This is a multicenter, double-blind, active-controlled, randomized, 3-stage, biomarker
enrichment design featuring early futility stopping and sample-size re-estimation with safety
run-in designed to evaluate the efficacy and safety of tazemetostat in combination with R2 in
subjects with R/R FL, who have completed at least 1 prior systemic chemotherapy,
immunotherapy, or chemoimmunotherapy.
Stage 1 is a safety run-in phase, stage 2 is an efficacy and safety phase for an assessment
of the EZH2 Mutant Type population and overall FL population regardless of EZH2 mutation
status, and optional stage 3 with efficacy and safety phase for subjects with EZH2 mutation.
Stage 3 with Mutant Type population alone will be executed in case the efficacy of the
overall population in stage 2 fails whilst the efficacy of EZH2 Mutant Type is sufficiently
promising. Stage 2 will include 2 futility interim analyses based on ORR for the first
futility and PFS for the second one. In addition, there is a possible sample size
re-estimation based on PFS. This is to ensure early detection of the presence/absence of
clinical efficacy benefit as well as ensuring adequate powering based on the trial results to
demonstrate a meaningful efficacy difference.
Inclusion Criteria:
1. Have voluntarily agreed to provide written informed consent and demonstrated
willingness and ability to comply with all aspects of the protocol.
2. Males or females are ≥18 years of age at the time of providing voluntary written
informed consent.
3. Life expectancy ≥3 months before enrollment.
4. Subjects with a history of hepatitis B or C are eligible on the condition that
subjects have adequate liver function as defined by Inclusion Criterion #15 and are
hepatitis B surface antigen negative and/or have undetectable hepatitis C virus (HCV)
RNA.
5. Have histologically confirmed FL, grades 1 to 3A.
6. Must have been previously treated with at least 1 prior systemic chemotherapy,
immunotherapy, or chemoimmunotherapy:
1. Systemic therapy includes treatments such as:
i. Rituximab monotherapy ii. Chemotherapy given with or without rituximab iii.
Radioimmunoconjugates such as 90Y-ibritumomab tiuxetan and 131I-tositumomab.
b. Systemic therapy does not include, for example: i. Local involved field
radiotherapy for limited-stage disease ii. Helicobacter pylori eradication Prior
investigational therapies will be allowed provided the subject has received at least
1 prior systemic therapy as discussed in Inclusion Criteria #6a. 7. 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).
8. Have measurable disease as defined by the Lugano Classification (Cheson, 2014).
9.Time between prior anticancer therapy and first dose of tazemetostat as follows:
1. Cytotoxic chemotherapy - At least 21 days.
2. Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days.
3. Nitrosoureas - At least 6 weeks.
4. Monoclonal antibody(ies) - At least 28 days.
5. Radiotherapy -At least 6 weeks from prior radioisotope therapy; at least 12 weeks from
50% pelvic or total body irradiation. 13. Adequate renal function defined as
calculated creatinine clearance ≥40 mL/minute per the Cockcroft and Gault formula or
local institutional standard formula.
10. Adequate renal function defined as calculated creatinine clearance ≥40 mL/minute
per the Cockcroft and Gault formula or local institutional standard formula.
11. Adequate bone marrow function. 12. Females must not be lactating or pregnant at
Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin
[β-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG). A
separate baseline assessment is required if a negative screening pregnancy test was
obtained more than 72 hours before the first dose of study treatment. All females will
be considered to be of childbearing potential unless they are postmenopausal (at least
12 months consecutively amenorrhoeic, in the appropriate age group, and without other
known or suspected cause) or have been sterilized surgically (ie, bilateral tubal
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1
month before dosing).
13. Females of childbearing potential must not have had unprotected sexual intercourse
within 30 days prior to study entry and must agree to use a highly effective method of
contraception, from the last menstrual period prior to randomization, during treatment
cycles, and for 30 days after the final dose of study treatment, and have a male
partner who uses a condom. Highly effective contraception includes:
- Double barrier methods of contraception such as condom plus diaphragm or
cervical/vault cap with spermicide.
- Placement of an intrauterine device.
- Established hormonal contraceptive methods: oral, injectable, or implant. Females
who are using hormonal contraceptives must have been on a stable dose of the same
hormonal contraceptive product for at least 4 weeks prior to dosing and must
continue to use the same contraceptive during the study and for 30 days after
study drug discontinuation.
NOTE: Female subjects exempt from this requirement are subjects who practice total
abstinence or have a male partner who is vasectomized. If currently abstinent, the subject
must agree to use a highly effective method of contraception as described above if they
become sexually active during treatment cycles, and for 30 days after study drug
discontinuation. 14. All study participants enrolled must be registered into the mandatory
Revlimid REMS™ program and be willing and able to comply with the requirements of the
Revlimid REMS™ program as appropriate for the country in which the drug is being used.
a. Female subjects of childbearing potential must adhere to the scheduled pregnancy testing
as required in the Revlimid REMS™ program. Female subjects exempt from this requirement are
subjects who have been in natural menopause for at least 2 years OR have had both ovaries
and/or uterus removed.
15. Male subjects must have had either a successful vasectomy OR they and their female
partner must meet the criteria above (ie, not of childbearing potential OR practicing
highly effective contraception and use a condom throughout the study period and for 30 days
after study drug discontinuation).
Exclusion Criteria:
All Subjects
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
2. Prior exposure to lenalidomide for the treatment of FL.
3. Subjects who have mixed or transformed histology.
4. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE Version 5.0
criteria) or any prior history of myeloid malignancies, including myelodysplastic
syndrome (MDS).
5. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute
lymphoblastic leukemia (T-ALL).
6. Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of
previously treated brain metastases.
7. Subjects taking medications that are known potent cytochrome P450 (CYP)3A4
inducers/inhibitors (including St. John's wort) (Flockhart, 2007; U. S. Food and Drug
Administration, February 2015).
8. Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their
diet.
9. Major surgery within 4 weeks before the first dose of study drug.
a. Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter
placement, shunt revision) is permitted within 3 weeks prior to enrollment.
10. Are unable to take oral medication OR have malabsorption syndrome or any other
uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might
impair the bioavailability of tazemetostat.
11. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
unstable angina, myocardial infarction, or stroke within 6 months of the first dose of
study drug; or cardiac ventricular arrhythmia.
12. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to >480 msec
at screening or history of long QT syndrome.
13. Venous thrombosis or pulmonary embolism within the last 3 months before starting
tazemetostat.
a. whereas subjects greater than 3 months since deep vein thrombosis/pulmonary
embolism are eligible but recommended to receive prophylaxis.
14. Have an active infection requiring systemic therapy.
15. Known hypersensitivity to any component of tazemetostat, lenalidomide, or rituximab.
16. Inability to be treated with a Pneumocystis prophylaxis medication.
17. Have an active infection with hepatitis B virus (as measured by positive hepatitis B
surface antigen), HCV (as measured by positive hepatitis C antibody), human
immunodeficiency virus, OR human T-cell lymphotropic virus 1.
a. Exceptions: Subjects with a history of hepatitis B or C who have normal ALT AND are
hepatitis B surface antigen negative and/or have undetectable HCV RNA.
18. Any other major illness that, in the Investigator's judgment, will substantially
increase the risk associated with the subject's participation in this study OR
interfere with their ability to receive study treatment or complete the study.
19. Female subjects who are pregnant or breastfeeding.
20. Subjects who have undergone a solid organ transplant.
21. Subjects with malignancies other than FL. a. Exception: Subjects with another
malignancy who have been disease-free for 5 years, or subjects with a history of a
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
are eligible.
