Please select the eligibility criteria that correspond to the clinical trial below.
Title: International Phase III Randomised Study to Evaluate the Efficacy of Maintenance Therapy With Olaparib and Cediranib or Olaparib Alone in Patients With Relapsed Ovarian Cancer Following a Response to Platinum-based Chemotherapy
Brief Summary: ICON 9 will assess the efficacy, safety and tolerability of maintenance olaparib in combination with cediranib compared to maintenance olaparib alone following a response to platinum-based chemotherapy in women with relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer. Prognostic and predictive factors will be studied from tumour and blood samples.


Options:
A: Inclusion Criteria:

1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
2. Patients with the following histologic cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, malignant Brenner's tumor or adenocarcinoma not otherwise specified.
3. Patient must have measurable disease as defined by RECIST 1.1.
4. Patients must have received treatment with a platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment.

   Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease.

   Patients are allowed to have received, but are not required to have received, biologic/targeted therapy (e.g., bevacizumab and/or PARP inhibitor) as part of their primary treatment regimen or for management of recurrent or persistent disease.
5. Patients must have platinum-resistant disease, defined as having a platinum-free interval (PFI) of \< 12 months after first- or second-line platinum-based chemotherapy, or having disease progression while receiving second-line platinum-based chemotherapy.
6. Patients must have adequate bone marrow, renal, hepatic, and neurologic functions as defined by the following:

   * Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3. This ANC cannot have been induced or supported by granulocyte colony stimulating factors. Platelets ≥ 100,000/mm3. Hemoglobin ≥ 9 g/dL.
   * Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN).
   * Hepatic function: bilirubin \< 1.2 mg/dL, SGOT (AST) and SGPT (ALT) ≤ 3.0 x ULN and alkaline phosphatase ≤ 2.5 x ULN.
7. Patients must have recovered from effects of recent surgery, radiotherapy or chemotherapy:

   * Patients should be free of active infection requiring parenteral antibiotics.
   * Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration. Continuation of hormone replacement therapy is permitted.
   * Any other prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted agents and immunologic agents, must be discontinued at least three weeks prior to registration.
   * Any prior radiation therapy must be completed at least four weeks prior to registration.
8. Patients must have a GOG performance status of 0 or 1.
9. Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception. If applicable, patients must discontinue breastfeeding prior to study entry.
10. Patients must meet the entry requirements and undergo the baseline procedures.
11. Patients must have signed an IRB-approved informed consent form and authorization permitting release of personal health information.

Exclusion Criteria:

1. Patients who have had treatment with VTX-2337, doxorubicin, PLD, or any other anthracycline.
2. Patients who have received an investigational agent \< 30 days prior to registration.
3. Patients who have received oral or parenteral corticosteroids \< 2 weeks prior to registration or who require ongoing systemic immunosuppressive therapy for any reason.
4. Patients with active autoimmune disease. "Active" refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis.
5. Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of the other malignancy being present within the last three years.
6. Patients who have received prior radiotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded.
7. Patients who have received prior chemotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded.
8. Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study.
9. Patients with clinically significant cardiovascular disease.
10. Patients who are pregnant or nursing.
11. Patients under the age of 18.
12. Patients with clinical symptoms or signs of gastrointestinal obstruction and/or who require parenteral hydration or nutrition.
B: Registration Inclusion Criteria:

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

   * Ovary
   * Fallopian tube
   * or peritoneum, progressing \>6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with platinum-based chemotherapy on the basis of radiological evidence of disease or following surgical resection of recurrent disease.
3. Patients must have had CT or MRI proven relapsed disease (measureable or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse.
4. Patients showing evidence of response to chemotherapy mid-treatment (post 3 or 4 cycles), either by CA125 or CT/MRI scan, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/ or somatic). Patients who underwent surgical debulking must show no evidence of disease progression by the assessments above (CA125 and CT/MRI scan) in order to be approached for 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 from secondary debulking surgery with adequate neoplastic cell content (\>30%), must be available for central BRCA testing. For inclusion in i) the genetic HRD Test and ii) the biomarker research, patients must complete the consent form. Translational blood samples 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 childbearing potential: negative urine or serum pregnancy test within 28 days prior to study treatment 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 hormonal treatments
   * Luteinizing hormone (LH) and Follicle stimulating hormone (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
   * 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:

1. Patients must have received at least 4 cycles, and a maximum of 6 cycles of second-line platinum-based chemotherapy.
2. 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 CA125 requirements:

   1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
   2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
3. 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 following CA125 requirements:

   1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
   2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
4. Patients who have had debulking surgery at first relapse must have no evidence of disease progression on imaging (CT or MRI) and meet one of the following CA125 requirements:

   1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
   2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
5. 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.
6. 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 14 days 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 more than one week apart then a 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours or 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 mucinous carcinomas.
2. Arterial thrombotic event (including transient ischemic attack, cerebrovascular accident, and peripheral arterial embolus) within the last 12 months.
3. Patients unable to swallow orally administered medication and patients with gastrointestinal impairment that could affect ability to take, or absorption of oral medicines including sub-acute or complete bowel obstruction.
4. Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior 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 be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula.
7. Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease or ulcerative colitis).
8. Patients with an ileostomy will be excluded.
9. Evidence of severe or uncontrolled cardiac disease.

   1. Myocardial infarct or unstable angina within the last 6 months
   2. New York Health Association (NHYA) ≥ grade 2 congestive heart failure
   3. Cardiac ventricular arrhythmias requiring medication
   4. History of 2nd or 3rd degree atrioventricular conduction defects
10. Resting ECG with QTcF \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
11. Evidence of active bleeding or bleeding diathesis.

    Significant haemorrhage of \>30ml in a single episode within the last 3 months or any haemoptysis (\>5ml fresh blood in last 4 weeks).
12. Malignancy treated within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage 1, grade 1 endometrial carcinoma.
13. Previous treatment with VEGFR tyrosine kinase inhibitors or PARP inhibitors are not permitted.
14. Patients with a known hypersensitivity to excipients of cediranib or olaparib.
15. Persisting ≥ grade 2 CTCAE toxicity (except alopecia and neuropathy) from previous anti-cancer treatment.
16. Major surgery within 14 days before anticipated start of treatment and patients must have recovered from any effects of major surgery.
17. Inability to attend or comply with treatment or follow-up scheduling.
18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicated the use of an investigation drug or puts the patients at high risk for treatment-related complications.
19. Pregnant or breast-feeding women are excluded. Women of childbearing potential will be excluded unless effective methods of contraception are used from signing of the informed consent, throughout the period of taking study treatment and for at least 6 weeks after last dose of trial drug(s).
20. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment (randomisation).
21. 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 or moderate CYP3A inhibitors (e.g. systemic Ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
22. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
23. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
24. Other psychological, psychiatric, 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.
25. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids.
26. Immunocompromised patients e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
27. Patients with symptomatic uncontrolled brain or meningeal metastases. A scan to confirm the absence of brain metastases is not required. The patient 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.
28. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
29. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
C: Inclusion Criteria:

* Female patients ≥18 years of age.
* Patients with histologically confirmed epithelial ovarian or fallopian tube carcinoma or primary peritoneal carcinoma, including mixed Mullerian Tumours
* Recurrence or progression at least 6 months after the last chemotherapy cycle of a first line carboplatin + paclitaxel chemotherapy including bevacizumab (recurrence or progression might occur either during or after bevacizumab as maintenance)
* Patients can be included if they have a RECIST progression, with either measurable or non-measurable disease
* ECOG (Eastern Cooperative Oncology Group Performance) Status of 0-2.
* Life expectancy of at least 12 weeks.
* Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient's awareness and willingness to comply with the study requirements including blood samples for molecular analyses.
* Availability of tumour samples for molecular analyses from primary surgery (mandatory) and secondary surgery (when available)

Exclusion Criteria:

Cancer related

* Ovarian tumours with low malignant potential (i.e. borderline tumours)
* History or evidence of synchronous primary endometrial carcinoma, unless all of the following criteria related to the endometrial carcinoma are met:

  * stage ≤Ia
  * no more than superficial myometrial invasion
  * no lymphovascular invasion
  * not poorly differentiated (grade 3 or papillary serous or clear cell carcinoma).
* Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.

Prior current or planned treatment:

* More than one previous chemotherapy line
* Previous therapy with other anti-angiogenetic agents different from bevacizumab.
* Any prior radiotherapy to the pelvis or abdomen.
* Surgery (including open biopsy) within 4 weeks prior to the first bevacizumab dose.Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (except for line patency, in which case international normalized ratio \[INR\] must be maintained below 1.5). Post operative prophylaxis with low molecular weight heparin sc is allowed.
* Current or recent (within 30 days of first study dosing) treatment with any other investigational drug.

Laboratory:

* Inadequate bone marrow function: ANC (absolute neutrophil count): \<1500/mm3, or platelet count \<100,000/mm3 or Haemoglobin \<9 g/dl. Patients may be transfused to maintain haemoglobin values ≥9 g/dl.
* Inadequate coagulation parameters:

  * activated partial thromboplastin time (APTT) \>1.5 x upper limit of normal (ULN) or
  * INR (international normalized ratio) \>1.5
* Inadequate liver function, defined as:

  * serum (total) bilirubin \>1.5 x ULN for the institution
  * AST/SGOT or ALT/SGPT \> 2.5 x ULN.
* Inadequate renal function, defined as:

  * serum creatinine \>2.0 mg/dl or \>177 micromol/l
  * urine dipstick for proteinuria \>2+. Patients with ≥ 1+ proteinuria at baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection.

Prior or concomitant conditions or procedures:

* History or evidence of brain metastases or spinal cord compression.
* Pregnant or lactating females.
* History or evidence of thrombotic or haemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or sub-arachnoid haemorrhage within ≤6 months prior to the first study treatment).
* Uncontrolled hypertension (sustained systolic \>150 mm Hg and/or diastolic \>100 mm Hg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including:
* myocardial infarction or unstable angina within ≤6 months prior to the first study treatment
* New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF)
* serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia)
* peripheral vascular disease ≥grade 3 (i.e. symptomatic and interfering with activities of daily living requiring repair or revision).
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess, or with signs of impending bowel obstruction within 6 months prior to the first study treatment.
* Non-healing wound, ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require three weekly wound examinations.
* Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
D: Inclusion Criteria:

* Female 18 years of age or older at the time the written informed consent is obtained
* Gynecologic Oncology Group (GOG) Performance Status of 0 or 1
* Life expectancy \>= 3 months (per investigator opinion)
* Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (Subjects with pseudomyxoma , mesothelioma, unknown primary tumor, sarcoma, or neuroendocrine histology, with borderline ovarian cancer, ie, subjects with low malignant potential tumors, and with clear cell or mucinous histology are excluded)
* Subjects must have undergone surgery for ovarian cancer, primary peritoneal cancer, or fallopian tube cancer including at least a unilateral oophorectomy
* Radiologically evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with modifications
* Subjects must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, high-dose therapy, consolidation therapy, bevacizumab or extended therapy administered after surgical or non-surgical assessment.
* Adequate organ and hematological function
* Generally well controlled blood pressure with systolic blood pressure \<= 140 mmHg and diastolic blood pressure \<= 90 mmHg prior to randomization. The use of anti-hypertensive medications to control hypertension is permitted
* Radiographically documented disease progression either on or following the last dose of prior chemotherapy regimen for epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer

Exclusion Criteria:

* Subjects who have received more than 3 previous regimens of anti-cancer therapy for epithelial ovarian, primary peritoneal or fallopian tube cancers
* Subjects who have received paclitaxel as consolidation therapy, maintenance, or monotherapy are excluded
* Subjects with primary platinum-refractory disease
* Subjects with platinum-free interval (PFI) \> 12 months from their last platinum based therapy
* Radiotherapy \<= 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities
* Previous abdominal or pelvic radiotherapy
* History of arterial or venous thromboembolism within 12 months prior to randomization
* History of clinically significant bleeding within 6 months prior to randomization
* History of central nervous system metastasis
* Has not yet completed a 21 day washout period prior to randomization for any previous anti cancer systemic therapies (30 days for prior bevacizumab)
* Enrolled in or has not yet completed at least 30 days (prior to randomization) since ending other investigational device or drug, or currently receiving other investigational treatments
* Unresolved toxicities from prior systemic therapy that are Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 \>= Grade 2 in severity except alopecia
* Known active or ongoing infection (except uncomplicated urinary tract infection \[UTI\]) within 14 days prior to randomization
* Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
* Treatment within 30 days prior to randomization with strong immune modulators including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, and lenalidomide
* Clinically significant cardiovascular disease within 12 months prior to randomization
* Major surgery within 28 days prior to randomization or still recovering from prior surgery
* Minor surgical procedures, except placement of tunneled central venous access device within 3 days prior to randomization. Diagnostic laparoscopy is regarded as a minor surgical procedure.

Answer: B