A LYSA Phase Ib Study of tazemetostat (EPZ-6438) plus R-CHOP in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients with poor prognosis features. - Université de Lille Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2020

A LYSA Phase Ib Study of tazemetostat (EPZ-6438) plus R-CHOP in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients with poor prognosis features.

Résumé

Purpose: 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 dose-escalation 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 Cmax 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.

Dates et versions

hal-04247626 , version 1 (18-10-2023)

Identifiants

Citer

Clémentine Sarkozy, Franck Morschhauser, Sydney Dubois, Thierry Molina, Jean Marie Michot, et al.. A LYSA Phase Ib Study of tazemetostat (EPZ-6438) plus R-CHOP in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients with poor prognosis features.. Clinical Cancer Research, 2020, Clinical Cancer Research, 26 (13), pp.3145-3153. ⟨10.1158/1078-0432.CCR-19-3741⟩. ⟨hal-04247626⟩
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