Olaparib +/- Cediranib or Chemotherapy in Patients With Platinum-resistant Ovarian Cancer

Exclusion Criteria

• •1. Received previous single agent weekly paclitaxel for relapsed disease.
• •2. Pregnant or breast-feeding women or women of childbearing potential unless effective methods of contraception are used during the trial and for 6 months after stopping treatment. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. Pregnancy test will be performed monthly in women of child bearing potential.
• •Postmenopausal is defined as:
• •* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
• •* LH and FSH levels in the post-menopausal range for women under 50,
• •* radiation-induced oophorectomy with last menses \>1 year ago,
• •* chemotherapy-induced menopause with \>1 year interval since last menses, or surgical sterilisation (bilateral oophorectomy or hysterectomy).
• •3. Treatment with any other investigational agent, systemic chemotherapy, or participation in another interventional clinical trial within 28 days prior to enrolment.
• •4. Radiotherapy within 2 weeks from the last dose prior to study treatment
• •5. Started a stable dose of bisphosphonates for bone metastases less than 4 weeks prior to treatment with study drug e.g. patient is eligible and can continue to take bisphosphonates if these were started at least 4 weeks prior to treatment with study drug.
• •6. Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
• •7. Concomitant use of potent inducers of CYP3A4 such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John Wort.
• •8. Persistent toxicities (\>=CTCAE grade 2) caused by previous cancer therapy with the exception of alopecia.
• •9. Resting ECG with QTc \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
• •10. Blood transfusions within 1 month prior to study start
• •11. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
• •12. Patients with symptomatic, untreated, uncontrolled brain or meningeal metastases or tumour.
• •a. A scan to confirm the absence of brain metastases is not required. b. Patients with radiological evidence of stable brain metastases are eligible, providing that they are asymptomatic and: i. Do not require corticosteroids, or ii. Have previously been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids iii. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.
• •13. Major surgery within 14 days of starting study treatment
• •14. Patients who have not 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. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan
• •16. Any psychiatric disorder that prohibits obtaining informed consent.
• •17. Left Ventricular Ejection Fraction (LVEF) \< institutional lower limit of normal, when:
• •i. Prior treatment with anthracyclines (excluding liposomal doxorubicin) ii. Prior treatment with trastuzumab iii. A NYHA classification of II controlled with treatment (see Appendix 2) iv. Prior central thoracic RT, including RT to the heart v. History of myocardial infarction within the prior 12 months
• •18. Poorly controlled hypertension (persistently elevated \> 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication)
• •19. History of inflammatory bowel disease
• •20. History of cerebrovascular accident (including transient ischaemic attacks) within last 12 months.
• •21. Gastro intestinal impairment that could affect ability to take, or absorption of, oral medicines including sub- acute or complete bowel obstruction
• •22. Evidence of severe or uncontrolled cardiac disease
• •23. Evidence of active bleeding or bleeding diathesis. Defined as significant haemorrhage (\>30mL bleeding/episode in previous 3 months) or haemoptysis (\>5mL fresh blood in previous 4 weeks)
• •24. Known treatment-limiting hypersensitivity to cediranib, olaparib, paclitaxel or any of its excipients
• •25. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
• •26. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions, requiring treatment/or whose prognosis will prevent readout from trial endpoints.
• •27. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
• •28 Immunocompromised patients e.g., patients who are taking immunosuppressive drugs.