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

BACKGROUND: Bortezomib (PS-341, Velcade^R) 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.