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

NCT02889523 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: Epi-RCHOP
• Study Type: interventional
• Target: 214
• Locations: 2 countries
• Sites: 31

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

Conditions

Lymphoma; DLBCL; Follicular Lymphoma

Keywords

Front line therapy; Age-adjusted International Prognostic Index (aa-IPI) >1; 60 to 80 years

Outcome Measures

Primary Outcomes (4)

• Phase I : Number of Dose Limiting Toxicities

  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

  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

  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

  Complete response rate as determined by Cheson IWG 2014: Lugano Classification (Deauville scale 1-3)

  8 cycles (1 cycle is 21 days)

Secondary Outcomes (25)

• 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)

Study Arms (2)

DLBCL cohort

EXPERIMENTAL

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; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Doxorubicin; Drug: Prednisolone

FL cohort

EXPERIMENTAL

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; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Doxorubicin; Drug: Prednisolone

Interventions

Tazemetostat DRUG

Tablets 200 mg, to be administrated per os

Also known as: EPZ-6438

DLBCL cohort; FL cohort

Rituximab DRUG

375 mg/m²/dose, D1

Also known as: Mabthera

DLBCL cohort; FL cohort

Cyclophosphamide DRUG

750 mg/m²/dose, D1

DLBCL cohort; FL cohort

Vincristine DRUG

1.4 mg/m²/dose (max 2 mg), D1

DLBCL cohort; FL cohort

Doxorubicin DRUG

50 mg/m²/dose, D1

DLBCL cohort; FL cohort

Prednisolone DRUG

40 mg/m2 in the morning D1 to D5

DLBCL cohort; FL cohort

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• for Cohort DLBCL ONLY
• Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) with
• Phase Ib aaIPI ≥ 2
• Phase II: aaIPI ≥ 1ONLY
• \. Age between 60 and 80 years included
• for Cohort FOLLICULAR ONLY
• High Tumor Burden (as defined by GELF criteria \> 0) frontline follicular lymphoma (FL) with high risk FLIPI 3-5
• \. Aged between 18 years and 80 years included
• bis. 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
• bis- 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
• ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
• Signed informed consent
• Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
• Adequate renal function as calculated by a creatinine clearance \> 40 mL/min by local institutional formula

You may not qualify if:

• for Cohort DLBCL
• for Cohort FOLLICULAR ONLY
• Pregnant or lactating females
• For both Cohorts
• Central nervous system or meningeal involvement
• Contraindication to any drug contained in the chemotherapy regimen
• Prior treatment with tazemetostat or other inhibitor of EZH2
• 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
• Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
• Patients unwilling to exclude St. John's wort, Seville oranges, grapefruit juice and/or grapefruit from diet
• 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)
• Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat
• 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
• Not applicable
• Active uncontrolled infection requiring systemic therapy

Sponsors & Collaborators

• The Lymphoma Academic Research Organisation: lead
• Epizyme, Inc.: collaborator

Study Sites (31)

Institut Jules Bordet

Brussels, Belgium

Location

CHU de Liege

Liège, Belgium

Location

CHRU Mont Godinne

Yvoir, Belgium

Location

Centre Hospitalier Victor Dupouy

Argenteuil, France

Location

CH d'Avignon - Hôpital Henri Dufaut

Avignon, France

Location

CHU de Besançon - Hôpital Jean Minjoz

Besançon, France

Location

Polyclinique Bordeaux Nord Aquitaine

Bordeaux, France

Location

CH de Chambéry

Chambéry, France

Location

CHU d'Estaing

Clermont-Ferrand, France

Location

APHP - Hopital Henri Mondor

Créteil, France

Location

CHU de Dijon

Dijon, France

Location

CHU Grenoble

Grenoble, France

Location

CH Départemental de Vendée

La Roche-sur-Yon, France

Location

CHRU Lille - Hôpital Claude Huriez

Lille, France

Location

Chu de Limoges - Hopital Dupuytren

Limoges, France

Location

Centre Leon Berard

Lyon, France

Location

Institut Paoli Calmette

Marseille, France

Location

CHU de Montpellier - Hôpital Saint-Eloi

Montpellier, France

Location

CHU de Nantes - Hôtel Dieu

Nantes, France

Location

APHP - Hôpital de la Pitié Salpetrière

Paris, France

Location

APHP - Hôpital Saint Louis

Paris, France

Location

CH de Perpigan

Perpignan, France

Location

CHU Lyon Sud

Pierre-Bénite, France

Location

Chu de Poitiers - Hopital de Miletrie

Poitiers, France

Location

CHU de Rennes - Hôpital Pontchaillou

Rennes, France

Location

Centre Henri Becquerel

Rouen, 76000, France

Location

Centre Rene Hugenin

Saint-Cloud, France

Location

Institut de cancérologie de la Loire

Saint-Priest-en-Jarez, France

Location

CHRU de Strasbourg

Strasbourg, France

Location

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Related Publications (1)

• Sarkozy C, Morschhauser F, Dubois S, Molina T, Michot JM, Cullieres-Dartigues P, Suttle B, Karlin L, Le Gouill S, Picquenot JM, Dubois R, Tilly H, Herbaux C, Jardin F, Salles G, Ribrag V. 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. Clin Cancer Res. 2020 Jul 1;26(13):3145-3153. doi: 10.1158/1078-0432.CCR-19-3741. Epub 2020 Mar 2.

  PMID: 32122924 DERIVED

MeSH Terms

Conditions

Lymphoma; Lymphoma, Follicular

Interventions

tazemetostat; Rituximab; Cyclophosphamide; Vincristine; Doxorubicin; Prednisolone

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Study Officials

• 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

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2016
• First Posted: September 5, 2016
• Study Start: October 1, 2016
• Primary Completion: January 31, 2023
• Study Completion: April 1, 2026
• Last Updated: October 9, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (28); BE (3)