Phase 1, open-label, first-in-human study of ABBV-969, a dual variable antibody-drug conjugate, in patients with metastatic castration-resistant prostate cancer.

TPS5111 Background: Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease with high unmet need. Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is highly enriched in > 85% of prostate cancer (PC), 1 and prostate-specific membrane antigen (PSMA) expression is > 100-fold higher in patients (pts) with mCRPC. 2 These are well-established and actionable targets in mCRPC. ABBV-969, a dual variable domain IgG1 drug conjugate, targets STEAP1 and PSMA and includes a topoisomerase-1 inhibitor (Top1i) payload. Based on preclinical data, ABBV-969 is expected to have greater efficacy and wider activity than targeting either antigen alone. We describe a first-in-human study of ABBV-969 in pts with mCRPC. Methods: This phase 1 open-label study (NCT06318273) of ABBV-969 monotherapy evaluates safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Eligible pts, ≥ 18 years of age, have mCRPC treated with and progressed on ≥ 1 prior novel hormonal agent for mPC/CRPC and ≥ 1 taxane for PC (or have refused, are intolerant to, or unable to access taxanes). Pts must have a life expectancy > 6 months, serum testosterone levels ≤ 50 ng/dL, ≥ 1 metastatic lesion at baseline, and serum prostate-specific antigen (PSA) levels ≥ 1.0 ng/mL. Part 1 (dose escalation) of the study will enroll up to ~80 pts and is guided by the Bayesian optimal interval design primarily based on the dose-limiting toxicity rate. Part 2 (dose expansion) will randomize up to 60 pts in 2 (1:1) or 3 (1:1:1) dose levels (determined in part 1). Part 1 will enroll pts in US, Israel, Japan, and Australia with Canada, France, and Spain added in part 2. Optimal (recommended phase 2) dose will be determined by the totality of PK, PD, safety, and efficacy data. Pts will receive intravenous ABBV-969 until disease progression, intolerable toxicity, or other study discontinuation criteria are met. The study objectives and endpoints are shown in the Table. 1. Xu M, et al. Cancers 2022;14:4034. 2. Sweat SD, et al. Urology 1998;52:637–40. Clinical trial information: NCT06318273 . Objectives and endpoints. Objective Endpoint Primary Safety and tolerability Adverse events and dose-limiting toxicitiesClinical laboratory parameters, vital signs, ECG Secondary Preliminary efficacy Primary ≥ 50% prostate-specific antigen (PSA) decrease from baseline Secondary Confirmed complete response(CR)/partial response (PR) per RECIST v1.1PSA response durationDuration of response for pts with CR or PROverall survivalProgression-free survival Pharmacokinetic (PK) characterization PK parameters including C max , T max , t 1/2 , and area under the curve using noncompartmental methodsDetermination of antidrug antibodies Dose optimization Recommended phase 2 dose determined using all available information Previously presented at ESMO 2024, FPN: 1660TiP, Raanan Berger et al - reused with permission.