Solid Tumours
Conditions
Keywords
oncology,, cancer,, tumour,, anticancer drug,, pharmacokinetics,, olaparib,itraconazole,, neoplasm,, QT interval
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.
Interventions
PROCEDUREPharmacokinetic sampling
Blood samples taken pre and post dosing with olaparib+/- itraconazole
Olaparib tablets: Part A 100mg od, days 1 and 9 only. Part B 10x300mg doses over 5 days (300mg bd).
DRUGItraconazole
Itraconazole 200mg od Part A days 5 to 11 only
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
- For inclusion in the study, patients should fulfil the following criteria: 1. Provision of written informed consent prior to any study-specific procedures. 2. Patients aged greater than or equal to 18 years. 3. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists. 4. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of investigational product (IP) as defined below: Haemoglobin (Hb) greater than or equal to 10.0 g/dL, with no blood transfusions in the previous 28 days. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L. White blood cells (WBC) greater than 3 x 109/L. Platelet count greater than or equal to 100 x 109/L. Total bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN) (except in the case of Gilbert's disease). Aspartate aminotransferase (AST), alanine aminotransferase (ALT) less than or equal to 2.5 x institutional ULN unless liver metastases are present in which case it must be less than or equal to 5x ULN. Serum creatinine less than or equal to 1.5 x institutional ULN. Serum potassium, sodium, magnesium and calcium within the institutional normal range. 5. Calculated serum creatinine clearance greater than 50 mL/min (using Cockroft-Gault formula or by 24 hour urine collection). 6. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. 7. Patients must have a life expectancy of greater than or equal to 16 weeks. 8\. Evidence of non-childbearing status for women of childbearing potential, or post-menopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of Part A. Post-menopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments. Luteinising hormone and follicle stimulating hormone levels in the post-menopausal range for women under 50 years of age. Radiation-induced oophorectomy with last menses greater than1 year ago. Chemotherapy-induced menopause with greater than1 year interval since last menses. Surgical sterilisation (bilateral oophorectomy or hysterectomy). 9\. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 10\. Patients must be on a stable concomitant medication regimen (with the exception of electrolyte supplements), defined as no changes in medication or in dose within the 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab, and corticosteroids, which should be at a stable dose for at least 4 weeks prior to the start of olaparib dosing.
Exclusion criteria
- Patients should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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 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) |
Countries
Belgium, Denmark, Netherlands, United Kingdom
Outcome results
None listed