Rituximab, Cyclophosphamide, Bortezomib and Prednisone (R-CBorP): Final Results of a Phase I Trial Evaluating Two Dosing Schedules and the Safety of Overlapping Pegfilgrastim in Patients with Relapsed/Refractory Indolent and Mantle Cell Lymphomas.

To determine the safety and efficacy of substituting bortezomib (Bor) for vincristine in standard ‘R-CVP’. A separate safety analysis evaluated the safety of pegfilgrastim (PegG) overlapping with Bor administration.

Vincristine has marginal activity in indolent lymphomas, while preclinical and clinical data suggest that single agent Bor has significant activity in indolent and mantle cell (MCL) non-Hodgkin Lymphoma (NHL), and may also be synergistic with rituximab (R) and DNA-damaging agents.

In this phase I trial, Bor and cyclophosphamide (C) were alternately escalated. R (375 mg/m²) and C (750 mg/m² or 1000 mg/m²) were dosed on day one, and prednisone (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. Due to 2 neutropenic fevers in schedule 2 (twice-weekly Bor), the protocol was amended to allow for filgrastim (G) support, administered in between Bor dosing days. This allowed accrual to the highest planned dosing level. A separate cohort of 10 patients was added at the twice-weekly Bor 1.3 mg/m² + C 1000 mg/m² level to assess the safety of administering overlapping PegG instead of G. In this cohort, PegG was given with Bor on day 2. Patients with PR or SD after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. No DLT was seen at maximum doses of Bor and C in either schedule. Schedule 1 accrued 15 patients, with one DLT requiring cohort expansion at the second dose level. Schedule 2 accrued 40 patients.

Demographic variables were similar between the two groups, and both schedules were well tolerated with similar toxicity profiles. Most hematologic toxicities (HTs) and non-HTs across all dose levels and cycles were grade 1-2. Grade 3-4 non-HTs in the weekly treatment cohorts included grade 3 diarrhea (n=1), dehydration (n=1), neutropenic fever (n=1), infection (n=2) and anal incontinence (n=1, likely unrelated). Grade 3 toxicities in the twice-weekly groups included fatigue (n=3), neutropenic fever (n=2), fever (n=1), hypoxia (n=1) and neuropathy (n=2), along with one grade 4 neuropathy. Of the patients who developed neuropathy above baseline, resolution to baseline occurred in 8 of 9 (89%) of patients in the weekly group after a median of 0.7 months, and in 15 of 26 (58%) of patients in the twice-weekly group after a median of 4 months. To evaluate the safety of pegfilgrastim overlapping with 4 doses of Bor, toxicities and CBCs for patients in the PegG group were compared with those of patients treated at identical doses of R-CBorP given non-overlapping G support. All toxicities and CBC trends were similar, with the exception of a significant but mild decline in platelets in the PegG group. Overall response rates in the 13 evaluable weekly and 33 evaluable twice-weekly patients were 46% (23% CR) and 64% (36% CR), respectively.

R-CBorP is a well-tolerated and promising new regimen in patients with NHL. The safety of administering PegG overlapping with Bor has been established, and simplifies this regimen. Although response rates appeared to be greater in the twice-weekly schedule, a randomized study will be required to determine the true difference. Grade 3-4 neuropathy was seen only in the twice-weekly dosing group, and seemed to be less reversible and longer-lasting than in the weekly group. A randomized phase II study will soon begin enrollment to compare the toxicity and efficacy of these two dosing schedules in a larger group of patients with follicular lymphoma.

Gerecitano:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Off Label Use: bortezomib in combination with other active agents for indolent and mantle cell non-Hodgkin lymphomas. Hamlin:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees.