TAZEMETOSTAT for Diffuse large B-cell lymphoma (DLBCL) | High-risk follicular lymphoma (FL)

Inclusion criteria

• {"criterion_text":"- Cohort DLBCL: 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. Cohort FOLLICULAR : High Tumor Burden (as defined by at least one GELF criteria except isolated elevated LDH at baseline) frontline follicular lymphoma (FL) with high risk FLIPI 3-5"}
• {"criterion_text":"- Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan"}
• {"criterion_text":"- Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11)"}
• {"criterion_text":"- Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration"}
• {"criterion_text":"- Cohort FOLLICULAR : 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)"}
• {"criterion_text":"- Patient covered by any social security system (for France only)"}
• {"criterion_text":"- Patient who understands and speaks one of the country official languages"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Cohort DLBCL 2. Age between 60 and 80 years included Cohort FOLLICULAR :2. Aged between 18 years and 80 years included"}
• {"criterion_text":"- ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)"}
• {"criterion_text":"- Signed informed consent"}
• {"criterion_text":"- Life expectancy of ≥ 90 days (3 months) before starting tazemetostat"}
• {"criterion_text":"- Adequate renal function as calculated by a creatinine clearance > 40 mL/min by local institutional formula"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 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."}

Exclusion criteria

• {"criterion_text":"- Central nervous system or meningeal involvement"}
• {"criterion_text":"- Not applicable"}
• {"criterion_text":"- Active uncontrolled infection requiring systemic therapy"}
• {"criterion_text":"- Congenital immunodeficiency or known HIV (human immunodeficiency virus infection)"}
• {"criterion_text":"- Any other major illness, that in the investigator’s judgement, will substantially increase the risk associated with the patient’s participation in the study"}
• {"criterion_text":"- Patients who have undergone a solid organ transplant"}
• {"criterion_text":"- Cohort DLBCL : Previous treatment for B cell lymphoma, except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max). Cohort FOLLICULAR : Prior therapy for lymphoma including radiotherapy except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)"}
• {"criterion_text":"- Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy"}
• {"criterion_text":"- Cohort FOLLICULAR :Pregnant or lactating females"}
• {"criterion_text":"- Person deprived of his/her liberty by a judicial or administrative decision"}
• {"criterion_text":"- Adult person under legal protection"}
• {"criterion_text":"- Contraindication to any drug contained in the chemotherapy regimen"}
• {"criterion_text":"- Person hospitalized without consent"}
• {"criterion_text":"- Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness"}
• {"criterion_text":"- Prior treatment with tazemetostat or other inhibitor of EZH2"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John’s wort)"}
• {"criterion_text":"- Patients unwilling to exclude St. John’s wort, Seville oranges, grapefruit juice and/or grapefruit from diet"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat"}
• {"criterion_text":"- 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"}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"DLTs assessed in cycles 1 and 2; incidence and severity of treatment-emergent adverse events qualifying as protocol-defined dose-limiting toxicities to establish the MTD/RP2D"}

Secondary endpoints

• {"endpoint_text":"- PK parameters: maximum plasma concentration (Cmax), time to Cmax (tmax), area under the concentration-time curve from time 0 to last measurable concentration [AUC(0-t)], area under the concentration-time curve from time 0 to 12 hours post-dose [AUC(0-12)], and elimination half-life (t1/2) of cyclophosphamide, prednisolone, doxorubicin, doxorubicinol, methyl prednisolone, prednisone, vincristine, tazemetostat, and EPZ-6930, if data permit","definition_or_measurement_approach":"Standard pharmacokinetic parameters (Cmax, Tmax, AUC(0-t), AUC(0-12), t1/2) for listed drugs/metabolites as measured in plasma if data permit"}
• {"endpoint_text":"- Complete response rate as determined by Cheson IWG 2014: Lugano Classification (Deauville scale 1-3)","definition_or_measurement_approach":"Response assessed locally according to Cheson IWG 2014 / Lugano Classification; Complete Response defined as Deauville score 1-3"}

Belgium

Earliest CTIS Part Ii Submission Date

23-08-2024

Latest Decision Or Authorization Date

08-10-2024

Processing Time Days

46

Number Of Sites

2

Number Of Participants

19

France

Earliest CTIS Part Ii Submission Date

23-08-2024

Latest Decision Or Authorization Date

07-10-2024

Processing Time Days

45

Number Of Sites

29

Number Of Participants

195

Primary sponsor

Full Name

LYSARC

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

France