Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicenter Phase III Randomized Study With Second Line Chemotherapy Plus or Minus Bevacizumab in Patients With Platinum Sensitive Epithelial Ovarian Cancer Recurrence After a Bevacizumab/Chemotherapy First Line
Brief Summary: Bevacizumab has been found to prolong progression free survival in first line, and more recently, in second line treatment for platinum sensitive ovarian cancer patients who had not received prior treatment with bevacizumab.

Recently reported data suggest that patients with colon cancer who receive bevacizumab in more than one line of therapy (beyond progression) have better results. In ovarian cancer, the role of bevacizumab administered in both first and second-line therapies needs to be defined.

This study aims to evaluate whether administering bevacizumab in combination with chemotherapy in second-line therapy to patients with recurrent ovarian cancer who have received first-line bevacizumab will be more effective than chemotherapy alone.


Options:
A: Inclusion Criteria:

* Advanced, progressive, recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma, which has recurred following at least one platinum-containing regimen.
* Progressive disease according to RECIST 1.1 or GCIG criteria within 3-12 months of completing platinum containing therapy, although this need not be the immediately preceding regimen.
* World Health Organisation (WHO) performance status of 0 or 1 (Appendix 1).
* Measurable disease (RECIST 1.1 (Appendix 2) or Progressive Disease (PD) according to CA125 GCIG criteria with non-measurable disease on CT scan.
* Life expectancy of at least 12 weeks.
* Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient receives the first dose of Investigational Medicinal Product (IMP):

  * Haemoglobin (Hb) ≥ 90 g/L
  * Absolute neutrophil count ≥ 1.5 x 109/L
  * Platelet count ≥ 100 x 109/L
  * Serum potassium within normal range
  * Bilirubin ≤ 1.5 x upper limit of normal (ULN)
  * Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 2.5 x ULN unless raised due to hepatic metastatic disease in which case up to 5 x ULN is permissible
  * Either: Calculated creatinine clearance ≥ 40 mL/min (uncorrected value) Or: Isotope clearance measurement ≥ 40 mL/min (corrected)
  * Activated partial thromboplastin time (aPTT) ≤ 1.2 x ULN
  * Prothrombin Time (PT) or International normalised ratio (INR) ≤ 1.3 x ULN
  * Urine protein dipstick of less than or equal to 2+, or if 2+ or greater the patient must have a 24 hour urinary protein value of less than 2 g.
  * Clinically euthyroid.
  * Aged 18 years or over at the time of consent.
  * Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up.
  * Patients can have received bevacizumab prior to trial entry providing that the last dose was administered at least 6 months before the first dose of IMP.

Exclusion Criteria:

* Radiotherapy, surgery or tumour embolisation within 28 days before the first dose of IMP
* Endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and six weeks for investigational medicinal products) before the first dose of IMP.
* Ongoing grade ≥ 2 toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Chief and Principal Investigators should not exclude the patient; and grade 1 or 2 neurotoxicity considered to be due to paclitaxel.
* Female patients who are able to become pregnant (or are already pregnant or lactating). Those who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
* Major thoracic or abdominal surgery from which the patient has not yet recovered.
* At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
* Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
* History of any of the following cardiovascular conditions within the last six months:

  * Coronary revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG))
  * Acute coronary syndrome (myocardial infarction (MI), unstable angina)
  * Symptomatic peripheral vascular disease
  * Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (Appendix 4)
* Patients who have sustained hypertension, defined as a systolic blood pressure (SBP) of \> 140 mm Hg or diastolic blood pressure (DBP) of \> 90 mm Hg, on three occasions.
* ECG with evidence of clinically significant abnormalities.
* Patients with a QTc\> 480ms or taking any drug known to prolong the QTc interval that cannot be stopped for the duration of the trial (Appendix 4).
* Patients with pathologic bradycardia (\<60 b/m in non-athletes), heart block (excluding first-degree block, being PR interval prolongation only).
* History of cerebrovascular accident (including transient ischaemic attack (TIA)), pulmonary embolism or untreated deep vein thrombosis (DVT) within the past six months. Patients with recent DVT or pulmonary embolism who have been treated with therapeutic anti-coagulant agents for at least six weeks will be eligible, provided their INR (if taking oral anti-coagulants) has been stable for this period of time.
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously treated CNS metastases, are asymptomatic and have had no requirement for steroids or anti-convulsant medication for six months prior to the first dose of IMP.
* Clinically significant abnormalities that may increase the risk of gastrointestinal bleeding or perforation, including but not limited to:

  * Bleeding: Active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, Inflammatory bowel disease (Crohn's disease, ulcerative colitis);
  * Perforation: History of abdominal fistula or large pelvic mass; gastrointestinal perforation or intra-abdominal abscess within four weeks prior to first dose of IMP; previous bowel surgery which is judged by the investigator to increase significantly the risk of gastrointestinal complications from trial treatment
* Evidence of active bleeding or bleeding diathesis.
* Transfusion within one week prior to first dose of IMP.
* Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.
* Clinically significant haemoptysis, within eight weeks before the first dose of IMP.
* Previous treatment with pazopanib.
* Any participant that is participating in (or plans to participate in) another interventional clinical trial, whilst taking part in this Phase Ib/II study of fosbretabulin and pazopanib. Participation in an observational trial would be acceptable.
* Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
* Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy for at least 2 years.
* Hypersensitivity to Pazopanib or any of it's excipients
B: Inclusion Criteria:

* Patients with a histologic diagnosis of epithelial ovarian cancer, peritoneal primary carcinoma or fallopian tube cancer; International Federation of Gynecology and Obstetrics (FIGO) stage III with any gross (macroscopic or palpable) residual disease or FIGO stage IV, defined surgically at the completion of initial abdominal surgery and with appropriate tissue available for histologic evaluation; the minimum surgery required was an abdominal surgery providing tissue for histologic evaluation and establishing and documenting the primary site and stage, as well as a maximal effort at tumor debulking; if additional surgery was performed, it should have been in accordance with appropriate surgery for ovarian or peritoneal carcinoma described in the Gynecologic Oncology Group (GOG) Surgical Procedures Manual; however, the surgeon is not required to have performed all of the items contained in this section of the GOG Surgical Procedures Manual; those patients with stage III cancer in which the largest maximal diameter of any residual tumor implant at the completion of this initial surgery is no greater than 1 cm will be defined as "optimal;" all others will be defined as "suboptimal;" measurable disease on post-operative imaging studies is not required for eligibility
* Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S.); however, the histologic features of the tumor must be compatible with a primary Müllerian epithelial adenocarcinoma; if doubt exists, it is recommended that the investigator should have the slides reviewed by an independent pathologist or, if necessary, the Pathology Co-Chair, prior to entry; patients may have co-existing fallopian tube carcinoma in-situ so long as the primary origin of invasive tumor is ovarian, peritoneal or fallopian tube
* Absolute neutrophil count (ANC) greater than or equal to 1,500/µl equivalent to Common Toxicity Criteria for Adverse Events version (v)3.0 (CTCAE) grade 1; this ANC cannot have been induced or supported by granulocyte colony stimulating factors
* Platelets greater than or equal to 100,000/µl; (CTCAE grade 0-1)
* Creatinine =\< 1.5 x institutional upper limit normal (ULN), CTCAE grade 1
* Bilirubin less than or equal to 1.5 x ULN (CTCAE grade 1)
* Serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE grade 1)
* Neuropathy (sensory and motor) less than or equal to CTCAE grade 1
* Prothrombin time (PT) such that international normalized ratio (INR) is =\< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thrombo-embolus) and a partial thromboplastin time (PTT) \< 1.2 times the upper limit of normal
* Patients with a GOG Performance Status of 0, 1, or 2
* Patients must be entered between 1 and 12 weeks after initial surgery performed for the combined purpose of diagnosis, staging and cytoreduction
* Patients with measurable and non-measurable disease are eligible; patients may or may not have cancer-related symptoms
* Patients who have met the pre-entry requirements
* An approved informed consent and authorization permitting release of personal health information must be signed by the patient or guardian
* Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but not progestins for management of anorexia while on protocol directed therapy or prior to disease progression

Exclusion Criteria:

* Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly "tumors of low malignant potential") or recurrent invasive epithelial ovarian, primary peritoneal or fallopian tube cancer treated with surgery only (such as patients with stage Ia or Ib low grade epithelial ovarian or fallopian tube cancers) are not eligible; patients with a prior diagnosis of a borderline tumor that was surgically resected and who subsequently develop an unrelated, new invasive epithelial ovarian, peritoneal primary or fallopian tube cancer are eligible, provided that they have not received prior chemotherapy for any ovarian tumor
* Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
* Patients who have received prior chemotherapy for any abdominal or pelvic tumor including neo-adjuvant chemotherapy for their ovarian, primary peritoneal or fallopian tube cancer are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
* Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer
* Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: stage not greater than I-B; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO grade 3 lesions
* With the exception of non-melanoma skin cancer and other specific malignancies as noted above, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last five years or whose previous cancer treatment contraindicates this protocol therapy are excluded
* Patients with acute hepatitis or active infection that requires parenteral antibiotics
* Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days; patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations
* Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
* Patients with history or evidence upon physical examination of central nervous system (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
* Patients with clinically significant cardiovascular disease; this includes:
* Uncontrolled hypertension, defined as systolic \> 150 mm Hg or diastolic \> 90 mm Hg
* Myocardial infarction or unstable angina \< 6 months prior to registration
* New York Heart Association (NYHA) grade II or greater congestive heart failure
* Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate
* CTCAE grade 2 or greater peripheral vascular disease (at least brief (\< 24 hrs) episodes of ischemia managed non-surgically and without permanent deficit)
* History of CVA within six months
* Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
* Patients with clinically significant proteinuria; urine protein should be screened by urine protein-creatinine ratio (UPCR); the UPCR has been found to correlate directly with the amount of protein excreted in a 24 hour urine collection; specifically, a UPCR of 1.0 is equivalent to 1.0 gram of protein in a 24 hour urine collection; obtain at least 4 ml of a random urine sample in a sterile container (does not have to be a 24 hour urine); send sample to lab with request for urine protein and creatinine levels \[separate requests\]; the lab will measure protein concentration (mg/dL) and creatinine concentration (mg/dL); the UPCR is derived as follows: protein concentration (mg/dL)/creatinine (mg/dL); patients must have a UPCR \< 1.0 to allow participation in the study
* Patients with or with anticipation of invasive procedures as defined below:
* Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the first date of bevacizumab/placebo therapy (cycle 2)
* Major surgical procedure anticipated during the course of the study; this includes, but is not limited to abdominal surgery (laparotomy or laparoscopy) prior to disease progression, such as colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second look surgery; please consult with the study chair prior to patient entry for any questions related to the classification of surgical procedures
* Core biopsy, within 7 days prior to the first date of bevacizumab/placebo therapy (cycle 2)
* Patients with GOG Performance Grade of 3 or 4
* Patients who are pregnant or nursing; bevacizumab should not be administered to nursing women; patients of childbearing potential must agree to use contraceptive measures during study therapy and for at least six months after completion of bevacizumab therapy
* Patients who have received prior therapy with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab
* Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration and/or nutrition
* Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; the investigator should feel free to consult the study chair or study co-chairs for uncertainty in this regard
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:

* 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: C