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Trial record 18 of 22 for:    tazemetostat

Study in Subjects With Relapsed/Refractory Follicular Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04224493
Recruitment Status : Recruiting
First Posted : January 13, 2020
Last Update Posted : July 28, 2020
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 R2 in subjects with R/R 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 : 518 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Active Comparator: Tazemetostat + R2 Arm

tazemetostat 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.
Drug: Tazemetostat
Tazemetostat RP3D (tablets) administered PO 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. 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 ]
    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. Stage 2: Progression-free Survival (PFS) [ Time Frame: Time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification (Cheson, 2014) or death, whichever occurs first, assessed up to 72 months. ]
    Evaluate and compare progression-free survival (PFS), as assessed by Investigators, of tazemetostat + R2 versus placebo + R2 in subjects with R/R FL who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy


Secondary Outcome Measures :
  1. Pharmacokinetics of tazemetostat Maximum Plasma Concentration Cmax. [ Time Frame: Stage 1: Cycles 1 & 2 , days 1 & 15. (Each cycles is 28 days) ]
    Assess the pharmacokinetics of tazemetostat when administered concomitantly with R2 in subjects with R/R FL.

  2. 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 ]
    Stage 2: Evaluate and compare PFS by blinded independent review committee (IRC)

  3. Objective Response Rate [ Time Frame: up to 72 months ]
    Stage 2: Evaluate and compare objective response rate (ORR)

  4. Stage 2: Duration of response [ Time Frame: Through study of completion, up to 72 months ]
    Evaluate and compare the duration of response (DOR)

  5. Stage 2: Duration of complete response [ Time Frame: Through study of completion, up to 72 hours ]
    Evaluate and compare the duration of complete response (DOCR)

  6. Disease control rate [ Time Frame: Through study of completion, up to 72 hours ]
    Stage 2: Evaluate and compare the disease control rate (DCR)

  7. Overall Survival [ Time Frame: From day of randomization until death due to any cause or study completion, up to 72 months. o 72 hours ]
    Stage 2: Evaluate and compare the overall survival (OS)

  8. 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) ]
    Stage 2: Evaluate and compare health-related quality of life as measured by the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) instrument

  9. 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. ]
    Stage 2: Evaluate and compare safety and tolerability between tazemetostat + R2 vs Placebo + R2.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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.

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: Study Director, MD 855-500-1011 clinicaltrials@epizyme.com

Locations
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United States, California
Innovative Clinical Research Institute Recruiting
Whittier, California, United States, 90602
Principal Investigator: Eddie Thara, MD         
United States, New Jersey
Regional Cancer Associates LLC -Central Recruiting
East Brunswick, New Jersey, United States, 08816
Contact: Bruno Fang, MD         
Hackensack University Medical John Theurer Cancer Center Recruiting
Hackensack, New Jersey, United States, 07601
Principal Investigator: Lori Leslie, MD         
United States, New York
Memorial Sloan-Kettering Cancer Cente Recruiting
New York, New York, United States, 10021
Principal Investigator: Connie Batlevi, MD         
United States, North Carolina
Levine Cancer Institute/Atrium Health Recruiting
Chapel Hill, North Carolina, United States, 28204
Principal Investigator: Steven Park, MD         
United States, Ohio
Gabrail Cancer Center Research Recruiting
Canton, Ohio, United States, 44718
Principal Investigator: Nashat Gabrail, MD         
United States, Pennsylvania
West Penn Hospital Recruiting
Pittsburgh, Pennsylvania, United States, 15524
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Loretta Nastoupil, MD         
United States, Washington
Multicare Health System Recruiting
Spokane, Washington, United States, 99218
Principal Investigator: Brett Gourley, MD         
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: July 28, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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