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Overview Study details Eligibility Things to know Research Study plan

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A Study to Assess the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Tazemetostat in Combination With Lenalidomide Plus Rituximab Versus Placebo in Combination With Lenalidomide Plus Rituximab in Adult Patients at Least 18 Years of Age With Relapsed/Refractory Follicular Lymphoma.

PHASE3ACTIVE_NOT_RECRUITING

The participants of this study would have relapsed/refractory follicular lymphoma. Follicular lymphoma is a type of blood cancer. It is referred to as 'relapsed' when the disease has come back after a period of improvement after that follows a treatment regimen and 'refractory' when treatment no longer works.

Stage 1 of this trial will study the safety and the level that adverse effects of each of the study drug combinations can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for stage 2 and 3. Stage 1 of the study is completed.

Stages 2 and 3 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug in combination with other drug treatment versus the placebo (dummy drug) in combination with other drug treatment.

Study details:

In Stage 2, participants were enrolled into study cohorts based on whether they have a specific genetic mutation in the EZH2 gene. All participants received treatment in 28-day cycles. After 12 cycles, they continued with maintenance treatment using either the study drug or placebo, depending on their original treatment group.

However, following the urgent safety measure, treatment was permanently discontinued and no further interventional procedures are being conducted. The study included participants with and without the mutation in EZH2 gene. Enrollment was to be completed separately for each group.

In China, some participants also had extra blood tests to better understand how the drug behaves in the body; no further pharmacokinetic data are being collected following the urgent safety measure. Stage 3 focuses on long-term safety monitoring after the urgent safety measure. Participants treated with tazemetostat will be followed for up to 5 years after the last dose of tazemetostat.

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
Males or females are ≥18 years of age at the time of providing voluntary written informed consent.
Life expectancy ≥3 months before enrollment.
Meet requirement for hepatitis and human immunodeficiency virus (HIV) infection as follows: Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection; Negative test results for hepatitis C virus (HCV); If HIV positive, HIV infection is controlled.
Have histologically confirmed FL, Grades 1 to 3A.
Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.
Must have documented relapsed, refractory, or PD after treatment with systemic therapy (refractory defined as less than PR or disease progression <6 months after last dose).
Have measurable disease as defined by the Lugano Classification.
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Within 7 days prior to randomization, all clinically significant toxicity related to a prior anticancer treatment must have either resolved to Grade 1 per NCI CTCAE Version 5.0 OR are clinically stable and no longer clinically significant.
Have provided sufficient tumor tissue block or unstained slides for EZH2 mutation testing in all subjects to allow for stratification.
Time between prior anticancer therapy and first dose of tazemetostat as follows: Cytotoxic chemotherapy - At least 21 days; Noncytotoxic chemotherapy - At least 14 days; Nitrosoureas - At least 6 weeks; Monoclonal antibodies or CAR T - At least 28 days; Radiotherapy - At least 6 weeks from prior radioisotope therapy.
Adequate renal function defined as calculated creatinine clearance ≥30 mL/minute per the Cockcroft and Gault formula.
Adequate bone marrow function.
Adequate liver function.
International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
Females of childbearing potential (FCBP) must have a negative urine or serum pregnancy tests at screening within 10 to 14 days prior to first dose of study drug.
Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously.
All study participants enrolled must be registered into the applicable pregnancy prevention program for lenalidomide to be administered and be willing and able to comply with the requirements of the applicable program.
Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a pregnant female or FCBP.

Exclusion criteria

Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
Prior exposure to lenalidomide or drugs of the same class.
Grade 3b, mixed histology, or FL that has histologically transformed to diffuse large B-cell lymphoma (DLBCL).
Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 or any prior history of myeloid malignancies.
Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL).
Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers.
Are unwilling to exclude grapefruit juice, Seville oranges, and grapefruits from the diet.
Major surgery within 4 weeks before the first dose of study drug.
Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition.
Significant cardiovascular impairment.
Prolongation of corrected QT interval to ≥480 msec at screening or history of long QT syndrome.
Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
Have an active infection requiring systemic therapy.
Known hypersensitivity to any component of tazemetostat or lenalidomide.
Active viral infection with or seropositive for HBV.
Active viral infection with hepatitis C virus or known active infection with human T-cell lymphotropic virus.
Any other medical or social condition that, in the Investigator's judgment, will interfere with a participant's ability to provide informed consent.
Female subjects who are pregnant or lactating/breastfeeding.
Subjects who have undergone a solid organ transplant.
Subjects with malignancies other than FL, with exceptions for specific cases.

Eligibility

Age eligible for study : NA

Healthy volunteers accepted : No

Gender eligible for study: ALL

Things to know

Study dates

Study start:

Primary completion:

Study completion finish:

Study type

TREATMENT

Phase

PHASE3

Study ID

NCT04224493

Intervention or treatment

DRUG: Tazemetostat

DRUG: Placebo oral tablet

COMBINATION_PRODUCT: Lenalidomide

COMBINATION_PRODUCT: Rituximab

Conditions

Relapsed/Refractory Follicular Lymphoma
Follicular Lymphoma
Refractory Follicular Lymphoma

Condition: Relapsed/Refractory Follicular Lymphoma, Follicular Lymphoma and more
DRUG: Tazemetostat and other drugs
Adelaide, South Australia, Australia and more
Sponsor: Epizyme, Inc.

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Research sites nearby

Closest Location:

Royal Adelaide Hospital

Select from list below to view details:

Royal Adelaide Hospital
Adelaide, South Australia, Australia
Flinders Medical Centre
Bedford Park, South Australia, Australia
Monash Health
Clayton, Victoria, Australia
Barwon Health, University Hospital Geelong
Geelong, Victoria, Australia

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Who is running the clinical trial?

Epizyme, Inc.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Tazemetostat + R2 arm Stage 1 (Phase 1b): completed * Tazemetostat escalated 400mg PO twice daily to 600mg PO twice daily (BD) to 800mg PO BD in 28-day cycles * Rituximab 375mg/m2 IV on days 1, 8, 15, \& 22 of cycle 1; then on day 1 of cycles 2-5 * Lenalidomide 20mg or 10mg, administered PO QD on days 1-21 for 12 cycles Stage 2: * Tazemetostat 800mg administered PO BD in continuous 28-day cycles. * Rituximab 375mg/m2 IV on days 1, 8, 15, \& 22 of cycle 1; then on day 1 of cycles 2-5 * Lenalidomide 20mg or 10mg, administered PO QD on days 1-21 for 12 cycles Maintenance Therapy (Stages 1\&2): Tazemetostat 800mg PO BD dose for up to 2 years after the initial 12 months of combination therapy. Following an Independent Data Monitoring Committee review, an urgent safety measure was implemented and administration of tazemetostat was permanently discontinued. No further investigational treatment is administered. Participants previously exposed to tazemetostat enter protocol-specified long-term safety follow-up	Drug: Tazemetostat, Combination Product: Lenalidomide, Combination Product: Rituximab
PLACEBO_COMPARATOR: Placebo + R2 Arm Participants were assigned to receive placebo in combination with lenalidomide and rituximab. Following implementation of the urgent safety measure, placebo administration was permanently discontinued. No further investigational treatment is administered. Stage 2: * Placebo administered PO twice daily in continuous 28-day cycles. * Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. * Lenalidomide 20 mg or 10 mg (if creatinine clearance ≥60 mL/minute or \<60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles. Maintenance Therapy (Stage 2): Placebo will be administered as monotherapy twice daily dose for up to 2 years after the initial 12 months of combination therapy. During maintenance, placebo will be continued until disease progression or unacceptable toxicity, or participant withdraws consent.	Drug: Placebo oral tablet, Combination Product: Lenalidomide, Combination Product: Rituximab

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Tazemetostat + R2 arm

Stage 1 (Phase 1b): completed
* Tazemetostat escalated 400mg PO twice daily to 600mg PO twice daily (BD) to 800mg PO BD in 28-day cycles
* Rituximab 375mg/m2 IV on days 1, 8, 15, \& 22 of cycle 1; then on day 1 of cycles 2-5
* Lenalidomide 20mg or 10mg, administered PO QD on days 1-21 for 12 cycles
Stage 2:
* Tazemetostat 800mg administered PO BD in continuous 28-day cycles.
* Rituximab 375mg/m2 IV on days 1, 8, 15, \& 22 of cycle 1; then on day 1 of cycles 2-5
* Lenalidomide 20mg or 10mg, administered PO QD on days 1-21 for 12 cycles
Maintenance Therapy (Stages 1\&2):
Tazemetostat 800mg PO BD dose for up to 2 years after the initial 12 months of combination therapy. Following an Independent Data Monitoring Committee review, an urgent safety measure was implemented and administration of tazemetostat was permanently discontinued. No further investigational treatment is administered. Participants previously exposed to tazemetostat enter protocol-specified long-term safety follow-up

Drug: Tazemetostat, Combination Product: Lenalidomide, Combination Product: Rituximab

PLACEBO_COMPARATOR: Placebo + R2 Arm

Participants were assigned to receive placebo in combination with lenalidomide and rituximab.
Following implementation of the urgent safety measure, placebo administration was permanently discontinued. No further investigational treatment is administered.
Stage 2:
* Placebo administered PO twice daily in continuous 28-day cycles.
* Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5.
* Lenalidomide 20 mg or 10 mg (if creatinine clearance ≥60 mL/minute or \<60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.
Maintenance Therapy (Stage 2):
Placebo will be administered as monotherapy twice daily dose for up to 2 years after the initial 12 months of combination therapy. During maintenance, placebo will be continued until disease progression or unacceptable toxicity, or participant withdraws consent.

Drug: Placebo oral tablet, Combination Product: Lenalidomide, Combination Product: Rituximab

What is the study measuring?

Primary Outcome

Measure	Description	Time Frame
Recommended Phase 3 Dose (RP3D) of tazemetostat in combination with rituximab and lenalidomide (R2)	The safety and tolerability of tazemetostat in combination with R2 in subjects with R/R FL will be evaluated. RP3D of tazemetostat for further evaluation in phase 3 will be selected as assessed by the occurrence of treatment-emergent dose-limiting toxicities (DLTs) and adverse events (AEs).	Subjects are evaluated for DLTs during the first 28-day cycle. The RP3D for Phase 3 was selected at the end of Stage 1
Progression-Free Survival (PFS) in the Intent-to-treat wild-type (ITT-WT) population	PFS is defined as the time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification or death, whichever occurs first, as assessed by Investigators.	Stage 2: Up to 72 months
PFS in the Intent-to-treat mutant-type (ITT-MT) population	PFS is defined as the time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification or death, whichever occurs first, as assessed by Investigators.	Stage 2: Up to 72 months

Secondary Outcome

Measure	Description	Time Frame
Pharmacokinetics (PK) of tazemetostat: Maximum (peak) Observed Plasma Drug Concentration (Cmax).	Cmax will be recorded from the PK blood samples collected.	Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
PK of tazemetostat, EPZ 6930 (desethyl metabolite), and lenalidomide as data permit: Time to Maximum Observed Drug Concentration (Tmax)	Not Specified	Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
PK of tazemetostat: area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration [AUC(0-t)],	Not Specified	Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
PK of tazemetostat: area under the plasma concentration-time curve (AUC) from time 0 to infinity [AUC(0-∞)]	Not Specified	Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
The apparent terminal elimination half-life (t1/2) of tazemetostat, EPZ 6930 (desethyl metabolite), and lenalidomide as data permit	Not Specified	Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
Complete Response Rate (CRR) in ITT-WT population	CRR is defined as the proportion of participants achieving CR according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded Independent Review Committee (IRC).	Stage 2: Up to 96 months
CRR in ITT-MT population	CRR is defined as the proportion of participants achieving CR according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded IRC.	Stage 2: Up to 96 months
CRR in the Relapsed/Refractory (R/R) Follicular Lymphoma (FL) population regardless of mutation status	CRR is defined as the proportion of participants achieving CR according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded IRC.	Stage 2: Up to 96 months
Objective Response Rate (ORR) in the ITT-WT population	ORR is defined as the proportion of participants achieving a best overall response (BOR) of partial response (PR) or complete response (CR) according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded IRC.	Stage 2: Up to 96 months
ORR in the ITT-MT population	ORR is defined as the proportion of participants achieving a best overall response (BOR) of partial response (PR) or complete response (CR) according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded IRC.	Stage 2: Up to 96 months
ORR in the R/R FL population regardless of mutation status	ORR is defined as the proportion of participants achieving a best overall response (BOR) of partial response (PR) or complete response (CR) according to the 2014 Lugano Classification, as assessed by the Investigator and a blinded IRC.	Stage 2: Up to 96 months
Overall Survival (OS) in the ITT-WT population	OS is defined as the time from the date of randomization until death due to any cause.	Stage 2: Up to 96 months
OS in the ITT-MT population	Not Specified	Stage 2: Up to 96 months
OS in the R/R FL population regardless of mutation status	Not Specified	Stage 2: Up to 96 months
PFS in the ITT-WT population, assessed by a blinded IRC	Not Specified	Stage 2: Up to 96 months
PFS in the ITT-MT population, assessed by a blinded IRC	Not Specified	Stage 2: Up to 96 months
PFS in the R/R FL population regardless of mutation status, assessed by a blinded IRC	Not Specified	Stage 2: Up to 96 months
PFS in the R/R FL population regardless of mutation status, assessed by the Investigator	Not Specified	Stage 2: Up to 96 months
Duration Of Response (DOR) in the ITT-WT population	DOR is defined as the time from initial CR or PR to documented progression or death due to any cause, whichever occurs first, for those participants with a CR or PR, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DOR in the ITT-MT population	DOR is defined as the time from initial CR or PR to documented progression or death due to any cause, whichever occurs first, for those participants with a CR or PR, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DOR in the R/R FL population regardless of mutation status	DOR is defined as the time from initial CR or PR to documented progression or death due to any cause, whichever occurs first, for those participants with a CR or PR, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
Duration Of Complete Response (DOCR) in the ITT-WT population	DOCR is defined as the time from initial CR to documented progression or death due to any cause, whichever occurs first, for those participants with CR, assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DOCR in the ITT-MT population	DOCR is defined as the time from initial CR to documented progression or death due to any cause, whichever occurs first, for those participants with CR, assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DOCR in the R/R FL population regardless of mutation status	DOCR is defined as the time from initial CR to documented progression or death due to any cause, whichever occurs first, for those participants with CR, assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
Disease Control Rate (DCR) in the ITT-WT population	DCR, defined as the proportion of participants with best overall response of CR, PR, or stable disease (SD) lasting 12 or more months, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DCR in the ITT-MT population	DCR, defined as the proportion of participants with best overall response of CR, PR, or stable disease (SD) lasting 12 or more months, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
DCR in the R/R FL population regardless of mutation status	DCR, defined as the proportion of participants with best overall response of CR, PR, or stable disease (SD) lasting 12 or more months, as assessed by the Investigator and by a blinded IRC.	Stage 2: Up to 96 months
Population PK parameters of oral clearance (CL/F) of tazemetostat	CL/F will be used to generate estimates of tazemetostat AUC	Stage 2: In cycles 2, 4, 6, and 12 at Day 1 (28 days cycle)
Population PK parameters of oral volume of distribution (Vd/F) of tazemetostat.	Not Specified	Stage 2: In cycles 2, 4, 6, and 12 at Day 1 (28 days cycle)
Population PK parameters of first-order absorption rate constant (Ka) for tazemetostat.	Not Specified	Stage 2: In cycles 2, 4, 6, and 12 at Day 1 (28 days cycle)
Percentage of Participants Experiencing Adverse Events (AEs)	An Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to 36 months
Percentage of Participants with Clinically Significant Changes in Physical Examination	Percentage of participants with clinically significant changes in physical examination findings will be reported. The clinical significance will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for AEs (CTCAE) Version 5.0.	Up to 36 months
Percentage of Participants with Clinically Significant Changes in Vital Signs	Percentage of participants with clinically significant changes in vital signs findings will be reported. The clinical significance will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for AEs (CTCAE) Version 5.0.	Up to 36 months
Percentage of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Readings	Percentage of participants with clinically significant changes in ECG Readings will be reported. The clinical significance will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for AEs (CTCAE) Version 5.0.	Up to 72 months
Performance status evaluated by Eastern Cooperation Oncology Group (ECOG)	ECOG is a 6-point performance status scale used to assess performance using PA as a key indicator (e.g., 0 = fully active, 2 = up and about more than 50% of walking hours, 5 = dead) Performance status will be assessed per usual clinical practice and will be recorded in the medical record.	Up to 72 months
Duration of Study Drug Exposure	Duration of exposure to study drug will be reported.	Up to 36 months
Percentage of study drug taken by participants	Not Specified	Up to 36 months
Quality of life questionnaires evaluation	Evaluate and compare health-related quality of life as measured by the EuroQOL 5-Dimension 5-Level (EQ-5D-5L) instrument and the Functional Assessment of Cancer Therapy -Lymphoma (FACT-Lym)	Up to 36 months

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References

Clinical Trials Gov: A Study to Assess the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Tazemetostat in Combination With Lenalidomide Plus Rituximab Versus Placebo in Combination With Lenalidomide Plus Rituximab in Adult Patients at Least 18 Years of Age With Relapsed/Refractory Follicular Lymphoma.

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