Phase 1 Study of Tru-016, An Anti-CD37 SMIP™ Protein in Naïve and Relapsed and/or Refractory CLL Patients

CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 protein therapeutic that has demonstrated 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. A recent phase 1 study in 57 relapsed and/or refractory CLL patients treated with TRU-016 found the maximum tested dose (20 mg/kg) safe and tolerable. We now report an extension of that study to better characterize the safety and activity of this agent.

Patients with naïve and relapsed/refractory CLL, adequate organ function and absolute neutrophil count >500/μL were eligible. Patients received 10, 20, or 30 mg/kg of TRU-016 administered IV once a week for 8 doses followed by 4 monthly doses. Patients treated in the dose escalation phase of the study were eligible for consideration as “roll-over” patients to be retreated in this expanded cohort study. Responses were determined using the 1996 NCI criteria.

26 patients (7 naïve, 16 relapsed/refractory, and 3 roll-over CLL) received TRU-016 in the expanded cohort with 12 patients in active follow up at the time of abstract submission. Patient characteristics: median age 69.5 yrs (range, 39–75), median prior regimens 2 (1–11), refractory to anti-CD20 therapy 33% (4/12), refractory to last regimen 35% (6/17) and bulky nodes ≥5 cm 50% (11/22).

There were 3 subjects with dose limiting toxicities; none occurred more than once in a dose cohort. A maximum tolerated dose was not identified. The most frequent adverse events were neutropenia, chills, diarrhea, and fatigue at 21% each and thrombocytopenia, nausea, back pain, cough, and headache at 17% each. The most frequent Grade 3 or 4 adverse events were: infection in 4 patients, neutropenia in 3 patients and febrile neutropenia in 2 patients; 3 of the infections were in patients with G3/4 neutropenia or febrile neutropenia. There were 9 serious adverse events reported by 4 patients, with 2 patients having events considered possibly related to TRU-016 (febrile neutropenia in one patient; pneumonia, atrial fibrillation and diarrhea in a second).

Lymphocyte reduction of ≥50% was observed in 81% (17/21) of naïve and relapse/refractory CLL and 33% (1/3) of roll-over CLL patients. Lymph node reduction of ≥50% by CT scan measurements was seen in 46% (6/13).

The ORR was 86% (6/7 PR) in naive CLL and 17% (3/17 PR) in relapsed/refractory CLL. Response in relapsed CLL patients was limited to those with 1–2 prior treatments, 33% (3/9 PR), as was previously observed in the dose escalation phase of the study.

TRU-016 treatment has a favorable safety profile and the MTD has not been reached. Clinical activity has been observed with a reduction in lymphocyte count and by a reduction in lymph node size by CT scans. The greatest response was seen in naïve CLL patients. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in pre-clinical models, a combination trial of TRU-016 with bendamustine has been initiated in relapsed CLL patients. Updated results from ongoing patient follow-up will be presented at the meeting.

Gopal:Millenium:. Stromatt:Emergent Product Development Seattle, LLC, Seattle, WA: Employment.