To Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib, and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients With Advanced Solid Tumours
- Conditions
- Solid Tumours
- Interventions
- Registration Number
- NCT01900028
- Lead Sponsor
- AstraZeneca
- Brief Summary
This is a 3-part study in patients with advanced solid tumours: Part A will assess the effect of itraconazole on the PK parameters of olaparib and will determine the effect of olaparib on the QT interval following single oral dosing; Part B will determine the effect of olaparib on the QT Interval following multiple oral dosing; Part C will allow patients continued access to olaparib after the PK and QT phases and will provide for additional safety data collection. A total of 48 patients are planned to be enrolled; at least 42 evaluable patients will be required to complete the study. Patients will participate as a single cohort in all parts of the study.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 85
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Olaparib alone, olaparib+itraconozole Pharmacokinetic sampling Sequential treatments of olaparib alone followed by olaparib+itraconazole, with a washout period in between. Olaparib alone, olaparib+itraconozole Olaparib tablet dosing Sequential treatments of olaparib alone followed by olaparib+itraconazole, with a washout period in between. Olaparib alone, olaparib+itraconozole Itraconazole Sequential treatments of olaparib alone followed by olaparib+itraconazole, with a washout period in between.
- Primary Outcome Measures
Name Time Method Pharmacokinetics of olaparib by assessment of maximum plasma olaparib concentration (Cmax) Blood samples are collected on Day 1& Day 9 at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A. Part B:Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax)
Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to infinity (AUC) Blood samples are collected on Day 1& Day 9 at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A. Part B:Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC)
Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately estimable). Blood samples are collected on Day 1& Day 9 at pre-dose, 0.25 , 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post olaparib dose Part A. Part B:Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point, (AUC0-t)
- Secondary Outcome Measures
Name Time Method Pharmacokinetics of itraconazole by assessment of itraconazole apparent clearance (CL/F) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of itraconazole by assessment of itraconazole apparent clearance (CL/F)
Pharmacokinetics of hydroxy-itraconazole by assessment of maximum plasma hydroxyl -itraconazole concentration (Cmax). PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of hydroxyl -itraconazole by assessment of maximum plasma hydroxyl -itraconazole concentration (Cmax).
Pharmacokinetics of olaparib by assessment of time to reach maximum plasma concentration for olaparib (tmax) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax)
Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)
Pharmacokinetics of olaparib by assessment of time olaparib apparent clearance (CL/F) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time olaparib apparent clearance (CL/F)
Pharmacokinetics of olaparib by assessment of olaparib apparent volume of distribution (Vz/F) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F)
Pharmacokinetics of olaparib by assessment of olaparib terminal half-life (t1/2). PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of olaparib following following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2).
Pharmacokinetics of itraconazole by assessment of maximum plasma itraconazole concentration (Cmax) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of itraconazole by assessment of maximum plasma itraconazole concentration (Cmax).
Pharmacokinetics of itraconazole by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ), PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of itraconazole by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)
Pharmacokinetics of itraconazole by assessment of time to reach maximum plasma concentration for itraconazole (tmax) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of itraconazole by assessment of time to reach maximum plasma concentration for itraconazole (tmax)
Pharmacokinetics of hydroxy-itraconazole by assessment of hydroxy-itraconazole apparent clearance (CL/F) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of hydroxy-itraconazole by assessment of hydroxy-itraconazole apparent clearance (CL/F)
Pharmacokinetics of hydroxy-itraconazole by assessment of time to reach maximum plasma concentration for hydroxyl-itraconazole (tmax) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of hydroxyl -itraconazole by assessment time to reach maximum plasma concentration for hydroxyl-itraconazole (tmax)
Pharmacokinetics of hydroxy-itraconazole by assessment of the area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ) PK samples taken on Day 1 & Day 9 at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, & 72 hours post dose (Part A). And in Part B, Day 5 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post dose Rate and extent of absorption of hydroxyl -itraconazole by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ)
Assessment of Electrocardiogram (ECG) intervals (including QT and QTc interval) Digital ECGs recorded Day -1, Day 1 & 9 of Part A: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, & 24 hours post olaparib dose. In Part B, Day -1, Day 5: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, &12 hours post dose. Assessment of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (the QT interval), uncorrected and corrected for heart rate (QTc) following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation.
Safety monitoring of olaparib by collection of adverse events From baseline until 30 days after last dose of olaparib, assessed up to 8 months Assessment of adverse events (AEs), graded by CTCAE (v4.0): Adverse events (AEs) will be collected from the time of signed informed consent throughout the treatment period in Part A and Part B up to and including the 30-day follow-up period. In Part C, AEs will be collected until 12 months after the last patient entered Part C, and including the 30 day follow-up period for any patients who discontinue
Safety monitoring of olaparib by collection of physical examination From baseline until 30 days after last dose of olaparib, assessed up to 8 months These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.
Safety monitoring of olaparib by collection of vital signs From baseline until 30 days after last dose of olaparib, assessed up to 8 months Assessment of vital signs (including BP and pulse). These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, all except ECG will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.
Safety monitoring of olaparib by collection of clinical laboratory results From baseline until 30 days after last dose of olaparib, assessed up to 8 months Assessment of laboratory parameters (clinical chemistry, hematology, and urinalysis) : These will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, all except ECG will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.
Trial Locations
- Locations (2)
Research site
🇩🇰Herlev, Denmark
Research Site
🇬🇧Sutton, United Kingdom