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

Study Overview
=================
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).

Official Title
-----------------
A Phase 1 Study of Tazemetostat in Patients With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

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

Intervention / Treatment
-----------------
* Drug: Tazemetostat


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tazemetostat 800 mg<br>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). | Drug: Tazemetostat<br>* Tazemetostat tablets.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 0 and Cycle 1 (Cycle 0=4 days, Cycle 1=28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the date of first dose up to 30 days after the last dose of study drug (up to 40 months) | 
| 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 | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | 
| 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 | 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]). | 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) | 
| 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. | Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days) | 
| 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) | 
| 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) | 
| 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 | 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. | Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days) | 
| 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 | 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. | 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): 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. | 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: 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. | 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) | 
| 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 | The fraction of dose excreted in urine was calculated as: Cumulative amount of unchanged drug excreted in urine (Ae)/Dose*100. | 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) | 
| 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 | 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. | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tazemetostat, Japan, E7438, relapsed or refractory B-cell non-Hodgkin's lymphoma