A Phase Lb Dose Escalation Trial Of Isatuximab (Sar650984, Anti-Cd38 Mab) Plus Lenalidomide And Dexamethasone (Len/Dex) In Relapsed/Refractory Multiple Myeloma (Rrmm): Interim Results From Two New Dose Cohorts.

8009 Background: Isatuximab (ISA), a humanized anti-CD38 monoclonal antibody, has demonstrated activity in patients (pts) with RRMM in combination with Len/Dex in an ongoing Phase 1b study (NCT01749969). Overall response rate (ORR) was 63% at ISA 10 mg/kg Q2W (n = 24). Here, we report data from 2 new cohorts evaluating a higher ISA dose and a different administration schedule. Methods: Pts with RRMM ( ≥ 2 prior MM therapies) were sequentially enrolled to ISA 10 or 20 mg/kg (weekly × 4 doses, then every 2 wks; initial infusion rate 175 and 250 mg/h at 10 and 20 mg/kg, respectively) plus Len 25 mg (days [D]1–21) and Dex 40 mg (D1, 8, 15, and 22), in 28-day cycles. Primary objective: to determine the maximum tolerated dose (MTD). Results: An additional 26 pts were treated in the 2 cohorts: median age 65 (42–76) yrs; median yrs from diagnosis 4.5 (1.8–16.6). Median 4.5 (1–8) & 6 (3–10) prior lines of therapy at 10 & 20 mg/kg, respectively; Len-refractory (67% & 86%), pomalidomide+carfilzomib-refractory (25% & 64%), immunomodulatory drug+proteasome inhibitor-refractory (50% & 86%). At data cut-off (Dec 2015), median duration of dosing was 21.5 wks (10 mg/kg) and 9.9 wks (20 mg/kg); 13 pts remain on treatment. 4 pts discontinued therapy due to adverse events (AEs) (grade [Gr] 3 infusion-associated reactions [IARs] [n = 3], dose-limiting toxicity of Gr 3 pneumonia [n = 1]), all at 20 mg/kg in Cycle 1; these pts were excluded from the efficacy analysis. Most frequent AEs were fatigue (46%), pyrexia (35%) and diarrhea (31%). IARs occurred in 65% of pts, mostly Gr ≤ 2, and > 90% during 1st infusion. MTD has not been reached. In evaluable pts, ORR (IMWG criteria; confirmed responses) was 50% in both cohorts (10 mg/kg [n = 12]: VGPR 25%; PR 25%. 20 mg/kg [n = 10]: VGPR 20%; PR 30%). Clinical benefit rate ( ≥ MR) was 83% and 50% in the 10 and 20 mg/kg cohorts, respectively. Median time to 1st response was 4 (4–16) wks. Conclusions: The combination of ISA ≥ 10 mg/kg and Len/Dex was generally tolerated and clinically active in heavily pretreated RRMM. Responses were observed after approximately 4 wks. PK, biomarker, and longer term follow-up data will be presented. Clinical trial information: NCT01749969.