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

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

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

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumours
• Intervention / Treatment: Drug: Olaparib; Drug: Olaparib; Drug: Paclitaxel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100021
    • Research Site
  • Beijing, China, 100071
    • Research Site
  • Hangzhou, China, 310003
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of fully informed consent
2. Patient aged ≥ 18 years
3. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy and for which no suitable effective standard therapy exists
4. life expectancy of ≥ 12 weeks
5. Patients for Cohort 2 must be eligible for paclitaxel treatment
6. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
7. ECOG performance status ≤ 2
8. 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
9. 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.
10. 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:

1. Involvement in the planning and/or conduct of the study.
2. Previous enrolment in the present study.
3. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
4. Any previous treatment with a Poly (ADP-ribose) polymerase (PARP) inhibitor, including olaparib.
5. 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.
6. 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.
7. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 4 weeks from the last dose prior to study treatment.
8. Concomitant use of known potent CYP3A4 (Cytochrome P450 3A4) inhibitors.
9. Patients with any ongoing toxicities (>CTCAE (Common Terminology Criteria for Adverse Events) grade 2), with the exception of alopecia, caused by previous cancer therapy.
10. Resting ECG with QTc (Heart Rate Corrected QT interval) > 470msec or family history of long QT syndrome.
11. Patients with interstitial pneumonia or diffused symptomatic fibrosis of the lungs.
12. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
13. Patients with symptomatic uncontrolled brain metastases.
14. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
15. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
16. Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
17. Patients with known active hepatic disease (i.e. Hepatitis B or C).
18. Patients with a known hypersensitivity to olaparib, paclitaxel or any of the excipients of the product.
19. Breastfeeding women.
20. Clinical judgement by the investigator that the patient should not participate in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Treat 15 patients, single dose olaparib 300mg followed by multiple dose olaparib 300mg twice a day	Drug: Olaparib; Tablet-150mg, Oral; Drug: Olaparib; Tablet-100mg, Oral
Experimental: Cohort 2; 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: Olaparib; Tablet-150mg, Oral; Drug: Olaparib; Tablet-100mg, Oral; Drug: Paclitaxel; Injection

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Binghe Xu, MD, Cancer Institute and Hospital (CIH), Chinese Academy of Medical Sciences and Peking Union Medical College; Principal Investigator: Jianming Xu, MD, 307 Hospital of Military Medical Sciences; Principal Investigator: Jianzhong Shentu, No.1 Affiliated Hospital of College of Medicine, Zhejiang University

Publications and helpful links

General Publications

• Yuan P, Shentu J, Xu J, Burke W, Hsu K, Learoyd M, Zhu M, Xu B. Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours. Cancer Chemother Pharmacol. 2019 May;83(5):963-974. doi: 10.1007/s00280-019-03799-1. Epub 2019 Mar 18.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2015
• Primary Completion (Actual): July 27, 2016
• Study Completion (Actual): April 28, 2017

Study Registration Dates

• First Submitted: April 7, 2015
• First Submitted That Met QC Criteria: April 27, 2015
• First Posted (Estimate): April 30, 2015

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 18, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Chinese Patients
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Poly(ADP-ribose) Polymerase Inhibitors; Paclitaxel; Olaparib
• Other Study ID Numbers: D081BC00002