Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) Versus Pegylated Liposomal Doxorubicin or Topotecan in Patients With Platinum-resistant Ovarian Cancer (CORAIL Trial)
Brief Summary: Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate the activity and safety of PM01183 versus PLD or topotecan as control arm in patients with platinum-resistant ovarian cancer. PM01183 will be explored as single agent in the experimental arm (Arm A) versus PLD or topotecan in the control arm (Arm B).


Options:
A: 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.
B: Inclusion Criteria:

* Age \>/= 18 years
* Confirmed diagnosis of unresectable epithelial ovarian, fallopian tube or primary peritoneal cancer.
* Platinum-resistant disease (PFI: 1-6 months after last platinum-containing chemotherapy).
* Evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria
* No more than three prior systemic chemotherapy regimens
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ECOG PS) ≤ 2
* Adequate hematological, renal, metabolic and hepatic function

Exclusion Criteria:

* Concomitant diseases/conditions: cardiac disease, immunodeficiency, chronic active hepatitis or cirrhosis, uncontrolled infection, bowel obstruction, any other major illness
* Prior treatment with PM01183, trabectedin, or with both PLD and topotecan.
* Requirement of permanent or frequent (i.e., once per week) external drainages within two weeks prior to randomization
C: Inclusion Criteria:

* Histological diagnosed with epithelial ovarian carcinoma with measurable disease
* Recurrent epithelial ovarian carcinoma or disease progression following failure of first-line, platinum-based chemotherapy with no more than one prior platinum based regimen therapy
* Adequate laboratory values of bone marrow function, renal function, liver function, and echocardiogram tests
* Agrees to use protocol-defined effective contraception. A woman must agree not to donate eggs (ova, oocytes) for the purpose of assisted reproduction
* Disease-free from prior malignancies for more than 5 years with the exception of curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

Exclusion Criteria:

* Females who are pregnant or breast feeding or planning to become pregnant while enrolled in this study or within 1 year after the last dose of study medication
* Myocardial infarct within 6 months before enrollment, class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
* Uncontrolled systemic infection that requires systemic anti-infective treatment
* Prior therapy with CAELYX or topotecan HCl
* Prior chemotherapy within 28 days of first dose of study medication (or 42 days if participant has received a nitrosourea or mitomycin)
D: Inclusion Criteria:

* 18 years of age or older
* Confirmed diagnosis of ovarian, fallopian or peritoneal cancer
* No more than three chemotherapy regimens
* Most recent regimen must have been platinum based

Exclusion Criteria:

* Have an unresolved bowel obstruction
* Have had previous chemotherapy within 3 weeks
* Recovering from any surgery for any cause

Other protocol-defined inclusion/exclusion criteria will apply.

Answer: B