2 years. IV. To determine the rate of discordance between Positron Emission Tomography (PET)/Computerized tomography (CT) response and ctDNA/MRD response. V. To determine the incidence of adverse events, including immune-related adverse events, in patients receiving pembro GVD and pembrolizumab consolidation. VI. To assess health-related quality of life (HRQOL) and patient-reported outcomes (PROs) as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) 29 and Functional Assessment of Cancer Therapy-COmprehensive Score for financial Toxicity (FACIT-COST). VII. To determine the proportion of patients with relapsed or refractory cHL for whom baseline Foresight CLARITY LDT genotyping from the peripheral blood is successful EXPLORATORY OBJECTIVES: I. To evaluate the kinetics of ctDNA/MRD clearance in the peripheral blood after pembro GVD. II. To evaluate the ctDNA/MRD-negative complete response (CR) rate and 2-year PFS stratified by cHL molecular subgroup at diagnosis (H1 vs H2 genotype). III. To evaluate long term efficacy and toxicity outcomes for up to 5 years. IV. To compare the performance of identification of phased variants from plasma genotyping with identification of phased variants from archival tissue genotyping. OUTLINE: Participants will undergo response assessment and ctDNA/MRD assessment using phased variant enrichment and detection sequencing (PhasED-Seq) using Foresight CLARITY LDT. A composite response assessment will be used to determine eligibility for non-transplant consolidation. Participants who achieve a response after 2 cycles of pembro GVD will be eligible for non-transplant consolidation with 8 cycles of pembrolizumab and/or 30 Gray (Gy) involved-site radiotherapy (ISRT). Participants not achieving a response will discontinue study therapy and proceed to study follow-up, during which time participants can receive standard of care salvage therapy and ASCT, if eligible. Participants will be followed for up to 5 years from trial entry for long term efficacy and toxicity outcomes.

Hodgkin Lymphoma, Adult ; Refractory Hodgkin Lymphoma ; Classic Hodgkin Lymphoma

Foresight Diagnostics,Gateway for Cancer Research,UC Hematologic Malignancies Consortium (UCHMC)

University of California, San Diego

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Re-Radiochemotherapy and Pembrolizumab vs. Immuno(Chemo)Therapy for Locoregionally Recurrent PD-L1 Positive (CPS 1) HNSCC

Prospective, open-label, randomized controlled phase III trail that aims to investigate whether Re-Radiochemotherapy (Re-RCT) and sequential immunotherapy with pembrolizumab improves overall survival compared to the standard treatment with pembrolizumab alone ( chemotherapy) in locoregionally recurrent PD-L1 positive (CPS 1) HNSCC.

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ASTRAEA: ReinvigorAting ReSponse To ImmunotheRApy in MEtAstatic TNBC With Combination Myeloid Inhibition and Radiation

Open label, single-arm, prospective therapeutic trial. Pembrolizumab (MK-3475), 200 mg IV Q3W starting at C1D1/Week 1 for up to 2 years, until disease progression, or treatment intolerance. RT, 8 Gy x 3 fractions over 3 consecutive days at C1D8/Week 2; Axatilimab (SNDX-6352; INCA034176), 1 mg/kg, IV, Q2W starting 1 week post- RT C1D15/Week 3 until disease progression or treatment intolerance.

Checkpoint blockade-mediated immunotherapy (IO) is an emerging cornerstone in the treatment of triple negative breast cancer (TNBC) in both the metastatic and curative intent settings. Initial studies of IO monotherapy in heavily pretreated metastatic TNBC were disappointing with low objective response rate (ORR) (5.3%: KEYNOTE-086, KEYNOTE-119) and no effect in OS (1-3). However, recent studies in patients with previously untreated metastatic TNBC, showed IO combinations with chemotherapy were associated with improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone in patients with "PD-L1 positive" disease (IMpassion130 and KEYNOTE-355) (4-7). Nonetheless, nearly half of patients on IMpassion130 had grade 3 or higher toxicity, leading to a discontinuation rate of 16.9%, and over 70% of all patients on first-line IO containing regimens will experience disease progression within one year. Based on these data, IO-containing regimens have become the standard-of-care treatment option for metastatic TNBC, albeit with a high failure rate and a non-trivial toxicity profile. Second line antibody-drug conjugate Sacituzumab govitecan while also improving response in metastatic TNBC still has 85% of patients fail at 1 year (ASCENT, Bardia NEJM 2021). Therefore, novel strategies that augment IO-enhanced tumor-specific responses and limit treatment-associated toxicities are critically important in TNBC. Lastly, radiotherapy (RT), commonly used in palliation of metastatic TNBC, is a potent modulator of the immune response, and can produce responses in unirradiated tumors in combination with IO (8-11).

Pembrolizumab ; Axatilimab ; CSF-1R inhibitor ; potent humanized immunoglobulin G4 (IgG4) ; Radiation Therapy

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The aim of this study was to investigate the efficacy and safety of pembrolizumab combined with albumin paclitaxel and cisplatin versus albumin paclitaxel and cisplatin or 5-fluorouracil and cisplatin in neoadjuvant therapy for stage II-IVa resectable esophageal squamous cell carcinoma. The study plans to enroll 114 eligible patients who will be randomly assigned in a 1:1:1 ratio to receive 3 cycles of neoadjuvant immunochemotherapy (pembrolizumab plus albumin paclitaxel and cisplatin;Pembrolizumab plus 5-fluorouracil and cisplatin) or chemotherapy alone (5-fluorouracil and cisplatin), followed by surgery 3 weeks later, followed by 16 cycles of adjuvant immunotherapy (pembrolizumab).Patients were followed up for efficacy and safety during treatment.Tumor evaluation will be performed at screening, after neoadjuvant therapy, before surgery, and after adjuvant therapy until objective disease progression is confirmed.

The aim of this study was to investigate the efficacy and safety of pembrolizumab combined with albumin paclitaxel and cisplatin versus albumin paclitaxel and cisplatin or 5-fluorouracil and cisplatin in neoadjuvant therapy for stage II-IVa resectable esophageal squamous cell carcinoma. The study plans to enroll 114 eligible patients who will be randomly assigned in a 1:1:1 ratio to receive 3 cycles of neoadjuvant immunochemotherapy (pembrolizumab plus albumin paclitaxel and cisplatin;Pembrolizumab plus 5-fluorouracil and cisplatin) or chemotherapy alone (5-fluorouracil and cisplatin), followed by surgery 3 weeks later, followed by 16 cycles of adjuvant immunotherapy (pembrolizumab).Patients were followed up for efficacy and safety during treatment.Tumor evaluation will be performed at screening, after neoadjuvant therapy, before surgery, and after adjuvant therapy until objective disease progression is confirmed. Study Endpoints Primary Endpoints PCR: This was assessed by examining the postoperative pathological tissue for the absence of tumor cells in the primary tumor and lymph nodes. Safety: Adverse reactions during neoadjuvant therapy were recorded following CTCAE version 5.0 guidelines. Perioperative complications were assessed using the Clavien-Dindo classification. Grade I complications included any deviation from the normal postoperative recovery process without requiring medical, surgical, endoscopic, or radiological intervention. Acceptable medical management included antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physical therapy. Bedside open incisional infections were included under this category. Grade II complications were those that required medications beyond those used for treating Grade 1 complications, including blood transfusions and total parenteral nutrition. Grade III complications were those that required surgical, endoscopic, or radiological intervention. Grade IV complications were those considered life-threatening and requiring mid-term care or admission to an intensive care unit (including central nervous system complications, such as cerebral hemorrhage, ischemic stroke, and subarachnoid hemorrhage, and excluding transient ischemic attacks). Grade V complications included patient deaths. Secondary Endpoints 1) Major pathological response (MPR) refers to the proportion of residual tumor cells in the primary tumor and lymph nodes in the postoperative pathological tissue being 10%, or the primary tumor completely disappearing, and the number of positive lymph nodes being 1. 2) R0 resection rate: R0 resection was defined as achieving negative upper and lower resection margins. 3) RECIST Criteria Assessment: Complete response (CR): complete response of target lesions; PR: 30% regression of target lesions; Non-CR/Non-PD: target lesions did not completely disappear and did not increase by 20%, or other new lesions appeared in the body; Stable disease (SD): target lesions were reduced or increased by 20%; Progressive disease (PD): target lesions had increased by 20%. Statistical Methods The sample size was determined using Simon's two-stage design. With a minimum expected pCR of 20% and an expected pCR of 40%, a Type I error (α) of 0.05, and a Type II error of 80%, a sample size of 34 was calculated. In the first stage, 17 patients were enrolled. The study was carefully monitored to limit the number of pCR cases to three or below, and any increase in the risk of surgery and mortality due to the treatment regimen would have led to its discontinuation. All continuous variables were presented as frequencies. Statistical significance was set at P 0.05.

Neoadjuvent ; PD-1 Inhibitor ; Chemotherapy ; Esophageal Squamous Cell Carcinoma

Hongtao Duan,Tangdu Hospital of the Fourth Millitary Medical University

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Carboplatin Paclitaxel Cetuximab (PCC) After Failure of Pembrolizumab /- First-line Chemotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

This study targets an adult population of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), who have failed after a first line of treatment with pembrolizumab associated or not with chemotherapy and having an indication for a second line of treatment. Patients will be recruited in France in medical oncology departments. The main objective is to evaluate the objective response rate of PCC in patients with HNSCC with locoregional and/or distant 2nd line metastatic disease after failure of pembrolizumab /- chemotherapy. The secondary objectives of the study are to evaluate other efficacy parameters by monitoring the progression of the disease, the tolerance of the treatment by collecting adverse effects and quality of life. The duration of participation in the research is 12 months.

Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer worldwide. First-line treatment was shaken up in 2019 by showing that a combination of platinum, 5-fluorouracil (5-FU) and the anti-cell death program-1 (PD-1) immunotherapy, pembrolizumab, improved significantly improved overall survival (OS) compared to the standard EXTREME regimen (platinum, 5-FU and cetuximab). After this first line and in the absence of a randomized therapeutic trial, the therapeutic strategy is not known. Possible chemotherapies are paclitaxel or methotrexate. Systemic treatment is indicated for patients with locoregional recurrence not eligible for radiotherapy or surgery with curative intent, or progression of distant metastatic disease. Cetuximab is approved as a second-line treatment in the United States. For patients whose tumor progresses on pembrolizumab maintenance therapy with a platinum-free interval of at least 3 months, restarting platinum therapy is potentially effective. The combination of platinum with cetuximab and paclitaxel is then possible and potentially more effective than monotherapy, including in fragile patients. The use of cetuximab in the second line appears all the more interesting since its use immediately after anti-PD-1 immunotherapy gives hope for a form of potentiation, as has been reported in several publications since 2020. Very recently, the results of a French retrospective study evaluating the effectiveness of chemotherapy based on taxane cetuximab /- platinum in 99 patients with HNSCC tumor progression and locoregional or metastatic recurrence after immune checkpoint inhibitors was presented by the team of Peers from the Gustave Roussy Institute. They suggest that this combination was effective in this situation and deserved further investigation. The only existing prospective study was reported during ASCO meeting in 2023. The Japanese team evaluated in a Phase II trial the efficacy of combining paclitaxel with cetuximab in 35 patients with R/M HNSCC after platinum-based chemotherapy and anti-PD1 immunotherapy. The ORR was 69.7%. The median progression-free survival was 5.6 months, and the overall survival was 13.4 months. A multicenter retrospective study was presented at ESMO 2023. It analyzed the efficacy of paclitaxel alone (69 patients) and the combination of paclitaxel with cetuximab (83 patients) in patients with R/M HNSCC refractory to platinum-based chemotherapy, taxane-naive, and progressive under immune checkpoint inhibitors. An increase of ORR was assessed for the combination of paclitaxel and cetuximab. The median progression-free survival was 4.9 months, and the overall survival was 9.4 months. Finally, in a study investigating the efficacy of paclitaxel and cetuximab in 57 patients with R/M HNSCC after failure of first-line treatment including an immune checkpoint inhibitor, the ORR was 47.4%. The median duration of response was 5.5 months and disease control was achieved in 42 patients, resulting in a DCR of 71.9%. The median PFS was 5.9 months and the median OS was 14.0 months. The 6-month PFS and OS rates were 48% and 74%, respectively.

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Neoadjuvant ADT Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in Molecularly Stratified High-Risk Prostate Cancer

This is a single-arm, phase II study of neoadjuvant combination therapy of Androgen Deprivation Therapy (ADT), \[Gonadotropin-Releasing Hormone (GnRH) agonist Leuprolide\], androgen receptor (AR)-antagonist Darolutamide and Pembrolizumab in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-radical prostatectomy (RP). Patients with National Comprehensive Cancer Network (NCCN) high-risk non-metastatic prostate cancer (localized or locally advanced) (defined as Gleason 8, disease stage \ cT3a, or PSA l \ 20 ng/mL) will be risk-stratified at a biopsy using Decipher, a commercial standard-of-care diagnostic assay. Patients satisfying all three criteria of high-risk genomic characteristics listed below as per the Decipher grid results will be enrolled in the study: 1. Decipher Genomic classifier, GC\ 0.6 2. AR activity score/AR-output gene signature (ARoS)\ 11.0 3. High Luminal B score/ PAM50 subtype signature

The objectives of this study are to evaluate if the neoadjuvant ADT, Darolutamide and Pembrolizumab treatment in high-risk prostate cancer patients stratified based on their genomic characteristics will lead to minimum residual disease (MRD). A total of 40 men 18 years of age with non-metastatic adenocarcinoma of the prostate, having NCCN high risk localized disease, risk stratified at biopsy based on Decipher score, AR activity score and Luminal B score will be enrolled.

Dimple Chakravarty,Ashutosh Kumar Tewari,Ashutosh K Tewari

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Induction Chemotherapy Followed by Pembrolizumab Before Chemoradiation and Pembrolizumab Maintenance Compared to Standard Chemoradiation With Pembrolizumab Followed by Pembrolizumab Maintenance in High-Risk Cervical Cancer

This phase III trial compares the addition of induction chemotherapy, with carboplatin, paclitaxel and pembrolizumab, to chemotherapy and radiation, with cisplatin and pembrolizumab followed by pembrolizumab maintenance for the treatment of patients with cervical cancer that has spread to nearby tissue or lymph nodes (locally advanced). Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Adding induction chemotherapy to the usual treatment of chemotherapy and radiation followed by maintenance may be more effective in treating patients with high risk, locally advanced cervical cancer.

PRIMARY OBJECTIVE: I. To determine whether induction immunotherapy (IO) and chemotherapy prior to concurrent chemoradiation therapy (CCRT) IO improves progression-free survival (PFS) compared to CCRT IO alone. SECONDARY OBJECTIVES: I. To assess whether induction IO and chemotherapy prior to CCRT IO improves the overall survival (OS) compared to CCRT IO alone. II. To determine the nature and degree of toxicity of induction IO and chemotherapy prior to CCRT IO as compared to concurrent CCRT IO as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. III. To determine the impact on CCRT start, CCRT completion time, and number of cycles of cisplatin administered; with induction IO and chemotherapy prior to CCRT IO arm as compared to CCRT IO. IV. To assess the association between allostatic load and PFS/OS. V. To assess the predictive value of the integrated biomarker: PD-L1 expression at baseline for progression free survival. VI. To assess the prognostic and predictive value of the integrated biomarker: circulating tumor deoxyribonucleic acid (ctDNA) at baseline and at 3 months post radiation therapy (RT) for progression free survival. VII. To explore radiotherapy quality pretreatment scores conducted by expert review with assistance from artificial intelligence (AI) models and correlation with outcomes. EXPLORATORY OBJECTIVES: I. To assess the evolution of T cell receptor (TCR) repertoire on treatment and its correlation with clinical outcomes. II. To identify pre-treatment tumor microenvironment biomarkers predictive of outcomes. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: CHEMORADIATION: Patients receive cisplatin intravenously (IV) once weekly (QW) for 5 weeks and pembrolizumab IV over 30 minutes every 3 weeks (Q3W) for 5 doses. Patients also undergo radiation therapy once daily 5 days per week for 25-29 treatments followed by brachytherapy up to twice per week for 4-5 treatments. Treatment given in the absence of disease progression or unacceptable toxicity MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes every 6 weeks (Q6W) for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo positron emission tomography (PET) scan, computed tomography (CT) scan, chest x-ray and/or magnetic resonance imaging (MRI) and blood sample collection throughout the study. ARM 2: INDUCTION: Patients receive carboplatin IV and paclitaxel IV QW on weeks 1-3 and pembrolizumab IV over 30 minutes Q3W on weeks 1 for each cycle. Cycles repeat every 3 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. CHEMORADIATION: Patients receive cisplatin IV QW for 5 weeks and pembrolizumab IV over 30 minutes every Q3W for 5 doses. Patients also undergo radiation therapy once daily 5 days per week for 25-29 treatments followed by brachytherapy up to twice per week for 4-5 treatments. Treatment given in the absence of disease progression or unacceptable toxicity MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes Q6W for 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET scan, CT scan, chest x-ray and/or MRI and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months for 3 years.

Locally Advanced Cervical Adenocarcinoma ; Locally Advanced Cervical Adenosquamous Carcinoma ; Locally Advanced Cervical Squamous Cell Carcinoma ; Stage IIIA Cervical Cancer FIGO 2018 ; Stage IIIB Cervical Cancer FIGO 2018 ; Stage IIIC1 Cervical Cancer FIGO 2018 ; Stage IIIC2 Cervical Cancer FIGO 2018 ; Stage IVA Cervical Cancer FIGO 2018

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Multi-classifier System for Stratifying Stage III Papillary Renal Cell Carcinoma of Receiving Adjuvant Therapy

The goal of this trial is to test whether patients with stage III papillary renal cell carcinoma (pRCC) could benefit from adjuvant therapy or not. The investigators invented a multi-classifier system that was successfully categorise patients with stage III pRCC into high-risk and low-risk groups. Here the investigators randomly assign classifier-defined high risk patients of stage III pRCC into adjuvant pembrolizumab group placebo group. Disease-free survival and overall survival are the end points of observation.

kidney cancer represented 4.2% of all new cancer cases, and its incidence has been increasing. Over 90% of kidney cancer cases are renal cell carcinoma (RCC), which includes various subtypes with distinct histologic features, clinical courses, and responses to therapy. Clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) are the most common histologic subtypes of RCC, accounting for approximately 75% and 20% of all cases, respectively. Adjuvant pembrolizumab showed promising efficacy in ccRCC, however, whether high-risk pRCC patients could benefit from adjuvant pembrolizumab remain unknown. Participants will be assigned to continue with the study treatment until any of the following occurs: the recurrence of the disease; the emergence of unacceptable adverse events (AEs); the presence of an intercurrent illness that precludes further administration of the treatment; the decision of the Investigator to withdraw the participant; noncompliance with the study treatment or procedural mandates; administrative reasons necessitating the discontinuation of treatment; or the completion of 17 treatment cycles (approximately one year), with each cycle 3 weeks long.

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Intravesical Chemotherapy in Combination With Systemic Pembrolizumab in NMIBC Unresponsive to BCG Therapy

interventional study of intravesical chemotherapy and sistemic immunotherapy in NMIBC

patients will receive intrravesical chemotherapy every 3 weeks and systemic pembrolizumb every 6 week. for a total of 1 year of treatment

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Evaluating the Efficacy and Safety of Pembrolizumab Plus Standard Chemotherapy in the Neoadjuvant Treatment of Local Advanced (LA) HNSCC

This study is a prospective, open-label, multi-center phase III study; patients with untreated stage IIIA to stage IVB head and neck squamous cell carcinoma (including oral cavity cancer, oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer) who meet the inclusion criteria are randomized 1:1 and given pembrolizumab 200 mg d1 chemotherapy for 2 cycles (experimental group), 2 cycles of chemotherapy (control group), and then stratified according to the patient's condition. If the imaging evaluation after neoadjuvant treatment is (complete response, CR), adjuvant radiotherapy (60-66Gy) will be given; if the imaging evaluation is (partial response, PR) or (stable disease, SD), surgery (within 2 weeks) will be performed, followed by standard treatment. The main research hypothesis of this study: pembrolizumab combined with standard chemotherapy can significantly improve the rate of pathological complete response (pCR) compared with standard chemotherapy.

This study is a prospective, open-label, multi-center phase III study; patients with untreated stage IIIA to stage IVB head and neck squamous cell carcinoma (including oral cavity cancer, oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer) who meet the inclusion criteria are randomized 1:1 and given pembrolizumab 200 mg d1 chemotherapy for 2 cycles (experimental group), 2 cycles of chemotherapy (control group), and then stratified according to the patient's condition. If the imaging evaluation after neoadjuvant treatment is CR, adjuvant radiotherapy (60-66Gy) will be given; if the imaging evaluation is PR or SD, surgery (within 2 weeks) will be performed, followed by standard treatment. The main research hypothesis of this study: pembrolizumab combined with standard chemotherapy can significantly improve the rate of pathological complete response (pCR) compared with standard chemotherapy. If the imaging evaluation is (progressive disease, PD), the patients will be removed from the group and given standard treatment. The enrolled patients must closely monitor the adverse reactions of chemotherapy, and record the time, grading, treatment measures, outcome, etc. All patients were reviewed every 3 months for 1 year; after 1 year, they were reviewed every 6 months for 3 years; recurrence and survival data were recorded. The investigators speculate that, compared with the traditional docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy regimen, the induction regimen of pembrolizumab combined with standard chemotherapy may be safer and more effective, and easier for clinical application. At present, there are no research reports on the induction regimen of pembrolizumab combined with standard chemotherapy for patients with locally advanced operable head and neck squamous cell carcinoma at home and abroad. The investigators intend to conduct a randomized controlled study on the efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in Chinese patients with operable head and neck squamous cell carcinoma. Provide a basis for future neoadjuvant treatment options.

Head and Neck Squamous Cell Carcinoma ; Neoadjuvant Therapy ; Pembrolizumab

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IBI363 Combined With Chemotherapy or Pembrolizumab Combined With Chemotherapy as Neoadjuvant Therapy in Resectable Stage IB-III Non-Squamous Non-Small Cell Lung Cancer

This study is a randomized, open-label Phase 2 study to compare the efficacy and safety of IBI363 Combined with Chemotherapy or Pembrolizumab Combined with Chemotherapy as Neoadjuvant Therapy in Resectable Stage IB-III Non-Squamous Non-Small Cell Lung Cancer.

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4 Courses vs 2 Courses of Pembrolizumab Combined With Carboplatin and Albumin-binding Paclitaxel of Neoadjuvant Therapy in HNSCC

In this study, 200 patients with resectable head and neck squamous cell carcinoma (T3 or T4, N0) were enrolled and preoperatively combined with pembrolizumab (PD-1 inhibitor), carboplatin, and albumin-binding paclitaxel. The subjects were randomly divided 1:1 into four treatments and two treatments. The imaging and pathological changes of tumor and paracancer tissues before and after treatment were observed. Clinical information, such as pathological grade, stage, treatment, prognosis, serology, imaging, etc., was collected to evaluate the safety and efficacy of 4-course pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with 2-course neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma. This is a prospective, one-arm, phase II clinical study. Main purpose By calculating pathological complete response (pCR) in the experimental group, we evaluated the efficacy (optimality) of four courses of pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with two courses of neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma (T3 or T4, N0). At the same time, this study evaluated the safety of medication, specifically: The severity of adverse events associated with neoadjuvant therapy will be graded according to NCI CTCAE (version 5.0) during this study and during follow-up, and the occurrence of adverse events in the experimental and control groups will be compared. To evaluate the safety of 4-course Pembrolizumab combined with carboplatin and albumin-binding paclitaxel compared with 2-course neoadjuvant therapy for resectable oral and oropharyngeal squamous cell carcinoma (T3 or T4, N0). Secondary Purpose 1. The event-free survival (EFS) of the two groups were compared; 2. The main pathological response rate (MPR) of the two groups were compared; 3. pTR of the two groups was compared; 4. Overall survival (OS) of the two groups was compared; 5. The radiological responses of the two groups were compared; 6. The operation delay rate of the two groups was compared; Exploratory purpose For the response of enrolled patients after treatment, group treatment was conducted according to the guidelines, and stratified factors influencing the prognosis and treatment plan of immunotherapy were explored according to stratification. The stratification factors taken into consideration are: P16 status, smoking history, TNM stage, tumor reduction (MPR condition), presence of risk factors (according to the guidelines, risk factors are presence of episopercular invasion, positive incisal margin, proximal incisal margin, pT3 or pT4, pN2 or pN3 lymph nodes located in the IV and V regions of the neck, Nerve invasion, vascular invasion, etc.). The purpose of this study was to stratified risk factors for evaluating the efficacy of pembrolizumab combined with carboplatin and albumin-paclitaxel in neoadjuvant therapy for resectable head and neck squamous cell carcinoma. At the same time, hematological, pathological and fecal indicators collected in the design of the experiment were collected. Correlation analysis was conducted to statistically analyze the relationship between these indicators and the therapeutic effect of the program.

Sun Yat-sen Memorial Hospital

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Study of Datopotamab Deruxtecan Plus Carboplatin or Cisplatin Versus Gemcitabine Plus Carboplatin or Cisplatin in Participants With Locally Advanced or Metastatic Urothelial Carcinoma

This is a global, multicenter, randomized, open-label, Phase 2/3 study of Dato-DXd plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin in participants with la/mUC who progressed during or after EV plus pembrolizumab combination treatment. This trial will start with part A, Phase 2. During part A, Phase 2, preliminary efficacy and safety will be assessed, and the recommended Phase 3 dose (RP3D) will be identified when the data allow sufficient assessment of activity, safety, and tolerability. The Phase 3 part will start contingent upon the assessment in the Phase 2 part, taking into consideration the totality of information.

Urothelial Carcinoma ; Dato-DXd ; TROPION ; DS-1062a ; Datopotamab Deruxtecan

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A Cancer Vaccine (Labvax 3(22)-23) and GM-CSF Alone or in Combination With Pembrolizumab for the Treatment of Advanced Stage Adenocarcinoma

This phase 1/2 trial tests the safety and effectiveness of a cancer vaccine called Labvax 3(22)-23 and GM-CSF alone or in combination with pembrolizumab in treating adenocarcinoma that has spread to other places in the body (advanced stage). Labvax 3(22)-23 is designed to target a specific antigen (labyrinthin), which is a protein found on the surface of adenocarcinoma tumor cells. Labyrinthin is a protein that is not expressed on normal cells in the skin, lungs, salivary glands, pancreas, nor other tissues. In adenocarcinoma, the tumor cells produce too much labyrinthin causing them to express this protein on the surface of the tumor cells. One way to control the growth of these tumor cells is to teach the immune system to generate an immune response against the labyrinthin protein by vaccination against labyrinthin. GM-CSF, or sargramostim, is a protein that acts as a white blood cell growth factor. It has also been shown to stimulate immune system. Thus, administration of GM-CSF may help to boost the immune system response when given together with the vaccine. This study may improve the general knowledge about Labvax 3(22)-23 and how the body may generate an immune response to kill adenocarcinoma tumor cells. In the second phase of the study, participants will also receive pembrolizumab, which may improve anti-cancer activity when given with Labvax 3(22)-23 and GM-CSF.

Phase 1: Up to 10 participants with advanced/ metastatic or recurrent adenocarcinoma of any primary site will be enrolled. Participants will be given LabVax 3(22)-23 (intradermally) and adjuvant GM-CSF (subcutaneously) on weeks 1, 2, 4, 8, and 12. Participants will be evaluated for 16 weeks, which include a follow-up exam 4 weeks after the last injection of vaccine or last injection, if injection(s) are stopped earlier. The study will be terminated if one death or two subjects have 3 adverse events that are at least possibly related to the study treatment. [Note: Phase 1 enrollment was completed as of December 2022] Phase 2: Up to 67 participants with advanced/ metastatic or recurrent lung adenocarcinoma (Cohort A) or non-lung adenocarcinomas (Cohort B). Pembrolizumab will be given intravenously every 3 weeks for up to 12 cycles on Day 1 of Weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, and 34. Subjects will be given LabVax 3(22)-23 (intradermally) and adjuvant GM-CSF (subcutaneously) on weeks 7, 8, 10, 14, and 18. Participants will receive study treatment over 34 weeks if tolerating the treatment without tumor progression; a safety follow-up visit will occur 30 days post-last dose of study treatment. The participant's chart will be reviewed for up to 12 months post-last dose of study treatment. The study will be terminated if safety is insufficient following the lead-in period or if response is insufficient in Cohort A following the first expansion.

Advanced Adenocarcinoma ; Advanced Malignant Solid Neoplasm ; Metastatic Adenocarcinoma ; Metastatic Malignant Solid Neoplasm ; Recurrent Adenocarcinoma ; Recurrent Malignant Solid Neoplasm

Comprehensive Cancer Center,University of California, Davis

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OT-101 in Combination With Pembrolizumab in Subjects With Malignant Pleural Mesothelioma Failing to Respond to Checkpoint Inhibition

This is a study of OT-101, a TGF-b2 inhibitor in combination of pembrolizumab in patients with malignant pleural mesothelioma. Both efficacy assessment, and safety and tolerability of various dose of OT-101 in combination of pembrolizumab are evaluated.

This is a phase 2, open label, non-randomized, single arm Simon's two stage study in subjects with malignant pleural mesothelioma failing to achieve or maintain response to checkpoint inhibition. Before the efficacy assessment portion, the study will first embark a run-in dose-escalation phase to evaluate safety and tolerability of various dose of OT-101 in combination of pembrolizumab, and to determine a recommended Phase 2 dose (RP2D) of 4 days continuous I.V. infusion for every two weeks regimen. Subjects received the RP2D in the run-in dose-escalation phase will be part of the first stage of the Simon's two-stage design for effectiveness evaluation.

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Pembrolizumab and Lenvatinib for Platinum- Sensitive Recurrent Ovarian Cancer

This is a study of pembrolizumab (MK-3475, KEYTRUDA ) in combination with lenvatinib (E7080) for the treatment of platinum sensitive recurrent ovarian cancer. Participants will receive pembrolizumab and lenvatinib.

This will be a phase-2, open-label, single-arm, single-center study to assess the effect of pembrolizumab and Lenvatinib combination therapy on platinum-sensitive recurrent ovarian cancer (ROC) patients. Female patients 18 years of age or older with histologically-confirmed epithelial ovarian cancer (EOC) - excluding low grade tumors and mucinous histology - and documented disease recurrence following primary or interval debulking surgery and 1-2 prior lines of chemotherapy (including a frontline platinum-based regimen) and a platinum-free interval greater than 6 months will be eligible to enroll in the study. Twenty-four patients will be included in the study. The study diagram is shown in Figure 1 and the schedule of assessments (SoA) is shown in Section 6.0. After signing the informed consent, eligible subjects according to the inclusion and exclusion criteria will receive oral Lenvatinib 20 mg once daily (QD) plus intravenous (IV) pembrolizumab 200 mg every three weeks (Q3W) until evident progressive disease by CT (RECIST), or unacceptable toxicity, or until completion of 35 treatment cycles with pembrolizumab. Disease status will be evaluated radiologically by computed tomography (CT) every 9 weeks, in comparison to pretreatment CT, until progression. In case of study withdrawal due to other reasons, radiological evaluation will be maintained every 9 weeks until disease progression or patient's withdrawal of consent or a new anticancer regimen is given. Patients with contrast media allergy will undergo chest CT without contrast medium as well as abdominal and pelvic magnetic resonance imaging (MRI). Toxicity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Ver. 5.0 (NCI-CTCAE). Dose reductions and modification of Lenvatinib will be performed according to the indications in Section 5.2.3. Pembrolizumab dose will not be reduced but the dose can be delayed for up to 9 weeks in case of toxicity which requires steroid. treatment and steroids withdrawal (refer to Section 5.2.2 on pembrolizumab dose interruptions). Refer to section 5.2.4 for dose modifications for overlapping toxicities. Health-related quality of life will also be evaluated. Collateral research will focus on potential biomarkers of response to treatment and on micro- and macro-environmental changes occurring during the course of treatment. To that end, tumor biopsies, stool and vaginal swabs and blood (plasma, serum and peripheral blood mononuclear cells (PBMC)) samples will be collected at Screening and during the study. Analyses will be performed to determine pre- and post-treatment changes as well as differences between responders to treatment and non-responders. Participants who stop study treatment after receiving 35 administrations of pembrolizumab for reasons other than disease progression or intolerability, or participants who attain a complete response (CR) and stop study treatment may be eligible for up to 1 year of treatment with pembrolizumab (17 cycles) Lenvatinib upon experiencing disease progression (Second Course Phase). Participants who complete treatment with pembrolizumab after 35 cycles (approximately 2 years) or CR will continue to receive Lenvatinib alone until disease progression, development of unacceptable toxicity, or withdrawal of consent.

Ovarian Cancer ; Platinum sensitive ; Ovarian Epithelial ; Neoplasms ; Genital Neoplasms

Ovarian Neoplasms ; Carcinoma, Ovarian Epithelial ; Neoplasm of Stomach ; Ovarian Diseases ; Genital Neoplasms, Female ; Ovarian Epithelial Tumor ; Urogenital Neoplasms ; Neoplasms, Glandular and Epithelial

Ronnie Shapira-Frommer

Ronnie.Shapira@sheba.health.gov.il

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Pembrolizumab Monotherapy Following Tri-modality Treatment for Selected Patients With Muscle-invasive Bladder Cancer

This is a Phase II, single-arm, study of pembrolizumab as maintenance therapy in
muscle-invasive bladder cancer (MIBC) participants who have received maximum TURBT and
tri-modality treatment (TMT) and achieved CR. All participants will receive pembrolizumab
monotherapy per 21 days no longer than 17 cycles until disease progression or death.

Radical cystectomy (RC) has long been the standard of care for the treatment of
muscle-invasive bladder cancer (MIBC). Modern RC series have demonstrated 5-yr overall
survival (OS) rates of 56-66%. There has been an increasing trend of utilizing
organ-preserving therapies in the management of bladder cancer over the past several decades.
A multidisciplinary approach has led to the development of bladder-sparing approaches using
maximal transurethral resection (TURBT) followed by radiotherapy with concomitant
radio-sensitizing chemotherapy for MIBC. Multiple tri-modality treatment (TMT) series have
suggested that TMT can yield favorable results in well-selected patients. The 5-yr OS is
48-75%, and 75-80% of the survivors have preserved their native bladder. Even if local
recurrence occurred after concurrent radio-chemotherapy, salvage cystectomy can also bring
50-57.6% of 5-year disease-specific survival (DSS) without more complications associated with
surgery. So, NCCN guidelines have regarded this TMT strategy as a preferred choice for
patients with MIBC since 2019.

However, distant metastasis after TMT was still the main concern. Giacalone NJ, et al.
reported that the 5-yr distant metastasis rate was 32% in MIBC patients who received an
organ-preserving strategy. Up to now, there was no consensus on adjuvant therapy after
concurrent radio-chemotherapy. Some retrospective studies demonstrated that adjuvant
chemotherapy had no survival benefit, and only approximately 50% of patients completed the
planned adjuvant chemotherapy due to intolerable toxicities.

These years, studies on PD-(L)1 inhibitors for urothelial carcinoma showed the efficacy and
safety. FDA has approved indications of pembrolizumab used as 1L (selected patients) and 2L
treatment for metastatic urothelial carcinoma. Checkmate-274 has reported that adjuvant
immunotherapy improved disease-free survival (DFS) in MIBC patients after RC. Javelin Bladder
100 prolonged OS of mUC patients by Avelumab as maintenance therapy who achieved CR, PR or PD
after 1L chemotherapy. These results support our hypothesis that, for those MIBC patients who
have received bladder-preserving TMT and achieved CR, pembrolizumab monotherapy as
maintenance therapy is superior to observation.

Bladder Cancer ; Bladder Neoplasms ; Bladder Tumors ; Urinary Bladder Cancer ; Neoplasms, Bladder

Zhisong He,Zhi-song He

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This trial is a randomized, multicenter, open label phase II clinical study. The main objective is to evaluate the efficacy of three perioperative immunotherapy modalities (atezolizumab adjuvant therapy, nivolumab neoadjuvant therapy, pembrolizumab neoadjuvant adjuvant therapy) in early-stage resectable NSCLC patients. The enrolled patients are randomly assigned in a 1:1:1 ratio to receive relevant treatment in the three perioperative immunotherapy groups mentioned above, and undergoing short-term pathological efficacy evaluation and long-term prognosis follow-up after surgery.

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Phase II Study Evaluating the Efficacy and Safety of Ociperlimab in Combination With Tislelizumab and Chemotherapy as First-line Treatment for Participants With Advanced Triple Negative Breast Cancer

The primary scientific question of interest of this study is whether the combination of ociperlimab, tislelizumab and chemotherapy improves progression-free survival (PFS) compared to the combination of placebo, pembrolizumab and chemotherapy as first-line therapy for adult men and women with advanced triple negative breast cancer (TNBC) whose tumors express programmed death ligand 1 (PD - L1) [combined positive score (CPS) 10], regardless of study treatment discontinuation or start of new anti-neoplastic therapy.

This is a randomized, double-blind, placebo-controlled, multicenter, Phase II study evaluating the efficacy and safety of ociperlimab in combination with tislelizumab and chemotherapy as first-line treatment for participants with advanced TNBC whose tumors express PD-L1 (CPS 10). Additionally, the efficacy and safety of the triple combination (ociperlimab tislelizumab chemotherapy) will be assessed in Arm D (a separate single-arm, open-label cohort) in 30 participants with advanced TNBC whose tumors express PD-L1 (CPS 1 to 10). Study treatment will continue until the participant experiences one of the following: disease progression per investigator's assessment by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, unacceptable toxicity, pregnancy, treatment is discontinued at the discretion of the investigator or participant, start of a new antineoplastic therapy, withdrawal of consent, lost to follow-up, death, or study is terminated by the sponsor.

TNBC ; Triple Negative Breast Cancer ; PD-L1 ; Ociperlimab ; Tislelizumab ; WCD118 (BGB-A1217) ; VDT482 (BGB-A317) ; Pembrolizumab ; Carboplatin ; Gemcitabine ; Paclitaxel ; Nab-paclitaxel ; TIGIT ; Combination immunotherapy

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Pembrolizumab and Odetiglucan in Liver Predominant Metastatic Colorectal Adenocarcinoma

This study will evaluate the safety and effectiveness of the combination of pembrolizumab and odetiglucan in patients with metastatic colorectal cancer that is predominantly in the liver.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*l7zty5itnxqjdopcinfj6euevq000000/overview

Binimetinib Encorafenib Pembrolizumab /- Stereotactic Radiosurgery in BRAFV600 Melanoma With Brain Metastasis

This study evaluates the addition of stereotactic radiosurgery (SRS) to the combination of binimetinib encorafenib pembrolizumab in the treatment of BRAFⱽ⁶⁰⁰ mutation-positive melanoma with brain metastases (MBM).

This is a Phase 2, randomised, controlled, open-label, multicentric, parallel trial with a safety lead-in phase, to assess the efficacy and safety of adding upfront SRS to binimetinib-encorafenib-pembrolizumab combination therapy in the treatment of BRAFⱽ⁶⁰⁰ mutation-positive MBM. The study will incorporate a safety lead-in (SLI) phase to assess the tolerability of binimetinib-encorafenib-pembrolizumab combination therapy /- SRS in the first six patients enrolled. Safety will be assessed by the occurrence of predefined dose limiting toxicity (DLT) events. The safety data will be reviewed by an independent data monitoring committee (IDMC). The trial plans to enrol 150 patients who will be randomly assigned (1:1) to receive treatment with either: - Arm A: Encorafenib binimetinib pembrolizumab - Arm B: Upfront stereotactic radiosurgery of all lesions 5 mm in diameter (or 3 mm if other cerebral metastases 5 mm); followed by encorafenib binimetinib pembrolizumab . The treatment should be started more than 24 hours and less than 8 days (excluded) after the SRS. Patients will be treated until disease progression. Pembrolizumab will be discontinued after a maximum of 35 administrations. Treatment may also be terminated early at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient All patients will be followed for a total of 5 years post-randomisation.

Melanoma ; BRAF V600 ; Brain metastases ; Encorafenib ; Binimetinib ; Pembrolizumab ; Stereotaxic ; SRS

Ambroise Paré Hospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*dzpesjrlct7wwzkmxhauszsk5q000000/overview

Phase II study of Pembrolizumab plus Lenvatinib in relapsed/refractory Classic Kaposi Sarcoma (CKS). After a screening phase of up to 28 days, each participant will receive study intervention of pembrolizumab plus lenvatinib until reaching a discontinuation criterion: disease progression; unacceptable adverse event(s) (AEs); intercurrent illness that prevents further administration of treatment; participant withdraws consent; pregnancy of participant; non-compliance with study intervention or procedure requirements; or administrative reasons requiring cessation of treatment. After the end of treatment, each participant will be followed for the occurrence of AEs and spontaneously reported pregnancy. Participants who discontinue for reasons other than PD will have post-treatment follow-up for disease status until PD is documented clinically by a team of committed dermatologists, and/or radiographically per RECIST 1.1, a non-study anticancer treatment is initiated, consent is withdrawn, or the participant becomes lost to follow-up. All participants will be followed for overall survival (OS) until death, withdrawal of consent,lost to follow-up, or the end of the study. The end of the study will be when the last participant completes the last study-related telephone call or visit,withdraws from the study, or is lost to follow-up.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*x4dzqp7aesms3qzmfc6ncdchv4000000/overview

T-Cell Repertoire Sequencing: Assessing Pembrolizumab Efficacy in Advanced Non-small Lung Cancer

This is a single site, non-randomized trial for the assessment of intravenous (IV) pembrolizumab (also known as MK-3475) combined with pemetrexed/platinum-based chemotherapy in subjects with advanced or metastatic non-squamous non-small lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease and in whom directed therapy is not indicated. Approximately 30 subjects will be enrolled in this trial to examine the clonality and diversity dynamics matched with disease response evaluated by RECIST 1.1.

Subjects will receive pembrolizumab 200 mg combined with pemetrexed and platinum (investigator's choice of cisplatin or carboplatin), as indicated below: Pembrolizumab 200 mg pemetrexed 500 mg/m2 (with vitamin supplementation) cisplatin 75 mg/m2 OR carboplatin AUC 5, all on Day 1 every 3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg pemetrexed 500 mg/m2 Q3W until progression. Treatment with pembrolizumab and pemetrexed will continue until 35 trial treatments have been administered, documented disease progression or unacceptable adverse event(s). Patients will be stratified according to clinical and histopathological parameters: 1. PD-L1 status (PD-L1 / 1 or 1) 2. Age 65 vs 65 3. Smoking history yes vs no 4. Platinum chemotherapy: cisplatin vs. carboplatin 5. Immune-related adverse events (irAEs). TCR repertoire clonality and diversity will serve as an assessment measure for treatment response, along with PET/CT-scans, tumor exomal profile and ctDNA dynamics.

Tel Aviv Medical Center,Tel-Aviv University school of medicine

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*k6cyngolo2xtm3ejl5xeyuas3m000000/overview

A Study Evaluating the Efficacy and Safety of De Trastuzumab (T-DXd) in Combination with Immunotherapy for the Neoadjuvant Treatment of HR-positive HER2 Low-expressing Chinese Patients with Early-stage Breast Cancer

This is a prospective, open-label, multicenter, single-arm clinical study designed to compare the efficacy and safety of neoadjuvant treatment with T-DXd in combination with an immune checkpoint inhibitor in patients with primary intermediate- to high-risk HR-positive, HER2-overexpressing early-stage breast cancer.

Neoadjuvant therapy, a systemic therapy administered prior to localized treatments such as surgery, has become a key component in the management of non-metastatic breast cancer. Neoadjuvant chemotherapy is often used to treat early-stage, high-risk hormone receptor-positive (HR ) breast cancer; however, the rate of pathological complete remission(pCR) is only 5-8 %. Moreover, neoadjuvant chemotherapy has significant toxicity, with approximately 25-40% of patients discontinuing chemotherapy or reducing their dosage due to side effect. Much evidence suggests that immune checkpoint inhibitors (ICIs) combined with chemotherapy significantly increase pCR rates in HR breast cancer. The CheckMate 7FL study evaluated the efficacy of ICI (nabulizumab) in early-stage HR-positive breast cancer, and ICI in combination with chemotherapy increased the pCR rate to 24%, compared to 13.8% in the chemotherapy arm\[4\]. The Keynote756 clinical trial demonstrated for the first time that the addition of an ICI (pembrolizumab) to a neoadjuvant chemotherapy regimen for early-stage, high-risk ER /HER2- breast cancer significantly increased patients' pCR rates. These clinical trials imply that ICIs in combination with chemotherapy can provide more benefit to patients with early-stage breast cancer compared to traditional neoadjuvant chemotherapy treatments. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeted antibody-drug coupling (ADC) approved by the FDA and NMPA for the treatment of HER2-positive and HER2-low expressing metastatic breast cancer. The BEGONIA study showed that Dato-DXd in combination with ICI (doxorubicinumab) for advanced triple-negative breast cancer had an ORR of up to 79%, which is superior to the efficacy of current ICIs in combination with chemotherapy; The DS8201-A-U105 study evaluated the efficacy of T-DXd in combination with navulizumab in HER2 and HER2-low advanced breast cancer, with an ORR of 65.6% in the HER2 and 50% in the HER2-low-expressing population, and the combination of T-DXd with navulizumab did not increase any overall toxicity. The TALENT study explored the efficacy of T-DXd neoadjuvant therapy in patients with HR-positive HER2 low-expression early breast cancer. The results showed that T-DXd alone or in combination with ET achieved promising efficacy, with an ORR of 68% and a CR of 8% for T-DXd alone, indicating that T-DXd can also demonstrate very significant anti-tumor effects in early-stage breast cancer. In view of the impressive efficacy and manageable safety of T-DXd in combination with ICIs in breast cancer patients, we designed this investigator-initiated clinical study with intermediate- and high-risk HR-positive HER2 low-expressing early-stage breast cancer patients to evaluate the efficacy and safety of T-DXd in combination with ICIs in early-stage HR-positive HER2 low-expressing breast cancer patients in a Chinese population. This is a prospective, open-label, multicenter, single-arm clinical study designed to compare the efficacy and safety of neoadjuvant treatment with T-DXd in combination with an immune checkpoint inhibitor in patients with primary intermediate- to high-risk HR-positive, HER2-overexpressing early-stage breast cancer. Subjects who are eligible for the study and have signed informed consent will receive T-DXd in combination with an immunosuppressant. The specific dosing regimen is as follows: T-DXd (5.4 mg/kg i.v. q3w) every 3 weeks for a total of 8 courses. Teraplizumab (240 mg/kg i.v. q3w), 1 course of treatment every 3 weeks for a total of 8 courses of treatment Upon discontinuation of the study, subjects will receive post-neoadjuvant therapy according to local clinical criteria. Subjects will end study treatment if disease progression, intolerable toxicity, withdrawal of informed consent, or discontinuation of dosing is necessary in the judgment of the investigator occurs during the study treatment period, after which they will continue to receive follow-up, including metastatic disease recurrence and safety follow-up. Subjects who complete surgical treatment will be followed for at least 3 years for the study endpoints of event-free survival (EFS), invasive disease-free survival (IDFS), overall survival (OS), and safety assessment. Safety data will be collected from the time of signing the informed consent form until 28 days after the end of study treatment.

Women and Children's Medical Center of Guangzhou Medical University

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*yd7ptpymovnoq2zpjnmnkrnmzi000000/overview

The goal of this clinical trial is to evaluate the efficacy and safety of Viscum album extract when used in combination with pembrolizumab as adjuvant chemotherapy in adult patients (aged 19 and older) who have been diagnosed with malignant neoplasm of unilateral breast and have completed surgery. The main questions it aims to answer are: Does the addition of Viscum album improve clinical outcomes when combined with pembrolizumab as adjuvant chemotherapy? Is Viscum album safe and tolerable for use in this patient population?

The goal of this clinical trial is to evaluate the efficacy and safety of Viscum album extract when used in combination with pembrolizumab as adjuvant chemotherapy in adult patients (aged 19 and older) who have been diagnosed with malignant neoplasm of unilateral breast and have completed surgery. This clinical trial aims to recruit 40 adult participants aged 19 years or older who have been diagnosed with malignant neoplasm of the unilateral breast and require adjuvant chemotherapy, including immune checkpoint inhibitors, after completing surgical tumor resection and radiotherapy. Potential participants will receive a full explanation of the study's purpose and procedures and will voluntarily provide written informed consent. After screening for eligibility based on inclusion and exclusion criteria, only those who meet the criteria will be enrolled and proceed with the study. Participants in the treatment group will receive Viscum album concurrently with pembrolizumab as part of their adjuvant chemotherapy regimen for 18 weeks in order to evaluate the efficacy and safety of Viscum album. Participants in the waitlist control group will undergo scheduled assessments without any additional intervention for the first 18 weeks, followed by a 4-week intervention phase starting from week 19. Researchers will compare the treatment group receiving pembrolizumab plus 18 weeks of Viscum album to the waitlist control group, who will not receive any intervention for the first 18 weeks, to see if early administration of Viscum album leads to better outcomes compared to delayed intervention. Participants will: Sign informed consent after receiving full explanation of the study Be screened for eligibility based on inclusion and exclusion criteria If eligible, participants will be assigned to either the treatment or control group Receive subcutaneous injections of Viscum album three times per week for 18 weeks (treatment group only) Undergo scheduled clinical assessments throughout the study period

triple negative breast cancer ; adjuvant chemotherapy ; pembrolizumab ; mistletoe

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*lokunhnh2odvmqdmuqqy43bhiy000000/overview

A Study of SKB264 in Combination with Pembrolizumab Versus Chemotherapy in Combination with Pembrolizumab As First-Line Treatment for PD-L1 Negative Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

The study aims to evaluate the efficacy and safety of SKB264 in combination with pembrolizumab versus chemotherapy in combination with pembrolizumab in the first-line treatment of patients with locally advanced or metastatic non-squamous NSCLC with PD-L1 negative.

This is a randomized, open-label, multicenter, Phase 3 study to evaluate the efficacy and safety of SKB264 in combination with pembrolizumab versus chemotherapy in combination with pembrolizumab in the first-line treatment of patients with locally advanced or metastatic non-squamous NSCLC with PD-L1 negative.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*knvvm6yuek4yxhofuhc3hiywqm000000/overview

The goal of this phase 2 clinical trial is to test efficacy and tolerability of combining propranolol and pembrolizumab in patients with advanced angiosarcoma or undifferentiated pleomorphic sarcoma. The main questions aims to answer: - Primary: determine the progression-free survival rate (PFSR) at 3 months Secondary: determine the objective response rate (ORR), duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS). Ensure the safety and tolerability, Determine Quality of Life (QoL) • Exploratory: Characterize the TME Participants will be asked to ensure - Baseline biopsy and further optional biopsies - Treatment propranolol 40 mg BID and pembrolizumab 2 mg/kg Q3 weeks - Evaluation, blood counts, QoL and blood samples for biomarkers according to schedule

Soft tissue sarcomas (STS) are mesenchymal derived tumors consisting of more than 50 subtypes, showing high metastatic features in approximately 50% of patients with intermediate and high-grade tumors. In spite of optimizing sequence of conventional systemic treatments with chemotherapy and tyrosine kinase inhibitors with an increase in overall survival from 12 to 18 months, the prognosis has not changed and is still a dismal 8% overall survival at 5 years. After four decades doxorubicin is still first line treatment as no new drugs has proven more effective and/or less toxic. Thus, new treatment modalities are needed. Angiosarcomas (AS) and Undifferentiated Pleomorphic Sarcoma (UPS), comprising approximately 2% and 10% of STS respectively, are by definition high grade sarcomas characterized by an aggressive course. In the non-resectable advanced and metastatic setting treatment options are limited with short term palliative intent with median overall survival (OS) 12 months. Patients are often elderly and with co-morbidities, increasing risk of severe toxicity from chemotherapy leading to significant deterioration of Quality of Life. New therapeutic options are needed. Emerging results on immune modulating therapy with immune checkpoint inhibitors (ICI), have shown promising signals of potential benefit in certain subtypes of STS, especially in UPS and AS. In tumors, neovascularization facilitate hypoxia, glucose deprivation and increased VEGF production leading to an immune suppressive tumor microenvironment (TME). This can in part be reverted by anti-angiogenic therapy including multitarget tyrosine kinase inhibitors. A proposed novel approach for targeting angiogenesis and potential immune modulatory mechanisms is through beta-adrenergic receptor (βAR) signaling. Preclinical data support combining βAR blockade with propranolol in combination with anti PD-1, and recently a phase 1 study showed the combination propranolol and pembrolizumab was well tolerated in melanoma patients. This study is an open label, Simon two-stage single arm phase 2 study of pembrolizumab and propranolol in two separate cohorts. Patients will receive pembrolizumab 2 mg/kg every 3 weeks and propranolol 40 mg x2 daily until progression, unacceptable toxicity or patient withdrawal for a maximum of two years. Up to 40 patients will be included in each separate cohort. Up to 18 patients in stage 1 and up to 22 patients in stage 2. The primary objective is to determine progression-free survival rate (PFSR) at 3 months by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) The secondary objectives are to determine objective response rate (ORR) and duration of Response (DOR) using RECIST v 1.1, PFS and OS. Ensure safety and tolerability according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0), and determine Quality of Life (QoL) using the 30 item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) questionnaire The explorative objective is to characterize the TME, immune cells and markers both in tumors and in peripheral blood.

Soft Tissue Sarcoma Adult ; Angiosarcoma ; Undifferentiated Pleomorphic Sarcoma

Herlev and Gentofte Hospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*7bettiyfcaedpiyvzbeogcaf3i000000/overview

Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer

MSI is a molecular indicator of defective DNA mismatch repair (dMMR). The MSI/dMMR status is observed in all tumor types, representing notably 5% of metastatic colorectal cancers (mCRC), 25% of advanced endometrial cancer and 8% of metastatic gastric cancer. MSI/dMMR cancers are highly immunogenic. MSI/dMMR tumors are characterized by a high tumor mutational burden with highly immunogenic neoantigens. These tumors are associated with an upregulation of immune checkpoints (PD1, PDL1, CTLA4, etc.) that protects MSI cancer cells from their hostile immune micro-environment, characterized by a high infiltration of activated cytotoxic T CD8 and NK lymphocytes. Consequently, MSI/dMMR cancers are highly sensitive to ICIs, whatever the tumor location. MSI/dMMR status is a predictive biomarker for the efficacy of immunotherapy, regardless of the tumor type. Then, by several phase II and III studies The efficacy of immunotherapy has been demonstrated as front-line treatment for patients with chemotherapy-naive MSI/dMMR mCRC and gastric cancer. The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSI/dMMR mCRC demonstrated its superiority over first-line chemotherapy, with a significant improvement of health-related quality of life. At final analysis, the median follow-up was 44.5 months. Median PFS was 16.5 versus 8.2 months (HR 0.59; 95%CI 0.45-0.79). The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P 0.0359), despite a 60% effective crossover rate. Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSI/dMMR mCRC and is now the standard of care for this population. Also, the phase III CHECKMATE-649 trial reveal that the Combination of immunotherapy and cytotoxic chemotherapy is the new standard of care for patients with newly diagnosed metastatic oesogastric cancer. Importantly, results of the CHECKMATE-649 are outstanding for the subgroup population of MSI/dMMR gastric cancer patients (N 44). Indeed, the unstratified hazard ratio for OS with nivolumab plus chemotherapy versus chemotherapy alone was 0.33 (95% CI 0.12-0.87) for patients with MSI/dMMR tumors. All in all, ICIs are the standard of care in first-line setting for patients with mCRC or metastatic oesogastric cancer. Besides, several phase II studies suggest that ICI combinations might overcome primary resistance to anti-PD1 monotherapy These data justify the development of bispecific monoclonal antibodies targeting both PD1 and CTLA4 such as MEDI5752. MEDI5752 has been developed based on the observation that there is a higher expression of PD-1/CTLA-4 on tumor resident versus peripheral T cells. Preclinical data show MEDI5752 fully suppresses PD-1 and preferentially inhibits CTLA-4 in the tumor versus the periphery, which is meant to uncouple CTLA-4 dependant peripheral toxicity from antitumor activity Natural killer cells are integral to the functioning of the innate immune system and play an important role in innate antitumor immunity. There is a growing body of evidence for targeting the NKG2A/HLA-E axis in combination with other ICIs to sensitize tumors to ICI therapy. NKG2A recognizes the non-classical HLA class I molecule HLA-E. The NKG2A receptor is found on peripheral NK cells and subsets of T cells in cancer patients. It is also present in tumor-infiltrating NK and cytotoxic T cells. Importantly, NK cells and the NKG2A/HLA-E axis play a crucial role in MSI/dMMR tumors. Therefore, a combined blockade of non-redundant checkpoint pathways to unleash NK and T cells seems particularly promising for MSI/dMMR neoplasms. Monalizumab specifically binds and blocks the inhibitory receptor NKG2A. Monalizumab has been investigated in combination with ibrutinib (in chronic lymphoid leukemia), cetuximab /- durvalumab (in squamous cell carcinoma of the head and neck, and in solid tumors), durvalumab /- FOLFOX (in solid tumors). In the first-in-human dose escalation of monalizumab plus durvalumab, a manageable toxicity profile was shown. Taken together, these data provide a strong rational to combine an inhibitor of the NKG2A/HLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for patients with metastatic MSI/dMMR cancers.

MONAMI is a multicenter (4 French hospitals) single-arm phase II trial according to A'Hern's design with a safety lead-in. For the achievement of the main objectif and primary endpoint, the tumor measurements using CT-scan (preferred option) or MRI will be performed at baseline, 6 weeks, 12 weeks, 18 weeks and 24 weeks. The same type of imaging (CT or MRI) as the one used at baseline will have to be performed for all tumor imaging evaluation. The study contains a safety lead-in (N 9) in which the safety and tolerability of monalizumab plus MEDI5752 will be assessed after the second cycle (the first 42 days of treatment). The Data Safety Monitoring Board (DSMB) will evaluate the safety data at pre-specified intervals (every 4 weeks and at the end of the safety lead-in) and at additional points during the conduct of the safety lead-in, if necessary. The tolerability assessment will be based upon occurrence of dose-limiting toxicities. Additional patients will be enrolled based on assessments of the safety data by the DSMB during the safety lead-in Enrollment will be put on hold after the inclusion of the first patient in the safety lead-in until the end of the DLT period and until a discussion with the DSMB can occur. After every 3 new included patients in the safety lead-in until the end of the DLT period of the last included patient and until a discussion with the DSMB can occur. During this period, if 3 patients experience dose-limiting toxicities until a discussion with the DSMB can occur and after the inclusion of all the patients of the safety lead-in, until the end of the DLT period of the last patient and until a discussion with the DSMB can occur for the authorization to initiate the second part of the phase II study. Patients will be treated with monalizumab 750 mg and MEDI5752 750 mg every 3 weeks intravenously, for 32 infusions (or less in case of RECIST disease progression or limiting toxicity, whichever occurs first). Monalizumab will be supplied by AstraZeneca as a lyophilized product for concentrate for solution for infusion MEDI5752 will be supplied by AstraZeneca as a lyophilized product for concentrate for solution for infusion Because of the possibility of an initial increase in tumor burden caused by immune-cell infiltration in the setting of a T-cell response (termed "pseudoprogression") with cancer immunotherapy, radiographic progression per RECIST v1.1 may not be indicative of true disease progression. During the study, participants who meet criteria for disease progression per RECIST v1.1 (unconfirmed disease progression per iRECIST criteria: iuPD) and show evidence of clinical benefit may continue study treatment at the Investigator's discretion provided that the participants meet all of the following criteria: - Absence of clinically important symptoms and signs (including worsening of laboratory values) indicative of disease progression - Investigator-assessed potential clinical benefit for the participant - The participant is tolerating study drugs - No decline in ECOG Performance Status - Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention For participants receiving treatment beyond progression, an additional radiographic assessment/scan should be performed within 6 weeks of initial progression to determine whether there has been a stabilization or decrease in the tumor size or continued PD (confirmed disease progression per iRECIST criteria; icPD). Study treatment should be discontinued permanently upon documentation of further progression. Safety lead-in cohort : 9 Phase II study : 29 Total : 43 patients maximum - 38 evaluable patients - If necessary, inclusions may be continued to reach the required number of evaluable patients within the limit of 5 additional participants Duration of enrolment period (including safety lead-in cohort with interruption of inclusion after the first 9 participants): 2 years The length of participation for participants, of which: - Maximum period between screening and treatment initiation: 21 days - Treatment duration: 2 years maximum - Duration of follow-up period: 3 years from inclusion in the study Total study duration: 5 years and 21 days Patients included in the safety lead-in will be analyzed as part of the overall population of the phase II study

Cancer ; MSI/dMMR tumors ; Monalizumab ; MEDI5257 ; Efficacy ; Safety/tolerability ; Pharmacokinetic ; MSI phenotype ; Immune Checkpoint Inhibitors ; Immunotherapy ; Cytotoxic chemotherapy

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*5izuubbjihkrefqc2x4britf7i000000/overview

Neoadjuvant Gemcitabine and Cisplatin in Combination With Perioperative Pembrolizumab Versus Upfront Surgery for Patients With Primary Resectable and Borderline Resectable Perihilar and Distal Cholangiocarcinoma

Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive cancer with poor prognosis. ECCA can be further subcategorised in perihilar and distal cholangiocarcinoma (pCCA and dCCA). Surgical resection is the only potential cure, but only one-third of patients are eligible. Even among those deemed resectable, a significant portion ( 30%) experience disease progression before surgery, while another 30% are found unresectable during exploration. High recurrence rates and postoperative complications further limit survival, with 5-year overall survival ranging from 13% (R1 resection) to 40% (R0 resection). Given the long preoperative work-up period and lack of treatment during this phase, a neoadjuvant approach may improve outcomes by increasing R0 resections, reducing recurrence, and optimizing patient selection. This multicenter, randomized phase 2B/3 trial aims to assess whether neoadjuvant gemcitabine and cisplatin plus perioperative pembrolizumab improves event-free survival in patients with resectable and borderline resectable pCCA and dCCA.

Extrahepatic cholangiocarcinoma ; Perihilar Cholangiocarcinoma ; Distal Cholangiocarcinoma ; Resectable ; Borderline resectable

Extrahepatic Cholangiocarcinoma ; Perihilar Cholangiocarcinoma ; Distal Cholangiocarcinoma ; Resectable ; Borderline Resectable

Erasmus MC,University Medical Center Groningen,Wilhelmina Children Hospital,Maastricht University Medical Center

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*ygylpjbpvvgmp3z3x64nah3lvq000000/overview

A Study of Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer

Neoadjuvant accelerated methotrexate/vinblastine/adriamycin/cisplatin (AMVAC) in combination with nivolumab is under evaluation for the treatment of muscle invasive bladder cancer (MIBC). Patients with pre-specified tumor mutations and complete clinical response with neoadjuvant therapy will preserve their bladders and go on active surveillance.

Muscle invasive bladder cancer (MIBC) constitutes 20-25% of all cases with 5 year survival estimated at 45% regardless of treatment.1-4 Although neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy or cystoprostatectomy with a lymph node dissection is the preferred treatment choice for MIBC in the United States, there are several drawbacks and challenges with this approach. Patients must be fit to undergo a surgical intervention. Grade 2 through 5 complications have been documented in 53% of patients undergoing cystectomy at a tertiary care center, and the surgical mortality rate is 1.5%.5, 6 Furthermore, urinary diversion commonly requires an ileal conduit and an external appliance, impacting patient's quality of life. By incorporating neoadjuvant nivolumab with AMVAC, our goal in RETAIN-2 is to increase the number of patients who would be eligible for bladder preservation while maintaining the long-term oncologic outcomes. Nivolumab, an anti-PD1 therapy, is FDA approved for treatment of metastatic urothelial carcinoma post platinum-based chemotherapy.20 Recently, neoadjuvant pembrolizumab (anti-PD1) and atezolizumab (anti-PDL1) was tested in MIBC in the PURE-01 and ABACUS studies, and a pT0 rate of 38.6% and 29%, respectively, was achieved.21, 22 Additionally, recent work by Kim et al. presented at AACR 2019 demonstrated that AMVAC induces gene signatures in luminal tumors and may have a synergistic response with immunotherapy. Given the impressive activity of both AMVAC and nivolumab in the neoadjuvant setting, in this study the investigators hypothesize that using the combination of neoadjuvant nivolumab and AMVAC will lead to higher cT0 rate and metastasis-free survival at 2 years. At the same time by using the risk adapted strategy, a select group of patients will be able to preserve their bladders and significantly improve their quality-of-life.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*cxckcp7hht2ysbplklx74lpwua000000/overview

GM103 Intratumoral Injection in Patients With Locally Advanced, Unresectable, Refractory and/or Metastatic Solid Tumors

The purpose of this study is to measure safety, tolerability, and preliminary antitumor efficacy of GM103 administered alone and in combination with pembrolizumab in patients with locally advanced, unresectable, refractory and/or metastatic solid tumors (including but not limited to head and neck cancer, malignant melanoma, CRC, renal cell carcinoma, cervical cancer, and breast cancer). Study details include:

Part A, B - Primary Objectives - To determine the MTD and RP2D based on safety and tolerability of GM103 as monotherapy. - To evaluate overall safety profile of GM103 as monotherapy. - Secondary Objectives - To assess preliminary anti-tumor efficacy of GM103 at the RP2D, as monotherapy. Part C - Primary Objectives - To determine the MTD and RP2D based on safety and tolerability of GM103 in combination with pembrolizumab. - To evaluate overall safety profile of GM103 in combination with pembrolizumab . - Secondary Objectives - To assess preliminary anti-tumor efficacy of GM103 at the RP2D, in combination with pembrolizumab.

Head and Neck Cancer ; Malignant Melanoma ; Colorectal Cancer ; Renal Cell Carcinoma ; Cervical Cancer ; Breast Cancer

Korea University,Severance Hospital, Yonsei University Health System

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*xdx3lrai7xhwsrbdrdg4h4xdfa000000/overview

Avelumab and Methotrexate in in Low-risk Gestational Trophoblastic Neoplasias as First Line Treatment

Gestational trophoblastic neoplasias (GTN) are characterized by the persistence of elevated hCG titers after complete uterine evacuation of a partial hydatidiform mole (PHM) or a complete hydatidiform mole. Low-risk GTN patients (FIGO score 6) are commonly treated with single agent treatment (methotrexate or actinomycin-D) The cure rate, assessed by hCG normalization, is obtained in 65 to 75% of patients with these agents GTN patients with resistance to these treatments are treated with another single agent drug or polychemotherapy regimens, such as EMA-CO or BEP regimen. Chemotherapy standard regimens are old and toxic for these young lady patients, with potential long term effects detrimental for further maternity and quality of life There is a strong rational for investigating the anti-PDL1 monoclonal antibody avelumab in chemoresistant GTN patients. Several elements suggest that the normal pregnancy immune tolerance is "hijacked" by GTN cell for proliferating : - Spontaneous regressions of metastastic GTN are regularly observed, thereby the role of immune system for rejecting GTN cells. - Strong and constant overexpression of PDL1 and NK cells has been found in all subtypes and settings of GTN tumors from French reference gestational trophoblastic center. - Complete and durable responses to pembrolizumab were reported in 3 patients with multi-chemoresistant GTN in United Kingdom. - Three cases of hCG normalization with avelumab in 6 patients with chemo-resistant GTN enrolled in TROPHIMMUN cohort A (resistant to a mono-chemotherapy). - Cytotoxicity of avelumab is mediated through antibody dependent cell cytotoxicity (ADCC) by NK cells.

avelumab ; methotrexate ; PDL1 ; gestational trophoblastic neoplasias, GTN ; hydatiform mole ; hCG,

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*abkfs2oigwa7yjm2znb7njqmji000000/overview

pBI-11 & TA-HPV (With Pembrolizumab as Treatment for Patients w/Advanced, PD-L1 CPS 1, hrHPV Oropharyngeal Cancer

This phase II trial tests how well pB1-11 and human papillomavirus tumor antigen (TA-HPV) vaccines in combination with pembrolizumab work in treating patients with oropharyngeal cancer that has come back (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic) and that is PD-L1 and human papillomavirus (HPV) positive. Oropharyngeal cancer is a type of head and neck cancer involving structures in the back of the throat (the oropharynx), such as the non-bony back roof of the mouth (soft palate), sides and back wall of the throat, tonsils, and back third of the tongue. Scientists have found that some strains or types of a virus called HPV can cause oropharyngeal cancer. pBI-11 is a circular deoxyribonucleic acid (DNA) (plasmid) vaccine that promotes antibody, cytotoxic T cell, and protective immune responses. TA-HPV is an investigational recombinant vaccina virus derived from a strain of the vaccina virus which was widely used for smallpox vaccination. Vaccination with this TA-HPV vaccine may stimulate the immune system to mount a cytotoxic T cell response against tumor cells positive for HPV, resulting in decreased tumor growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread by inhibiting the PD-1 receptor. These investigational vaccines could cause or enhance an immune response in the body against HPV, during which time the activity of pembrolizumab against oropharyngeal cancer associated with HPV may be strengthened. These drugs in combination may be more effective in increasing the ability of the immune system to fight oropharyngeal cancer than pembrolizumab alone.

PRIMARY OBJECTIVE: I. To assess the safety and feasibility of intramuscular PVX7 (pBI-11/pBI-11/human papillomavirus tumor antigen vaccine [TA-HPV]) immunization in patients with HPV recurrent/metastatic (R/M) oropharyngeal carcinoma (OPC) undergoing treatment with pembrolizumab. SECONDARY OBJECTIVE: I. To assess the response rate (RR) of the addition of pBI-11 and TA-HPV to pembrolizumab (P) as first line therapy for patients with PD-L1 (combined positive score [CPS] 1), HPV , R/M OPC. EXPLORATORY OBJECTIVES: I. To evaluate the overall survival (OS), progression free survival (PFS) and safety of the combination of PVX7 and pembrolizumab in this population. II. To evaluate correlates of clinical activity by: (1) comparing HPV16/18 E6/E7-specific cellular and humoral immunity in pre- versus (vs.) post-pBI-11 and TA HPV-treated OPC patients that are pembrolizumab responders (R) and/or non-responders (NR). OUTLINE: Patients receive pBI-11 vaccine intramuscularly (IM), TA-HPV vaccine IM, and pembrolizumab intravenously (IV) on study. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection during screening and on study. Patients may undergo tumor biopsy during screening and on study.

Vanderbilt-Ingram Cancer Center,Vanderbilt University/Ingram Cancer Center

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*6d4mexnuvq5alwnivu3ocxtp2a000000/overview

A Study to Compare Uliledlimab Combined With Toripalimab, Toripalimab Monotherapy, and Pembrolizumab Monotherapy in Patients With Previously Untreated Locally Advanced Unresectable or Metastatic PD-L1- and CD73- Selected Non-Small Cell Lung Cancer

This is a Phase II/III, randomized, open-label, active-controlled, multicenter study to compare intravenous uliledlimab combined with toripalimab, toripalimab monotherapy, and pembrolizumab monotherapy in patients with previously untreated locally advanced unresectable or metastatic PD-L1-positive (tumor proportion score \[TPS\] 1%) and CD73-positive (TC/IC \ 30%; TC/IC defined as the higher of either the proportion of CD73-positive tumor cells or the proportion of CD73-positive immune cells at any intensity \[IHC1 or above\]) NSCLC who are not suitable for targeted therapies such as EGFR, ALK, etc. The number of enrolled subjects with PD-L1 TPS 50% will be limited to approximately 60% of the total sample size to reflect the natural prevalence of advanced NSCLC. Patients who have received adjuvant or neoadjuvant therapy other than immune checkpoint inhibitor treatments are allowed to participate in this study, provided that such treatments have been completed at least 12 months prior to the occurrence of recurrence or metastasis. During the screening period, tumor samples will be collected in advance and tested by the central laboratory for PD-L1 expression levels using the PD-L1 IHC 22C3 pharmDx assay and CD73 expression levels using the CD73 antibody assay (immunohistochemistry). Previous PD-L1 testing results obtained using the PD-L1 IHC 22C3 pharmDx assay will be accepted. Patients with PD-L1 positive expression (TPS 1%) and high CD73 expression (TC/IC \ 30%) will meet the inclusion criteria. Patients who do not meet the eligibility criteria as judged by the investigator may be re-screened once. Patients with non-squamous NSCLC will be required to confirm the absence of EGFR-sensitive mutations or ALK fusion; patients with unknown EGFR and ALK expression status will be required to undergo testing and provide clinical laboratory test results prior to study enrollment, and may be enrolled after relevant driver gene mutations are ruled out. Meanwhile, patients with other definite actionable driver gene alterations (such as: ROS1 fusions, RET fusions, NTRK1/2/3 fusions, BRAF V600E mutations, MET14 exon skipping mutations, etc.) will be excluded from this study. Controversial cases with actionable gene mutations will be submitted to the study expert panel for joint decision. This study includes Phase II and Phase III stages. Approximately 150 subjects will be enrolled in the Phase II stage. Based on the evaluation of the efficacy, safety, PK, and PD results of the Phase II study, a decision will be made on whether to proceed to the Phase III study. Approximately 300 subjects will be enrolled in the Phase III stage.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*kpzfz5tl6dq772ozu626tj7hce000000/overview

Safety and Efficacy of Pembrolizumab in Combination With FLOT About Gastroesophageal Junction Cancer:

At present, surgery is still the main treatment for gastroesophageal junction cancer. At the same time, multimodal comprehensive treatment such as chemotherapy and molecular targeted therapy can effectively alleviate pathological progression, facilitate R0 resection and improve the overall survival of patients.Pembrolizumab, as a PD-1 inhibitor, has been shown to have antitumor activity and a manageable safety profile in gastroesophageal junction cancer.Pembrolizumab combined with chemotherapy has become a research hotspot. However, to date, there is no clinical study related to gastroesophageal junction cancer. In this study, Pembrolizumab combined with FLOT was used as the first-line treatment for gastroesophageal junction cancer, aiming to explore the experience chemotherapy mode for gastroesophageal junction cancer.

Gastric cancer, including gastroesophageal junction cancer, is the fifth most common cancer and the third leading cause of death in the world. Among them, although the incidence of distal gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction cancer is increasing. At present, surgery is still the main treatment for gastroesophageal junction cancer. At the same time, multi-mode comprehensive treatment such as chemotherapy and molecular targeted therapy can effectively alleviate pathological progression, facilitate R0 resection and improve the overall survival of patients. A large number of previous clinical trials on the combination of first-line chemotherapy and molecular targeted drugs in the treatment of gastric and gastroesophageal junction cancer have shown that only trastuzumab can improve the overall survival rate of Her-2 positive patients. In addition, despite various clinical chemotherapy regimens, the median survival time of gastric cancer and gastroesophageal junction cancer is not high. Therefore, the treatment mode of gastroesophageal junction cancer, especially for Her-2 negative patients, needs to be explored and improved. In recent years, immune checkpoint inhibitors represented by programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1) inhibitors have been applied to the treatment of a variety of solid tumors such as melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and urothelial cancer. It has become another important treatment strategy after surgery, chemotherapy, radiotherapy and targeted therapy. Studies have shown that PD-L1 is highly expressed in tumor cells and immune cells in gastric cancer and gastroesophageal junction cancer and plays a key role in tumor immune escape, therefore, the PD-1/ PD-L1 pathway will become an important target for effective intervention in gastroesophageal junction cancer. As a PD-1 inhibitor, Pembrolizumab has been shown to have anti-tumor activity and manageable safety in gastroesophageal junction cancer, and was approved by the US FDA in September 2017 for advanced PD-L1-positive gastric or gastroesophageal junction cancer . The phase Ⅱ KEYNOTE-059 trial used Pembrolizumab as a single agent in the third-line treatment of advanced gastric or gastroesophageal junction cancer, and the results showed that it had controllable safety in patients with PD-L1 positive, with obvious advantages in objective response rate (ORR) and median duration of response (DOR) [12]. Chemotherapy enhances tumor immune responses by enhancing tumor cell immunogenicity and sensitivity to immune killing, and the combination of chemotherapy and immune checkpoint inhibitors has been shown to improve overall survival in several cancer types. Therefore, PD-1/ PD-L1 immunosuppressant combined with chemotherapy has become a hot spot in the research of advanced gastric cancer or gastroesophageal junction cancer . The phase 3 KEYNOTE-062 trial compared Pembrolizumab plus chemotherapy (cisplatin plus 5-FU or capecitabine) with chemotherapy alone or Pembrolizumab alone in the first-line treatment of advanced gastric or gastroesophageal junction cancer. However, compared with chemotherapy alone, Pembrolizumab combined with chemotherapy could not significantly prolong the overall survival of patients, and the overall effect was not better than chemotherapy alone . In contrast, the phase III KEYNOTE-590 study, designed to compare the efficacy and safety of Pembrolizumab plus chemotherapy (cisplatin plus fluorouracil) versus chemotherapy alone as first-line treatment for advanced esophageal and Siwert type I gastroesophageal junction cancer, showed that Pembrolizumab combined with chemotherapy was significantly superior to chemotherapy alone . Neither the KEYNOTE-062 trial nor the KEYNOTE-590 trial analyzed a separate population of patients with gastroesophageal junction cancer, and there are some differences in response to drugs by tissue type. Therefore, The efficacy of Pembrolizumab plus chemotherapy in the only patient population with gastroesophageal junction cancer warrants further investigation.

Xijing Hospital of Digestive Diseases

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*jukd3bwi3t5unvdwcqngprscpa000000/overview

A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity

This is an open-label, multi-institutional phase II randomized study comparing neoadjuvant radiotherapy followed by surgical resection to neoadjuvant pembrolizumab with concurrent radiotherapy, followed by surgical resection and adjuvant pembrolizumab. The total duration of pembrolizumab will be one year in the experimental arm.

This is a multicenter, randomized phase II trial with an initial safety run-in to test the safety and efficacy of neoadjuvant pembrolizumab with image-guided radiotherapy and adjuvant pembrolizumab compared to radiation therapy alone in patients with clinically localized extremity soft tissue sarcoma at high risk for developing metastatic disease (tumor size 5 cm, intermediate- to high-grade; approximately 50% risk for distant disease at 2 years). Histologies will be limited to undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma based on preliminary data from SARC028. Other terms for undifferentiated pleomorphic sarcoma may include, but are not limited to. pleomorphic undifferentiated sarcoma, unclassified spindle cell sarcoma, spindle cell sarcoma not otherwise specified, pleomorphic spindle cell sarcoma, pleomorphic fibroblastic sarcoma, undifferentiated high-grade pleomorphic sarcoma, pleomorphicsarcoma with prominent inflammation, pleomorphic sarcoma with giant cells, malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes), fibrosarcoma, and myxofibrosarcoma (located deep to the fascia in muscle). Radiation therapy with three cycles of pembrolizumab will be administered as neoadjuvant therapy for patients randomized to the experimental arm. These patients will also receive up to fourteen cycles of adjuvant pembrolizumab after surgical resection. Patients in the standard of care arm will receive neoadjuvant radiotherapy (50 Gy in 25 fractions) followed by surgical resection as in RTOG 0630.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*egckn6j43y3oso4xk7mbqiuztu000000/overview

Combining Intratumoral Flu Vaccine and Systemic Pembrolizumab in Patients With Early pMMR Colorectal Cancer

Immune checkpoint inhibitor (ICI) treatment has produced striking results in patients with colorectal cancer (CRC) of the subtype deficient mismatch repair (dMMR). The majority of patients, however, have proficient MMR (pMMR) tumors, with limited effect of ICIs. The key difference between dMMR and pMMR tumors is the infiltration of cytotoxic T-cells. dMMR tumors have increased infiltration and thus increased efficacy from ICI treatment. The investigators conducted a proof of concept study where the investigators applied an intratumoral (IT) unaltered flu vaccine in ten patients with non-metastatic pMMR CRC. The intervention increased infiltration of cytotoxic T-cells and the immune checkpoint PD-L1, suggesting that IT flu vaccine primes pMMR tumors to ICI treatment. The investigators aim to test the combination of IT flu vaccine and ICI treatment in patients with non-metastatic pMMR CRC in a new trial. The hypothesis is that IT flu vaccine and ICI treatment will synergistically to induce cancer cell death.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*yir3oarrvf2ze3voyyspffquyu000000/overview

The goal of this clinical trial is to explore whether additional treatments can help strengthen the participant's immune system to fight cancer caused by the Human Papillomavirus (HPV), a virus spread through intimate skin-to-skin contact. The trial will also monitor the safety of these treatments. The main questions it aims to answer are: Does the combination of treatments help the participant's body fight the cancer more effectively when used alongside standard therapy? What side effects or medical issues arise when using these experimental treatments? Researchers will use three experimental therapies along with the participant's standard treatment to find out if these therapies work better together than standard treatment alone. Participants will: Receive HPV vaccinations during the 2nd and 4th week of radiation, and again at weeks 8, 10, 12, and 16 after completing radiation. Have blood samples taken, tumor cells brushed from the surface, and imiquimod cream applied during each visit. Take a daily metformin pill and apply an imiquimod suppository three times a week for two weeks after each visit.

The goal of this clinical trial is to determine whether stimulating tumor immunity through sequential, targeted intratumoral vaccinations using the FDA-approved quadrivalent HPV-L1 antigen vaccine, in combination with chemotherapy, radiotherapy, pembrolizumab, imiquimod, and metformin, improves outcomes for patients with locally advanced cervical, vaginal, or vulvar carcinoma. The primary objective is to assess the impact of this approach on 24-month progression-free survival when used alongside whole pelvic radiotherapy, chemotherapy, and brachytherapy. The trial will also monitor the safety and potential side effects of combining intratumoral HPV vaccination with topical imiquimod and oral metformin during and after chemoradiation. Additionally, researchers aim to evaluate specific immune markers to understand how these treatments boost the immune system and enhance the effects of standard care. Participants will: Receive intratumoral HPV vaccinations during the 2nd and 4th week of radiation, and after completing radiation at weeks 8, 10, 12, and 16. Have blood samples taken, tumor cells brushed, and imiquimod cream applied during each visit. Take a daily metformin pill and apply an imiquimod suppository three times a week for two weeks after each visit. Throughout the trial, immune biomarker assays will be conducted at the beginning, middle, and end of treatment to measure markers such as CD4, CD8, NK, TNF alpha and beta, IL2, HPV viral load, TGF Beta, Ki67, and IgG. Blood tests will also be done for IgG L1 and L2, E6 and E7, and a CBC, to track immune changes across the three treatment groups.

metformin ; HPV ; Imiquimod ; Human Papillomavirus 9-valent Vaccine ; Recombinant ; Cytobrush ; cervical cancer ; vaginal cancer ; vulvar cancer ; chemoradiation ; tumor ; immunotherapy ; metastatic ; intratumoral ; Endometrial cancer

Cervical Carcinoma ; Vaginal Carcinoma ; Vulvar Carcinoma ; HPV (Human Papillomavirus)-Associated Carcinoma

Dan L Duncan Comprehensive Cancer Center,Baylor St. Luke's Medical Center,Harris Health

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*e33e7bhtfifjc2a6sh6666iut4000000/overview

Study of XNW5004 Tablet in Combination With KEYTRUDA (Pembrolizumab) in Subjects With Advanced Solid Tumors Who Failed Standard Treatments (KEYNOTE F19)

In this study, participants with different types of advanced solid tumors who failed standard treatments will be treated with XNW5004 in combination with KEYTRUDA (pembrolizumab) .

XNW5004 ; EZH2 inhibitor ; KEYTRUDA® (pembrolizumab) ; immune checkpoint inhibitors

Carcinoma ; Squamous Cell Carcinoma of Head and Neck ; Urothelial Carcinoma ; Prostate Cancer ; Small-cell Lung Cancer ; Non-small Cell Lung Cancer ; Cervical Cancer ; Other Solid Tumors

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*upoh3vncavildhq3wmksqkqpl4000000/overview

First-line CBDCA/PTX/LEN/Pembrolizumab Combination for Previously Untreated Advanced or Recurrent Thymic Carcinomas (Artemis)

A phase II, investigator-initiated, non-randomized, open-label, single-arm, multicenter study to evaluate the efficacy and safety of Carboplatin/Paclitaxel/Lenvatinib/Pembrolizumab combination for previously untreated advanced or recurrent thymic carcinomas

This is a phase II, investigator-initiated, non-randomized, open-label, single-arm, multicenter study to evaluate the efficacy and safety of Carboplatin/Paclitaxel/Lenvatinib/Pembrolizumab combination for previously untreated advanced or recurrent thymic carcinomas. Induction chemotherapy consists of carboplatin paclitaxel pembrolizumab lenvatinib for 3 weeks (21 days) as 1 cycle, up to a maximum of 4 cycles. Then, maintenance therapy with pembrolizumab and lenvatinib will be continued until progression or unacceptable adverse events.

National Cancer Center Hospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*pswnfduhs5znyycox3q7zywh7e000000/overview

This is a phase II clinical study testing a more personalized and lighter chemotherapy approach for women with stage I or II triple-negative breast cancer. The treatment is adjusted based on signs from the immune system (called tumor-infiltrating lymphocytes, or TILs) and imaging results during treatment. Patients with stage I triple-negative breast cancer (regardless of TIL levels) and those with stage II disease and high TILs (50% or more) will receive a combination of two chemotherapy drugs (carboplatin and a taxane) for four cycles. If imaging shows the tumor has completely disappeared after this treatment, the patient will go straight to surgery. If the tumor is still visible, the treatment will be strengthened with additional chemotherapy drugs (anthracycline and cyclophosphamide), with or without a medicine called pembrolizumab, which helps the immune system fight cancer. The main goal of the study is to see how many patients have a complete disappearance of the cancer after treatment. Other goals include understanding how imaging results relate to what is found during surgery and tracking how long patients live without the cancer coming back.

This is a phase II, single-arm clinical trial investigating a de-escalated neoadjuvant chemotherapy regimen for stage I and II triple-negative breast cancer (TNBC), guided by tumor-infiltrating lymphocytes (TILs) and radiologic response. Patients with stage I TNBC (regardless of TIL levels) and stage II TNBC with TILs 50% will receive four cycles of carboplatin and a taxane. Those who achieve a complete radiologic response will proceed to surgery, while patients without a complete radiologic response will be escalated to a regimen including anthracycline and cyclophosphamide, with or without pembrolizumab. The primary objective is to evaluate the pathological complete response rate. Secondary outcomes include the correlation between radiologic and pathologic response, event-free survival, and overall survival.

TILs ; Breast cancer ; radiological response ; Descalonation of neoadjuvant treatment

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*i3wm4fcjfcgzh3hqmo7ukpylqu000000/overview

Perioperative Chemotherapy and Immunotherapy for Locally Recurrent Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southern China and southeast Asia. Despite intensive radical therapy, between 15% and 30% of NPC patients develop relapse. Recent phase III randomized-controlled trials conducted in China demonstrated an improvement of progression-free survival with combinational therapy immune checkpoint inhibitors (ICI) (camrelizumab, toripalimab, and tislelizumab, respective) and chemotherapy gemcitabine (G) and cisplatin (P) compared with chemotherapy GP alone for recurrent or metastatic NPC. However, none of these studies have described in details the treatment outcomes of those subjects with locally recurrent NPC only, and whether any of these patients would undergo radical surgery to remove the residual locally recurrent NPC after ICI and chemotherapy. Continuation of the same ICI as maintenance therapy may only be the treatment option for these patients who were recruited into these phase III trials, unless if they withdrew from the study and opted for radical resection. While continuing the same ICI may still lead to persistent objective response and disease control, there is a possibility of tumor recurrence leading to unresectable disease and a worse survival outcome, or unexpected, rare but recognized immune-related emergent adverse events with ICI. Radical resection after maximal response to ICI and chemotherapy for patients with locally recurrent NPC only may provide a chance of cure of the disease and these patients may be obviated from continuous exposure to ICI therapy. In view of the above, we are now proposing a phase II single-arm study on perioperative pembrolizumab and chemotherapy followed by radical surgery for locally recurrent NPC. As a collateral study, we will also perform single-cell DNA and RNA sequencing and proteomics study to observe the tumor and immune microenvironment which certainly helps us decipher the mechanisms of tumor response at genomic, transcriptomic and proteomic levels.

This is a multi-centre single-arm phase II study on perioperative treatment with pembrolizumab and chemotherapy GP for 6 cycles followed by radical surgery and maintenance pembrolizumab for another 11 cycles (up to 17 cycles of pembrolizumab in total). All eligible patients shall receive preoperative treatment with pembrolizumab at 200mg fixed dose, with chemotherapy G: 1000-1250mg/m2 on day 1 and day 8 and P: 80-100mg/m2 on day 1 (or carboplatin AUC 5 on day 1 replacing cisplatin at the treating physician's discretion), given every 3 weeks for 6 cycles followed by radical surgery (open or minimally invasive surgery) at the discretion of treating surgeons, and subsequently maintenance pembrolizumab for another 11 cycles (up to 17 cycles of pembrolizumab for 1 year). All recruited patients will undergo reassesment imaging scans after 3 and 6 cycles of pembrolizumab and chemotherapy GP. They will then undergo radical surgery within 4 to 6 weeks of the 6th cycle of pembrolizumab and chemotherapy GP. Subsequently, within 4 to 6 weeks of radical surgery, they will continue the remaining 11 cycles of pembrolizumab 200mg fixed dose every 3 weeks up to 17 cycles in total. Magnetic resonance imaging (MRI) of the head and neck and positron emission tomography with integrated computed tomography (PET-CT) scan will be performed at baseline before study intervention and after 3 and 6 cycles of pembrolizumab and chemotherapy GP and before radical surgery, to evaluate tumour response. After radical surgery, all recruited subjects will undergo repeat MRI and contrast-enhanced CT scan of the thorax and abdomen every 3 months during the 1st year, then every 4 months during the 2nd year, every 6 months during the 3rd and 4th year, and yearly from the 5th year onwards.

Nasopharyngeal carcinoma ; Locally recurrent ; Perioperative treatment ; Immune checkpoint inhibitor ; Chemotherapy ; Minimally invasive surgery

National University of Singapore,Sun Yat-Sen University,Changhua Christian Hospital

department of clinical oncology, the university of hong kong

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*b6vg6akuzc7cirkiio2toghi74000000/overview

Sacituzumab Tirumotecan Combined With Pembrolizumab for Neoadjuvant Treatment of TNBC Breast Cancer

This is a prospective, single center, phase II study to enroll participants with stage II or III TNBC who have not previously undergone systemic therapy. The primary endpoint is pCR in the ITT population. The study aims to enroll 52 participants. Eligible participants will receive a combination therapy of SKB264 and Pembrolizumab. Experimental arm: SKB264 will be administered intravenously (IV) at a dose of 4 mg/kg every two weeks (Q2W); Pembrolizumab will be administered intravenously at a dose of 200mg every three weeks (Q3W) All enrolled participants will initially receive SKB264 plus Pembrolizumab for 8 weeks. Based on early imaging and biopsy assessment, patients who deemed as responders continue to receive combined drug therapy for 10 weeks, followed by surgical treatment. Patients who assessed as non-responders will be treated at the discretion of the physician. Participants will undergo regular tumor assessments based on RECIST 1.1 criteria. Imaging assessments will be conducted every 9 weeks ( 1 week) for the first 18 weeks following treatment initiation, and every 12 weeks ( 1 week) thereafter, until confirmed disease progression, initiation of a new antitumor treatment, withdrawal of consent, loss to follow-up, death, or study end, whichever occurs first. After termination of the study treatment, participants must complete the EOT visit and a safety follow-up, and undergo survival visits every 3 months ( 14 days) post the last dose to collect information on survival, new antitumor treatments received.

Neoadjuvant Therapy ; Stage II to III (T1cN1-2 or T2-4N0-2) TNBC Breast Cancer

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A Prospective Study of Pembrolizumab Combining Chemotherapy in Advanced NSCLC Patients With EGFR Exon 21 Point Mutation.

A phase II, single-arm, open-label study evaluating efficacy, safety and feasibility of combined chemotherapy and pembrolizumab as first line therapy and Osimertinib as second line therapy in advanced non squamous NSCLC adult patients with epidermal growth factor receptor (EGFR) exon 21 point mutation and programmed cell death receptor ligand 1 (PD-L1) positive.

Four cycles of platinum and pemetrexed in combination with pembrolizumab will be administered as first line therapy and up to 31 cycles pemetrexed and pembrolizumab maintenance therapy every 3 weeks. Osimertinib will be the sequential treatment strategy at progression.

Non Small Cell Lung Cancer ; Immune Checkpoint Inhibitor ; EGFR Exon 21 Mutation

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*lcy4zzmgyxks7rux77d632oumi000000/overview

This clinical trial is to clarify whether treatment with a checkpoint inhibitor alone (pembrolizumab) or two in combination (ipilimumab and nivolumab), results in clinical benefit for MM patients with brain metastases and in need of steroid treatment. Patients will be treated in four arms depending on steroid dose level at inclusion ( 10 25 mg prednisolone or 25 mg prednisolone) and treatment (pembrolizumab alone or the combination of ipilimumab and nivolumab).

Cancer immunotherapy with checkpoint inhibitors (CPI) has demonstrated significant response rates, with clinical responses of exceptional duration observed in pivotal clinical trials for multiple types of solid tumors. Results from clinical trials demonstrate a considerable survival benefit of CPI over standard treatments, leading to registration of CPI for lung-, head and neck-, bladder-, renal cancer, lymphomas and metastatic melanoma (MM). To date, CPI appear to hold the key for longterm survival - at least for patients treated in clinical trials. Patients enrolled in pivotal clinical trials for immunotherapy of MM are highly selected and does not include patients with brain metastases. Small phase II studies lend support to CPI to yield responses in melanoma that has metastasized to the brain. However, a large proportion of patients that develop brain metastasis will require continued systemic treatment with steroids to alleviate symptoms from the central nervous system (CNS). This group of patients are not offered treatment with CPI, as it is generally assumed that steroid treatment hamper their clinical efficacy. Thus, this group of patients face a large unmet need. Due to the immune inhibiting effects, steroids are used to manage immune-related adverse events (irAEs) induced by CPI treatment. However, patients receiving steroids in this context are still able to achieve and maintain clinical benefit even after stopping treatment. It is not known whether steroid treatment at the time of initiation of CPI treatment diminishes the treatment effect, as patients in need of steroid treatment are generally excluded from clinical trials.

Immune therapy ; checkpoint inhibitor ; pembrolizumab ; ipilimumab ; nivolumab ; steroid ; brain metastasis ; BRAF inhibitor ; MEK inhibitor

Troels H Borch,HENRIK SCHMIDT,Lars Bastholt

Herlev Universityhospital,Herlev Hospital,Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology,Aarhus Universityhospital,Odense Universityhospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*reeoeelxsmnugu2mer7zsl7pxe000000/overview

This study is a prospective, multicenter, randomized, open controlled clinical trial aimed at evaluating the effectiveness and safety of serplulimab plus chemoradiotherapy in FIGO 2018 stage III or IVA cervical squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma patients who have not received prior treatment.

Cervical cancer is the most prevalent malignant tumor of the female reproductive system in China, with an estimated 150,700 new cases and 55,700 new deaths annually. Concurrent chemoradiotherapy (CRT) remains the standard treatment for locally advanced cervical cancer (LACC). However, for high-risk LACC (HR-LACC) patients, the 2-year progression-free survival (PFS) rate is only 57%-62%, and the 5-year overall survival (OS) rate is 52%-64%, which are the leading causes of patient mortality. The KEYNOTE-A18 study demonstrated that the combination of pembrolizumab and CRT reduced the progression risk and death risk by 30% and 27%, respectively, for HR-LACC patients. Following this, the FDA approved pembrolizumab in combination with CRT for the treatment of newly diagnosed stages III-IVA cervical cancer in January 2024. This prospective, multicenter, randomized, controlled clinical trial study aims to evaluate the effectiveness and safety of serplulimab induced and combined chemoradiotherapy in FIGO 2018 stage III or IVA cervical squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma patients who have not received prior treatment.

Lingying Wu,Ling Ying Wu

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*vqg6kaivgplh5zwht5ogwabhxu000000/overview

Determine safety and efficacy of pre-operative combination immunotherapy with Talimogene Laherparepvec (T-VEC)/Pembrolizumab given prior to complete lymph node dissection in resectable stage 3 cutaneous melanoma with clinically apparent lymph node metastases.

This is a single arm Phase 2 study of pre-operative combination immunotherapy with pembrolizumab and T-VEC given for 6 months prior to complete lymph node dissection for stage 3 resectable cutaneous melanoma with clinically apparent lymph node metastases.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*jgnlqkiz5thz33gcmzm34rfcv4000000/overview

Phase II Trial of Anti-PD-1 Antibody Treatment and Radiotherapy in Early-stage Favorable Classic Hodgkin Lymphoma

By the implementation of the anti-PD-1 antibody pembrolizumab and given its possible synergy with RT, the aim of the present trial is to develop a chemotherapy-free first-line treatment for patients with newly diagnosed early-stage favorable cHL.

University Hospital of Cologne

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*uqyxpzp425l4kvzebn3fafq5p4000000/overview

A Study of Combining Cabozantinib and Atezolizumab for Advanced/Metastatic NSCLC (Cabatezo-1)

NSCLC patients with low expression level of PD-L1, esp. those with its level less than 1%, do not derive much benefit from anti-PD-1/L1 therapy (e.g. atezoilzumab). In this study, investigators hypothesize that the combination of cabozantinib (a multi-kinase inhibitor) and atezolizumab will result in better therapeutic value.

For metastatic/advanced non-small cell (NSCLC) patients who do not have targetable mutations, the combination of chemotherapy with immunotherapy targeting the programmed death-1 and its ligand (PD-1/L1) is now a standard of care. In addition, recent studies also demonstrated that immunotherapy doublet using anti-PD-1 agent nivolumab and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agent ipilimumab could be another valid option. However, largely due to the immunosuppressive tumor microenvironment, the therapeutic response remains suboptimal in NSCLC patients with PD-L1 tumor proportion score (TPS) lower than 1% (aka PD-L1 negative). For example, the objective response rate (ORR) in KEYNOTE-189 was 32.3% using pembrolizumab plus chemotherapy, and only 27.3% in Checkmate 227 study using nivolumab and ipilimumab, in the PD-L1 negative population. These observations necessitate the search for novel combinations to benefit our PD-L1 negative NSCLC patients. The investigators hypothesize that the combination of cabozantinib and atezolizumab is such an innovative strategy based on the following rationales: 1) cabozantinib is a multi-kinase inhibitor, and some of the targets, for example the vascular endothelial growth factor (VEGF) pathway is notorious to confer immune suppressive tumor microenvironment. In fact, our previous study has demonstrated that anti-VEGF synergizes anti-PD-1 in preclinical model. Consistent with this, cabozantinib has been shown to increase tumor infiltrative cytotoxic CD8 T cells, reduce immune suppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as activate anti-tumor innate immunity in multiple solid tumors; 2) at the animal level, cabozantinib was found synergistic with anti-PD-1 agents to elicit anti-tumor immune response; and 3) more importantly, at the human level, the combination of cabozantinib with atezolizumab was found safe in Cohort 7 of the phase 1b COSMIC-021 study and achieved 27% ORR in previously immunotherapy-treated NSCLC - suggesting a potentially higher efficacy if such combination is to be used in the 1st line setting. The investigators therefore propose here the combination of cabozantinib and atezolizumab to be used as the 1st line treatment for advanced/metastatic NSCLC with negative PD-L1 expression.

Lung Cancer ; NSCLC Stage IV ; Metastatic NSCLC - Non-Small Cell Lung Cancer ; Advanced NSCLC

University of Kansas Medical Center

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*byt476ljzyjebhnhqeumhvg6ry000000/overview

The purpose of this study is to explore the efficacy and safety of a combination of GP chemotherapy and tislelizumab in neoadjuvant therapy combined with tislelizumab in adjuvant therapy of locoregionally advanced nasopharyngeal carcinoma patients.

Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma(NPC). Gemcitabine plus cisplatin(GP) has been demonstrated an effective chemotherapy regimen for NPC patients in previous studies. The results of GP combined with concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma showed 10% of locoregionally advanced NPC patients had complete response after three cycles of GP neoadjuvant chemotherapy, and GP neoadjuvant chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival (85.3% vs 76.5%) and overall survival (94.6% vs 90.3%) among locoregionally advanced NPC patients , as compared with chemoradiotherapy alone. Therefore, GP regimen has been established as the highest level of evidence-based neoadjuvant chemotherapy in the 2020 National Comprehensive Cancer Network (NCCN) guidelines. Recently, immune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1)monoclonal antibody has shown promising efficacy in the treatment of tumor patients. Clinical trials have shown objective response rates of 20.5%-34% in patients with recurrent or metastatic NPC patients receiving anti PD-1 monoclonal antibody immunotherapy including pembrolizumab, nivolumab, camrelizumab, and toripalimab. The current NCCN guidelines recommend anti PD-1 monoclonal antibody as a second-line treatment for recurrent or metastatic NPC. More and more evidence show that immunotherapy combined with chemotherapy has a synergistic effect in treating tumors. GP chemotherapy combined with anti PD-1 antibody has achieved the initial effect in NPC. Phase 1 trials have shown the combination of camrelizumab plus GP chemotherapy in recurrent or metastatic NPC led to a proportion of 91% patients achieving an objective response. In addition, previous studeis showed that PD-1 antibody adjuvant therapy had good feasibility and effectiveness in the treatment of nasopharyngeal carcinoma. Tislelizumab, approved by the National Medical Products Administration in China, is an anti-PD-1 monoclonal IgG4 antibody with higher affinity to PD-1 than pembrolizumab and nivolumab and was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Multiple clinical trials have shown strong anti-neoplastic activity of tislelizumab in various tumors including NPC. Clinical trial has shown an objective response rates of 43% in patients with recurrent metastatic nasopharyngeal carcinoma treated with tirelizumab, which is superior to other anti PD-1 monoclonal antibodys. So we hypothesize that GP neoadjuvant chemotherapy combined with tislelizumab and tislelizumab adjuvant therapy could further improve survival of patients with locaregionally advanced NPC. Based on this, this study aims to evaluate the efficacy and safety of gemcitabine plus cisplatin chemotherapy combined with tislelizumab neoadjuvant therapy, followed by cisplatin based concurrent chemoradiotherapy, then followed by tislelizumab adjuvant therapy in the patients with locoregionally advanced nasopharyngeal carcinoma, to provide new evidence for individualized comprehensive treatment in NPC.

Sun Yat-Sen University,Cancer Hospital of Guizhou Province,affiliated hospital of guangdong medical college

Hai-qiang Mai,Haiqiang Mai

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*62gcg3r5guyqnjdl33ikctuunm000000/overview

Pembrolizumab Plus Neoadjuvant Chemotherapy vs. Neoadjuvant Chemoradiotherapy for Locally Advanced ESCC (KEYSTONE-002)

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter.

Preoperative chemoradiotherapy with radical surgery is the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC) in the NCCN guidelines. But many patients refused or abandon radiotherapy because of the intolerable adverse effects. The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin as neoadjuvant therapy followed by surgery, and pembrolizumab as adjuvant therapy, compared with neoadjuvant chemoradiotherapy and surgery for locally advanced ESCC in multicenter. The primary study hypothesis is that Event Free Survival (EFS) is superior with pembrolizumab plus neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy in participants with ESCC.

Ruijin Hospital,Shanghai Zhongshan Hospital,Tang-Du Hospital,Weifang People's Hospital,Shanxi Province Cancer Hospital,Hebei Medical University Fourth Hospital,Shandong Jining No.1 People's Hospital,Liaoning Tumor Hospital & Institute,harbin medical university,Shanghai Chest Hospital

Hecheng Li,Haiquan Chen,Zhigang Li,Hengxiao Lu,HAIBO CAI,Yegang Ma,Shiping Guo,Tao Jiang,Lijie Tan,Ziqiang Tian,Jianqun Ma

Department of minimally invasive esophageal surgery, Tianjin Medical University Cancer Institute and Hospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*jpnq4oxga6mrrkvp4n3vtpc7py000000/overview

Pembrolizumab in Progressive Multifocal Leukoencephalopathy (PML) in Immunocompromised Patients Without HIV Infection

This study aims to assess the efficacy and safety of pembrolizumab in immunocompromised patients with progressive multifocal leukoencephalopathy (PML). This phase II, multicenter, single-arm study includes patients with an underlying cause of immunosuppression hardly reversible, i.e. not the patients with HIV nor those receiving biologics for chronic inflammatory diseases. Patients will receive intravenous pembrolizumab (2 mg/kg, maximum 200 mg) at month 0, 1 and 2 (total of three doses). The primary endpoint will be achieving at least one negative result of JCV viral load in cerebrospinal fluid (CSF) within the M0 to M3 period.

Progressive Multifocal Leukoencephalopathy ; Checkpoint inhibitors ; Pembrolizumab

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*f7rfrprd5opvksn462fowrqs6i000000/overview

Paclitaxel, Pembrolizumab and Olaparib in Previously Treated Advanced Gastric Adenocarcinoma

The purpose of this study is to evaluate the safety and clinical activity of paclitaxel plus olaparib and pembrolizumab in patients with previously treated advanced Gastric Cancer (GC).

Paclitaxel ; Olaparib ; Pembrolizumab ; Immunotherapy ; Anti-PD-1 ; PARP inhibitors ; Gastric Cancer

Johns Hopkins Medical Institution

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*zpz2o7h6acnacf4j34ij3oltti000000/overview

Pembrolizumab and Olaparib in Recurrent/Metastatic, Platinum Resistant Nasopharyngeal Cancer

Recurrence rate after curative treatment for locally advanced Nasopharyngeal carcinoma (NPC) is reported varying from 15% to 30% of cases, while approximately 5-11% of patients present with de novo metastatic disease. In NPC, the immunogenicity of the cancer cell is derived from accumulated somatic mutations, but also from genomic and proteomic differences between host and Epstein Barr Virus (EBV). However, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including strategies to escape anti-cancer immunity. One of this is switch to immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals like PD-L1, that is over expressed in NPC. In 2017, the landmark KEYNOTE-028 trial firstly reported promising antitumor activities and safety profiles of pembrolizumab in previously treated RM-NPC Overall, after the treatment of PD-1 inhibitors, about 25% and 60% of the recurrent or metastatic nasopharyngeal carcinoma patients achieved ORR and DCR, respectively, with a profile of toxicities in line with the use of immune checkpoint inhibitors in other diseases. Recently, it was found that some non-BRCA-mutated tumors often harbor other alterations in HR genes except for germline BRCA deleterious mutations, thus making these tumors could benefit from PARPi treatment. PARP could contribute to resistance to chemotherapy induced DNA damage, NPC cell platinum resistant could use PARP to repair and escape apoptosis. In nasopharyngeal carcinoma PARP1 is overexpressed in comparison with normal nasopharyngeal cells, LMP1 (latent membrane protein one) activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. A preclinical study demonstrates that LMP1 cells are more sensitive to PARP1 inhibition. After receiving PARPi treatment, accumulated chromosome rearrangements generate plenty of neoantigens and elevate the immunogenicity of tumor, PARPi-mediated acute inflammation remodels tumor immune microenvironment and drives a systemic Th1-skewing immune response. Patients in the POINT trial will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week dosing cycle (Q3W) and olaparib 300 mg capsules twice a day (BID) every day starting from Day 1 of Cycle 1. Treatment with protocol therapy will continue until objective disease progression, any prohibitive toxicity or until a maximum of 35 treatment cycles (up to 2 years).

Before any study specific procedure is performed the patient will sign an informed consent form. Every effort should be done to obtain a new tumor biopsy from relapsed-metastatic disease, but a new biopsy is not necessary to participate to the study. Patients will undergo radiologic staging investigations according to guidelines, including pre-treatment head and neck MRI and whole body FDG-PET (or thorax and abdomen CT scan) and clinical evaluation with fiberendoscopy. Patients will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week dosing cycle (Q3W) and olaparib 300 mg capsules twice a day (BID) every day starting from Day 1 of Cycle 1. Treatment with protocol therapy will continue until objective disease progression, any prohibitive toxicity or until a maximum of 35 treatment cycles (up to 2 years). Patients who must discontinue one of the two drugs in the combination due to adverse events may continue the study with the other combination drug. Once patients have been discontinued from study treatment, other treatment options will be at the discretion of the investigator. Dose reductions will be allowed according to protocol-specified rules. Tumor response will be evaluated by clinical/endoscopic evaluation every 3 weeks and by radiological imaging every 9 weeks ( 7 days) since treatment start. After the first year, the radiological imaging frequency can be modified as clinically indicated. Radiologic response will be assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Blood samples for plasmatic EBV-DNA analysis will be performed at baseline, and, if positive, at week 3, week 9 and then every 9 weeks since treatment start (however in concomitance with the radiological imagining) and at every follow up visit (in case of EBER-positive tumor). Patients will be evaluated for treatment safety at each clinical visit by means of clinical and laboratory exams. All adverse events will be recorded by Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; the investigator will assess whether those events are drug related or not. All enrolled patients will be included in overall safety analyses. Change in the Quality-of-Life (QoL) since baseline using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-HN43) will be evaluated at first visit, every 9 weeks during treatment and at the follow up visit.

ASST Spedali Civili di Brescia

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*rq6y2ritqmxrwggseqzwqkx5ly000000/overview

Neo-adjuvant Pembrolizumab and Radiotherapy in Localised MSS Rectal Cancer

This project investigates the clinical and biological impact of combining immunotherapy
(pembrolizumab) with short course radiotherapy (5Gy, five times) in the neo-adjuvant
treatment of localised microsatellite stable (MSS) rectal cancer.

Rectal cancer ; Immunotherapy ; Short course radiotherapy ; 5x5Gy ; Pembrolizumab ; Localised rectal cancer

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*37vp3iutrhn5ydxjhmqijwkf2i000000/overview

Combination of QLS31905, QL2107 and Chemotherapy as First-line Therapy in CLDN18.2-positive Unresectable Locally Advanced or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

This is an open-label, multicenter Phase II clinical study aimed at evaluating the tolerability, safety, efficacy, PK profile, and immunogenicity of QLS31905 for Injection combined with QL2107 Injection and XELOX regimen in the first-line treatment of CLDN18.2-positive unresectable locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

QLS31905 is a bispecific antibody targeting CD3 and CLDN18.2 independently developed by Qilu Pharmaceutical Co., Ltd. QL2107 is a biosimilar of pembrolizumab (Keytruda ) developed by Qilu Pharmaceutical Co., Ltd. This is an open-label, multicenter Phase II clinical study aimed at evaluating the tolerability, safety, efficacy, PK profile, and immunogenicity of QLS31905 for Injection combined with QL2107 Injection and XELOX regimen in the first-line treatment of CLDN18.2-positive unresectable locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*dsf2dkkqudoc2ed5tqy2vptbci000000/overview

Preoperative Immunotherapy Combined With Stereotactic Radiation Therapy Boost in the Treatment of HER2-negative Breast Cancer

The goal of the study is to assess the safety and effectiveness of the combination of anti-PD1 immunotherapy (pembrolizumab) and radiotherapy in the preoperative treatment of HER2-negative breast cancer resistant to classical chemotherapy. The subject of the intervention will be: 1. Randomly assigned in a 2:1 ratio and double-blinded addition of pre-operative immunotherapy with pembrolizumab or placebo to standard chemotherapy 2. Addition of preoperative radiotherapy boost delivered with a CyberKnife radiosurgery system concomitantly with the use of paclitaxel ( /- carboplatin) and pembrolizumab / placebo.

The study aims to assess the safety and effectiveness of the combination of anti-PD1 (PD-1, programmed cell death-1) immunotherapy (pembrolizumab) with radiotherapy in the preoperative treatment of triple-negative or luminal HER2-negative (HER2, Human epidermal growth factor receptor 2) (breast cancer, stage IIA/IIB/III/IV (with an acceptable oligometastatic form), resistant to classical chemotherapy After screening and administration of standard induction chemotherapy, the study will be conducted in a group of patients selected on the basis of lack of metabolic response after the 1st cycle of chemotherapy, and the subject of the intervention will be: * addition of preoperative immunotherapy with pembrolizumab or placebo to standard chemotherapy, using a double-blind randomized trial in a ratio of 2:1, respectively * addition of a boost of preoperative robotic stereotactic radiotherapy in all patients, simultaneously with the use of paclitaxel /- carboplatin and pembrolizumab/placebo.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*jdl53lowebujgkxycf77w3ymhm000000/overview

Neo-adjuvant Pembrolizumab as an Alternative Treatment for MMRd Uterine Cancer

The goal of this clinical trial is to establish the fraction of patients that achieve a major pathological response (MPR) after 9 cycles of pembrolizumab, with the ultimate aim of informing a follow-up randomized trial. Participants will receive 9 cycles of pembrolizumab before their standard of care hysterectomy.

Objective: Based on the success of the pilot feasibility study, we propose a phase 2 trial to establish the fraction of patients that achieve a major pathologic response (MPR) after 9 cycles of pembrolizumab, with the ultimate aim of informing a follow-up randomized trial. MPR was chosen as primary endpoint to align with ongoing randomized phase 3 ICB trials on neo-adjuvant vs. adjuvant treatment in other tumor types (e.g. the NADINA trial in melanoma; NCT04949113). Study design: Patients will be treated with neo-adjuvant pembrolizumab (200mg IV Q3W, for a total of 9 administrations), followed by SoC surgery and adjuvant therapy where indicated. Tumor responses to pembrolizumab will be assessed by a pathologist (primary endpoint) using material from the SoC surgery. In addition, tumor response will be evaluated by MRI (secondary endpoint) after the second, fourth, sixth, and last cycle of pembrolizumab. In case of suspicion of progressive disease, the hysterectomy will immediately take place. Peripheral blood and tumor samples will be used to explore dynamics of tumor and immune responses during therapy. Follow-up: Adverse events will be followed up to 6 months after the final pembrolizumab administration. Outside the study protocol patients will be followed-up according SoC guidelines for uterine cancer. Patients will be asked to participate in follow-up of disease progression (2-year recurrence-free survival). Study population: Primary MMRd UC patients at high-risk of recurrence (endometrioid grade 3 or clear cell histology) who are intended to be treated with a hysterectomy. Intervention: Pembrolizumab, 200mg IV Q3W for a total of 9 administrations per patient, prior to SoC therapy.

Endometrial Cancer ; Uterine Cancer ; MMRd ; Grade 3 ; Clear Cell ; Neo-adjuvant ; Pembrolizumab

Hans W Nijman,Mathilde Jalving

University Medical Centre Groningen

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*xirnvgxv6dvexhpilxjsdc6iei000000/overview

The goal of this clinical trial is to test a combined therapy approach (allogeneic cytomegalovirus [CMV]-specific T cells and pembrolizumab) in patients with brain cancer. The type of brain cancer being studied is glioblastoma multiforme/astrocytoma grade 4. The purpose of part 1 of this study is to determine the maximum-tolerated dose and/or recommended dose(s) for future exploration of allogeneic CMV-specific T cells as monotherapy or in combination with pembrolizumab in patients with recurrent GBM/astrocytoma grade 4. Part 2 of the study aims to investigate the anti-tumour activity of allogeneic CMV-specific T cells as monotherapy or in combination with pembrolizumab, assessed by magnetic resonance imaging and survival, in patients with recurrent or newly diagnosed GBM/grade 4 astrocytoma.

This is a multi-centre, non-randomised, open-label, dose escalation and expansion trial of allogeneic cytomegalovirus (CMV)-specific T cells as monotherapy and in combination with pembrolizumab in participants with recurrent and newly diagnosed glioblastoma multiforme (GBM)/astrocytoma grade 4. The trial will be conducted in two parts. Part 1 is a single-arm, sequential 3 3 dose-escalation of allogeneic CMV-specific T cells as a monotherapy and in combination with a fixed dose of pembrolizumab to determine the recommended dose(s) for future exploration. Up to 18 participants will be recruited for part 1. Part 2 will involve two arms and will examine the clinical impact of the CMV-specific T cells as monotherapy and in combination with pembrolizumab. Forty participants will be recruited for part 2 - 20 with newly diagnosed GBM/astrocytoma grade 4 and 20 with recurrent GBM/astrocytoma grade 4. Part 2 will only be initiated if the data and safety monitoring board (DSMB) determines that the proposed dose level(s) for future exploration are safe and well tolerated. Additional groups may be explored depending on emergent safety, pharmacodynamics and/or clinical efficacy data. Following screening and enrolment, each participant will receive four weekly infusions (Q1W) of allogeneic CMV-specific T cells, followed by up to 18 infusions of pembrolizumab. Pembrolizumab infusions will commence seven days ( 3 days) after the final T-cell infusion, and be administered every 6 weeks (Q6W). The total duration of participation for each participant is approximately 26 months. Efficacy of the combination therapy will be evaluated according to the modified Response Assessment in Neuro-Oncology (RANO) and immunotherapy (i)RANO criteria, through radiographic imaging. For group A and group B the appropriate measures for progression-free survival (PFS), overall survival (OS), disease control rate and duration of response will be assessed.

Austin Hospital, Melbourne Australia,Merck Sharp & Dohme LLC,The Newro Foundation,CUREator,Princess Alexandra Hospital, Brisbane, Australia,Royal Brisbane and Women's Hospital

David Walker,Zarnie Lwin,mark pinkham,Hui Gan,Rajiv Khanna

NEWRO Foundation,QIMR Berghofer Medical Research Institute

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*fa4i6dqnoonmcylzxql2tez3uu000000/overview

Trial Exploring Combined Neoadjuvant Therapy With Pembrolizumab/Lenvatinib Adjuvant Pembrolizumab in Pat. With NSCLC

The primary aim of this single arm, phase II study is to determine the efficacy of the combination therapy Pembrolizumab/Lenvatinib regarding the rate of major pathological response (MPR-Rate). The investigators expect to improve the MPR-Rate of 20% in Anti-PD1/-PD-L1 monotherapy (observed in recent trials) to a MPR-Rate of 40% with the combination therapy Pembrolizumab/Lenvatinib.

In Tyrol lung cancer is the fourth most incident cancer in women and the second most in men (1). Mortality related to lung cancer is highest in both sex groups, which supports the huge unmet medical need for improved lung cancer therapies in the near future (2). In very recent years, many novel therapies have entered the clinical scene, particular for treatment of non-small cell lung cancer (NSCLC) and many of those drugs target the tumor microenvironment (TME) (3-6). Both, anti-angiogenic-treatment (AAT) and immunotherapy target the TME and have been successfully established as standard therapeutic options in NSCLC (6-9). Recent preclinical studies strongly suggest that AAT and immune-checkpoint-inhibitors act synergistically and first clinical studies also proved an acceptable safety profile (6, 10, 11). However, response and therapeutic efficacy of these approaches is still limited to certain subgroups of patients and therefore the search for biomarker(s) predicting response and/or toxicity for improved patient selection is of utmost importance. This knowledge would definitely allow a more rational and efficient clinical use of these compounds. Neoadjuvant "window of opportunity" trials may offer an important way of answering relevant translational research questions related to optimized (biomarker-driven) patient selection, as they allow sequential tissue sampling during diagnostic work-up and subsequently (after neoadjuvant therapy) upon surgical tumor resection. Most studies investigating immunotherapy combinational approaches mainly focused on the characterization of the immune cell compartment, while the influence on the vascular network as well as on their mutual regulation, particularly in case both compartments are targeted in parallel, has not sufficiently been addressed. Standard neoadjuvant therapy is a mainstay of combinational chemotherapy with high toxicity and complication rates (12, 13). Several recent early clinical trials have shown promising pathologic response rates and good tolerability with neoadjuvant immune-checkpoint antibody therapy (14-16). Recently, neoadjuvant immune-checkpoint antibody monotherapy (ICA) with the PD-1 blocking monoclonal antibody Nivolumab showed high pathological response rates and good tolerability (14). Adjuvant treatment with immune-checkpoint-inhibitors has been shown to be effective and safe in the treatment of early stage melanoma (17, 18). In NSCLC prospective randomized trials with the aim of recapitulating these beneficial effects are ongoing. A high medical need in the adjuvant therapy setting is to select the optimal candidates for therapy and liquid-biopsies drawn during adjuvant treatment offer important opportunities for patients selection: (i) the kinetics of cell-free tumor-DNA (ct-DNA) can be used to monitor remission status and potentially early sense later overt clinical relapse (19-22); (ii) longitudinal assessment of patient-specific tumor alterations may predict therapy recurrence (iii) together with measurements of immune cell populations ct-DNA kinetics might gain insights into the dynamics within the TME during a prolonged period of checkpoint-blockade. Combining these informations might lead to a better understanding of potentially beneficial neo-/adjuvant treatment effects finally leading to relapse-prevention. The present phase II investigator-initiated trial (IIT) investigates the efficacy of the neoadjuvant combination therapy of the PD-1 inhibitor Pembrolizumab with the antiangiogenic kinase inhibitor Lenvatinib (primary endpoint: major pathological response) and how this therapy shapes the TME. Furthermore, the disease kinetics and the effects on cellular and soluble immune-biomarkers will be monitored during an additional adjuvant treatment-phase with Pembrolizumab via liquid-biopsies, multi-dimensional flow cytometry and cytokine quantification. In total 33 patients with early stage NSCLC will be included in this trial. The scientific program provides a comprehensive mapping of the TME prior to and after neoadjuvant intervention using various single cell analysis platforms to depict the composition of the TME. Consecutively collected plasma and blood probes will be analysed and correlated with routine response assessment, TME patterns and the clinical endpoints. In conclusion, the present phase II study aims for identification of potential biomarkers and biomarker combinations relevant for combination therapy of immunotherapy and anti-angiogenic agents in early stage NSCLC.

Georg.Pall@i-med.ac.at

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*732kp4o2doc6w3hnikqejtqiz4000000/overview

Study of PembrolizumAb combiNeD With Cisplatin or carbOplatin and Etoposide in Treatment naïve Advanced meRkel Cell cArcinoma (MCC)

This is an open label, multicenter, phase II study evaluating the activity and safety of pembrolizumab combined with cisplatin/carboplatin and etoposide as first line treatment in patients with advanced MCC.

Sara Cingarlini,Anna Maria Di Giacomo,Sara Pusceddu

Azienda Ospedaliera Universitaria Integrata (AOUI),AOUS Policlinico Le Scotte,fondazione irccs istituto nazionale tumori milano

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*udembaopmeklhs5sufsrniiw4u000000/overview

A phase II, single-arm, open-label study evaluating feasibility, safety and efficacy of combined chemotherapy and pembrolizumab as neoadjuvant/adjuvant therapy in stage IIa-IIIB NSCLC adult patients followed by adjuvant PD-(L)1 inhibitor treatment for up to 1 year

Two to four cycles of neoadjuvant chemotherapy in combination with pembrolizumab will be administered before surgery, followed by another one to two cycles of chemotherapy plus pembrolizumab after surgery (4 cycles neoadjuvant/adjuvant chemotherapy in total ) then use pembrolizumab monotherapy for up to 1 year.

Non Small Cell Lung Cancer ; Neoadjuvant Therapy ; Immune Checkpoint Inhibitor

Mengzhao Wang,Wang Mengzhao

Peking Union Medical College Hospital

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*44wkbqk2jd7tupkub3mr745yfu000000/overview

Assessment of Safety and Efficacy of OPM-101 Combined With Anti-PD-1 in Patients With Advanced Melanoma Showing Resistance to Anti-PD-1

This is a phase 1b/2a study including a dose escalation part (Phase 1b) and an extension part (Phase 2a). Both parts will be open-label, multicenter study of OPM-101 combined with the anti-PD-1 pembrolizumab as per standard of care in patients with MM who have been receiving an anti-PD-1-based treatment and have shown resistance to it, as defined by the Society for Immunotherapy of Cancer (SITC) criteria (Kluger, 2020). The objective of the study is to assess whether the addition of OPM-101 will resensitisze the tumour to the anti-PD-1-based treatment. Potential patients will be screened for this study during the period between initial evidence of disease progression on anti-PD-1 treatment and the required radiographic confirmation of disease progression. The intent is to initiate treatment with OPM-101 once the suspicion of disease progression on anti-PD-1-based therapy is confirmed, and the patient has signed the study Information and Consent Form. No anti-PD-1-based treatment should be administered within 4 weeks prior to study treatment initiation. In the dose escalation part (Phase 1b) of the study, two different doses of OPM-101 will be evaluated (75 mg bid and 150 mg bid) in combination with pembrolizumab. Patients will receive the dose and regimen of pembrolizumab, as per the authorised product SmPC, in sequential cohorts using a 3 3 design, escalating if 0 of 3 (or 1 of 6) patients experience a dose-limiting toxicity (DLT) during the first 6 weeks of treatment and not escalating if 2 of 6 patients experience a DLT. The RP2D of OPM-101 for the second part of the study (Phase 2a) in combination with pembrolizumab will be based on the rate of DLTs, incidence and severity of Treatment-Related AEs (AEs) and SAEs, and frequency of dose holds, reductions and discontinuations. A Data and Safety Monitoring Board (DSMB) will assess the safety criteria and make recommendations about dose escalation/de-escalation during the Phase 1b part, and on the RP2D to be used for further patients in the Phase 2a. The selection of the dose level for the Phase 2a will be based on safety and on preliminary PK/PD or even trends of efficacy. The DSMB will also review periodically the data during the Phase 2a and make recommendations about the continuation of the study. The cohort expansion part (Phase 2a) of the study will be conducted once the Phase 1b is completed and a safe and tolerated dose (potentially 150 mg bid) has been determined. Patients will receive daily oral treatment with OPM-101, while taking pembrolizumab for at least 12 weeks, i.e., at the time of the radiographic assessment of the disease for the primary endpoint evaluation. Patients who show a treatment response with Disease Control (CR, PR or SD) at 12 weeks will continue treatment with \[OPM-101 pembrolizumab\] up to 24 weeks, when the second radiographic disease assessment is performed.

OPM-101 ; Melanoma ; resistance ; Anti-PD1 ; RIPK2 ; advanced ; immuno-oncology ; anti-PD1 refractory ; pembrolizumab

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*zmsxqp3gyuh3dj4zo4f5yhi4ia000000/overview

Neoadjuvant Pembrolizumab, Carboplatin and Paclitaxel in Triple-negative Breast Cancer

This is a phase II, single-centered, open-label, single-armed study in patients with early triple-negative breast cancer that will evaluate the pathological complete response (pCR) rate of a non-anthracycline-based chemo-immunotherapy regimen. The trial includes a lead-in cycle of pembrolizumab, then a combination of paclitaxel, carboplatin, and pembrolizumab in the neoadjuvant setting.

The cure rate of stage I and II triple-negative breast cancer treated with anthracycline-based chemotherapy is high but comes at the price of substantial toxicity. This is a phase II, single-centered, open-label, single-armed study in patients with early triple-negative breast cancer that will evaluate the pathological complete response (pCR) rate and immune effects of a non-anthracycline-based chemo-immunotherapy regimen. The trial includes a lead-in cycle of pembrolizumab, then a combination of paclitaxel, carboplatin, and pembrolizumab in the neoadjuvant setting.

Immunotherapy ; Pembrolizumab ; Breast cancer ; Triple-negative breast cancer

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*2hmwgyifsytlyodmylpiohwoou000000/overview

This research study is studying Pembrolizumab as a possible treatment for this diagnosis for metastases in the central nervous system (brain and spinal cord).

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. Pembrolizumab may help the immune system fight cancer. The FDA (the U.S. Food and Drug Administration) has approved pembrolizumab FDA for some diseases that are being treated on this study, but not for central nervous system metastases. Researchers hope to study the effects of pembrolizumab. Many cancers use specific pathways (such as PD-1/PD-L1 and CTLA-4) to evade the body's immune system. Pembrolizumab works by blocking the PD-1/PD-L1 pathways and thus releasing the brakes on the immune system so it can stop or slow cancer. Researchers hope to study the effects of pembrolizumab in cancer that has metastasized to the brain. These drugs work by stimulating the immune system to fight cancer.

Priscilla Kaliopi Brastianos,Eudocia Quant Lee

Dana-Farber Cancer Institute

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*fuiut6jbwrohejfgw5vmo6zrci000000/overview

A Study of BL-B01D1 Pembrolizumab Bevacizumab in Patients With Recurrent or Metastatic Cervical Cancer and Endometrial Cancer

This Phase II study is a clinical trial to evaluate the efficacy and safety of BL-B01D1 pembrolizumab dual therapy with or without bevacizumab (BL-B01D1 pembrolizumab bevacizumab) in patients with recurrent or metastatic cervical cancer and endometrial cancer.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*r63psuxnwoa6kgulnogmozu72i000000/overview

A Study of BL-B01D1 Axitinib Without or With Pembrolizumab in Patients With Locally Advanced or Metastatic Renal Cancer

This Phase II study is a clinical study to explore the efficacy and safety of BL-B01D1 axitinib without or with pembrolizumab (BL-B01D1 axitinib pembrolizumab) in patients with locally advanced or metastatic renal cancer.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*mtc6tq5jb44aqkjow4unjyv7tm000000/overview

Pembrolizumab in Combination with Flutamide Treatment for Recurrence / Metastasis HNSCC

This study is a single center, single arm clinical trial for newly diagnosed patients with locally advanced head and neck squamous cell carcinoma. The main purpose is to evaluate the efficacy and safety of flutamide combined with standard immunotherapy for advanced / recurrent head and neck squamous cell carcinoma. In our previous study, we found that AR can affect the occurrence and development of tumors by regulating the differentiation of cd8 t cells. We used three different castration drugs (flutamide, goserelin and abiraterone) in animal models to treat primary and tumor bearing head and neck squamous cell carcinoma mice respectively, and found that castration treatment could significantly inhibit the tumor growth of head and neck squamous cell carcinoma. In addition, in animal models, we compared the efficacy of the combination of castration therapy and low-dose cisplatin with that of the existing first-line chemotherapy drug cisplatin, and found that the combination of castration therapy and low-dose cisplatin can significantly improve the treatment effect of head and neck squamous cell carcinoma and reduce the adverse reactions brought by the drug. Therefore, we infer that flutamide combined with standard immunotherapy can fully inhibit the growth of HNSCC and improve the prognosis of HNSCC patients.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*dxv26pbzdk577fjzhsk2cxu4nm000000/overview

DF9001-001 is a study of a new molecule that targets natural killer (NK) cells and T-cell activation signals to specific receptors on cancer cells. The study will occur in two phases. The first phase will be a dose escalation phase, enrolling patients with various types of solid tumors that express epidermal growth factor receptor (EGFR). The second phase will include a dose expansion using the best dose selected from the first phase of the study. Multiple cohorts will be opened with eligible patients having selected solid tumors (monotherapy and in combination with pembrolizumab).

EGFR ; NK Cell ; Immunotherapy ; Non-Small Cell Lung Cancer ; Head and Neck Squamous Cell Carcinoma ; Renal Cell Carcinoma ; pembrolizumab ; KEYTRUDA®

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*akwzrkb3qxvq3u3whfe63cfhdm000000/overview

This study is designed to assess the efficacy and safety of induction therapy with MK-3475 and ASG-22CE and radiation therapy with MK-3475 in patients with cT2-4aN0M0 muscle invasive bladder cancer who are unfit for or refuse radical cystectomy.

Astellas Pharma,University of Tsukuba,kobe city medical center general hospital,Merck Sharp & Dohme LLC,Osaka Metropolitan University

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*swg6kafpxjm5j53tyiebzj2zpq000000/overview

Study of Efficacy and Safety of Ociperlimab in Combination With Tislelizumab and Platinum-based Doublet Chemotherapy as First-line Treatment for Participants With Locally Advanced or Metastatic NSCLC.

The primary scientific question of interest is whether the addition of ociperlimab to platinum-based chemotherapy and tislelizumab improve progression-free survival (PFS) or overall survival (OS) compared to pembrolizumab and platinum-based chemotherapy as first-line therapy for participants with locally advanced or metastatic squamous or non-squamous NSCLC with PD-L1 expression of 1%.

This is a randomized, double-blind, placebo controlled, multicenter, phase III study evaluating the efficacy and safety of ociperlimab in combination with tislelizumab and platinum-based doublet chemotherapy as first-line treatment for participants with locally advanced or metastatic NSCLC without actionable driver mutations. Participants will receive study treatment every three weeks and will continue to receive it until RECIST 1.1 disease progression as determined by Investigator and confirmed by BIRC, unacceptable toxicity that precludes further treatment, treatment is discontinued at the discretion of the Investigator or participant, participant withdrawal of consent, pregnancy, lost to follow-up, or death.

AdvanTIG-306 ; ociperlimab ; tislelizumab ; pembrolizumab ; carboplatin ; cisplatin ; paclitaxel ; nab-paclitaxel ; pemetrexed ; squamous ; non-squamous ; non-small cell lung cancer ; NSCLC ; PD-L1

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*vgzye5ctei2ablwdsm72egzley000000/overview

IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 / KN-D18)

Phase 3, multicenter, international, open-label, randomized, 2-arm trial investigating the safety and efficacy of IO102-IO103 in combination with pembrolizumab as first-line treatment for patients with previously untreated unresectable or metastatic (advanced) melanoma. Patients will be stratified on the basis of the following factors; Disease stage: Stage III (unresectable) and IV M1a-b versus stage IV M1c-d and BRAFV600 mutation status: mutated vs wild type. All patients will receive pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles (up to 2 years treatment). Patients randomized to IO102-IO103 dual-antigen, immunotherapeutic arm will also be given IO102-IO103 Q3W with an additional dose given during the induction period on Day 8 of cycles 1 and 2. IO102 IO103 will thereafter be administered subcutaneous every 3 weeks during the maintenance period. Each patient can be treated for a maximum of 37 administrations in total (up to 2 years of treatment). The primary objective is to investigate the efficacy of IO102-IO103 in combination with pembrolizumab (compared with pembrolizumab alone) in terms of progression free survival.

Metastatic melanoma ; Unresectable melanoma ; Immunotherapy ; Progression free survival ; IO102-IO103 ; Pembrolizumab

Institut for Klinisk Medicin, Herlev-Gentofte Hospital; Denmark

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*enbpgr65ykeyd5nkjggk5o23ce000000/overview

Study Evaluating the Efficacy of a Double Immunotherapy Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes After Olaparib Treatment

The study propose to generate a clinical trial based on precision medicine to evaluate the use of immunotherapy in patients with altered homologous recombination repair genes and without progression after prior targeted therapy.

With the development of cost effective and rapid technology of genome sequencing, precision medicine becomes a new way to think oncology. Current targets involve mainly tyrosine kinase, but DNA repair machinery could also be targetable. Some of DNA repair aberrations have been associated with sensitivity to platinum and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors like Olaparib, suggesting that treatment with a PARP inhibitor may exploit a synthetic lethal interaction when the presence of alteration of the homologous repair pathway was observed. PARP is involved in multiple aspects of DNA repair, and the PARP inhibitor Olaparib has recently been approved for treating ovarian cancers with BRCA1/2 mutations. In addition, it showed that using a high-throughput, next-generation sequencing assay in prostate cancer, detection of genomic alteration in genes involved in homologous repair pathway BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2, is associated with response to olaparib. Thus demonstrating the clinical validation of the usage of precision medicine to position PARP inhibitor like olaparib in different cancer types based on molecular analysis. Preclinical studies showed DNA damage promotes neoantigen expression. It is possible that increased DNA damage by PARPi would yield greater mutational burden and expand neoantigen expression, leading to greater immune recognition of the tumor. PARPi is also associated with immunomodulation. The PARPi talazoparib increases the number of peritoneal CD8 T cells and natural killer cells and increases production of interferon (IFN)-γ and tumor necrosis factor-α in a BRCA1-mutated ovarian cancer xenograft model. Hence, addition of PARPi to immune checkpoint blockade could complement the clinical benefit of immune checkpoint inhibition. Such high level of mutation results in high number of neoantigen and antitumor immune response thus given the rational to use immunotherapy to target such type. A recent paper validate this strategy using the anti PD-1 pembrolizumab Some case reports suggest also that other mutations that induce hypermutated tumor (POLD, POLE, or MYH) could gain benefit from anti PD-1 therapy. Additional DNA repair machinery dysfunction may lead to accumulation of mutations. And such level of mutations could induce better response to immunotherapy. In the lung non-small cell setting high mutation rate were associated with better efficacy of both nivolumab and pembrolizumab.

https://insight.orbit.com/#/b/~*lakm5quojpubyakescmlvhxxhfemkgvs5wyuq6ke7ni5xw6ru4l36x4qwf674gdvrpizrrgjdgmn6000/technology-landscape/clinicaltrial/~*eug636e6zcyayf7vfmknf2oksu000000/overview