Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma.

Abstract

BACKGROUND:

Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity.

METHODS:

Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations.

RESULTS:

As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment.

CONCLUSIONS:

Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.

• Authors: Wataru Munakata, Yukari Shirasugi, Kensei Tobinai, Makoto Onizuka, Shinichi Makita, Rikio Suzuki, Dai Maruyama, Hidetsugu Kawai, Koji Izutsu, Tadashi Nakanishi, Sari Shiba, Seichiro Hojo, Kiyoshi Ando
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 3 Pg. 1123-1131 (Mar 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33492746 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Benzamides
• Biphenyl Compounds
• Morpholines
• Pyridones
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• tazemetostat

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Biphenyl Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Drug Resistance, Neoplasm (genetics)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, genetics)
• Female
• Humans
• Japan
• Lymphoma, B-Cell (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Morpholines (administration & dosage, adverse effects, pharmacokinetics)
• Mutation
• Neoplasm Recurrence, Local (drug therapy, genetics, pathology)
• Pyridones (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome