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1 | Kasey Altman Treatment Options Working Document | |||||||||||||||||||||||||||
2 | ||||||||||||||||||||||||||||
3 | This working document records the wide-ranging brainstorming of treatment options for Kasey Altman gathered and reviewed between June and August 2021. The lists were clustered into: | |||||||||||||||||||||||||||
4 | -- Kasey's Treatment Options Short List (validated, available) = Prioritized contingency plan in case Kasey has a relapse ("Plans B, C, and D") | |||||||||||||||||||||||||||
5 | -- Treatment Options for Keeping Kasey's Cancer at Bay (No Evidence of Disease) | |||||||||||||||||||||||||||
6 | -- Future Treatment Options (Keep an eye on as they develop) | |||||||||||||||||||||||||||
7 | -- Treatment Options Considered and Dismissed | |||||||||||||||||||||||||||
8 | The treatment options short list was input to a prioritization process in which a treatment strategy was developed and Kasey's best next treatments were identified. | |||||||||||||||||||||||||||
9 | ||||||||||||||||||||||||||||
10 | Context | |||||||||||||||||||||||||||
11 | Challenge: Kasey has a rare cancer that responds well to chemotherapy, but it comes back in 70% of cases. There are no known (effective) treatments in case of a relapse. | |||||||||||||||||||||||||||
12 | Drivers of Kasey's tumor: The PAX3-FOX01 fusion and MYCN amplification. "Probably anything else will be secondary." Her tumor cells have mutant TP-53 (deletion), are positive for B7-H3; negative for NY-ESO-1, Her2, PD-L1, EGFR. | |||||||||||||||||||||||||||
13 | Problem: Targeting these alterations. The TRACK molecular tumor board outlined what is known about targeting them. Unfortunately, this is an evolving field, and the knowledge re targeting them is far from definitive. Need to dig into the literature. | |||||||||||||||||||||||||||
14 | ||||||||||||||||||||||||||||
15 | Kasey's Treatment History | |||||||||||||||||||||||||||
16 | Date | Name | Molecular Target | Recommended by | Where | Research link | Editorial Comments | |||||||||||||||||||||
17 | 11/2020 | VAC (Vincristine, Actinomycin-D, Cyclophosphamide) | Wexler | MSK | ||||||||||||||||||||||||
18 | 1/2021 | Vinorelbine/Irinotecan | Wexler | MSK | ||||||||||||||||||||||||
19 | 3-4/2021 | 33 Cycles Proton Therapy (VAC prior and VAC minus Actinomycin during) | Wexler & Wolden | NY Proton Center | ||||||||||||||||||||||||
20 | 5-8/2021 | VAI (Ifosfamide substituted for Cyclophosphamide) | Wexler | MSK | ||||||||||||||||||||||||
21 | ||||||||||||||||||||||||||||
22 | Kasey's Next Step ("Plan A") | |||||||||||||||||||||||||||
23 | Personalized vaccine (expected start October 2021) | Ezra Cohen | UCSD | https://clinicaltrials.gov/ct2/show/NCT03568058 | Dr. Cohen presented the personalized vaccine clinical trial he is running and answered questions at our meeting on July 1. Please see the notes and recording for more. He is open to suggestions, feedback or considerations as Kasey's vaccine is being developed | |||||||||||||||||||||||
24 | ||||||||||||||||||||||||||||
25 | Kasey's Treatment Options Short List (validated, available) = Prioritized contingency plan in case Kasey has a relapse ("Plans B, C, and D") | |||||||||||||||||||||||||||
26 | update 8/4//21 Treatment Prioritization Strategy: [David Shalinsky:] Prioritize currently-approved anticancer drugs available for off-label use, potentially in combination with cytotoxic or targeted agents, based on practical availability. In addition, approved drugs undergoing clinical trials with novel agents and/or regimens are attractive, albeit to a lesser degree based on the uncertainties associated clinical trials. The rationale for which drugs/test agents to use should be based on target expression/activity (and mechanism-of-action) in Kasey's malignancy along with preclinical and/or clinical data demonstrating proof-of-mechanism of target inhibition, modulation (or efficacy). Fortunately, there are a number of currently-approved drugs (for example, mTOR inhibitors (e.g., Temsirolimus), HDAC inhibitors, PARP inhibitors (e.g., Olaparib), BET-BRD4 inhibitors, MEK inhibitors, ALK inhibitors (e.g., Crizotinib), and even a BCL2 modulator (e.g.,Venetoclax), for which a rationale can be developed. Despite many caveats, the COG Working Group's white paper on prioritization of novel therapies offers preclinical/clinical guidance generated with great due diligence (Pacenta et.al., J Clin Med 10, 1416, 2021). The clinical treatment plan rests solely with the clinical oncologist and his/her team. Our goal is to help Kasey's clinical oncology team to evaluate and prioritize potential therapies based on the strongest rationale. Biomarker interrogation of Kasey's archival biopsy(ies) is key, e.g., demonstration of PAX3-FOXO1 fusion. Additional biomarker interrogation may be informative. This summary is a working draft in progress. | |||||||||||||||||||||||||||
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28 | ||||||||||||||||||||||||||||
29 | Date | Name | Molecular Target | Suggested as an option to be explored by | Where | Information link | Editorial Comments | |||||||||||||||||||||
30 | 7/22/21 | Mivebresib (ABBV-075) next gen bromodomain inhibitors for fp rms | BRD4 | Berkley Gryder | https://clincancerres.aacrjournals.org/content/25/21/6309.abstract | |||||||||||||||||||||||
31 | 7/22/21 | Omomyc | MYC/MYCN | Berkley Gryder | https://stm.sciencemag.org/content/11/484/eaar5012 | |||||||||||||||||||||||
32 | 6/7/21 | Temsirolimus + Cytotoxic | mTor + chemo | TRACK molecular tumor board - Jim Palma, Razelle Kurzrock | Target Cancer Foundation | https://docs.google.com/document/d/1afHi6x3sPtR4ulKy9xmKPgXuUrVumHLeqNelJPCf69k/edit | ||||||||||||||||||||||
33 | 6/16/21 | Temsirolimus L.A. Children's | mTor | Charles Keller | L.A. Children's visit in person | 6/16/21 - Recommended to meet Leo Mascarenhas in person re: Temsirolimus, evidenced based, Clinically actionable | ||||||||||||||||||||||
34 | 6/14/21 | B7-H3 CAR-T (Clinical Trial) | B7-H3-CAR-T | 8/21Bluestone, Wexler, Keller, Orentus; 7/16/21 Navin Pinto, P.I. of trial said bispecific modification added | Seattle Children's | https://clinicaltrials.gov/ct2/show/NCT04483778 | Elena Brin (June 17): CAR-T therapy for B7-H3 is worth keeping an eye on. CAR-Ts target any tumor antigens that are overexpressed, which is the case here. The targeted tumor antigen doesn't have to be driving the tumor (though ideally it would). It doesn't have to have any functionality within the tumor, but it has to be greatly overexpressed over normal tissue. It is an immunotherapy, but in this case, B7-H3 is just simply being used as a tag to find tumor cells versus normal cells. CAR-T had great success in hematological cancers; in solid tumors immunosuppressive TME can be an issue, combination with checkpoint inhibitors (e.g. anti-PD-1) might help boost CAR-T effectiveness. | |||||||||||||||||||||
35 | 7/15/21 | The B7-H3–Targeting Antibody–Drug Conjugate | Javed Khan | https://clincancerres.aacrjournals.org/content/27/10/2938 (possibly ask John Maris from Chop?) | The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models | |||||||||||||||||||||||
36 | 7/21/21 | Enoblituzumab (B7-H3 inhibitor) | rick stanton | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211166/ | ||||||||||||||||||||||||
37 | 7/21/21 | DS-7300a (B7H3-topoisomerase I inhibitor ADC; Daiichi Sankyo) | topoisomerase-B7H3mAb (ADC) | Elena Brin | Ph1 & 2 (recruiting) ; Locations include NY & LA | https://clinicaltrials.gov/ct2/show/NCT04145622?term=DS-7300a&draw=2&rank=1 | ||||||||||||||||||||||
38 | 6/16/21 | Mocetinostat With Vinorelbine | HDAC +tubulin inhibitor | Arun Singh / Noah Federman | UCLA | https://www.clinicaltrials.gov/ct2/show/NCT04299113 | Beth Cranston in Dec 2020, Faheem and Chuck Baum 6/2021 | |||||||||||||||||||||
39 | 6/14/21 | Entinostat | HDAC | Berkley Gryder | Case Western | |||||||||||||||||||||||
40 | *7/8/21 | (additional resource supporting Entinostat ) | Robert Brown, UT Pathologist Chair | https://mail.google.com/mail/u/0/?tab=cm#inbox/FMfcgzGkZGnTNJZLcHfSJzXRfPShKqjs?projector=1&messagePartId=0.1 | ||||||||||||||||||||||||
41 | *7/15/21 | CUDC-907 - possibly superior to Entinostat, more toxic? | HDAC | Charles Keller | Delsee article - combining PARP and HDAC inhibitor: https://jeccr.biomedcentral.com/articles/10.1186/s13046-020-01728-2 | |||||||||||||||||||||||
42 | 7/21/21 | Vorinostat (HDAC inhibitor) and the combination of vincristine, irinotecan, and temozolomide | HDAC+ tubulin inhibitor+topoisomerase I+ DNA alkylator | Elena Brin | Ph 1; NY | https://clinicaltrials.gov/ct2/show/NCT04308330?term=HDAC&recrs=ab&draw=3&rank=71 | ||||||||||||||||||||||
43 | 6/21/21 | Venetoclax (VENCLYXTO) by Abbvie | Bcl2 | Johannes Omer (via Rebecca Owens) | (added by Delsee-relevance?) https://sciprofiles.com/publication/view/b618241d3ffea308cbd93d971206a305 | 6/22/21: It's a specific Bcl-2 inhibitor (ABT-199) which in our preclinical data at least showed some mild effects on aRMS cells. However, these are by far not as strong as with Navitoclax and in that case we would still be missing the AuroraKinase inhibition or maybe another drug. | ||||||||||||||||||||||
44 | 6/21/21 | Volasertib | PLK-1 inhibitor | Grace Cordovano | https://oncoheroes.com/ | http://biotech-spain.com/en/articles/volasertib-a-potential-new-treatment-for-rhabdomyosarcoma-receives-orphan-drug-designation-from-the-u-s-fda/?fbclid=IwAR1JJOzflj1IbJHoFfYgy-7QNlynOK0zg9u5Dk28ajZ8BazPyYjhcR25s6s | Please see my comments | |||||||||||||||||||||
45 | 7/7/21 | Therapeutic Strategies Based on Evolutionary Tumor Board* | Delsee (Damon Reed presented) | Moffitt Cancer Center | https://clinicaltrials.gov/ct2/show/NCT04343365 | *Must be a patient enrolled at Moffit Center | ||||||||||||||||||||||
46 | 8/19/21 | ASSESSMENT/ Prioritization possible of current RMS clinical trials? | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922213/table/jcm-10-00804-t001/?report=objectonly | |||||||||||||||||||||||||
47 | 7/8/21 | Can MYCN be targeted in a vaccine?see mycn-targeting vaccine article | Berkley Gryder, Christian Seitz, David Shalinsky | https://innovationdistrict.childrensnational.org/novel-cancer-vaccine-targets-oncogenes-known-to-evade-immunity/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027715/ | EB: it might be challenging to mount an immune response to an antigen present during development. T cells able to recognize self antigens are eliminated in early development to avoid autoimmunity. | ||||||||||||||||||||||
48 | ||||||||||||||||||||||||||||
49 | Treatment Options for Keeping Kasey's Cancer at Bay (No Evidence of Disease) | |||||||||||||||||||||||||||
50 | 6/29/21 | Filtricine (starves the tumors of non-essential amino acids) | Xiyan Li | Filtricine | https://www.filtricine.com, | |||||||||||||||||||||||
51 | 7/21/21 | Metronomic therapy with Bevacizumab, Cyclophosphamide, Valproic Acid and Temsirolimus | Elena Brin | CA; study data has not been updated for a few years | https://clinicaltrials.gov/ct2/show/NCT02446431?term=HDAC&recrs=ab&draw=3&rank=66 | |||||||||||||||||||||||
52 | ||||||||||||||||||||||||||||
53 | Future Treatment Options (Keep an eye on as they develop) | |||||||||||||||||||||||||||
54 | 7/4/21 | Car-NK | Brad Power | https://medicalxpress.com/news/2021-06-cells-malignant-tumor-rest.html | EB: a promising technology, the specific drug (NK-CAR) would have a receptor (CAR) that recognises a tumor-specific antigen overexpressed on patient's cancer cells (e.g. B7-H3). | |||||||||||||||||||||||
55 | 8/16/21 | Any feasible option available only outside the U.S. | Jeff Altman | |||||||||||||||||||||||||
56 | ||||||||||||||||||||||||||||
57 | Treatment Options Considered and Dismissed | |||||||||||||||||||||||||||
58 | 6/21/21 | Navitoclax and Alisertib | Johannes Omer (via Rebecca Owens) | 6/22/21: When I was working on that publication with Navitoclax and Alisertib both were in investigated in different phase I and II clinical trials in different cancer \entities (mostly haematological cancers). Navitoclax apparently has shown certain difficult adverse events (thrombocytopenia) potentially through an "on-target" effect on Bcl-Xl. Abbvie likely has suspended their trials due to that but the effect we can observe in our research likely is dependent on exactly that effect on Bcl-Xl. | ||||||||||||||||||||||||
59 | 6/22/21 | INBRX-109 - DR-5 Agonist | Mark Lappe CEO (John Reed originally) | INHBRx, La Jolla CA | Dr. Wexler & CEO deem too early for contention; https://inhibrx.com/inbrx-109/; https://pubmed.ncbi.nlm.nih.gov/22577581/ | Mark Lappe: There are publications on DR5 agonists in preclinical rhabdomyosarcoma models, but we are not aware of any clinical data in this disease. Most importantly, we have not had any rhabdomyosarcoma patients in the INBRX-109 studies. We have seen promising single agent data in chondrosaracoma and just started a registration study, we also have a study starting shortly in Ewings sarcoma in combination with irinotecan and pre-clinically it looks very promising. We did a study in synovial sarcoma as a single agent and the activity was minimal. That said, we are not sure if 109 would be viable in rhabdomyosarcoma. | ||||||||||||||||||||||
60 | 7/14/21 | Tazemetastat? | Kasey - child with ATRT (MYCN?) at CHOP | https://www.tazverik.com/hcp/follicular-lymphoma/mechanism-of-action?gclid=CjwKCAjwlrqHBhByEiwAnLmYUFlryG-OalTSxDH7nrtsGEHqEJO8o4f4hnlYYWpOFeJxEnPI2w6cKBoCiZ8QAvD_BwE | ||||||||||||||||||||||||
61 | 7/6/21 | Haplo transplant? | Dr. Wexler | 8/3/21 Dr. Wexler does not recommend for Kasey and she agreed given quality of life issues with low level of promise | ||||||||||||||||||||||||
62 | 6/22/21 | Qarziba (only if GD2 positive) | Christian Seitz from Germany (Rimus Orentas contact) | Dr. Wexler unlikely Kasey GD2 positive - not worth IHC | https://www.ema.europa.eu/en/medicines/human/EPAR/qarziba | |||||||||||||||||||||||
63 | 6/8/21 | Bedaquiline | Kasey's friend | https://medicalxpress.com/news/2021-06-cancer-power-failure-tumor-cells.html | ||||||||||||||||||||||||
64 | 7/15/21 | Losartan? | added 7/21/21: Intriguing: oleic acid coating on cells after passing through lymphatic system. "Secret of lymph: How lymph nodes help cancer cells spread" https://www.sciencedaily.com/releases/2020/08/200819110921.htm | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504574/ The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment | ||||||||||||||||||||||||
65 | 7/8/21 | Bevacizumab for mutant p53 (Note that Kasey's is deleted) | Ally Perlina | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823886/ | Delsee added: Temsirolimus superior - Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcomahttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823886/ | |||||||||||||||||||||||
66 | ||||||||||||||||||||||||||||
67 | ARTICLES outlining treatment options: | |||||||||||||||||||||||||||
68 | 6/30/21 | 2020 European Systematic review of treatment options for cases similar to Kasey’s (inoperable, pelvic region soft tissue & bone sarcoma) | ||||||||||||||||||||||||||
69 | https://online.boneandjoint.org.uk/doi/full/10.1302/2058-5241.5.200069 | |||||||||||||||||||||||||||
70 | 6/30/21 | Therapeutic options for treatment of Pax3 Fox01 - Great Diagrams (2018 Fred Barr) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278278/ | ||||||||||||||||||||||||||
71 | ||||||||||||||||||||||||||||
72 | 7/6/21 | April 2021: Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force | ||||||||||||||||||||||||||
73 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037615/ | |||||||||||||||||||||||||||
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76 | 7/28/21 | List of clinical trials for rhabdo - Relapsed Rhabdomyosarcoma | ||||||||||||||||||||||||||
77 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922213/ | |||||||||||||||||||||||||||
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79 | 8/15/21 | Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies | ||||||||||||||||||||||||||
80 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034661/ | |||||||||||||||||||||||||||
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82 | 9/15/21 | From 2019 European list of rhabdo tx | ||||||||||||||||||||||||||
83 | table: https://www.frontiersin.org/files/Articles/502837/fonc-09-01458-HTML/image_m/fonc-09-01458-t001.jpg | |||||||||||||||||||||||||||
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