Tazemetostat (EPZ-6438) is an orally administered, first-in-class, small molecule EZH2 inhibitor, which has recently been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA)for the treatment of patients with R/R DLBCL with EZH2-activating mutations. 1
EZH2 is a Histone Methyltransferase (HMTs) and is mutated or overexpressed in a diverse range of cancer cells, and is a key player in cell proliferation. Tazemetostat selectively binds and inhibits wild type and mutated EZH2, and the resulting decrease in methylation alters gene expression patterns in cancer pathways leading to decreased proliferation in cancer cells harboring EZH2 mutations. 2
The first-in-human, dose-escalation trial ( NCT01897571) of tazemetostat as a single-agent in advanced solid tumors and B-cell lymphomas determined the Recommended Phase 2 Dose (RP2D) to be 800mg orally twice daily (BID). 3The phase II portion of this trial is now underway, which aims to investigate the safety and efficacy of tazemetostat in five independent cohorts as defined by histology, Cell of Origin (CoO), and EZH2 mutation status. The phase II portion is restricted to subjects with R/R DLBCL, including Primary Mediastinal B-Cell Lymphoma (PMBL), who are unfit/ineligible for ASCT, and R/R FL patients with no curative option with other available therapies.
Tazemetostat is also being evaluated in combination with 8 cycles of R-CHOP 21 in patients with previously untreated DLBCL, including de novoand transformed indolent disease. The estimated primary completion date is this summer (June 2017; NCT02889523).
Epizyme is also collaborating with Genentech to carry out a phase Ib clinical trial, which will evaluate combining tazemetostat with Tecentriq TM(atezolizumab) is patients with R/R DLBCL. 4