Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Bendamustine Vs Bendamustine Alone in Relapsed Chronic Lymphocytic Leukemia

CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic) that has shown significantly greater direct killing of CLL cells than rituximab and greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. In preclinical in vitro and in vivo models significant activity of TRU-016 with bendamustine was observed. In a phase 1 study in 57 relapsed and/or refractory CLL patients treated with TRU-016, the maximum tested dose (20 mg/kg) was well tolerated. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in preclinical models, this trial of TRU-016 with bendamustine was conducted to establish the maximum tolerated dose, overall safety, and clinical activity of TRU-016 in combination with bendamustine in patients with relapsed CLL.

Patients with relapsed CLL who had 1–3 prior treatments (without prior bendamustine), adequate organ function, ECOG ≤2, and absolute neutrophil count ≥1200/μL were eligible. Patients received TRU-016 (15 or 20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. Bendamustine (70 mg/m²) was administered on Days 1 and 2 of each cycle by IV infusion for up to six 28-day cycles. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 2008 IWCLL Criteria.

12 patients have been treated to date (6 pts at each dose level). Patient characteristics: median age 67 yrs (range, 54–81), 7 patients received 1 and 2 patients received 2 prior regimens, 5 patients had bulky nodes ≥7 cm, 1 had del(17p13.1). All patients were intermediate to high-risk (Rai I/II=75%, III/IV=25%).

The most frequent adverse events (>2 pts) were: nausea (8); neutropenia (6); anemia, pyrexia, decreased appetite, hypokalemia, headache, cough (4 each); febrile neutropenia, constipation, diarrhea, dry mouth (3 each); and chills (2). The only grade 3/4 adverse events that occurred in >2 patients were: neutropenia (6) and febrile neutropenia (3). There were 10 serious adverse events reported on 4 patients. Related serious events were febrile neutropenia in 2 patients and autoimmune hemolytic anemia (pre-existing) and urinary tract infection in 1 patient each. There was no apparent dose relationship to adverse event frequency.

The best overall response rate at any time according to the investigator was 100% (4 CRs, 2 at each dose) with 9/12 responses occurring at cycle 1. CT scan data, which is necessary to determine IWCLL response, is pending and will be presented. There was no apparent dose relationship to response.

TRU-016 in combination with bendamustine was well tolerated and showed a positive response. A randomized trial of TRU-016/bendamustine vs. bendamustine alone is ongoing.

Jaeger:Emergent Product Development: Consultancy, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc./Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONYX: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Speakers Bureau; Amgen: Speakers Bureau. Stromatt:Emergent Product Development: Employment.