SYMPHONY-2, A Trial to Examine Combination of Tazemetostat With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma

Study Overview
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Brief Summary
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This study evaluates the safety and efficacy of combining the EZH2 inhibitor tazemetostat with rituximab in R/R FL subjects previously treated with at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used.

Detailed Description
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This is a phase 2, multicenter, open-label study of oral tazemetostat in combination with rituximab in subjects with relapsed or refractory (R/R) follicular lymphoma (FL). This study is designed to evaluate the safety and efficacy of tazemetostat in combination with rituximab in subjects previously treated with at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used, and used and features early futility stopping to maintain subject safety.

Official Title
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SYMPHONY-II: A Phase II Open-Label, Multicenter Trial of Oral Tazemetostat in Combination With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Tazemetostat
* Combination Product: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women of 18 years of age and older Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol Eastern Cooperative Oncology Group (ECOG) score of 0 </=, 1 or 2 Life expectancy (in the opinion of the investigator) of >3 months before enrollment Have histologically confirmed FL, Grade 1 to 3a. Subjects may have R/R disease following at least 2 standard prior systemic treatment regimens where at least 1 anti- CD20-based regimen was used Treatment recommended in accordance with the Groupe d'Etude des Lymphomes b Folliculaires (GELF) criteria Meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion dependence Hemoglobin ≥ 8 g/dL Serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ Incl3.0 x ULN, unless related to disease involvement Total bilirubin ≤ 1.5 x ULN, unless due to disease involvement, Gilbert's syndrome, or hemolytic anemia Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 40 mL/min At least one bi-dimensionally measurable nodal lesion > 1.5 cm in its longest diameter by computed tomography (CT) scan or magnetic resonance imaging (MRI) Any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy), except for alopecia, either resolved to ≤ Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or is clinically stable and no longer clinically significant Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection Negative test results for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Females of childbearing potential (FCBP) must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening and within 24 hours prior to the first dose of study drug. FCBP must either practice complete abstinence or agree to use a highly effective method of contraception beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), for 6 months after tazemetostat discontinuation, and for 12 months after rituximab discontinuation. . Male subjects must have had a successful vasectomy (with medically confirmed azoospermia) OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a FCBP from the 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 Grade 2b, mixed histology, or transformed FL Treatment with any of the following anticancer therapies within the timeframe of a specific treatment prior to first dose of study drug: Cytotoxic chemotherapy within 21 days Noncytotoxic chemotherapy (e.g. small molecule inhibitor) within 14 days Nitrosoureas within 6 weeks Prior immunotherapy within 4 weeks Radiotherapy- within 6 weeks from prior radioisotope therapy; within 12 weeks from 50% pelvic or total body irradiation Any investigational treatment within 4 weeks or at least 5 half lives, whichever is shorter History of solid organ transplant Major surgery within 4 weeks of the start of study treatment Thrombocytopenia, neutropenia, or anemia of Grade > 3 (per CTCAE v5.0 criteria) or any prior history of myeloid malignancies, including MDS/AML or MPN Prior history of T-LBL/T-ALL Unwillingness to exclude grapefruit juice-containing products, Seville oranges, and grapefruits from the diet and/ or consumed within 1 week of the first dose of study drug Subjects taking medications that are known strong cytochrome P450 (CYP)3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort) Any uncontrolled illness History of clinically significant cardiovascular abnormalities History of clinically significant gastrointestinal (GI) conditions Other diagnosis of cancer that is likely to require treatment in the next 2 years Females who are pregnant or lactating/breastfeeding Received a live virus vaccination within 28 days of first dose of rituximab Concurrent participation in a separate investigational therapeutic study Psychiatric illness/social situations that would interfere with study compliance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tazmetostat in combination with rituximab<br>Tazemetostat 800 mg BID is administered daily starting on Cycle 1 Day 1 (C1D1). Tazemetostat will be administered from C1D1 to the end of Cycle 24, for 24 months of therapy or until disease progression, unacceptable toxicity, or withdrawal of consent. Rituximab will be administered by either subcutaneous injection or IV infusion according to the regional product prescribing information, labeling and institutional guidelines. Rituximab will be administered at a dose of 375 mg/m2 on Day 1, 8, 15, and 22 of Cycle 1, and then on Day 1 of Cycles 3 through 6, accounting for an additional 4 doses, i.e., a total of 8 doses of rituximab in 6 cycles. | Drug: Tazemetostat<br>* Study Drug<br>* Other names: EPZ-6438;Combination Product: Rituximab<br>* Partner Drug<br>* Other names: Rituximab Hyaluronidase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants with WT EZH2 status who achieved a complete response (CR) or partial response (PR) according to the 2014 Lugano Classification as assessed by investigator and blinded independent review committee (IRC). CR = complete metabolic response per positron emission tomography-computed tomography (PET-CT) based response or complete radiologic response per CT-based response. PR = partial metabolic response per PET-CT-based response or partial remission per CT-based response. | Planned to be assessed during Cycles 3, 6, 12, 18, and 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time from first dose of study drug to the time of the earliest date of CR or PR per the 2014 Lugano Classification or death, whichever occurred first, as assessed by an IRC. CR= complete metabolic response per PET-CT based response or complete radiologic response per CT-based response. PR= partial metabolic response per PET-CT-based response or partial remission per CT-based response. | Planned to be assessed from first dose of study drug to earliest date of disease progression or death as assessed up to 24 months by an IRC | 
| Duration of Response (DOR) | DOR was defined as the time from the earliest date of CR or PR per the 2014 Lugano Classification to documented progression or death, whichever comes first, as assessed by an IRC. CR= complete metabolic response per PET-CT based response or complete radiologic response per CT-based response. PR= partial metabolic response per PET-CT-based response or partial remission per CT-based response. | Planned to be assessed from earliest date of CR or PR to documented progression or death as assessed up to 24 months by an IRC | 
| ORR in a Subset of Participants With MT EZH2 | ORR was assessed according to 2014 Lugano Classification, in the pooled group regardless of mutation status and in a subset of participants with MT EZH2. | Planned to be assessed at the following timepoints: Cycles 3, 6, 12, 18, and 24 | 
| ORR in Rituximab Refractory Participants | ORR was assessed according to 2014 Lugano Classification, in rituximab refractory participants. | Planned to be assessed at the following timepoints: Cycle 3, Cycle 6, Cycle 12, Cycle 18, and Cycle 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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follicular lymphoma, relapse follicular lymphoma, refractory follicular lymphoma, rituximab, tazemetostat