Phase I/II Study of Dasatinib In Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL)

Abstract 288

This is phase I/II trial designed to evaluate the safety and clinical activity of Dasatinib, a potent, broad spectrum inhibitor of 5 critical oncogenic tyrosine kinase families: BCR-ABL, SRC, c-KIT, PDGF receptors (α and β) and ephrin (EPH) receptor kinases, in NHL. The primary end point was maximum tolerable dose (MTD) of dasatinib in the phase I stage and overall response rate (ORR) in phase II stage of the study. Eligible patients must be at least 19 y/o with relapsed or refractory NHL after at least one prior systemic therapy, ECOG performance status 0–2, and able to take oral medications. The Phase I trial utilized a 3+3 design where patients received Dasatinib once daily for 28 day cycles in one of 3 dose cohorts (100, 150, 200 mg daily). Patients continued on Dasatinib until disease progression. NCI grade IV non-hematological toxicity defined dose-limiting toxicity (DLT) in phase I. The phase II stage used a two-stage design. Patients who are in complete or partial remission (CR or PR) after one cycle were considered responders.

The study enrolled 27 patients until June 2010. The median age was 58 years (range 34–87). 12 were females and 15 were males. The median number of prior therapies was 4 (range 1–20). The median follow-up period for survivors was 24 months (range 2–30 months). 14 patients were treated in the phase I part of the study and 13 patients were enrolled in phase II so far. 3 patients received 100 mg, 3 patients received 150 mg, and 8 patients received 200 mg daily. The MTD was determined to be 200 mg PO daily. This was later reduced to 150 mg PO daily when a higher incidence of grade 3 pleural effusions was noted (2 of 10 patients receiving 200 mg dose in the first stage of phase II) . 19 patients were evaluable for clinical response after 2 cycles of treatment and are as follows: CR 2, PR 4, SD 8, and PD 5. The ORR was 6/19 (32%). PFS was 17% (with a 95% CI of 5–34%) at 1 year, and 13% (3-29%) at 2 years. Overall survival was 60% (95% CI 38–76%) at 1 year and 50% (95% CI 29–68%) at 2 years. The 2 patients who sustained a CR had peripheral T-cell lymphoma (PTCL). Both patients remained alive, and disease free, for over 2 years since start of treatment. The histological subtypes of the 4 patients who had a PR were: diffuse center follicular lymphoma (2), marginal zone lymphoma (1), and peripheral T-cell lymphoma (1). NCI grade III-IV toxicities noted were hematological (5 thrombocytopenia, 2 anemia, 1 leukopenia, 3 neutropenia), pleural effusion (6), rash (1), diarrhea (2), weakness/orthostasis (1), prolonged QTc interval (1), flash pulmonary edema (1), and skin graft failure (1).

In conclusion, Dasatinib shows encouraging activity in heavily pre-treated, recurrent or refractory NHL patients. Toxicity is acceptable and pleural effusions, in addition to cytopenias, were the major toxicities. Dasatinib may be particularly effective in patients with PTCL; possibly because of high expression of PDGFR-α. Phase II of the study is ongoing.