Study of Tazemetostat as Single Agent in Solid Tumors or B-cell Lymphomas and in Combination With Prednisolone in DLBCL

Study Overview
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Brief Summary
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This is an open-label, multicenter, Phase 1/2 study of tazemetostat as a single agent in subjects with advanced solid tumors or with B-cell lymphomas and tazemetostat in combination with prednisolone in subjects with diffuse large B-cell lymphoma (DLBCL).

Detailed Description
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This is a multicenter, open-label, Phase 1/2 study conducted in two parts: The Phase 1 part comprised dose escalation and expansion to establish the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) when tazemetostat was given twice daily (BID) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat were evaluated. The Phase 2 part was initiated once the RP2D was established. Phase 2 enrolled subjects with relapsed/ refectory (R/R) DLBCL (Cohorts 1-3 and 6) and subjects with R/R FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and enhancer of zeste homologue 2 (EZH2) mutation status.

Official Title
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An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With Diffuse Large B Cell Lymphoma

Conditions
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B-cell Lymphomas (Phase 1), Advanced Solid Tumors (Phase 1), Diffuse Large B-cell Lymphoma (Phase 2), Follicular Lymphoma (Phase 2), Transformed Follicular Lymphoma, Primary Mediastinal Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Tazemetostat
* Drug: Prednisolone
* Drug: Tazemetostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG performance status of 0 to 2. Life expectancy of at least 3 months before starting tazemetostat. Voluntary agreement to provide written informed consent and willing to adhere to all protocol requirements Subjects with 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. Adequate renal and liver function Phase 1: Males or females aged ≥ 16 years at time of informed consent. Phase 2: Males or females aged ≥ 18 years at the time of informed consent . Females must not be lactating or pregnant at screening or baseline as documented by a negative pregnancy test All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrheic, 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 dose). 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 6 months after the last final dose of study drug; any male partner must use a condom. Male subjects must have had a successful vasectomy (with confirmed azoospermia) 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 3 months after study drug discontinuation). Nonvasectomized male subjects must also agree to refrain from donating sperm from first dose of tazemetostat until 3 months following the last dose of tazemetostat Phase 1 only: Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B-cell lymphomas that have progressed after treatment with approved therapies or for which there are no standard therapies available. Phase 2, Groups 1-6 only: Subjects must satisfy all of the following criteria: Have histologically confirmed DLBCL (including primary mediastinal B-cell lymphoma), with relapsed or refractory disease following at least 2 lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or equivalent) AND must be considered unable to benefit from intensification treatment with autologous hematopoietic stem cell transplantation (ASCT) as defined by meeting at least 1 of the following criteria: Relapsed following, or refractory to, previous ASCT Did not achieve at least a partial response to a standard salvage regimen (eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP]) Ineligible for intensification treatment due to age or significant comorbidity Ineligible for intensification treatment due to failure to mobilize an acceptable number of hematopoietic stem cells Refused intensification treatment and/or ASCT or Have histologically confirmed Follicular Lymphoma (FL), all grades. Subjects may have relapsed/refractory disease following at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used. Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a systemic treatment regimen. Have provided sufficient archival tumor tissue that has been successfully tested for EZH2 mutation status and cell of origin (DLBCL only) Have measurable disease as defined by International Working Group-Non-Hodgkin's Lymphoma (IWG-NHL) Exclusion Criteria: Prior exposure to tazemetostat or other inhibitor(s) of EZH2. Subjects with leptomeningeal metastases or brain metastases or history of previously treated brain metastases. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has a prior history of T-cell lymphoblastic lymphoma(T-LBL) or T-cell lymphoblastic leukemia (T-ALL). Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. Johns Wort) 6. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from their diet. Any unstable or unresolved prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy) toxicities at time of enrollment. Major surgery within 4 weeks before the first dose of study drug. . Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or 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. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat. Active infection requiring systemic therapy. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV). Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study. Females who are pregnant or breastfeeding. Phase 2 only: Subjects with noncutaneous malignancies other than B-cell lymphomas. 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Patients in the Phase 1 portion of the study. | Drug: Tazemetostat<br>* Patients who received 100 mg to 1600 mg of tazemetostat, BID, administered in continuous 28-day cycles.<br>* Other names: E7438;|
| Experimental: Phase 2 Group 1: Tazemetostat in R/R FL with Mutant EZH2<br>Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. | Drug: Tazemetostat<br>* Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.<br>* Other names: E7438;|
| Experimental: Phase 2 Group 2: Tazemetostat in R/R FL with Wild-Type EZH2<br>Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. | Drug: Tazemetostat<br>* Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.<br>* Other names: E7438;|
| Experimental: Phase 2 Group 3: Tazemetostat in R/R DLBCL<br>Patients with R/R DLBCL treated with tazemetostat as a single agent or tazemetostat in combination with prednisolone in Phase 2 of the study. | Drug: Tazemetostat<br>* Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.<br>* Other names: E7438;Drug: Prednisolone<br>* Patients who received 40 mg/m^2 prednisolone once daily on Days 1-5 and 15-19 of Cycles 1-4.<br>* Other names: Millipred DP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) of Tazemetostat as a Single-Agent and in Combination With Prednisolone (Phase 1 Only) | Recommended Phase 2 dose (RP2D) of tazemetostat as administered orally twice daily (BID), continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas as determined by incidence, seriousness, toxicity grade, and relatedness of treatment emergent dose limiting toxicities | The first 28-day cycle of therapy | 
| Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) (Phase 2) | Number of patients achieving an objective response (CR or PR)/number of patients treated x 100%. ORR was calculated as the percentage of patients with a confirmed complete response (CR) or partial response (PR) relative to the total number of patients in the analysis population per response evaluation criteria in solid tumors (RECIST) version (v)1.1. Complete Response (CR) was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 millimeter (mm) in the short axis. Partial Response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. | Radiologic tumor assessments performed at baseline(within 28 days before start of study treatment)and every 8 weeks during Cycles 2 to 6,and then every 12 weeks thereafter until confirmed disease progression (PD)/death,a maximum of approximately 82 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only) | The time (in months) from the date of the initial response (CR or PR, whichever was first) until the date of the first documented disease progression per an Independent Review Committee (for Groups 1 and 2), per Investigator (Group 3), or death due to any cause. Patients who were alive and progression free at the time of the analysis were censored at the last date where the patient was known to be in response. Note: the DOR was censored, meaning data collection was stopped early for analysis, making the top limit of the 95% confidence interval not estimable (NE). Per RECIST v.1.0, CR was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 mm in the short axis. The PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. | Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months | 
| Progression Free Survival for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only) | The time (in months) from the date of first dose of tazemetostat until the earliest date of disease progression or death from any cause. Per RECIST v1.0, CR was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 mm in the short axis. The PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. | Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epizyme, Tazverik, Tazemetostat (EPZ-6438)