Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Open-Label Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)
Brief Summary: The purpose of this study is to determine which patients with ovarian, fallopian tube, and primary peritoneal cancer will best respond to treatment with rucaparib.


Options:
A: Inclusion Criteria:

* Patients must be ≥ 18 years of age
* Patients with histologically diagnosed relapsed high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease \>6 months (\>/=183 days) after completion of their last platinum therapy.
* Documented germline mutation in Breast Cancer susceptibility genes: BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
* At least one lesion that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment.
* Patients must have received at least 2 prior platinum based lines of chemotherapy - Patients must be partially platinum sensitive or platinum sensitive
* Patients must be suitable to start treatment with single agent chemotherapy based on physician's choice
* Patients must have normal organ and bone marrow function measured within 28 days of randomisation,
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Patients must have a life expectancy ≥ 16 weeks
* Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing.

Exclusion Criteria:

* BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental
* Exposure to any investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation
* Any previous treatment with a Polyadenosine 5'diphosphoribose polymerisation (PARP) inhibitor, including olaparib.
* Patients who have platinum resistant or refractory disease
* Patients receiving any systemic chemotherapy within 3 weeks prior to first dose of study treatment
* Previous single agent exposure to the selected chemotherapy regimen for randomisation. - Prior malignancy in the last 5 years, unless curatively treated and recurrence free (few exceptions apply).
B: Inclusion Criteria:

1. Female patients, age ≥ 16 years with relapsed epithelial ovarian, primary peritoneal or fallopian tube cancer who have relapsed within 12 months of previous platinum-based therapy. Their most recent chemotherapy does not have to have been platinum-based.
2. Patients can have received prior PARP inhibitor, but there must be a \> 6 month interval since treatment.
3. Patients can have received prior antiangiogenic therapy, but there must be a \> 6 month interval since treatment; except for bevacizumab where a 6 week interval is required.
4. Measurable disease by RECIST Version 1.1 performed in past 4 weeks. At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
5. Sufficient archival tissue confirming histological diagnosis available.
6. ECOG PS 0-2
7. Able to swallow and retain oral medications.
8. Life expectancy \> 12 weeks in terms of disease related mortality
9. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
10. Written (signed and dated) informed consent prior to any study specific procedures and be capable of co-operating with protocol.
11. Patients must have

    • Haemoglobin ≥ 9.0 g/dL and no blood transfusions in the 28 days prior to randomisation
12. Patients must have normal organ and bone marrow function measured within 14 days prior to administration of study treatment as defined below:

    * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    * Platelet count \> 100 x 109/L
    * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
    * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN
    * Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or calculated creatinine clearance \>50 ml/min calculated using Cockroft-Gault, Jelliffe or Wright (see Appendix 4)
    * 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.

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.
C: Inclusion Criteria:

* Histologically confirmed high grade serous and/or undifferentiated carcinoma of ovary, fallopian tube or peritoneum
* Oestrogen, progesterone and HER2 negative advanced adenocarcinoma of the breast
* Known BRCA positive breast cancer or ovarian cancer, that is not high grade serous or undifferentiated tubo-ovarian carcinoma.
* Performance status of no more than 2.

Exclusion Criteria:

* Any chemotherapy, radiotherapy ( except palliative), endocrine or immunotherapy within 4 weeks prior to entry
* Major surgery with 4 weeks of entering the study and must have recovered from effects of any major surgery .
D: The following eligibility criteria pertain to patients enrolling into PART 2 of the study:

Inclusion:

* Have a histologically confirmed diagnosis of high grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
* Received at least 3 prior chemotherapy regimens. Non-chemotherapy regimens and maintenance therapies administered as single agent treatment will not count as a chemotherapy regimen
* Relapsed/progressive disease as confirmed by CT scan
* Have biopsiable and measurable disease. Note: biopsy is optional for patients known to harbor a deleterious gBRCA mutation
* Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue available for planned analyses

Exclusion:

* History of prior cancers except for those that have been curatively treated, with no evidence of cancer currently (provided all chemotherapy was completed \>6 months prior and/or bone marrow transplant \>2 years prior to first dose of rucaparib).
* Prior treatment with any PARP inhibitor
* Symptomatic and/or untreated central nervous system metastases
* Pre-existing duodenal stent and/or any other gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
* Hospitalization for bowel obstruction within 3 months prior to enrollment

Answer: D