PF623 PHASE 1/2 STUDY OF ISATUXIMAB MONOTHERAPY FOR RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA IN JAPANESE PATIENTS

Background: CD38 is highly and uniformly expressed on multiple myeloma (MM) cells and is a cell surface receptor target for antibody‐based therapeutics in MM and other malignancies. Isatuximab (ISA) is an anti‐CD38 monoclonal antibody that targets a specific epitope on CD38, and demonstrates significant direct inhibition of CD38 ectoenzyme activity in MM and other hematologic cancer cell lines. Isatuximab acts through a number of IgG Fc‐dependent mechanisms including antibody‐dependent cellular cytotoxicity, complement‐dependent cytotoxicity, antibody‐dependent cellular phagocytosis, and direct apoptosiss. In this Phase 1/2 study, we tested tolerability/safety and efficacy of ISA monotherapy in Japanese patients (pts) with relapsed/refractory multiple myeloma (RRMM) pretreated with at least 3 prior lines. Aims: In Phase 1: To evaluate safety and tolerability of ISA. In Phase 2: To evaluate efficacy of ISA at recommended dose, and to further evaluate the overall response rate (ORR; ≥Partial Response [PR]) of ISA. Methods: This study was an open‐label, non‐randomized, single arm and multi‐center study in pts with RRMM. Phase 1 was designed as a dose‐escalation study to evaluate the safety, PK, and efficacy of ISA. Pts were sequentially assigned to two dose levels using the 3+3 standard design. Cohort 1 (10 mg/kg every week [QW] in Cycle 1 [4 weeks] followed by 10 mg/kg every 2 weeks [Q2W] in subsequent cycles) and Cohort 2 (20 mg/kg QW in Cycle 1 [4 weeks] followed by 20 mg/kg Q2W in subsequent cycles).. Decisions to escalate the dose were based on the dose limiting toxicities (DLTs) observed during Cycle 1. Phase 2 was designed as a single arm study and commenced after completion of the DLT observation period of the last pt treated in Cohort 2 and determination of the recommended dose to be used in Phase 2. Results: In Phase 1, ISA was administered to 3 and 5 pts at 10 mg/kg and 20 mg/kg, respectively, and no DLT was observed in both cohorts. The recommended dose for phase 2 was determined as 20 mg/kg. The overall safety profile was consistent with the current knowledge of ISA. The ORRs were 66.7% (2/3 pts) and 60.0% (3/5 pts) in 10 mg and 20 mg cohorts, respectively. In Phase 2, the ORR was 32.1% (9/28 pts). In addition, six pts (21.4%) had the benefit of a minimal response (MR), 5 pts (17.9%) with a PR and 3 pts (10.7%) with a very good PR (VGPR). One pt (3.6%) achieved a complete response (CR). The ORR and clinical benefit rate (CBR; ≥MR) at the recommended dose of 20 mg/kg QW/Q2W in all treatment population (Phase 1 [N = 5] and Phase 2 [N = 28]) were 36.4% (12/33 pts) and 54.5% (18/33 pts), respectively. The null hypothesis (the true response rate <10%) was tested using a one‐sided exact binominal test with a significance level of 0.025 and the result was statistically significant ( P  < 0.0001). In Phase 2, the median progression free survival (PFS) was 4.7 (3.75‐NC; 95%CI) months. Median overall survival (OS) was not reached at the cut‐off (approximately 4 months after the last patient in); median and duration of follow‐up was 19.2 (3.6 to 44.6) weeks. The most common ISA‐related adverse events in the all treatment population were infusion reactions (41.7%; 15/36 pts), all of which were grade 1/2 and predominantly occurred during the first infusion. Summary/Conclusion: ISA monotherapy is well tolerated and effective in heavily pretreated Japanese patients with RRMM.