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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02430311

Enrollment

Registered

2015-04-30

Start date

2015-06-10

Completion date

2017-04-28

Last updated

2019-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced Solid Tumours

Keywords

Chinese Patients

Brief summary

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

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.

Interventions

DRUGOlaparib

Tablet-150mg, Oral

DRUGPaclitaxel

Injection

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Single Dose PK Parameter--Cmax	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 summary for olaparib in monotherapy by dose - Cmax (PK analysis set)
Single Dose PK Parameter--AUC	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 summary for olaparib in monotherapy by dose - AUC (PK analysis set)
Single Dose PK Parameter--tmax	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 summary for olaparib in monotherapy by dose - tmax (PK analysis set)
Single Dose PK Parameter--t1/2, λz	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 summary for olaparib in monotherapy by dose - t1/2, λz (PK analysis set)
Single Dose PK Parameter--Vz/F	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 summary for olaparib in monotherapy by dose - Vz/F (PK analysis set)
Single Dose PK Parameter--CL/F	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 summary for olaparib in monotherapy by dose - CL/F (PK analysis set)
Steady State PK Parameter--Cmax, ss and Cmin, ss at Day 8	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set)
Steady State PK Parameter--AUCss at Day 8	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set)
Steady State PK Parameter--tmax, ss at Day 8	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set)
Steady State PK Parameter--RAC and TCP at Day 8	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - RAC and TCP (PK analysis set)
Steady State PK Parameter--Cmax, ss and Cmin, ss at Day 9	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set)
Steady State PK Parameter--AUCss at Day 9	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set)
Steady State PK Parameter--tmax, ss at Day 9	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set)
Steady State PK Parameter--CLss/F at Day 8	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 pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - CLss/F (PK analysis set)

Countries

China

Participant flow

Recruitment details

This study was performed at 3 study centres in China.The first patient entered the study on 10 June 2015 and the last patient completed Part A of the study on 02 August 2016, and the date of last patient last visit in Part B was 28 April 2017.

Pre-assignment details

47 patients were screened in the study. 11 patients were not assigned to treatment due to eligibility criteria not fulfilled. 5 patients excluded from the PK analysis set due to previous gastric surgery. 1 of the 5 patients was also excluded due to vomiting within 3 hours of dosing on a PK day or on the 3 days prior to a multiple dose PK Day.

Participants by arm

Arm	Count
Cohort 1 Olaparib 300 mg alone	20
Cohort 2 Olaparib 100 mg bd in combination with paclitaxel	16
Total	36

Withdrawals & dropouts

Period	Reason	FG000	FG001
Part A	Adverse Event	0	1
Part A	Withdrawal by Subject	1	0
Part B	Adverse Event	1	0
Part B	Death	1	0
Part B	Meet study-specific withdrawal criteria	6	6
Part B	Withdrawal by Subject	2	2

Baseline characteristics

Characteristic	Cohort 1	Cohort 2	Total
Age, Continuous	47.7 years STANDARD_DEVIATION 10.43	49.3 years STANDARD_DEVIATION 9.49	48.4 years STANDARD_DEVIATION 9.92
Age, Customized ≥50 <65 years	9 Participants	6 Participants	15 Participants
Age, Customized <50 years	11 Participants	9 Participants	20 Participants
Age, Customized ≥65 <75 years	0 Participants	1 Participants	1 Participants
Age, Customized ≥75 years	0 Participants	0 Participants	0 Participants
Body mass index	23.91 kg/m2 STANDARD_DEVIATION 4.144	23.78 kg/m2 STANDARD_DEVIATION 3.599	23.85 kg/m2 STANDARD_DEVIATION 3.857
Height	164.9 cm STANDARD_DEVIATION 6.25	160.3 cm STANDARD_DEVIATION 4.81	162.8 cm STANDARD_DEVIATION 6.04
Race/Ethnicity, Customized Chinese	20 Participants	16 Participants	36 Participants
Sex: Female, Male Female	13 Participants	15 Participants	28 Participants
Sex: Female, Male Male	7 Participants	1 Participants	8 Participants
Weight	64.8 kg STANDARD_DEVIATION 10.35	60.9 kg STANDARD_DEVIATION 8.71	63.1 kg STANDARD_DEVIATION 9.71

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	11 / 20	8 / 16	16 / 16	18 / 19	2 / 2	15 / 15
serious Total, serious adverse events	0 / 20	0 / 16	4 / 16	0 / 19	0 / 2	1 / 15

Outcome results

Primary

Single Dose PK Parameter--AUC

Single dose PK parameter summary for olaparib in monotherapy by dose - AUC (PK analysis set)

Time frame: 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)