A Randomised, Open-label, Three-part, Phase I Study to Determine the Effect of Food on the Pharmacokinetics of Olaparib and to Provide Data on the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients with Advanced Solid Tumours
- Conditions
- Cancer: Solid tumour (Malignant solid tumour)Solid tumourCancer
- Registration Number
- NL-OMON40265
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 12
1. Provision of written informed consent prior to any study specific procedures
2. Patients aged >=18 years
3. Able to eat a high-fat meal within a 30-minute period, as provided by the study site
4. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy or for which no suitable effective standard therapy exists
5. Normal organ and bone marrow function measured within 28 days prior to administration of investigational product (IP) as defined below:
* Haemoglobin >=10.0 g/dL, with no blood transfusions in the previous 28 days
* Absolute neutrophil count (ANC) >=1.5 x 109/L
* White blood cells (WBC) >3 x 109/L
* Platelet count >=100 x 109/L
* Total bilirubin <=1.5 x institutional upper limit of normal (ULN) except in the case of Gilbert's disease
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT) <=2.5 x institutional ULN unless liver metastases are present in which case it must be <=5 x ULN
* Serum creatinine <=1.5 x institutional ULN
* Serum potassium, sodium, magnesium and calcium within the institutional normal range
6. Calculated serum creatinine clearance >50 mL/min (using Cockroft-Gault formula or by 24-hour urine collection)
7. Eastern Cooperative Oncology Group (ECOG) performance status <=2
8. Patients must have a life expectancy of >=16 weeks.
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 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 postmenopausal range for women under 50 years of age
* Radiation-induced oophorectomy with last menses >1 year ago
* Chemotherapy-induced menopause with >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
11. 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.
1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, its agents, and/or staff at the study site)
2. Previous enrolment in the present study
3. 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)
4. 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.
5. Patients who have received or are receiving inhibitors or inducers of CYP3A4 (see Section 5.6.1 for guidelines and washout periods)
6. Toxicities (>=CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia
7. 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.
8. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
9. Patients unable to fast for up to 14 hours
10. 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.
11. Patients with a history of poorly controlled hypertension with resting blood pressure (BP) >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.
12. Patients with a history of heart failure or left ventricular dysfunction, and patients who require calcium channel blockers
13. Patients with type I or type II diabetes
14. Patients who have gastric, gastro-oesophageal or oesophageal cancer
15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with absorption of olaparib.
16. Breastfeeding women
17. Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV)
18. Patients with known active hepatic disease (ie, hepatitis B or C)
19. Patients with a known hypersensitivity to olaparib or any of the excipients of the product
20. Mean QTc with Fridericia's correction (QTcF) >470 ms in screening ECG or history of famil
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>To investigate the effect of food on the<br /><br>pharmacokinetics (PK) of olaparib following oral<br /><br>dosing of the tablet formulation in patients with<br /><br>advanced solid tumours<br /><br><br /><br>Primary outcome variable(s):<br /><br>Maximum plasma concentration (Cmax), time to<br /><br>reach maximum plasma concentration (tmax), area<br /><br>under the plasma concentration time curve from<br /><br>zero to the last measurable time point (AUC0-t),<br /><br>area under the plasma concentration time curve<br /><br>from zero to infinity (AUC), apparent clearance<br /><br>following oral administration (CL/F), apparent<br /><br>volume of distribution (Vz/F), terminal rate<br /><br>constant (!z), and terminal half-life (t1/2). Other<br /><br>parameters may be determined if deemed<br /><br>appropriate.</p><br>
- Secondary Outcome Measures
Name Time Method <p>To investigate the effect of olaparib on the QT<br /><br>interval following oral dosing of the tablet<br /><br>formulation in patients with advanced solid<br /><br>tumours<br /><br><br /><br>Secondary outcome variables:<br /><br>ECG intervals (including QT and QTc interval)<br /><br><br /><br><br /><br>To assess the safety and tolerability of olaparib<br /><br>following oral dosing of the tablet formulation in<br /><br>patients with advanced solid tumours<br /><br><br /><br>Secondary outcome variables:<br /><br>Assessment of AEs, graded by CTCAE (v4.03),<br /><br>physical examination (including BP and pulse),<br /><br>and evaluation of laboratory parameters (clinical<br /><br>chemistry, haematology, and urinalysis)<br /><br><br /><br><br /><br>AE adverse event; BP blood pressure; CTCAE Common Terminology Criteria for<br /><br>Adverse Event; ECG<br /><br>electrocardiogram</p><br>