Study of Tazemetostat in Participants With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma With EZH2 Gene Mutation

Study Overview
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Brief Summary
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This is a multicenter, open-label, Phase 2 study to assess the efficacy and safety of tazemetostat in participants with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) with EZH2 gene mutation.

Official Title
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A Phase 2 Study of Tazemetostat in Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma With EZH2 Gene Mutation

Conditions
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Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Tazemetostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with histological diagnosis of B-cell non-Hodgkin's lymphoma (NHL) as follows: Cohort 1: Follicular lymphoma (FL) Cohort 2: Diffuse large B-cell lymphoma (including primary mediastinal B-cell lymphoma and transformed FL) Participants who have confirmed EZH2 gene mutation of tumor in central laboratory Participants who have measurable disease Participants who had previous therapy with systemic chemotherapy and/or antibody therapy and for which no standard therapy exists Participants who had progressive disease or did not have response (complete response or partial response) in previous systemic therapy, or relapsed or progressed after previous systemic therapy Participants with Eastern Cooperative Oncology Group performance status of 0 to 1 Participants with life expectancy of ≥3 months from starting study drug administration Participants with adequate renal, liver, and bone marrow function Male and female participants ≥20 years of age at the time of informed consent Participants who has provided written consent to participate in the study Exclusion Criteria: Participants with prior exposure to EZH2 inhibitor Participants with a history or a presence of central nerves invasion Participants with malignant pleural effusion, cardiac effusion, or ascites retention Participants with allogeneic stem cell transplantation Participants with medical need for the continued use of potent inhibitors of Cytochrome P450 3A (CYP3A)or potent inducer of CYP3A (including St. John's wort) Participants with significant cardiovascular impairment · Participants with prolongation of corrected QT interval using Fridericia's formula to > 480 milliseconds (msec) Participants with venous thrombosis or pulmonary embolism within the last 3 months before starting study drug Participants with complications of hepatic cirrhosis, interstitial pneumonia or pulmonary fibrosis Participants with active infection requiring systemic therapy Women of childbearing potential or man of impregnate potential who don't agree that both the participant and his/her partner will use a medically effective method for contraception for periods from before informed consent to during the clinical study and 30 days later (for males 90 days later) from last administration of study drug Woman who are pregnant or breastfeeding Participants who were deemed as inappropriate to participate in the study by the investigator or sub-investigator Have any prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia or myeloid malignancies, including myelodysplastic syndrome

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FL with EZH2 gene mutation<br>Participants with follicular lymphoma (FL) with the EZH2 gene mutation will receive oral tazemetostat at a starting dose of 800 milligrams (mg) twice daily (1600 mg total daily dose) by continuous regimen, no less than 8 hours between doses. | Drug: Tazemetostat<br>* Tazemetostat will be provided as a 200 mg oral tablet.<br>|
| Experimental: DLBCL with EZH2 gene mutation<br>Participants with diffuse large B-cell lymphoma (DLBCL) with the EZH2 gene mutation will receive oral tazemetostat at a starting dose of 800 mg twice daily (1600 mg total daily dose) by continuous regimen, no less than 8 hours between doses. | Drug: Tazemetostat<br>* Tazemetostat will be provided as a 200 mg oral tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on Independent Reviewer Assessment | ORR was defined as percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) using independent reviewer assessment based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD and there are no unequivocal new lesions, and no progression of non-target disease. The 2-sided 95% confidence interval (CI) was calculated by Clopper-Pearson method. | From date of first dose of study drug administration to date of PD or death, whichever occurred first (up to 3 years 4 months) | 
| ORR Based on Investigator Assessment | ORR was defined as percentage of participants with confirmed BOR of CR or PR using investigator assessment based on RECIST 1.1. BOR of CR and PR was confirmed by a subsequent CR assessment and CR or PR assessment. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis <10 mm. PR: at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD and there are no unequivocal new lesions, and no progression of non-target disease. The 2-sided 95% CI was calculated by Clopper-Pearson method. | From date of first dose of study drug administration to date of PD or death, whichever occurred first (up to 3 years 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Based on Independent Reviewer Assessment | PFS was assessed by independent reviewer assessment based on RECIST 1.1. PFS was defined as the time from the date of the first dose of study drug to the date of the first documentation of PD or death, whichever occurred first. PD for target lesion, a minimum 20% increase and a minimum 5 mm absolute increase in SOD compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir: Lowest measure SOD of target lesion at any time point from baseline onward. The 95% CI was calculated using Kaplan-Meier estimate. | From date of first dose of study drug administration to date of PD or death, whichever occurred first (up to 3 years 4 months) | 
| PFS Based on Investigator Assessment | PFS was assessed by investigator assessment based on RECIST 1.1. PFS was defined as the time from the date of the first dose of study drug to the date of the first documentation of PD or death, whichever occurred first. PD for target lesion, a minimum 20% increase and a minimum 5 mm absolute increase in SOD compared to nadir, or PD for non-target lesion(s) or unequivocal new lesion(s). Nadir: Lowest measure SOD of target lesion at any time point from baseline onward. The 95% CI was calculated using Kaplan-Meier estimate. | From date of first dose of study drug administration to date of PD or death, whichever occurred first (up to 3 years 4 months) | 
| Duration of Response (DOR) Based on Independent Reviewer Assessment | DOR: time from date of confirmation of the first response and the date of confirmation of the PD using independent reviewer assessment as per RECIST 1.1. BOR of CR and PR was confirmed by subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD, there are no unequivocal new lesions, and no progression of non-target disease. PD for target lesion, a minimum 20% increase and a minimum 5mm absolute increase in SOD compared to nadir, or PD for non-target lesions or unequivocal new lesions. Nadir: Lowest measure SOD of target lesions at any time point from baseline onward. The 95% CI was calculated using Kaplan-Meier estimate. | From the date of first confirmed objective response (OR) to PD or death due to confirmed PR or CR (up to 3 years 4 months) | 
| DOR Based on Investigator Assessment | DOR: time from date of confirmation of the first response and the date of confirmation of the PD using independent reviewer assessment as per RECIST 1.1. BOR of CR and PR was confirmed by subsequent CR assessment and CR or PR assessment, respectively at least 4 weeks later. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD, there are no unequivocal new lesions, and no progression of non-target disease. PD for target lesion, a minimum 20% increase and a minimum 5mm absolute increase in SOD compared to nadir, or PD for non-target lesions or unequivocal new lesions. Nadir: Lowest measure SOD of target lesions at any time point from baseline onward. The 95% CI was calculated using Kaplan-Meier estimate. | From the date of first confirmed OR to PD or death due to any cause for those participants with a confirmed PR or CR (up to 3 years 4 months) | 
| Time to Response (TTR) Based on Independent Reviewer Assessment | TTR was defined as the time from the first dose of the study drug to date of first observation of CR or PR using independent reviewer assessment based on RECIST 1.1. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD and there are no unequivocal new lesions, and no progression of non-target disease. | From the date of first dose until date of first observation of CR or PR (up to 3 years 4 months) | 
| TTR Based on Investigator Assessment | TTR was defined as the time from the first dose of the study drug to date of first observation of CR or PR using investigator assessment based on RECIST 1.1. CR: disappearance of all measurable, non-measurable lesions and no unequivocal new lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD and there are no unequivocal new lesions, and no progression of non-target disease. | From the date of first dose until date of first observation of CR or PR (up to 3 years 4 months) | 
| Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE is defined as an AE that emerged during time from the first dose of study drug to 30 days after the participant's last dose. An AE was any untoward medical occurrence in participant administered with an investigational product. An SAE was any untoward medical occurrence that at any dose: resulted in death; life threatening; requires participant hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). | From the first dose of study drug to 30 days after the last dose (up to 3 years 5 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tazemetostat, EZH2 gene mutation, Diffuse large B-cell lymphoma, Follicular lymphoma