Phase 1b Study Of Otlertuzumab (TRU-016), An Anti-CD37 ADAPTIR™ Protein, In Combination With Rituximab In Patients With Previously Untreated 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™(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. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with previously untreated CLL.

Patients with untreated CLL that required treatment, had adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL were eligible. Patients were ineligible for chemotherapy as first-line therapy due to patient age, comorbidity, or patient refusal of chemotherapy Patients received otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then once a month for 4 months. Rituximab (375 mg/m² the first dose then 500 mg/m²) was administered after otlertuzumab by IV infusion on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria.

24 patients have been treated. Patient characteristics and adverse events are shown in the table. The majority of the patients have not completed 6 cycles of therapy. The preliminary response by investigator assessment using NCI criteria at the last assessment is an ORR 88% (21/24); 2 patients have had PD. Six patients have had CT scans and bone marrow assessments 3 months after their last dose of study drug; by IWCLL criteria 1 has a CR, 4 have a PR and 1 has SD. The patient with a CR was MRD negative by five color flow cytometry of bone marrow aspirate. One patient discontinued therapy for a systemic inflammatory response. Severe (Grade 3 or 4) neutropenia was reported in 13% of patients; the incidence of severe infections was low (8%). Serious adverse events were reported for 4 patients: pneumonia, systemic inflammatory response, and deep vein thrombosis in 1 patient; and lymph node pain, worsening sinusitis, and fever in 1 patient each.

The preliminary response rate with otlertuzumab in combination with rituximab is promising. Follow-up is ongoing and the IWCLL response rate will be presented.

O'Brien:Emergent Product Development: Research Funding. Stromatt:Emergent Biosolutions: Employment. Awan:Lymphoma Research Foundation - Research Funding: Research Funding, Speakers Bureau; Spectrum Pharmaceuticals, Inc. - Speakers bureau: Research Funding, Speakers Bureau.