Résumé
Introduction:
Epigenetic modulation of histones plays a critical role in lymphomagenesis. The histone-methyl transferase EZH2 is the catalytic subunit of the PRC2 complex, and plays an important role in transcriptional repression during germinal center formation. Mutations in EZH2 have been observed in ~20% of DLBCL and aberrant EZH2 activity (in the presence or not of mutation) has been implicated as an oncogenic driver. Tazemetostat is a potent, orally available, selective oral EZH2 inhibitor that demonstrated a favorable safety profile and activity in pts with either EZH2 wild type or mutant B-cell NHL. Elderly pts with a high (2-3) age-adjusted IPI (international prognostic index) represent the most challenging population with the higher primary refractory rate leading to poor overall survival. We report here the safety results of the phase Ib Tazemetostat R-CHOP combination study (Epi-RCHOP, NCT02889523), in pts 60-80 years of age with newly diagnosed DLBCL.
Methods:
Pts were recruited in LYSA centers and enrolled using 3+3 pts per dose level algorithm to identify the maximum tolerated dose (MTD) and to determine a recommended phase 2 dose (RP2D) of tazemetostat plus R-CHOP. Pts received standard R-CHOP regimen every 21 days in combination with continuous tazemetostat at 400 mg, 600 mg, or 800 mg BID starting on day 2 of R-CHOP cycle 1. For dose escalation purpose, toxicities assigned as dose-limiting toxicity (DLTs) were assessed during cycle 1 and 2 and pts who did not receive at least 85% of tazemetostat-planned doses were not evaluable and replaced. We report here the safety and preliminary pharmacokinetics (PK) data during the DLT period across all doses explored in dose escalation used to determine RP2D.
Results:
From Oct. 2016 to March 2018, 17 pts were enrolled and started tazemetostat R-CHOP. Median age was 68 years (61-76), 13 (76.5%) had a stage IV disease and 4 a stage III (23.5%), aaIPI was 2 in all patients. Two pts included in the 800mg BID cohort were not evaluable for DLT (and replaced) one due due to noncompliance and one due to lymphoma related hepatic cholestasis. Two other pts had a DLT and discontinued the treatment. The first DLT was a grade 3 right colonic stercoral stasis at 400 mg BID. The second DLT was a grade 5 pneumocystis jirovecii in a context of influenza at 800mg BID. Thirteen pts did not discontinue R-CHOP plus tazemetostat. During cycle 1 and 2, non-hematological adverse events (AE) occurring in ≥10% of the 17 pts, were: gastro-intestinal toxicity (16/17 pts, 94%), infection (6/17, 35%), neurological symptom (6/17, 35%), asthenia (4/17, 24%), pain (4/17, 24%), weight decrease (3/17, 18%), cholestasis (2/17, 12%), dysgeusia (2/17, 12%), hypokalaemia (2/17, 12%), mucosal inflammation (2/17, 12%). Grade 3 or more toxicities observed in more than 10% of the pts were gastro-intestinal toxicity (24%), hypokalaemia and infection (12% each). Beside the 2 DLT, there were 3 events considered as serious AE during the DLT period: 1 grade 2 post lumbar punction syndrome, 1 grade 3 febrile neutropenia, 1 grade 3 hypokalaemia. Importantly, no organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). PK results of doxorubicin (DOX), its major metabolite, doxorubicinol (DOXol), and cyclophosphamide (CP) were compared using the cycle 2/cycle 1 geometric mean ratio (GMR) and 90% confidence interval (CI) for area under the curve (AUC) and Cmax values after R-CHOP alone (Cycle 1) or R-CHOP plus tazemetostat (400 or 800mg, cycle 2). Tazemetostat had no significant impact on DOX and DOXol AUC and although Cmax of DOX was slightly lower in the 800 mg cohort (GMR 0.68; 90%CI 0,47-0.99), Cmax of DOXol was similar (GMR 0.928; 90%CI 0.691, 1.25). CP AUC was similar in the 400 mg cohort (GMR 1.05; 90%CI 0.87-1.26) and slightly lower in the 800 mg cohort (GMR 0.83; 90%CI: 0.77-0.9)) with a similar Cmax (GMR 0.89; 90%CI 0.74-1.07). At 800 mg, AUC and Cmax of tazemetostat were similar compared to single agent study (E7438-G000-101). At the time of data lock (July, 3rd 2018), all the patients (N=7) who had completed the 8 cycles with monitored responses data reached a metabolic complete response.
Conclusion:
R-CHOP plus tazemetostat is generally well tolerated; safety and PK results appear comparable to R-CHOP alone. A RP2D of tazemetostat combined with R-CHOP would be 800 mg BID, consistent with the same daily dose as all tazemetostat monotherapy studies in adults.