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

NCT03028103 | Completed Phase 1 Results FDA Drug

• 1 other identifier: EZH-105
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (11)

• 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

Study Arms (1)

Part A and B

EXPERIMENTAL

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; Drug: Fluconazole; Drug: Omeprazole; Drug: Repaglinide

Interventions

Tazemetostat DRUG

Tazemetostat is a selective oral small molecule inhibitor of EZH2

Also known as: EPZ-6438, E7438

Part A and B

Fluconazole DRUG

200mg will be orally administered QD for 4 days in order to determine CYP3A4 inhibition when administered concomitantly with tazemetostat

Part A and B

Omeprazole DRUG

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.

Part A and B

Repaglinide DRUG

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.

Part A and B

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 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.
• 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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Epizyme, Inc.: lead

Study Sites (3)

University of Arizona Cancer Center

Tucson, Arizona, 85719, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone

Interventions

tazemetostat; Fluconazole; Omeprazole; repaglinide

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Kemly Calixte
• Organization: Epizyme

kcalixte@epizyme.com

617-500-0608

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2016
• First Posted: January 23, 2017
• Study Start: March 27, 2017
• Primary Completion: October 31, 2019
• Study Completion: November 29, 2019
• Last Updated: June 26, 2023
• Results First Posted: April 19, 2021

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)