This is a phase I, multi-center, open-label, multi-dose, two-part PK and safety study to characterize the DDI potential of oral Tazemetostat.
Name: Tazemetostat
Name: Itraconazole
Name: Rifampin
Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
Measure: 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: 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.Description: AUC0-72: area under the plasma concentration-time curve from time 0 to 72 hours post dose
Measure: 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: 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.Description: Cmax: observed maximum plasma concentration
Measure: 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: 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.Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
Measure: 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: 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.Description: AUC0-48: area under the plasma concentration-time curve from time 0 to 48 hours post dose
Measure: 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: 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.Description: Cmax: observed maximum plasma concentration
Measure: 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: 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.Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
Measure: 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: 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.Description: Cmax: observed maximum plasma concentration
Measure: 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: 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.Description: Tmax: observed time at Cmax
Measure: 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: 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.Description: λz: terminal phase elimination rate constant
Measure: 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: 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.Description: t1/2: terminal elimination half-life
Measure: 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: 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.Description: AUC0-t: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration
Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, AUC0-t. Time: 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.Description: Cmax: observed maximum plasma concentration
Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Cmax. Time: 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.Description: Tmax: observed time at Cmax
Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, Tmax. Time: 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.Description: λz: terminal phase elimination rate constant
Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, λz. Time: 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.Description: t1/2: terminal elimination half-life
Measure: Part 2: To evaluate the steady-state PK of Tazemetostat and its metabolites after administration alone and with rifampin, t1/2. Time: 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.Description: 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.
Measure: To evaluate the number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0. Time: 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.Description: 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.
Measure: To evaluate the number of abnormalities or changes in intensity of conditions noted during the physical exam. Time: 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.Description: Investigators will note any clinically significant changes from baseline in systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg).
Measure: To evaluate change in blood pressure. Time: 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.Description: Investigators will note any clinically significant changes from baseline in heart rate measured in units of beats per minute (BPM).
Measure: To evaluate change in heart rate Time: 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.Description: Investigators will note any clinically significant changes from baseline in body temperature measured in degrees Fahrenheit or Celsius.
Measure: To evaluate change in body temperature. Time: 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.Description: Investigators will note any changes in concomitant medications from baseline in all subjects with at least 1 dose or partial dose of tazemetostat.
Measure: To evaluate changes in concomitant medications. Time: 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.Description: Investigators will report any clinically significant changes from baseline in the RR interval (sec) as noted by a 12 lead electrocardiogram (ECG).
Measure: To evaluate change in electrical activity of the heartbeat, RR interval. Time: 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.Description: Investigators will report any clinically significant changes from baseline in the PR interval (sec) as noted by a 12 lead electrocardiogram (ECG).
Measure: To evaluate change in electrical activity of the heartbeat, PR interval. Time: 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.Description: Investigators will report any clinically significant changes from baseline in the QRS complex (sec) as noted by a 12 lead electrocardiogram (ECG).
Measure: To evaluate change in electrical activity of the heartbeat, QRS complex. Time: 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.Description: Investigators will report any clinically significant changes from baseline in the QT interval (sec) as noted by a 12 lead electrocardiogram (ECG).
Measure: To evaluate change in electrical activity of the heartbeat, QT interval. Time: 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.Description: 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.
Measure: To evaluate changes in clinical laboratory values, hematology. Time: 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.Description: 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.
Measure: To evaluate changes in clinical laboratory values, serum chemistry. Time: 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.Description: 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.
Measure: To evaluate changes in clinical laboratory values, urinalysis. Time: 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.Allocation: Non-Randomized
Parallel Assignment
There is one SNP
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. --- V617F ---