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Clinical Trial 19324

Cancer Type: Malignant Hematology
Interventions:EPZ-6438 (Tazemetostat); Fluconazole; Repaglinide; Tazemetostat; omeprazole (Prilosec)

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Julio Chavez

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

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 Lymphomas or Advanced Solid Tumors

Summary

This study is being done to determine what happens to tazemetostat (either higher or lower amounts of tazemetostat in the participants bloodstream) in their body when it is taken with a drug called fluconazole (commonly prescribed for fungal infections). This study also intends to find out how safe it is to take tazemetostat and what effects, good and/or bad, it has on participants and their cancer.

Objective

Primary Objectives Part A: To determine the effect of CYP3A inhibition by fluconazole on the pharmacokinetics (PK) of tazemetostat. Part B: To investigate the potential of tazemetostat to inhibit or induce CYP2C8 using repaglinide as a probe substrate. To investigate the potential of tazemetostat to inhibit or induce CYP2C19 using omeprazole as a probe substrate. To investigate the effect of increased gastric pH by omeprazole on the PK of tazemetostat. Secondary Objectives Part A: To investigate the safety profile of tazemetostat 400 mg twice daily (BID) after co-administration with fluconazole. To determine the PK of tazemetostat and its metabolites after administration alone and with fluconazole. To determine the systemic exposure of fluconazole after administration of 400 mg once daily for 4 days. Part B: To investigate the safety profile of tazemetostat, repaglinide, and omeprazole after co-administration. To determine the PK of repaglinide and its metabolites after administration with omeprazole and administration with omeprazole and tazemetostat. To determine the PK of omeprazole and its metabolites after administration with repaglinide and administration with repaglinide and tazemetostat. To determine the PK of tazemetostat and its metabolites after repeated dose of tazemetostat alone and with fluconazole. Parts A and B: To assess antitumor activity of tazemetostat in subjects with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), or advanced solid tumors. Exploratory Objectives: To investigate the effects of variations in genes encoding for CYP enzymes and transporters on the potential drug-drug interaction profile of tazemetostat. To explore the effect of tazemetostat on overall survival (OS).

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 histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or histologically and/or cytologically confirmed advanced or metastatic solid tumor and have relapsed or refractory disease following at least two standard lines of systemic 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: 1.) Relapsed following, or refractory to, previous ASCT; 2.) 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); 3.) Ineligible for intensification treatment due to age or significant comorbidity; 4.) Ineligible for intensification treatment due to failure to mobilize an acceptable number of hematopoietic stem cells; 5.) Refused intensification treatment and/or ASCT.
  • Transformed disease is permitted
  • 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
  • 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 potential participant and the subsequent within range screening result may be used to determine their eligibility.
  • Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
  • Potential participants 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 participants 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 participants with a female partner of childbearing potential must follow specific contraception guidelines as outlined in the study protocol
  • Female partners of male participants who are of childbearing potential must also adhere specific contraception guidelines as outlined in the study protocol
  • Women of childbearing potential or female partners of male participants 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: Potential participant who has been disease-free for 3 years, or a participant with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
  • Has thrombocytopenia 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-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
  • Taking medications that are known potent or moderate inducers/ inhibitors of CYP3A4 (including St. John's Wort)
  • Has an active infection or recent history (less than 30 days before study drug administration) requiring systemic treatment
  • Is immunocompromised, including participants 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 participant'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.