A Phase 1b/3 double-blind, randomized, active-controlled, 3-stage, biomarker adaptive study of tazemetostat or placebo in combination with lenalidomide plus rituximab in subjects with relapsed/refractory follicular lymphoma.
1. Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
4. Males or females are ≥18 years of age (≥20 years for Taiwan) at the time of providing voluntary written informed consent.
5. Life expectancy ≥3 months before enrollment.
6. Subjects with a history of hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #15 and are hepatitis B Surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA.
7. Have histologically confirmed FL, Grades 1 to 3A.
8. Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.
9. Must have documented relapsed, refractory, or PD after treatment with systemic therapy (refractory defined as less than partial response (PR) or disease progression <6 months after last dose).
10. Have measurable disease as defined by the Lugano Classification
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
12. For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy).
13. Have provided sufficient tumor tissue for EZH2 mutation testing and to allow for
Stratification
14. 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 weeksfrom 50% pelvic or total body irradiation.
15. Adequate renal function defined as calculated creatinine clearance ≥40 mL/minute per the Cockcroft and Gault formula.
16. Adequate bone marrow function: a. Absolute neutrophil count (ANC) ≥1,000/mm3 (≥1.0 × 109/L) if no lymphoma infiltration of bone marrow OR ANC ≥750/mm3 (≥0.75 × 109/L) with bone marrow infiltration • Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days. b. Platelets ≥75,000/mm3 (≥75 × 109/L) • Evaluated at least 7 days after platelet transfusion. c. Hemoglobin ≥9.0 g/dL • May receive transfusión.
17. 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), ALT, and AST ≤3 × ULN (≤5 × ULN if subject has liver metastases).
18. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0).
19. Females of childbearing potential (FCBP) must have two negative urine or serum pregnancy tests (beta-human chorionic gonadotropin [β-hCG] tests with a mínimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening prior to dosing.
20. Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously.
21. All study participants enrolled must be registered into the mandatory Revlimid REMS™ program for the US or Revlimid Global PPP for ex-US and be willing and able to comply with the requirements of the Revlimid REMS™ or Revlimid Global PPP program as appropriate for the country in which the drug is being used.
22. 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.
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
2. Prior exposure to lenalidomide.
3. Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL (subjects transformed from DLBCL to FL may be enrolled).
4. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3.
5. Has a prior history of T-LBL/T-ALL.
6. Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
7. Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers.
8. Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet.
9. Major surgery within 4 weeks before the first dose of study drug.
10. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition.
11. Significant cardiovascular impairment.
12. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to ≥480 msec at screening or history of long QT syndrome.
13. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
14. Have an active infection requiring systemic therapy.
15. Known hypersensitivity to any component of tazemetostat or lenalidomide.
16. Inability to be treated with a Pneumocystis prophylaxis medication.
17. Active viral infection with or seropositive for hepatitis B virus.
18. Active viral infection with hepatitis C virus.
23. Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study OR interfere with their ability to receive study treatment or complete the study.
24. Female subjects who are pregnant or lactating/breastfeeding.
25. Subjects who have undergone a solid organ transplant.
26. Subjects with malignancies other than FL.
This is a multicenter, double-blind, active-controlled, randomized, 3-stage, biomarker enrichment design featuring early futility stopping and sample-size re-estimation with safety run-in designed to evaluate the efficacy and safety of tazemetostat in combination with R2 in subjects with R/R FL, who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy. Stage 1 is a safety run-in phase, Stage 2 is an efficacy and safety phase for an assessment of the EZH2
MT population and overall FL population regardless of EZH2 mutation status, and the optional Stage 3 is a efficacy and safety phase for subjects with EZH2 mutation. Stage 3 with MT population alone will be executed in case the efficacy of the overall population in Stage 2 fails whilst the efficacy of EZH2 MT is sufficiently promising. Stage 2 will include 2 futility interim analyses based on ORR for the first futility and PFS for the second one. In addition, there is a possible sample size re-estimation based on PFS. This is to ensure early detection of the presence/absence of clinical efficacy benefit as well as ensuring adequate powering based on the trial results to demonstrate a meaningful efficacy difference.
