The purpose of this study is to determine whether AZD1775 has any effect on the pharmacokinetics (PK) of three compounds (caffeine, omeprazole, and midazolam) that are probes for common drug-metabolizing enzymes (caffeine-CYP1A2, omeprazole-CYP2C19, midazolam-CYP3A). The study also seeks to determine the effect of AZD1775 on the QTc interval, which is a common measure of cardiac (heart) function.
This is a Phase I, 2-part study (Part A and Part B) in patients with advanced solid tumours. Part A: Part A of this study is an open-label, non-randomised, 2-period design. The treatment starts with the administration of a cocktail of 3 medications: caffeine, omeprazole and midazolam (Day -8), followed by pharmacokinetic (PK) sampling for 24 hours (Period 1) and a washout period of at least 7, but no more than 14 days. In Period 2, AZD1775 will be administered twice daily (bid) until steady state for 2.5 days (total of 5 doses) and the final dose will be administered in combination with the cocktail in the morning of Day 3. Part B: Part B is an open-label, non-randomised study in the same patients who participated in Part A. On Day -1, baseline dECG assessments will be performed at clock times matched to planned/scheduled dECG assessment times on Days 1 and 3. Starting on Day 1, each patient will receive AZD1775 (225 mg) bid for 2.5 days and will undergo dECG and PK assessments pre-dose and for 12 hours post AZD1775 dose. On Day 3, patients will receive their final AZD1775 dose and undergo dECG and PK assessments pre-dose and for 12 hours post-dose. On completion of Part B (ie, collection of the 24-hour PK sample/dECG and safety assessments on Day 4) patients will enter a 4-day washout period relative to the last dose of AZD1775. Within 3 days after the washout period, patients will be required to attend an end of treatment (EoT) visit. Patients will be evaluated for their eligibility and interest to enrol into the open-label continued access (CA) study (D6014C00007).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.
In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.
Research Site
Bingham Farms, Michigan, United States
Research Site
Detroit, Michigan, United States
Research Site
Lebanon, New Hampshire, United States
Research Site
Cincinnati, Ohio, United States
Part A: Area under the plasma concentration-time curve from zero to infinity for cocktail parent compounds (midazolam, omeprazole and caffeine)
To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)
Time frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose
Part A: Area under the plasma concentration-time curve from time zero to the time "t" of the last quantifiable concentration for cocktail parent compounds (midazolam, omeprazole and caffeine)
To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)
Time frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose
Part A: maximum plasma drug concentration for cocktail parent compounds (midazolam, omeprazole and caffeine)
To assess the effect of AZD1775 on the PK of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam)
Time frame: Blood samples are collected on Day -8 and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post cocktail dose
Part B: dECG intervals (QTcF) for absolute values and time-matched change from baseline
To assess the effect on QT interval corrected for heart rate (QTc) following multiple oral doses of AZD1775
Time frame: dECGs are measured on Day -1, Day 1 and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post AZD1775 dose
Time to reach maximum plasma concentration for cocktail parent compounds (midazolam, omeprazole and caffeine)
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
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In Part A, Period 1, patients will be administered a 3 drug cocktail of caffeine, omeprazole and midazolam on Day -8 followed by a washout period of at least 7 but no more than 14 days. In Part A, Period 2, AZD1775 capsules will be administered orally, 225 mg bid, until steady state for 2.5 days (total of 5 doses) and administered together with the cocktail on the morning of Day 3.
Patients should be administered Kytril (granisetron) 1 mg orally, under fasted conditions (-2 to 2 hours away from meals), 30 minutes prior to administration of the AZD1775 capsules with a small amount of water.
Multiple doses of 225 mg AZD1775, (3 x 75 mg, printed capsules) administered orally. The drug class of AZD1775 is Wee-1 kinase inhibitor.
Research Site
Providence, Rhode Island, United States
Research Site
Greenville, South Carolina, United States
Research Site
Dallas, Texas, United States
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Terminal half-life for cocktail parent compounds (midazolam, omeprazole and caffeine)
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Elimination rate constant for cocktail parent compounds (midazolam, omeprazole and caffeine)
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Apparent clearance following oral administration for cocktail parent compounds (midazolam, omeprazole and caffeine)
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Apparent volume of distribution for cocktail parent compounds (midazolam, omeprazole and caffeine)
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Area under the plasma concentration-time curve from zero to infinity for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Area under the plasma concentration-time curve from time zero to the time "t" of the last quantifiable concentration for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Time to reach maximum plasma concentration for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Maximum plasma drug concentration for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Terminal half-life for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Elimination rate constant for cocktail metabolites
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 1, Part B Only: Area under the plasma concentration-time curve from time zero to 12 hours for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose
Day 1, Part B only: Time to reach maximum plasma concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose
Day 1, Part B only: Maximum plasma drug concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 1 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose
Day 3, Parts A & B: Area under the plasma concentration-time curve from time zero to 12 hours for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12 hours post dose
Day 3, Parts A & B: Time to reach maximum plasma concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 3, Parts A & B: Maximum plasma drug concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 3, Parts A & B: Minimum plasma drug concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 3, Parts A & B: Average concentration over a dosing interval for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 3, Parts A & B: Apparent clearance at steady state for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Day 3, Parts A & B: Fluctuation index (FI) over a dosing interval for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 3 of Part A and B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Part B only: Accumulation ratio for area under the plasma concentration-time curve from time zero to twelve hours for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 1 and 3 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Part B only: Accumulation ratio for maximum plasma drug concentration for AZD1775
To describe the PK of AZD1775 following single and multiple dose administration
Time frame: Blood samples are collected on Day 1 and 3 of Part B at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
dECG intervals (heart rate, RR, PR, QRS, QTcB, QTcF and QT) for absolute values and time-matched change from baseline
To evaluate the effect of single and multiple doses of AZD1775 on cardiac (ECG) parameters
Time frame: dECG intervals are performed on Day -1, Day 1, and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose
Changes in dECG morphology
To evaluate the effect of single and multiple doses of AZD1775 on cardiac (ECG) parameters
Time frame: dECG intervals are performed on Day -1, Day 1, and Day 3 of Part B at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose
Area under the plasma concentration-time curve from time zero to infinity ratios in relation to parent compound
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose
Maximum plasma drug concentration ratios in relation to parent compound
To describe the PK of midazolam, omeprazole and caffeine and their metabolites (1'-hydroxy-midazolam, 5-hydroxy-omeprazole, and paraxanthine) in the absence and presence of AZD1775
Time frame: Blood samples are collected on Day -8, and Day 3 of Part A at pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post dose