The Pharmacokinetics and Safety of Olaparib Alone and With Paclitaxel in Chinese Patients With Advanced Solid Tumour.

Study Overview
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Brief Summary
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This is a 2 parts phase I, open label trial of olaparib monotherapy and olaparib in combination with paclitaxel in patients with solid tumours. Part A will assess the single and multiple dose pharmacokinetics of olaparib monotherapy and multiple dose pharmacokinetics of olaparib in combination with paclitaxel. Part B will assess the safety of multiple doses of olaparib in Cohort 1 and of olaparib when co-administered with paclitaxel in Cohort 2

Detailed Description
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Part A will access the pharmacokinetics of olaparib: Cohort 1 will investigate the single and multiple dose pharmacokinetics of olaparib following 300mg bd monotherapy dose(s); Cohort 2 will investigate the single and multiple dose pharmacokinetics of olaparib following 100mg bd monotherapy dose(s) and the multiple dose pharmacokinetics in the presence of co-administered paclitaxel (80mg/m2 weekly on days 1, 8 and 15 of a single 28-day cycle). In Part B: Safety profile of olaparib 300mg bd as monotherapy and olaparib 100mg bd in combination with weekly paclitaxel will also be investigated in Chinese patients.

Official Title
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A Phase I, Open Label, 2 Part Study to Determine the Pharmacokinetics of Olaparib 300 mg bd Administered as Monotherapy and Olaparib 100 mg bd as Monotherapy and in Combination With Paclitaxel in Chinese Patients With Advanced Solid Tumours

Conditions
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Advanced Solid Tumours

Intervention / Treatment
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* Drug: Olaparib
* Drug: Paclitaxel
* Drug: Olaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of fully informed consent Patient aged ≥ 18 years Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy and for which no suitable effective standard therapy exists life expectancy of ≥ 12 weeks Patients for Cohort 2 must be eligible for paclitaxel treatment Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations ECOG performance status ≤ 2 Satisfactory organ and bone marrow function measured within 28 days prior to administration of study treatment including - Haemoglobin ≥ 10.0 g/dL and no blood transfusion in the 4 weeks prior to the first dosing of study drug. - Absolute neutrophil count ≥ 1.5 × 109/L Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1. Patients must be on a stable concomitant medication regimen, defined as no changes in medication or in dose within 2 weeks prior to start of olaparib dosing, except for bisphosphonates, denosumab and corticosteroids, which should be stable for at least 4 weeks prior to start of olaparib dosing. Exclusion criteria: Involvement in the planning and/or conduct of the study. Previous enrolment in the present study. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used). Any previous treatment with a Poly (ADP-ribose) polymerase (PARP) inhibitor, including olaparib. Patients with other malignancy within the last 5 years, except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, ductal carcinoma in situ, Stage 1, Grade 1 endometrial cancer, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. These include patients with gastric or intestinal cancer or patients with prior surgical procedures such as full or partial gastrectomy. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 4 weeks from the last dose prior to study treatment. Concomitant use of known potent CYP3A4 (Cytochrome P450 3A4) inhibitors. Patients with any ongoing toxicities (>CTCAE (Common Terminology Criteria for Adverse Events) grade 2), with the exception of alopecia, caused by previous cancer therapy. Resting ECG with QTc (Heart Rate Corrected QT interval) > 470msec or family history of long QT syndrome. Patients with interstitial pneumonia or diffused symptomatic fibrosis of the lungs. Patients with myelodysplastic syndrome/acute myeloid leukaemia. Patients with symptomatic uncontrolled brain metastases. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV). Patients with known active hepatic disease (i.e. Hepatitis B or C). Patients with a known hypersensitivity to olaparib, paclitaxel or any of the excipients of the product. Breastfeeding women. Clinical judgement by the investigator that the patient should not participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Treat 15 patients, single dose olaparib 300mg followed by multiple dose olaparib 300mg twice a day | Drug: Olaparib<br>* Tablet-150mg, Oral<br>|
| Experimental: Cohort 2<br>Treat 15 patients, single dose olaparib 100mg followed by multiple dose olaparib 100 mg twice a day and then in combination with paclitaxel (80mg/m2 weekly on days 1, 8 and 15 of a single 28-day cycle) | Drug: Paclitaxel<br>* Injection<br>Drug: Olaparib<br>* Tablet-100mg, Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Dose PK Parameter--Cmax | Single dose PK parameter summary for olaparib in monotherapy by dose - Cmax (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Single Dose PK Parameter--AUC | Single dose PK parameter summary for olaparib in monotherapy by dose - AUC (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Single Dose PK Parameter--tmax | Single dose PK parameter summary for olaparib in monotherapy by dose - tmax (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Single Dose PK Parameter--t1/2, λz | Single dose PK parameter summary for olaparib in monotherapy by dose - t1/2, λz (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Single Dose PK Parameter--Vz/F | Single dose PK parameter summary for olaparib in monotherapy by dose - Vz/F (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Single Dose PK Parameter--CL/F | Single dose PK parameter summary for olaparib in monotherapy by dose - CL/F (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) | 
| Steady State PK Parameter--Cmax, ss and Cmin, ss at Day 8 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 8 | 
| Steady State PK Parameter--AUCss at Day 8 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 8 | 
| Steady State PK Parameter--tmax, ss at Day 8 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 8 | 
| Steady State PK Parameter--RAC and TCP at Day 8 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - RAC and TCP (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 8 | 
| Steady State PK Parameter--Cmax, ss and Cmin, ss at Day 9 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set) | PK samples were collected pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 9 | 
| Steady State PK Parameter--AUCss at Day 9 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 9 | 
| Steady State PK Parameter--tmax, ss at Day 9 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 9 | 
| Steady State PK Parameter--CLss/F at Day 8 | Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - CLss/F (PK analysis set) | PK samples were collected pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose of Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chinese Patients