A Phase 1 Trial of TRU-016, An Anti-CD37 Small Modular Immunopharmaceutical (SMIP^TM) Protein in Relapsed and Refractory CLL: Early Promising Clinical Activity.

CD37 is a tetraspanin family member expressed predominantly on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP protein. Pre-clinical studies have demonstrated CD37 SMIP protein mediates significantly greater direct killing of CLL cells than rituximab that is dependent upon tyrosine phosphorylation changes at 65 and 50-55 kD. Tru16 also mediates greater NK cell mediated killing of CLL cells as compared to either alemtuzumab or rituximab. A phase I study with TRU-016 was initiated based upon these data.

Patients with relapsed/refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm³ were eligible. Seven doses and two different schedules have been studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses. The second schedule tests 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 weekly doses. Dose escalation and de-escalation is based on CTC AE toxicity grades.

To date, 32 patients have been treated with TRU-016. In the weekly treatment schedule: 1 patient in each of the first 3 cohorts (0.03, 0.1, and 0.3 mg/kg); 3 patients at 1 mg/kg, 4 patients at 3 mg/kg, 7 patients at 6 mg/kg, and 5 patients at 10 mg/kg. In the TIW loading dose schedule: 8 patients at 3 mg/kg and 2 patients at 6 mg/kg. Genomic data is available for 27 patients and 19 have high risk genomic features [del(17p13.1), n=10, del(11q22.3), n=7, both=2]. The maximum tolerated dose (MTD) has not been reached. 12 serious adverse events have been reported and three may have been related to study drug, including G4 neutropenia, presumed zoster and ITP. Mild (grade 1-2) infusion toxicity has been observed. Limited pharmacodynamic data suggest changes in phosphotyrosine proteins observed pre-clinically that correlated with apoptosis have been observed at 30 minutes and 4 hours into treatment on day 1. Pharmacokinetic data from cohorts 1-7 demonstrate rapid clearance in earlier cohorts with patients in cohort 7 maintaining 10μg/ml plasma concentrations during treatment. Beginning with the 0.3 mg/kg dose, evidence of biological activity has been observed: one partial response (PR) in a patient with 17p del, two patients with leukemia cutis had partial or complete clearing, and in patients with peripheral lymphocytosis the median reduction was 83% (range 13% to 98%). Improvement in cytopenias has also been observed. Enrollment to cohort 8 and 11 is complete and further up-to-date data will be presented.

To date, TRU-016 is a well tolerated treatment with minimal infusional toxicity and the MTD has not been reached. One PR and a median reduction of 83% in peripheral lymphocytosis have been observed. Encouraging reduction in lymph node/spleen size and improvement in normal hematopoietic function in patients with high risk genomic CLL have been observed at low doses of CD37. The protocol has been amended to explore higher saturating doses of CD37. Future single agent and combination studies of Tru16 in CLL are warranted.

Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stromatt:Trubion Pharmaceuticals: Employment.