To Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of Olaparib, and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation to Patients with Advanced Solid Tumours

Exclusion Criteria

• -
• Patients should not enter the study if any of the following exclusion criteria are fulfilled:
• 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.
• 6. Toxicities (greater than or equal to CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia.
• 7. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the end of Part A.
• 8. 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.
• 9. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• 10. Patients unable to fast for up to 14 hours.
• 11. 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 computer tomography (HRCT) scan, or any psychiatric disorder that prohibits obtaining informed consent.
• 12. Patients with a history of poorly controlled hypertension with resting blood pressure (BP) greater than150/100 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.
• 13. Patients with a history of heart failure, or left ventricular dysfunction, and patients who require calcium channel blockers.
• 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 the 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 itraconazole or any of the excipients of the product.
• 20. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
• 21. Mean QTc with Fridericia’s correction (QTcF) greater than 470 ms in screening ECG or history of familial long QT syndrome:
• A marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval greater than 470 ms).
• A history of additional risk factors for Torsade de pointes (eg, heart failure, hypokalaemia, family history of long QT syndrome).
• 22. The use of concomitant medications that prolong the QT/QTc interval.
• 23. Concomitant medication contraindicated for use with itraconazole (including, but not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, ergot alkaloids metabolized by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
• 24. Clinical judgment by the investigator that the patient should not participate in the study