Phase I/II Trial of Bortezomib + CHOP-Rituximab in Diffuse Large B Cell (DLBCL) and Mantle Cell Lymphoma (MCL): Phase I Results.

Abstract

BACKGROUND: Bortezomib (PS-341, VelcadeR) is a proteasome inhibitor with anti-tumor activity in B cell malignancies including MCL. These effects, which in part may be mediated via NF-kappaB pathways, could sensitize tumor cells to standard chemotherapy-based treatment regimens and enhance efficacy. We report phase I findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL and MCL patients. METHODS: Thirty-five patients have been enrolled and initiated treatment, with the first 20 subjects comprising the phase I group. Patients received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n= 9) or 1.3 mg/m2 (Arm 2, n=7 in phase I, then all subsequent patients in phase II) on days 1,4 of each cycle. Phase 1 dose assignments were conducted according to the continual reassessment method as patients entered the study. RESULTS: Phase I included 16 DLBCL and 4 MCL patients. Median age was 65 years (range 29–84) and all patients were treatment-naïve except for 1 MCL subject who had received prior local radiotherapy. Fourteen subjects (70%) had stage IV disease at study entry, and 11 (55%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 7 subjects (35%) and 3 or 4 in 10 subjects (50%). Median followup of the phase I cohort is 9 months (range 5 – 18 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 15 subjects (75%), with 65% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity (platelets and/or white blood cells) was observed in 7 subjects (35%). Three subjects did not complete therapy (1 withdrawal by patient request with subsequent death, 1 due to dose-limiting pulmonary toxicity and 1 with concurrent lyme meningitis). Intent to treat overall response rate (n=20) is 95% with 80% CR/CRu and 80% of subjects currently alive without progression. CONCLUSIONS: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Further safety and efficacy analyses, as well as molecular correlative studies, are ongoing with both the phase I and II cohorts. Preliminary findings with the combination regimen in this adverse prognosis group of patients are encouraging.

Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia

“…These results are in keeping with data from most other studies in which bortezomib has been combined with conventional chemotherapy in other settings (Leonard et al , 2005; Barr et al , 2009; Ribrag et al , 2009; Sehn et al , 2009). One report has however suggested that when combined with rituximab, bortezomib is better tolerated and has greater efficacy when given weekly, to patients with recurrent or refractory follicular or marginal‐zone lymphoma, (de Vos et al , 2009).…”

“…This was originally conceived as a phase I/II study, the objective of the phase I component being to determine the optimal weekly or twice‐weekly dose of bortezomib when given in conjunction with rituximab. However, after the first seven patients had been treated (in the Phase I component), in the light of data from a phase II study conducted in the United States , (Leonard et al , 2005) the protocol was amended to proceed directly to the randomized phase II component. The primary end points were: toxicity, which was monitored at each visit (using World Health Organization criteria) and overall response rate.…”

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low‐grade B‐cell lymphomas

“…In a phase 1 trial, patients with DLBCL (n ¼ 40) and mantle cell lymphoma (n ¼ 36) received standard-dose R-CHOP on a 21-day schedule for 6 cycles with 1 of 3 dose levels of bortezomib (0.7 mg/m 2 , 1.0 mg/m 2 or 1.3 mg/m 2 ) administered on days 1 and 4 of each cycle. 17,33 The MTD of bortezomib with R-CHOP was not reached, and the 1.3 mg/m 2 dose level had acceptable toxicity. Peripheral neuropathy was observed in 64% of patients.…”

“…In 69% of patients, the neuropathy returned to baseline within 6 months after the completion of therapy. 33 In another trial of patients with previously untreated B-cell lymphomas, 49 patients received standard R-CHOP and were randomized to biweekly or weekly schedules of bortezomib, with both schedules doseescalated (biweekly up to 1.3 mg.m 2 on days 1, 4, 8, and 11 or weekly up to 1.6 mg/m 2 on days 1 and 8). 18 The CR/unconfirmed CR rate was 84% for all subtypes combined.…”

Stochastic Approximation and Modern Model-Based Designs for Dose-Finding Clinical Trials

“…For treatments involving combination of drugs administered multiple times over a fixed period, each subsequent dose may involve increasing doses and/or frequency of different drugs. For example, Table 1 describes the dose schedules of bortezomib used in a dosefinding trial in patients with lymphoma (Leonard Table 1 Dose schedules of bortezomib used in Leonard et al (2005)…”