Clinical trial NCT04762160: SYMPHONY-2, A Trial to Examine Combination of Tazemetostat With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma
Official title: SYMPHONY-II: A Phase II Open-Label, Multicenter Trial of Oral Tazemetostat in Combination With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Follicular Lymphoma
Keywords: follicular lymphoma
relapse follicular lymphoma
refractory follicular lymphoma
rituximab
tazemetostat
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
Collaborators: name: Swedish Cancer Institute
First posted: 2021-02-21
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Planned to be assessed during Cycles 3, 6, 12, 18, and 24.
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 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
measure: Duration of Response (DOR)
timeFrame: 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
measure: ORR in a Subset of Participants With MT EZH2
timeFrame: Planned to be assessed at the following timepoints: Cycles 3, 6, 12, 18, and 24
measure: ORR in Rituximab Refractory Participants
timeFrame: Planned to be assessed at the following timepoints: Cycle 3, Cycle 6, Cycle 12, Cycle 18, and Cycle 24.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Oncology
state: Alabama
city: Fountain Valley
country: United States
facility: Compassionate Cancer Care
state: California
city: Boulder
country: United States
facility: USOR/Rocky Mountain Cancer Centers
state: Colorado
city: Niles
country: United States
facility: USOR/ Illinois Cancer Specialists
state: Illinois
city: Rolling Meadows
country: United States
facility: XCancer/ Northwest Oncology & Hematology
state: Illinois
city: Farmington Hills
country: United States
facility: Revive/Oakland Medical Group
state: Michigan
city: Sterling Heights
country: United States
facility: Revive/Hematology Oncology Associates of Rockland
state: Michigan
city: Albany
country: United States
facility: USOR/ NY Oncology Hematology
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: USOR/ Oncology & Hematology Care Clinical Trials
state: Ohio
city: Kettering
country: United States
facility: XCancer/Dayton Physicians Network
state: Ohio
city: Knoxville
country: United States
facility: XCancer/Tennessee Cancer Specialists
state: Tennessee
city: Austin
country: United States
facility: USOR/ Texas Oncology
state: Texas
city: Dallas
country: United States
facility: USOR/Texas Oncology
state: Texas
city: San Antonio
country: United States
facility: USOR/ Texas Oncology
state: Texas
city: Tyler
country: United States
facility: USOR/ Texas Oncology
state: Texas
city: Weslaco
country: United States
facility: USOR/Texas Oncology
state: Texas
city: Gainesville
country: United States
facility: USOR/Virginia Cancer Specialists
state: Virginia
city: Roanoke
country: United States
facility: USOR/Oncology & Hematology Associates of Southwest Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: