Phase 1b/3 Study of Tazemetostat with Lenalidomide and Rituximab in Relapsed/Refractory Follicular Lymphoma Patients
- Trial ID
- 2024-510690-16-00
- Protocol
- EZH-302
- Sponsor
- Epizyme Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of tazemetostat in combination with lenalidomide plus rituximab (R2) in patients with relapsed/refractory follicular lymphoma (R/R FL) during Phase 1b (Stage 1, Safety Run-In). This includes selecting a recommended Phase 3 dose (RP3D) of tazemetostat for further evaluation. Additionally, in Phase 3 (Stages 2 and 3, Randomized), the study aims to evaluate and compare progression-free survival (PFS) of tazemetostat + R2 versus placebo + R2 in patients with R/R FL, specifically in the EZH2 wild-type (WT) and EZH2 mutant (MT) populations separately. The clinical relevance of these objectives lies in determining the optimal dosing and assessing the efficacy of tazemetostat in improving PFS, which is a critical endpoint in the management of R/R FL.
Secondary objectives include: - Phase 1b (Stage 1, Safety Run-In): Assessing the clinical activity and pharmacokinetics (PK) of tazemetostat when administered concomitantly with R2 in patients with R/R FL. - Phase 3 (Stages 2 and 3, Randomized): Evaluating and comparing complete response rate (CRR), objective response rate (ORR), overall survival (OS), progression-free survival (PFS) as assessed by the Investigator and by a blinded independent review committee (IRC), duration of response (DOR), disease control rate (DCR), population PK parameters including exposure-response of tazemetostat, safety and tolerability, and health-related quality of life (QoL) as measured by the EQ-5D-5L instrument and the FACT-Lym in patients with R/R FL in EZH2 WT and EZH2 MT patient populations separately, and in all patients regardless of mutation status.
Participants
The clinical trial involves a total of **316 participants** diagnosed with **relapsed/refractory follicular lymphoma**. The study population includes both male and female subjects, aged **18 years and older**, who have a life expectancy of at least three months. Participants were selected based on their ability to provide informed consent and their willingness to comply with the study protocol. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating a range from fully active to ambulatory and capable of all self-care but unable to carry out any work activities. Participants must have adequate renal, bone marrow, and liver function, and meet specific criteria regarding prior anticancer therapies. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to a pregnancy prevention program if applicable. The trial population includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. Key inclusion criteria include having histologically confirmed follicular lymphoma, grades 1 to 3A, and having been previously treated with at least one prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy. Participants must have documented relapsed or refractory disease after treatment with systemic therapy.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **tazemetostat** in combination with **lenalidomide** and **rituximab** versus a placebo in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma. This study is structured as a Phase 1b/3, double-blind, randomized, active-controlled, and biomarker-adaptive trial. The trial is divided into three stages, with the first stage focusing on safety and dose selection, and the subsequent stages evaluating progression-free survival in different genetic populations. The estimated duration of the trial is from June 2020 to March 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including performance status, tumor tissue availability for mutation testing, and adequate organ function. Following the screening, eligible participants will be randomized to receive either the investigational drug combination or the placebo combination. The trial includes regular follow-up visits to monitor safety, efficacy, and pharmacokinetics, with assessments such as blood tests, imaging, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement varies depending on the treatment arm and response to therapy, with a maximum treatment period of 36 months for the investigational drug. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to comply with the study protocol, including adherence to contraception requirements and regular health assessments, to ensure the integrity and safety of the trial.
Treatment
The clinical trial involves the administration of several treatments, including experimental and non-experimental medications. **Tazemetostat** is the primary experimental medication, administered in the form of a film-coated tablet. The maximum daily dose is 1600 mg, and it is administered orally. The treatment period for tazemetostat extends up to 36 months. This medication is classified as a chemical substance and is designated as an orphan drug for this study.
**Rituximab** is used in the trial in two formulations: MabThera and Truxima. MabThera is available as a 100 mg and 500 mg concentrate for solution for infusion, while Truxima is available in the same concentrations. Both formulations are administered intravenously. The maximum total dose for rituximab is 375 mg/m², with a treatment period of up to 5 months. Rituximab is a biological substance, specifically a protein of other origin.
**Lenalidomide** is utilized in various formulations, including Revlimid, Lenalidomide Mylan, and Lenalidomide Ratiopharm, with dosages ranging from 2.5 mg to 20 mg in hard capsule form. The administration route is oral, with a maximum daily dose corresponding to the specific formulation and strength. The treatment period for lenalidomide is up to 12 months. Lenalidomide is classified as a chemical substance.
A **placebo** is also employed in the study, which is not identical to the investigational medicinal product (IMP). The major ingredients of the placebo include microcrystalline cellulose, starch, magnesium stearate, and opadry red or yellow. The placebo serves as a comparator in the trial to evaluate the efficacy and safety of the experimental treatments.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the evaluation of the Recommended Phase 3 Dose (RP3D) of **tazemetostat** in combination with **rituximab** and **lenalidomide** (R2) by assessing the safety and tolerability in subjects with relapsed/refractory follicular lymphoma (R/R FL). This will be determined by the occurrence of treatment-emergent dose-limiting toxicities (DLTs) and adverse events (AEs). Additionally, Progression-Free Survival (PFS) will be evaluated in both the Intent-to-treat wild-type (ITT-WT) and mutant-type (ITT-MT) populations, defined as the time from randomization to confirmed disease progression or death, as assessed by Investigators.
Secondary endpoints include pharmacokinetic parameters such as the maximum observed plasma drug concentration (Cmax), time to maximum observed drug concentration (Tmax), and area under the plasma concentration-time curve (AUC) for **tazemetostat** and its metabolites. Complete Response Rate (CRR) and Objective Response Rate (ORR) will be assessed in various populations, including ITT-WT, ITT-MT, and R/R FL populations, according to the 2014 Lugano Classification. Overall Survival (OS) and Duration of Response (DOR) will also be measured, along with Disease Control Rate (DCR) and Duration Of Complete Response (DOCR). These efficacy parameters will be assessed by both the Investigator and a blinded Independent Review Committee (IRC).
The trial will utilize validated scales and classification systems, such as the 2014 Lugano Classification, to ensure consistent and reliable measurement of efficacy outcomes. The schedule for measuring these parameters will align with the trial's design, ensuring comprehensive data collection throughout the study duration. The trial will also incorporate quality of life assessments using instruments like the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) and the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) to evaluate health-related quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
- Within 7 days prior to randomization, all clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy must have either resolved to Grade 1 per NCI CTCAE Version 5.0 OR are clinically stable and no longer clinically significant.
- Males or females are ≥18 years of age, or per country adult legal age regulations, at the time of providing voluntary written informed consent.
- Life expectancy ≥3 months before enrollment.
- Meet requirements for hepatitis and human immunodeficiency virus (HIV) infection as follows: • Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection Note: Participants whose HBV infection status could not be determined by serologic test results have to be negative for HBV-DNA by PCR to be eligible for study participation. Participants seropositive for HBV with undetectable HBV DNA by PCR are permitted with appropriate antiviral prophylaxis. • Negative test results for hepatitis C virus (HCV) Note: Participants who are positive for HCV antibody must be negative for HCV RNA by PCR to be eligible for study participation • If HIV positive, HIV infection is controlled. Based on Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections - Guidance for Industry (https://www.fda.gov/media/121319/download), patients with HIV should be considered eligible if they have CD4+ T-cell counts ≥ 350 cells/uL and in general, if they have not had an opportunistic infection within the past 12 months. Other exclusion criteria should be considered regarding the drug-drug interaction if antiviral drugs are used. Therefore, in case of controlled HIV infection, since antiviral drugs are used, trial patients should be on established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment.
- Have histologically confirmed FL, Grades 1 to 3A.
- Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy: a. Systemic therapy includes treatments such as: i. Rituximab monotherapy ii. Chemotherapy given with or without rituximab iii. Radioimmunoconjugates such as 90Y-ibritumomab tiuxetan and 131I- tositumomab. b. Systemic therapy does not include, for example: i. Local involved field radiotherapy for limited-stage disease ii. Helicobacter pylori eradication c. Prior investigational therapies will be allowed provided the subject has received at least 1 prior systemic therapy as discussed in Inclusion Criterion #6a. d. Prior autologous/allogeneic hematopoietic stem cell transplant (HSCT) will be allowed. e. Prior chimeric antigen receptor T-cell therapy (CAR T) will be allowed.
- Must have documented relapsed, refractory, or PD after treatment with systemic therapy (refractory defined as less than PR or disease progression <6 months after last dose).
- Have measurable disease as defined by the Lugano Classification (Cheson, 2014; Appendix 5).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- Have provided sufficient tumor tissue block or unstained slides for EZH2 mutation testing in all subjects to allow for stratification a. If EZH2 mutation status is known from site-specific testing, subjects can be enrolled. Tumor tissue will be required for confirmatory testing of EZH2 status at study-specific laboratories. If the archival tumor sample was collected more than 24 months prior to the anticipated administration of the first dose (cycle 1 day 1), then a fresh biopsy must be provided. Fresh tumor biopsy is appropriate except for procedures deemed to result in unacceptable risk because of the anatomical location including brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel. Archival tumor biopsy sections mounted on slides are also acceptable. NOTE: Confirmatory testing will also be performed for Stage 1, if local EZH2 testing is conducted, unless there is insufficient tumor tissue to perform testing after discussion with the Sponsor’s or Designee Medical Monitor.
- Time between prior anticancer therapy and first dose of tazemetostat as follows: a. Cytotoxic chemotherapy – At least 21 days. b. Noncytotoxic chemotherapy (eg, small molecule inhibitor) – At least 14 days. c. Nitrosoureas – At least 6 weeks. d. Monoclonal and/or bispecific antibodies or CAR T – At least 28 days. e. Radiotherapy – At least 6 weeks from prior radioisotope therapy; at least 12 weeks from 50% pelvic or total body irradiation.
- Adequate renal function defined as calculated creatinine clearance ≥30 mL/minute per the Cockcroft and Gault formula.
- Adequate bone marrow function: a. Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 × 10^9/L) if no lymphoma infiltration of bone marrow OR ANC ≥750/mm3 (≥75 × 10^9/ L) with bone marrow infiltration • Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days. b. Platelets ≥75,000/mm3 (≥75 × 10^9/L) • Evaluated at least 7 days after last platelet transfusion. c. Hemoglobin ≥9.0 g/dL • May receive transfusion
- Adequate liver function: a. Total bilirubin ≤1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome. b. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver infilration).
- International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects with thromboembolism risk, prophylactic anticoagulation, or antiplatelet therapy at investigator discretion is recommended.
- Females of childbearing potential (FCBP) must have a negative urine or serum pregnancy tests (beta-human chorionic gonadotropin [β-hCG] tests with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening within 10 to 14 days prior to first dose of study drug. The subject may not receive study drug until the study doctor has verified that the results of pregnancy tests are negative. All females will be considered to be of childbearing potential unless they are naturally postmenopausal (at least 24 months consecutively amenorrhoeic [amenorrhea following cancer therapy does not rule out childbearing potential] and without other known or suspected cause) or have been sterilized surgically (ie, total hysterectomy and/or bilateral oophorectomy, with surgery completed at least 1 month before dosing).
- Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously. This includes ONE highly effective method of contraception and ONE additional effective contraceptive method. Contraception must begin at least 28 days prior to first dose of study drug, continue during study treatment (including during dose interruptions), and for 12 months after study drug discontinuation. Female subjects must also refrain from breastfeeding for 12 months following last dose of study drug. If the below contraception methods are not appropriate for the FCBP, she must be referred to a qualified contraception provider to determine the medically effective contraception method appropriate for the subject. The following are examples of highly effective and additional effective methods of contraception: Examples of highly effective methods: • Intrauterine device (IUD) • Hormonal (ovulation inhibitory combined [estrogen and progesterone] birth control pills or intravaginal/transdermal system, injections, implants, levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills [e.g. desogestrel]) NOTE: There is a potential for tazemetostat interference with hormonal contraception methods due to enzymatic induction. • Bilateral tubal ligation • Partner’s vasectomy (if medically confirmed [azoospermia] and sole sexual partner). Examples of additional effective methods: • Male latex or synthetic condom, • Diaphragm, • Cervical Cap NOTE: Female subjects of childbearing potential exempt from these contraception requirements are subjects who practice complete abstinence from heterosexual sexual contact. True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception.
- All study participants enrolled must be registered into the applicable pregnancy prevention program (e.g. REVLIMID REMS in the US, Pregnancy Prevention Programme [PPP] in Europe) for lenalidomide to be administered and be willing and able to comply with the requirements of the applicable program as appropriate for the country in which the drug is being used. a. Female subjects of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the applicable pregnancy prevention program. During study treatment, FCBP must agree to have pregnancy testing weekly for the first 28 days of study participation and then every 28 days for FCBP with regular or no menstrual cycles OR every 14 days for FCBP with irregular menstrual cycles. FCBP must also have a pregnancy test at end of lenalidomide treatment, at day 14 (for FCBP with irregular menstrual cycles) and day 28 following the last dose of lenalidomide and at overall treatment discontinuation (at the End-of-Treatment/30-day safety Follow-up visit). Female subjects exempt from this requirement are subjects who have been naturally postmenopausal for at least 24 consecutive months OR are surgically sterilized (ie, total hysterectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose of study treatment.
- Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a pregnant female or FCBP from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
Exclusion Criteria
- Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
- Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.
- Prior exposure to lenalidomide or drugs of the same class.
- Grade 3b, mixed histology, or FL that has histologically transformed to diffuse large B-cell lymphoma (DLBCL) (subjects transformed from DLBCL to FL may be enrolled).
- Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE Version 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
- Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL).
- Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
- Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. John’s wort).
- Are unwilling to exclude grapefruit juice, Seville oranges, and grapefruits from the diet and/or consumed within 1 week of the first dose of study drug and for the duration of the study.
- Major surgery within 4 weeks before the first dose of study drug. a. Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
- Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.
- Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to ≥480 msec at screening or history of long QT syndrome.
- Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat. a. Note: Participants who have experienced deep vein thrombosis/ pulmonary embolism more than 3 months before enrollment are eligible but are recommended to receive prophylaxis
- Have an active infection requiring systemic therapy.
- Known hypersensitivity to any component of tazemetostat or lenalidomide; known severe hypersensitivity to any component of rituximab requiring hospitalization or resuscitation.
- Active viral infection with or seropositive for HBV: HBV surface antigen (HBsAg) positive OR HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable HBV DNA. NOTE: Subjects who are HBsAg negative, anti-HBs positive and/or anti-HBc positive, but with undetectable viral DNA and normal ALT are eligible. Subjects who are seropositive due to HBV vaccination (HBsAg negative, HBV surface antibody [anti-HBs] positive, and HBV core antibody [anti-HBc] negative) are eligible.
- Active viral infection with hepatitis C virus (as measured by positive HCV antibody and detectable viral RNA, HIV), or known active infection with human T-cell lymphotropic virus. NOTE: Subjects with a history of hepatitis C infection (HCV antibody reactive) who have normal ALT and undetectable HCV RNA are eligible.
- Any other medical or social condition that, in the Investigator’s judgment, will interfere with a participant’s ability to provide informed consent, to receive study drugs, or meet study demands, or that substantially increases the risk associated with the subject’s participation in the study, or that may interfere with interpretation of results.
- Female subjects who are pregnant or lactating/breastfeeding.
- Subjects who have undergone a solid organ transplant.
- Subjects with malignancies other than FL. a. Exception: Subjects with another malignancy who have been disease-free for 3 years, or subjects with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 11 Jun 2020 | 10 |
 France | Recruiting | 11 Jun 2020 | 70 |
 Germany | Recruiting | 11 Jun 2020 | 14 |
 Hungary | Recruiting | 11 Jun 2020 | 12 |
 Italy | Recruiting | 11 Jun 2020 | 50 |
 Poland | Recruiting | 11 Jun 2020 | 38 |
 Spain | Recruiting | 11 Jun 2020 | 32 |
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 |
|---|---|---|---|---|---|---|
MabThera 100 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 0 | 5 | PRD2154041 |
Lenalidomide Mylan 2.5 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 2.5 | 12 | PRD8601756 |
Lenalidomide Mylan 15 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 15 | 12 | PRD8601766 |
Lenalidomide Mylan 2.5 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 2.5 | 12 | PRD8601757 |
Lenalidomide ratiopharm 15 mg, harde capsules | Comparator | HARDE CAPSULES | ORAL USE | 15 | 12 | PRD6842653 |
Lenalidomide ratiopharm 2,5 mg, harde capsules | Comparator | HARDE CAPSULES | ORAL USE | 2.5 | 12 | PRD6842634 |
Lenalidomide Mylan 20 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 20 | 12 | PRD8601769 |
Revlimid 10 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 10 | 12 | PRD9264283 |
Lenalidomide Mylan 15 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 15 | 12 | PRD8601765 |
Placebo not identical to IMP, major ingredients: microcrystalline cellulose, starch, magnesium stearate, opadry red or yellow | Placebo | N/A | — | — | — | N/A |