Phase I/II Study of MLN4924 Alone Followed by Dose-Adjusted EPOCH-Rituximab + MLN4924 With Gene Expression Profiling and Mutational Analysis in Relapsed/Refractory de Novo Diffuse Large B-Cell Lymphoma

Background:

• Diffuse large B-cell lymphomas (DLBCL) have been molecularly sub-classified into germinal center like B-cell (GCB) and activated B-cell like (ABC) DLBCL.
• Clinically, the ABC subtype has a significantly higher rate of drug resistance and lower survival. The ABC subtype has constitutive activation of the NF-KappaB pathway which may account for the drug resistance.
• The ability of NF-KappaB to inhibit responses to cancer therapeutic agents may also contribute to the refractory clinical behavior of ABC subtype, and inhibition of NF-KappaB can synergize with chemotherapy to kill tumor cells.
• Because a phase II randomized design is not clinically or technically practical at this early stage to address the scientific endpoints, we have designed a novel endpoint based on relative efficacy of DA-EPOCH-R + MLN 4924 (DA-EPOCH-RN) in ABC and GCB DLBCL. Based on our study that shows that survival of relapsed ABC and GCB DLBCL are comparable and poor following initial R-CHOP, we hypothesize that significantly improved survival of ABC compared to GCB DLBCL after DA-EPOCH-RN is strongly indicative of preferential activity of MLN4924 in ABC DLBCL.

Objectives:

• Assess response of MLN4924 in relapsed/refractory DLBCL
• Assess toxicity and safe tolerated dose of MLN4924 and DA-EPOCH-R
• Assess difference in response (CR/PR) and OS in ABC and GCB DLBCL

Eligibility: