A Phase Ib Dose Escalation Trial of SAR650984 (Anti-CD-38 mAb) in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Background: SAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor and may induce anti-tumor effects via antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptosis induction without secondary crosslinking and/or allosteric inhibition on CD38 enzymatic activity. Preclinical and xenograft data supported the clinical use of SAR in combination with lenalidomide (LEN). Safety, response and progression free survival (PFS) data after a median follow-up of 6 months are reported (cutoff date: June 7, 2014). (NCT01749969)

Methods: Patients with relapsed or refractory myeloma (RRMM) were treated with SAR at one of three dose levels (DL) 3, 5 and 10 mg/kg, every 2 weeks, in combination with LEN and dexamethasone (Dex). SAR was given IV on day 1 and 15 with dose escalation following the classic 3+3 design. Standard doses of LEN (25 mg days 1 – 21 adjusted to 10 mg if baseline creatinine clearance ≤ 60mL/min) and Dex (40 mg days 1, 8, 15 and 22) were given in 28- day cycles. An expansion cohort of 18 patients was to be treated at the maximum tolerated dose (MTD) or the highest dose to be tested (10 mg/kg).

Results: A total of 31 patients have been treated, including 24 patients (6 + 18) at the 10 mg/kg DL since the MTD was not reached. The median time from initial MM diagnosis to first dose of SAR was 4.5 years (1.1 – 11.7) and the median number of prior treatment regimens was 6 (range 2 - 12). Over 95% of patients received prior IMiD^® therapy (LEN=29, pomalidomide (POM) =9) and more than 85% of these patients (27/31) were relapsed or refractory to at least one prior IMiD^®-based therapy. More than 90% of patients received bortezomib (BOR) and 48% received prior carfilzomib (CAR).

No dose limiting toxicities were reported. The most common treatment emergent adverse events (TEAEs- all grades) regardless of relationship included fatigue (41.9%), nausea (38.7%), upper respiratory tract infection (38.7%) and diarrhea (35.5%). Infusion associated reactions (IAR - all grades) occurred in 38.7% (n = 12) of patients, which predominantly occurred at cycle 1. Grade 3 IAR’s occurred in 2 patients resulting in treatment discontinuation. No other TEAEs led to discontinuation and there were no related TEAE with a fatal outcome. The safety profile appears uniform across the DLs. The pharmacokinetic analysis did not reveal any drug-drug interaction between SAR and Len.

With a median follow-up of 6 months, the ORR (all treated patients) was 64.5% (sCR = 2, VGPR = 8, PR = 10) and clinical benefit response (CBR) was 71%. Of note, among the 24 patients who were relapsed and refractory to their last regimen containing LEN, the ORR was 62.5 % and CBR was 70.8% (VGPR = 8, PR = 7, MR = 2). In addition, patients relapsed and refractory to both IMiD® and proteasome inhibitors (n = 21) had an ORR of 52.4 % and CBR of 61.9% (VGPR = 4, PR = 7, MR =2). The median time to first response among all treated patients was 4.2 weeks (4 – 10.1) with median time to best response of 8.5 weeks (4 – 32.6). Nine patients had improvement of response after a median of 16.1 weeks (8.1– 32.6) of therapy: PR → sCR n = 1, VGPR → sCR n = 1, PR → VGPR n = 5, MR → PR n = 2. Median time on treatment was 26.4 weeks (2 - 61). 14 patients remained on treatment at the cutoff date. Median duration of response was 23.1 weeks (0.1 – 54.7).

Overall 15 (48.4%) patients had PFS events (deaths n =1 [unrelated] or progression n = 14) and median PFS was 6.2 months. For patients previously treated with LEN, BOR and at least one of the newer agents (CAR and/or POM and/or elotuzumab) (n=17), median PFS was 4.8 months.

Conclusion: With a median follow-up of 6 months SAR/LEN/Dex administered to heavily pre-treated patients with RRMM appears effective with an ORR of 64.5%, CBR of 71% and PFS of 6.2 months. Responses were seen following the first cycle of therapy and deepen with continued treatment. The ORR was 62.5% in patients relapsed or refractory to their last regimen containing LEN. SAR in combination with LEN/Dex was well tolerated with impressive durable responses and warrants further evaluation.