Clinical Trial 20831

• Overview

  Study Title:

  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

  Summary:

  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 lenalidomide and rituximab (R2) in patients with relapsed or refractory (R/R) follicular lymphoma (FL), who have completed at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.

  Objective:

  Primary Objective: 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. Secondary Objective: Assess the clinical activity and pharmacokinetics of tazemetostat when administered concomitantly with R2 in subjects with R/R FL. Stage 2 and Optional Stage 3 (Based on Stage 2 Futility Analysis) Primary Objective: 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. Secondary Objectives: 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.

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  CC-5013 (Lenalidomide); EPZ-6438 (Tazemetostat); Lenalidomide (Revlimid); Rituxan (rituximab); Tazemetostat (); Tazemetostat/Placebo (); rituximab ()

• Inclusion Criteria

  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.
  • Patients with a history of hepatitis B or C are eligible on the condition that patients have adequate liver function as defined by Inclusion Criterion #15 but with normal ALT and are hepatitis B surface antigen negative with undetectable HBV DNA and/or have undetectable hepatitis C virus (HCV) RNA if HCV antibody positive. See Exclusion Criteria 17 and 18.
  • Have histologically confirmed FL, Grades 1 to 3A.
  • 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 patient 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 > Have measurable disease as defined by the Lugano Classification
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 10. For patients who have experienced any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy):
  • At the time the patient 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. 11. Have provided sufficient tumor tissue for EZH2 mutation testing in all patients to allow for stratification and for CNG determination in a subset of WT EZH2 patients from the Phase 3 portion of the study.
  • If EZH2 mutation status is known from site-specific testing, patients can be enrolled, but additional tumor tissue will be required for confirmatory testing of EZH2 status at study-specific laboratories. If the archival tumor sample was collected more than 15 months prior to 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.
  • Time between prior anticancer therapy and first dose of tazemetostat as follows: Cytotoxic chemotherapy - At least 21 days, Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days, Nitrosoureas - At least 6 weeks, Monoclonal and/or bispecific antibodies or CAR T - At least 28 days, Radiotherapy - At least 6 weeks from prior radioisotope therapy; at least 12 weeks from 50% pelvic or total body irradiation.
  • Other criteria apply

• Exclusion Criteria

  Exclusion Criteria:
  • Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
  • Prior exposure to lenalidomide.
  • Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL (subjects transformed from DLBCL to FL may be enrolled).
  • 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).
  • Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL).
  • Patients with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
  • Patients taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort)
  • Are unwilling to exclude Seville oranges, 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. AND grapefruit from their diet.
  • 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.
  • 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.
  • 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
  • Prolongation of corrected QT interval using Fridericia's formula (QTcF) 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; known severe hypersensitivity to any component of rituximab requiring hospitalization or resuscitation.
  • Inability to be treated with a Pneumocystis prophylaxis medication.
  • 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: Patients who are HBsAg negative, anti-HBs positive and/or anti-HBc positive, but with undetectable viral DNA and normal ALT are eligible. Patients who are seropositive due to HBV vaccination (HBsAg negative, HBV surface antibody [anti-HBs] positive, and HBV core antibody [anti-HBc] negative) are eligible.
  • 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: Patients with a history of hepatitis C infection (HCV antibody reactive) who have normal ALT and undetectable HCV RNA are eligible. 19. 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.
  • Female patients who are pregnant or lactating/breastfeeding. 21. Subjects who have undergone a solid organ transplant. 22. Subjects with malignancies other than FL.

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