1842TiP - Phase II randomized trial of two dose levels of vobramitamab duocarmazine in participants with metastatic castration resistant prostate cancer (mCRPC; TAMARACK)

Background

B7-homolog 3 (B7-H3) is highly expressed in multiple solid tumors including mCRPC (Guo, PMID 36114082) with limited expression in normal tissue, may play an immune suppressive role, and favors cancer growth. Vobramitamab duocarmazine (vobra duo, or MGC018) is an investigational anti–B7-H3 IgG1 antibody-drug conjugate with a duocarmycin-based DNA-alkylating payload that can damage DNA in both dividing and nondividing cells, causing cell death (Scribner, PMID 32967924). Phase 1 testing of vobra duo (NCT03729596) demonstrated acceptable safety at doses up to 4.0 mg/kg IV every 3 weeks (Q3W) in patients with solid tumors (Jang, ASCO 2021, Abstract 2631). In an mCRPC cohort, 4/16 (25%) evaluable patients had an objective response and 21/39 (53.8%) had reduction in PSA from baseline of > 50% (PSA50) (Shenderov, ESMO 2021, Abstract 620P). In this cohort, which received vobra duo at 3.0 mg/kg Q3W, adverse events resulted in discontinuation, dose reduction, or interruption of drug in 10%, 30%, and 55% of participants respectively, and the median number of doses received was 3.5 (range 1.0-8.0) (Shenderov, ESMO 2021, Abstract 620P). Lowering the starting dose may improve tolerability, extend treatment duration, and enhance effectiveness.

Trial design

TAMARACK is a randomized, open-label, Phase 2 dose selection (Simon, PMID 4075313) study assessing the efficacy, safety, and tolerability of two dose levels of vobra duo (2.0 mg/kg and 2.7 mg/kg IV Q4W). The study will enroll participants with mCRPC previously treated with one prior ARAT (abiraterone, enzalutamide, or apalutamide) for prostate cancer. Approximately 100 participants will be randomized 1:1 between the two study treatment arms. The primary endpoint of the study is radiographic progression-free survival by investigator assessment using Prostate Cancer Working Group 3 criteria. Secondary endpoints include frequency and severity of adverse events, PSA50 response rate, objective response rate, and occurrence of symptomatic skeletal events. One futility analysis based on PSA50 response rate will be performed for each arm after 20 evaluable patients are enrolled. Enrollment is ongoing.

Clinical trial identification

NCT05551117.

Editorial acknowledgement

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, Menarini Silicon Biosystems, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: BMS; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme; Financial Interests, Institutional, Funding, Pfizer are providing funding to my institution for the conduct of an investigator initiated clinical trial: Pfizer; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and don’t receive any renumeration for this: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of BMS sponsored studies and don't receive any renumeration for this: BMS; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and don’t receive any compensation for this: Novartis; Non-Financial Interests, Principal Investigator, I am the Principal Investigator for several AstraZeneca sponsored studies and am not remunerated for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a BMS sponsored trial and I do not receive renumeration for this: BMS. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis. J. Sun, A. Ward: Financial Interests, Personal, Full or part-time Employment: MacroGenics; Financial Interests, Personal, Stocks/Shares: MacroGenics. E.S. Antonarakis: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Eli Lilly, Bayer, AstraZeneca, BMS, ESSA, Clovis, Merck, Curium, Blue Earth Diagnostics, Foundation Medicine, Exact Sciences, Invitae; Financial Interests, Institutional, Research Funding: Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, BMS, MacroGenics, Constellation, Bayer, AstraZeneca, Clovis, Merck.