Phase 2 Study of Bortezomib Weekly or Twice Weekly Plus Rituximab in Patients with Follicular (FL) or Marginal Zone (MZL) Lymphoma: Final Results.

Abstract

Background: Bortezomib (btz, VELCADE®) has single-agent activity in relapsed/refractory non-Hodgkin's lymphoma (NHL), including FL and MZL, on a twice-weekly schedule. Rituximab (R) is approved for relapsed/refractory CD20+ B-cell NHL. Preclinical studies show additive activity in lymphoma cell lines and lymphoma-bearing SCID mice. Btz and R have no overlapping toxicity. Weekly btz is active and safe in multiple myeloma trials.Methods: Patients (pts) with measurable CD20+ FL or MZL, KPS ≥50%, and a response with TTP ≥4 months to any prior R-containing regimen, were randomized to btz 1.3mg/m2 twice weekly (d 1, 4, 8, 11 of 21-d cycle, 5 cycles, Arm A) or btz 1.6mg/m2 weekly (d 1, 8, 15, 22 of 35-d cycle, 3 cycles, Arm B). R 375mg/m2 was given weekly for 4 weeks from d 1, cycle 1, in both arms. Response was evaluated by independent radiology review (IRR) and by investigators using the IWRC.Results: 81 pts (41 Arm A, 40 Arm B) were enrolled; median age: 64 yrs (63.0, 64.5); FL: 86% (80%, 93%); Stage IV: 47% (44%, 50%); KPS <90%: 20% (17%, 23%); LDH >ULN: 27% (32%, 23%); ≥1 extranodal site: 43% (41%, 45%); FLIPI score ≥2: 69% (71%, 68%). In total, 56% (54%, 58%) had ≥2 prior lines of therapy, 81% (80%, 82%) had prior CHOP/CVP ±R, 84% (78%, 90%) had prior R (alone or combination), and 8% (7%, 8%) had prior SCT. Median % of planned cumulative btz dose received: 75% (Arm A) and 99% (Arm B); median total btz: 19.5 and 19.0mg/m2; median dosing intensities per week: 1.6 and 1.3mg/m2. Response rates and TTP in evaluable pts are shown in Table 1. TTP curves by IRR are broadly overlapping between the arms (Figure). Most common AEs were fatigue, GI events, and peripheral neuropathy. Grade ≥3 AEs were more common in Arm A (54%) vs Arm B (35%), notably thrombocytopenia (10% vs 0%) and neutropenia (10% vs 3%), as were grade ≥4 AEs and serious AEs.Conclusion: Weekly and twice weekly btz + R are active and well tolerated in relapsed/refractory CD20+ indolent NHL. The more convenient weekly regimen appears to offer similar efficacy with less toxicity. Weekly btz 1.6mg/m2 + R is being compared with R in a phase 3 study.Response rates and time to events dataBy investigatorBy IRRArm A, N=37Arm B, N=40*Arm A, N=37*Arm B, N=40*Response rate (CR+CRu+PR), n (%)21 (57)21 (53)17 (46)15 (38)CR+CRu7 (19)6 (15)4 (11)1 (3)PR14 (38)15 (38)13 (35)14 (35)SD9 (24)13 (33)8 (22)17 (43)PD7 (19)5 (13)11 (30)7 (18)Median TTP, mo9.99.05.29.7*1 pt with no post-baseline assessment [Display omitted]