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

Lymphoma Clinical Trial

— Epi-RCHOP  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02889523
• Other study ID #: Epi-RCHOP
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: October 2016
• Est. completion date: April 2026

Study information

• Verified date: March 2023
• Source: The Lymphoma Academic Research Organisation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 214
• Est. completion date: April 2026
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

• 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

Related Conditions & MeSH terms

• DLBCL
• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

Drug:
• Tazemetostat
Tablets 200 mg, to be administrated per os
• Rituximab
375 mg/m²/dose, D1
• Cyclophosphamide
750 mg/m²/dose, D1
• Vincristine
1.4 mg/m²/dose (max 2 mg), D1
• Doxorubicin
50 mg/m²/dose, D1
• Prednisolone
40 mg/m2 in the morning D1 to D5

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
The Lymphoma Academic Research Organisation	Epizyme, Inc.

Countries where clinical trial is conducted

Belgium,  France, 

Outcome

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