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
Mené sur 17 patients atteints d'un lymphome diffus à grandes cellules B récemment diagnostiqué (âge : 60-80 ans), cet essai de phase IB évalue la dose maximale tolérée du tazémétostat (un inhibiteur de EZH2) en combinaison avec un traitement de type R-CHOP
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 60-80 years with newly diagnosed diffuse large B cell lymphoma. Experimental Design: The primary objective of this dose escalation study was to evaluate the safety of the combination and to determine the recommended phase 2 dose (RP2D) of tazemetostat. Results: 17 patients were enrolled. During C1 and C2, 2 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 AE 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 to the single agent study (E7438-G000-101). Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg BID. The association presents safety and PK comparable to R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase 2 trial are warranted.