a lysa phase ib study of tazemetostat (epz-6438) …...epi-r-chop 1 a lysa phase ib study of...

Epi-R-CHOP

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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 Clémentine Sarkozy1, Franck Morschhauser2, Sydney Dubois3, Thierry Molina4, Jean Marie Michot5,

Peggy Cullières-Dartigues6, Benjamin Suttle7, Lionel Karlin8, Steven Le Gouill9, Jean-Michel Picquenot10, Romain Dubois11, Hervé Tilly3, Charles Herbaux2, Fabrice Jardin3, Gilles Salles1,8, and

Vincent Ribrag5

1- INSERM 1052, Charles Mérieux Lyon-1 Faculty, Claude Bernard University, Lyon, France; 2- Department of

Haematology, U1245 Centre Hospitalier RU de Lille, France; 3- Department of Haematology, U918 Centre Henri

Becquerel, Rouen, France; 4- Pathology Department, Necker Enfants Malades Hospital, Université Paris, APHP,

France; 5- Department of Haematology, Gustave Roussy, Université Paris-Saclay, INSERM U1170, Villejuif,

France; 6- Department of Pathology, Gustave Roussy, Université Paris-Saclay, INSERM U1170, Villejuif, France;

7- qPharmetra, Raleigh, NC USA.; 8- Department of Haematology, Hospices Civils de Lyon, Centre Hospitalier

Lyon-Sud, Pierre Bénite cedex; 9- Department of Haematology, CHU Nantes, France; 10- Department of

Pathology, U918 Centre Henri Becquerel, Rouen, France; 11- Department of Pathology, Centre Hospitalier RU

de Lille, France

Running title: Phase Ib Study of tazemetostat plus R-CHOP in DLBCL

Corresponding author: Dr V. Ribrag : [email protected], Institut Gustave Roussy, 114 Rue Edouard Vaillant 94800, Villejuif, France Body of the manuscript: 3734 Table: 4, Figure: 3 References: 31 Authors individual contributions: CS and VR designed the clinical trial and wrote the manuscript. TM, JMP, PD and RD performed central pathology review. BS performed pharmacokinetics analysis. FM, SD, LK, SLG, HT, CH, FJ, GS, CS and VR included patients in the study. All the authors reviewed the manuscript. Conflict of interest:

Charles Herbaux: Honoraria Abbvie, Janssen, Gilead, Takeda, Roche.

Gilles Salles has received financial compensations for participating to advisory boards or

consulting from :Abbvie, Autolus, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck,

Morphosys, Novartis, Roche, Servier, Takeda. For participation du educational events from :

Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Servier, Takeda.

Jean-Marie Michot: PERSONAL FEES (Monies paid to you for services rendered, generally honoraria,

royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-

boards, etc.): Celgene, Bristol-Myers Squibb, AstraZeneca, Janssen. NON-FINANCIAL SUPPORT (Drugs,

equipment supplied by the entity, travel paid by the entity, writing assistance, administrative

support, etc.): AstraZeneca, Roche, Novartis, Gilead, Celgene, Bristol-Myers Squibb.

Vincent Ribrag: Personal financial interests: Honoraria from Infinity Pharmaceuticals, BMS, Eisai,

PharmaMar, Gilead Sciences ; Consulting/Advisory Role for Infinity Pharmaceuticals, BMS,

Research. on April 12, 2020. © 2020 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 2, 2020; DOI: 10.1158/1078-0432.CCR-19-3741

http://clincancerres.aacrjournals.org/

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PharmaMar, Gilead Sciences, NanoString Technologies, Incyte, BMS, MSD, Roche/Genentech,

Epizyme, AZ, immune design. Research Funding from arGEN-X BVBA ; Patents, Royalties, Other

Intellectual Property regarding BAY1000394 studies on MCL ; Expert testimony for Servier ; Travel,

Accommodations, Expenses from Roche, BMS, AZ.

Fabrice Jardin: Personnal fees : Amgen, Celgene, Roche, Servier, Pfizer. Grants for research : Roche

Foundation, Celgene.

Franck Morschhauser: Consultancy: Roche/Genentech, Celgene, epizyme. Adboard: Roche, Gilead,

Celgene, BMS,Novartis. Scientific lectures: roche, Celgene, Janssen Funding: This study was funded by Epizyme and sponsored by the LYSARC (The Lymphoma Academic

Research Organisation).




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Translational relevance (149 w):

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. In

patients older than 60 years, 30-40% will present a primary refractory disease to the standard of care

(R-CHOP) and represent an unmet need. EZH2 mutations and loss-of-function abnormalities in the

SWI/SNF complex are both reported in 20% of DLBCL. They induce an aberrant proliferative

dependency on EZH2 and can be targeted by the oral EZH2 inhibitor, tazemetostat. This phase Ib

study enrolled newly diagnosed DLBCL patients with high risk features (60-80y, high IPI) and

evaluated the safety of tazemetostat/R-CHOP combination. Results suggest that the combination is

safe without increasing toxicity with tazemetostat dosage escalation. Pharmacokinetics are

comparable to R-CHOP and tazemetostat alone. The recommended phase 2 dose of tazemetostat in

combination with RCHOP was the same as tazemetostat single agent, 800mg. Preliminary efficacy

data are encouraging. The combination warrants further exploration in phase II.




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Abstract (245 w) Background: 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. Methods: 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.

Findings: 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). Interpretation: 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.

Key words: diffuse large B cell lymphoma, EZH2, phase I




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Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL)

accounting for about 30% of all lymphoid neoplasms. The incidence increases with age, around 50%

of the patients being older than 60 years and almost one third over 75 years[1]. Importantly, despite

their age, the vast majority of these patients are eligible and treated with the standard of care

immunochemotherapy regimen, namely R-CHOP (rituximab (R) in association with prednisolone,

doxorubicin, cyclophosphamide, and vincristine (CHOP))[1, 2]. Age-adjusted IPI (aaIPI), a derivative of

the IPI score based on LDH, stage and ECOG performance status, can stratify the patients at diagnosis

and predicts outcome[3]. In patients older than 60 years, DLBCL can be cured in 50 to 60% of the

cases following first line R-CHOP[4-6] and 30 to 40% will present a R-CHOP primary refractory or an

early relapse disease[7, 8]. Those “poor responders” to R-CHOP have a 1-year overall survival (OS) of

less than 20% and still represent a group of patients with a clear unmet medical need[7]. Among all

DLBCL, elderly patients with a high aaIPI represent the most challenging population with the higher

primary refractory rate leading to poor OS[5, 9].

Epigenetic modulation of histones plays a critical role in oncogenic transformation in many

malignancies and is now an area of intense clinical research[10]. Next generation sequencing of B-cell

NHL genomes has uncovered frequent mutations affecting histone-modifying proteins especially in

lymphomas derived from the germinal center [11]. One of them, EZH2, is the catalytic subunit of the

chromatin remodeling polycomb repressive complex 2 (PRC2), and the only human protein

methyltransferase that can methylate histone 3 lysine 27 (H3K27) leading to the transcriptional

repressive mark H3K27me3. During hematopoiesis, EZH2 plays an important role where it represses

genes involved in cell cycle arrest and terminal differentiation. Later during germinal center (GC)

formation, EZH2 activity becomes increasingly opposed by the SWI/SNF (Switch/Sucrose Non-

Fermentable) chromatin-remodelling multiprotein complex, which facilitate gene expression and

terminal differentiation [12, 13]. Disrupting this differentiation process through hyper-trimethylation

of H3K27, gain of function mutations in EZH2 are reported in 20% of GC B cell lymphoma, resulting in

an aberrant proliferative dependency on EZH2 activity[14-16]. In normal lymph nodes, genetic

deletion or pharmacological inhibition of EZH2 suppresses GC formation in vivo, suggesting that EZH2

plays a key role in GC differentiation and that its inhibition might be active against DLBCL, even

without EZH2 activating mutations[12].

Tazemetostat (EPZ-6438) is a potent, oral highly selective oral EZH2 inhibitor under clinical

investigation. In a first in human phase I trial, tazemetostat demonstrated favorable safety with

uncommon grade 3 or worse treatment-related adverse-events (AE) and one dose-limiting toxicity

(DLT) of grade 4 (thrombocytopenia at 1600mg). Durable objective responses, including complete




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responses (CR), were observed in 38% of patients with B-cell NHL. Based on composite evaluation of

AEs, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity, the recommended

phase 2 (RP2D) was determined to be 800 mg twice daily [17].

This phase Ib part of Epi-R-CHOP explored the safety and preliminary signal of activity of combining

Tazemetostat with R-CHOP in patients with DLBCL at diagnosis.

Material and methods

o Study design

We performed a Phase 1b open label, multi-center, dose escalation study of tazemetostat (EPZ-6438)

in combination with standard doses of intravenous rituximab plus CHOP in high risk elderly DLBCL

patients (ClinicalTrials.gov identifier: NCT02889523, Eudract : 2016-001499-31). The study protocol

was approved by the institutional review board and ethics committee at participating institutions in

accordance with the International Conference on Harmonisation guidelines, including good clinical

practice and the ethical principles originating from the Declaration of Helsinki. A written informed

consent was obtained from all the included patients.

Patients were recruited in 4 LYSA centers and enrolled using 3+3 patients per dose level (starting at

400mg BID) algorithm to identify the MTD and determine RP2D of tazemetostat plus R-CHOP.

Patients received up to 8 cycles of standard R-CHOP regimen every 21 days (rituximab 375 mg/m2

D1, prednisolone oral 40 mg/m2 D1-5, doxorubicine 50 mg/m2 D1, cyclophosphamide 750 mg/m2

D1, vincristine 1.4 mg/m2 D1) in combination with continuous tazemetostat at 400 mg, 600 mg, or

800 mg BID starting on day 2 of R-CHOP cycle 1 (C1) until day 21 of cycle 8. Prevention of febrile

neutropenia was allowed with G-CSF, according to the ASCO recommendations[18]. Valacyclovir and

cotrimoxazole prophylaxis were mandatory. Dose adaptation was allowed after the first 2 cycles

(DLT period). A full list of the dose adaptation rules is provided in the supplemental appendix.

o Inclusion and exclusion criteria

Eligible patients were aged between 60 and 80 years and had been diagnosed with an untreated high

risk DLBCL (aaIPI 2-3). Other eligible criteria were: ECOG performance status of 0-1, adequate renal

function (creatinine clearance > 40mL/min), bone marrow function (ANC ≥ 1,500/mm3, platelets ≥

75,000/mm3, hemoglobin ≥ 9g/dL), liver function, left ventricular ejection fraction > 50%. Patients

were excluded if they presented a central nervous system or 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 in the supplemental Appendix.

o Safety assessment




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For dose escalation purpose, toxicities assigned as dose-limiting toxicity (DLTs) were assessed during

C1 and C2 (42 days) to be able to perform pharmacokinetic (PK) analysis of R-CHOP component with

and without tazemetostat (cf bellow). The DLT set includes all patients having signed their informed

consent and who completed at least C1 and C2 unless the discontinuation reason was a DLT.

Consequently, patients who did not receive 85% of tazemetostat-planned doses for another reason

than DLT were not evaluable and replaced.

For adverse events (AE) assessment, clinical examinations and laboratory safety tests were obtained

prior to drug administration, every week during the 2 first cycles (and at day 2 and 4 of C1 for blood

cell counts, BCC), before each cycle of treatment, and up to 28 days after the last study treatment

administration. AEs/TEAEs (treatment emergent AE) type, severity, duration and seriousness were

assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events

[NCI-CTCAE] v. 4.03. Laboratory abnormalities were assessed according to the NCI-CTCAE v. 4.03. A

DLT was defined as an AE or clinically significant abnormal laboratory value attributable to

tazemetostat or to the combination of tazemetostat and R-CHOP and unrelated to disease

progression, intercurrent illness or concomitant medication.

After completion of C2 in each cohort, all available safety data were reviewed by a Safety Review

Committee (SRC) and the decision to proceed (or not) to the next dose cohort was made. If 0 out of

3, or 1 out of 6 patients demonstrated DLT(s), then enrollment proceeded to the next dose level. If 2

patients in any cohort demonstrated a DLT(s) during cycle 1 or 2, enrollment stopped and dose

escalation was discontinued. The dose would have been reduced to the previously completed dose

level for which no more than 1 DLT had been observed. The highest dose level resulting in one or

less of six patients with DLTs was considered as the MTD/RP2D.

o Preliminary anti-tumor activity assessment

Tumor assessment was performed at baseline, after 4 cycles (CT scan) and after cycle 8 by PET-CT

according to the Lugano classification[19].

o Pharmacokinetic analysis

Serial blood samples for PK analysis were collected on C1D1, before any tazemetostat intake, and

C2D1, after 1 cycle of tazemetostat, for doxorubicin (DOX), its major metabolite, doxorubicinol

(DOXol), vincristine and cyclophosphamide (CP). PK results were compared using the C2/C1

geometric mean ratio (GMR) and 90% confidence interval (CI) for area under the curve (AUC) and

Cmax values after R-CHOP alone (C1) or R-CHOP plus tazemetostat (C2). PK analysis of tazemetostat

was performed at C2D2 and compared to tazemetostat PK as single agent (E7438-G000-101).

o Molecular analysis




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Nucleic acid extraction was performed on FFPE samples according to standard procedure. Gene

expression-based Cell of origin was assessed thanks to RT-MLPA (Reverse Transcription and

Multiplex Ligation-dependent Probe Amplification) and sequencing of a panel of 36 genes

recurrently mutated in lymphoma (design provided in supplementary table), done with an amplicon-

based technic as previously published [20, 21].

Results

o Patient characteristics (table 1)

Seventeen patients, enrolled between October 2016 and March 2018, received at least one dose of

tazemetostat R-CHOP (full analysis set). Initial characteristics of the full analysis set are described in

table 1. The median age was 68 years (61-76). The 17 patients had a disseminated disease, 13

(76.5%) with a stage IV and 9 (53%) with 2 or more extra-nodal involvement. LDH were higher than

the upper normal limit (UNL) in all the cases, and all had an aaIPI score at 2. For the 15 cases with

available data for RT-MLPA analysis (2 nucleic acid extraction failure), 8 were classified as GC-DLBCL

NOS , 5 as ABC-DLBCL NOS , 1 as unclassified DLBCL NOS and 1 as EBV + DLBCL

o Dose escalation and DLT assessment (C1-C2):

Toxicities assigned as DLT were assessed during C1 and C2. Two patients (800mg cohort) were not

evaluable for DLT and replaced (1 non-compliance and 1 lymphoma related hepatic cholestasis)

leading to a DLT set of 15 patients. One patient on cohort 1 (400 mg BID) experienced a DLT during

C1 (grade 3 constipation). No DLT was observed on cohort 2 (600mg BID). Another DLT was observed

on cohort 3 (800mg BID): a grade 5 pneumocystis jirovecii (PJ) in a context of documented influenza

during cycle 1. This patient was a 67 years old women with medical history of bronchial dilatation

and tuberculosis sequela. The patient had a high tumor burden with a large mass in the cervical area

(>10cm) responsible of an upper respiratory tract compression. During cycle 1, she presented a

neutropenia (grade 3, starting D7) that resolved at D11. She was admitted on D14 to intensive care

unit (ICU) due to grade 4 respiratory distress on a pneumopathy. The final diagnosis of influenzae

and PJ was then performed. Despite respiratory assistance and adapted PJ treatment, the patient

died in ICU on D39. No other DLT was observed in the next 3 consecutive patients treated at the

highest planned dose (800 mg BID), which was considered as the RP2D.

During the DLT period, 2 other SAEs were reported: 1 grade 3 febrile neutropenia and 1 grade 3

hypokalemia.

Non-hematologic AE occurring in >10% of the 17 patients are represented in figure 1A and table 2.

Gastro-intestinal toxicities were the most recurrent (constipation (N=10, 59%), nausea (N=10, 59%),

vomiting (N=9, 53%), abdominal pain (N=5, 29%), diarrhea (N=4, 23%)), followed by neurological AE

(N=6, 35%), infectious (N=6, 35%), weight loss (N=5, 29%), musculo-skeletal pain (N=4, 23%), fatigue




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(N=4, 23%), headache (N=4, 23%) and anxiety, chest pain, cholestasis, hypokalaemia, mucositis (N=2,

12% each)). Most of these AE were of grade 1 or 2. Grade 3 or more toxicities observed >10% of the

patients were constipation, (N=4, 24%), nausea (N=2, 12%) and hypokalemia (N=2, 12%).

Hematologic AE occurring in >10% of the patients were: neutropenia (N=8, 47%), anemia (N=7, 41%),

leukopenia (N=7, 41%) and thrombocytopenia (N=2, 12%) (Table 3). Grade 3 to 4 hematologic AE

were recorded in 8 patients (47%): neutropenia (N=8, 47%), leukopenia (N=5, 29%), anemia (N=3,

18%) and thrombocytopenia (N=2, 12%).

No organ-oriented toxicity increased with tazemetostat dosage escalation (severity or incidence).

More particularly, only 2 grade 3-5 infectious AE occurred including 1 febrile neutropenia.

o AE during C3 to C8 (figure 2A and 2B):

Fourteen patients were treated after the DLT period. When compared with C1-C2, the incidence of

hematologic AE during C3-C8 was stable with neutropenia, anemia and thrombocytopenia reported

in 42.9%, 50% and 21.4% of the 14 patients respectively. Grade 3+ hematologic AE reported by more

than 10% of the patients were leukopenia and neutropenia (28.6%) and thrombocytopenia (21.4%).

Incidence of grade 3 thrombocytopenia was higher but did not necessitate platelet transfusion. No

febrile neutropenia was observed. No grade 3 or more non-hematologic AE occurred in more than

10% of the patients. One patient presented with 2 SAEs after the DLT period: one acute

pyelonephritis with staphylococci bacteremia with a grade 1 renal failure and a post lumbar puncture

syndrome.

In conclusion, no serious organ-oriented toxicity was observed after the DLT period.

o R-CHOP and Tazemetostat administration

R-CHOP relative dose intensity (RDI) (table 4)

R-CHOP RDI was calculated as the ratio between the total dose received by the patient and the

planned dose for each started cycle. The results are presented in table 4 and shows that the mean

administration dosage for each R-CHOP component, except vincristine, was close to 100%. Indeed,

94%, 100% and 100% of the patients received more than 90% of the expected dosage of rituximab,

doxorubicine and cyclophosphamide respectively. However, significant reduction of vincristine

dosage (i.e 50% of dose reduction) was necessary in 7 patients (41%, due to peripheral neuropathy

and/or constipation) that received less than 75% of the expected dosage.

The duration between D1 of each cycle was stable throughout the treatment and between the 3

cohorts (mean time between C1 and C2 was 21.4 days versus 22.8 (range 19-24) days between C7

and C8 (range 21-28).

Tazemetostat RDI after the DLT period (cycle 1 and 2)

During the DLT period (C1 and C2), 2 patients in the 800 mg cohort received less than 85% of the

expected dose due to reasons not related to AE (non-compliance and lymphoma related cholestasis)




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and were replaced, another patient had a grade 5 infectious DLT. The C1-C2 RDI was greater than

90% for the remaining patients.

Fourteen patients were treated after the DLT period: 1 stopped tazemetostat at C4 (investigator

decision) and 13 received 8 cycles of tazemetostat-R-CHOP. For the C3 to C8 cycles, the median

tazemetostat RDI remained greater than 90%, except at C7 for the 400mg cohort (median RDI 69%)

and no significant reduction in mean dosage administration could be observed within dose escalation

for the treated patients.

For the full analysis set, the average total missing daily dose of tazemetostat per patient (17 patients)

was 9.4 (1-29) and 13 patients had a temporary interruption with at least one caused by an AE in 7

(total missing dose 11.8 in average) whereas oversight was the only reason in 6 patients (total

missing dose 7.8 in average). AE leading to treatment temporary interruption all recovered.

Pharmacokinetic analysis

Plasma concentration-time profiles of DOX, DOXol, CP, and vincristine are presented in

supplementary figure 1. Tazemetostat had no significant impact on DOX and DOXol AUC and

although Cmax of DOX was lower after administration with 800 mg tazemetostat relative to

administration without tazemetostat (GMR 0.68; 90%CI 0,47-0.99), Cmax of its metabolite, DOXol,

was similar (GMR 0.928; 90%CI 0.691, 1.25), suggesting no significant effect on the metabolism of

the drug. 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).

Importantly, we did not observed any increase in haematological toxicities associated with this

slightly decreases in AUC, suggesting no meaningfull impact. At 800 mg, AUC (3590 vs 3340 ng*h/mL)

and Cmax (782 vs 829 ng/mL) of tazemetostat were similar compared to single agent study (E7438-

G000-101). Plasma vincristine concentrations were not adequate to calculate reliable PK parameters

in all subjects, given that vincristine was the last component administred. However, there appeared

to be no effect of tazemetostat administration on vincristine concentrations (see supplementary

figure 1). These data suggest no significant drug-drug interaction between doxorubicin,

cyclophosphamide, vincristine and tazemetostat.

o Preliminary Anti-Tumor Activity Data (figure 3)

At 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 respectively. Out of the 17 included, 1 died at cycle 1 (AE), 1 discontinued

the treatment due to investigator decision and 2 for reasons other than AE or progression (non-

compliance and lymphoma relatd cholestasis), and were considered as non-responder, and 13

completed the 8 cycles of treatment and reached a metabolic CR (mCR, Lugano criteria). Therefore,

the mCR rate was 76.5% (13/17). During follow-up, 2 patients presented a relapse. One early relapse

was salvaged by R-ICE regimen followed by an autologous stem cell transplant and reached second




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CR. One late relapse is under salvage treatment (R-DHAOX). Eleven patients remain in CR (CR

duration 2 to 14 months).

o Molecular Analysis

DNA and RNA were successfully extracted for 15 patients. The most recurrently mutated genes were

CREBBP (N=8 cases), BCL2, MYC and PIM1 (N=4 cases each), CARD11, EZH2, FOXO1, TNFRSF14, TP53

(N=3 cases each) (supplementary figure 2). The 3 EZH2 mutated cases had a GCB phenotype in

RTMPLA. Among them, 1 died at C1 (infectious related death), 1 was excluded and not evaluable for

response (lymphoma related cholestasis) and 1 reached a CR. Among the 2 relapsing patients, none

had an EZH2 mutation and both presented a TP53 mutation (with PLCG2 and IRF4 for one and

MYD88 for the other).

Discussion:

Epi-R-CHOP is the first trial to evaluate the PK and safety of the combination of the EZH2 inhibitor

tazemetostat, and R-CHOP, in previously untreated high-risk elderly DLBCL. This phase Ib study with a

prolonged DLT period of 42 days was unable to identify a MTD and 800 mg BID was considered as the

RP2D, identical to tazemetostat dosage in monotherapy.

In this high-risk elderly DLBCL population, 1 patient discontinued the treatment due to DLT at C1

(grade 5), 1 due to investigator decision at C4 (DLT experienced at C1). Two other patients

discontinued the treatment during C1 due to reasons other than DLT (non-compliance and

cholestasis related to the lymphoma).

The most recurrent AEs were cytopenias and gastro-intestinal toxicities. Importantly, the incidence

and severity of neutropenia and anemia did not increase with time. However, grade 3-4

thrombocytopenia were slightly more frequent during C3 to C8 (21.4%) vs C1-C2 (11.8%), but no

platelet transfusion was necessary. The incidence of neutropenia is in line with other R-CHOP studies

such as the recent GOYA trial that reported 38.1% of grade 3 to 5 neutropenia [6]. In GOYA 7.5% of

the R-CHOP treated patients presented a grade 3-5 anemia, which is similar to the incidence

reported in Epi-R-CHOP between C3-C8 (7%) whereas the incidence during C1-C2 (17.6%, 3 patients)

was slightly higher in Epi-R-CHOP. This might in part be related to the initial characteristic of the

population in EpiRCHOP as 2 of these 3 patients presented an initial grade 2 anemia. Of note, 100%

of the patients had a high-intermediate or high IPI score in Epi-R-CHOP versus 42% in GOYA.

Importantly, this did not result in a high rate of red blood cell transfusion (only 10 RBC transfusions

for the 110 cycles, including 2 at diagnosis) and the dose intensity of the R-CHOP backbone was

maintained. Finally (supplementary table 1) the incidence of cytopenia, and more particularly of

febrile neutropenia, does not exceed what is reported in phase Ib trials combining R-CHOP with

other targeted therapies [22-27] in this elderly population. In Epi-R-CHOP, G-CSF prophylaxis might

explain the low incidence of febrile neutropenia and severe infectious events. We observed one




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grade 5 infectious event due to a PJ infection in a context of documented influenzae 10 days after

the treatment initiation in a patient presenting a background of pulmonary fibrosis. Although the

event was regarded as a DLT, the link with the study drug is very unlikely. The global incidence of

17.5% of grade 3-5 infections (N=3), including 11.7% (N=2) of febrile neutropenia, does not exceed

what is reported in the literature for R-CHOP or R-CHOP combination trials. Indeed, in the recent

GOYA trial, 19.2% of the patients presented a grade 3-5 infectious and 17.5% a grade 3-5 febrile

neutropenia. Furthermore, when treated with venetoclax, vorinostat, ibrutinib, lenalidomide,

bortezomib or polatuzumab vedotin plus R-CHOP 33.3%, 38%, 18%, 9.5%, 13.5% and 18% of the

patients presented a febrile neutropenia respectively [22-27, 30].

Constipation, nausea and vomiting were the most frequent non-hematologic AEs in this elderly

population (59%, 59% and 53% respectively) with 24% and 12% of grade 3 constipation and nausea

respectively. The severity and incidence of constipation seem to be higher when compared with

other trials (42% in ibrutinib-RCHOP, 33% in venetoclax RCHOP, 38% in vorinostat-RCHOP, 26% in

polatuzumab-RCHOP) and led to the first DLT (stercoral stasis). Consequently, as opposed to the

other R-CHOP components, vincristine dosage reduction was applied in few patients. The higher

incidence of GI toxicities might in part be explained by the study design that collected AE every week

during C1 and C2 but also by the older age of the patients, as the elderly population is more subject

to constipation with vincristine-based chemotherapy[28]. Based on PK analysis, there appeared to be

no effect of tazemetostat administration on vincristine concentrations to explain the incidence of

constipation. No significant drug-drug interaction between doxorubicin, cyclophosphamide and

tazemetostat was found either. These GI AE were not reported in tazemetostat single agent (3% of

constipation, grade 1-2 only) [17]. The GI adverse events are probably explained by the exhaustive

weekly collection of the AE in this elderly population that received 8 cycles of R-CHOP. A reduction to

6 cycles of RCHOP, ie the recently accepted new standard of care in this population[6], should be

considered in the phase II part of the trial. Improvement in concomitant medications and anti-emetic

prophylactic measures are clearly warranted in this elderly population treated with chemotherapy

[28].

The PK-related risks of the study included the risk that tazemetostat would induce doxorubicin and

cyclophosphamide metabolism to the more active species and increase toxicity. All in all, the data

presented here indicated that the toxicity of RCHOP was globally not increased with tazemetostat.

The PK analysis of the main R-CHOP drugs suggest a similar metabolism of the anthracycline (with

identical DOXol PK in C1 vs C2) and modest modification regarding cyclophosphamide (similar Cmax

and lower AUC for at 800mg (MGR 0.83)) that might warrant further investigation. However, the

absence of increase in the haematological toxicities are reassuring and suggest no relevant

consequences on cyclophosphamide metabolism when combined with Tazemetostat. Furthermore,




Epi-R-CHOP

13

vincristine is a CYP3A substrate, with a non-active primary metabolite, and tazemetostat is a weak

CYP3A inducer[31], suggesting that vincristine drug exposure should not be increased with the

association.

Preliminary anti-tumor activity data showed a mCR rate of 76.5% (13/17 of the included patients,

and all the 13 evaluable patients that completed the 8 cycles of tazemetostat-R-CHOP were in mCR).

Two relapses were observed in the EZH2 wild type population, both presenting a TP53 mutation.

Although exploratory and reflecting only preliminary data, this rate of mCR is encouraging

(supplementary table 2) and supports the necessity of a phase 2 trial.

In conclusion, the phase Ib Epi-R-CHOP study showed that the combination of R-CHOP plus

tazemetostat is generally well tolerated and the addition of tazemetostat to R-CHOP does not appear

to substantially change the expected R-CHOP toxicities. The MTD was not reached and the RP2D of

tazemetostat combined with R-CHOP is 800 mg BID. Based on these results, further investigation is

warranted and the expansion phase 2 Epi-R-CHOP study for 60-80 years old patients with newly

diagnosed aaIPI 1 or higher DLBCL will be enrolling shortly.




Epi-R-CHOP

14

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Epi-R-CHOP

17

Tables: Table 1: Patient characteristics in the full analysis set.

Full Set N=17 400mg, N=6 600mg, N=3 800mg, N=8

Sex Female/ Male

11 / 6

4 / 2

1 / 2

6 / 2

Age, y Min-Max Median

61-76 68

63-76 66

61-75 73

61-72 68

Ann Arbor Stage I-II III IV

0 3 14

0 0 6

0 1 2

0 2 6

ENodal site >1 Yes No

9 (53%) 8 (47%)

6 0

0 3

3 5

LDH > UNL 17 6 3 8

ECOG PS : 0-1 >=2

17 0

6 0

3 0

8 0

IPI : 0-1 2 3 4-5

0 0 8 (47%) 9 (53%)

0 0 0 6

0 0 3 0

0 0 5 3

aaIPI : 0 1 2-3

0 0 17

0 0 6

0 0 3

0 0 8

Bone Marrow : Involved Non-Involved NA

1 12 2

1 5 0

0 3 0

0 4 2

Histology : DLBCL Transformed FL

15 (88%) 2 (12%)

5 1

3 0

7 1

Abbreviations: Ly: lymphoma, NA: not available, aaIPI: age-adjusted international prognostic index,

LDH: lactate dehydrogenase, UNL: upper normal limit, PS: performance status, ENodal: extra-nodal,

FL: follicular lymphoma




Epi-R-CHOP

18

Table 2: Non-hematologic (Hem) AE during DLT period

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.

Abbreviations: AE: adverse event, DLT: dose liminting toxicity, Abdo: abdominal, Tox: toxicity

Neurological AE refers to post lumbar puncture syndrom (N=1, 1 AE), dysgeusia (N=2 patients, 3 AE),

neuralgia (N=1 patient, 1AE), peripheral neuropathy (N=3 patients, 3 AE). Among the 8 neurological

AE, 1 was considred as related to tazemetostat (Dysgeusia), 1 to both tazemetostat and R-CHOP

(peripheral neuropathy) and 6 to R-CHOP.

Non-Hem AE Safety Set, N=17 400mg, N=6 600mg, N=3 800mg, N=8

Grade All ≧ 3 All ≧ 3 All ≧ 3 All ≧ 3

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%)

Neurological tox. 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%)

Abdo. pain 5 (29%) 0 (0%) 1 (17%) 0 (0%) 1 (33%) 0 (0%) 3 (38%) 0 (0%)

Weight decrease 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%)

Diarrhoea 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%)

Hypokaliemia 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%)




Epi-R-CHOP

19

Table 3: Hematologic AE during DLT period

Hem. AA Safety Set, N=17 400mg, N=6 600mg, N=3 800mg, N=8

Grade All ≧ 3 All ≧ 3 All ≧ 3 All ≧ 3

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%)

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

Abbreviations: AE: adverse vent, DLT: dose limiting toxicty




Epi-R-CHOP

20

Table 4: relative dose administration.

RDI 400*, N=6 600, N=3 800**, N=8 Total, N=17

Prednisone

>90%

Mean

5 (83%)

99.6% (SD 8.9%)

3 (100%)

100.7% (SD 4.8%)

8 (100%)

101.9% (SD 8.2%)

16 (94.1%)

100.9% (SD 7.6%)

Rituximab

>90%

Mean

5 (83%)

95.6% (SD 10.8%)

3 (100%)

98.1% (SD 2.5%)

8 (100%)

100.5% (SD 5.6%)

16 (94.1%)

98.3% (SD 7.5%)

Vincristine

<75%

75-90%

>90%

Mean

1 (17%)

1 (17%)

4 (66.7%)

90.2% (SD 13.6%)

2 (66.7%)

1 (33%)

0 (0%)

66.7% (SD 15.7%)

4 (50%)

0 (0%)

4 (50%)

78.9% (SD 22.9%)

7 (41.2%)

2 (12%)

8 (47%)

80.7% (SD 19.8%)

Doxorubicine

>90%

Mean

6 (100%)

100.3% (SD 3.1%)

3 (100%)

98.3% (SD 3.6%)

8 (100%)

101.8% (SD 7.4%)

17 (100%)

100.6% (SD 5.5%)

Cyclophosphamide

>90%

Mean

6 (100%)

100.3% (SD 3.02%)

3 (100%)

98.1% (SD 2.2%)

8 (100%)

100% (SD 5.5%)

17 (100%)

99.8% (SD 4.2%)

R-CHOP component relative dose intensity (RDI) was calculated as the ratio between the total dose

received by the patient and the planned dose for each started cycle.

*:1 patient discontinued the treatment at C3.

**: 3 patients discontinued the treatment at C1.




Epi-R-CHOP

21

Figures legends: Figure 1 A: non-hematologic AE reported by more than 10% of the patients, during cycles 1 and 2,

and all grade 3+ AE.

Abbreviation: AE: adverse event

Frequency: number of patients presenting the AE/number of patients included in the safety set

(N=17).

Figure 1 B: Hematologic AE reported by more than 10% of the patients, during cycle 1 and 2, and all

grade 3+ hematologic AE

Frequency: number of patients presenting the AE/number of patients included in the safety set

(N=17)

Figure 2A: non-hematologic AE reported by more than 10% of the patients, during cycle 3 to 8, and

all grade 3+ AE.

Frequency: number of patients presenting the AE/number of patients treated after C3 (N=14)

Figure 2B: Hematologic AE reported by more than 10% of the patients, during cycle 3 and 8, and all

grade 3+ AE.

Frequency: number of patients presenting the AE/number of patients treated after C3 (N=14)

Figure 3: swimmer plot representing the follow-up and treatment response for the 17 patients.

This swimmerplot shows the quality of response and follow-up for the 17 included patients. On the

left part of the plot are indicated the cell of origin status as assessed by RTMLPA (GCB: germinal

center B or ABC: activated B cell. Of note, one case was a 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 had a final response

assesment. Among the 4 cases not evaluable for response (early protocol discontinuation), 1 died

from treatment related toxicity (infection), 1 patient stopped the protocol due to investigator

decision post AE at C3, 2 were excluded at C1 (1 due to non-compliance to the study drug, and 1 to

cholestasis lymphoma related).

Abbreviation: CMR: complete metabolic response, PMR: partial metabolic response.




Epi-R-CHOP

22

Acknoledgments: we thank the patients and their family. The LYSARC and Alexia Schwartzmann for

managing the study; all the LYSA investigators and centers for including patients; The LYSA-P and

Nadine Vailhen for managing the central review and biological studies. Elodie Bohers (NGS),

Pascaline Etancelin (banking) and Pierre Julien Viailly (bioinfo) from the U1245 Centre H.Bequerel for

the sequencing analysis.




Published OnlineFirst March 2, 2020.Clin Cancer Res Clémentine Sarkozy, Franck Morschhauser, Sydney Dubois, et al. (DLBCL) patients with poor prognosis featuresR-CHOP in newly diagnosed Diffuse Large B Cell Lymphoma A LYSA Phase Ib Study of tazemetostat (EPZ-6438) plus

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