A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Abstract

Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). Otlertuzumab was administered weekly for up to 8 weeks followed by 1 dose per month for 4 months ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 to 30 mg/kg in the dose-expansion phase. Responses were determined by using the 1996 National Cancer Institute (NCI-96) and 2008 International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. A maximum-tolerated dose was not identified. Response occurred in 19 (23%) of 83 treated patients by NCI-96 criteria. All responses were partial and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1 to 2 prior therapies (12/28) vs 3 or more therapies (1/48). Twenty percent (12/61) with serial computed tomography scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea and were not dose related. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. This trial was registered at www.clinicaltrials.gov as #NCT00614042.

Figures

Figure 1

Lymphocytes and lymph node size from baseline to end of treatment. (A) The total absolute lymphocyte count was compared from day 1 prior to the first dose of otlertuzumab to the end of treatment visit which occurred 1 to 2 weeks after the last dose of otlertuzumab. A decrease of greater than 50% was observed at most dose levels and was present overall in 75.5% of patients with an elevated lymphocyte count at day 1. Patients who received otlertuzumab weekly for 4 weeks are included in this graph. (B) Lymph node sum of product diameters from CT scans obtained during screening were compared with CT scans at the end of treatment. A reduction of 50% or greater was observed at 6 mg/kg and higher. Patients who received otlertuzumab weekly for 4 weeks are included in this graph.

Figure 2

Progression-free survival of patients treated with otlertuzumab based on treatment status.