Phase Ib-II Evaluation of Tazemetostat with R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma and High-Risk Follicular Lymphoma Patients
- Trial ID
- 2024-515846-18-00
- Protocol
- Epi-RCHOP
- Sponsor
- Lysarc
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended Phase II dose (RP2D) for **tazemetostat** in patients with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high-risk Follicular Lymphoma (FL) treated with R-CHOP. This is clinically relevant as establishing the RP2D is crucial for optimizing therapeutic efficacy and minimizing adverse effects in subsequent treatment phases. Additionally, the study aims to determine the Complete Response Rate (CRR) based on local assessment according to Cheson IWG 2014: Lugano Classification at the end of treatment or at permanent treatment discontinuation for both DLBCL and FL cohorts. This assessment is vital for evaluating the effectiveness of the treatment regimen in achieving complete remission.
Secondary objectives include:
- Assessing the pharmacokinetics of the CHOP 21 components and tazemetostat, including its metabolite EZH-6930, in combination.
- Evaluating the preliminary anti-tumor activity of tazemetostat in patients treated with R-CHOP 21 using Cheson IWG 2014 criteria.
- Determining the safety of tazemetostat at the end of treatment or at permanent treatment discontinuation in both DLBCL and FL cohorts.
- Determining the Complete Response Rate (CRR) by central review at the end of treatment.
- Evaluating the overall response rate (ORR), progression-free survival (PFS), duration of response, and overall survival (OS) at specified intervals and overall.
- Evaluating the Best Overall Response (BOR).
- Determining the PET EOI CRR rate by central review.
- Determining the complete response rate and overall response rate at the end of rituximab maintenance according to Lugano 2014 Classification.
- Evaluating progression-free survival (PFS) overall and at 24 months, event-free survival (EFS) overall and at 24 months, and overall survival (OS).
Participants
The clinical trial involves participants diagnosed with **Diffuse Large B Cell Lymphoma** or high-risk Follicular Lymphoma treated with R-CHOP. The study population includes both male and female subjects, with age ranges from 18 to 80 years for the Follicular Lymphoma cohort and 60 to 80 years for the Diffuse Large B Cell Lymphoma cohort. Participants are required to have a life expectancy of at least 90 days and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. The trial does not include a vulnerable population. Participants must have adequate renal, liver, and bone marrow function, and males and females of childbearing potential must adhere to specific contraception guidelines. The sponsor has not provided the total number of participants involved in the trial. The selection criteria emphasize untreated de novo or transformed lymphoma cases, with specific requirements for measurable disease and adequate tissue for pathology review. Lifestyle factors such as diet and physical activity are not specified in the trial data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **tazemetostat** in combination with R-CHOP in patients with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high-risk Follicular Lymphoma (FL). This study is structured as a Phase Ib-II trial, incorporating a randomized, double-blind, controlled methodology. The trial is expected to span from September 2020 to December 2026, with participant involvement lasting until the end of treatment or permanent treatment discontinuation. The primary objective in Phase Ib is to determine the recommended Phase II dose (RP2D) of tazemetostat, while Phase II aims to assess the Complete Response Rate (CRR) based on the Cheson IWG 2014: Lugano Classification.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. The trial includes multiple follow-up visits to monitor treatment response and adverse events, with assessments conducted at the end of each treatment cycle. The end-of-study visit will occur after the completion of 6 cycles of Epi-RCHOP 21 plus 2 cycles of tazemetostat and **rituximab**, or upon permanent treatment discontinuation. The expected length of participant involvement is approximately 8 cycles, with each cycle lasting 21 days.
Participants may be subject to early termination from the study if they experience severe treatment-emergent adverse events, fail to comply with study protocols, or withdraw consent. The trial will also evaluate secondary endpoints, including pharmacokinetic parameters and the complete response rate according to the Lugano Classification. The study drugs, including **cyclophosphamide**, **doxorubicin**, **vincristine**, and **prednisolone**, will be administered via intravenous infusion or oral use, depending on the specific medication. The trial's rigorous design ensures a comprehensive assessment of the investigational treatment's potential benefits and risks in the target patient population.
Treatment
The clinical trial involves the administration of several **experimental medications** and auxiliary treatments for patients diagnosed with Diffuse Large B Cell Lymphoma (DLBCL) or high-risk Follicular Lymphoma (FL). The primary experimental medication is **Tazemetostat**, a chemical compound provided in the form of a film-coated tablet. It is administered orally. The dosing schedule for Tazemetostat is determined during the Phase Ib of the trial to establish the recommended phase II dose (RP2D). Participant compliance with the oral administration is monitored through regular assessments.
**Cyclophosphamide** is utilized as an auxiliary treatment in this study. It is a chemical substance formulated as a solution for injection and is administered via intravenous infusion. The frequency and dosage are aligned with the standard R-CHOP regimen, which is a common chemotherapy protocol for lymphoma treatment.
**Rituximab** is another auxiliary treatment used in the trial, available in two pharmaceutical forms: a concentrate for solution for infusion and a solution for injection. It is administered both intravenously and subcutaneously, depending on the specific formulation. Rituximab is a monoclonal antibody that targets CD20-positive B cells, and its administration is consistent with the R-CHOP regimen.
**Prednisolone** is included as an auxiliary treatment, provided in tablet form for oral use. It is a glucocorticoid used to reduce inflammation and modulate immune response, administered according to the R-CHOP protocol.
**Doxorubicin** is administered as a solution for injection via intravenous infusion. It is an anthracycline antibiotic that interferes with DNA replication, and its use is part of the standard R-CHOP chemotherapy regimen.
**Vincristine** is also part of the auxiliary treatments, provided as a solution for injection and administered through intravenous infusion. It is a vinca alkaloid that inhibits microtubule formation, contributing to the cytotoxic effects of the R-CHOP regimen.
Throughout the trial, participant compliance with the treatment regimen is monitored through regular clinical assessments and documentation of drug administration. The trial aims to evaluate the efficacy and safety of the combined treatment regimen, with a focus on determining the complete response rate in the specified patient cohorts.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of the **Complete Response Rate (CRR)** in patients with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) or high-risk Follicular Lymphoma (FL) treated with the Epi-RCHOP regimen. The CRR will be determined based on local assessment according to the Cheson IWG 2014: Lugano Classification, specifically using categories 1-3 on the 5-point Deauville scale. This assessment will occur at the end of treatment or upon permanent treatment discontinuation. The end of treatment is defined as after 6 cycles of Epi-RCHOP 21 plus 2 cycles of Tazemetostat and Rituximab. Permanent treatment discontinuation is defined as the cessation of all treatments, including Rituximab, CHOP, and Tazemetostat.
Secondary efficacy endpoints include pharmacokinetic (PK) parameters such as 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 various drugs including cyclophosphamide, prednisolone, doxorubicin, doxorubicinol, methyl prednisolone, prednisone, vincristine, tazemetostat, and EPZ-6930, if data permit. These PK parameters will provide additional insights into the drug's behavior in the body, contributing to the overall assessment of efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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
- Cohort DLBCL 2. Age between 60 and 80 years included Cohort FOLLICULAR :2. Aged between 18 years and 80 years included
- ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
- Signed informed consent
- Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
- Adequate renal function as calculated by a creatinine clearance > 40 mL/min by local institutional formula
- 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)
- 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.
- Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
- Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11)
- Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
- 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)
- Patient covered by any social security system (for France only)
- Patient who understands and speaks one of the country official languages
Exclusion Criteria
- Central nervous system or meningeal involvement
- Contraindication to any drug contained in the chemotherapy regimen
- Prior treatment with tazemetostat or other inhibitor of EZH2
- 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
- Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John’s wort)
- Patients unwilling to exclude St. John’s wort, Seville oranges, grapefruit juice and/or grapefruit from diet
- 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)
- Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat
- 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
- Not applicable
- Active uncontrolled infection requiring systemic therapy
- Congenital immunodeficiency or known HIV (human immunodeficiency virus infection)
- Any other major illness, that in the investigator’s judgement, will substantially increase the risk associated with the patient’s participation in the study
- Patients who have undergone a solid organ transplant
- 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)
- Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy
- Cohort FOLLICULAR :Pregnant or lactating females
- Person deprived of his/her liberty by a judicial or administrative decision
- Adult person under legal protection
- Person hospitalized without consent
- Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 30 Sept 2020 | 19 |
 France | Not Recruiting | 30 Sept 2020 | 195 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CYCLOPHOSPHAMIDE | Other | — | INTRAVENIOUS INFUSION | — | — | SUB06859MIG |
RITUXIMAB | Other | — | SUBCUTANEOUS | — | — | SUB12570MIG |
RITUXIMAB | Other | — | INTRAVENIOUS INFUSION | — | — | SUB12570MIG |
TAZEMETOSTAT | Test | — | ORAL USE | — | — | SUB178719 |
PREDNISOLONE | Other | — | ORAL USE | — | — | SUB10018MIG |
VINCRISTINE | Other | — | INTRAVENIOUS INFUSION | — | — | SUB00059MIG |
DOXORUBICIN | Other | — | INTRAVENIOUS INFUSION | — | — | SUB06391MIG |
RITUXIMAB | Other | — | INTRAVENIOUS INFUSION | — | — | SUB12570MIG |