Clinical Trials List
Protocol NumberEZH-302
NCT Number(ClinicalTrials.gov Identfier)NCT04224493
Active
2020-04-01 - 2032-06-30
Others
Not yet recruiting1
Recruiting4
ICD-10C82.90
Follicular lymphoma, unspecified, unspecified site
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
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Trial Applicant
PAREXEL INTERNATIONAL CO., LTD.
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Sponsor
Epizyme, Inc.
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Trial scale
Multi-Regional Multi-Center
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Update
2025/12/01
Investigators and Locations
Co-Principal Investigator
- Tsai-Yun Chen Division of General Internal Medicine
- Sin-Syue Li Division of General Internal Medicine
- Ya-Ping Chen Division of General Internal Medicine
- Chun-Hui Lee Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 劉鴻霖 Division of General Internal Medicine
- 邱玲榕 Division of General Internal Medicine
- 廖碧涵 Division of General Internal Medicine
- 黃永成 Division of General Internal Medicine
- 馬銘君 Division of General Internal Medicine
- 陳韋廷 Division of General Internal Medicine
- 許獻文 Division of General Internal Medicine
- 廖浚凱 無
- 林偉哲 Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- YU-HSUAN SHIH Division of General Internal Medicine
- PO-WEI LIAO Division of General Internal Medicine
- Tsung -Chih Chen 無
- 陳文賢 Division of General Internal Medicine
- CHENG-HSIEN LIN Division of General Internal Medicine
- Chieh-Lin Teng Division of General Internal Medicine
- ZHENG-WEI ZHOU Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Jih-Luh Tang Division of Hematology & Oncology
- Chieh-Lung Cheng Division of Hematology & Oncology
- Huai-Hsuan Huang Division of Hematology & Oncology
- 柯紀綸 Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Tai-Chung Huang Division of Hematology & Oncology
- 田豐銘 Division of Hematology & Oncology
- 劉高郎 Division of Hematology & Oncology
- MING YAO Division of Hematology & Oncology
- Chien-Chin Lin Division of Hematology & Oncology
- WEI-LI MA Division of Hematology & Oncology
- Wen-Chien Chou Division of Hematology & Oncology
- CHENG-HONG TSAI Division of Hematology & Oncology
- - - Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Condition/Disease
relapsed/refractory follicular lymphoma
Objectives
Primary:
Stage 1, Safety Run-In
•To evaluate the safety and tolerability of tazemetostat in combination with R2 in subjects with R/R FL and to select a RP3D of tazemetostat for further evaluation in phase 3
Secondary:
Stage 1, Run-In
•To assess the clinical activity and pharmacokinetics of tazemetostat when administered concomitantly with R2 in subjects with R/R FL
Primary:
Stage 2 and Optional Stage 3 (Based on Stage 2 Futility Analysis)
•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:
Stage 2 and Optional Stage 3 (Based on Stage 2 Futility Analysis)
•Evaluate and compare PFS by blinded independent review committee (IRC)
•Evaluate and compare ORR
•Evaluate and compare the duration of response (DOR)
•Evaluate and compare the duration of complete response (DOCR)
•Evaluate and compare the disease control rate (DCR)
•Evaluate and compare health-related quality of life as measured by the EQ-5D-5L instrument and the FACT-Lym
•Evaluate and compare the OS•Assess population PK parameters, including exposure-response of tazemetostat when administered in combination with R2
•Evaluate and compare safety and tolerability
Exploratory
•Assessment of genetic changes in enhancer of zeste homolog 2 (EZH2) that may emerge during the course of treatment
•Determine status of EZH2 copy number, mRNA expression, protein levels and global H3K27me3 signal in pretreatment tumor tissue samples for correlation with clinical outcome
Test Drug
Tazemetostat
Active Ingredient
Tazemetostat hydrobromide
Dosage Form
Tablet
Dosage
200 mg/ tablet (as Tazemetostat)
Endpoints
Primary Outcome Measures :
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).
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
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).
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
Inclution Criteria
Inclusion Criteria:
Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
Males or females are ≥18 years of age at the time of providing voluntary written informed consent.
Life expectancy ≥3 months before enrollment.
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.
Have histologically confirmed FL, grades 1 to 3A.
Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy:
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:
Cytotoxic chemotherapy - At least 21 days.
Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days.
Nitrosoureas - At least 6 weeks.
Monoclonal antibody(ies) - At least 28 days.
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).
Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
Males or females are ≥18 years of age at the time of providing voluntary written informed consent.
Life expectancy ≥3 months before enrollment.
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.
Have histologically confirmed FL, grades 1 to 3A.
Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy:
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:
Cytotoxic chemotherapy - At least 21 days.
Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days.
Nitrosoureas - At least 6 weeks.
Monoclonal antibody(ies) - At least 28 days.
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
Exclusion Criteria:
All Subjects
Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
Prior exposure to lenalidomide for the treatment of FL.
Subjects who have mixed or transformed histology.
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).
Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL).
Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
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).
Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet.
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.
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.
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.
Prolongation of corrected QT interval using Fridericia's formula (QTcF) to >480 msec at screening or history of long QT syndrome.
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.
Have an active infection requiring systemic therapy.
Known hypersensitivity to any component of tazemetostat, lenalidomide, or rituximab.
Inability to be treated with a Pneumocystis prophylaxis medication.
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.
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.
Female subjects who are pregnant or breastfeeding.
Subjects who have undergone a solid organ transplant.
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.
All Subjects
Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
Prior exposure to lenalidomide for the treatment of FL.
Subjects who have mixed or transformed histology.
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).
Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL).
Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
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).
Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet.
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.
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.
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.
Prolongation of corrected QT interval using Fridericia's formula (QTcF) to >480 msec at screening or history of long QT syndrome.
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.
Have an active infection requiring systemic therapy.
Known hypersensitivity to any component of tazemetostat, lenalidomide, or rituximab.
Inability to be treated with a Pneumocystis prophylaxis medication.
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.
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.
Female subjects who are pregnant or breastfeeding.
Subjects who have undergone a solid organ transplant.
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.
The Estimated Number of Participants
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Taiwan
30 participants
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Global
612 participants
