Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma
Conditions
Keywords
relapsed or refractory B-cell non-Hodgkin's lymphoma, tazemetostat, Japan, E7438
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).
Interventions
DRUGTazemetostat
Tazemetostat tablets.
Sponsors
Eisai Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 0 and Cycle 1 (Cycle 0=4 days, Cycle 1=28 days) | 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
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | — |
| Tmax: Time to Reach Maximum Plasma Concentration (Cmax) of Tazemetostat and Its Metabolite ER-897387 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | — |
| 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 | Cycle 0 Day 1: 0-12 hours post-dose (Cycle 0 length=4 days) | — |
| 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 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | — |
| AUC(0-infinity): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of Tazemetostat and Its Metabolite ER-897387 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | — |
| Lambda z: Terminal Phase Elimination Rate Constant of Tazemetostat and Its Metabolite ER-897387 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | 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 | 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) | — |
| CL/F: Apparent Total Body Clearance of Tazemetostat | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | — |
| Vz/F: Apparent Volume of Distribution at Terminal Phase of Tazemetostat | 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) | 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 | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | 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 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
| Css,Av: Average Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the date of first dose up to 30 days after the last dose of study drug (up to 40 months) | 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. |
| Css,Min: Minimum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
| PTF: Peak-trough Fluctuation Ratio of Tazemetostat and Its Metabolite ER-897387 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | 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 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
| CLss/F: Apparent Total Body Clearance of Tazemetostat at Steady State | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
| Rac (Cmax): Accumulation Ratio of Cmax for Tazemetostat and Its Metabolite ER-897387 | 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) | 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 | 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) | 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 | 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) | 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 | 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) | — |
| Fe: Fraction of Tazemetostat Dose Excreted in Urine | 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) | 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 | 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) | — |
| Percentage of Participants With Objective Response | 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) | 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. |
| Css,Max: Maximum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | — |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in Japan from 10 January 2017 to 17 June 2020.
Pre-assignment details
A total of 7 participants were screened and enrolled to receive study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Tazemetostat 800 mg Participants received tazemetostat 800 mg tablets, orally on Day 1 of Cycle 0 and 800 mg tablets, orally, twice daily as continuous dosing in Cycle 1 and later cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or study termination by the sponsor (up to 39 months). Cycle 0 duration was 4 days, Cycle 1 and later cycles duration was 28 days. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 5 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Tazemetostat 800 mg |
|---|---|
| Age, Continuous | 72.3 years STANDARD_DEVIATION 8.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Japanese | 7 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 2 / 7 |
Outcome results
Primary
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.
Time frame: Cycle 0 and Cycle 1 (Cycle 0=4 days, Cycle 1=28 days)
Population: DLT analysis set included all participants who completed treatment Cycles 0 and 1 without major protocol deviations with at least 75% of treatment compliance in Cycle 1 and were assessed for DLT, and participants who experienced DLT during Cycles 0 and 1. Participants with less than 75% treatment compliance in Cycle 1 due to a reason other than toxicity up to Cycle 1 Day 28 were not included in this analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tazemetostat 800 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Ae: Amount of Unchanged Drug Tazemetostat Excreted in Urine | Cycle 0 Day 1 | 15.1 mg | Geometric Coefficient of Variation 51.6 |
| Tazemetostat 800 mg | Ae: Amount of Unchanged Drug Tazemetostat Excreted in Urine | Cycle 1 Day 15 | 6.81 mg | Geometric Coefficient of Variation 33.7 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | 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 | Tazemetostat | 4080 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 61.3 |
| Tazemetostat 800 mg | 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 | ER-897387 | 4500 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 72.4 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | AUC(0-infinity): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 5220 ng*h/mL | Geometric Coefficient of Variation 63.2 |
| Tazemetostat 800 mg | AUC(0-infinity): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 6570 ng*h/mL | Geometric Coefficient of Variation 74.9 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 4220 ng*h/mL | Geometric Coefficient of Variation 42.6 |
| Tazemetostat 800 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 10200 ng*h/mL | Geometric Coefficient of Variation 39.1 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | 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 | Tazemetostat | 5180 ng*h/mL | Geometric Coefficient of Variation 63.6 |
| Tazemetostat 800 mg | 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 | ER-897387 | 6540 ng*h/mL | Geometric Coefficient of Variation 75.3 |
Secondary
CL/F: Apparent Total Body Clearance of Tazemetostat
Time frame: Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tazemetostat 800 mg | CL/F: Apparent Total Body Clearance of Tazemetostat | 153 liter per hour (L/h) | Geometric Coefficient of Variation 63.2 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | CLR: Renal Clearance of Tazemetostat | Cycle 0 Day 1 | 2.62 L/h | Geometric Coefficient of Variation 15.2 |
| Tazemetostat 800 mg | CLR: Renal Clearance of Tazemetostat | Cycle 1 Day 15 | 1.62 L/h | Geometric Coefficient of Variation 25.6 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tazemetostat 800 mg | CLss/F: Apparent Total Body Clearance of Tazemetostat at Steady State | 190 L/h | Geometric Coefficient of Variation 42.6 |
Secondary
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)
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Cmax: Maximum Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 988 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.1 |
| Tazemetostat 800 mg | Cmax: Maximum Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 790 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 78.8 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Css,Av: Average Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 351 ng/mL | Geometric Coefficient of Variation 42.7 |
| Tazemetostat 800 mg | Css,Av: Average Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 852 ng/mL | Geometric Coefficient of Variation 39 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Css,Max: Maximum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 1170 ng/mL | Geometric Coefficient of Variation 51.6 |
| Tazemetostat 800 mg | Css,Max: Maximum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 1800 ng/mL | Geometric Coefficient of Variation 47.4 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Css,Min: Minimum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 88.4 ng/mL | Geometric Coefficient of Variation 43.8 |
| Tazemetostat 800 mg | Css,Min: Minimum Steady State Plasma Concentration of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 293 ng/mL | Geometric Coefficient of Variation 46.7 |
Secondary
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.
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Fe: Fraction of Tazemetostat Dose Excreted in Urine | Cycle 0 Day 1 | 1.89 percentage of dose | Geometric Coefficient of Variation 51.4 |
| Tazemetostat 800 mg | Fe: Fraction of Tazemetostat Dose Excreted in Urine | Cycle 1 Day 15 | 0.852 percentage of dose | Geometric Coefficient of Variation 33.8 |
Secondary
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.
Time frame: Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Lambda z: Terminal Phase Elimination Rate Constant of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 0.0925 per hour | Geometric Coefficient of Variation 17.9 |
| Tazemetostat 800 mg | Lambda z: Terminal Phase Elimination Rate Constant of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 0.0794 per hour | Geometric Coefficient of Variation 16.9 |
Secondary
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.
Time frame: Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | MRT: Mean Residence Time of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 8.25 hours | Geometric Coefficient of Variation 29.3 |
| Tazemetostat 800 mg | MRT: Mean Residence Time of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 10.7 hours | Geometric Coefficient of Variation 31 |
Secondary
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.
Time frame: From the date of first dose up to 30 days after the last dose of study drug (up to 40 months)
Population: The safety analysis set included all participants who received at least 1 administration of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tazemetostat 800 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 7 Participants |
| Tazemetostat 800 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Secondary
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.
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)
Population: The efficacy analysis set included all participants who received at least 1 administration of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tazemetostat 800 mg | Percentage of Participants With Objective Response | 57.1 percentage of participants |
Secondary
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.
Time frame: Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | PTF: Peak-trough Fluctuation Ratio of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 303 percentage fluctuation | Geometric Coefficient of Variation 40.8 |
| Tazemetostat 800 mg | PTF: Peak-trough Fluctuation Ratio of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 171 percentage fluctuation | Geometric Coefficient of Variation 39.8 |
Secondary
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.
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Rac (AUC): Accumulation Ratio of AUC for Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 1.04 ratio | Geometric Coefficient of Variation 37.6 |
| Tazemetostat 800 mg | Rac (AUC): Accumulation Ratio of AUC for Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 2.27 ratio | Geometric Coefficient of Variation 58.5 |
Secondary
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.
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Rac (Cmax): Accumulation Ratio of Cmax for Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 1.19 ratio | Geometric Coefficient of Variation 56.7 |
| Tazemetostat 800 mg | Rac (Cmax): Accumulation Ratio of Cmax for Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 2.28 ratio | Geometric Coefficient of Variation 59.9 |
Secondary
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.
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Rss: Steady State Accumulation Ratio of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 0.809 ratio | Geometric Coefficient of Variation 35 |
| Tazemetostat 800 mg | Rss: Steady State Accumulation Ratio of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 1.56 ratio | Geometric Coefficient of Variation 53.1 |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tazemetostat 800 mg | T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat (Cycle 0 Day 1) | 7.76 hour |
| Tazemetostat 800 mg | T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat (Cycle 1 Day 15) | 4.10 hour |
| Tazemetostat 800 mg | T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387 | ER-897387 (Cycle 0 Day 1) | 8.68 hour |
| Tazemetostat 800 mg | T1/2: Terminal Half-life of Tazemetostat and Its Metabolite ER-897387 | ER-897387 (Cycle 1 Day 15) | 3.55 hour |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tazemetostat 800 mg | Tmax: Time to Reach Maximum Plasma Concentration (Cmax) of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 1.97 hours |
| Tazemetostat 800 mg | Tmax: Time to Reach Maximum Plasma Concentration (Cmax) of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 1.97 hours |
Secondary
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tazemetostat 800 mg | Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Tazemetostat and Its Metabolite ER-897387 | Tazemetostat | 1.05 hours |
| Tazemetostat 800 mg | Tss,Max: Time to Reach the Maximum Plasma Concentration (Cmax) at Steady State of Tazemetostat and Its Metabolite ER-897387 | ER-897387 | 1.07 hours |
Secondary
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 (\[lambda z\]\*\[AUC0-tau\]).
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)
Population: The PK analysis set included all participants who received at least 1 administration of the study drug and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tazemetostat 800 mg | Vz/F: Apparent Volume of Distribution at Terminal Phase of Tazemetostat | Cycle 0 Day 1 | 1660 liter (L) | Geometric Coefficient of Variation 64.1 |
| Tazemetostat 800 mg | Vz/F: Apparent Volume of Distribution at Terminal Phase of Tazemetostat | Cycle 1 Day 15 | 1170 liter (L) | Geometric Coefficient of Variation 93 |