AZD1775 combined with Olaparib in Patients with Refractory Solid Tumors

Exclusion Criteria

• 1. Prior treatment with a PARP inhibitor.
• 2. Use of an investigational drug during the past 30 days or 5 half-lives (whichever is longer) prior to 1st dose of study treatment.
• 3. Use of anti-cancer treatment drug ≤ 21 days or 5 half-lives (whichever is shorter) prior to 1st dose of study treatment. For drugs for which 5 half-lives is ≤ 21 days, a minimum of 10 days between termination of the prior treatment and administration of study treatment is required.
• 4. Radiotherapy (except for palliative reasons) within ≤ 21 days prior to study treatment.
• 5. No other anti-cancer therapy (except for palliative local radiotherapy), biological therapy, or other novel agent is permitted while the patient is receiving study medication. Patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator.
• 6. Major surgical procedures ≤ 28 days of beginning study treatment, or minor surgical procedures ≤ 7 days. Patients must have recovered from any of the effects of any major surgery. No waiting period required following port-a-cath placement.
• 7. Persistent Grade >1 toxicity from prior cancer therapy (except alopecia or anorexia).
• 8. Patient has an inability to swallow oral medications. Note: Patients with percutaneous endoscopic gastrostomy (PEG) tube or receiving total parenteral nutrition (TPN) are not eligible.
• 9. Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases, defined as metastasis having no evidence of progression or haemorrhage for at least 2 weeks after treatment. Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.
• 10. Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks prior to the olaparib PK sub-study dosing and withheld throughout the study until 2 weeks after the last dose of study drug.
• 11. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin are prohibited in this study. Co-administration of aprepitant or fosaprepitant during this study is prohibited.
• 12. Caution should be exercised when inhibitors or substrates of P-glycoprotein (P-gp), substrates of CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates with a narrow therapeutic range are administered with AZD1775.
• 12. Herbal preparations are not allowed throughout the study, including but not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop using these herbal medications 7 days prior to first dose of study treatment.
• 13. Any known hypersensitivity or contraindication to the components of the study drug AZD1775 or olaparib.
• 14. Patients with either previous or current myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML.
• 15. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2.
• • Unstable angina pectoris
• • Congestive heart failure
• • Acute myocardial infarction
• • Conduction abnormality not controlled with pacemaker or medication
• • Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
• 16. AZD1775 should not be given to patients who have a history of Torsades des pointes (TdP) unless all risk factors that contributed to TdP have been corrected.
• 17. Mean resting corrected QTc interval using the Fridericia formula [QTcF]) ≥ 470 msec for female patients and ≥ 450 msec for male patients from 3 electrocardiograms (ECGs) performed 2-5 minutes apart at study entry or congenital long QT syndrome. .
• 18. Pregnant or breastfeeding.
• 19. Serious known active infection at the time of enrolment, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment.
• 20. Presence of other known active invasive cancers.
• 21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with protocol.
• 22. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (< 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
• 23. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• 24. Previous allogeneic bone marrow transplant or non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection will exclude patients from the pharmacogenetic portion of the study. If a patient declines to participate in the optional exploratory pharmacogenetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.