newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high risk Follicular Lymphoma (FL) MedDRA version: 20.0 Level: HLT Classification code 10012819 Term: Diffuse large B-cell lymphomas System Organ Class: 100000004851 MedDRA version: 24.0 Level: LLT Classification code 10029473 Term: Nodular (follicular) lymphoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: tazemetostat
Product Code: EPZ-6438
Pharmaceutical Form: Tablet
INN or Proposed INN: TAZEMETOSTAT
CAS Number: 1467052-75-0
Current Sponsor code: EPZ-6438
Concentration unit: mg milligram
Sponsors
LYSARC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: ___Cohort DLBCL : 1. Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) Or CD20+ Follicular lymphoma grade 3B with - Phase Ib aaIPI = 2 - Phase II: aaIPI = 1 2. Age between 60 and 80 years included ____Cohort FOLLICULAR : 1. High Tumor Burden (at least one GELF criteria except isolated elevated LDH at baseline) frontline follicular lymphoma (FL) with high risk FLIPI 3-5 2.Aged between 18 years and 80 years included 11 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 treatment (R-CHOP, tazemetostat, Rituximab) ____Both cohorts DLBCL and Follicular : 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 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 33 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: ___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 ___DLBCL cohort 15. Previous treatment for B cell lymphoma, except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max) ___ Follicular cohort 15. Prior therapy for lymphoma including radiotherapy except glucocorticoids (no more than 7 days before inclusion, 1mg/kg/day max) 17. Pregnant or lactating females
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib: to determine the recommended phase II dose (RP2D) for tazemetostat in patients treated with R-CHOP 21 Phase II – DLBCL cohort: • to determine the Complete Response Rate (CRR) based on local assessment according to Cheson IWG 2014: Lugano Classification (i.e. categories 1- 3 on the 5 point Deauville scale) at the end of treatment or at permanent treatment discontinuation.End of treatment is defined as after 6 cycles of Epi-RCHOP 21 + 2 cycles of Tazemetostat and Rituximab. Phase II – FL cohort: • to determine the Complete Response Rate (CRR) based on local assessment at the end of induction or at permanent treatment discontinuation according to Cheson IWG 2014: Lugano Classification (i.e. Deauville scale 1-3). End of induction is defined as after 6 cycles of Epi-RCHOP 21 + 2 cycles of Tazemetostat and Rituximab.;Secondary Objective: Phase Ib: - to assess the pharmacokinetics of the CHOP 21 components +/- tazemetostat - to assess the pharmacokinetics of tazemetostat and its metabolite, EPZ-6930 + R-CHOP 21 - to evaluate the preliminary anti-tumor activity of tazemetostat using Cheson IWG 2014 Phase II – DLBCL cohort: • To determine the safety of tazemetostat • To determine CRR by central review at the end of treatment • To evaluate the overall response rate and progression free survival at 52 and 104 w and overall • To evaluate duration of response and overall survival • To evaluate the Best Overall Response Phase II – FL cohort : • To determine the safety of tazemetostat • To determine PET EOI CRR rate • To determine the complete response rate and overall response rate at the end of rituximab maintenance • To evaluate progression free survival overall and at 24 months, event-free survival overall and at 24 months, and overall survival . • To evaluate duration of response • To evaluate BOR ;Primary end point(s): Phase I : - RP2D Phase II - DLBCL cohort - CRR Phase II - Follicular lymphoma cohort - CRR Phase I : - RP2D;Timepoint(s) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I : - PK CHOP21 +/- tazemetostat - PK tazemetostat and EPZ-6930 + CHOP 21 - CR Phase II - ORR - PFS - PK CHOP21 +/- tazemetostat - PK tazemetostat and EPZ-6930 + CHOP 21 - OS;Timepoint(s) of evaluation of this end point: Phase I - PK CHOP21 +/- tazemetostat = C1D1 and C2D1 - PK tazemetostat and EPZ-6930 + CHOP 21 = C1D1 and C2D1 - CR = 8 cycles Phase II - ORR = 52 and 104 days, end of study - PFS = 52 and 104 days, end of study - PK CHOP21 +/- tazemetostat = C1D1 and C2D1 - PK tazemetostat and EPZ-6930 + CHOP 21 = C1D1 and C2D1 | — |
Countries
Belgium, France
Contacts
Public ContactProject Manager
LYSARC
Outcome results
None listed