An open-label, multicenter, phase II study of AT-101 in combination with rituximab (R) in patients with untreated, grade 1-2, follicular non-Hodgkin's lymphoma (FL)

Abstract

8582 Background: Bcl-2 family proteins are overexpressed in the majority of patients with FL and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. It is active as a single agent and in combination with R in NHL tumor models. Methods: Patients with untreated FL who did not require immediate chemotherapy were eligible. Treatment consisted of an induction cycle of AT-101 (30mg po daily × 21) and R (375 mg/m 2 weekly × 4) followed by up to 4 maintenance cycles of AT-101 (30mg po daily × 21) and R (375 mg/m 2 ) every 8 weeks in nonprogressors. Endpoints evaluated the response rate (RR) at week 8 (primary), overall response rate (ORR), molecular response rate (BCL-2JH rearrangement in blood and bone marrow), and safety of the combination. A mini-Max, 2-stage design (52 pts planned) was used to detect >70% RR with power of 90% and alpha of 0.10. Results: 23 pts enrolled: median age 64 yrs; FLIPI 0–5: 0%/17%/65%/13%/4%; Grade 1/2: 61%/39%; bulky disease (>5cm 3 ): 35%; stage: 1–4 4%/4%/30%/61%; bone marrow + 48%. All pts received induction and 18 pts received 1 or more maintenance cycles. RR following induction was 26% (95%CI=10.2–48.4), 4% CR and the best ORR was 70% (95%CI=47.1–86.8), 35% CR. Molecular response analysis is ongoing. Grade 3/4 AEs that occurred in ≥2 pts: nausea 4(17%), vomiting 2(9%), abdominal pain 2(9%), fatigue 2(9%), and small bowel obstruction 2(9%). AT-101 was reduced to 20mg daily x 21 which improved GI tolerability. Conclusions: The combination of AT-101 and R was well tolerated. The week 8 RR did not meet statistical criteria to enroll stage II. The best ORR is at the upper limit of reported ORR for R alone; therefore a randomized trial is required to definitively determine activity of the combination. [Table: see text]