Solid Tumours
Conditions
Keywords
oncology, cancer, tumour, anticancer drug, pharmacokinetics, olaparib, rifampicin, neoplasm, CYP P450 inducer
Brief summary
This is a 2-part study in patients with advanced solid tumours. Part A will investigate the effect of rifampicin on the PK parameters of olaparib in patients; Part B will allow patients continued access to olaparib after the PK phase and will provide additional safety data.
Interventions
PROCEDUREPharmacokinetic sampling
Blood sampling to measure olaparib, rifampicin and 4β-hydroxycholesterol
DRUGRifampicin
Rifampicin (CYP inducer) 600mg taken once daily from Day 5 to Day 14 (Part A)
Olaparib 300mg tablet taken on Days 1 and 14 (Part A). Part B dosing is 300mg olaparib bi-daily
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 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. 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 than 1 year ago. Chemotherapy-induced menopause with greater than 1 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 olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax). Olaparib doses are first without, then with rifampicin. |
| Pharmacokinetics of olaparib by assessment of area under the plasma concentration time curve from zero to infinity (AUC) | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC). Olaparib doses are first without, then with rifampicin. |
| 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 olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single 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, if AUC is not adequately estimable. Olaparib doses are first without, then with rifampicin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of olaparib by assessment of olaparib apparent volume of distribution (Vz/F). | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F). Olaparib doses are first without, then with rifampicin. |
| Pharmacokinetics of olaparib by assessment of olaparib terminal half-life (t1/2). | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2). Olaparib doses are first without, then with rifampicin. |
| Pharmacokinetics of rifampicin by assessment of plasma concentrations of rifampicin during rifampicin dosing period. | Rifampicin is dosed daily from Days 5 to 17 in Part A. Blood samples are collected on Days 5, 9, 14 and 17 at 2 hours post rifampicin dose | Rate and extent of absorption of rifampicin following multiple doses of rifampicin by assessment of plasma concentrations of rifampicin during rifampicin dosing period. |
| Demonstration of induction of CYP by assessment of plasma concentrations of 4β-hydroxycholesterol during rifampicin dosing period. | Blood samples are collected on Days 5, 9, 14 and 17 at pre-dose of rifampicin in Part A | Demonstration of CYP induction by assessment of plasma concentrations of 4β-hydroxycholesterol during rifampicin dosing period. |
| Assessment of the safety and tolerability of olaparib by collection of adverse event reports | Part A: From baseline, every visit until 30 days after last dose. Part B, from start to 12 months after the last patient has entered Part B | Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 |
| Pharmacokinetics of olaparib by assessment of time to reach maximum plasma concentration for olaparib (tmax). | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax). Olaparib doses are first without, then with rifampicin. |
| Determine safety and tolerability of olaparib by physical examination | Part A: baseline, Day -1 and within 30 days after last dose. Part B: Day 1. | Assessment of physical examination |
| Determine safety and tolerability of olaparib by assessment of vital signs | Part A: baseline, Days 1,2 and 3. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose. | Assessment of standard vital signs (including blood pressure, pulse) |
| Determine safety and tolerability of olaparib by assessment of clinical chemistry results | Part A: baseline, Days -1, 9, 14, 17. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose. | Assessment of laboratory parameters (clinical chemistry) |
| Determine safety and tolerability of olaparib by assessment of haematology results | Part A: baseline, Days -1, 9, 14, 17. Part B: Days 1,8,15,22,29 then every 4 weeks. Final assessment within 30 days after last dose. | Assessment of laboratory parameters (haematology) |
| Determine safety and tolerability of olaparib by assessment of urinalysis results | Part A: baseline, Days -1, 14, 17. Part B: Day 1 only | Assessment of laboratory parameters (urinalysis) |
| Determine safety and tolerability of olaparib by assessment of 12 lead electrocardiograms | Part A: baseline, Days -1, 17 (and within 30 days post last olaparib dose if not in Part B). | Assessment of standard 12 lead electrocardiograms (ECGs) |
| Pharmacokinetics of olaparib by assessment of olaparib area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ). | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib area under the plasma concentration time curve from zero to the last measurable time point (AUC0-τ). Olaparib doses are first without, then with rifampicin. |
| Pharmacokinetics of olaparib by assessment of olaparib apparent clearance (CL/F). | Blood samples are collected on olaparib dosing days (Day 1 and 14) 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. | Rate and extent of absorption of olaparib following single oral doses of olaparib tablet formulation by assessment of olaparib apparent clearance (CL/F). Olaparib doses are first without, then with rifampicin. |
Countries
Belgium, Netherlands
Outcome results
None listed