A Non-randomised, Open-label, Sequential, Multicentre, Two-part, Phase I Study to Assess the Effect of Rifampicin, a CYP Inducer, on the Pharmacokinetics of Olaparib Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours
Overview
- Phase
- Phase 1
- Intervention
- Pharmacokinetic sampling
- Conditions
- Solid Tumours
- Sponsor
- AstraZeneca
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Pharmacokinetics of olaparib by assessment of maximum plasma olaparib concentration (Cmax)
- Status
- Completed
- Last Updated
- 9 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •For inclusion in the study, patients should fulfil the following criteria:
- •Provision of written informed consent prior to any study-specific procedures.
- •Patients aged greater than or equal to 18 years.
- •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.
- •Calculated serum creatinine clearance greater than 50 mL/min (using Cockroft-Gault formula or by 24 hour urine collection).
- •Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
- •Patients must have a life expectancy of greater than or equal to 16 weeks.
Exclusion Criteria
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled.
- •Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, its agents, and/or staff at the study site).
- •Previous enrolment in the present study.
- •Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
- •Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 2 weeks prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study, as long as these were started at least 4 weeks prior to treatment.
- •Patients who have received or are receiving inhibitors or inducers of CYP3A
- •Toxicities (greater than or equal to Common Toxicity Criteria for Adverse Events \[CTCAE\] Grade 2) caused by previous cancer therapy, excluding alopecia.
- •Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the end of Part A.
- •Patients with brain metastases. A scan to confirm the absence of brain metastases is not required.
- •Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery.
Arms & Interventions
Olaparib alone, olaparib+rifampicin
Sequential treatments of olaparib alone followed by olaparib+rifampicin, with a washout period inbetween.
Intervention: Pharmacokinetic sampling
Olaparib alone, olaparib+rifampicin
Sequential treatments of olaparib alone followed by olaparib+rifampicin, with a washout period inbetween.
Intervention: Rifampicin
Olaparib alone, olaparib+rifampicin
Sequential treatments of olaparib alone followed by olaparib+rifampicin, with a washout period inbetween.
Intervention: Olaparib tablet dosing
Outcomes
Primary Outcomes
Pharmacokinetics of olaparib by assessment of maximum plasma olaparib concentration (Cmax)
Time Frame: 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)
Time Frame: 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.
Time Frame: 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 Outcomes
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- Determine safety and tolerability of olaparib by assessment of urinalysis results(Part A: baseline, Days -1, 14, 17. Part B: Day 1 only)
- 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.)
- 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.)
- 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).)
- 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.)
- 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)
- 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)
- 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)