Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients

Registration Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures and the abilityto comply with the protocol for the duration of the study, including undergoingtreatment and scheduled visits and examinations.
2. Females aged ≥ 18 years with previous histologically proven diagnosis of high gradeserous or endometrioid carcinoma of the

• Ovary
• Fallopian tube
• or peritoneum, progressing >6 months after day 1 of the last cycle of first-lineplatinum-based chemotherapy and requiring treatment with platinum-basedchemotherapy on the basis of radiological evidence of disease or followingsurgical resection of recurrent disease.

3. Patients must have had CT or MRI proven relapsed disease (measureable ornon-measureable abnormalities supported by GCIG CA125 criteria of progression), orhave had debulking surgery for first relapse.
4. Patients showing evidence of response to chemotherapy mid-treatment (post 3 or 4cycles), either by CA125 or CT/MRI scan, should be approached for ICON9 trialregistration to allow for BRCA mutation status to be assessed (germline and/ orsomatic). Patients who underwent surgical debulking must show no evidence of diseaseprogression by the assessments above (CA125 and CT/MRI scan) in order to be approachedfor registration.
5. Prior front-line maintenance therapy with bevacizumab is permitted.
6. ECOG performance status 0-1.
7. Formalin fixed, paraffin embedded (FFPE) archival/diagnostic tumour sample or fromsecondary debulking surgery with adequate neoplastic cell content (>30%), must beavailable for central BRCA testing. For inclusion in i) the genetic HRD Test and ii)the biomarker research, patients must complete the consent form. Translational bloodsamples are also required, see Laboratory Manual for further details.
8. Patients should have a life expectancy ≥ 16 weeks.
9. Postmenopausal or evidence of non-childbearing status for women of childbearingpotential: negative urine or serum pregnancy test within 28 days prior to studytreatment and confirmed prior to treatment on day 1. Postmenopausal is defined as age ≥60 years, or:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments
• Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in thepost-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
• Surgical sterilisation (bilateral oophorectomy or hysterectomy)

10. Adequately controlled blood pressure (systolic blood pressure [SBP] ≤140 mmHg;diastolic blood pressure [DBP] ≤ 90mmHg) on maximum of 2 antihypertensive medications.
11. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction. Randomisation Inclusion Criteria:
12. Patients must have received at least 4 cycles, and a maximum of 6 cycles ofsecond-line platinum-based chemotherapy.
13. In patients with measurable disease, end of treatment scans must have a RECIST v1.1 'partial response' or 'complete response' and meet one of the following CA125requirements:
14. If the first screening CA125 value is below the ULN the patient is eligible forrandomisation and a second CA125 assessment is not required.
15. If the first screening CA125 value is greater than ULN then a second assessmentis required at least 7 days after the first to confirm eligibility. If the secondCA125 value has risen by ≥ 15% then the patient will not be eligible.
16. In patients with non-measurable disease, who have not undergone debulking surgery,they must have had a GCIG CA125 response to chemotherapy and meet one of the followingCA125 requirements:
17. If the first screening CA125 value is below the ULN the patient is eligible forrandomisation and a second CA125 assessment is not required.
18. If the first screening CA125 value is greater than ULN then a second assessmentis required at least 7 days after the first to confirm eligibility. If the secondCA125 value has risen by ≥ 15% then the patient will not be eligible.
19. Patients who have had debulking surgery at first relapse must have no evidence ofdisease progression on imaging (CT or MRI) and meet one of the following CA125requirements:
20. If the first screening CA125 value is below the ULN the patient is eligible forrandomisation and a second CA125 assessment is not required.
21. If the first screening CA125 value is greater than ULN then a second assessmentis required at least 7 days after the first to confirm eligibility. If the secondCA125 value has risen by ≥ 15% then the patient will not be eligible.
22. Expected to be able to commence treatment within 7 days post randomisation, and within 4-8 weeks post day 1 of the last cycle of chemotherapy.
23. Adequate bone marrow function as defined below:

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/l
• Platelet (Plt) ≥ 90 x 109/l
• Haemoglobin (Hb) ≥ 100g/l required and no packed blood transfusions in the 14days prior to starting trial treatment

7. Adequate liver function as defined below:

• Serum bilirubin ≤ 1.5 x ULN (or ≤ 3 for cases of known Gilbert's syndrome)
• Serum transaminases ≤3 x ULN
• Serum transaminases ≤ 5 x ULN if liver metastasis present

8. Adequate renal function as defined below: • Serum creatinine ≤ 1.5 x ULN and calculated glomerular filtration rate (GFR) ≥50ml/min (calculated as per local practice using Wright or Cockroft-gault formula)
9. Urine dipstick for proteinuria <2+. If urine dipstick is ≥ 2+ on two occasions morethan one week apart then a 24-hour urine must demonstrate ≤ 1 g of protein in 24 hoursor protein/creatinine ratio < 1.5.
10. Adequately controlled blood pressure (systolic blood pressure [SBP] ≤140 mmHg;diastolic blood pressure [DBP] ≤ 90mmHg) on maximum of 2 antihypertensive medications.
11. Germline and/or somatic BRCA mutation status must be known prior to randomisation.

Exclusion Criteria:

1. Non-epithelial ovarian cancer, carcinosarcoma, clear cell carcinoma and mucinouscarcinomas.
2. Arterial thrombotic event (including transient ischemic attack, cerebrovascularaccident, and peripheral arterial embolus) within the last 12 months.
3. Patients unable to swallow orally administered medication and patients withgastrointestinal impairment that could affect ability to take, or absorption of oralmedicines including sub-acute or complete bowel obstruction.
4. Clinically significant signs and/or symptoms of bowel obstruction within 3 monthsprior to starting treatment.
5. History of intra-abdominal abscess within 3 months prior to starting treatment (randomisation).
6. History of GI perforation. Patients with a history of abdominal fistula will beconsidered eligible if the fistula was surgically repaired, there has been no evidenceof fistula for at least 6 months prior to starting treatment, and patient is deemed tobe at low risk of recurrent fistula.
7. Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease orulcerative colitis).
8. Patients with an ileostomy will be excluded.
9. Evidence of severe or uncontrolled cardiac disease.
10. Myocardial infarct or unstable angina within the last 6 months
11. New York Health Association (NHYA) ≥ grade 2 congestive heart failure
12. Cardiac ventricular arrhythmias requiring medication
13. History of 2nd or 3rd degree atrioventricular conduction defects
14. Resting ECG with QTcF > 470msec on 2 or more time points within a 24 hour period orfamily history of long QT syndrome.
15. Evidence of active bleeding or bleeding diathesis. Significant haemorrhage of >30ml in a single episode within the last 3 months or anyhaemoptysis (>5ml fresh blood in last 4 weeks).
16. Malignancy treated within the last 5 years except: adequately treated non-melanomaskin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage 1, grade 1 endometrial carcinoma.
17. Previous treatment with VEGFR tyrosine kinase inhibitors or PARP inhibitors are notpermitted.
18. Patients with a known hypersensitivity to excipients of cediranib or olaparib.
19. Persisting ≥ grade 2 CTCAE toxicity (except alopecia and neuropathy) from previousanti-cancer treatment.
20. Major surgery within 14 days before anticipated start of treatment and patients musthave recovered from any effects of major surgery.
21. Inability to attend or comply with treatment or follow-up scheduling.
22. Evidence of any other disease, metabolic dysfunction, physical examination finding orlaboratory finding giving reasonable suspicion of a disease or condition thatcontra-indicated the use of an investigation drug or puts the patients at high riskfor treatment-related complications.
23. Pregnant or breast-feeding women are excluded. Women of childbearing potential will beexcluded unless effective methods of contraception are used from signing of theinformed consent, throughout the period of taking study treatment and for at least 6weeks after last dose of trial drug(s).
24. Treatment with any other investigational agent, or participation in anotherinterventional clinical trial within 28 days prior to enrolment (randomisation).
25. Concomitant use of known strong CYP3A4 inhibitors (such as systemic ketoconazole,itraconazole, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir, telithromycin and clarithromycin ormoderate CYP3A inhibitors (e.g. systemic Ciprofloxacin, erythromycin, diltiazem,fluconazole, verapamil). The required washout period prior to starting olaparib is 2weeks.
26. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents.
27. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
28. Other psychological, psychiatric, social or medical condition, physical examinationfinding or a laboratory abnormality that the Investigator considers would make thepatient a poor trial candidate or could interfere with protocol compliance or theinterpretation of trial results.
29. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk oftransmitting the infection through blood or other body fluids.
30. Immunocompromised patients e.g., patients who are known to be serologically positivefor human immunodeficiency virus (HIV) and are receiving antiviral therapy.
31. Patients with symptomatic uncontrolled brain or meningeal metastases. A scan toconfirm the absence of brain metastases is not required. The patient can receive astable dose of corticosteroids before and during the study as long as these werestarted at least 4 weeks prior to treatment.
32. Patients with spinal cord compression unless considered to have received definitivetreatment for this and evidence of clinically stable disease for 28 days.
33. Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).