Overview

This trial is active, not recruiting.

Condition advanced solid tumours
Treatments olaparib, paclitaxel
Phase phase 1
Target PARP
Sponsor AstraZeneca
Start date June 2015
End date July 2016
Trial size 47 participants
Trial identifier NCT02430311, D081BC00002

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

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification pharmacokinetics study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Treat 15 patients, single dose olaparib 300mg followed by multiple dose olaparib 300mg twice a day
olaparib
Tablet-150mg, Oral
(Experimental)
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)
paclitaxel
Injection
olaparib
Tablet-100mg, Oral

Primary Outcomes

Measure
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of maximum plasma (peak) drug concentration after single dose (Cmax)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of time of peak drug concentration(tmax)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of area under the curve from 0 to 12 hours post-dose (AUC(0-12))
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of area under plasma concentration-time curve from zero to infinity (AUC)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of apparent volume of distribution at steady state (Vss/F)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of apparent Oral Clearance (CL/F)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of elimination rate constant (Kel)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of mean residence time (MRT)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (single dose) pharmacokinetic(PK) profile in terms of terminal half-life (t½)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 (Day 2) and 48 h (Day 3) post dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of maximum plasma concentration at steady state (Cmax, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of minimum plasma concentration at steady state (Cmin, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of time to maximum plasma concentration for steady state (tmax, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of area under the curve during the dosing interval at steady state (AUCss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of accumulation ratio (index) (Rac)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of degree of fluctuation (DF)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of apparent plasma clearance for steady state (CLss/F)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose
Description of the olaparib (in combination with paclitaxel) pharmacokinetic(PK) profile in terms of maximum plasma concentration at steady state (Cmax, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Description of the olaparib (in combination with paclitaxel) pharmacokinetic(PK) profile in terms of time to maximum plasma concentration for steady state (tmax, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Description of the olaparib (in combination with paclitaxel) pharmacokinetic(PK) profile in terms of minimum plasma concentration at steady state (Cmin, ss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Description of the olaparib (in combination with paclitaxel) pharmacokinetic(PK) profile in terms of area under the curve during the dosing interval at steady state (AUCss)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Description of the olaparib (in combination with paclitaxel) pharmacokinetic(PK) profile in terms of apparent plasma clearance for steady state (CLss/F)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Description of the olaparib (multiple dose) pharmacokinetic(PK) profile in terms of Temporal change parameter(TCP)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning dose

Secondary Outcomes

Measure
Description of the safety profile in terms of AEs (adverse events) and SAEs (serious adverse events)
time frame: From screening until follow up (28 days after last dose of study medication). Approximately 1 year
Description of the safety profile in terms of physical examinations, ECOG (Eastern Cooperative Oncology Group) performance status, vital signs, clinical laboratory tests, 12-lead electrocardiograms and concomitant medications
time frame: From screening until follow up (28 days after last dose of study medication). Approximately 1 year
Ratio of maximum plasma concentration at steady state (Cmax, ss ratio)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Ratio of minimum plasma concentration at steady state (Cmin, ss ratio)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose
Ratio of area under the curve during the dosing interval at steady state (AUCss ratio)
time frame: Samples collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post morning olaparib dose

Eligibility Criteria

Male or female participants from 18 years up to 100 years old.

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.

Additional Information

Official title 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
Principal investigator Binghe Xu, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by AstraZeneca.