Study of Tazemetostat in Newly Diagnosed Diffuse Large B Cell and Follicular Lymphoma Patients Treated by Chemiotherapy
- Conditions
- Interventions
- Registration Number
- NCT02889523
- Lead Sponsor
- The Lymphoma Academic Research Organisation
- 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 :
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- 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.
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Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 214
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description DLBCL cohort Tazemetostat 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 DLBCL cohort Doxorubicin 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 DLBCL cohort Rituximab 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 DLBCL cohort Cyclophosphamide 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 DLBCL cohort Vincristine 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 DLBCL cohort Prednisolone 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 FL cohort Tazemetostat 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) FL cohort Rituximab 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) FL cohort Vincristine 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) FL cohort Cyclophosphamide 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) FL cohort Doxorubicin 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) FL cohort Prednisolone 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)
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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 : best overall response (BOR) 104 weeks Phase II - FL cohort : Number of AE/SAE 13 months Phase II - DLBCL Cohort : Overall response rate (ORR) by central review 104 weeks Phase II - DLBCL Cohort : progression free survival (PFS) 104 weeks Phase II - DLBCL Cohort : duration of response (DR) 104 weeks Phase II - FL cohort : Duration of Response (DR) 31 months Phase II - FL cohort : Best Overall Response 31 months Phase II - DLBCL Cohort : overall survival (OS) 104 weeks Phase II - FL cohort : Overall Survival (OS) 24 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) 31 months Phase II - FL cohort : Event Free Survival (EFS) 24 months
Trial Locations
- Locations (31)
APHP - Hôpital Saint Louis
🇫🇷Paris Cedex 10, France
Centre Henri Becquerel
🇫🇷Rouen, France
Institut Gustave Roussy
🇫🇷Villejuif, France
CHRU Mont Godinne
🇧🇪Yvoir, Belgium
CHU de Liege
🇧🇪Liege, Belgium
Institut Jules Bordet
🇧🇪Bruxelles, Belgium
Centre Hospitalier Victor Dupouy
🇫🇷Argenteuil, France
CH d'Avignon - Hôpital Henri Dufaut
🇫🇷Avignon, France
CH de Chambéry
🇫🇷Chambéry, France
CHU d'Estaing
🇫🇷Clermont-Ferrand, France
CHU de Dijon
🇫🇷Dijon, France
CHRU Lille - Hôpital Claude Huriez
🇫🇷Lille Cedex, France
Institut Paoli Calmette
🇫🇷Marseille, France
CHU de Montpellier - Hôpital Saint-Eloi
🇫🇷Montpellier, France
CHU de Rennes - Hôpital Pontchaillou
🇫🇷Rennes, France
Centre Rene Hugenin
🇫🇷Saint Cloud, France
Polyclinique Bordeaux Nord Aquitaine
🇫🇷Bordeaux, France
CHU de Besançon - Hôpital Jean Minjoz
🇫🇷Besançon, France
APHP - Hopital Henri Mondor
🇫🇷Creteil, France
CHU Grenoble
🇫🇷Grenoble, France
Centre Leon Berard
🇫🇷Lyon, France
CH Départemental de Vendée
🇫🇷La Roche sur Yon, France
Chu de Limoges - Hopital Dupuytren
🇫🇷Limoges, France
CHU de Nantes - Hôtel Dieu
🇫🇷Nantes, France
APHP - Hôpital de la Pitié Salpetrière
🇫🇷Paris, France
CH de Perpigan
🇫🇷Perpignan, France
CHU Lyon Sud
🇫🇷Pierre-Bénite Cedex, France
Chu de Poitiers - Hopital de Miletrie
🇫🇷Poitiers, France
CHRU de Strasbourg
🇫🇷Strasbourg, France
Institut de cancérologie de la Loire
🇫🇷Saint Priest en Jarez, France
Institut Universitaire du Cancer de Toulouse - Oncopole
🇫🇷Toulouse, France