A Phase I/II Study of AZD0305, a Novel Antibody-Drug Conjugate (ADC) Targeting GPRC5D, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Background and Significance: GPRC5D (G Protein-coupled Receptor, Class C, Group 5, Member D) is a known therapeutic target for multiple myeloma (MM). The GPRC5D bispecific T-cell-engager talquetamab was conditionally approved recently by the FDA and EMA for the treatment of RRMM in adults with at least 4 prior lines of therapy. However, there is still a need to explore additional approaches to target this protein without reliance on immune fitness. AZD0305 is a first-in-class ADC that binds specifically to GPRC5D. AZD0305 has shown preclinical activity against MM and has the potential to be active in patients with RRMM who have exhausted or cannot tolerate standard of care options. In addition to payload-mediated cytotoxicity, AZD0305 can potentially drive the killing of tumor cells through antibody-dependent cellular cytotoxicity. Study Design and Methods: NCT06106945 is a modular Phase I/II, open-label, multicenter, dose escalation, and dose expansion/optimization study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and preliminary efficacy of AZD0305 in patients with RRMM. Module 1 includes Phase Ia (Dose escalation) and Phase Ib (Dose expansion/optimization). The total enrollment is estimated to be approximately 84. Patients with RRMM >18 years of age, treated with at least 3 prior lines of treatment including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody are eligible. Patients must have measurable disease by IMWG criteria and an ECOG performance status of ≤2. Patients with peripheral neuropathy Grade ≥2, known COPD, or previous history of interstitial lung disease, uncontrolled cardiovascular disease and primary refractory MM are excluded. Further, patients who previously received anti-GPRC5D or MMAE-containing treatment are excluded. The primary endpoints of the phase I include occurrence of dose-limiting toxicities (dose escalation only) and incidence and severity of adverse events and serious adverse events. Secondary endpoints include but are not limited to objective response rate, duration of response, progression free survival, pharmacokinetics of AZD0305 and immunogenicity of AZD0305. This study is currently recruiting patients for phase I in North America, Europe, Asia and Australia.