A phase I study evaluating two dosing schedules of bortezomib (Bor) with rituximab (R), cyclophosphamide (C) and prednisone (P) in patients with relapsed/refractory indolent and mantle cell lymphomas

Abstract

8512 Background: To determine the safety and efficacy of Bor with modified R-CVP (omitting vincristine). Rationale: Vincristine has marginal activity in indolent lymphomas, and preclinical data suggests that Bor dosed after chemotherapy may be synergistic and overcome drug resistance. Methods: In this phase I trial, Bor (see doses below) and C (750 mg/m2 or 1000 mg/m2) were alternately escalated. R (375 mg/m2) and C were dosed on day one, and P (100 mg daily) on days 2–6. In schedule 1, Bor was given on days 2 and 8, with doses escalated from 1.3 to 1.8 mg/m2. In schedule 2, Bor was given on days 2, 5, 9 and 12 with doses escalated from 1.1 to 1.5 mg/m2. Patients with PR or SD (modified Cheson (1999) criteria) after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. DLT was defined as: grade ≥ 3 nonhematologic toxicity (NHT); grade 4 neutropenia (NTP) ≥ 7 days and/or neutropenic fever (NTPF); platelets ≤ 25k/mm3 for 7 days or requiring transfusion, or <10k/mm3 for 1 day. Results: The median patient age was 65. Histologies included: 18 FL, 9 MCL, 4 SLL, 3 MZL, 5 transformed lymphoma. Schedule 1: 15 patients were accrued. The only cohort expansion was triggered by a grade 3 diarrhea in cohort 2. No DLT was seen at maximum doses of Bor and C. Schedule 2: Has accrued 24 of 27 planned patients at the time of submission. Due to 2 neutropenic fevers, G-CSF was added, allowing accrual to the highest planned dosing level. Both schedules were well tolerated, with similar toxicity profiles. Most hematologic toxicities (HTs) and NHTs across all dose levels and cycles were grade 1–2. Significant grade 3–4 NHTs included diarrhea (n=1), dehydration (n=1), and neuropathy (n=2). Of 12 patients assessable for response on schedule 1, 2CR, 5 PR, and 5 SD were seen. Of 15 patients thus far assessable on schedule 2, 3 CR, 8 PR, 3 SD and 1 POD were seen. Conclusions: R-CBorP is well-tolerated in patients with NHL when Bor is dosed on a weekly schedule up to 1.8 mg/m2 and twice-weekly up to 1.5 mg/m2. A randomized phase II study is planned to compare these two dosing schedules at their respective MTDs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Millennium Millennium