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

Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03009344
• Other study ID #: E7438-J081-106
• Status: Completed
• Phase: Phase 1
• Start date: January 10, 2017
• Est. completion date: June 17, 2020

Study information

• Verified date: April 2022
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: June 17, 2020
• Est. primary completion date: July 12, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

Intervention

Drug:
• Tazemetostat
Tazemetostat tablets.

Locations

Country	Name	City	State
Japan	Eisai Trial Site	Chuo-ku	Tokyo
Japan	Eisai Trial Site	Isehara	Kanagawa

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Co., Ltd.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Cycle 0 and Cycle 1 (Cycle 0=4 days, Cycle 1=28 days)
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.	From the date of first dose up to 30 days after the last dose of study drug (up to 40 months)
Secondary	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)
Secondary	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)
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		Cycle 0 Day 1: 0-12 hours post-dose (Cycle 0 length=4 days)
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		Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Secondary	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)
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.	Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Secondary	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)
Secondary	CL/F: Apparent Total Body Clearance of Tazemetostat		Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
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]).	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)
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.	Cycle 0 Day 1: 0-72 hours post-dose (Cycle 0 length=4 days)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
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.	Cycle 1 Day 15: 0-12 hours post-dose (Cycle 1 length=28 days)
Secondary	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)
Secondary	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)
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.	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)
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.	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)
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.	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)
Secondary	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)
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.	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)
Secondary	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)
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.	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)