Study of tazemetostat in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients treated by R-CHOP

• Register: EUCTR
• Last refreshed on: 24 October 2016
• Main ID: EUCTR2016-001499-31-FR
• Date of registration: 19/10/2016
• Prospective Registration: No
• Primary sponsor: LYSARC
• Public title: Study of tazemetostat in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients treated by R-CHOP
• Scientific title: A Phase Ib-II Study of tazemetostat (EPZ-6438) in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients with poor prognosis treated by R-CHOP
• Date of first enrolment: 09/08/2016
• Target sample size: 133
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001499-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: Project Management - A Schwartzmann
• Affiliation: LYSARC

• Name: Project Management - A Schwartzmann
• Affiliation: LYSARC

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) with aaIPI = 2
2. Age between 60 and 80 years included
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 asparatate aminotransferase (AST) = 3 X ULN (or = 5 X ULN if there is lymphoma involvement of the liver)
- 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, HCV RNA is undetectable.
9. Left ventricular ejection fraction (LVEF) > 50% of echocardiography or multiple gated acquisition (MUGA) scan
10. Adequate tissue for central retrospective testing of EZH2 mutation status and cell of origin (15 slides of tumor biopsy must be available at screening)
11. Males with partners of childbearing potential must agree to use reliable forms of contraception

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:
1. Symptomatic 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
5. Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John’s wort) or known substrates of CYP2C8.
6. Patients unwilling to exclude 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. Prolonged QTcF >480 msec
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
15. Previous treatment for B cell lymphoma, except low dose radiotherapy for follicular lymphoma and glucocorticoids (no more than 14 days before inclusion, 1 mg/kg/day max)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL)
MedDRA version: 19.0 Level: HLT Classification code 10012819 Term: Diffuse large B-cell lymphomas System Organ Class: 100000004851

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

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(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Main Objective: Phase Ib: to determine the recommended phase II dose (RP2D) for tazemetostat in patients treated with R-CHOP 21

Phase II:
- to determine the safety of tazemetostat in patients treated with 8 cycles of R-CHOP 21
- to determine the complete response rate according to Cheson IWG 2014: Lugano Classification (i.e. ; categories 1- 3 on the 5 point Deauville scale ) after 8 cycles of Epi-RCHOP 21

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:
- to evaluate the overall response rate (ORR) and progression free survival (PFS) at 52 and 104 weeks and overall
- to estimate the pharmacokinetics of the CHOP 21 components in +/-tazemetostat
- to estimate the pharmacokinetics of tazemetostat and EPZ-6930 + R-CHOP 21

Exploratory Objectives for Both Phases
- to evaluate the duration of response and overall survival (OS) at 52 and 104 weeks and overall
- to assess tumor tissue and/or blood for candidate markers of prognosis and clinical effect of tazemetostat,
- to assess mutational landscape of HSC before and after tazemetostat therapy in case of hematological toxicity unexpected according to phase I DLT criteria.

Primary end point(s): Phase I :
- RP2D

Phase II
- safety
- CR

Timepoint(s) of evaluation of this end point: Phase I
- RP2D = 2 cycles

Phase II
- sécurité = 8 cycles
- CR = 8 cycles

Secondary Outcome(s)

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

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

Secondary ID(s)

Epi-RCHOP

Source(s) of Monetary Support

Epizyme