Effects of Itraconazole and Rifampin on the Blood Tazemetostat Levels

NCT04537715 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: EZH-1082020-002669-33
• Study Type: interventional
• Target: 42
• Locations: 2 countries
• Sites: 10

Brief Summary

The participants of this study will have advanced malignancies (also known as advanced cancer). The main aim of this trial will be to study the blood levels (known as pharmacokinetics) of the tazemtostat (the study drug) when administered in combination with another drug. Part 1 of the study will evaluate the interaction between the drugs tazemetostat and itraconazole. Part 2 of the study will evaluate the interaction between the drugs tazemetostat and rifampin For both Parts 1 and 2, safety and the level that effects of the study drug can be tolerated (known as tolerability) will be assessed throughout.

Conditions

All Malignancies; Advanced Malignancies; Hematologic Malignancy; Solid Tumor; Follicular Lymphoma (FL); Non-Hodgkin Lymphoma (NHL); Diffuse Large B-Cell Lymphoma (DLBCL); Epithelioid Sarcoma (ES); Synovial Sarcoma; Renal Medullary Carcinoma; Mesothelioma; Rhabdoid Tumor

Keywords

Epizyme; Tazverik; Tazemetostat (EPZ-6438); Itraconazole; CYP3A4 inhibitor; Rifampin; CYP3A4 inducer; Drug-Drug Interaction (DDI); Pharmacokinetics (PK)

Outcome Measures

Primary Outcomes (4)

• Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours of Quantifiable Concentration (AUC0-12h) of Tazemetostat

  Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

• Part 1: Maximum Observed Plasma Concentration (Cmax) of Tazemetostat

  Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, 48, and 72 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

• Part 2: AUC0-12h of Tazemetostat

  Blood samples were collected at specified timepoints. AUC0-12h was assessed using non-compartmental data analysis method. AUC0-12h was estimated by a combination of linear trapezoidal method on concentrations going up and logarithmic trapezoidal method on concentrations going down (Linear up/Log down method).

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

• Part 2: Cmax of Tazemetostat

  Blood samples were collected at specified timepoints. Cmax was assessed using non-compartmental data analysis method.

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

Secondary Outcomes (16)

• Part 1: AUC0-12h of EPZ-6930 After Tazemetostat Alone at Steady-State

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 15

• Part 1: AUC0-12h of Tazemetostat and EPZ-6930 After Tazemetostat at Steady-State With Itraconazole

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 36

• Part 1: Cmax of EPZ-6930 After Tazemetostat Alone at Steady-State

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15

• Part 1: Cmax of Tazemetostat and EPZ-6930 After Tazemetostat at Steady State With Itraconazole

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 36

• Part 1: Observed Time at Cmax (Tmax) of Tazemetostat and EPZ-6930 After Tazemetostat Alone at Steady-State

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 36, and 72 hours post-dose on Cycle 1 Day 15

Other Outcomes (10)

• Part 1: Least Squares Geometric Mean Ratio of Observed Accumulation Ratio of AUC0-12h for Tazemetostat

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 15

• Part 1: Least Squares Geometric Mean Ratio of Cmax Accumulation Ratio for Tazemetostat

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8,12, 36, 48 post-dose on Cycle 1 Day 1, and 72 hours post-dose on Cycle 1 Day 15

• Part 1: Least Squares Geometric Mean Ratio of AUC0-12h After Single Dose of Tazemetostat With Itraconazole

  Pre-dose (0 hour), 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours post-dose on Cycle 1 Day 1 (without itraconazole) and Cycle 1 Day 21 (with itraconazole)

Study Arms (2)

Part 1: Tazemetostat and Itraconazole Drug Interaction Cycle 1

EXPERIMENTAL

Participants in Part 1 of the study will receive a single oral, 400 mg dose of tazemetostat on Day 1, 15, and Day 36. The study participants will receive tazemetostat (oral 400 mg) tablets to be taken twice daily on Days 3 - 14 and Days 21 - 35. In addition, the participants will receive oral 200 mg itraconazole once daily on Days 18 - 38. Study participants may continue tazemetostat from Day 40+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles.

Drug: Tazemetostat; Drug: Itraconazole

Part 2:Tazemetostat and Rifampin Drug Interaction Cycle 1

EXPERIMENTAL

Participants in Part 2 of the study will receive a single oral, 800 mg dose of tazemetostat on Days 1, 15, and Day 36. The study participants will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily on Days 3 - 14 and Days 17 - 23. In addition, the participants will receive oral 200 mg rifampin once daily on Days 17 - 25. Study participants may continue tazemetostat from Day 27+ at the recommended therapeutic dose (oral 800 mg twice daily) in 28-day cycles.

Drug: Tazemetostat; Drug: Rifampin

Interventions

Tazemetostat DRUG

A single, oral, 400 mg dose of tazemetostat on Day 1, Day 15, and Day 36; and tazemetostat (oral 400 mg) tablets twice daily on Days 3 - 14 and Days 21 - 35.

Also known as: EPZ-6438, Tazverik

Part 1: Tazemetostat and Itraconazole Drug Interaction Cycle 1

Itraconazole DRUG

Oral 200 mg itraconazole once daily on Days 18 - 38

Also known as: Sporanox

Part 1: Tazemetostat and Itraconazole Drug Interaction Cycle 1

Rifampin DRUG

Oral 600 mg rifampin once daily on Days 17 - 25.

Also known as: RIF, Rifampicin, Rifadin, Rimactane

Part 2:Tazemetostat and Rifampin Drug Interaction Cycle 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years age at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
• Has the ability to understand informed consent, and provide signed written informed consent.
• Life expectancy of \> 3 months.
• Histologically and/or cytologically confirmed advanced metastatic or unresectable solid tumors has progressed after treatment for which there are no standard therapies available OR histologically and/or cytologically confirmed hematologic malignancies that have relapsed, or refractory disease, following at least 2 standard lines of systemic therapy for which there are no standard therapies available.
• Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a separate systemic treatment regimen.
• Must have evaluable or measurable disease.
• Has all prior treatment (ie, chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 or are clinically stable and not clinically significant, at time of consent.
• All subjects must have completed any prior chemotherapy, targeted therapy and major surgery ≥ 28 days before study entry. For daily or weekly chemotherapy without the potential for delayed toxicity, a washout period of 14 days or 5 half-lives, whichever is shorter may be acceptable.
• Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow \[BM\] and coagulation factors) and renal function.
• Able to swallow and retain orally-administered medication and without clinically significant gastrointestinal abnormalities that could alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• Females of childbearing potential (FCBP) must have a negative serum pregnancy test and must either practice complete abstinence or agree to use a highly effective method of contraception.
• Male subjects must have had a successful vasectomy OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a female of childbearing potential (FCBP) during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
• NOTE: Male subjects must not donate sperm during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
• Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec.

You may not qualify if:

• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression or primary glioblastoma multiforme.
• Clinically significant bleeding diathesis or coagulopathy.
• Known hypersensitivity to any of the components of Tazemetostat, itraconazole, or rifampin.
• Use of concurrent investigational agent or anticancer therapy.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements.
• Have a known active infection with hepatitis B virus (HBV), hepatitis C virus (HCV), AND/OR human T-cell lymphotropic virus 1.
• Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. John's Wort).
• Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from 24 hours prior to the first dose of study drug until the last dose of study drug.
• Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk.
• Has a prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN) or T-cell lymphoblastic lymphoma (T-LBL)/ T-cell acute lymphoblastic leukemia (T-ALL).
• Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1 until the end of Cycle 1 (Day 39 for Part 1 and Day 26 for Part 2). Regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (2 units equals 40mL \[a can\] of beer, 175mL \[a standard glass\] of wine, or 50 mL \[2 small shots\] of spirits
• Any form of marijuana use.
• History of drug abuse (including alcohol) within the last 6 months prior to screening.

Sponsors & Collaborators

• Epizyme, Inc.: lead

Study Sites (10)

California Cancer Associates for Research and Excellence, Inc. (cCARE)

Encinitas, California, 92024, United States

Location

The Angeles Clinic and Research Institute

Los Angeles, California, 90025, United States

Location

Northwestern University-Robert H. Lurie Comprehensive Cancer Center

Chicago, Illinois, 60611, United States

Location

South Texas Accelerated Research Therapeutics (START) Midwest

Grand Rapids, Michigan, 49546, United States

Location

Gabrail Cancer Center

Canton, Ohio, 44718, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45267, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75230, United States

Location

Onkologikoa

Donostia / San Sebastian, Gipuzkoa, 20014, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Related Links

• Lay language results summary

MeSH Terms

Conditions

Hematologic Neoplasms; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Sarcoma; Sarcoma, Synovial; Mesothelioma; Rhabdoid Tumor

Interventions

tazemetostat; Itraconazole; Rifampin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, B-Cell; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms, Mesothelial; Neoplasms, Complex and Mixed

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Medical Lead or Designee
• Organization: Epizyme, Inc.

clinicaltrials@epizyme.com

(855) 500-1011

Study Officials

• Ipse Medical Director

  Ipsen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: September 3, 2020
• Study Start: April 23, 2020
• Primary Completion: April 3, 2023
• Study Completion: April 3, 2023
• Last Updated: February 19, 2025
• Results First Posted: August 26, 2024

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (7); ES (3)