Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Placebo Controlled, Multicenter Phase II Study to Assess the Efficacy and Safety of Sorafenib Added to Standard Treatment With Topotecan in Patients With Platinum-resistant Recurrent Ovarian Cancer
Brief Summary: It is assumed, that the patients of the standard arm show a median progression-free survival time of 4.4 months those of the experimental arm of at least 6.9 months. Assuming a recruitment period of 18 months and follow-up for at least 12 months a total sample size of 174 patients is required (two-sided, α=0.05, 80% power). To account for 5% drop-outs 184 patients will be randomized.

A Data Monitoring and Safety Board (DMSB) will be established. This board will evaluate the safety profile of the drug combination after 6 patients and after 12 patients have received 1 cycle of treatment.


Options:
A: Inclusion Criteria:

1. Patients with histologically confirmed epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer
2. Patients must have platinum resistant (relapse-free interval \< 6 months of a platinum-containing primary or secondary therapy) or platinum refractory (progression during primary or secondary platinum treatment) disease defined by measurable disease according to RECIST or elevated CA-125 level according the GCIG-criteria.

   Definition of relapse: Demonstration of measurable or non-measurable tumour according to RECIST criteria by an imaging procedure (where applicable before relapse surgery) or increase in the tumour marker CA-125 to twice the upper laboratory value of normal for the hospital or histological confirmation of tumour relapse by biopsy or surgery.
3. No more than 2 prior treatment regimens for recurrent epithelial ovarian cancer.
4. Elevated CA-125-value before study entry in order to assess the response according the GCIG-criteria (see below). Patients without elevated CA-125 may be enrolled if they show a measurable or not-measurable disease (according RECIST) evaluated by imaging techniques (measurable disease - at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan) or histologically or cytologically confirmed relapse
5. ECOG Performance Status of 0 or 1
6. ≥ 18 years age
7. The patient must be recovered from a prior operation. The operation must be performed at least 4 weeks prior to start of study drug,
8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening

   * Hemoglobin ≥ 9.0 g/dl
   * Leucocyte count ≥ 3.000/micro liter
   * Absolute neutrophil count (ANC) major than 1.500/micro liter
   * Platelet count ≥ 100.000/micro liter
   * PT-INR/PTT \< 1.5 x upper limit of normal \[Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists\].
   * Total bilirubin \< 1,0 times the upper limit of normal
   * ALT and AST \< 2,5 x upper limit of normal (\< 5 x upper limit of normal for patients with liver involvement of their cancer); Alkaline phosphatase \< 4 x ULN
   * Calculated creatinine clearance ≥ 50 ml/min or serum creatinine ≤ 1,2 x upper limit of institutional values (according to Cockcroft and Gault)
9. Life expectancy of at least 12 weeks
10. Signed and dated written informed consent before the start of specific protocol procedures.

Exclusion Criteria:

1. History of cardiac disease: congestive heart failure \>NYHA class 2; active coronary artery disease (CAD) or myocardial infarction within the past 6 months (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled arterial hypertension with systolic blood pressure \>160 mmHg or diastolic blood pressure \> 90 mm Hg despite optimal treatment
2. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors \[Ta, Tis \& T1\] or any cancer curatively treated \> 5 years prior to study entry
3. Prior radiological or clinical evidence of CNS metastases including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by head CT scan or MRI
4. Known or suspected hypersensitivity reaction to topotecan or any ingredient of topotecan or sorafenib or any ingredient of sorafenib
5. Active clinically serious infections (\> grade 2 NCI-CTC version 3.0)
6. History of HIV infection or chronic hepatitis B or C
7. History of organ allograft
8. Patients with history of colon perforation
9. Patients with history of colitis or neutropenia colitis
10. Patients with evidence or history of bleeding diathesis
11. Serious non healing wound, fracture or ulcer
12. Patients undergoing renal dialysis
13. Patients unable to swallow oral medications
14. Significant disease which, in the investigator's opinion, would exclude the patient from the study
15. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
16. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
17. Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
18. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
19. Legal incapacity or limited legal capacity
20. Participation in another clinical study with experimental therapy within the 30 days before start of treatment
21. Subjects housed in an institution on official or legal orders.

    Excluded therapies and medications, previous and concomitant:
22. Patients with prior therapy containing topotecan
23. Patients with prior therapy containing Avastin or other VEGFR TK1
24. Any other anticancer chemotherapy or immunotherapy or investigational drug therapy outside of this trial during the study or within 4 weeks prior to study entry.
25. Radiotherapy during study or within 4 weeks prior to start of study drug and prior radiotherapy of \> 25% of the bone marrow (exception: palliative radiotherapy of non-target lesions or pain therapy or local bone irradiation)
26. Autologous bone marrow transplant or stem cell rescue within 4 months of study
B: Inclusion criteria

1. Patients were diagnosed with ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by previous pathology, and the pathological type was non-mucinous adenocarcinoma.There were previous surgical wax preservation.
2. Initial platinum-resistant relapse, the recurrence time was less than 6 months after the last chemotherapy.
3. Complicated with malignant pleural effusion or ascites, or with recurrent lesions that can be evaluated clinically.
4. ECOG physical status score 0 or 1.
5. The expected survival time is ≥ 4 months.
6. In the previous treatment, there was no antivascular targeted therapy;
7. Patients without pleural effusion or ascites should be confirmed by CT or MRI according to the standard of RECIST1.1 version, requiring the patient to have at least one measurable focus as the target focus. If the target focus is a lymph node with a short diameter of more than 1.5 cm, and the target focus is not suitable for surgical treatment, the target focus has not received radiotherapy or relapsed in the radiotherapy field.
8. The baseline blood routine conforms to the following criteria:

   1. neutrophil count ≥ 1.5x109 /L;
   2. platelet count ≥ 100x109 PG L;
   3. hemoglobin ≥ 9g/dL (blood transfusion is allowed to achieve or maintain this target) .
9. Liver function meets the following criteria:

   1. total bilirubin\<1.5 normal limit (ULN);
   2. glutamic oxaloacetic transaminase (AST), glutamic pyruvic transaminase (ALT)\<2.5xULN, which is allowed\<5xULN in patients with liver metastasis.
10. Serum creatinine ≤ 1.25xULN or calculated creatinine clearance ≥ 50mL/min.

Exclusion criteria

1. Have received more than two chemotherapy regimens in the past.
2. Currently or recently (within 30 days before enrollment) using another research drug or participating in another clinical study.
3. other malignant tumors have occurred within 5 years (except adequately treated cervical carcinoma in situ or skin squamous cell carcinoma, or controlled basal cell carcinoma of the skin).
4. Patients with hypertension that cannot be reduced to normal range after antihypertensive treatment (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90 mmHg).
5. Suffer from myocardial ischemia or myocardial infarction above II grade and poorly controlled arrhythmias (including QTc interval ≥ 470ms in females).
6. According to the NYHA standard, there were previous or present cardiac insufficiency of grade II or above, or color Doppler echocardiography showed that the left ventricular ejection fraction ((LVEF)) was less than 50% or the lower limit of the normal value.
7. Abnormal coagulation function (INR\>1.5 or prothrombin time (PT) \> ULN+4 seconds or APTT\>1.5xULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy.
8. There were significant clinical bleeding symptoms or definite bleeding tendency in the first 3 months, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood or above, or suffering from vasculitis.
9. Major surgical operations or severe traumatic injuries, fractures or ulcers occurred within the first 4 weeks of randomization.
10. There are significant factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction.
11. Urine routine indicates urinary protein ≥++, or confirms 24-hour urinary protein ≥ 1.0g.
12. The researchers judged other conditions that may affect the conduct of clinical studies and the determination of research results.
13. Allergic or heterogeneous reactions to doxorubicin and / or related substances.
14. The cumulative dose of doxorubicin (including previous anthracycline, if any) is expected to reach or exceed 550 mg after 4 courses of doxorubicin liposome injection treatment.
15. Uncontrollable arrhythmias or electrocardiograms abnormalities determined by the lead researcher to be at risk.
16. A history of doxorubicin liposome therapy in recent half a year.
17. Have previously received local radiotherapy of the pelvis or lower abdomen.
C: Inclusion Criteria:

* Confirmed diagnosis of high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer.
* Received ≥2 prior platinum-based treatment regimens including platinum based regimen that must have been administered immediately prior to maintenance therapy in this trial.
* Received no more than 1 non-platinum chemotherapy regimen. Prior hormonal therapy will not be counted as a non-platinum regimen.
* Must have had at least a 6-month disease-free period following prior treatment with the penultimate platinum-based chemotherapy and achieved a response.
* For the last chemotherapy course prior to study entry, patients must have received a platinum-based doublet chemotherapy regimen and have achieved a CR or PR (as defined by RECIST) and/or a GCIG CA-125 response.
* Have sufficient archival tumor tissue for analysis.

Exclusion Criteria:

* History of prior cancer except for non-melanoma skin cancer, breast cancer curatively \> 3 years ago, curatively treated solid tumor (\>5 years ago without evidence of recurrence), and synchronous endometrial cancer (Stage 1A) with ovarian cancer.
* Prior treatment with any PARP inhibitor, including rucaparib. Patients who received prior iniparib are eligible.
* Untreated or symptomatic central nervous system metastases.
* Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of study drug.
* Required drainage of ascites during the final 2 cycles of their last platinum-based regimen and/or during the period between the last dose of chemotherapy of that regimen and randomization to maintenance treatment in this study.
D: Inclusion Criteria:

* Signed Informed Consent Form
* Age ≥ 18 years
* Documented ovarian, primary peritoneal, or fallopian tube carcinoma that has recurred
* No prior chemotherapy in the recurrent setting
* Measurable disease
* Recovered from prior radiation therapy or surgery

Exclusion Criteria:

* Prior chemotherapy treatment for recurrent ovarian, primary peritoneal, or fallopian tube carcinoma
* History of abdominal fistula, gastrointestinal perforation (GIP), or intra-abdominal abscess
* Patients with clinical symptoms or signs of gastrointestinal (GI) obstruction or who require parenteral hydration, parenteral nutrition, or tube feeding
* Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure
* Current, recent, or planned participation in an experimental drug study
* History of systemic bevacizumab (Avastin) or other vascular endothelial growth factor (VEGF) or VEGF receptor-targeted agent use
* Inadequately controlled hypertension
* Prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association Class II or greater congestive heart failure (CHF)
* History of myocardial infarction or unstable angina
* History of stroke or transient ischemic attack (TIA)
* Known central nervous system (CNS) disease except for treated brain metastasis
* Significant vascular disease or recent peripheral arterial thrombosis
* History of hemoptysis
* Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

Answer: A