1804P - APEX-01: First-in-human phase I/II study of ARX517 an anti- prostate-specific membrane antigen (PSMA) antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Background

ARX517 is a novel ADC composed of a fully humanized anti-PSMA mAb conjugated to amberstatin-269, a potent tubulin inhibitor. ARX517 was designed to reduce off-target ADC instability-related toxicity issues observed in earlier anti-PSMA ADCs by using site-specific synthetic amino acids and stable oxime conjugation chemistry to minimize premature payload release in the human circulation.

Methods

An i3+3 dose escalation design was used. Eligible pts had ≥ 2 FDA-approved treatments for mCRPC with progression by Prostate Cancer Working Group criteria. Key objectives include safety, PK and clinical efficacy. Baseline PSMA PET expression was not required for eligibility but was evaluated as a biomarker.

Results

24 pts received ARX517 q3w at escalating doses (Table). Pts had a median of 4 prior lines of therapy; 100% received ≥ 1 androgen pathway inhibitor, 50% received taxane, and 12.5% received PSMA-targeted radionuclide. Grade (Gr) 1/2 treatment-related adverse events (TRAEs) were dry mouth (41.7%), fatigue (33.3%), diarrhea and platelet count decrease (20.8% each). Four Gr3 TRAEs were reported at 1.7, 2.4, and 2.88 mg/kg (two lymphopenia, two platelet count decrease). No DLTs, treatment-related serious AEs (SAEs), or ≥ Gr 4 AEs were reported. At higher doses (Cohorts 4-8), median duration on-treatment was 6.3 months (range 0.7+, 11.8+). Additionally, > 50% PSA and ctDNA decline were observed (Table); 2/7 pts had confirmed RECIST v1.1 responses. PK profiles for total antibody and ADC were similar, suggesting strong stability of ARX517 with minimal premature payload release. Table: 1804P

PSA and ctDNA decline, confirmed responses, DLTs, and Grade 3/4/5 TRAEs by dose level

*Data cut-off 03May23; n/d = no data available

Conclusions

ARX517 treatment resulted in PSA declines and RECIST v1.1 responses without treatment-related SAEs. Dose expansion has begun, additional safety, PD, efficacy, and PSMA PET data will be presented.

Clinical trial identification

NCT04662580.

Editorial acknowledgement

Mark English, PhD, of Cancer Communications and Consultancy Ltd, Cheshire, UK, provided editorial assistance (funded by Ambrx).

Legal entity responsible for the study

Ambrx.

Funding

Ambrx.

Disclosure

J. Shen: Financial Interests, Personal, Advisory Board: Bayer, Kite/Gilead, Sanofi, AstraZeneca; Financial Interests, Local PI: Ambrx, Arvinas, BMS, MacroGenics, Merck, Eli Lilly, Exelixis. R. Pachynski: Financial Interests, Personal, Advisory Role: Bayer, Blue Earth Diagnostics, BMS, Dendreon, EMD Serono, Genomic Health, Jounce Therapeutics, Pfizer/EMD Serono, Sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Dendreon, Genentech/Roche, Genomic Health, Merck, Sanofi; Financial Interests, Institutional, Advisory Board: BMS, Exelixis, Janssen, Pharmacyclics; Financial Interests, Institutional, Local PI: BMS. N. Adra: Financial Interests, Personal, Advisory Board: Exelixis, Sanofi, Astellas, BMS, Aveo; Financial Interests, Personal, Other, Scientific Committee for clinical trial: Merck; Financial Interests, Institutional, Research Grant, Investigator Sponsored Research: Exelixis, Genentech, Merck, Natera; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Novartis, Ambrx, Promontory Therapeutics, Gilead, Merck. M.A. Bilen: Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Board: Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, Sanofi; Financial Interests, Personal, Local PI: Merck, Xencor; Financial Interests, Institutional, Local PI: Bayer, BMS, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome and Company, AAA, Peloton Therapeutics, Ambrx, Pfizer. R. Aggarwal: Financial Interests, Personal, Advisory Board: Bayer, Amgen, Merck, AstraZeneca, Bioexcel Therapeutics; Financial Interests, Personal, Other, Consultant: Boxer Capital, Tersara, Cepton, Lumanity, EcoR1; Financial Interests, Personal, Invited Speaker: OncLive, Targeted Oncology, Grand Rounds in Urology; Financial Interests, Personal, Other, Data and Safety Monitoring Board: Prostate Cancer Clinical Trials Consortium; Financial Interests, Institutional, Invited Speaker: Janssen, Fortis Therapeutics; Financial Interests, Institutional, Funding: Merck, Zenith Epigenetics, Amgen. Z. Reichert: Financial Interests, Institutional, Local PI: Ambrx. M. Schweizer: Financial Interests, Personal, Advisory Board: Sanofi, AstraZeneca; Financial Interests, Personal, Other, Consultant: PharmaIn; Financial Interests, Institutional, Local PI: Zenith Epigenetics, BMS, Merck, Janssen, Pfizer, Hoffmann-La Roce, Tmunity, Epigenetix, Incyte, Ambrx Inc; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Signal One. A. Iravani: Financial Interests, Institutional, Advisory Role: Ambrx. S. Aung, C. Hessel: Financial Interests, Personal, Full or part-time Employment: Ambrx. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, Myovant, EMD Serono; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Promontory. All other authors have declared no conflicts of interest.