Advanced Solid Tumor, Diffuse Large B Cell Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Primary Mediastinal Lymphoma
Conditions
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.
Interventions
DRUGTazemetostat
Tazemetostat is a selective oral small molecule inhibitor of EZH2
DRUGFluconazole
200mg will be orally administered QD for 4 days in order to determine CYP3A4 inhibition when administered concomitantly with tazemetostat
DRUGOmeprazole
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.
DRUGRepaglinide
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.
Sponsors
Epizyme, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 18 years of age at time of consent 2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 3. Has the ability to understand informed consent and provided signed written informed consent Must meet one of the following criteria: 4. 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: 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 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 5. 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 6. 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 7. Must have evaluable or measurable disease 8. 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 9. Time required between the last dose of the latest therapy and the first dose of study drug: 1. Chemotherapy: cytotoxic At least 21 days 2. Chemotherapy: nitrosoureas At least 6 weeks 3. Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) At least 14 days 4. Monoclonal antibody (ies) At least 28 days 5. Non-antibody immunotherapy (e.g., tumor vaccine) At least 42 days 6. At least 14 days for stereotactic radiosurgery 7. At least 12 weeks for craniospinal, ≥50% radiation of pelvis, or total body irradiation prior to first dose of study drug 8. Autologous hematopoietic cell infusion after high dose therapy At least 60 days 9. Hematopoietic growth factor At least 14 days 10. Has adequate hematologic (bone marrow \[BM\] and coagulation factors), renal and hepatic function 1. Hemoglobin ≥9 g/dL 2. Platelets ≥75,000/mm3 (≥75 × 10\^9/L) 3. 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), 4. PT \<1.5 ULN 5. PTT \<1.5 ULN 6. eGFR ≥ 50 mL/min/1.73 m2 7. Conjugated bilirubin \<1.5 × ULN 8. AST \<3 × ULN 9. 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. 11. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec 12. 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. 13. 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 14. Male subjects with a female partner of childbearing potential must: 1. Be vasectomized, or 2. 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. 15. Female partners of male subjects who are of childbearing potential must also adhere to one of the following: 1. Placement of an intrauterine device or intrauterine system. 2. Established use of oral, injected, or implanted hormonal methods of contraception or use of a barrier method of contraception. 3. Progesterone only oral contraception, where inhibition of ovulation is not the primary mode of action. 16. Women of childbearing potential or female partners of male subjects must abide by the contraception measures defined by the protocol
Exclusion criteria
1. Is pregnant or nursing 2. Has active central nervous system (CNS) or leptomeningeal metastasis 3. 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. 4. 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. 5. Has a prior history of T-LBL/T-ALL. 6. 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. 7. 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 8. 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 9. Subjects taking medications that are known potent or moderate inducers/ inhibitors of CYP3A4 (including St. John's Wort) 10. Has an active infection or recent history (\<30 days before study drug administration) requiring systemic treatment 11. Is immunocompromised, including subjects with known human immunodeficiency virus (HIV) infection 12. Has known hypersensitivity to any of the components of IP. 13. 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 14. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements. 15. Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of IP. 16. 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. 17. 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. 18. Regular alcohol consumption averaging more than seven drinks/week for women and 14 drinks/week for men within 6 months of screening.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Part A: Cmax of Fluconazole After Administration of 400mg Once Daily for 4 Days | Day 19, 0 to 8 hours post-dose | — |
| 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. | — |
| 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 . | Within 28 days of Day 1, 8 weeks, 16 weeks, 24 weeks | 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. |
| Part A: Tmax of Fluconazole After Administration of 400mg Once Daily for 4 Days | Day 19, 0 to 8 hours post-dose | — |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A Subjects enrolled in Part A received treatment with oral tazemetostat tablets 400 mg twice daily for 24 days beginning on Day 1. Blood samples for the analysis of plasma tazemetostat and its metabolites concentrations were collected predose and over 8 hours after the morning dose of tazemetostat on Day 15. Subjects received fluconazole 400 mg once daily for 4 days starting on Day 16. On Day 19, blood samples for the analysis of plasma tazemetostat, its metabolites, and fluconazole were collected predose and over 8 hours after the morning tazemetostat dose. Tazemetostat 400 mg twice daily continued through Day 24. Subjects then received tazemetostat 800 mg twice daily starting on Day 25. | 16 |
| Part B Subjects enrolled in Part B received single oral doses of repaglinide 0.25 mg and omeprazole 20 mg on Day 1. Administration of tazemetostat 800 mg twice daily began on Day 2. On Day 16, subjects again received single oral doses of repaglinide 0.25 mg and omeprazole 20 mg approximately 1 hour after the morning dose of tazemetostat. Subjects also received omeprazole 20 mg once daily in the morning on Days 16 through 19. Blood samples for analysis of plasma repaglinide, repaglinide metabolites, omeprazole, 5-OH-omeprazole, and omeprazole sulfone were collected predose and over 7 hours after administration on Day 1 and Day 16. Blood samples for analysis of plasma tazemetostat and metabolites were collected over 8 hours after administration of the morning dose on Day 16 and Day 19. | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Part A | Part B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 11 Participants | 20 Participants |
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 15.1 | 48.8 Years STANDARD_DEVIATION 17.75 | 55.8 Years STANDARD_DEVIATION 17.73 |
| Baseline Disease Characteristics and Prior Therapies Advanced Solid tumors | 6 Participants | 13 Participants | 19 Participants |
| Baseline Disease Characteristics and Prior Therapies Lymphoma | 10 Participants | 3 Participants | 13 Participants |
| Baseline Disease Characteristics and Prior Therapies Progressive disease prior to study entry | 16 Participants | 16 Participants | 32 Participants |
| Baseline Disease Characteristics and Prior Therapies Stage at diagnosis: I | 0 Participants | 0 Participants | 0 Participants |
| Baseline Disease Characteristics and Prior Therapies Stage at diagnosis: II | 1 Participants | 1 Participants | 2 Participants |
| Baseline Disease Characteristics and Prior Therapies Stage at diagnosis: III | 5 Participants | 3 Participants | 8 Participants |
| Baseline Disease Characteristics and Prior Therapies Stage at diagnosis: IV | 8 Participants | 10 Participants | 18 Participants |
| Baseline Disease Characteristics and Prior Therapies Stage at diagnosis: Unknown | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 13 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 12 Participants | 26 Participants |
| Region of Enrollment United States | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 3 / 16 |
| other Total, other adverse events | 12 / 16 | 14 / 16 |
| serious Total, serious adverse events | 4 / 16 | 6 / 16 |
Outcome results
Primary
Part A: Cmax of Tazemetostat During Co-administration With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Cmax of Tazemetostat During Co-administration With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 | 426 ng/mL | Standard Deviation 337 |
| Part A | Part A: Cmax of Tazemetostat During Co-administration With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6438 | 968 ng/mL | Standard Deviation 801 |
Primary
Part A: Effect of CYP3A Inhibition by Fluconazole on the PK of Tazemetostat (AUC0-t, AUC0-8)
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Effect of CYP3A Inhibition by Fluconazole on the PK of Tazemetostat (AUC0-t, AUC0-8) | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 | 1340 h*ng/mL | Standard Deviation 1180 |
| Part A | Part A: Effect of CYP3A Inhibition by Fluconazole on the PK of Tazemetostat (AUC0-t, AUC0-8) | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6438 | 4100 h*ng/mL | Standard Deviation 2680 |
Primary
Part B: Cmax of Omeprazole During Co-administration With Tazemetostat
Time frame: Days 1 and 16, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Cmax of Omeprazole During Co-administration With Tazemetostat | Part: B; Day 1; Treatment: Omeprazole Alone; Analyte: Omeprazole | 253 ng/mL | Standard Deviation 462 |
| Part A | Part B: Cmax of Omeprazole During Co-administration With Tazemetostat | Part: B; Day 16; Treatment: Omeprazole with Tazemetostat; Analyte: Omeprazole | 207 ng/mL | Standard Deviation 275 |
Primary
Part B: Cmax of Repaglinide During Co-administration With Tazemetostat
Time frame: Days 1 and 16, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Cmax of Repaglinide During Co-administration With Tazemetostat | Part: B; Day 1; Treatment: Repaglinide Alone; Analyte: Repaglinide | 5.14 ng/mL | Standard Deviation 8.28 |
| Part A | Part B: Cmax of Repaglinide During Co-administration With Tazemetostat | Part: B; Day 16; Treatment: Repaglinide with Tazemetostat; Analyte: Repaglinide | 7.75 ng/mL | Standard Deviation 8.73 |
Primary
Part B: Cmax of Tazemetostat During Co-administration With Omeprazole
Time frame: Days 16 and 19, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Cmax of Tazemetostat During Co-administration With Omeprazole | Part: B; Day 16; Treatment: Omeprazole with Tazemetostat; Analyte: EPZ-6438 | 521 ng/mL | Standard Deviation 627 |
| Part A | Part B: Cmax of Tazemetostat During Co-administration With Omeprazole | Part: B; Day 19; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 | 641 ng/mL | Standard Deviation 404 |
Primary
Part B: Effect of Increased Gastric pH by Omeprazole on the PK of Tazemetostat (AUC0-t, AUC0-8)
Time frame: Days 16 and 19, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Effect of Increased Gastric pH by Omeprazole on the PK of Tazemetostat (AUC0-t, AUC0-8) | Part: B; Day 16; Treatment: Omeprazole with Tazemetostat; Analyte: EPZ-6438 - AUC(0-t) | 1780 h*ng/mL | Standard Deviation 2010 |
| Part A | Part B: Effect of Increased Gastric pH by Omeprazole on the PK of Tazemetostat (AUC0-t, AUC0-8) | Part: B; Day 19; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 - AUC(0-t) | 2150 h*ng/mL | Standard Deviation 1030 |
Primary
Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞)
Time frame: Days 1 and 16, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞) | Part: B; Day 1; Treatment: Omeprazole Alone; Analyte: Omeprazole - AUC(0-t) | 600 h*ng/mL | Standard Deviation 1600 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞) | Part: B; Day 16; Treatment: Omeprazole with Tazemetostat; Analyte: Omeprazole - AUC(0-t) | 480 h*ng/mL | Standard Deviation 837 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞) | Part: B; Day 1; Treatment: Omeprazole Alone; Analyte: Omeprazole - AUC(0-∞) | 672 h*ng/mL | Standard Deviation 463 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C19 Using Omeprazole as Probe a Substrate (AUC0-t, AUC0-∞) | Part: B; Day 16; Treatment: Omeprazole with Tazemetostat; Analyte: Omeprazole - AUC(0-∞) | 1120 h*ng/mL | Standard Deviation 1530 |
Primary
Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞)
Time frame: Days 1 and 16, 0 to 8 hours post-dose
Population: In Part B, 13 subjects completed taking omeprazole and repaglinide on Day 1, with tazemetostat on Day 16 and 11 subjects completed taking tazemetostat alone on Day 19.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞) | Part: B; Day 1; Treatment: Repaglinide Alone; Analyte: Repaglinide - AUC(0-t) | 8.16 h*ng/mL | Standard Deviation 13.7 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞) | Part: B; Day 16; Treatment: Repaglinide with Tazemetostat; Analyte: Repaglinide - AUC(0-t) | 14.7 h*ng/mL | Standard Deviation 15.1 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞) | Part: B; Day 1; Treatment: Repaglinide Alone; Analyte: Repaglinide - AUC(0-∞) | 12.7 h*ng/mL | Standard Deviation 19.4 |
| Part A | Part B: The Potential of Tazemetostat to Inhibit or Induce CYP2C8 Using Repaglinide as a Probe Substrate (AUC0-t, AUC0-∞) | Part: B; Day 16; Treatment: Repaglinide with Tazemetostat; Analyte: Repaglinide - AUC(0-∞) | 17 h*ng/mL | Standard Deviation 15.7 |
Secondary
Incidence of Treatment-emergent Adverse Events as a Measure of Safety
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE | 12 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Grade 3 or 4 | 7 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TEAE | 9 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TEAE Grade 3 or 4 | 4 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Dose Reduction | 2 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Study Drug Interruption | 3 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Study Drug Discontinuation | 0 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TESAE | 4 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TESAE | 1 Participants |
| Part A | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Protocol Defined AE of Special Interest | 0 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TESAE | 6 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE | 14 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Study Drug Interruption | 6 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Grade 3 or 4 | 8 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Protocol Defined AE of Special Interest | 0 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TEAE | 10 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Study Drug Discontinuation | 0 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TEAE Grade 3 or 4 | 3 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any Treatment-Related TESAE | 0 Participants |
| Part B | Incidence of Treatment-emergent Adverse Events as a Measure of Safety | Any TEAE Leading to Dose Reduction | 2 Participants |
Secondary
Part A: Cmax of Fluconazole After Administration of 400mg Once Daily for 4 Days
Time frame: Day 19, 0 to 8 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A | Part A: Cmax of Fluconazole After Administration of 400mg Once Daily for 4 Days | 25900 ng/mL | Standard Deviation 6500 |
Secondary
Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6930 (ER-897387) | 629 ng/mL | Standard Deviation 270 |
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6930 (ER-897387) | 548 ng/mL | Standard Deviation 288 |
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ006931 | 166 ng/mL | Standard Deviation 105 |
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ006931 | 167 ng/mL | Standard Deviation 153 |
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ034163 | 46 ng/mL | Standard Deviation 56.7 |
| Part A | Part A: Cmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ034163 | 47.1 ng/mL | Standard Deviation 61.4 |
Secondary
Part A: Exposure of Fluconazole After Administration of 400 mg Once Daily for 4 Days (AUC0-8)
Time frame: Day 19, 0 to 8 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A | Part A: Exposure of Fluconazole After Administration of 400 mg Once Daily for 4 Days (AUC0-8) | 170000 h*ng/mL | Standard Deviation 48300 |
Secondary
Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8)
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6930 (ER-897387) | 2590 h*ng/mL | Standard Deviation 1200 |
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6930 (ER-897387) | 2860 h*ng/mL | Standard Deviation 1600 |
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ006931 | 770 h*ng/mL | Standard Deviation 630 |
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ006931 | 921 h*ng/mL | Standard Deviation 780 |
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ034163 | 276 h*ng/mL | Standard Deviation 415 |
| Part A | Part A: PK of Tazemetostat and Its Metabolites After Administration Alone and With Fluconazole (AUC0-t, AUC0-8) | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ034163 | 295 h*ng/mL | Standard Deviation 430 |
Secondary
Part A: t1/2 of Tazemetostat After Administration Alone and With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: t1/2 of Tazemetostat After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 | 2.88 hours | Standard Deviation 0.491 |
| Part A | Part A: t1/2 of Tazemetostat After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6438 | 3.56 hours | Standard Deviation 0.453 |
Secondary
Part A: t1/2 of Tazemetostat Metabolites After Administration Alone and With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: t1/2 of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6930 (ER-897387) | 2.89 hours | Standard Deviation 0.358 |
| Part A | Part A: t1/2 of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6930 (ER-897387) | 3.92 hours | Standard Deviation 0.621 |
| Part A | Part A: t1/2 of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ006931 | 3.24 hours | Standard Deviation 0.565 |
Secondary
Part A: Tmax of Fluconazole After Administration of 400mg Once Daily for 4 Days
Time frame: Day 19, 0 to 8 hours post-dose
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A | Part A: Tmax of Fluconazole After Administration of 400mg Once Daily for 4 Days | 1.48 hours | Standard Deviation 1.95 |
Secondary
Part A: Tmax of Tazemetostat After Administration Alone and With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Tmax of Tazemetostat After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6438 | 1.13 hours | Standard Deviation 0.87 |
| Part A | Part A: Tmax of Tazemetostat After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6438 | 2 hours | Standard Deviation 0.84 |
Secondary
Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole
Time frame: Days 15 and 19, 0 to 8 hours post-dose
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ-6930 (ER-897387) | 2.01 hours | Standard Deviation 0.65 |
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ-6930 (ER-897387) | 2.02 hours | Standard Deviation 0.86 |
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ006931 | 2.01 hours | Standard Deviation 0.89 |
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ006931 | 2.47 hours | Standard Deviation 0.9 |
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 15; Treatment: Tazemetostat Alone; Analyte: EPZ034163 | 2.02 hours | Standard Deviation 1.26 |
| Part A | Part A: Tmax of Tazemetostat Metabolites After Administration Alone and With Fluconazole | Part: A; Day 19; Treatment: Tazemetostat with Fluconazole; Analyte: EPZ034163 | 2.02 hours | Standard Deviation 1.27 |
Secondary
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.
Time frame: Within 28 days of Day 1, 8 weeks, 16 weeks, 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A | 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 . | Complete response (CR) | 1 Participants |
| Part A | 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 . | Partial response (PR) | 1 Participants |
| Part A | 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 . | Stable disease (SD) | 0 Participants |
| Part A | 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 . | Progressive disease (PD) | 2 Participants |
| Part A | 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 . | Not evaluable, missing, or unknown | 9 Participants |
| Part A | 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) | 2 Participants |
| Part A | 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 . | Disease control rate (DCR) at 24 weeks | 2 Participants |
| Part A | 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 . | Number of responders (achieving a CR or PR) | 2 Participants |
| Part B | 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 . | Number of responders (achieving a CR or PR) | 2 Participants |
| Part B | 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 . | Complete response (CR) | 0 Participants |
| Part B | 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 . | Not evaluable, missing, or unknown | 3 Participants |
| Part B | 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 . | Partial response (PR) | 2 Participants |
| Part B | 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 . | Disease control rate (DCR) at 24 weeks | 4 Participants |
| Part B | 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 . | Stable disease (SD) | 9 Participants |
| Part B | 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) | 2 Participants |
| Part B | 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 . | Progressive disease (PD) | 5 Participants |