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A phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma.
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Background: SAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on human CD38 receptor. SAR kills tumor cells via antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptosis induction without secondary crosslinking and allosteric inhibition on CD38 enzymatic activity. We present data on the dose escalation phase of the study (NCT01749969). Methods: Three dose levels (DL) of SAR 3, 5 and 10 mg/kg were evaluated in combination with lenalidomide (LEN) and dexamethasone (Dex). LEN 25 mg was given on days (d) 1 – 21 and D 40 mg on d 1, 8, 15 and 22 every 28 d’s. SAR was given IV on d 1 and 15 and escalated using the classic 3+3 design. Results: 13 patients (pts) with RRMM were treated; median age 61 yrs (48 - 73); median prior treatment regimens 6 (2 - 12), 100% had received prior LEN (23% prior pomalidomide) and 92.3% previously received bortezomib (38.5% prior carfilzomib). The median time from diagnosis to first SAR dosing was 4.5 yrs (3 - 11). The maximum tolerated dose was not reached. The most frequent adverse events included nausea, cough (n = 6 each); fatigue, muscle spasm, infection (n = 5 each); vomiting, diarrhea, dehydration and insomnia (n = 4 each). Grade (G) ≥ 3 hematologic abnormalities were neutropenia (n = 4) and thrombocytopenia (n = 3). One pt discontinued therapy (cycle 1, d 1) due to an infusion reaction (bronchospasm G 3). The ORR (≥ PR), according to IMWG criteria, among 12 evaluable pts was 58 %. Responses occurred at each DL of 3mg/kg (1PR), 5mg/kg (1PR, 1 VGPR) and 10 mg/kg (1PR, 3 VGPR). Clinical benefit response (≥ MR) was 67 % with 1 MR at 3 mg/kg. Median time on treatment was 20.6 weeks (0 - 35) and 7 pts remain on therapy. PK showed non linearity at select dose levels, SAR plasma trough levels were above target for tumor eradication from preclinical data. Conclusions: The combination of SAR with LEN/Dex was tolerated and no DLT’s were reported at any DL. SAR + LEN/Dex demonstrated encouraging efficacy in pts with heavily pretreated RRMM. An expansion cohort of 18 pts recently enrolled on the trial and the results will be reported at the meeting. Clinical trial information: NCT01749969.
Abstracts by Thomas G. Martin:
Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM).Meeting: 2015 ASCO Annual Meeting | Abstract No: 8523
A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma.Meeting: 2014 ASCO Annual Meeting | Abstract No: 8532
Presentations by Thomas G. Martin:
A Phase Ib Dose-Escalation Trial of SAR650984 (Anti-CD38 mAb) in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple MyelomaMeeting: 2014 ASCO Annual Meeting Abstract No: 8512Session: Myeloma (Oral Abstract Session)