Study of Tazemetostat Versus Placebo When Given in Combination With Lenalidomide and Rituximab in Participants With Relapsed/Refractory Follicular Lymphoma

Follicular Lymphoma Clinical Trial

— SYMPHONY-1  

Official title:

Symphony-1: A Phase 1b/3 Double-Blind, Randomized, Active-Controlled, 3-Stage, Biomarker Adaptive Study Of Tazemetostat Or Placebo In Combination With Lenalidomide Plus Rituximab In Subjects With Relapsed/Refractory Follicular Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04224493
• Other study ID #: EZH-302
• Secondary ID: 2019-003333-42
• Status: Recruiting
• Phase: Phase 3
• Start date: June 11, 2020
• Est. completion date: March 1, 2029

Study information

• Verified date: June 2024
• Source: Ipsen
• Contact: Ipsen Clinical Study Enquiries
• Phone: See e mail
• Email: clinical.trials[@]ipsen.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 612
• Est. completion date: March 1, 2029
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. 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

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:

a. 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

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 [ß-hCG] tests with a minimum sensitivity of 25 mIU/mL or equivalent units of ß-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.

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular
• Refractory Follicular Lymphoma
• Relapsed/Refractory Follicular Lymphoma

Intervention

Drug:
• Tazemetostat
Stage 1 (Phase 1b): Tazemetostat was escalated from a starting dose of 400 mg orally twice daily to 600 mg orally twice daily to 800 mg PO twice daily in 28-day cycles as tolerated in a standard 3 + 3 design. Tazemetostat will be administered as monotherapy at an 800 mg twice daily dose for up to 2 years after the initial 12 months of combination therapy.
• Tazemetostat
Stage 2: Tazemetostat 800 mg administered orally twice daily in continuous 28-day cycles for 12 cycles. Tazemetostat will be administered as monotherapy at an 800 mg twice daily dose for up to 2 years after the initial 12 months of combination therapy.
• Placebo oral tablet
Stage 2: Placebo administered orally twice daily in continuous 28-day cycles. Placebo will be administered as monotherapy twice daily dose for up to 2 years after the initial 12 months of combination therapy.

Combination Product:
• Lenalidomide
Lenalidomide 20 mg capsules or 10 mg capsules (if creatinine clearance =60 mL/minute or <60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles.
• Rituximab
Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5.

Locations

Country	Name	City	State
Australia	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	Hollywood Private Hospital	Nedlands	Western Australia
Belgium	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen
Belgium	UZ Leuven - Campus Gasthuisberg	Leuven	Vlaams Brabant
Belgium	CHU Dinant Godinne UCL Namur	Yvoir	Namur
Canada	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montréal	Quebec
Canada	Sir Mortimer B Davis/Jewish General Hospital	Montréal	Quebec
Canada	University Health Network Princess Margaret Hospital	Toronto	Ontario
China	Peking University Third Hospital	Beijing
China	The First Bethune Hospital of Jilin University	Changchun	Jinlin
China	Hunan Cancer Hospital	Changsha	Hunan
China	Fujian Medical University Union Hospital	Fuzhou	Fujian
China	The Affiliated Hospital of Guizhou Medical University	Guiyang	Guizhou
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Ruijin Hospital, Shanghai Jiaotong University School of Medicine	Shanghai	Shanghai
China	The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	Shanxi Bethune Hospital	Taiyuan	Shanxi
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin
China	The First Affiliated Hospital of Xiamen University	Xiamen	Fujian
China	The Second Affiliated Hospital Zhejiang University School of Medicine	Zhejiang	Hangzhou
China	Henan Cancer Hospital	Zhengzhou	Henan
China	Henan Provincial People's Hospital	Zhengzhou	Henan
France	CHRU de Besançon- Hopital Jean Minjoz	Besancon
France	Institut Bergonie	Bordeaux	Gironde
France	CHRU Brest Hôp Morvan	Brest	Bretagne
France	CHU Caen	Caen
France	CHU de Clermont-Ferrand, site Estaing	Clermont-Ferrand
France	Hopital Henri Mondor - Hemopathies Lymphoides	Créteil	Île-de-France
France	CHU de Grenoble - Hopital Albe	La Tronche	Isere
France	Centre Hospitalier Le Mans	Le Mans	Sarthe
France	CHRU de Lille Hop Claude Huriez	Lille	Nord
France	CHU de Limoges Dupuytren	Limoges	Haute-Vienne
France	Centre Hosp Mulh Hop Emile Muller	Mulhouse	Haut-Rhin
France	CHU de Nantes - Hematologie	Nantes	Loire-Atlantique
France	L'Hôpital Privé Confluent	Nantes
France	Hopital Saint Louis	Paris
France	Centre Hospitalier Universitaire de Bordeaux-Hopital du Haut Leveque	Pessac Cedex	Aquitaine
France	Centre Henri Becquerel	Rouen	Haute-Normandie
France	CHU de Nancy Brabois	Vandœuvre-lès-Nancy
France	Centre Hospitalier Bretagne Atlantique	Vannes
Germany	Universitaetsklinikum Bonn AöR	Bonn	Nordrhein-Westfalen
Germany	Städt. Krankenhaus Kiel	Kiel	Schleswig-Holstein
Germany	Universitätsmedizin Mainz	Mainz	Hessen
Germany	Kliniken Maria Hilf GmbH	Moenchengladbach	Nordrhein-Westfalen
Germany	Klinikum Der Universität München AöR	München	Bayern
Germany	Klinikum rechts der Isar der Technischen Universitat Muenche	München	Bayern
Germany	Diakoneo Diak Schwaebisch Hall gGmbH	Schwäbisch Hall	Baden-Württemberg
Hungary	Del-pesti Centrumkorhaz Orszagos Hematologiai és Infektologiai Intezet	Budapest
Hungary	Országos Onkológiai Intézet	Budapest
Hungary	Semmelweis Egyetem Általános Orvostudományi Kar	Budapest
Hungary	Debreceni Egyetem Klinikai Központ	Debrecen	Hajdú-Bihar
Italy	ASST Spedali Civili di Brescia	Brescia
Italy	PO Garibaldi-Nesima, ARNAS Garibaldi	Catania
Italy	AOU Careggi	Firenze
Italy	Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori IRCCS	Meldola	Forli-Cesena
Italy	AOU Federico II	Napoli	Campania
Italy	Catholic University Of Sacred Heart	Roma
Italy	Azienda Ospedaliera Santa Maria di Terni	Terni
Korea, Republic of	Samsung Medical Center	Seoul	Seoul Teugbyeolsi [Seoul-T'ukp
Korea, Republic of	Seoul National University Hospital	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul	Seoul Teugbyeolsi [Seoul-T'ukp
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul	Seoul Teugbyeolsi [Seoul-T'ukp]
Poland	Pratia Onkologia Katowice	Katowice
Poland	Pratia MCM Krakow	Kraków
Poland	Centrum Medyczne Pratia Poznan	Skorzewo	Wielkopolskie
Poland	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.	Slupsk
Poland	MICS Centrum Medyczne Torun	Torun
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa	Mazowieckie
Poland	Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu	Wroclaw
Spain	Hospital Del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona	Cataluny
Spain	Hospital Univ. Infanta Leonor	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Costa del Sol	Marbella	Málaga
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Nuestra Señora de Valme	Sevilla
Taiwan	Chang Gung Medical Foundation - Kaohsiung Chang Gung Memorial Hospital - Hemato-Oncology	Kaohsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Western General Hospital - Haematology	Edinburgh	Edinburgh, City Of
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Imperial College Healthcare NHS Trust - Hammersmith Hospital	London	London City
United Kingdom	St Bartholomew's Hospital Barts Health NHS Trust	London	London, City Of
United States	New York Oncology Hematology, P.C.	Albany	New York
United States	New Mexico Cancer Care Alliance	Albuquerque	New Mexico
United States	Texas Oncology - Amarillo	Amarillo	Texas
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Messino Cancer Center	Asheville	North Carolina
United States	Texas Oncology-Austin Midtown	Austin	Texas
United States	University of Maryland	Baltimore	Maryland
United States	Rocky Mountain Cancer Centers (RMCC) - Boulder	Boulder	Colorado
United States	Gabrail Cancer Center Research	Canton	Ohio
United States	TOI - Clinical Research	Cerritos	California
United States	Tennessee Oncology, PLLC	Chattanooga	Tennessee
United States	Peninsula Cancer Institute	Chesapeake	Virginia
United States	The office of Frederick P. Smith, MD, P.C.	Chevy Chase	Maryland
United States	University of Chicago	Chicago	Illinois
United States	Oncology Hematology Care (OHC), Inc. - Kenwood Office	Cincinnati	Ohio
United States	UCSF Fresno	Clovis	California
United States	Levine Cancer Institute - Concord	Concord	North Carolina
United States	Texas Oncology - Medical City Dallas Pediatric Hematology	Dallas	Texas
United States	Texas Oncology-Baylor Charles A. Sammons Cancer Center	Dallas	Texas
United States	Astera Cancer Care	East Brunswick	New Jersey
United States	Astera Cancer Center	East Brunswick	New Jersey
United States	Willamette Valley Cancer Institute and Research Center - Oncology	Eugene	Oregon
United States	Cancer Specialists of North Florida	Fleming Island	Florida
United States	Florida Cancer Specialists & Research Institute (FCS) - Fort Myers Cancer Center	Fort Myers	Florida
United States	Regional Cancer Care Associates-Freehold	Freehold	New Jersey
United States	Virginia Cancer Specialists	Gainesville	Virginia
United States	St. Mary's Hospital and Regional Medical Center - St. Mary's	Grand Junction	Colorado
United States	SCL Health Lutheran Medical Center	Greeley	Colorado
United States	Hackensack University Medical John Theurer Cancer Center	Hackensack	New Jersey
United States	Kaiser Permanente Hawaii Moanalua Medical Center	Honolulu	Hawaii
United States	Millennium Physicians - Oncology	Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Regional Cancer Care Associates LLC - Howell	Howell	New Jersey
United States	Mayo Clinic	Jacksonville	Florida
United States	Mayo Clinic - Cancer Clinical Research Office	Jacksonville	Florida
United States	University of Tennessee Medical Center - Cancer Institute	Knoxville	Tennessee
United States	UC San Diego Health Sciences	La Jolla	California
United States	Northwell Health/Monter Cancer Center	Lake Success	New York
United States	Regional Cancer Care Associates LLC - Little Silver	Little Silver	New Jersey
United States	Miami Cancer Institute	Miami	Florida
United States	Southern Cancer Center	Mobile	Alabama
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Columbia U - Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medicine-New York Presbyterian Hospital	New York	New York
United States	Mass General Cancer Center at Newton-Wellesley	Newton	Massachusetts
United States	Illinois Cancer Specialists	Niles	Illinois
United States	Hematology Oncology Associates of Rockland, P.C.	Nyack	New York
United States	Florida Cancer Affiliates/Ocala Oncology - Clinic	Ocala	Florida
United States	University Of Nebraska Medical Center	Omaha	Nebraska
United States	The University of Kansas Cancer Center	Overland Park	Kansas
United States	FirstHealth of the Carolinas	Pinehurst	North Carolina
United States	University of Pittsburgh Medical Center - Oncology	Pittsburgh	Pennsylvania
United States	Western Pennsylvania Hospital Hematology & Cellular Therapy	Pittsburgh	Pennsylvania
United States	Texas Oncology	Plano	Texas
United States	BRCR Medical Center, INC	Plantation	Florida
United States	Oncology and Hematology Associates of Southwest Virginia Inc.	Roanoke	Virginia
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Saint Louis University Cancer Center	Saint Louis	Missouri
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	Huntsman Cancer Institute; The University of Utah	Salt Lake City	Utah
United States	Utah Cancer Specialists/ IHO Corp	Salt Lake City	Utah
United States	Mays Cancer Center	San Antonio	Texas
United States	UCLA Clinical Research Unit Hematology/Oncology	Santa Monica	California
United States	June E. Nylen Cancer Center	Sioux City	Iowa
United States	MC Rockwood Cancer Bl Specialty Ctr - North	Spokane	Washington
United States	Florida Cancer Specialists - Panhandle	Tallahassee	Florida
United States	H Lee Moffitt Cancer Center and Research Institute I	Tampa	Florida
United States	Arizona Oncology Associates - Tuscon-Rusadill Road	Tucson	Arizona
United States	USO Texas Oncology - Tyler	Tyler	Texas
United States	UT Health East Texas HOPE Cancer Center - Tyler	Tyler	Texas
United States	Texas Oncology- Weslaco	Weslaco	Texas
United States	Florida Cancer Specialists & Research Institute (FCS) - Atlantis	West Palm Beach	Florida
United States	Yakima Valley Memorial Hospital - North Star Lodge Cancer Center	Yakima	Washington
United States	St. Joseph Mercy Hospital	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Epizyme, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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)
Secondary	PK of tazemetostat, EPZ 6930 (desethyl metabolite), and lenalidomide as data permit: Time to Maximum Observed Drug Concentration (Tmax)		Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
Secondary	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)],		Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
Secondary	PK of tazemetostat: area under the plasma concentration-time curve (AUC) from time 0 to infinity [AUC(0-8)]		Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
Secondary	The apparent terminal elimination half-life (t1/2) of tazemetostat, EPZ 6930 (desethyl metabolite), and lenalidomide as data permit		Stage 1: In cycles 1 and 2 on days 1 and 15 (28 days cycle)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	OS in the ITT-MT population		Stage 2: Up to 96 months
Secondary	OS in the R/R FL population regardless of mutation status		Stage 2: Up to 96 months
Secondary	PFS in the ITT-WT population, assessed by a blinded IRC		Stage 2: Up to 96 months
Secondary	PFS in the ITT-MT population, assessed by a blinded IRC		Stage 2: Up to 96 months
Secondary	PFS in the R/R FL population regardless of mutation status, assessed by a blinded IRC		Stage 2: Up to 96 months
Secondary	PFS in the R/R FL population regardless of mutation status, assessed by the Investigator		Stage 2: Up to 96 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Population PK parameters of oral volume of distribution (Vd/F) of tazemetostat.		Stage 2: In cycles 2, 4, 6, and 12 at Day 1 (28 days cycle)
Secondary	Population PK parameters of first-order absorption rate constant (Ka) for tazemetostat.		Stage 2: In cycles 2, 4, 6, and 12 at Day 1 (28 days cycle)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of Study Drug Exposure	Duration of exposure to study drug will be reported.	Up to 36 months
Secondary	Percentage of study drug taken by participants		Up to 36 months
Secondary	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