Clinical Trials /

Study in Subjects With Relapsed/Refractory Follicular Lymphoma

NCT04224493

Description:

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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study in Subjects With Relapsed/Refractory Follicular Lymphoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: EZH-302
  • NCT ID: NCT04224493

Conditions

  • Relapsed/Refractory Follicular Lymphoma

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438Tazemetostat + R2 Arm
Placebo oral tabletPlacebo + R2 Arm

Purpose

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.

Detailed Description

      Stage 1 is a safety run-in phase, stage 2 is an efficacy and safety phase for an assessment
      of the EZH2 Mutant Type population and overall FL population regardless of EZH2 mutation
      status, and optional stage 3 with efficacy and safety phase for subjects with EZH2 mutation.
      Stage 3 with Mutant Type population alone will be executed in case the efficacy of the
      overall population in stage 2 fails whilst the efficacy of EZH2 Mutant Type 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.
    

Trial Arms

NameTypeDescriptionInterventions
Tazemetostat + R2 ArmActive Comparatortazemetostat RP3D administered PO twice daily in continuous 28-day cycles. rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. lenalidomide 20 mg (if creatinine clearance ≥60 mL/minute) or 10 mg (if creatinine clearance <60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.
  • Tazemetostat
Placebo + R2 ArmPlacebo Comparatorplacebo administered PO twice daily in continuous 28-day cycles. rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. lenalidomide 20 mg (if creatinine clearance ≥60 mL/minute) or 10 mg (if creatinine clearance <60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.
  • Placebo oral tablet

Eligibility Criteria

        Inclusion Criteria:

          1. Have voluntarily agreed to provide written informed consent and demonstrated
             willingness and ability to comply with all aspects of the protocol.

          2. Males or females are ≥18 years of age at the time of providing voluntary written
             informed consent.

          3. Life expectancy ≥3 months before enrollment.

          4. 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.

          5. Have histologically confirmed FL, grades 1 to 3A.

          6. Must have been previously treated with at least 1 prior systemic chemotherapy,
             immunotherapy, or chemoimmunotherapy:

               1. Systemic therapy includes treatments such as:

             i. Rituximab monotherapy ii. Chemotherapy given with or without rituximab iii.
             Radioimmunoconjugates such as 90Y-ibritumomab tiuxetan and 131I-tositumomab.

             b. Systemic therapy does not include, for example: i. Local involved field
             radiotherapy for limited-stage disease ii. Helicobacter pylori eradication Prior
             investigational therapies will be allowed provided the subject has received at least

        1 prior systemic therapy as discussed in Inclusion Criteria #6a. 7. Must have documented
        relapsed, refractory, or PD after treatment with systemic therapy (refractory defined as
        less than PR or disease progression <6 months after last dose).

        8. Have measurable disease as defined by the Lugano Classification (Cheson, 2014).

        9.Time between prior anticancer therapy and first dose of tazemetostat as follows:

          1. Cytotoxic chemotherapy - At least 21 days.

          2. Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days.

          3. Nitrosoureas - At least 6 weeks.

          4. Monoclonal antibody(ies) - At least 28 days.

          5. Radiotherapy -At least 6 weeks from prior radioisotope therapy; at least 12 weeks from
             50% pelvic or total body irradiation. 13. Adequate renal function defined as
             calculated creatinine clearance ≥40 mL/minute per the Cockcroft and Gault formula or
             local institutional standard formula.

             10. Adequate renal function defined as calculated creatinine clearance ≥40 mL/minute
             per the Cockcroft and Gault formula or local institutional standard formula.

             11. Adequate bone marrow function. 12. Females must not be lactating or pregnant at
             Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin
             [β-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG). A
             separate baseline assessment is required if a negative screening pregnancy test was
             obtained more than 72 hours before the first dose of study treatment. All females will
             be considered to be of childbearing potential unless they are postmenopausal (at least
             12 months consecutively amenorrhoeic, in the appropriate age group, and without other
             known or suspected cause) or have been sterilized surgically (ie, bilateral tubal
             ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1
             month before dosing).

             13. Females of childbearing potential must not have had unprotected sexual intercourse
             within 30 days prior to study entry and must agree to use a highly effective method of
             contraception, from the last menstrual period prior to randomization, during treatment
             cycles, and for 30 days after the final dose of study treatment, and have a male
             partner who uses a condom. Highly effective contraception includes:

               -  Double barrier methods of contraception such as condom plus diaphragm or
                  cervical/vault cap with spermicide.

               -  Placement of an intrauterine device.

               -  Established hormonal contraceptive methods: oral, injectable, or implant. Females
                  who are using hormonal contraceptives must have been on a stable dose of the same
                  hormonal contraceptive product for at least 4 weeks prior to dosing and must
                  continue to use the same contraceptive during the study and for 30 days after
                  study drug discontinuation.

        NOTE: Female subjects exempt from this requirement are subjects who practice total
        abstinence or have a male partner who is vasectomized. If currently abstinent, the subject
        must agree to use a highly effective method of contraception as described above if they
        become sexually active during treatment cycles, and for 30 days after study drug
        discontinuation. 14. All study participants enrolled must be registered into the mandatory
        Revlimid REMS™ program and be willing and able to comply with the requirements of the
        Revlimid REMS™ program as appropriate for the country in which the drug is being used.

        a. Female subjects of childbearing potential must adhere to the scheduled pregnancy testing
        as required in the Revlimid REMS™ program. Female subjects exempt from this requirement are
        subjects who have been in natural menopause for at least 2 years OR have had both ovaries
        and/or uterus removed.

        15. Male subjects must have had either a successful vasectomy OR they and their female
        partner must meet the criteria above (ie, not of childbearing potential OR practicing
        highly effective contraception and use a condom throughout the study period and for 30 days
        after study drug discontinuation).

        Exclusion Criteria:

        All Subjects

          1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.

          2. Prior exposure to lenalidomide for the treatment of FL.

          3. Subjects who have mixed or transformed histology.

          4. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE Version 5.0
             criteria) or any prior history of myeloid malignancies, including myelodysplastic
             syndrome (MDS).

          5. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute
             lymphoblastic leukemia (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 potent cytochrome P450 (CYP)3A4
             inducers/inhibitors (including St. John's wort) (Flockhart, 2007; U. S. Food and Drug
             Administration, February 2015).

          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.

             a. Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter
             placement, shunt revision) is permitted within 3 weeks prior to enrollment.

         10. Are unable to take oral medication OR have malabsorption syndrome or any other
             uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might
             impair the bioavailability of tazemetostat.

         11. Significant cardiovascular impairment: history of congestive heart failure greater
             than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
             unstable angina, myocardial infarction, or stroke within 6 months of the first dose of
             study drug; or cardiac ventricular arrhythmia.

         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.

             a. whereas subjects greater than 3 months since deep vein thrombosis/pulmonary
             embolism are eligible but recommended to receive prophylaxis.

         14. Have an active infection requiring systemic therapy.

         15. Known hypersensitivity to any component of tazemetostat, lenalidomide, or rituximab.

         16. Inability to be treated with a Pneumocystis prophylaxis medication.

         17. Have an active infection with hepatitis B virus (as measured by positive hepatitis B
             surface antigen), HCV (as measured by positive hepatitis C antibody), human
             immunodeficiency virus, OR human T-cell lymphotropic virus 1.

             a. Exceptions: Subjects with a history of hepatitis B or C who have normal ALT AND are
             hepatitis B surface antigen negative and/or have undetectable HCV RNA.

         18. 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.

         19. Female subjects who are pregnant or breastfeeding.

         20. Subjects who have undergone a solid organ transplant.

         21. Subjects with malignancies other than FL. a. Exception: Subjects with another
             malignancy who have been disease-free for 5 years, or subjects with a history of a
             completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
             are eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Stage 1: RP3D of tazemetostat in combination with R2
Time Frame:Each cohort minimum 3 subjects. Evaluated for DLTs during the first 28 day cycle. 2-3 subjects 1 of the 6 subjects in the cohort experiences a DLT, the next dose level/cohort will be assessed. The RP3D for Phase 3 will be selected at in cohort experience
Safety Issue:
Description:The safety and tolerability of tazemetostat in combination with R2 in subjects with R/R FL will be evaluated. RP3D of tazemetostat for further evaluation in phase 3 will be selected as assessed by the occurrence of treatment-emergent dose-limiting toxicities (DLTs) and adverse events (AEs).

Secondary Outcome Measures

Measure:Pharmacokinetics of tazemetostat Maximum Plasma Concentration Cmax.
Time Frame:Stage 1: Cycles 1 & 2 , days 1 & 15. (Each cycles is 28 days)
Safety Issue:
Description:Assess the pharmacokinetics of tazemetostat when administered concomitantly with R2 in subjects with R/R FL.
Measure:PFS
Time Frame:R2 arm (n = 178) versus investigator assessment of 14.3 months and 14.1 months by IRC in the placebo plus rituximab arm (n = 180) with a hazard ratio (HR) of 0.51 and 0.46, respectiv
Safety Issue:
Description:Stage 2: Evaluate and compare PFS by blinded independent review committee (IRC)
Measure:Objective Response Rate
Time Frame:up to 72 months
Safety Issue:
Description:Stage 2: Evaluate and compare objective response rate (ORR)
Measure:Stage 2: Duration of response
Time Frame:Through study of completion, up to 72 months
Safety Issue:
Description:Evaluate and compare the duration of response (DOR)
Measure:Stage 2: Duration of complete response
Time Frame:Through study of completion, up to 72 hours
Safety Issue:
Description:Evaluate and compare the duration of complete response (DOCR)
Measure:Disease control rate
Time Frame:Through study of completion, up to 72 hours
Safety Issue:
Description:Stage 2: Evaluate and compare the disease control rate (DCR)
Measure:Overall Survival
Time Frame:From day of randomization until death due to any cause or study completion, up to 72 months. o 72 hours
Safety Issue:
Description:Stage 2: Evaluate and compare the overall survival (OS)
Measure:EuroQOL
Time Frame:Measured at Screening, on Day 1 and Day 15 of Cycles 1 and 2, on Day 1 and optionally on Day 15 of each cycle from Cycle 3 and beyond, and at end of treatment visit, up to 3 years. (Each cycle is 28 days)
Safety Issue:
Description:Stage 2: Evaluate and compare health-related quality of life as measured by the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) instrument
Measure:Number of participants with treatment-related adverse events
Time Frame:From date of consent until 30 days after discontinuation of study treatment, up to 72 months.
Safety Issue:
Description:Stage 2: Evaluate and compare safety and tolerability between tazemetostat + R2 vs Placebo + R2.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Epizyme, Inc.

Last Updated

January 8, 2020