Phase 1 Dose Escalation Study of TRU-016, An Anti-CD37 SMIP™ Protein In Relapsed and Refractory CLL

CD37 is a member of the tetraspanin superfamily of molecules which are implicated in diverse processes including cellular activation and proliferation, cell motility, and cell-cell adhesion. Studies in CD37-deficient mice suggest that CD37 is involved in the regulation of B-cell function, but is not required for B-cell development. CD37 is a heavily glycosylated cell surface protein expressed constitutively at high levels on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP™ protein, which is a single chain Fv-FC fusion protein. Pre-clinical studies have demonstrated that anti-CD37 SMIP protein mediates significantly greater direct killing of CLL cells than rituximab. TRU-016 also has greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab.

The objective of the Phase 1 study was to establish the maximum tolerated dose, overall safety and clinical activity of TRU-016 in patients with advanced CLL and SLL. Response was determined using the 1996 NCI working group criteria. Patients with relapsed/refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm³ were eligible. Nine dose levels, ranging from 0.03 mg/kg to 20 mg/kg IV given once a week for 4 to 12 doses (weekly), were studied. A second schedule tested 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 to 11 weekly doses (TIW). Dose escalation and de-escalation was based on NCI CTCAE toxicity grades.

57 patients were treated with TRU-016. The median number of prior treatment regimens was 4; median number of prior anti-CD20 treatment regimens was 2 and in those with data available, 59% were refractory to their prior therapy for CLL. The median age was 66 years and 68.5% were Rai stage 3 or 4. Genomic data are available for 53 patients and 35 (66%) had high-risk genomic features [del(17p13.1), n=20 (38%), del(11q22.3), n=11 (21%), both=4 (8%)]. 19 patients reported serious adverse events (SAEs); the following events, regardless of causality, occurred in more than one patient: 3 febrile neutropenia, 3 pneumonia, 2 infusion reactions, 2 pyrexia, and 2 dyspnea. There was no apparent dose relationship to the SAEs. There were 3 dose limiting toxicities (DLTs); grade 4 neutropenia at 6 mg/kg, grade 4 thrombocytopenia (ITP) at 3 mg/kg TIW and grade 4 neutropenia at 15 mg/kg. There were no SAEs or DLTs at the highest dose of 20 mg/kg, so a maximum tolerated dose (MTD) was not reached. Mild to moderate (grade 1–2) infusion toxicity was observed on the day of infusion; the most common consisted of nausea (23%) and chills (21%). There were 2 serious infusion reactions; 1 grade 2 and the other grade 3. Both resolved with interruption of study drug infusion. Pharmacokinetic data demonstrate rapid clearance of TRU-016 in the lower dose cohorts. Accumulation was noted at the 3 mg/kg TIW and 6 mg/kg weekly and higher dose cohorts. Beginning with the 3 mg/kg TIW dose cohort, serum concentrations were usually maintained above 10 μ g/ml during treatment. 7 partial responses (PR) by investigator assessment of best response were reported, including 2 PRs in patients with del(17p13.1). For patients with 1 or 2 prior therapies, the ORR rate was 44% (7/16), all PRs, and the median reduction in peripheral lymphocytes was 92%. In patients with 3 or more prior therapies (n=41), no responses were obtained, although there was a median reduction in lymphocytes of 67% (n=21 with baseline lymphocytosis and end of treatment data available).

TRU-016 treatment has a favorable safety profile and the MTD has not been reached. Partial responses with single agent TRU-016 have been observed in patients with 1–2 prior therapies including those with del(17p13.1). Given the demonstrated single-agent clinical activity of TRU-016 and synergistic or additive impact of TRU-016 with multiple agents in preclinical models, further dose escalation and combination drug trials of TRU-016 have been initiated.

Forero-Torres:Trubion Pharmaceuticals: Research Funding. Singhal:Facet Biotech: Employment, Equity Ownership. Stromatt:Trubion Pharmaceuticals: Employment, Equity Ownership.