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

March 16, 2023 updated by: The Lymphoma Academic Research Organisation

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

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

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

214

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Belgium
      • Bruxelles, Belgium
        • Institut Jules Bordet
      • Liege, Belgium
        • CHU de Liège
      • Yvoir, Belgium
        • CHRU Mont Godinne
  • France
      • Argenteuil, France
        • centre hospitalier Victor Dupouy
      • Avignon, France
        • CH d'Avignon - Hôpital Henri Dufaut
      • Besançon, France
        • CHU de Besançon - Hôpital Jean Minjoz
      • Bordeaux, France
        • Polyclinique Bordeaux Nord Aquitaine
      • Chambéry, France
        • CH de Chambery
      • Clermont-Ferrand, France
        • Chu D'Estaing
      • Creteil, France
        • APHP - Hopital Henri Mondor
      • Dijon, France
        • CHU de Dijon
      • Grenoble, France
        • Chu Grenoble
      • La Roche sur Yon, France
        • CH Départemental de Vendée
      • Lille Cedex, France
        • CHRU LILLE - Hôpital Claude Huriez
      • Limoges, France
        • CHU de Limoges - Hôpital Dupuytren
      • Lyon, France
        • Centre Léon Bérard
      • Marseille, France
        • Institut Paoli Calmette
      • Montpellier, France
        • CHU de Montpellier - Hôpital Saint-Eloi
      • Nantes, France
        • CHU de Nantes - Hôtel Dieu
      • Paris, France
        • APHP - Hopital de la Pitie Salpetriere
      • Paris Cedex 10, France
        • APHP - Hopital Saint Louis
      • Perpignan, France
        • CH de Perpigan
      • Pierre-Bénite Cedex, France
        • CHU Lyon Sud
      • Poitiers, France
        • Chu de Poitiers - Hopital de Miletrie
      • Rennes, France
        • CHU de Rennes - Hôpital Pontchaillou
      • Rouen, France, 76000
        • Centre Henri Becquerel
      • Saint Cloud, France
        • Centre Rene Hugenin
      • Saint Priest en Jarez, France
        • Institut de Cancerologie de la Loire
      • Strasbourg, France
        • CHRU de Strasbourg
      • Toulouse, France
        • Institut Universitaire du Cancer de Toulouse - Oncopole
      • Villejuif, France
        • Institut Gustave Roussy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • 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
      • 2. 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
      • 2. 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

      • 7. 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)

      • 8. 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.
      • 9. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
      • 10. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11
      • 11. Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
      • 12. Patient covered by any social security system (for France only)
      • 13. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I : Number of Dose Limiting Toxicities
Time Frame: 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
1 cycle (1 cycle is 21 days)
Phase I : Number of Dose Limiting Toxicities
Time Frame: 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
2 cycles (1 cycle is 21 days)
Phase II - DLBCL Cohort : Complete Response Rate based on local assessment
Time Frame: 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)
8 cycles (1 cycle is 21 days)
Phase II - FL Cohort : Complete Response Rate based on local assessment
Time Frame: 8 cycles (1 cycle is 21 days)
Complete response rate as determined by Cheson IWG 2014: Lugano Classification (Deauville scale 1-3)
8 cycles (1 cycle is 21 days)

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Lymphoma Academic Research Organisation

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2016

Primary Completion (Actual)

January 31, 2023

Study Completion (Anticipated)

April 1, 2026

Study Registration Dates

First Submitted

July 11, 2016

First Submitted That Met QC Criteria

August 30, 2016

First Posted (Estimate)

September 5, 2016

Study Record Updates

Last Update Posted (Actual)

March 17, 2023

Last Update Submitted That Met QC Criteria

March 16, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Epi-RCHOP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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