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

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.

• Authors: Clémentine Sarkozy, Franck Morschhauser, Sydney Dubois, Thierry Molina, Jean Marie Michot, Peggy Cullières-Dartigues, Benjamin Suttle, Lionel Karlin, Steven Le Gouill, Jean-Michel Picquenot, Romain Dubois, Hervé Tilly, Charles Herbaux, Fabrice Jardin, Gilles Salles, Vincent Ribrag
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 13 Pg. 3145-3153 (07 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32122924 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Benzamides
• Biomarkers, Tumor
• Biphenyl Compounds
• Morpholines
• Pyridones
• R-CHOP protocol
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• tazemetostat
• Prednisone

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzamides (administration & dosage, pharmacokinetics)
• Biomarkers, Tumor (genetics)
• Biphenyl Compounds (administration & dosage, pharmacokinetics)
• Cyclophosphamide (adverse effects, therapeutic use)
• Doxorubicin (adverse effects, therapeutic use)
• Female
• Humans
• Lymphoma, Large B-Cell, Diffuse (diagnosis, drug therapy, etiology, mortality)
• Male
• Middle Aged
• Morpholines (administration & dosage, pharmacokinetics)
• Neoplasm Grading
• Neoplasm Staging
• Prednisone (adverse effects, therapeutic use)
• Prognosis
• Pyridones (administration & dosage, pharmacokinetics)
• Retreatment
• Rituximab (adverse effects, therapeutic use)
• Treatment Outcome
• Vincristine (adverse effects, therapeutic use)