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

Study Overview
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Brief Summary
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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

Detailed Description
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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

Official Title
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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

Conditions
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Lymphoma, DLBCL, Follicular Lymphoma

Intervention / Treatment
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* Drug: Tazemetostat
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Doxorubicin
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DLBCL cohort<br>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<br>* Tablets 200 mg, to be administrated per os<br>* Other names: EPZ-6438;Drug: Rituximab<br>* 375 mg/m²/dose, D1<br>* Other names: Mabthera;Drug: Cyclophosphamide<br>* 750 mg/m²/dose, D1<br>Drug: Vincristine<br>* 1.4 mg/m²/dose (max 2 mg), D1<br>Drug: Doxorubicin<br>* 50 mg/m²/dose, D1<br>Drug: Prednisolone<br>* 40 mg/m2 in the morning D1 to D5<br>|
| Experimental: FL cohort<br>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<br>* Tablets 200 mg, to be administrated per os<br>* Other names: EPZ-6438;Drug: Rituximab<br>* 375 mg/m²/dose, D1<br>* Other names: Mabthera;Drug: Cyclophosphamide<br>* 750 mg/m²/dose, D1<br>Drug: Vincristine<br>* 1.4 mg/m²/dose (max 2 mg), D1<br>Drug: Doxorubicin<br>* 50 mg/m²/dose, D1<br>Drug: Prednisolone<br>* 40 mg/m2 in the morning D1 to D5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Front line therapy, Age-adjusted International Prognostic Index (aa-IPI) >1, 60 to 80 years