Phase Ib Study of the Novel Anti-CXCR4 Antibody Ulocuplumab (BMS-936564) in Combination with Lenalidomide Plus Low-Dose Dexamethasone, or with Bortezomib plus Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma

Background: CXCR4 is a chemokine receptor over-expressed on > 75% of cancers, including malignant plasma cells. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal anti-CXCR4 antibody which inhibits the binding of CXCR4 to CXCL12. Ulocuplumab induces apoptosis of CXCR4+ multiple myeloma cell lines and has single agent activity in vivo in MM tumor xenograft models. It is thus hypothesized that Ulocuplumab may improve the overall response rate to standard therapy in relapsed-refractory multiple myeloma (rel/ref MM) by distinct mechanisms of action, i.e., mobilization and apoptosis of malignant plasma cells and immune regulation.

Objective:This study aimed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of Ulocuplumab alone and in combination with lenalidomide plus low-dose dexamethasone (Len-Dex), or in combination with bortezomib plus dexamethasone (Bor-Dex) in subjects with rel/ref MM.

Methods: Ulocuplumab (i.e., 1, 3 and 10 mg/kg) was dose escalated with a 3-plus-3 design with doses of Len-Dex orBor-Dex to identify MTD. For Cycle 1, Ulocuplumab was administered as monotherapy on Days 1 and 8. Starting on Day 15, Ulocuplumab was administered in combination with lenalidomide [25 mg/d/21 days of a 28 day cycle] plus low dose dexamethasone [40 mg/week] and monitored for incidence of DLT(s) within Cycle 1 (42 Days) of study treatment. For the Bor-Dex group, also starting on Day 15, Ulocuplumab was administered in combination with bortezomib (1.3 mg/m²Days 1, 4, 8, 11 of a 21 day cycle] plus dexamethasone [days 1,2,4,5,8,9,11,12] and monitored for incidence of DLT(s) within Cycle 1 (35 Days) of study treatment. For the expansion phase, subjects received 10mg/kg Ulocuplumab monotherapy on Days 1 and 8 followed by weekly doses in combination with Len-Dex (28-day cycles). Subjects were assessed at day 14 and after every cycle by IMWG criteria.

Results: Forty four subjects were evaluated (median age, 59.5 yrs; range, 44-77). The median number of prior therapies was 4, (range, 1-9), with 76% of subjects having received ≥ 3. Subjects had received bortezomib in 93% of the cases, lenalidomide in 86% , thalidomide in 30%, carfilzomib in 20% and pomalidomide in 11%. Thirty subjects in escalation received Ulocuplumab alone and in combination with Len-Dex : One subject in the U-Bor-Dex group experienced a DLT in which there was delayed platelet recovery to ≤ Grade 1 or baseline which resulted in a delay of dosing of ≥ 21 days. Ulocuplumab was escalated to a maximum of 10 mg/kg without reaching MTD in monotherapy or in combination therapy. Twenty one subjects were treated in expansion phase. There were no grade 4 toxicities with Ulocuplumab monotherapy and Grade 3 toxicities with monotherapy included thrombocytopenia (6.5%), anemia (4.3%), respiratory infections (4.3%), femur fracture (4.3%), lymphopenia (2.2%), neutrophil count decreased (2.2%), platelet count decreased (2.2%) and cerebrovascular accident (2.2%). The safety profile of Ulocuplumab with Len-Dex or Bor-Dex was similar to either combination alone. Two subjects (4.5%) presented reversible G2 infusion reactions. The overall response rate (≥ PR) for all subjects in escalation and expansion was 50% (22/44), including 1 CR, 6 VGPR and 15 PR. The ORR by group was 55.1 % (16/29) and 40% (6/15) for U-Len-Dex and U-Bor-Dex, respectively. Furthermore, the ORR in expansion with 10 mg/kg U-Len-Dex was 57% (12/21) with 4 VGPRs and 8 PRs. Eight subjects in this expansion group had at least SD with a mean duration of 159 days (range, 46-437 days), resulting in 95% of subjects with clinical benefit. A median 2-fold mobilization of leukocytes into the peripheral circulation was reported after each infusion of Ulocuplumab at 3 and 10 mg/kg. Samples showed rapid mobilization of leukocytes at 2 hours post-Ulocuplumab with a partial decrease at 3-4 days post-administration without reaching baseline. Mobilization of plasma cells was also documented in some subjects.

Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis by Ulocuplumab is safe and shows a high response rate of over 50% in the Len-dex arm of patients with relapsed/refractory myeloma who have been previously treated with lenalidomide and bortezomib. The distinct mechanisms of action of this antibody make it a new class of anti-myeloma drug that deserves further exploration in clinical trials.