A Phase Ib-II Study of tazemetostat (EPZ-6438) in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high risk Follicular Lymphoma (FL) patients treated by R-CHOP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lysarc

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

19 Sep 2016 → ongoing

Decision date (initial)

2024-10-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-515846-18-00

EudraCT number

2016-001499-31

ClinicalTrials.gov

NCT02889523

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Dose response, Pharmacokinetic, Therapy, Efficacy

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.
Permanent treatment discontinuation is defined as the discontinuation of all treatments (Rituximab, CHOP and Tazemetostat)
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.
Permanent treatment discontinuation is defined as the discontinuation of all treatments (Rituximab, CHOP and Tazemetostat)

Secondary objectives 14

1. Phase Ib: • To assess the pharmacokinetics of the CHOP 21 components in the presence and absence of tazemetostat
2. To assess the pharmacokinetics of tazemetostat and its metabolite, EZH-6930, in the presence of CHOP 21
3. To evaluate the preliminary anti-tumor activity of tazemetostat in patients treated with R-CHOP 21 as assessed by complete response rate using Cheson IWG 2014 criteria
4. Phase II – DLBCL cohort: • To determine the safety of tazemetostat at the end of treatment or at permanent treatment discontinuation
5. • To determine CRR by central review at the end of treatment
6. • To evaluate the overall response rate (ORR) and progression free survival (PFS) at 52 and 104 weeks and overall
7. • To evaluate duration of response and overall survival (OS) at 52 and 104 weeks and overall
8. • To evaluate the Best Overall Response (BOR)
9. Phase II – FL cohort: • To determine the safety of tazemetostat, at the end of induction and then after 6 months maintenance or at permanent treatment discontinuation
10. • To determine PET EOI CRR rate by central review
11. • To determine the complete response rate and overall response rate at the end of rituximab maintenance according to Lugano 2014 Classification
12. • To evaluate progression free survival (PFS) overall and at 24 months (POD24), event-free survival overall (EFS) and at 24 months (EFS24), and overall survival (OS).
13. • To evaluate duration of response
14. • To evaluate BOR

Conditions and MedDRA coding

Newly diagnosed Diffuse Large B Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 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
2. 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. Cohort DLBCL 2. Age between 60 and 80 years included Cohort FOLLICULAR :2. Aged between 18 years and 80 years included
4. ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
5. Signed informed consent
6. Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
7. Adequate renal function as calculated by a creatinine clearance > 40 mL/min by local institutional formula
8. 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)
9. 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.
10. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
11. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11)
12. Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
13. 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)
14. Patient covered by any social security system (for France only)
15. Patient who understands and speaks one of the country official languages

Exclusion criteria 21

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
15. 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)
16. Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy
17. Cohort FOLLICULAR :Pregnant or lactating females
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 2

1. 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
2. Complete response rate as determined by Cheson IWG 2014: Lugano Classification (Deauville scale 1-3)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lysarc

Sponsor organisation

LYSARC

Address

2d Lyon Sud Batiment

City

Pierre Benite Cedex

Postcode

69495

Country

France

Scientific contact point

Organisation

LYSARC

Contact name

Franck MORSCHHAUSER

Public contact point

Organisation

LYSARC

Contact name

Anne VIOLA

Locations

2 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications