Follicular Lymphoma
Conditions
Keywords
follicular lymphoma, relapse follicular lymphoma, refractory follicular lymphoma, rituximab, tazemetostat
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.
Interventions
DRUGTazemetostat
Study Drug
COMBINATION_PRODUCTRituximab
Partner Drug
Sponsors
Swedish Cancer Institute
Epizyme, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Planned to be assessed during Cycles 3, 6, 12, 18, and 24. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 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 | 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. |
| Duration of Response (DOR) | 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 | 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. |
| ORR in a Subset of Participants With MT EZH2 | Planned to be assessed at the following timepoints: Cycles 3, 6, 12, 18, and 24 | 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. |
| ORR in Rituximab Refractory Participants | Planned to be assessed at the following timepoints: Cycle 3, Cycle 6, Cycle 12, Cycle 18, and Cycle 24. | ORR was assessed according to 2014 Lugano Classification, in rituximab refractory participants. |
Countries
United States
Participant flow
Recruitment details
This Phase 2, open-label study was conducted in participants with relapsed/refractory follicular lymphoma who received oral tazemetostat in combination with rituximab. The study was terminated early due to business reasons prior to enrolling the target number of participants needed to achieve target power and was insufficient to produce statistically reliable results.
Pre-assignment details
This study was to include a 28-day screening period, a 2-year (24-cycle) treatment period, and a follow-up period. In treatment period, participants were to be treated in 28-day cycles with tazemetostat in combination with rituximab through Cycle 6 then tazemetostat alone through Cycle 24, for 24 months of therapy or until disease progression, unacceptable toxicity, or withdrawal of consent. Overall 5 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Tazmetostat in Combination With Rituximab Participants were to receive tazemetostat 800 mg BID starting on Cycle 1 Day 1 until the end of Cycle 24, for 24 months of therapy or until study termination. Participants were also to receive rituximab, administered by either as SC injection or IV infusion according to the regional product prescribing information, labeling, and institutional guidelines. Rituximab was to be administered at a dose of 375 mg/m\^2 on Cycle 1 Days 1, 8, 15, and 22 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). Each cycle was 28 days. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Study terminated early due to business reasons | 5 |
Baseline characteristics
| Characteristic | Tazmetostat in Combination With Rituximab |
|---|---|
| Age, Continuous | 70.2 years STANDARD_DEVIATION 10.83 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants |
| Race/Ethnicity, Customized Other/Unknown | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
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.
Time frame: Planned to be assessed during Cycles 3, 6, 12, 18, and 24.
Population: The study was terminated early due to business reasons and only five participants were enrolled, of whom only three were evaluable. No summary statistics are available given the limited data from the small number of evaluable participants and individual participant data are also not presented to protect the privacy of the individuals.
Secondary
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.
Time frame: 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
Population: The study was terminated early due to business reasons and only five participants were enrolled, of whom only three were evaluable. No summary statistics are available given the limited data from the small number of evaluable participants and individual participant data are also not presented to protect the privacy of the individuals.
Secondary
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.
Time frame: Planned to be assessed at the following timepoints: Cycles 3, 6, 12, 18, and 24
Population: The study was terminated early due to business reasons and only five participants were enrolled, of whom only three were evaluable. No summary statistics are available given the limited data from the small number of evaluable participants and individual participant data are also not presented to protect the privacy of the individuals.
Secondary
ORR in Rituximab Refractory Participants
ORR was assessed according to 2014 Lugano Classification, in rituximab refractory participants.
Time frame: Planned to be assessed at the following timepoints: Cycle 3, Cycle 6, Cycle 12, Cycle 18, and Cycle 24.
Population: The study was terminated early due to business reasons and only five participants were enrolled, of whom only three were evaluable. No summary statistics are available given the limited data from the small number of evaluable participants and individual participant data are also not presented to protect the privacy of the individuals.
Secondary
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.
Time frame: 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
Population: The study was terminated early due to business reasons and only five participants were enrolled, of whom only three were evaluable. No summary statistics are available given the limited data from the small number of evaluable participants and individual participant data are also not presented to protect the privacy of the individuals.