Non-Hodgkin Lymphoma: Is 1 Plus 1 Greater Than 2?

Phase II Trial of Bortezomib and Vorinostat in Mantle Cell and Diffuse Large B-Cell Lymphomas

Southeast Phase II Consortium (SEP2C) of the H. Lee Moffitt Cancer Center (Tampa) in conjunction with the VCU Massey Cancer Center (Richmond)

H. Lee Moffitt Cancer Center

NCT00703664 Participating Centers: 8 participating centers supported by NCI N01 programs representing, in addition to the SEP2C, the New York and University of Chicago Phase II Consortia

This is a phase II non-randomized study utilizing a two-stage mini-max design. The two cohorts are as follows: A) bortezomib-naïve patients with mantle cell lymphoma (MCL) and B) patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Both cohorts achieved first-stage response endpoints and will proceed to second-stage accrual. Patients receive vorinostat 400 mg PO on days 1-5 and 8-12 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11 every 21 days. The primary endpoint is the objective response rate. Secondary endpoints are safety and tolerability, progression-free survival and response duration, and relationship between pre-treatment lymphoma cell nuclear RelA (NF-κB) and response. Projected trial duration is three years.

79 subjects (39 in Cohort A, 40 in Cohort B)

The proteasome inhibitor bortezomib is highly active in untreated or relapsed/refractory multiple myeloma and has moderate activity in relapsed MCL. The drug is FDA-approved for both of these diseases (in the case of MCL, approval is for patients who have received at least one prior therapy). Bortezomib has minimal single-agent activity in DLBCL, but it may be of value in combination with conventional cytotoxic chemotherapy in a subset of patients [those with the activated B-cell (ABC) subtype]. Histone deacetylase inhibitors (HDACIs) are approved for the treatment of cutaneous T-cell lymphoma, and, in preclinical studies designed to test activity against a diverse group of malignant hematopoietic cell types (including multiple myeloma and non-Hodgkin lymphoma), these agents have shown synergism when combined with proteasome inhibitors. In support of these observations, initial results of clinical studies testing a combination of proteasome and HDACIs in patients with multiple myeloma have been encouraging. The goal of the current trial is to determine whether HDACIs can enhance efficacy in diseases in which bortezomib has limited (MCL) or negligible (DLBCL) single-agent activity.

This phase II study will help to determine whether abundant pre-clinical evidence of proteasome/HDAC inhibitor synergism translates into improved clinical outcomes for patients with MCL, DLBCL, or both. Early results from the MCL arm are encouraging (8/17 responses). Achievement of the second-stage goals will lay the foundation for establishing the efficacy of this strategy more definitively in a phase III trial. Additionally, correlative studies may identify subsets of patients more likely to benefit from this combination.