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Trial record 1 of 1 for:    EZH-302
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Study in Subjects With Relapsed/Refractory Follicular Lymphoma

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ClinicalTrials.gov Identifier: NCT04224493
Recruitment Status : Recruiting
First Posted : January 13, 2020
Last Update Posted : June 23, 2022
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.

Brief Summary:
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 lenalidomide and rituximab (R2) in subjects with relapsed or refractory (R/R) follicular lymphoma (FL), who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.

Condition or disease Intervention/treatment Phase
Relapsed/Refractory Follicular Lymphoma Drug: Tazemetostat Drug: Placebo oral tablet Combination Product: Lenalidomide Combination Product: Rituximab Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 540 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: SYMPHONY-1: 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
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : March 2026
Estimated Study Completion Date : March 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Active Comparator: Tazemetostat + R2 Arm

tazemetostat 800mg 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.
Drug: Tazemetostat
Tazemetostat 800mg (tablets) administered orally twice daily in continuous 28-day cycles for 12 cycles.
Other Name: EPZ-6438

Combination Product: Lenalidomide
Lenalidomide 20 mg capsules (if creatinine clearance ≥60 mL/minute) or 10 mg capsules (if creatinine clearance <60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.

Combination Product: Rituximab
Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5.

Placebo Comparator: Placebo + R2 Arm

placebo 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.
Drug: Placebo oral tablet
Placebo tablets administered PO twice daily in continuous 28-day cycles for 12 cycles.

Combination Product: Lenalidomide
Lenalidomide 20 mg capsules (if creatinine clearance ≥60 mL/minute) or 10 mg capsules (if creatinine clearance <60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.

Combination Product: Rituximab
Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5.




Primary Outcome Measures :
  1. Recommended Phase 3 Dose o(RP3D) of tazemetostat in combination with R2 [ Time Frame: Subjects are evaluated for DLTs during the first 28-day cycle. The RP3D for Phase 3 will be selected at the end of Phase 1b ]
    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).

  2. Progression-free Survival (PFS) [ Time Frame: up to 72 months ]
    PFS is defined as the time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification or death, whichever occurs first, as assessed by Investigators.


Secondary Outcome Measures :
  1. PFS [ Time Frame: up to 72 months ]
    PFS is defined as the time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification or death, whichever occurs first, as assessed by blinded independent review committee (IRC).

  2. Objective Response Rate (ORR) [ Time Frame: up to 72 months ]
    ORR is defined as the proportion of subjects achieving partial response (PR) or complete response (CR) according to the 2014 Lugano Classification as assessed by Investigator and IRC.

  3. Duration of response (DOR) [ Time Frame: up to 72 months ]
    DOR is defined as the time from initial CR or PR to documented progression or death, whichever occurs first, as assessed by Investigator and IRC.

  4. Duration of complete response (DOCR) [ Time Frame: up to 72 months ]
    DOCR, defined as the time from initial CR to documented progression or death, whichever occurs first, as assessed by Investigator and IRC.

  5. 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) ]
    Evaluate and compare health-related quality of life as measured by the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) instrument and the Functional Assessment of Cancer Therapy -Lymphoma (FACT-Lym)

  6. Overall Survival (OS) [ Time Frame: up to 100 weeks ]
    OS is defined as the time from the date of randomization until death due to any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (≥20 years for Taiwan) 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 but with normal ALT and are hepatitis B surface antigen negative with undetectable HBV DNA and/or have undetectable hepatitis C virus (HCV) RNA if HCV antibody positive. See Exclusion Criteria 17 and 18.
  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: a. 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 c. Prior investigational therapies will be allowed provided the subject has received at least

1 prior systemic therapy as discussed in Inclusion Criterion #6a. d. Prior autologous/allogeneic hematopoietic stem cell transplant (HSCT) will be allowed.

e. Prior chimeric antigen receptor T-cell therapy (CAR T) will be allowed. 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; Appendix 5). 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 10. For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy):

a. At the time the subject provides voluntary written informed consent, all toxicities have either resolved to Grade 1 per National Cancer Institute CTCAE Version 5.0 OR are clinically stable and no longer clinically significant. 11. Have provided sufficient tumor tissue for EZH2 mutation testing in all subjects to allow for stratification and for CNG determination in a subset of WT EZH2 subjects from the Phase 3 portion of the study.

  1. If EZH2 mutation status is known from site-specific testing, subjects can be enrolled, but additional tumor tissue will be required for confirmatory testing of EZH2 status at study-specific laboratories. If the archival tumor sample was collected more than 15 months prior to administration of the first dose (cycle 1 day 1), then a fresh biopsy must be provided. Fresh tumor biopsy is appropriate except for procedures deemed to result in unacceptable risk because of the anatomical location including brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel. Archival tumor biopsy sections mounted on slides are also acceptable. NOTE: Confirmatory testing will also be performed for Stage 1, if local EZH2 testing is conducted, unless there is insufficient tumor tissue to perform testing after discussion with the Sponsor's or Designee Medical Monitor. 12. 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 and/or bispecific antibodies or CAR T - 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 ≥30 mL/minute per the Cockcroft and Gault formula.

    14. Adequate bone marrow function:

  1. Absolute neutrophil count (ANC) ≥1000/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.
  2. Platelets ≥75,000/mm3 (≥75 × 109/L)

    • Evaluated at least 7 days after last platelet transfusion.
  3. Hemoglobin ≥9.0 g/dL • May receive transfusion 15. Adequate liver function:
  1. Total bilirubin ≤1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
  2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases). 16. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects with thromboembolism risk, prophylactic anticoagulation, or antiplatelet therapy at investigator discretion is recommended.

    17. Females of childbearing potential (FCBP) must have two negative urine or serum pregnancy tests (beta-human chorionic gonadotropin [β-hCG] tests with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening prior to dosing. The first pregnancy test must be performed within 10 to 14 days prior to first dose of study drug and the second pregnancy test must be performed within 24 hours prior to first dose of study drug. The subject may not receive study drug until the study doctor has verified that the results of these pregnancy tests are negative. All females will be considered to be of childbearing potential unless they are naturally postmenopausal (at least 24 months consecutively amenorrhoeic [amenorrhea following cancer therapy does not rule out childbearing potential] and without other known or suspected cause) or have been sterilized surgically (ie, total hysterectomy and/or bilateral oophorectomy, with surgery completed at least 1 month before dosing).

    18. Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously. This includes ONE highly effective method of contraception and ONE additional effective contraceptive method. Contraception must begin at least 28 days prior to first dose of study drug, continue during study treatment (including during dose interruptions), and for 12 months after study drug discontinuation. Female subjects must also refrain from breastfeeding for 12 months following last dose of study drug. If the below contraception methods are not appropriate for the FCBP, she must be referred to a qualified contraception provider to determine the medically effective contraception method appropriate for the subject. The following are examples of highly effective and additional effective methods of contraception:

    • Examples of highly effective methods:

      • Intrauterine device (IUD)
      • Hormonal (ovulation inhibitory combined [estrogen and progesterone] birth control pills or intravaginal/transdermal system, injections, implants, levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills [e.g. desogestrel])

    NOTE: There is a potential for tazemetostat interference with hormonal contraception methods due to enzymatic induction.

    - Bilateral tubal ligation

    - Partner's vasectomy (if medically confirmed [azoospermia] and sole sexual partner)

    • Examples of additional effective methods:

    - Male latex or synthetic condom

    • Diaphragm
    • Cervical Cap NOTE: Female subjects of childbearing potential exempt from these contraception requirements are subjects who practice complete abstinence from heterosexual sexual contact. True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception.

      19. 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.

a. Female subjects of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the Revlimid REMS™ program (for the US) or Revlimid Global PPP (for ex-US). During study treatment, FCBP must agree to have pregnancy testing weekly for the first 28 days of study participation and then every 28 days for FCBP with regular or no menstrual cycles OR every 14 days for FCBP with irregular menstrual cycles. FCBP must also have a pregnancy test at end of lenalidomide treatment, and at days 14 and 28 following the last dose of lenalidomide. Female subjects exempt from this requirement are subjects who have been naturally postmenopausal for at least 24 consecutive months OR have had a total hysterectomy and/or bilateral oophorectomy.

20. 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.

NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.

Exclusion Criteria:

All Subjects

  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 (per CTCAE Version 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
  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 strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort) (See Section 12.1.1.1.3 and https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions- table-substrates-inhibitors-and-inducers; https://druginteractions.

    medicine.iu.edu/MainTable.aspx).

  8. Are unwilling to exclude Seville oranges, grapefruit juice, Seville oranges, and grapefruits from the diet and/or consumed within 1 week of the first dose of study drug and for the duration of the study. 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 (Appendix 3).
  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 or lenalidomide; known severe hypersensitivity to any component of rituximab requiring hospitalization or resuscitation.
  16. Inability to be treated with a Pneumocystis prophylaxis medication.
  17. Active viral infection with or seropositive for hepatitis B virus (HBV): HBV surface antigen (HBsAg) positive OR HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable HBV DNA.

NOTE: Subjects who are HBsAg negative, anti-HBs positive and/or anti-HBc positive, but with undetectable viral DNA and normal ALT are eligible. Subjects who are seropositive due to HBV vaccination (HBsAg negative, HBV surface antibody [anti-HBs] positive, and HBV core antibody [anti-HBc] negative) are eligible.

18. Active viral infection with hepatitis C virus (as measured by positive HCV antibody and detectable viral RNA), human immunodeficiency virus (HIV), AND/OR human T-cell lymphotropic virus 1 (as measured by positive HTLV-1 antibody). NOTE: Subjects with a history of hepatitis C infection (HCV antibody reactive) who have normal ALT and undetectable HCV RNA are eligible. 19. 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.

20. Female subjects who are pregnant or lactating/breastfeeding. 21. Subjects who have undergone a solid organ transplant. 22. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04224493


Contacts
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Contact: Clinical Trial +1 (855) 500-1011 clinicaltrials@epizyme.com

Locations
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Sponsors and Collaborators
Epizyme, Inc.
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04224493    
Other Study ID Numbers: EZH-302
First Posted: January 13, 2020    Key Record Dates
Last Update Posted: June 23, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Epizyme, Inc.:
Epizyme
Tazverik
Tazemetostat (EPZ-6438)
Lenalidomide
Revlimid
Rituximab
Rituxan
Follicular lymphoma
EZH2
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Lenalidomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors