To Determine the Effect of Food on the Pharmacokinetics of Olaparib and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours

NCT01921140 | Completed Phase 1

• 1 other identifier: D0816C00004
• Study Type: interventional
• Target: 60
• Locations: 4 countries
• Sites: 12

Brief Summary

This is a 3 part study for patients with solid tumours. The purpose of Part A is to measure the amount of olaparib or its breakdown products in the bloodstream for up to 72 hours after eating and the effect of olaparib on QT interval following a single oral dose of olaparib tablets. Part B will determine the effect of olaparib on the QT interval following multiple oral dosing. Part C will allow patients continued access to olaparib tablets and will provide additional safety data collection.

Conditions

Solid Tumours

Keywords

Oncology, cancer, tumour, neoplasm, anticancer drug, food, area under the curve, pharmacokinetics, olaparib, neoplasm, metabolites, QT interval effects

Outcome Measures

Primary Outcomes (8)

• Pharmacokinetics of olaparib: area under the plasma-time curve from zero to infinity (AUC)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib:maximum olaparib concentration (Cmax)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib: area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately estimable (AUC0-t)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) 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.

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib time to reach maximum plasma concentration for olaparib (tmax)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib olaparib apparent clearance (CL/F)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent clearance (CL/F)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib:apparent volume of distribution (Vz/F)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib :terminal rate constant (λz)

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of terminal rate constant (λz)

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• Pharmacokinetics of olaparib:terminal half-life (t1/2).

  Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2).

  Blood samples will be collected in both treatment periods of Part A: pre-dose, 0.25, 0.5, 1, 1.5 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post olaparib dose. In Part B Day -1 and Day 5: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

Secondary Outcomes (3)

• Assessment of electrocardiogram (ECG) intervals (including QT and QTc interval)

  Digital ECG's will be recorded at Day-1, Day 1 of both treatment periods in Part A at: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post olaparib dose. Part B Day -1 & Day 5: pre-dose, 1, 1.5, 2, 3, 4, 6, 8, & 12 hours post dose.

• To assess the safety and tolerability of olaparib following oral dosing

  Part A&B: Adverse events (AEs) will be collected from the time of signed informed consent up to and including the 30-day follow-up period. In Part C, AEs will be collected for 12 months

• To assess safety and tolerability of oral olaparib dosing

  Laboratory and vital sign assessments will be carried out at baseline and then at every scheduled visit until 30 days post last dose

Study Arms (2)

Fasted

OTHER

Olaparib tablets following no breakfast

Drug: Olaparib tablets; Procedure: Pharmacokinetic sampling; Other: Dietary Fasted

High-fat meal

OTHER

Olaparib tablets after high-fat breakfast

Drug: Olaparib tablets; Procedure: Pharmacokinetic sampling; Other: Dietary High Fat

Interventions

Olaparib tablets DRUG

Olaparib dosing (2X 150mg tablets) following allocated meal

Fasted; High-fat meal

Pharmacokinetic sampling PROCEDURE

Blood samples taken pre and post dosing with 2x 150 mg olaparib tablet

Fasted; High-fat meal

Dietary Fasted OTHER

2x 150 mg olaparib tablet formulation taken in fasted state. 5-14 days washout period

Fasted

Dietary High Fat OTHER

2x 150 mg olaparib tablet formulation taken 30 minutes after allocated meal. 5-14 days washout period.

High-fat meal

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent prior to any study specific procedures.
• Patients aged greater than or equal to 18 years.
• Able to eat a high-fat meal within a 30-minute period, as provided by the study site.
• Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists.
• Normal organ and bone marrow function measured within 28 days prior to administration of investigational product (IP) as defined below:
• Haemoglobin 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 5 x ULN.
• Serum creatinine less than or equal to 1.5 x institutional ULN. Serum potassium, sodium, magnesium and calcium within the institutional normal range.
• 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 2. 8. Patients must have a life expectancy of greater than or equal to 16 weeks.
• \. Evidence of non-childbearing status for women of childbearing potential, or post-menopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on Day 1 of the first treatment period in Part A. Postmenopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments. Luteinising hormone and follicle stimulating hormone levels in the post-menopausal range for women under 50 years of age.
• Radiation-induced oophorectomy with last menses greater than 1 year ago. Chemotherapy-induced menopause with greater than 1 year interval since last menses.
• Surgical sterilisation (bilateral oophorectomy or hysterectomy). 10. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
• \. Patients must be on a stable concomitant medication regimen (with the exception of electrolyte supplements), 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.

You may not qualify if:

• 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 CYP3A4.
• Toxicities (greater than or equal to CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with asymptomatic brain metastases or with symptomatic but stable brain metastases can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• Patients unable to fast for up to 14 hours.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, uncontrolled seizures, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive bilateral interstitial lung disease on high resolution computed tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent.
• Patients with a history of poorly controlled hypertension with resting blood pressure (BP) greater than 150/100 mm Hg in the presence or absence of a stable regimen of hypertensive therapy. Measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mm Hg, an additional reading should be obtained and averaged.
• Patients with a history of heart failure or left ventricular dysfunction, and patients who require calcium channel blockers.
• Patients with type I or type II diabetes.
• Patients who have gastric, gastro-oesophageal or oesophageal cancer.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with absorption of olaparib.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (12)

Research Site

Brussels, 1090, Belgium

Location

Research Site

Leuven, 3000, Belgium

Location

Research Site

Liège, 4000, Belgium

Location

Research Site

Herlev, 2730, Denmark

Location

Research Site

København Ø, 2100, Denmark

Location

Research Site

Maastricht, 6202 AZ, Netherlands

Location

Research Site

Nijmegen, 6525 GA, Netherlands

Location

Research Site

Utrecht, 3584 CX, Netherlands

Location

Research Site

London, SE1 9RT, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Research Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Research Site

Surrey, SM1 2DL, United Kingdom

Location

Related Publications (1)

• Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Greve J, Lolkema MP, Soetekouw P, Mau-Sorensen M, Nielsen D, Spicer J, Fielding A, So K, Bannister W, Molife LR. Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2015 Oct;76(4):723-9. doi: 10.1007/s00280-015-2836-2. Epub 2015 Aug 5.

  PMID: 26242220 DERIVED

Related Links

• D0816C00004\_Study\_Synopsis\_Redacted.pdf
• D0816C00004\_food\_effect\_tablet\_protocol\_redacted\_SECURE

MeSH Terms

Conditions

Neoplasms

Interventions

olaparib

Study Officials

• Anitra Fielding

  AstraZeneca Sponsor Research Physician

  STUDY DIRECTOR

• Ruth Plummer, Prof

  Northern Centre for Cancer Care, Newcastle Upon Tyne Hospitals

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2013
• First Posted: August 13, 2013
• Study Start: September 24, 2013
• Primary Completion: April 8, 2014
• Study Completion: March 15, 2022
• Last Updated: November 22, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

NL (3); GB (4); BE (3); DK (2)