(EPZ-6438) Plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Published OnlineFirst March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3741

CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY

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 Clementine Sarkozy1, Franck Morschhauser2, Sydney Dubois3, Thierry Molina4, Jean Marie Michot5, Peggy Cullieres-Dartigues 6, Benjamin Suttle7, Lionel Karlin8, Steven Le Gouill9, Jean-Michel Picquenot10, Romain Dubois11, Herve Tilly3, Charles Herbaux2, Fabrice Jardin3, Gilles Salles1,8, and Vincent Ribrag5

ABSTRACT ◥ Purpose: The histone-methyl transferase EZH2, catalytic sub- or more toxicities observed in more than 10% of the patients were unit of the PRC2 complex involved in transcriptional regulation, is constipation (24%), nausea (12%), and hypokalemia (12%). mutated in approximately 25% of germinal center B-cell lympho- Grade 3 to 4 hematologic adverse events were recorded in 8 mas. Aberrant proliferative dependency on EZH2 activity can be patients (47%): neutropenia (47%), leukopenia (29%), anemia targeted by the orally available EZH2 inhibitor tazemetostat (EPZ- (18%), and thrombocytopenia (12%). The tazemetostat RP2D 6438). We report the results of the phase Ib tazemetostat plus R- was 800 mg. No organ-oriented toxicity increased with tazeme- CHOP combination (NCT02889523), in patients 60 to 80 years of tostat dosage escalation (severity and incidence). At 800 mg, age with newly diagnosed diffuse large B-cell lymphoma. AUC and Cmax of tazemetostat were similar compared with the Patients and Methods: The primary objective of this dose- single-agent study (E7438-G000-101). escalation study was to evaluate the safety of the combination and Conclusions: The RP2D of tazemetostat combined with to determine the recommended phase II dose (RP2D) of tazemetostat. R-CHOP is 800 mg twice a day. The association presents safety Results: A total of 17 patients were enrolled. During C1 and C2, and PK comparable with R-CHOP alone. Preliminary efﬁcacy two dose-limiting toxicities were observed: one grade 3 constipation data are encouraging and further investigations in phase II trial at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 are warranted.

Introduction vincristine (CHOP; refs. 1, 2)]. Age-adjusted IPI (aaIPI), a derivative of the IPI score based on lactate dehydrogenase (LDH), stage, and ECOG Diffuse large B-cell lymphoma (DLBCL) is the most common performance status, can stratify the patients at diagnosis and predicts subtype of non-Hodgkin lymphoma (NHL) accounting for about outcome (3). In patients older than 60 years, DLBCL can be cured in 30% of all lymphoid neoplasms. The incidence increases with age, 50% to 60% of the cases following ﬁrst-line R-CHOP (4–6) and 30% to around 50% of the patients being older than 60 years and almost one 40% will present a R-CHOP primary refractory or an early-relapse third over 75 years (1). Importantly, despite their age, the vast majority disease (7, 8). Those “poor responders” to R-CHOP have a 1-year of these patients are eligible and treated with the standard-of-care overall survival (OS) of less than 20% and still represent a group of immunochemotherapy regimen, namely R-CHOP [rituximab (R) in patients with a clear unmet medical need (7). Among all DLBCL, association with prednisolone, doxorubicin, cyclophosphamide, and elderly patients with a high aaIPI represent the most challenging population with the higher primary refractory rate leading to poor OS (5, 9). 1 INSERM 1052, Charles Merieux Lyon-1 Faculty, Claude Bernard University, Lyon, Epigenetic modulation of histones plays a critical role in oncogenic France. 2Department of Hematology, U1245 Centre Hospitalier RU de Lille, Lille, transformation in many malignancies and is now an area of intense France. 3Department of Hematology, U918 Centre Henri Becquerel, Rouen, France. 4Department of Pathology, Necker Enfants Malades Hospital, Universite clinical research (10). Next-generation sequencing of B-cell NHL Paris, APHP, Paris, France. 5Department of Hematology, Gustave Roussy, Uni- genomes has uncovered frequent mutations affecting histone- versite Paris-Saclay, INSERM U1170, Villejuif, France. 6Department of Pathology, modifying proteins especially in lymphomas derived from the germi- Gustave Roussy, Universite Paris-Saclay, INSERM U1170, Villejuif, France. 7qPhar- nal center (11). One of them, EZH2, is the catalytic subunit of the 8 metra, Raleigh, Durham, North Carolina. Department of Hematology, Hospices chromatin remodeling polycomb repressive complex 2 (PRC2), and Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre Benite cedex, France. the only human protein methyltransferase that can methylate histone 3 9Department of Hematology, CHU Nantes, Nantes, France. 10Department of Pathology, U918 Centre Henri Becquerel, Rouen, France. 11Department of lysine 27 (H3K27) leading to the transcriptional repressive mark Pathology, Centre Hospitalier RU de Lille, Lille, France. H3K27me3. During hematopoiesis, EZH2 plays an important role where it represses genes involved in cell-cycle arrest and terminal Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). differentiation. Later during germinal center (GC) formation, EZH2 activity becomes increasingly opposed by the SWI/SNF (Switch/ Corresponding Author: Clementine Sarkozy, University Lyon 1, Centre Hospi- Sucrose Non-Fermentable) chromatin-remodeling multiprotein com- talier Lyon-Sud, Pierre-Benite 69310, France. Phone: 604-675-8000; E-mail: [email protected] plex, which facilitates gene expression and terminal differentiation (12, 13). Disrupting this differentiation process through hyper- Clin Cancer Res 2020;XX:XX–XX trimethylation of H3K27, gain-of-function mutations in EZH2 are doi: 10.1158/1078-0432.CCR-19-3741 reported in 20% of GC B-cell lymphoma, resulting in an aberrant 2020 American Association for Cancer Research. proliferative dependency on EZH2 activity (14–16). In normal lymph

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D1-5, doxorubicine 50 mg/m2 D1, cyclophosphamide 750 mg/m2 Translational Relevance D1, vincristine 1.4 mg/m2 D1) in combination with continuous Diffuse large B cell lymphoma (DLBCL) is the most common tazemetostat at 400 mg, 600 mg, or 800 mg twice a day starting on subtype of non-Hodgkin lymphoma. In patients older than day 2 of R-CHOP cycle 1 (C1) until day 21 of cycle 8. Prevention of 60 years, 30%–40% will present a primary refractory disease to febrile neutropenia was allowed with G-CSF, according to the ASCO the standard of care (R-CHOP) and represent an unmet need. recommendations (18). Valacyclovir and cotrimoxazole prophylaxis EZH2 mutations and loss-of-function abnormalities in the SWI/ were mandatory. Dose adaptation was allowed after the first two SNF complex are both reported in 20% of DLBCL. They induce an cycles (DLT period). A full list of the dose adaptation rules is provided aberrant proliferative dependency on EZH2 and can be targeted by in the Supplementary Appendix. the oral EZH2 inhibitor, tazemetostat. This phase Ib study enrolled patients with newly diagnosed DLBCL with high-risk features (60– Inclusion and exclusion criteria 80 years, high IPI) and evaluated the safety of tazemetostat/R- Eligible patients were aged between 60 and 80 years and had been CHOP combination. Results suggest that the combination is safe diagnosed with an untreated high-risk DLBCL (aaIPI 2-3). Other without increasing toxicity with tazemetostat dosage escalation. eligible criteria wereas follows: ECOG performance status of 0–1, Pharmacokinetics are comparable with R-CHOP and tazemetostat adequate renal function (creatinine clearance > 40 mL/min), bone alone. The recommended phase II dose of tazemetostat in com- marrow function (ANC ≥ 1,500/mm3, platelets ≥ 75,000/mm3, hemo- bination with RCHOP was the same as tazemetostat single agent, globin ≥ 9 g/dL), liver function, left ventricular ejection fraction > 50%. 800 mg. Preliminary efficacy data are encouraging. The combina- Patients were excluded if they presented a central nervous system or tion warrants further exploration in phase II. meningeal involvement, had received prior treatment with any EZH2 inhibitor, any previous lymphoma treatment, or had any conditions that might compromise their safety or the study according to the investigator. A full list of inclusion/exclusion criteria is provided nodes, genetic deletion or pharmacologic inhibition of EZH2 sup- in the Supplementary Appendix. presses GC formation in vivo, suggesting that EZH2 plays a key role in GC differentiation and that its inhibition might be active against Safety assessment DLBCL, even without EZH2-activating mutations (12). For dose-escalation purpose, toxicities assigned as DLTs were Tazemetostat (EPZ-6438) is a potent, oral highly selective oral assessed during C1 and C2 (42 days) to be able to perform pharma- EZH2 inhibitor under clinical investigation. In a first-in-human cokinetic (PK) analysis of R-CHOP component with and without phase I trial, tazemetostat demonstrated favorable safety with tazemetostat (cf below). The DLT set includes all patients having uncommon grade 3 or worse treatment-related adverse-events (AE) signed their informed consent and who completed at least C1 and C2 and one dose-limiting toxicity (DLT) of grade 4 (thrombocytopenia unless the discontinuation reason was a DLT. Consequently, patients at 1,600 mg). Durable objective responses, including complete who did not receive 85% of tazemetostat-planned doses for another responses (CR), were observed in 38% of patients with B-cell NHL. reason than DLT were not evaluable and replaced. On the basis of composite evaluation of AEs, pharmacokinetics, For adverse events (AE) assessment, clinical examinations and pharmacodynamics, and preliminary antitumor activity, the recom- laboratory safety tests were obtained prior to drug administration, mended phase II (RP2D) was determined to be 800 mg twice every week during the first two cycles (and at day 2 and 4 of C1 for daily (17). blood cell counts, BCC), before each cycle of treatment, and up to This phase Ib part of Epi-R-CHOP explored the safety and pre- 28 days after the last study treatment administration. AEs/TEAEs liminary signal of activity of combining tazemetostat with R-CHOP in (treatment emergent AE) type, severity, duration, and seriousness were patients with DLBCL at diagnosis. assessed according to the National Cancer Institute Common Termi- nology Criteria for Adverse Events [NCI-CTCAE] v. 4.03. Laboratory abnormalities were assessed according to the NCI-CTCAE v. 4.03. A Patients and Methods DLT was defined as an AE or clinically significant abnormal laboratory Study design value attributable to tazemetostat or to the combination of tazemeto- We performed a Phase 1b open-label, multicenter, dose- stat and R-CHOP and unrelated to disease progression, intercurrent escalation study of tazemetostat (EPZ-6438) in combination with illness, or concomitant medication. standard doses of intravenous rituximab plus CHOP in elderly After completion of C2 in each cohort, all available safety data were patients with high-risk DLBCL (ClinicalTrials.gov identifier: reviewed by a Safety Review Committee (SRC) and the decision to NCT02889523, Eudract: 2016-001499-31). The study protocol was proceed (or not) to the next dose cohort was made. If 0 of 3, or 1 of approved by the institutional review board and ethics committee 6 patients demonstrated DLT(s), then enrollment proceeded to the at participating institutions in accordance with the International next dose level. If 2 patients in any cohort demonstrated a DLT(s) Conference on Harmonisation guidelines, including good clinical during cycle 1 or 2, enrollment stopped and dose escalation was practice and the ethical principles originating from the Declaration discontinued. The dose would have been reduced to the previously of Helsinki. A written informed consent was obtained from all the completed dose level for which no more than 1 DLT had been included patients. observed. The highest dose level resulting in one or less of 6 patients Patients were recruited in four LYSA centers and enrolled using with DLTs was considered as the MTD/RP2D. 3 þ 3 patients per dose level (starting at 400 mg twice a day) algorithm to identify the MTD and determine RP2D of tazemetostat Preliminary antitumor activity assessment plus R-CHOP. Tumor assessment was performed at baseline, after 4 cycles Patients received up to eight cycles of standard R-CHOP regimen (CT scan) and after cycle 8 by PET-CT according to the Lugano every 21 days (rituximab 375 mg/m2 D1, prednisolone oral 40 mg/m2 classification (19).

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Pharmacokinetic analysis Table 1. Patient characteristics in the full-analysis set. Serial blood samples for PK analysis were collected on C1D1, before any tazemetostat intake, and C2D1, after 1 cycle of tazemetostat, for Full set 400 mg, 600 mg, 800 mg, N ¼ N ¼ N ¼ N ¼ doxorubicin, its major metabolite, doxorubicinol, vincristine, and 17 6 3 8 cyclophosphamide. PK results were compared using the C2/ Sex C1 geometric mean ratio (GMR) and 90% confidence interval (CI) Female/male 11/6 4/2 1/2 6/2 for area under the curve (AUC) and Cmax values after R-CHOP alone Age, years (C1) or R-CHOP plus tazemetostat (C2). PK analysis of tazemetostat Min–max 61–76 63–76 61–75 61–72 was performed at C2D2 and compared with tazemetostat PK as single Median 68 66 73 68 agent (E7438-G000-101). Ann Arbor stage I—II 0 0 0 0 Molecular analysis III 3 0 1 2 IV 14 6 2 6 Nucleic acid extraction was performed on FFPE samples according ENodal site >1 – to standard procedure. Gene expression based cell of origin was Yes 9 (53%) 6 0 3 assessed thanks to RT-MLPA (Reverse Transcription and Multiplex No 8 (47%) 0 3 5 Ligation-dependent Probe Amplification) and sequencing of a panel of LDH > UNL 17 6 3 8 36 genes recurrently mutated in lymphoma (design provided in ECOG PS Supplementary Table), done with an amplicon-based technic as 0–117638 previously published (20, 21). ≥20000 IPI 0–10000 Results 20000 3 8 (47%) 0 3 5 Patient characteristics (Table 1) 4–5 9 (53%) 6 0 3 Seventeen patients, enrolled between October 2016 and March aaIPI 2018, received at least one dose of tazemetostat R-CHOP (full- 00000 analysis set). Initial characteristics of the full-analysis set are described 10000 in Table 1. The median age was 68 years (61–76). The 17 patients had a 2–317638 disseminated disease, 13 (76.5%) with a stage IV, and 9 (53%) with 2 or Bone marrow more extranodal involvement. LDH were higher than the upper Involved 1 1 0 0 normal limit (UNL) in all the cases, and all had an aaIPI score at 2. Noninvolved 12 5 3 4 NA 2 0 0 2 For the 15 cases with available data for RT-MLPA analysis (2 nucleic fi Histology acid extraction failure), 8 were classi ed as GC-DLBCL NOS, 5 as DLBCL 15 (88%) 5 3 7 fi þ ABC-DLBCL NOS, 1 as unclassi ed DLBCL NOS, and 1 as EBV Transformed FL 2 (12%) 1 0 1 DLBCL Abbreviations: NA, not available; PS, performance status; ENodal, extra-nodal; Dose escalation and DLT assessment (C1-C2) FL, follicular lymphoma. Toxicities assigned as DLT were assessed during C1 and C2. Two patients (800 mg cohort) were not evaluable for DLT and replaced (1 noncompliance and 1 lymphoma-related hepatic cholestasis) leading 23%), followed by neurologic AE (N ¼ 6, 35%), infectious (N ¼ 6, to a DLT set of 15 patients. One patient on cohort 1 (400 mg twice a 35%), weight loss (N ¼ 5, 29%), musculoskeletal pain (N ¼ 4, 23%), day) experienced a DLT during C1 (grade 3 constipation). No DLT was fatigue (N ¼ 4, 23%), headache (N ¼ 4, 23%) and anxiety, chest pain, observed on cohort 2 (600 mg twice a day). Another DLT was observed cholestasis, hypokalemia, mucositis (N ¼ 2, 12% each)]. Most of these on cohort 3 (800 mg twice a day): a grade 5 pneumocystis jirovecii (PJ) AEs were of grade 1 or 2. Grade 3 or more toxicities observed ≥ 10% of in a context of documented influenza during cycle 1. This patient was a the patients were constipation, (N ¼ 4, 24%), nausea (N ¼ 2, 12%), and 67-year-old woman with a medical history of bronchial dilatation and hypokalemia (N ¼ 2, 12%). Hematologic AEs occurring in ≥10% of the tuberculosis sequela. The patient had a high tumor burden with a large patients were as follows: neutropenia (N ¼ 8, 47%), anemia (N ¼ 7, mass in the cervical area (>10 cm) responsible of an upper respiratory 41%), leukopenia (N ¼ 7, 41%), and thrombocytopenia (N ¼ 2, tract compression. During cycle 1, she presented with a neutropenia 12%; Table 3). Grade 3 to 4 hematologic AEs were recorded in 8 (grade 3, starting D7) that resolved at D11. She was admitted on D14 to patients (47%): neutropenia (N ¼ 8, 47%), leukopenia (N ¼ 5, 29%), intensive care unit (ICU) due to grade 4 respiratory distress on a anemia (N ¼ 3, 18%), and thrombocytopenia (N ¼ 2, 12%). pneumopathy. The final diagnosis of influenzae and PJ was then No organ-oriented toxicity increased with tazemetostat dosage performed. Despite respiratory assistance and adapted PJ treatment, escalation (severity or incidence). More particularly, only two grade the patient died in ICU on D39. No other DLT was observed in the next 3–5 infectious AEs occurred including one febrile neutropenia. three consecutive patients treated at the highest planned dose (800 mg twice a day), which was considered as the RP2D. AEs during C3 to C8 (Fig. 2A and B) During the DLT period, two other SAEs were reported: 1 grade 3 Fourteen patients were treated after the DLT period. When com- febrile neutropenia and 1 grade 3 hypokalemia. pared with C1-C2, the incidence of hematologic AEs during C3-C8 was Nonhematologic AEs occurring in ≥10% of the 17 patients are stable with neutropenia, anemia, and thrombocytopenia reported in represented in Fig. 1A and Table 2. Gastrointestinal toxicities were the 42.9%, 50%, and 21.4% of the 14 patients, respectively. Grade 3þ most recurrent [constipation (N ¼ 10, 59%), nausea (N ¼ 10, 59%), hematologic AEs, reported by more than 10% of the patients, were vomiting (N ¼ 9, 53%), abdominal pain (N ¼ 5, 29%), diarrhea (N ¼ 4, leukopenia and neutropenia (28.6%) and thrombocytopenia (21.4%).

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Figure 1. A, Nonhematologic AEs reported by more than 10% of the patients, during cycles 1 and 2, and all grade 3þ AEs. Frequency: number of patients presenting with the AE/ number of patients included in the safety set (N ¼ 17). B, Hematologic AEs reported by more than 10% of the patients, during cycle 1 and 2, and all grade 3þ hematologic AEs. Frequency: number of patients presenting with the AE/number of patients included in the safety set (N ¼ 17).

Incidence of grade 3 thrombocytopenia was higher but did not R-CHOP and tazemetostat administration necessitate platelet transfusion. No febrile neutropenia was observed. R-CHOP relative dose intensity (Table 4) No grade 3 or more nonhematologic AE occurred in more than 10% of R-CHOP relative dose intensity (RDI) was calculated as the ratio the patients. One patient presented with two SAEs after the DLT between the total dose received by the patient and the planned period: one acute pyelonephritis with staphylococci bacteremia with a dose for each started cycle. The results are presented in Table 4 grade 1 renal failure and a postlumbar puncture syndrome. and shows that the mean administration dosage for each R-CHOP In conclusion, no serious organ-oriented toxicity was observed after component, except vincristine, was close to 100%. Indeed, 94%, the DLT period. 100%, and 100% of the patients received more than 90% of the

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Table 2. Nonhematologic AEs during DLT period.

Nonhematologic AE Safety set, N ¼ 17 400 mg, N ¼ 6 600 mg, N ¼ 3 800 mg, N ¼ 8 Grade All 33All 33All 33All 33

Constipation 10 (59%) 4 (24%) 3 (50%) 2 (33%) 2 (67%) 1 (33%) 5 (63%) 1 (13%) Nausea 10 (59%) 2 (12%) 4 (67%) 2 (33%) 2 (67%) 0 (0%) 4 (50%) 0 (0%) Vomiting 9 (53%) 1 (6%) 4 (67%) 1 (17%) 2 (67%) 0 (0%) 3 (38%) 0 (0%) Neurologic toxicity 6 (35%) 0 (0%) 3 (50%) 0 (0%) 2 (67%) 0 (0%) 1 (13%) 0 (0%) Infection 6 (35%) 1 (6%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 4 (50%) 1 (13%) Abdominal pain 5 (29%) 0 (0%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 3 (38%) 0 (0%) Weight decreased 5 (29%) 0 (0%) 2 (33%) 0 (0%) 2 (67%) 0 (0%) 1 (13%) 0 (0%) Muscle pain 4 (24%) 0 (0%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 2 (25%) 0 (0%) Diarrhea 4 (24%) 0 (0%) 2 (33%) 0 (0%) 1 (33%) 0 (0%) 1 (13%) 0 (0%) Asthenia 4 (24%) 1 (6%) 2 (33%) 0 (0%) 0 (0%) 0 (0%) 2 (25%) 1 (13%) Headache 4 (24%) 0 (0%) 2 (33%) 0 (0%) 0 (0%) 0 (0%) 2 (25%) 0 (0%) Anxiety 2 (12%) 0 (0%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 0 (0%) 0 (0%) Chest pain 2 (12%) 0 (0%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (13%) 0 (0%) Cholestase 2 (12%) 1 (6%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 1 (13%) 1 (13%) Hypokalemia 2 (12%) 2 (12%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 2 (25%) 2 (25%) Mucositis 2 (12%) 0 (0%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 0 (0%) 0 (0%)

Note: Neurologic AEs refer to postlumbar puncture syndrome (N ¼ 1 patient, 1 AE), dysgeusia (N ¼ 2 patients, 3 AEs), neuralgia (N ¼ 1 patient, 1 AE), peripheral neuropathy (N ¼ 3 patients, 3 AEs). Among the eight neurologic AEs, one was considered as related to tazemetostat (dysgeusia), one to both tazemetostat and R-CHOP (peripheral neuropathy), and six to R-CHOP. Are presented AE that occurred during the DLT period (C1 and C2) in 10% or more of the patients and all grade 3–5 events. expected dosage of rituximab, doxorubicine, and cyclophospha- For the full-analysis set, the average total missing daily dose of mide, respectively. However, significant reduction of vincristine tazemetostat per patient (17 patients) was 9.4 (1–28, 25) and 13 dosage (i.e., 50% of dose reduction) was necessary in 7 patients patients had a temporary interruption with at least one caused by an (41%, due to peripheral neuropathy and/or constipation) that AE in 7 (total missing dose 11.8 in average), whereas oversight was the received less than 75% of the expected dosage. only reason in 6 patients (total missing dose 7.8 in average). AEs The duration between D1 of each cycle was stable throughout the leading to treatment-temporary interruption all recovered. treatment and between the three cohorts (mean time between C1 and C2 was 21.4 days versus 22.8 (range 19–24) days between C7 and C8 Pharmacokinetic analysis (range 21–28). Plasma concentration–time profiles of doxorubicin, doxorubicinol, cyclophosphamide, and vincristine are presented in Supple- Tazemetostat RDI after the DLT period (cycle 1 and 2) mentary Fig. S1. Tazemetostat had no significant impact on During the DLT period (C1 and C2), 2 patients in the 800 mg doxorubicin and doxorubicinol AUC; and although Cmax of doxo- cohort received less than 85% of the expected dose due to reasons rubicin was lower after administration with 800 mg tazemetostat not related to AE (noncompliance and lymphoma-related chole- relative to administration without tazemetostat (GMR 0.68; 90%CI, – stasis) and were replaced, another patient had a grade 5 infectious 0.47 0.99), Cmax of its metabolite, doxorubicinol, was similar DLT. The C1-C2 RDI was greater than 90% for the remaining (GMR 0.928; 90%CI, 0.691–1.25), suggesting no significant effect patients. on the metabolism of the drug. Cyclophosphamide AUC was Fourteen patients were treated after the DLT period: 1 stopped similar in the 400 mg cohort (GMR 1.05; 90%CI, 0.87–1.26) and tazemetostat at C4 (investigator decision) and 13 received 8 cycles slightly lower in the 800 mg cohort (GMR 0.83; 90%CI, 0.77–0.9) of tazemetostat-R-CHOP. For the C3 to C8 cycles, the median with a similar Cmax (GMR 0.89; 90%CI, 0.74–1.07). Importantly, tazemetostat RDI remained greater than 90%, except at C7 for the we did not observe any increase in hematologic toxicities asso- 400 mg cohort (median RDI 69%), and no significant reduction ciated with these slight decreases in AUC, suggesting no meaningful in mean dosage administration could be observed within dose impact. At 800 mg, AUC (3,590 vs. 3,340 ng h/mL) and Cmax (782 vs. escalation for the treated patients. 829 ng/mL) of tazemetostat were similar compared with single-agent

Table 3. Hematologic AEs during DLT period.

Hematologic AE Safety set, N ¼ 17 400 mg, N ¼ 6 600 mg, N ¼ 3 800 mg, N ¼ 8 Grade All 33All33All 33All 33

Neutropenia 8 (47%) 8 (47%) 4 (67%) 4 (67%) 1 (33%) 1 (33%) 3 (38%) 3 (38%) Anemia 7 (41%) 3 (17%) 4 (67%) 3 (50%) 2 (67%) 0 (0%) 1 (13%) 0 (0%) Leukopenia 7 (41%) 5 (29%) 4 (67%) 3 (50%) 1 (33%) 0 (0%) 2 (25%) 2 (25%) Thrombocytopenia 2 (12%) 2 (12%) 2 (33%) 2 (33%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Note: Are presented AE that occurred during the DLT period C1 and C2 in 10% or more of patients and all grade 3–5 events.

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Figure 2. A, Nonhematologic AEs reported by more than 10% of the patients, during cycle 3 to 8, and all grade 3þ AEs. Frequency: number of patients presenting with the AE/ number of patients treated after C3 (N ¼ 14). B, Hematologic AEs reported by more than 10% of the patients, during cycle 3 and 8, and all grade 3þ AEs. Frequency: number of patients presenting with the AE/number of patients treated after C3 (N ¼ 14)

study (E7438-G000–101). Plasma vincristine concentrations were not reasons other than AE or progression (noncompliance and lympho- adequate to calculate reliable PK parameters in all subjects, given that ma-related cholestasis), and were considered as nonresponders, and 13 vincristine was the last component administered. However, there completed the 8 cycles of treatment and reached a metabolic CR (mCR, appeared to be no effect of tazemetostat administration on vin- Lugano criteria). Therefore, the mCR rate was 76.5% (13/17). During cristine concentrations (see Supplementary Fig. S1). These data suggest follow-up, 2 patients presented with a relapse. One early relapse was no signiﬁcant drug–drug interaction between doxorubicin, cyclophos- salvaged by R-ICE regimen followed by an autologous stem cell phamide, vincristine, and tazemetostat. transplant and reached second CR. One late relapse is under salvage treatment (R-DHAOX). Eleven patients remain in CR (CR duration 2– Preliminary antitumor activity data (Fig. 3) 14 months). At the time of analysis, the median follow-up was 20.6 months, 14.5 months, and 7.5 months in the 400, 600, and 800 mg cohort, Molecular analysis respectively. Out of the 17 included, one died at cycle 1 (AE), one DNA and RNA were successfully extracted for 15 patients. The discontinued the treatment due to investigator decision, and two for most recurrently mutated genes were CREBBP (N ¼ 8 cases); BCL2,

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Table 4. Relative dose administration.

RDI 400a, N ¼ 6 600, N ¼ 3800b, N ¼ 8 Total, N ¼ 17

Prednisone >90% 5 (83%) 3 (100%) 8 (100%) 16 (94.1%) Mean 99.6% (SD 8.9%) 100.7% (SD 4.8%) 101.9% (SD 8.2%) 100.9% (SD 7.6%) Rituximab >90% 5 (83%) 3 (100%) 8 (100%) 16 (94.1%) Mean 95.6% (SD 10.8%) 98.1% (SD 2.5%) 100.5% (SD 5.6%) 98.3% (SD 7.5%) Vincristine <75% 1 (17%) 2 (66.7%) 4 (50%) 7 (41.2%) 75%–90% 1 (17%) 1 (33%) 0 (0%) 2 (12%) >90% 4 (66.7%) 0 (0%) 4 (50%) 8 (47%) Mean 90.2% (SD 13.6%) 66.7% (SD 15.7%) 78.9% (SD 22.9%) 80.7% (SD 19.8%) Doxorubicine >90% 6 (100%) 3 (100%) 8 (100%) 17 (100%) Mean 100.3% (SD 3.1%) 98.3% (SD 3.6%) 101.8% (SD 7.4%) 100.6% (SD 5.5%) Cyclophosphamide >90% 6 (100%) 3 (100%) 8 (100%) 17 (100%) Mean 100.3% (SD 3.02%) 98.1% (SD 2.2%) 100% (SD 5.5%) 99.8% (SD 4.2%)

Note: R-CHOP component RDI was calculated as the ratio between the total dose received by the patient and the planned dose for each started cycle. aOne patient discontinued the treatment at C3. bThree patients discontinued the treatment at C1.

MYC, and PIM1 (N ¼ 4 cases each); CARD11, EZH2, FOXO1, not result in a high rate of red blood cell transfusion (only 10 TNFRSF14, TP53 (N ¼ 3 cases each; Supplementary Fig. S2). The RBC transfusions for the 110 cycles, including two at diagnosis) and three EZH2-mutated cases had a GCB phenotype in RTMPLA. Among the dose intensity of the R-CHOP backbone was maintained. Finally them, one died at C1 (infection-related death), one was excluded and (Supplementary Table S1) the incidence of cytopenia, and more not evaluable for response (lymphoma-related cholestasis), and one particularly of febrile neutropenia, does not exceed what is reported reached a CR. Among the two relapsing patients, none had an EZH2 in phase Ib trials combining R-CHOP with other targeted therapies mutation and both presented with a TP53 mutation (with PLCG2 and (22–27) in this elderly population. In Epi-R-CHOP, G-CSF prophy- IRF4 for one and MYD88 for the other). laxis might explain the low incidence of febrile neutropenia and severe infectious events. We observed one grade 5 infectious event due to a PJ infection in a context of documented influenzae 10 days Discussion after the treatment initiation in a patient presenting with a background Epi-R-CHOP is the first trial to evaluate the PK and safety of the of pulmonary fibrosis. Although the event was regarded as a DLT, combination of the EZH2 inhibitor tazemetostat, and R-CHOP, in the link with the study drug is very unlikely. The global incidence of elderly patients with previously untreated high-risk DLBCL. This 17.5% of grade 3–5 infections (N ¼ 3), including 11.7% (N ¼ 2) of phase Ib study with a prolonged DLT period of 42 days was unable febrile neutropenia, does not exceed what is reported in the literature to identify a MTD and 800 mg twice a day was considered as the RP2D, for R-CHOP or R-CHOP combination trials. Indeed, in the recent identical to tazemetostat dosage in monotherapy. GOYA trial, 19.2% of the patients presented with a grade 3–5 infectious In this high-risk elderly DLBCL population, 1 patient discontinued and 17.5% a grade 3–5 febrile neutropenia. Furthermore, when treated the treatment due to DLT at C1 (grade 5), 1 due to investigator decision with venetoclax, vorinostat, ibrutinib, lenalidomide, bortezomib, at C4 (DLT experienced at C1). Two other patients discontinued the or polatuzumab vedotin plus R-CHOP 33.3%, 38%, 18%, 9.5%, treatment during C1 due to reasons other than DLT (noncompliance 13.5%, and 18% of the patients presented with a febrile neutropenia, and cholestasis related to the lymphoma). respectively (22–27, 29). The most recurrent AEs were cytopenias and gastrointestinal Constipation, nausea, and vomiting were the most frequent non- toxicities. Importantly, the incidence and severity of neutropenia and hematologic AEs in this elderly population (59%, 59%, and 53%, anemia did not increase with time. However, grade 3–4 thrombocy- respectively) with 24% and 12% of grade 3 constipation and nausea, topenia was slightly more frequent during C3-C8 (21.4%) versus respectively. The severity and incidence of constipation seem to be C1-C2 (11.8%), but no platelet transfusion was necessary. The inci- higher when compared with other trials (42% in ibrutinib-RCHOP, dence of neutropenia is in line with other R-CHOP studies such as the 33% in venetoclax RCHOP, 38% in vorinostat-RCHOP, 26% in recent GOYA trial that reported 38.1% of grade 3 to 5 neutropenia (6). polatuzumab-RCHOP) and led to the first DLT (stercoral stasis). In the GOYA trial, 7.5% of the R-CHOP–treated patients presented Consequently, as opposed to the other R-CHOP components, vin- with a grade 3–5 anemia, which is similar to the incidence reported in cristine dosage reduction was applied in few patients. The higher Epi-R-CHOP between C3 and C8 (7%), whereas the incidence during incidence of GI toxicities might, in part, be explained by the study C1-C2 (17.6%, 3 patients) was slightly higher in Epi-R-CHOP. This design that collected AEs every week during C1 and C2 but also by the might, in part, be related to the initial characteristics of the population older age of the patients, as the elderly population is more subject to in EpiRCHOP as 2 of these 3 patients presented with an initial grade 2 constipation with vincristine-based chemotherapy (28). On the basis anemia. Of note, 100% of the patients had a high intermediate or high of PK analysis, there appeared to be no effect of tazemetostat admin- IPI score in Epi-R-CHOP versus 42% in GOYA. Importantly, this did istration on vincristine concentrations to explain the incidence of

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Sarkozy et al.

Figure 3. Swimmer plot representing the follow-up and treatment response for the 17 patients. This swimmer plot shows the quality of response and follow-up for the 17 included patients. On the left part of the plot is indicated the cell-of-origin status as assessed by RTMLPA (GCB: germinal center B or ABC: activated B cell. Of note, 1 case was an RTMLPA failure and was GCB as assessed by Hans algorithm (GCB). One case had a DLBCL with T-cell–rich subtype signature (T_rich), and a non-GCB phenotype based on Hans algorithm. EZH2 mutational status is also displayed on the left side as mutated (MUT) or wild-type (WT). Among the 17 included patients, 13 patients had a ﬁnal response assessment. Among the 4 cases not evaluable for response (early protocol discontinuation), 1 patient died due to treatment-related toxicity (infection), 1 patient stopped the protocol due to investigator decision post AE at C3, 2 patients were excluded at C1 (1 due to noncompliance to the study drug and 1 due to lymphoma-related cholestasis). Abbreviations: CMR, complete metabolic response; PMR, partial metabolic response.

constipation. No significant drug–drug interaction between doxo- patients that completed the 8 cycles of tazemetostat-R-CHOP were rubicin, cyclophosphamide, and tazemetostat was found either. These in mCR). Two relapses were observed in the EZH2 wild-type GI AEs were not reported in tazemetostat single agent (3% of con- population, both presenting with a TP53 mutation. Although stipation, grade 1–2 only; ref. 17). The GI AEs are probably explained exploratory and reflecting only preliminary data, this rate of mCR by the exhaustive weekly collection of the AEs in this elderly popu- is encouraging (Supplementary Table S2) and supports the necessity lation that received 8 cycles of R-CHOP. A reduction to 6 cycles of of a phase II trial. RCHOP, that is, the recently accepted new standard of care in this In conclusion, the phase Ib Epi-R-CHOP study showed that the population (6), should be considered in the phase II part of the trial. combination of R-CHOP plus tazemetostat is generally well tolerated Improvement in concomitant medications and antiemetic prophylac- and the addition of tazemetostat to R-CHOP does not appear to tic measures are clearly warranted in this elderly population treated substantially change the expected R-CHOP toxicities. The MTD was with chemotherapy (28). not reached and the RP2D of tazemetostat combined with R-CHOP is The PK-related risks of the study included the risk that tazemeto- 800 mg twice a day. On the basis of these results, further investigation is stat would induce doxorubicin and cyclophosphamide metabolism to warranted and the expansion phase II Epi-R-CHOP study for 60- to the more active species and increase toxicity. All in all, the data 80-year-old patients with newly diagnosed aaIPI 1 or higher DLBCL presented here indicated that the toxicity of RCHOP was globally not will be enrolling shortly. increased with tazemetostat. The PK analysis of the main R-CHOP drugs suggest a similar metabolism of the anthracycline (with identical Disclosure of Potential Conflicts of Interest doxorubicinol PK in C1 vs. C2) and modest modification regarding F. Morschhauser is a paid advisory board member for Epizyme and Roche, and cyclophosphamide [similar Cmax and lower AUC for at 800 mg (MGR reports receiving speakers bureau honoraria from Roche and Celgene. J. Michot is an 0.83)] that might warrant further investigation. However, the absence unpaid consultant/advisory board member for Celgene, Iqone, Amgen, and Merck. of increase in the hematologic toxicities is reassuring and suggests B. Suttle is an employee of Epizyme. G. Salles is a paid consultant for Epizyme. V. Ribrag reports receiving other commercial research support from Epizyme and Argen-X, and no relevant consequences on cyclophosphamide metabolism when is an unpaid consultant/advisory board member for Infinity, Bristol-Myers Squibb, combined with tazemetostat. Furthermore, vincristine is a CYP3A Parmamar, Gilead, Incyte, MSD, Servier, Nanostring, Roche, and Immune Design. No substrate, with a nonactive primary metabolite, and tazemetostat is a potential conflicts of interest were disclosed by the other authors. weak CYP3A inducer (30), suggesting that vincristine drug exposure should not be increased with the association. Authors’ Contributions Preliminary antitumor activity data showed an mCR rate of Conception and design: C. Sarkozy, B. Suttle, G. Salles, V. Ribrag 76.5% (13/17 of the included patients, and all the 13 evaluable Development of methodology: C. Sarkozy, S. Dubois, F. Jardin, G. Salles, V. Ribrag

OF8 Clin Cancer Res; 2020 CLINICAL CANCER RESEARCH

Phase Ib Study of Tazemetostat Plus R-CHOP in DLBCL

Acquisition of data (provided animals, acquired and managed patients, provided investigators and centers for including patients; The LYSA-P and Nadine facilities, etc.): C. Sarkozy, F. Morschhauser, T. Molina, J.-M. Michot, P. Cullieres- Vailhen for managing the central review and biological studies; Elodie Bohers Dartigues, L. Karlin, S. Le Gouill, J.-M. Picquenot, R. Dubois, H. Tilly, C. Herbaux, (NGS), Pascaline Etancelin (banking), and Pierre Julien Viailly (bioinfo) from F. Jardin, G. Salles, V. Ribrag the U1245 Centre H.Bequerel for the sequencing analysis. This study was Analysis and interpretation of data (e.g., statistical analysis, biostatistics, funded by Epizyme and sponsored by the LYSARC (The Lymphoma Academic computational analysis): C. Sarkozy, F. Morschhauser, J.-M. Michot, B. Suttle, Research Organisation). H. Tilly, F. Jardin, G. Salles, V. Ribrag Writing, review, and/or revision of the manuscript: C. Sarkozy, F. Morschhauser, S. Dubois, T. Molina, J.-M. Michot, B. Suttle, S. Le Gouill, F. Jardin, G. Salles, V. Ribrag The costs of publication of this article were defrayed in part by the Administrative, technical, or material support (i.e., reporting or organizing payment of page charges. This article must therefore be hereby marked data, constructing databases): G. Salles advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate Study supervision: C. Sarkozy, V. Ribrag this fact.

Acknowledgments The authors thank the patients and their families. The authors thank Received November 14, 2019; revised January 16, 2020; accepted February 25, 2020; LYSARC and Alexia Schwartzmann for managing the study; all the LYSA published ﬁrst March 2, 2020.

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AACRJournals.org Clin Cancer Res; 2020 OF9

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

Clémentine Sarkozy, Franck Morschhauser, Sydney Dubois, et al.

Clin Cancer Res Published OnlineFirst March 2, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-19-3741

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