SYMPHONY-2, A Trial to Examine Combination of Tazemetostat With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma
Condition: Follicular Lymphoma
MeSH terms: Lymphoma; Lymphoma, Follicular
Intervention: Tazemetostat; Rituximab
Intervention description: Study Drug; Partner Drug
Intervention MeSH terms: Rituximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: follicular lymphoma; relapse follicular lymphoma; refractory follicular lymphoma; rituximab; tazemetostat

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men and women of 18 years of age and older

          2. Voluntary agreement to provide written informed consent and the willingness and
             ability to comply with all aspects of the protocol

          3. Eastern Cooperative Oncology Group (ECOG) score of 0 </=, 1 or 2

          4. Life expectancy (in the opinion of the investigator) of >3 months before enrollment

          5. 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

          6. Treatment recommended in accordance with the Groupe d'Etude des Lymphomes b
             Folliculaires (GELF) criteria

          7. Meet the following laboratory parameters:

               1. 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

               2. 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

               3. Hemoglobin ≥ 8 g/dL

               4. Serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤
                  Incl3.0 x ULN, unless related to disease involvement

               5. Total bilirubin ≤ 1.5 x ULN, unless due to disease involvement, Gilbert's
                  syndrome, or hemolytic anemia

               6. Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR]
                  using Cockcroft-Gault) ≥ 40 mL/min

          8. 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)

          9. 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

         10. Negative serologic or polymerase chain reaction (PCR) test results for acute or
             chronic hepatitis B virus (HBV) infection

         11. Negative test results for hepatitis C virus (HCV) and human immunodeficiency virus
             (HIV).

         12. 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.

         13. 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. .

         14. 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:

          1. Prior exposure to Tazemetostat or other inhibitor(s) of EZH2

          2. Grade 2b, mixed histology, or transformed FL

          3. Treatment with any of the following anticancer therapies within the timeframe of a
             specific treatment prior to first dose of study drug:

               1. Cytotoxic chemotherapy within 21 days

               2. Noncytotoxic chemotherapy (e.g. small molecule inhibitor) within 14 days

               3. Nitrosoureas within 6 weeks

               4. Prior immunotherapy within 4 weeks

               5. Radiotherapy- within 6 weeks from prior radioisotope therapy; within 12 weeks
                  from 50% pelvic or total body irradiation

               6. Any investigational treatment within 4 weeks or at least 5 half lives, whichever
                  is shorter

          4. History of solid organ transplant

          5. Major surgery within 4 weeks of the start of study treatment

          6. Thrombocytopenia, neutropenia, or anemia of Grade > 3 (per CTCAE v5.0 criteria) or any
             prior history of myeloid malignancies, including MDS/AML or MPN

          7. Prior history of T-LBL/T-ALL

          8. 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

          9. Subjects taking medications that are known strong cytochrome P450 (CYP)3A inhibitors
             and strong or moderate CYP3A inducers (including St. John's wort)

         10. Any uncontrolled illness

         11. History of clinically significant cardiovascular abnormalities

         12. History of clinically significant gastrointestinal (GI) conditions

         13. Other diagnosis of cancer that is likely to require treatment in the next 2 years

         14. Females who are pregnant or lactating/breastfeeding

         15. Received a live virus vaccination within 28 days of first dose of rituximab

         16. Concurrent participation in a separate investigational therapeutic study

         17. Psychiatric illness/social situations that would interfere with study compliance