Phase 2 Study Of Otlertuzumab (TRU-016), An Anti-CD37 ADAPTIR^TM Protein, In Combination With Bendamustine Vs Bendamustine Alone In Patients With Relapsed Chronic Lymphocytic Leukemia (CLL)

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. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIR^TM(modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. Preclinical in vitro and in vivo models showed significant activity of otlertuzumab with bendamustine (benda). In phase 1 of this study involving 12 relapsed and/or refractory CLL patients (pts), otlertuzumab plus benda was well tolerated and showed a positive response. This phase 2 trial was conducted to investigate the activity of this combination compared to benda alone.

Pts with relapsed CLL who had 1-3 prior treatments, adequate organ function, ECOG performance status ≤2, ANC ≥1200/μL and CrCl >40 mL/min were eligible. Pts were stratified at randomization based on Cumulative Illness Rating Score, CrCl and deletion or mutation of 17p13.1. Pts in the study drug arm received otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. In both arms, benda (70 mg/m²) was administered IV on Days 1 and 2 of each cycle 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 1996 NCI and 2008 IWCLL Criteria. Flow cytometry was performed on peripheral blood to quantitate and characterize lymphocyte populations.

65 pts have been treated in the randomized portion of the study, including 32 with otlertuzumab plus benda and 33 with benda alone. Pt characteristics and adverse events (AEs) are shown in the table. To date, 44 patients are evaluable for response assessment by the IWCLL criteria assessed 2.5 months after completion of therapy utilizing investigator assessment of CT scan and bone marrow data. The ORR for the combination of otlertuzumab and benda (n=20) was 80% (16) with a CR rate of 20% (4). For benda alone (n=24) the ORR was 42% (10) with a CR rate of 4% (1). Patients are still in treatment and follow-up but only 10% (2) have progressed on the combination of otlertuzumab and benda while 46% (11) have progressed on benda. The best response at anytime by NCI criteria using available data for the combination of otlertuzumab and benda (n=32) was ORR 78% and CR 16% and for benda alone (n=33) ORR 52% and CR 9%. There were no responses among pts with del17p; among pts with 17p mutation both pts in the combination arm had a response; no pts in the benda alone arm had a response. The frequency of all AEs was similar between treatment arms; hematologic and infection AEs were the most frequent in both arms. There were 13 serious AEs reported by 10 pts in the otlertuzumab+benda arm and 25 reported by 12 pts in the benda alone arm. The half-life of otlertuzumab is 11 days and there was no antidrug antibody in the 14 pts tested to date.

Preliminary response rate with otlertuzumab in combination with benda was higher than benda alone by IWCLL or NCI response criteria. The overall incidence of AEs was similar between the 2 treatment cohorts, with a higher incidence of pyrexia, neutropenia and thrombocytopenia with the combination. However, the addition of otlertuzumab did not appear to increase the number of serious adverse events. Pts are in the process of completing treatment and obtaining CT scans and bone marrows; the IWCLL and NCI response rate will be updated.

Robak:Gilead Sciences (Advisory board, research support): Consultancy, Honoraria, Research Funding; Emergent BioSolutions (Advisory board, research support): Consultancy, Honoraria, Research Funding; Celgene (Research support): Consultancy, Honoraria, Research Funding; GlaxoSmithKline (Research support): Consultancy, Honoraria, Research Funding; Roche (Advisory board, research support): Consultancy, Honoraria, Research Funding; Johnson & Johnson (Advisory board, research support): Consultancy, Honoraria, Research Funding. Off Label Use: Otlertuzumab is a CD37-specific therapeutic protein that has shown significant activity in CLL in preclinical and clinical studies. Mato:Emergent Product Development: Honoraria. Awan:Lymphoma Research Foundation - Reseach Funding: Research Funding, Speakers Bureau; Spectrum Pharmaceuticals, Inc. - Speakers bureau: Research Funding, Speakers Bureau. Hill:Teva Pharmaceuticals: Honoraria, Research Funding; Emergent Biosolutions: Honoraria, Research Funding. Stromatt:Emergent Product Development: Employment. Jaeger:Emergent: Honoraria, Research Funding.