A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features

Abstract

The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma.Patients and Methods: The primary objective of this doseescalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat.Results: A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and C max of tazemetostat were similar compared with the single-agent study (E7438-G000-101).Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.

EZH2: a novel target for cancer treatment

“…Phase 2 is designed to determine the safety of tazemetostat in patients treated with 8 cycles of R-CHOP 21 and to determine the complete response rate after 8 cycles of Epi-RCHOP (tazemetostat plus RCHOP) 21. Up to present, 17 patients were enrolled and further evaluation in phase 2 is warranted while this therapeutic method showed preliminary efficacy in phase 1 [98].…”

New agents and regimens for diffuse large B cell lymphoma

“…Other trials of tazemetostat in DLBCL indications include a phase I/II study evaluating tazemetostat in combination with R-CHOP for high-risk newly diagnosed DLBCL patients. Phase Ib of this study determined 800 mg as the recommended phase 2 dose [ 132 ]. Preliminary efficacy data were encouraging with a metabolic CR rate of 76.5% (13/17), and the duration of CR was 2–14 months [ 132 ].…”

“…Phase Ib of this study determined 800 mg as the recommended phase 2 dose [ 132 ]. Preliminary efficacy data were encouraging with a metabolic CR rate of 76.5% (13/17), and the duration of CR was 2–14 months [ 132 ]. Long-term safety and overall survival of patients treated with tazemetostat will be evaluated in the rollover study TRuST (NCT02875548).…”

Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies

“…Several EZH2-specific inhibitors have been developed [95] and their safety and efficacy have been evaluated in clinical trials (Table 2) [96][97][98][99]. Except for two clinical trials (NCT03456726, NCT03213665), most of them included patients without EZH2 mutations.…”

“…The efficacy of tazemetostat has also been tested in combination with other drugs. For instance, attempts have been made to add tazemetostat to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which is the standard of care for diffuse large B-cell lymphoma (DLBCL) (NCT02889523) [98]. EZH2 inhibitors and prednisolone were shown to have synergistic anti-tumor activity in a DLBCL mouse model [100].…”