Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize Effects of a Moderate CYP3A Inhibitor on PK of Tazemetostat, Effects of Tazemetostat on PK of CYP2C8 and CYP2C19 Substrates, and Effect of Increased Gastric pH on PK of Tazemetostat in B-cell Lymphoma or Advanced Solid Tumor Patients

Study Overview
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Brief Summary
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This is a Phase 1, open-label, two-part, safety, PK, and activity study designed to characterize the DDI potential of tazemetostat. Tazemetostat will be taken orally BID continuously in 28-day cycles in both study parts.

Official Title
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An Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize the Effects of a Moderate CYP3A Inhibitor on the Pharmacokinetics of Tazemetostat (EPZ-6438) (Part A), the Effects of Tazemetostat on the Pharmacokinetics of CYP2C8 and CYP2C19 Substrates, and the Effect of Increased Gastric pH on the Pharmacokinetics of Tazemetostat (Part B) in Subjects With B-cell Lymphoma or Advanced Solid Tumors

Conditions
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Diffuse Large B Cell Lymphoma, Primary Mediastinal Lymphoma, Mantle Cell Lymphoma, Advanced Solid Tumor, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: Tazemetostat
* Drug: Fluconazole
* Drug: Omeprazole
* Drug: Repaglinide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female ≥ 18 years of age at time of consent Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Has the ability to understand informed consent and provided signed written informed consent Must meet one of the following criteria: Has histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) and have relapsed or refractory disease following at least two lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (R-CHOP; rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone or prednisone, 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 one of the following criteria: Relapsed following, or refractory to, previous ASCT Did not achieve at least a partial response (PR) to a standard salvage regimen (e.g., R-ICE; rituximab, ifosfamide, carboplatin, etoposide, or R-DHAP; rituximab, dexamethasone, cytarabine, cisplatin) 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 Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a separate systemic treatment regimen. Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a separate systemic treatment regimen. OR Has histologically confirmed FL, all grades. Subjects must have relapsed/refractory disease following at least 2 standard lines of systemic therapy, including at least 1 anti-CD20-based regimen (eg, rituximab), as well as alkalating agents (eg, cyclophosphamide or bendamustine), and have no curative option with other available therapies OR have a contra-indication to their use. Subjects with prior ASCT may be included. Transformed disease is permitted. Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a separate systemic treatment regimen. OR Histologically and/or cytologically confirmed advanced or metastatic solid tumor that has progressed after treatment with approved therapies or for which there are no standard therapies available Must have evaluable or measurable disease Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per NCI CTCAE, Version 4.03 or are clinically stable and not clinically significant, at time of consent Time required between the last dose of the latest therapy and the first dose of study drug: Chemotherapy: cytotoxic At least 21 days Chemotherapy: nitrosoureas At least 6 weeks Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) At least 14 days Monoclonal antibody (ies) At least 28 days Non-antibody immunotherapy (e.g., tumor vaccine) At least 42 days At least 14 days for stereotactic radiosurgery At least 12 weeks for craniospinal, ≥50% radiation of pelvis, or total body irradiation prior to first dose of study drug Autologous hematopoietic cell infusion after high dose therapy At least 60 days Hematopoietic growth factor At least 14 days Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function Hemoglobin ≥9 g/dL Platelets ≥75,000/mm3 (≥75 × 10^9/L) ANC: for patients with lymphoma ≥750/mm3 (≥0.75 × 10^9/L), for patients with advanced solid tumors ≥1,000/mm3 (≥1.0 × 10^9/L), PT <1.5 ULN PTT <1.5 ULN eGFR ≥ 50 mL/min/1.73 m2 Conjugated bilirubin <1.5 × ULN AST <3 × ULN ALT <3 × ULN NOTE: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec Subjects with a history of Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by the protocol and are hepatitis B surface antigen negative and/or have undetectable HCV RNA. Male subjects must refrain from donating sperm starting at the planned first dose of investigational product (IP) until 30 days following the last dose of IP Male subjects with a female partner of childbearing potential must: Be vasectomized, or Remain abstinent or use a condom as defined in Section 8.3.8.4.2, starting at the planned first dose of IP until 30 days following the last dose of IP. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female partners of male subjects who are of childbearing potential must also adhere to one of the following: Placement of an intrauterine device or intrauterine system. Established use of oral, injected, or implanted hormonal methods of contraception or use of a barrier method of contraception. Progesterone only oral contraception, where inhibition of ovulation is not the primary mode of action. Women of childbearing potential or female partners of male subjects must abide by the contraception measures defined by the protocol Exclusion criteria: Is pregnant or nursing Has active central nervous system (CNS) or leptomeningeal metastasis Has had a prior malignancy other than the malignancies under study Exception: Subject who has been disease-free for 3 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by the local laboratory. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy. Has a prior history of T-LBL/T-ALL. Has had major surgery within 3 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy, central venous catheter placement) is permitted within 3 weeks prior to enrollment. Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment Subjects taking medications that are known potent or moderate inducers/ inhibitors of CYP3A4 (including St. John's Wort) Has an active infection or recent history (<30 days before study drug administration) requiring systemic treatment Is immunocompromised, including subjects with known human immunodeficiency virus (HIV) infection Has known hypersensitivity to any of the components of IP. Is unable to take oral medications, has a history of surgery that would interfere with the administration or absorption of oral medication, has malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the bioavailability of IP Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of IP. A history of bleeding (i.e., hemoptysis, hematuria, gastrointestinal blood loss, epistaxis, or others with greater than Grade 1 according to NCI CTCAE Version 4.03) within 1 month prior to beginning therapy or any clinical indications of current active bleeding. Clinical history, current alcohol (ethanol), or illicit drug use which, in the judgment of the investigator, will interfere with the subject's ability to comply with the dosing schedule and protocol-specified evaluations. Regular alcohol consumption averaging more than seven drinks/week for women and 14 drinks/week for men within 6 months of screening.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A and B<br>Part A: Subjects enrolled in Part A will receive treatment with oral tazemetostat tablets 400 mg BID for 24 days beginning on Day 1. Subjects will receive fluconazole 400 mg once daily for 4 days starting on Day 16. Tazemetostat 400 mg BID will continue through Day 24. Subjects will then receive tazemetostat 800 mg BID starting on Day 25. Part B: Subjects enrolled in Part B will receive single oral doses of repaglinide 0.25 mg and omeprazole 20 mg on Day 1. Administration of tazemetostat 800 mg BID will begin on Day 2. On Day 16, subjects again will receive single oral doses of repaglinide 0.25 mg and omeprazole 20 mg approximately 1 hour after the morning dose of tazemetostat. Subjects also will receive omeprazole 20 mg once daily in the morning on Days 16 through 19. | Drug: Tazemetostat<br>* Tazemetostat is a selective oral small molecule inhibitor of EZH2<br>* Other names: EPZ-6438, E7438;Drug: Fluconazole<br>* 200mg will be orally administered QD for 4 days in order to determine CYP3A4 inhibition when administered concomitantly with tazemetostat<br>Drug: Omeprazole<br>* Using omeprazole as a probe substrate, 20mg will be orally administered for a total of 5 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C19. Omeprazole is also being used to determine the effect of increased gastric pH on metabolism of tazemetostat.<br>Drug: Repaglinide<br>* Using repaglinide as a probe substrate, 25mg will be orally administered for a total of 2 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C8.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Effect of CYP3A Inhibition by Fluconazole on the PK of Tazemetostat (AUC0-t, AUC0-8) |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: Cmax of Tazemetostat During Co-administration With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞) |  | Days 1 and 16, 0 to 8 hours post-dose | 
| Part B: Cmax of Repaglinide During Co-administration With Tazemetostat |  | Days 1 and 16, 0 to 8 hours post-dose | 
| Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞) |  | Days 1 and 16, 0 to 8 hours post-dose | 
| Part B: Cmax of Omeprazole During Co-administration With Tazemetostat |  | Days 1 and 16, 0 to 8 hours post-dose | 
| Part B: Effect of Increased Gastric pH by Omeprazole on the PK of Tazemetostat (AUC0-t, AUC0-8) |  | Days 16 and 19, 0 to 8 hours post-dose | 
| Part B: Cmax of Tazemetostat During Co-administration With Omeprazole |  | Days 16 and 19, 0 to 8 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events as a Measure of Safety |  | From the first dose of study treatment until the earlier of either 30 days after the discontinuation of study treatment or until the initiation of subsequent anticancer therapy, up to 2 years. | 
| Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: Tmax of Tazemetostat After Administration Alone and With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: t1/2 of Tazemetostat After Administration Alone and With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: t1/2 of Tazemetostat Metabolites After Administration Alone and With Fluconazole |  | Days 15 and 19, 0 to 8 hours post-dose | 
| Part A: Exposure of Fluconazole After Administration of 400 mg Once Daily for 4 Days (AUC0-8) |  | Day 19, 0 to 8 hours post-dose | 
| Part A: Cmax of Fluconazole After Administration of 400mg Once Daily for 4 Days |  | Day 19, 0 to 8 hours post-dose | 
| Part A: Tmax of Fluconazole After Administration of 400mg Once Daily for 4 Days |  | Day 19, 0 to 8 hours post-dose | 
| The Antitumor Activity of Tazemetostat Will be Assessed in Patients With Diffuse Large B-cell Lymphoma (DLBCL), Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL) or Advanced Solid Tumors . | Objective response rate (ORR: complete response [CR] or PR) and disease control rate (DCR: CR or PR, or stable disease lasting 24 weeks or longer from start of treatment with tazemetostat) using Lugano Classification for subjects with lymphoma, or Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with solid tumors. | Within 28 days of Day 1, 8 weeks, 16 weeks, 24 weeks |