Back to resultsA Study of Tazemetostat in Participants With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Primary Purpose
Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Tazemetostat
Sponsored by
About this trial
This is an interventional treatment trial for Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma focused on measuring relapsed or refractory B-cell non-Hodgkin's lymphoma, tazemetostat, Japan, E7438
Eligibility Criteria
Inclusion Criteria:
- Participants with histological diagnosis of B-cell non-Hodgkin's lymphoma
- Participant who has measurable disease
- Participant who had previous therapy with systemic chemotherapy and/or antibody therapy
- Participant who had progressive disease (PD) or did not have a response (complete response [CR] or partial response [PR]) in previous systemic therapy, or relapsed or progressed after previous systemic therapy
- Participant with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Participant with life expectancy of ≥3 months from starting study drug administration
- Participant with adequate renal, bone marrow, and liver function
- Participant with left ventricular ejection fraction (LVEF) > 50%
- Male and female participant ≥20 years of age at the time of informed consent
- Participant who has provided written consent to participate in the study
Exclusion Criteria:
- Participant with prior exposure to EZH2 inhibitor
- Participant with a history or a presence of central nerves invasion
- Participant with allogeneic stem cell transplantation
- Participant with medical need for the continued use of potent or moderate inhibitors of CYP3A or P-gp, or potent or moderate inducer of CYP3A (including St. John's wort).
- Participant with significant cardiovascular impairment
- Participant with prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 milliseconds (msec)
- Participant with venous thrombosis or pulmonary embolism within the last 3 months before starting study drug
- Participant with complications of hepatic cirrhosis, interstitial pneumonia, or pulmonary fibrosis
- Participant with active infection requiring systemic therapy
- Women of childbearing potential or man of impregnate potential who don't agree to use a medically effective method for contraception for periods from before informed consent to during the clinical study and 30 days later from last administration of study drug
- Woman who are pregnant or breastfeeding
- Participant who were deemed as inappropriate to participate in the study by the investigator or sub-investigator
Sites / Locations
- Eisai Trial Site
- Eisai Trial Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Tazemetostat 800 mg
Arm Description
Participants will receive oral tazemetostat at a starting dose of 800 milligrams (mg) as a single dose (Cycle 0) and 800 mg twice a day as continuous dosing (Cycle 1 and later) (Cycle 0 duration=4 days) (Cycle 1 and later duration= 28 days).
Outcomes
Primary Outcome Measures
Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03) were defined as: 1) Grade 4 neutropenia for greater than (>) 7 days; 2) greater than or equal to (>=) Grade 3 febrile neutropenia; 3) Grade 4 thrombocytopenia and Grade 3 thrombocytopenia with bleeding; 4) Grade 4 anemia or anemia requiring erythrocyte transfusion; 5) >=Grade 3 nausea, vomiting, or diarrhea that persisted >7 days despite maximal medical therapy; 6) >=Grade 3 non-hematological laboratory abnormalities with clinical symptoms that persisted >7 days; 7) Other Grade 3 toxicity lasting >7 days or Grade 4 non-hematological toxicity of any duration; 8) Failure to administer >=75 percent (%) of the planned administration number of study drug in Cycle 1 as a result of treatment-related toxicity. Here, number of participants who had DLT were reported.
Secondary Outcome Measures
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to pretreatment state, when AE was continuous. Number of participants with TEAEs were reported based on their safety assessments of laboratory tests, physical examination, regular measurement of vital signs, body weight, echocardiograms/multigated acquisition (MUGA) scans to assess left ventricular ejection fraction, eastern cooperative oncology group-performance status (ECOG-PS) and electrocardiograms parameter values. SAE was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria.
Cmax: Maximum Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Tmax: Time to Reach Maximum Plasma Concentration (Cmax) of Tazemetostat and Its Metabolite ER-897387
AUC(0-12 Hours): Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose of Tazemetostat and Its Metabolite ER-897387
AUC(0-t Hours): Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Tazemetostat and Its Metabolite ER-897387
AUC(0-infinity): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of Tazemetostat and Its Metabolite ER-897387
Lambda z: Terminal Phase Elimination Rate Constant of Tazemetostat and Its Metabolite ER-897387
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387
CL/F: Apparent Total Body Clearance of Tazemetostat
Vz/F: Apparent Volume of Distribution at Terminal Phase of Tazemetostat
Vz/F for Cycle 0 Day 1 was calculated as Dose divided by ([lambda z]*[AUC0-infinity]) and for Cycle 1 Day 15 was calculated as Dose divided by ([lambda z]*[AUC0-tau]).
MRT: Mean Residence Time of Tazemetostat and Its Metabolite ER-897387
MRT of tazemetostat and its metabolite ER-897387 was calculated as MRT=AUMC(0-infinity)/AUC(0-infinity), where AUMC(0-infinity) was the area under the first moment curve extrapolated to infinity and AUC(0-infinity) was area under the concentration-time curve from zero time extrapolated to infinite time.
AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Tazemetostat and Its Metabolite ER-897387
Css,Av: Average Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Css,Max: Maximum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Css,Min: Minimum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
PTF: Peak-trough Fluctuation Ratio of Tazemetostat and Its Metabolite ER-897387
The PTF within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav) multiplied by 100. Here, Cmin means the minimum plasma concentration, Cmax means the maximum plasma concentration and Cav means the average plasma concentration of drug and metabolite.
Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Tazemetostat and Its Metabolite ER-897387
CLss/F: Apparent Total Body Clearance of Tazemetostat at Steady State
Rac (Cmax): Accumulation Ratio of Cmax for Tazemetostat and Its Metabolite ER-897387
Rac (Cmax) was calculated as the ratio of maximum observed concentration at steady state (Css,max) on Cycle 1 Day 15 divided by Cmax on Cycle 0 Day 1.
Rac (AUC): Accumulation Ratio of AUC for Tazemetostat and Its Metabolite ER-897387
Rac (AUC) was calculated as the ratio of AUC(0-tau) on Cycle 1 Day 15 divided by AUC(0-12 hours) on Cycle 0 Day 1.
Rss: Steady State Accumulation Ratio of Tazemetostat and Its Metabolite ER-897387
Rss was calculated as the ratio of AUC(0-tau) on Cycle 1 Day 15 divided by AUC(0-infinity) on Cycle 0 Day 1.
Ae: Amount of Unchanged Drug Tazemetostat Excreted in Urine
Fe: Fraction of Tazemetostat Dose Excreted in Urine
The fraction of dose excreted in urine was calculated as: Cumulative amount of unchanged drug excreted in urine (Ae)/Dose*100.
CLR: Renal Clearance of Tazemetostat
Percentage of Participants With Objective Response
Objective response was assessed by investigator based on the Lugano Classification (CT-Based) response criteria. Objective response rate was defined as the percentage of participants who had a Best Overall Response (BOR) of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03009344
Brief Title
A Study of Tazemetostat in Participants With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Official Title
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
January 10, 2017 (Actual)
Primary Completion Date
July 12, 2017 (Actual)
Study Completion Date
June 17, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Co., Ltd.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a multicenter, single-arm, open-label, Phase 1 study to assess the tolerability, safety, pharmacokinetics, and preliminary anti-tumor activity of tazemetostat in participants with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Keywords
relapsed or refractory B-cell non-Hodgkin's lymphoma, tazemetostat, Japan, E7438
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tazemetostat 800 mg
Arm Type
Experimental
Arm Description
Participants will receive oral tazemetostat at a starting dose of 800 milligrams (mg) as a single dose (Cycle 0) and 800 mg twice a day as continuous dosing (Cycle 1 and later) (Cycle 0 duration=4 days) (Cycle 1 and later duration= 28 days).
Intervention Type
Drug
Intervention Name(s)
Tazemetostat
Intervention Description
Tazemetostat tablets.
Primary Outcome Measure Information:
Title
Number of Participants With Dose-limiting Toxicities (DLTs)
Description
DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03) were defined as: 1) Grade 4 neutropenia for greater than (>) 7 days; 2) greater than or equal to (>=) Grade 3 febrile neutropenia; 3) Grade 4 thrombocytopenia and Grade 3 thrombocytopenia with bleeding; 4) Grade 4 anemia or anemia requiring erythrocyte transfusion; 5) >=Grade 3 nausea, vomiting, or diarrhea that persisted >7 days despite maximal medical therapy; 6) >=Grade 3 non-hematological laboratory abnormalities with clinical symptoms that persisted >7 days; 7) Other Grade 3 toxicity lasting >7 days or Grade 4 non-hematological toxicity of any duration; 8) Failure to administer >=75 percent (%) of the planned administration number of study drug in Cycle 1 as a result of treatment-related toxicity. Here, number of participants who had DLT were reported.
Time Frame
Cycle 0 and Cycle 1 (Cycle 0=4 days, Cycle 1=28 days)
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
TEAE was defined as an adverse event (AE) that emerged during time from first dose to 30 days following last dose of drug, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to pretreatment state, when AE was continuous. Number of participants with TEAEs were reported based on their safety assessments of laboratory tests, physical examination, regular measurement of vital signs, body weight, echocardiograms/multigated acquisition (MUGA) scans to assess left ventricular ejection fraction, eastern cooperative oncology group-performance status (ECOG-PS) and electrocardiograms parameter values. SAE was defined as untoward medical occurrence that at any dose resulted in death; was life threatening; resulted in persistent or significant disability; was congenital anomaly or medically important due to other reasons than above mentioned criteria.
Time Frame
From the date of first dose up to 30 days after the last dose of study drug (up to 40 months)
Title
Cmax: Maximum Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
Tmax: Time to Reach Maximum Plasma Concentration (Cmax) of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
AUC(0-12 Hours): Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post-dose of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-12 hours post-dose (Cycle 0 length=4 days)
Title
AUC(0-t Hours): Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
AUC(0-infinity): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
Lambda z: Terminal Phase Elimination Rate Constant of Tazemetostat and Its Metabolite ER-897387
Description
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days); Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
CL/F: Apparent Total Body Clearance of Tazemetostat
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
Vz/F: Apparent Volume of Distribution at Terminal Phase of Tazemetostat
Description
Vz/F for Cycle 0 Day 1 was calculated as Dose divided by ([lambda z]*[AUC0-infinity]) and for Cycle 1 Day 15 was calculated as Dose divided by ([lambda z]*[AUC0-tau]).
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days); Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
MRT: Mean Residence Time of Tazemetostat and Its Metabolite ER-897387
Description
MRT of tazemetostat and its metabolite ER-897387 was calculated as MRT=AUMC(0-infinity)/AUC(0-infinity), where AUMC(0-infinity) was the area under the first moment curve extrapolated to infinity and AUC(0-infinity) was area under the concentration-time curve from zero time extrapolated to infinite time.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Title
AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Css,Av: Average Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Css,Max: Maximum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Css,Min: Minimum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
PTF: Peak-trough Fluctuation Ratio of Tazemetostat and Its Metabolite ER-897387
Description
The PTF within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav) multiplied by 100. Here, Cmin means the minimum plasma concentration, Cmax means the maximum plasma concentration and Cav means the average plasma concentration of drug and metabolite.
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Tazemetostat and Its Metabolite ER-897387
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
CLss/F: Apparent Total Body Clearance of Tazemetostat at Steady State
Time Frame
Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Rac (Cmax): Accumulation Ratio of Cmax for Tazemetostat and Its Metabolite ER-897387
Description
Rac (Cmax) was calculated as the ratio of maximum observed concentration at steady state (Css,max) on Cycle 1 Day 15 divided by Cmax on Cycle 0 Day 1.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) and Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Rac (AUC): Accumulation Ratio of AUC for Tazemetostat and Its Metabolite ER-897387
Description
Rac (AUC) was calculated as the ratio of AUC(0-tau) on Cycle 1 Day 15 divided by AUC(0-12 hours) on Cycle 0 Day 1.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) and Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Rss: Steady State Accumulation Ratio of Tazemetostat and Its Metabolite ER-897387
Description
Rss was calculated as the ratio of AUC(0-tau) on Cycle 1 Day 15 divided by AUC(0-infinity) on Cycle 0 Day 1.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) and Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Ae: Amount of Unchanged Drug Tazemetostat Excreted in Urine
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days); Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Fe: Fraction of Tazemetostat Dose Excreted in Urine
Description
The fraction of dose excreted in urine was calculated as: Cumulative amount of unchanged drug excreted in urine (Ae)/Dose*100.
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days); Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
CLR: Renal Clearance of Tazemetostat
Time Frame
Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days); Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Title
Percentage of Participants With Objective Response
Description
Objective response was assessed by investigator based on the Lugano Classification (CT-Based) response criteria. Objective response rate was defined as the percentage of participants who had a Best Overall Response (BOR) of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame
From the date of first dose of study drug to the date of first documentation of disease progression or death, whichever occurred first (up to 39 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participants with histological diagnosis of B-cell non-Hodgkin's lymphoma
Participant who has measurable disease
Participant who had previous therapy with systemic chemotherapy and/or antibody therapy
Participant who had progressive disease (PD) or did not have a response (complete response [CR] or partial response [PR]) in previous systemic therapy, or relapsed or progressed after previous systemic therapy
Participant with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Participant with life expectancy of ≥3 months from starting study drug administration
Participant with adequate renal, bone marrow, and liver function
Participant with left ventricular ejection fraction (LVEF) > 50%
Male and female participant ≥20 years of age at the time of informed consent
Participant who has provided written consent to participate in the study
Exclusion Criteria:
Participant with prior exposure to EZH2 inhibitor
Participant with a history or a presence of central nerves invasion
Participant with allogeneic stem cell transplantation
Participant with medical need for the continued use of potent or moderate inhibitors of CYP3A or P-gp, or potent or moderate inducer of CYP3A (including St. John's wort).
Participant with significant cardiovascular impairment
Participant with prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 milliseconds (msec)
Participant with venous thrombosis or pulmonary embolism within the last 3 months before starting study drug
Participant with complications of hepatic cirrhosis, interstitial pneumonia, or pulmonary fibrosis
Participant with active infection requiring systemic therapy
Women of childbearing potential or man of impregnate potential who don't agree to use a medically effective method for contraception for periods from before informed consent to during the clinical study and 30 days later from last administration of study drug
Woman who are pregnant or breastfeeding
Participant who were deemed as inappropriate to participate in the study by the investigator or sub-investigator
Facility Information:
Facility Name
Eisai Trial Site
City
Isehara
State/Province
Kanagawa
Country
Japan
Facility Name
Eisai Trial Site
City
Chuo-ku
State/Province
Tokyo
Country
Japan
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Study of Tazemetostat in Participants With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
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