Phase 1 Study of TRU-016, An Anti-CD37 SMIP™ Protein in Relapsed and/or Refractory NHL 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. Preclinical in vitro and in vivo models of NHL have demonstrated significant activity of TRU-016 against multiple cell lines. A recent phase 1 study in 57 relapsed and/or refractory CLL patients treated with TRU-016 identified the maximum tested dose (20 mg/kg) as safe and tolerable. We now report an extension of that study in patients with NHL.

Patients with relapsed/refractory follicular NHL (FL), mantle cell (MCL), or Waldenström's (WM), adequate organ function, ECOG ≤2, and absolute neutrophil count >500/μL were eligible. Patients received 20 mg/kg of TRU-016 administered IV once a week for 8 doses followed by 4 monthly doses. Responses were determined using standard disease specific criteria.

16 patients (8 FL; 4 MCL; and 4 WM) received TRU-016 in the expanded cohort with 4 patients in follow up at the time of abstract submission. Patient characteristics: median age 63 yrs (range, 41–81), median prior regimens 4 (1–7), refractory to last regimen 56% (9/16), refractory to anti-CD20 therapy 53% (8/15), bulky nodes ≥5 cm 57% (8/14), prior autologous stem cell transplant 13% (2/16). The most frequent adverse events were neutropenia 44% (7/16), fatigue 38% (6/16) and diarrhea, nausea and thrombocytopenia, at 25% (4/16) each. The most frequent Grade 3/4 adverse events were neutropenia 38% (6/16) and thrombocytopenia 13% (2/16); there were no Grade 3/4 infections. There were 2 serious adverse events reported by 2 patients, both were considered unrelated to TRU-016 by the investigators (a death due to an anaphylactic reaction to CT contrast and Grade 2 hypotension in another patient). Lymphocyte reduction of ≥50% was observed in 25% (4/16) of patients. Lymph node reduction of ≥50% by CT scan measurements was seen in 18% (2/11). One FL NHL patient had a PR, 6 had SD and 1 had PD. Two MCL patients had SD and 2 had PD. One WM patient had a Minor Response, 2 had SD and 1 had PD.

TRU-016 treatment has a favorable safety profile. Clinical activity was observed in this small cohort of highly refractory and heavily pretreated heterogeneous group of B-cell NHL patients including a reduction in lymphocyte count, reduction in lymph node size by CT scans and one PR. The single-agent clinical activity of TRU-016, and the synergistic or additive effect of TRU-016 with multiple agents in pre-clinical models warrants further clinical investigation in NHL. A combination trial of TRU-016 with bendamustine and rituximab has been initiated in relapsed indolent B-cell NHL patients. Updated results from ongoing patient follow-up will be presented at the meeting.

Stromatt:Emergent Product Development Seattle, LLC, Seattle, WA: Employment. Gopal:Abbott: Research Funding.