Study of tazemetostat in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients or high risk Follicular Lymphoma (FL) patientstreated by R-CHOP

Phase 1

• Conditions: newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high risk Follicular Lymphoma (FL); MedDRA version: 20.0Level: HLTClassification code 10012819Term: Diffuse large B-cell lymphomasSystem Organ Class: 100000004851; MedDRA version: 24.0Level: LLTClassification code 10029473Term: Nodular (follicular) lymphomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2016-001499-31-BE
• Lead Sponsor: YSARC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-04-15
• Last Update Posted: 8 October 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 201

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

___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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified