Treatment of Relapsed/Refractory Myeloma (excluding T-cell redirection therapy)
Category: Treatment of Relapsed/Refractory Myeloma (excluding T-cell redirection therapy)
First-in-Human, Open-Label, Phase 1 Trial Design of SAR446523, a Novel Anti-GPRC5D Antibody-dependent Cellular Cytotoxicity (ADCC)-enhanced Monoclonal Antibody for Multiple Myeloma
Prashant Kapoor, MD
Associate Professor
Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
Despite significant therapeutic advancements, heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) continue to have poor prognoses. GPRC5D, an orphan G-protein-coupled receptor, is highly expressed on plasma cells. GPRC5D-targeting T cell-redirection therapies (i.e., chimeric antigen receptors (CAR)-T and T cell engagers) have shown promising efficacy in heavily pretreated and high-risk patients with multiple myeloma, thus validating the clinical relevance of targeting GPRC5D. SAR446523, an anti-GPCR5D antibody-dependent cellular cytotoxicity (ADCC)-enhanced monoclonal antibody engages natural killer (NK) cells via CD16a, facilitating NK cell-mediated tumor cell lysis. SAR446523 demonstrated potent antimyeloma activity in both in vitro and in vivo preclinical models with a favorable cytokine release profile, potentially reducing the toxicity associated with T cell-redirected therapies. Here, we present the design of the ongoing first-in-human, Phase 1 trial investigating SAR446523 in patients with RRMM.
Methods: This Phase 1, open-label, dose-escalation (Part A) and dose-optimization (Part B) study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of SAR446523 in adults with RRMM (NCT06630806). SAR446523 will be administered subcutaneously at 6 dose levels, QW for Cycle 1 and Q2W for subsequent cycles with a cycle duration of 28 days. Eligible participants (N ~82) must have received ≥3 prior lines of therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody, and must be either relapsed and/or refractory to these therapies. Prior exposure to anti-GPRC5D or anti-BCMA therapy is allowed in Part A. There is a 90-day washout period for patients on prior NK cell-engaging therapy. Primary endpoints include dose-limiting toxicities (Part A) and overall response rate (Part B). Key secondary endpoints include the duration of response, progression-free survival, minimal residual disease negativity, patient-reported symptomatic adverse events, PK, and potential immunogenicity of SAR446523. The trial is currently recruiting across 3 countries.
Results: N/A
Conclusions: N/A