A Phase II Clinical Trial of Cediranib and Olaparib Maintenance in Advanced Recurrent Cervical Cancer

Inclusion Criteria: * Patients over 18 years of age * Histologically proven carcinoma of the cervix (squamous, adenocarcinoma or mixed adeno/squamous). * Completion of first line platinum-based chemotherapy for advanced /recurrent disease, leading to either a complete response, partial response or stable disease. * ECOG performance status 0 or 1 * Randomisation within 8 weeks of completion of chemotherapy * Patients may have received previous chemoradiotherapy and neoadjuvant chemotherapy given with a curative intent. * Creatinine Clearance ≥ 51mls/min * Adequate haematological and biochemical function, as follows: * Haemoglobin \> 10g/dl (with no blood transfusion in the 28 days prior to randomisation) Neutrophils \> 1.5 x 109/l * Platelets \> 100 x 109/l * Bilirubin \< 1.5 x ULN * ALT or AST/ SGOT \< 3 x ULN (or ≤5 x ULN if hepatic metastases present) * Alkaline Phosphatase \< 3 x ULN (or ≤5 x ULN if hepatic metastases present) * Adequate coagulation, as follows: * Prothrombin ratio (PTR) / INR ≤ 1.5 or * PTR / INR between 2.0 and 3.0 for patients on stable doses of anticoagulants * Partial thromboplastin time \<1.2 x control * Life expectancy \>12 weeks. * Informed written consent * Contrast enhanced computerised tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen and pelvis and a CT scan of the chest within 28 days prior to commencing randomisation (with RECIST 1.1) * Adequately controlled thyroid function, with no symptoms of thyroid dysfunction * Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib Exclusion Criteria: * Disease that is potentially treatable with exenterative surgery. * Relapse confined to the pelvis after radical surgery in circumstance where radiotherapy or chemoradiotherapy would be appropriate. * More than one line of prior chemotherapy for advanced/recurrent disease. Neoadjuvant chemotherapy is not counted. * Prior treatment with anti-angiogenic agents (with the exception of bevacizumab given as part of first line chemotherapy) * Persisting ≥Grade 2 CTCAE from previous anti-cancer previous systemic anti-cancer therapy except haematological toxicity (see inclusion criteria "Adequate haematological function") and alopecia. * History of other malignancy within the previous 5 years except for: * Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial carcinoma. * Curatively treated other solid tumors including lymphomas (without bone marrow involvement) with no evidence of disease for ≥5 years prior to start of IMPs. * Pregnant or lactating women. * Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards * Evidence of uncontrolled infection. (Defined as infection that cannot be resolved readily with antibiotics prior to patient entry into the trial for example a pelvic collection) * History of pelvic fistulae. * History of abdominal fistula that has been surgically corrected within 6 months of starting treatment. Patient should be deemed low risk of recurrent fistula * Sub-acute or acute intestinal obstruction. * Major surgery within 28 days or anticipated while on study. * Non-healing wound, ulcer or bone fracture. * Active bleeding. * History or evidence of thrombotic or haemorrhagic disorders. * History of stroke or transient ischemic attack within 6 months * Proteinuria \> 1+ on dipstick on two consecutive dipsticks taken no less than 1 week apart, unless urinary protein is \<1.5g in a 24 hour period. * Significant cardiovascular disease (arterial thrombotic event within 12 months, uncontrolled hypertension, myocardial infarction or angina within 6 months, NYHA grade 2 or worse congestive cardiac failure, grade ≥ 3 peripheral vascular disease or cardiac arrhythmia requiring medication). Patients with rate-controlled atrial fibrillation are eligible. * Prolonged QTc (corrected) interval of \>470ms on ECG or a family history of long QT syndrome. * Patients with symptomatic uncontrolled brain or meningeal metastases CNS disease (brain metastases, uncontrolled seizures or cerebrovascular accident/transient ischaemic attack /subarachnoid haemorrhage within 6 months). * (A scan to confirm the absence of brain metastases is not required) * A history of poorly controlled hypertension or resting BP\>140/90 mmHG in the presence or absence of a stable regimen of anti-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 two diastolic readings differ by more than 5mmHG, then an additional reading should be obtained and averaged). * History of significant gastrointestinal impairment. Defined as active inflammatory bowel disease, bowel obstruction or any condition judged by the investigator to adversely impact on drug absorption or within 3 months prior to starting treatment. * Patients with myelodysplastic syndrome/acute myeloid leukaemia. * Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications. * Patients who have been treated with potent inhibitors of CYP3A4 and 2C8 such as amiodaraone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin, montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other antivirals) and diltiazem within 2 weeks of the first planned dose of cediranib will be excluded \[NB These drugs are also prohibited during trial period\] * Patients treated with CYP3A inhibitors itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). Within 2 weeks of the first planned dose for strong inhibitors, and at least 1 week for moderate inhibitors. * Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatments is 5 weeks for enzalutamide or phenobarbital and 4 weeks for other agents. \[NB These drugs are also prohibited during trial period\] * Left ventricular ejection fraction (LVEF) \< lower limit of normal (LLN) per institutional guidelines, or \<55%, if threshold for normal not otherwise specified by institutional guidelines, for patients with the following risk factors: * prior anthracycline, trastuzumab , chest radiotherapy, history of myocardial infarction within 6 months prior to start of study drug or other significant impaired cardiac function within 6-12 months prior to start of IMPs * Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV, or who are receiving immunosuppressive treatment (with the exception of stable doses of steroids equivalent or less than prednisolone 10mg daily). * History of intra-abdominal abscess within 3 months prior to starting treatment. * Uncontrolled intercurrent illness including, but not limited to known ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or psychiatric illness/social situations that would limit compliance with study requirements. * Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation