Dose Escalation and Expansion of Abbv-383 in Combination with Anti-Cancer Regimens in Relapsed or Refractory Multiple Myeloma

Abstract

Background: Multiple myeloma (MM) is a plasma cell cancer that remains incurable despite recent advances in currently available therapies. Bispecific antibodies (BSAbs) are a new class of interventional agents that combine target specificity, safety profile of monoclonal antibodies and the potency of T-cell mediated cellular cytotoxicity. B-cell maturation antigen (BCMA) is a surface marker that is highly expressed on malignant plasma cells and amenable to targeting by BSAbs. ABBV-383 is a fully human BSAb that targets BCMA and CD3 on the surface of MM cells and T cells respectively, resulting in T-cell activation and selective destruction of BCMA-positive MM cells. ABBV-383 displays low affinity CD3 binding and bivalent BCMA binding, which potentially will lead to a favorable safety profile with more convenient dosing intervals and robust efficacy. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79%, with a very good partial response or better (≥VGPR) rate of 63%, and a complete response (CR) rate of 29% at the data cutoff date; with median time on study of 6.1 months (Blood (2021) 138 (Supplement 1): 900). These responses are expected to deepen with additional follow-up. The most common adverse events (AEs) occurring in ≥ 20% of patients was cytokine release syndrome which was predictable and manageable. Preclinical data support the hypothesis that combining ABBV-383 with current anti-MM regimen may increase the efficacy of ABBV-383. This study will evaluate the combination of ABBV-383 with pomalidomide-dexamethasone (Pd), lenalidomide-dexamethasone (Rd), daratumumab-dexamethasone (Dd) or nirogacestat (Niro) in patients with RRMM. Study design and methods: This open-label, multi-center, phase 1b, dose-escalation and expansion study (NCT05259839) will evaluate the safety profile, tolerability, preliminary efficacy, pharmacokinetics and recommend phase 2 dose of ABBV-383 in combination with Pd, Rd, Dd or Niro for the treatment of patients (n=270) with RRMM. Adult patients (≥ 18 or ≥20 years in Japan) with documented progression of RRMM after last treatment regimen based on IMWG criteria, and an ECOG performance test ≤ 2 will be enrolled across ~45 centers. Patients must be naïve to treatment with ABBV-383 or any BCMA-targeted therapy. Dose escalation of ABBV-383 will follow BOIN design with three planned dose levels. Treatment will be administered intravenously on Day 1 of each cycle. Dose-limiting toxicities (DLT) are defined per protocol and will be evaluated for dose escalation decisions in cycle 1. Patients will receive study treatment until documented disease progression according to IMWG response criteria per investigator assessment or patient meets other protocol criteria for discontinuation of treatment. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome will be graded according to American Society for Transplantation and Cellular Therapy 2019 guidelines. Other AEs will be graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 5.0. After the last dose of treatment, each patient will have an end of treatment visit, a safety follow-up approximately 90 days after the last dose, and a survival follow up every 12 weeks for up to 12 months. The primary endpoint of this study is to determine the DLTs of ABBV-383 when given in combination with anti-myeloma regimens (Pd, Rd, or Dd) or Niro in patients with RRMM. Efficacy endpoints include overall response rate (defined as partial response + VGPR + CR + stringent CR), VGPR, progression-free survival, duration of response, time to progression and minimal residual disease negativity. Safety and tolerability of ABBV-383 (in combination with anti-cancer regimens) will be assessed by evaluating AEs, physical examinations, and changes in laboratory data and vital signs, as well as drug discontinuation or dosing modification due to AEs. The number and percentage of subjects experiencing a DLT will be summarized. ABBV-383 pharmacokinetics will be summarized for each combination cohort and compared against the historical monotherapy data. Response rates will be summarized, and statistical analysis of time-to-event efficacy endpoints will be conducted using Kaplan-Meier methodology.