E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory follicular lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed/refractory follicular lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10016903 |
E.1.2 | Term | Follicle centre lymphomas, follicular grade I, II, III |
E.1.2 | System Organ Class | 10016903 - Follicle centre lymphomas, follicular grade I, II, III |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Stage 1, Safety Run-In Evaluate the safety and tolerability of tazemetostat in combination with lenalidomide + rituximab (R2) in subjects with relapsed/refractory (R/R) follicular lymphoma (FL) and to select a recommended phase 3 dose (RP3D) of tazemetostat for further evaluation in phase 3.
Stage 2 Evaluate and compare progression-free survival (PFS), as assessed by Investigators, of tazemetostat + R2 versus placebo + R2 in subjects with R/R FL who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.
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E.2.2 | Secondary objectives of the trial |
Stage 1, Safety Run-In: Assess the clinical activity and pharmacokinetics of tazemetostat when administered concomitantly with R2 in subjects with R/R FL
Stage 2 - Evaluate and compare PFS by blinded independent review committee (IRC) - Evaluate and compare objective response rate (ORR) - Evaluate and compare the duration of response (DOR) - Evaluate and compare the duration of complete response (DOCR) - Evaluate and compare the disease control rate (DCR) - 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) - Evaluate and compare the overall survival (OS) - Assess population pharmacokinetic (PK) parameters, including exposure-response of tazemetostat when administered in combination with R2 - Evaluate and compare safety and tolerability
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (≥20 years for Taiwan) 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 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: 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 Criteria #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. For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy): a. At the time the subject provides voluntary written informed consent, all toxicities have either resolved to Grade 1 per National Cancer Institute CTCAE Version 5.0 OR are clinically stable and no longer clinically significant. 9.Time between prior anticancer therapy and first dose of tazemetostat as follows: a. Cytotoxic chemotherapy - At least 21 days. b. Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days. c. Nitrosoureas - At least 6 weeks. d. Monoclonal and/or bispecific antibodies or CAR T - At least 28 days. e. Radiotherapy -At least 6 weeks from prior radioisotope therapy; at least 12 weeks from 50% pelvic or total body irradiation. 10. Adequate renal function defined as calculated creatinine clearance ≥40 mL/minute per the Cockcroft and Gault formula. 11. Adequate bone marrow function 12. Adequate liver function 13. 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. |
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E.4 | Principal exclusion criteria |
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2. 2. Prior exposure to lenalidomide. 3. Grade 3b, mixed histology, or FL that has histologically transformed to 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). 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. 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. 8. 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. 9. 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. 10. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to ≥480 msec at screening or history of long QT syndrome. 11. 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. 12. Have an active infection requiring systemic therapy. 13. Known hypersensitivity to any component of tazemetostat or lenalidomide; known severe hypersensitivity to any component of rituximab requiring hospitalization or resuscitation. 14. Inability to be treated with a Pneumocystis prophylaxis medication. 15. Active viral infection with or seropositive for hepatitis B virus (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 antiHBc 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. 16. Active viral infection with hepatitis C virus (as measured by positive HCV antibody and detectable viral RNA), human immunodeficiency virus (HIV), AND/OR human T-cell lymphotropic virus 1 (as measured by positive HTLV-1 antibody). NOTE: Subjects with a history of hepatitis C infection (HCV antibody reactive) who have normal ALT and undetectable HCV RNA are eligible. 17. 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. 18. Female subjects who are pregnant or lactating/breastfeeding. 19. Subjects who have undergone a solid organ transplant. 20. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Stage 1: RP3D of tazemetostat in combination with 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).
Stage 2: Progression-free Survival (PFS) Evaluate and compare progression-free survival (PFS), as assessed by Investigators, of tazemetostat + R2 versus placebo + R2 in subjects with R/R FL who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1: Each cohort has a minimum of 3 subjects. Subjects are evaluated for DLTs during the first 28 day cycle. If 0 of 3 subjects or 1 of the 6 subjects in the cohort experiences a DLT, the next dose level/cohort will be assessed.
Stage 2: Time from the date of randomization to the time of confirmed disease progression per the 2014 Lugano Classification or death, whichever occurs first, assessed by investigators.
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E.5.2 | Secondary end point(s) |
1. Pharmacokinetics of tazemetostat Maximum Plasma Concentration Cmax. 2. PFS Stage 2: Evaluate and compare PFS by blinded independent review committee (IRC) 3. Objective Response Rate Stage 2: Evaluate and compare objective response rate (ORR) 4. Stage 2: Duration of response Evaluate and compare the duration of response (DOR) 5. Stage 2: Duration of complete response. Evaluate and compare the duration of complete response (DOCR) 6. Disease control rate Stage 2: Evaluate and compare the disease control rate (DCR) 7. Overall Survival Stage 2: Evaluate and compare the overall survival (OS) 8. EuroQOL Stage 2: 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). 9. Safety and Tolerability Stage 2: Safety and tolerability as assessed by AEs, clinical laboratory assessments, physical examination, vital sign measurements, electrocardiogram (ECG) results, ECOG performance status, study drug exposure, and treatment compliance.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1, Safety Run-In: PK Cmax is evaluated on Cycles 1 & 2 , days 1 & 15. (Each cycles is 28 days).
Stage 2 from randomization to time of disease progression per the 2014 Lugano Classification or death, whichever occurs first, assessed by Investigators.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
evaluate the efficacy and safety of tazemetostat in combination with R2 |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Tazmetostat is studied in combination with R2 |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Lenalidomide plus rituximab |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
China |
Korea, Republic of |
Russian Federation |
Taiwan |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 4 |