A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma

Abstract Background The proteasome inhibitor bortezomib demonstrates marked pre-clinical activity when combined with the histone deacetylase inhibitor vorinostat in leukemia, multiple myeloma, and mantle cell lymphoma (MCL) cells. This study evaluated the efficacy and safety of the combination in patients with relapsed or refractory MCL and diffuse large B-cell lymphoma (DLBCL). Patients and methods This multicenter, non-randomized phase 2 trial used a Simon two-stage design with 3 cohorts: (A) MCL; no prior bortezomib (including untreated MCL), (B) MCL; prior bortezomib, and (C) relapsed or refractory DLBCL; no prior bortezomib. Vorinostat (400 mg) was administered orally on days 1-5 and 8-12 prior to bortezomib (1.3 mg/m 2 ) administered intravenously on days 1, 4, 8, and 11 of each 21-day cycle. Results Of 65 treated patients, 22 in Cohort A, 4 in Cohort B, 39 in Cohort C, the overall response rate was 31.8%, 0%, and 7.7% respectively. The median progression-free survival was 7.6 months for Cohort A and 1.8 months for Cohort C. In Cohort A, 7 patients had partial responses (PRs), 5 had stable disease (SD), 7 had progressive disease (PD), 1 was not assessed and 2 were not evaluable. In Cohort B, 2 had SD and 2 had PD. In Cohort C, 3 had PRs, 8 had SD, 23 had PD, and 5 were not assessed. Baseline NF-ĸB activation, measured as nuclear RelA by immunohistochemistry, did not correlate with clinical response. Conclusions The combination of bortezomib and vorinostat is safe and has modest activity in MCL and limited activity in DLBCL.