Overview
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.
Description
Stage 1 is a safety run-in phase, was designed to evaluate the safety of the combination of tazemetostat and R2, as well as to establish the RP3D for Stage 2, which is now completed.
Stage 2 is an efficacy and safety phase for an assessment of the FL population with the enhancer of zeste homolog 2 (EZH2) gain-of-function (GOF) mutation (EZH2 mutant-type [MT]) and without the EZH2 GOF mutation (EZH2 wild-type [WT]). In Stage 2, EZH2 WT and EZH2 MT patients will be randomly assigned in a 1:1 ratio to tazemetostat + R2 or placebo + R2. There will be 1 futility interim analysis (IA) and 1 efficacy IA for WT population and 1 efficacy IA for MT population.
Stage 3 is a long-term follow-up of patients for assessment of response and overall survival. All patients will be followed for survival until 5 years post last patient enrolled in the study.
Eligibility
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 Note: Participants whose HBV infection status could not be determined by serologic test results have to be negative for HBV-DNA by PCR to be eligible for study participation. Participants seropositive for HBV with undetectable HBV DNA by PCR are permitted with appropriate antiviral prophylaxis.
- Negative test results for hepatitis C virus (HCV) Note: Participants who are positive for HCV antibody must be negative for HCV RNA by PCR to be eligible for study participation
- 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:
- Systemic therapy includes treatments such as:
- 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
c. Prior investigational therapies will be allowed provided the subject has received
at least 1 prior systemic therapy as discussed in Inclusion Criterion #6a.
d. Prior autologous/allogeneic hematopoietic stem cell transplant (HSCT) will be
allowed.
e. Prior chimeric antigen receptor T-cell therapy (CAR T) will be allowed.
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;
Appendix 5).
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
10. Within 7 days prior to randomization, all clinically significant toxicity related to a
prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy must
have either resolved to Grade 1 per NCI CTCAE Version 5.0 OR are clinically stable and
no longer clinically significant.
11. Have provided sufficient tumor tissue block or unstained slides for EZH2 mutation
testing in all subjects to allow for stratification
a. If EZH2 mutation status is known from site-specific testing, subjects can be
enrolled. Tumor tissue will be required for confirmatory testing of EZH2 status at
study-specific laboratories. If the archival tumor sample was collected more than 24
months prior to the anticipated administration of the first dose (cycle 1 day 1), then
a fresh biopsy must be provided. Fresh tumor biopsy is appropriate except for
procedures deemed to result in unacceptable risk because of the anatomical location
including brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond
the esophagus, stomach, or bowel. Archival tumor biopsy sections mounted on slides are
also acceptable.
NOTE: Confirmatory testing will also be performed for Stage 1, if local EZH2 testing
is conducted, unless there is insufficient tumor tissue to perform testing after
discussion with the Sponsor's or Designee Medical Monitor.
12. 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 and/or bispecific antibodies or CAR T - 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 ≥30 mL/minute per
the Cockcroft and Gault formula.
14. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 × 10^9/L) if no lymphoma
infiltration of bone marrow OR ANC ≥750/mm3 (≥75 × 10^9/L) with bone marrow
infiltration
- Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.
b. Platelets ≥75,000/mm3 (≥75 × 10^9/L)
- Evaluated at least 7 days after last platelet transfusion.
c. Hemoglobin ≥9.0 g/dL
- May receive transfusion
15. Adequate liver function:
1. Total bilirubin ≤1.5 × the upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia of Gilbert's syndrome.
2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine
aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN
if subject has liver infilration).
16. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin
time (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects with
thromboembolism risk, prophylactic anticoagulation, or antiplatelet therapy at
investigator discretion is recommended.
17. Females of childbearing potential (FCBP) must have a negative urine or serum pregnancy
tests (beta-human chorionic gonadotropin [β-hCG] tests with a minimum sensitivity of
25 mIU/mL or equivalent units of β-hCG) at screening within 10 to 14 days prior to
first dose of study drug. The subject may not receive study drug until the study
doctor has verified that the results of pregnancy tests are negative. All females will
be considered to be of childbearing potential unless they are naturally postmenopausal
(at least 24 months consecutively amenorrhoeic [amenorrhea following cancer therapy
does not rule out childbearing potential] and without other known or suspected cause)
or have been sterilized surgically (ie, total hysterectomy and/or bilateral
oophorectomy, with surgery completed at least 1 month before dosing).
18. Females of childbearing potential (FCBP) enrolled must either practice complete
abstinence or agree to use two reliable methods of contraception simultaneously. This
includes ONE highly effective method of contraception and ONE additional effective
contraceptive method. Contraception must begin at least 28 days prior to first dose of
study drug, continue during study treatment (including during dose interruptions), and
for 12 months after study drug discontinuation. Female subjects must also refrain from
breastfeeding for 12 months following last dose of study drug. If the below
contraception methods are not appropriate for the FCBP, she must be referred to a
qualified contraception provider to determine the medically effective contraception
method appropriate for the subject. The following are examples of highly effective and
additional effective methods of contraception:
Examples of highly effective methods:
- Intrauterine device (IUD)
- Hormonal (ovulation inhibitory combined [estrogen and progesterone] birth control
pills or intravaginal/transdermal system, injections, implants,
levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone acetate
depot injections, ovulation inhibitory progesterone-only pills [e.g.
desogestrel]) NOTE: There is a potential for tazemetostat interference with
hormonal contraception methods due to enzymatic induction.
- Bilateral tubal ligation
- Partner's vasectomy (if medically confirmed [azoospermia] and sole sexual
partner).
Examples of additional effective methods:
- Male latex or synthetic condom,
- Diaphragm,
- Cervical Cap
NOTE: Female subjects of childbearing potential exempt from these contraception
requirements are subjects who practice complete abstinence from heterosexual sexual
contact. True abstinence is acceptable when this is in line with the preferred and
usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,
symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of
contraception.
19. All study participants enrolled must be registered into the applicable pregnancy
prevention program (e.g. REVLIMID REMS in the US, Pregnancy Prevention Programme [PPP]
in Europe, RevAid in Canada) for lenalidomide to be administered and be willing and
able to comply with the requirements of the applicable program as appropriate for the
country in which the drug is being used.
a. Female subjects of childbearing potential (FCBP) must adhere to the scheduled
pregnancy testing as required in theapplicable pregnancy prevention program. During
study treatment, FCBP must agree to have pregnancy testing weekly for the first 28
days of study participation and then every 28 days for FCBP with regular or no
menstrual cycles OR every 14 days for FCBP with irregular menstrual cycles. FCBP must
also have a pregnancy test at end of lenalidomide treatment, at days 14 and 28
following the last dose of lenalidomide and at overall treatment discontinuation (at
the End-of-Treatment/30-day safety Follow-up visit). Female subjects exempt from this
requirement are subjects who have been naturally postmenopausal for at least 24
consecutive months OR have had a total hysterectomy and/or bilateral oophorectomy.
20. Male subjects must either practice complete abstinence or agree to use a latex or
synthetic condom, even with a successful vasectomy (medically confirmed azoospermia),
during sexual contact with a pregnant female or FCBP from first dose of study drug,
during study treatment (including during dose interruptions), and for 3 months after
study drug discontinuation.
NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during
study treatment (including during dose interruptions), and for 3 months after study drug
discontinuation.
Exclusion Criteria:
All Subjects
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
2. Prior exposure to lenalidomide or drugs of the same class.
3. Grade 3b, mixed histology, or FL that has histologically transformed to diffuse large
B-cell lymphoma (DLBCL) (subjects transformed from DLBCL to FL may be enrolled).
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)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
5. 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).
6. Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of
previously treated brain metastases.
7. Subjects taking medications that are known strong CYP3A inhibitors and strong or
moderate CYP3A inducers (including St. John's wort).
8. Are unwilling to exclude grapefruit juice, Seville oranges, and grapefruits from the
diet and/or consumed within 1 week of the first dose of study drug and for the
duration of the study.
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 (Appendix 3).
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. Note: Participants who have experienced deep vein thrombosis/pulmonary embolism
more than 3 months before enrollment are eligible but are recommended to receive
prophylaxis.
14. Have an active infection requiring systemic therapy.
15. Known hypersensitivity to any component of tazemetostat or lenalidomide; known severe
hypersensitivity to any component of rituximab requiring hospitalization or
resuscitation.
16. Active viral infection with or seropositive for HBV: HBV surface antigen (HBsAg)
positive OR HBsAg negative, anti-HBs positive and/or anti-HBc positive with detectable
HBV DNA.
NOTE: Subjects who are HBsAg negative, anti-HBs positive and/or anti-HBc positive, but
with undetectable viral DNA and normal ALT are eligible. Subjects who are seropositive
due to HBV vaccination (HBsAg negative, HBV surface antibody [anti-HBs] positive, and
HBV core antibody [anti-HBc] negative) are eligible.
17. Active viral infection with hepatitis C virus (as measured by positive HCV antibody
and detectable viral RNA, HIV), or known active infection with human T-cell
lymphotropic virus.
NOTE: Subjects with a history of hepatitis C infection (HCV antibody reactive) who
have normal ALT and undetectable HCV RNA are eligible.
18. Any other medical or social condition that, in the Investigator's judgment, will
interfere with a participant's ability to provide informed consent, to receive study
drugs, or meet study demands, or that substantially increases the risk associated with
the subject's participation in the study, or that may interfere with interpretation of
results.
19. Female subjects who are pregnant or lactating/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 3 years, or subjects with a history of a
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
are eligible.