A Two-part Study to Characterize Drug-Drug Interaction Effects on Steady-State Pharmacokinetics of Oral Tazemetostat

Primary Outcome Measures

1. Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
2. Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-72. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose
3. Part 1: To evaluate the effect of CYP3A4 inhibition by itraconazole on the steady-state pharmacokinetics (PK) of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   Cmax: observed maximum plasma concentration
4. Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-t. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
5. Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, AUC0-48. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   AUC0-48: area under the plasma concentration-time curve from time 0 to 48 hours post dose
6. Part 2: To evaluate the effect of CYP3A4 induction by rifampin on the steady-state PK of Tazemetostat when administered as a single and twice daily oral dose in subjects with advanced malignancies, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   Cmax: observed maximum plasma concentration

Secondary Outcome Measures

1. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, AUC0-t. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
2. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   Cmax: observed maximum plasma concentration
3. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, Tmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   Tmax: observed time at Cmax
4. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, λz. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   λz: terminal phase elimination rate constant
5. Part 1: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with itraconazole, and to evaluate the effect of itraconazole on PK of a single 400 mg oral dose of Tazemetostat, t1/2. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3. 0 to 72 hours post-dose on Days 15 – 18 and 36 – 39. 0 to 24 hours post-dose on Days 21 – 22. 0 and 2 hours post-dose on Days 25, 28, 31, and 34. ]
   t1/2: terminal elimination half-life
6. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, AUC0-t. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
7. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Cmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   Cmax: observed maximum plasma concentration
8. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Tmax. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   Tmax: observed time at Cmax
9. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, λz. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
   λz: terminal phase elimination rate constant
10. Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, t1/2. [ Time Frame: 0 to 48 hours post-dose on Days 1 – 3, 15 – 17 and 24 – 26. 0 and 2 hours post-dose on Days 19 and 21. ]
    t1/2: terminal elimination half-life
11. To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Severity of adverse events experienced by all subjects with at least 1 dose or partial dose of tazemetostat will be evaluated by the Investigator based on the CTCAE, version 5.0.
12. To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any new clinically significant findings (e.g., not noted at screening) or changes in intensity of conditions that occurred after the initial tazemetostat administration.
13. To evaluate change in blood pressure. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg).
14. To evaluate change in heart rate [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM).
15. To evaluate change in body temperature. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius.
16. To evaluate changes in concomitant medications. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat.
17. To evaluate change in electrical activity of the heartbeat, RR interval. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG).
18. To evaluate change in electrical activity of the heartbeat, PR interval. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG).
19. To evaluate change in electrical activity of the heartbeat, QRS complex. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG).
20. To evaluate change in electrical activity of the heartbeat, QT interval. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG).
21. To evaluate changes in clinical laboratory values, hematology. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes in hematological clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.
22. To evaluate changes in clinical laboratory values, serum chemistry. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes in serum chemistry clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.
23. To evaluate changes in clinical laboratory values, urinalysis. [ Time Frame: Cycle 1, Part 1: Days 1-39 of the 39-day cycle. Cycle 1, Part 2: Days 1-26 of the 26-day cycle. Cycle 2+: Day 1 (±3 days) of every 28-day cycle. End of Study: 30 (±3) days after last dose of study drug. Annual Assessments: Yearly from Day 1 of Cycle 1. ]
    Investigators will note any clinically significant changes in urinalysis clinical laboratory values from baseline in all subjects with at least 1 dose or partial dose of tazemetostat using laboratory reference ranges.

Inclusion Criteria

1. Male or female ≥ 18 years age at the time of consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
3. Has the ability to understand informed consent, and provide signed written informed consent.
4. Life expectancy of > 3 months.
5. 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.
6. Must have evaluable or measurable disease.
7. 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.
8. 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, and questions related to this can be discussed with the Medical Monitor.
9. Has normal hepatic function (per NCI-ODWG criteria) as well as adequate hematologic (bone marrow [BM] and coagulation factors) and renal function:
   • Hemoglobin: ≥9 g/dL (90 g/L)
   • Platelets: ≥75,000/mm³ (≥75 × 10⁹/L)
   • ANC (Hematologic malignancy subjects): ≥750/mm³ (≥0.75 × 10⁹/L)
   • ANC (Solid tumor subjects): ≥1,000/mm³ (≥1.0 × 10⁹/L)
   • PT: <1.5 ULN
   • PTT: <1.5 ULN
   • Serum creatinine: ≤1.5 × ULN
   • Bilirubin and AST: ≤ 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. Subjects may be retested once within 2 weeks of the screening test. Samples must be reanalyzed at the local laboratory.

10. 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.
11. Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.
12. Male subjects must refrain from donating sperm from first dose of Tazemetostat until 3 months following the last dose of Tazemetostat.
13. Male subjects with a female partner of childbearing potential must:
    1. Be vasectomized, or
    2. Remain abstinent or use a condom starting at signing of informed consent until 3 months following the last dose of study drug. 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 (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
14. 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 plus an additional barrier method.
    3. Progesterone-only oral contraception, where inhibition of ovulation is not the primary mode of action.
15. Female subjects of childbearing potential:
    1. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    2. Must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year starting at least 7 days before the planned first dose of study drug until 6 months following the last dose of study drug.
    3. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
    4. Due to the potential of enzyme induction with Tazemetostat, female subjects who use hormonal contraceptives should use an additional barrier method of birth control while on study treatment and for 6 months after discontinuation of study treatment.
    5. 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 (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    6. Barrier methods must always be supplemented with the use of a spermicide.
16. Females of childbearing potential must have a negative serum pregnancy test at screening.
17. Has a QT interval corrected by Fridericia’s formula (QTcF) ≤450 msec.
18. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:
    1. No history of AIDS-defining opportunistic infections, or have not had an opportunistic infection within the past 12 months prior to enrollment.
    2. No history of AIDS-defining cancers (eg, Kaposi’s sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
    3. Subjects may take prophylactic antimicrobials, however subjects that are taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities should be excluded from study participation.
    4. Subjects should be on established anti-retroviral therapy for at least 4 weeks, and have an HIV viral load of < 400 copies/mL prior to enrollment.

Exclusion Criteria

1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. Subjects with primary glioblastoma multiforme are excluded.Note: Subjects with clinically stable brain metastases are eligible to enroll in the study.
2. Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Subjects on anticoagulation with low molecular weight heparin are allowed.
3. Known hypersensitivity to any of the components of Tazemetostat.
4. Use of concurrent investigational agent or anticancer therapy. Note: megestrol (Megace) if used as an appetite stimulant is allowed.
   1. Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of Tazemetostat. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis.
   2. The concurrent use of all herbal supplements is prohibited during the study as the composition, PK, and metabolism of many herbal supplements are unknown.
5. 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.
6. Have a known active infection with hepatitis B virus (HBV), as measured by positive hepatitis B surface antigen, hepatitis C virus (HCV, as measured by positive hepatitis C antibody), OR human T-cell lymphotropic virus 1.Exceptions: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) values and are hepatitis B surface antigen negative and/or have undetectable HCV RNA.
7. Subjects taking medications that are known CYP3A4 inducers or inhibitors (including St. John’s Wort).
8. 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.
9. Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk.
10. Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE v5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
11. Has abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and DNA sequencing.
12. Has a prior history of T-LBL/T-ALL.
13. Ingestion of alcohol within 72 hours prior to day 1 of Cycle 1, and until the 24, 48 or 72 hour post dose PK time point has been collected (whichever is the final sampling time point). Regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (1 unit equals 340mL of beer, 115mL of wine, or 43 mL of spirits) throughout the study until the end of treatment.
14. Any form of marijuana use.
15. History of drug abuse (including alcohol) within the last 6 months prior to screening.