The Schedule Dependent Combination of Bortezomib (Bor) with Rituximab (R), Cyclophosphamide (C) and Prednisone (P) Produces Minimal Toxicity, Even at Relatively High Doses of Proteasome Inhibitor, in Patients with Relapsed/Refractory Indolent B-Cell Lymphomproliferative Disorders.

Phase II studies have established the efficacy of single agent Bor in patients with B-cell non-Hodgkin’s Lymphoma (NHL). We sought to determine the safety and efficacy of combining Bor with a modified R-CVP chemotherapy regimen (omitting vincristine). The rationale for this regimen includes:

1. Vincristine has marginal single agent activity in indolent NHL;

2. The optimal dose and schedule for Bor in combination with R, C and P is unknown; and

3. Preclinical data suggests that Bor given after chemotherapy may be synergistic and overcome acquired drug resistance.

Patients were enrolled in a traditional 3 by 3 phase I trial. Bor and C were alternately escalated in subsequent cohorts from 1.3 mg/m² to 1.8 mg/m² (Bor) and from 750 mg/m² to 1000 mg/m² (C). R (375 mg/m²) and P (100 mg per day orally) were fixed. R and C were dosed on day one, followed by Bor on days 2 and 8. P was given on days 2–6. Interim staging was performed after 4 cycles, with additional cycles given to patients with partial response (PR) or stable disease (SD) (4 cycles), and complete response (CR)(2 cycles). Toxicity was assessed using NCI-CTC, v. 3.0. Dose-limiting toxicity (DLT) was defined as the following during cycle 1:

1. grade ≥ 3 nonhematologic toxicity (NHT);

2. grade 4 neutropenia (NTP) lasting ≥ 7 days and/or neutropenic fever (NTPF);

3. a platelet count ≤ 25,000/mm³ for 7 days or associated with bleeding requiring transfusion, or <10,000/mm³ for 1 day. Modified Cheson criteria were used to define responses.

Accrual on this schedule is complete with 16 patients. No DLT was seen at maximum doses of Bor (1.8 mg/m²) and C (1000 mg/m²). One patient is excluded from analysis because of withdrawal from study prior to Bor administration. The only cohort expansion was triggered by a grade 3 diarrhea in cohort 2. The most frequent hematologic toxicities (HTs) and NHTs across all dose levels and cycles were grade 1–2. Grade 3–4 HTs included lymphopenia (n=9), thrombocytopenia (n=3), leukopenia (n=9), and neutropenia (n=9, 3 with NTPF). Grade 3–4 NHTs included grade 3 diarrhea (n=1, as mentioned above), hypophosphatemia (n=3), dehydration (n=1), hypomagnesemia (n=1), and anal incontinence (n=1, due to an unrelated rectal prolapse). Of 9 patients assessable for response to date (all of whom had received prior R and CVP- or CHOP-based regimens), 2 achieved PR, 4 minor responses, 1 had no change, and 2 progressed. R-CBorP is well-tolerated in patients with NHL when Bor is dosed on a weekly schedule up to 1.8 mg/m². We have begun to accrue a second group of patients using this combination treatment with a traditional biweekly Bor administration. A phase II study is planned using the most promising dosing schedule based on the results of this study and emerging data from NHL patients treated with weekly single-agent Bor.