Epi-RCHOP: Study of Tazemetostat in Newly Diagnosed Diffuse Large B Cell and Follicular Lymphoma Patients Treated by Chemiotherapy

Sponsor

The Lymphoma Academic Research Organisation (Other)

Overall Status

Recruiting

CT.gov ID

NCT02889523

Collaborator

Epizyme, Inc. (Industry)

201

Enrollment

Locations

Arms

114

Anticipated Duration (Months)

6.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase I of the study is designed to determine the recommended phase II dose (RP2D) for tazemetostat in patients treated with 8 cycles of R-CHOP 21.

Phase II of the study is designed to determine the safety and the efficacy of tazemetostat in

DLBCL and FL patients :

DLBCL : tazemetostat with 6 cycles of R-CHOP 21 + 2 cycles of Rituximab FL : tazemetostat with 6 cycles of R-CHOP 21 + 2 cycles of Rituximab then maintenance with 6 months of tazemetostat and 24 months of Rituximab

Condition or Disease	Intervention/Treatment	Phase
Lymphoma DLBCL Follicular Lymphoma	Drug: Tazemetostat Drug: Rituximab Drug: Cyclophosphamide Drug: Vincristine Drug: Doxorubicin Drug: Prednisolone	Phase 1/Phase 2

Detailed Description

Phase I:

Up to 18 patients will be recruited, using a conventional dose-escalation algorithm (3+3 patients per dose level) to identify the maximum tolerated dose (MTD) which will be deemed the RP2D. Patients will receive 8 cycles of RCHOP every 21 days and tazemetostat every day, starting on day 2 of cycle 1.

4 cohorts are defined, according to dose levels of tazemetostat: 400mg Twice a day (BID) (cohort 1, starting level), 600mg BID (cohort 2), 800mg BID (cohort 3), 200mg BID (cohort -1), depending on the observed toxicities.

Phase II:

Up to 184 patients (122 DLBCL and 62 FL) will be recruited and treated with tazemetostat at the MTD and RCHOP.

Patients will receive 6 cycles of RCHOP every 21 days and tazemetostat at the MTD every day, starting on day 2 of cyle 1, + 2 cycles of Rituximab+tazemetostat. For FL, a maintenance of tazemetostat (6 months) + rituximab (24 months) is expected

Study Design

Study Type:

Interventional

Anticipated Enrollment :

201 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib-II Study of Tazemetostat (EPZ-6438) in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or High Risk Follicular Lymphoma (FL) Patients Treated by R-CHOP

Actual Study Start Date :

Oct 1, 2016

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

Apr 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DLBCL cohort RCHOP + tazemetostat: - RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1): Phase I : 8 cycles, every 21 days Phase II : 6 cycles, every 21 days Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days Tazemetostat: PO, doses according to dose cohorts for phase I, and at RP2D for phase II: continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID	Drug: Tazemetostat Tablets 200 mg, to be administrated per os Other Names: EPZ-6438 Drug: Rituximab 375 mg/m²/dose, D1 Other Names: Mabthera Drug: Cyclophosphamide 750 mg/m²/dose, D1 Drug: Vincristine 1.4 mg/m²/dose (max 2 mg), D1 Drug: Doxorubicin 50 mg/m²/dose, D1 Drug: Prednisolone 40 mg/m2 in the morning D1 to D5
Experimental: FL cohort RCHOP + tazemetostat: Induction RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1): 6 cycles, every 21 days Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days Tazemetostat: PO, RP2D, continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID Maintenance Tazemetostat : 6 months (every 8 weeks) Rituximab : 24 months (every 8 weeks)	Drug: Tazemetostat Tablets 200 mg, to be administrated per os Other Names: EPZ-6438 Drug: Rituximab 375 mg/m²/dose, D1 Other Names: Mabthera Drug: Cyclophosphamide 750 mg/m²/dose, D1 Drug: Vincristine 1.4 mg/m²/dose (max 2 mg), D1 Drug: Doxorubicin 50 mg/m²/dose, D1 Drug: Prednisolone 40 mg/m2 in the morning D1 to D5

Arm

Intervention/Treatment

Experimental: DLBCL cohort

RCHOP + tazemetostat: - RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1): Phase I : 8 cycles, every 21 days Phase II : 6 cycles, every 21 days Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days Tazemetostat: PO, doses according to dose cohorts for phase I, and at RP2D for phase II: continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID

Drug: Tazemetostat

Tablets 200 mg, to be administrated per os

Other Names:

EPZ-6438

Drug: Rituximab

375 mg/m²/dose, D1

Other Names:

Mabthera

Drug: Cyclophosphamide

750 mg/m²/dose, D1

Drug: Vincristine

1.4 mg/m²/dose (max 2 mg), D1

Drug: Doxorubicin

50 mg/m²/dose, D1

Drug: Prednisolone

40 mg/m2 in the morning D1 to D5

Experimental: FL cohort

RCHOP + tazemetostat: Induction RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1): 6 cycles, every 21 days Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days Tazemetostat: PO, RP2D, continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID Maintenance Tazemetostat : 6 months (every 8 weeks) Rituximab : 24 months (every 8 weeks)

Drug: Tazemetostat

Tablets 200 mg, to be administrated per os

Other Names:

EPZ-6438

Drug: Rituximab

375 mg/m²/dose, D1

Other Names:

Mabthera

Drug: Cyclophosphamide

750 mg/m²/dose, D1

Drug: Vincristine

1.4 mg/m²/dose (max 2 mg), D1

Drug: Doxorubicin

50 mg/m²/dose, D1

Drug: Prednisolone

40 mg/m2 in the morning D1 to D5

Outcome Measures

Primary Outcome Measures

Phase I : Number of Dose Limiting Toxicities [1 cycle (1 cycle is 21 days)]
Incidence and severity of treatment-emergent AEs qualifying as protocol defined DLT's in cycle 1 and 2 in order to establish the MTD/RP2D
Phase I : Number of Dose Limiting Toxicities [2 cycles (1 cycle is 21 days)]
Incidence and severity of treatment-emergent AEs qualifying as protocol defined DLT's in cycle 1 and 2 in order to establish the MTD/RP2D
Phase II - DLBCL Cohort : Complete Response Rate based on local assessment [8 cycles (1 cycle is 21 days)]
Complete response rate as determined by Cheson International Work Group (IWG) 2014: Lugano Classification (Deauville scale 1-3)
Phase II - FL Cohort : Complete Response Rate based on local assessment [8 cycles (1 cycle is 21 days)]
Complete response rate as determined by Cheson IWG 2014: Lugano Classification (Deauville scale 1-3)

Secondary Outcome Measures

Phase I : Serum concentration of CHOP components in presence/absence of Tazemetostat [Change between baseline - 1 month]
Phase I : Serum concentration of Tazemetostat and its metabolite (EZH 6930) in presence of CHOP [Change between baseline - 1 month]
Phase I : Complete response rate (CRR) by central review using Cheson IWG criteria [8 cycles (1 cycle is 21 days)]
Phase II - DLBCL Cohort : Number of Adverse Events (AE)/Serious Adverse Events (SAE) [8 cycles (1 cycle is 21 days)]
Phase II - DLBCL Cohort : Complete response rate (CRR) by central review using Cheson IWG criteria [8 cycles (1 cycle is 21 days)]
Phase II - DLBCL Cohort : Overall response rate (ORR) by central review [52 weeks]
Phase II - DLBCL Cohort : Overall response rate (ORR) by central review [104 weeks]
Phase II - DLBCL Cohort : progression free survival (PFS) [52 weeks]
Phase II - DLBCL Cohort : progression free survival (PFS) [104 weeks]
Phase II - DLBCL Cohort : duration of response (DR) [52 weeks]
Phase II - DLBCL Cohort : duration of response (DR) [104 weeks]
Phase II - DLBCL Cohort : overall survival (OS) [52 weeks]
Phase II - DLBCL Cohort : overall survival (OS) [104 weeks]
Phase II - DLBCL Cohort : best overall response (BOR) [104 weeks]
Phase II - FL cohort : Number of AE/SAE [8 cycles (1 cycle is 21 days)]
Phase II - FL cohort : Number of AE/SAE [13 months]
Phase II - FL cohort : PET Complete Response Rate (PET-CRR) by central review according to Lugano 2014 criteria [8 cycles (1 cycle is 21 days)]
Phase II - FL cohort : Complete Response Rate (CRR) [31 months]
Phase II - FL cohort : Overall Response Rate (CRR) [31 months]
Phase II - FL cohort : Progression Free Survival (PFS) [24 months]
Phase II - FL cohort : Progression Free Survival (PFS) [31 months]
Phase II - FL cohort : Event Free Survival (EFS) [24 months]
Phase II - FL cohort : Overall Survival (OS) [24 months]
Phase II - FL cohort : Duration of Response (DR) [31 months]
Phase II - FL cohort : Best Overall Response [31 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA
for Cohort DLBCL ONLY
1-Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) with
Phase Ib aaIPI ≥ 2
Phase II: aaIPI ≥ 1ONLY
1. Age between 60 and 80 years included
for Cohort FOLLICULAR ONLY
1-High Tumor Burden (as defined by GELF criteria > 0) frontline follicular lymphoma (FL) with high risk FLIPI 3-5
1. Aged between 18 years and 80 years included
11bis. Females of childbearing potential (FCBP) must agree to use one reliable form of contraception or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 12 months after discontinuation of any study treatments (R-CHOP, tazemetostat, Rituximab)
For both Cohorts
1bis- For phase II patients: Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan and/or clinical examination AND a FDG avid disease by PETscan
3.ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
4.Signed informed consent
5.Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
6.Adequate renal function as calculated by a creatinine clearance > 40 mL/min by local institutional formula
1. Adequate bone marrow function as defined as:
ANC ≥ 1500/mm3 (≥ 1.5 X 109/L)
Platelets ≥ 75,000/mm3 (≥ 75 X 109/L) without platelet transfusion dependency during the last 7 days
Hemoglobin ≥ 9 g/dL (may receive transfusion)
1. Adequate liver function as defined as:
Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN (or ≤ 5 X ULN if related to lymphoma involvement)
Patients with prior Hepatitis B and C are eligible if, for Hepatitis B detection, surface antigen is negative and/or HBV DNA is undetectable, and for Hepatitis C detection, if HCV RNA is undetectable.
1. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
1. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11
1. Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
1. Patient covered by any social security system (for France only)
1. Patient who understands and speaks one of the country official languages
EXCLUSION CRITERIA
for Cohort DLBCL

___15-Previous treatment for B cell lymphoma, except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)

for Cohort FOLLICULAR ONLY
14bis. Prior therapy for lymphoma including radiotherapy except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)
17-Pregnant or lactating females
For both Cohorts
1-Central nervous system or meningeal involvement
2-Contraindication to any drug contained in the chemotherapy regimen
3-Prior treatment with tazemetostat or other inhibitor of EZH2
4-Patients who are undergoing active treatment for another malignancy, exceptions include: A patient who has been disease free for 2 years, or a patient with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible Patients with prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia(AML) or prior history of T-LBL/T-ALL are excluded whatever receiving treatment or not and whatever date of diagnosis of these pathologies
5-Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
6-Patients unwilling to exclude St. John's wort, Seville oranges, grapefruit juice and/or grapefruit from diet
7-Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted within 2 weeks of enrollment)
8-Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat
9-Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of tazemetostat or ventricular arrhythmia
10-Not applicable
11-Active uncontrolled infection requiring systemic therapy
12-Congenital immunodeficiency or known HIV (human immunodeficiency virus infection)
13-Any other major illness, that in the investigator's judgement, will substantially increase the risk associated with the patient's participation in the study
14-Patients who have undergone a solid organ transplant
16-Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy
18-Person deprived of his/her liberty by a judicial or administrative decision
19-Adult person under legal protection
20-Person hospitalized without consent
21-Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Jules Bordet	Bruxelles	Belgium
2	CHU de Liege	Liege	Belgium
3	CHRU Mont Godinne	Yvoir	Belgium
4	Centre Hospitalier Victor Dupouy	Argenteuil	France
5	CH d'Avignon - Hôpital Henri Dufaut	Avignon	France
6	CHU de Besançon - Hôpital Jean Minjoz	Besançon	France
7	Polyclinique Bordeaux Nord Aquitaine	Bordeaux	France
8	CH de Chambéry	Chambéry	France
9	CHU d'Estaing	Clermont-Ferrand	France
10	APHP - Hopital Henri Mondor	Creteil	France
11	CHU de Dijon	Dijon	France
12	CHU Grenoble	Grenoble	France
13	CH Départemental de Vendée	La Roche sur Yon	France
14	CHRU Lille - Hôpital Claude Huriez	Lille Cedex	France
15	Chu de Limoges - Hopital Dupuytren	Limoges	France
16	Centre Leon Berard	Lyon	France
17	Institut Paoli Calmette	Marseille	France
18	CHU de Montpellier - Hôpital Saint-Eloi	Montpellier	France
19	CHU de Nantes - Hôtel Dieu	Nantes	France
20	APHP - Hôpital Saint Louis	Paris Cedex 10	France
21	APHP - Hôpital de la Pitié Salpetrière	Paris	France
22	CH de Perpigan	Perpignan	France
23	CHU Lyon Sud	Pierre-Bénite Cedex	France
24	Chu de Poitiers - Hopital de Miletrie	Poitiers	France
25	CHU de Rennes - Hôpital Pontchaillou	Rennes	France
26	Centre Henri Becquerel	Rouen	France	76000
27	Centre Rene Hugenin	Saint Cloud	France
28	Institut de cancérologie de la Loire	Saint Priest en Jarez	France
29	CHRU de Strasbourg	Strasbourg	France
30	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse	France
31	Institut Gustave Roussy	Villejuif	France

Sponsors and Collaborators

The Lymphoma Academic Research Organisation
Epizyme, Inc.

Investigators

Study Chair: Vincent Ribrag, MD, Institut Gustave Roussy Cancer Campus Grand Paris
Study Chair: Clémentine Sarkozy, MD, Institut Gustave Roussy Cancer Campus Grand Paris
Study Chair: Franck Morshhauser, Pr, Centre Régional Hospitalier de Lille
Study Chair: Loic Ysebaert, MD, IUCT Oncopole de Toulouse