Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Open Label, Phase II Trial of Bevacizumab Plus Weekly Paclitaxel Followed by Bevacizumab Monotherapy Maintenance Versus Weekly Paclitaxel Followed by Observation in Patients With Relapsed Ovarian Sex-cord Stromal Tumours
Brief Summary: Bevacizumab (called also Avastin ®) is a medicine preventing the creation of new blood vessels (a process called "angiogenesis"). This can reduce blood flow of the tumor and then decreasing the contribution of nutriments and oxygen to the cancer cells and prevent the tumor from growing.

In various types of cancers, as lung, breast, colorectal and renal cancer, addition of the bevacizumab to chemotherapy allowed to improve the disease outcome. The bevacizumab already benefits from a marketing authorization (MMA) for these various types of cancers.

The bevacizumab has also obtained MMA for the treatment of the ovarian cancer in its most frequent histological form (ovarian carcinoma). Clinical trials conducted in this indication demonstrated the importance to pursue the treatment by bevacizumab after the chemotherapy is ended.

This anti-angiogenic medicine is thought to be of a potential interest in sex cords- stromal since this tumors are very well vascularized.

The ALIENOR study aims to explore the interest and the clinical benefit of associating bevacizumab to the paclitaxel in order to treat patients suffering from recurring sex cords- stromal tumor treated beforehand by platinum chemotherapy


Options:
A: Inclusion Criteria:

1. Histologic diagnosis of International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, with the appropriate tissue available for histologic evaluation.
2. High-grade serous adenocarcinoma
3. Willing to undergo testing for gBRCA.
4. Adequate hematologic, renal, and hepatic function.
5. Neuropathy (sensory and motor) less than or equal to Grade 1.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. Participants who undergo primary cytoreductive surgery must be entered between 1 and 12 weeks after surgery. Participants undergoing interval surgery must have a tumor sample confirming the histological diagnosis prior to enrollment.
8. Participants with measurable disease or non-measurable disease are eligible. Participants may or may not have cancer-related symptoms.
9. Participant has one of the following available for pharmacodynamic analyses including somatic BRCA testing: Archived diagnostic formalin-fixed paraffin embedded (FFPE) tumor tissue; or tumor tissue biopsy collected prior to Cycle 1 Day 1.

Exclusion Criteria:

1. Endometrioid adenocarcinoma, carcinosarcoma, undifferentiated carcinoma, mixed epithelial adenocarcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, clear cell adenocarcinoma, low-grade serous adenocarcinoma, or malignant Brenner's tumor.
2. Participants with synchronous primary endometrial cancer, or a past history of endometrial cancer unless all of the following conditions are met: endometrial cancer stage not greater than IA, no vascular or lymphatic invasion, no poorly differentiated subtypes including serous, clear cell, or other FIGO grade 3 lesions.
3. Participants with any evidence of other invasive malignancy being present within the last 3 years (with the exception of non-melanoma skin cancer). Participants are also excluded if their previous cancer treatment contraindicates this protocol's therapy.
4. Received prior radiotherapy to any portion of the abdominal cavity or pelvis.
5. Received prior chemotherapy for any abdominal or pelvic tumor.
6. Clinically significant uncontrolled condition(s).
7. Known history of allergic reaction to Cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine (also known as FD\&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD\&C Yellow 6 or E110) or known contraindications to any study supplied drug.
8. History or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months of Cycle 1 Day 1.
B: Inclusion Criteria:

* Diagnosis of ovarian epithelial, primary peritoneal, or fallopian tube cancer
* Recurrent disease
* Must have received a prior platinum-based regimen
* Platinum-sensitive (treatment-free interval \> 6 months)
* No more than 2 prior chemotherapy regimens
* Measurable disease
* At least 1 unidimensionally measurable lesion \>= 20 mm by conventional techniques OR \>= 10 mm by spiral CT scan
* Not in a prior irradiation field
* No known brain metastases
* Performance status:

  * ECOG 0-2 OR
  * Karnofsky 80-100%
* Life expectancy:

  * More than 12 weeks
* Hematopoietic:

  * Absolute neutrophil count \>= 1,500/mm3
  * Platelet count \>= 100,000/mm3
  * Hemoglobin \>= 9 g/dL
  * No bleeding diathesis
* Hepatic:

  * Bilirubin \< 1.5 times upper limit of normal (ULN)
  * AST or ALT =\< 2 times ULN
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to sorafenib or other agents used in the study
* Patients who have had a reaction to a taxane or a platinum and have not yet been rechallenged may undergo a desensitization regimen on study
* No hypersensitivity to paclitaxel or drugs using the vehicle Cremophor El:
* Prior hypersensitivity reaction to paclitaxel allowed provided rechallenged successfully
* Renal:

  * Creatinine \< 2 mg/dL
* Cardiovascular:

  * Abnormal cardiac conduction (e.g., bundle branch block or heart block) allowed if stable for the past 6 months
  * No symptomatic congestive heart failure
  * No uncontrolled hypertension
  * No cardiac arrhythmia
  * No unstable angina pectoris;
  * No myocardial infarction within the past 6 months
* Negative pregnancy test
* Fertile patients must use effective contraception
* Adequate intestinal function
* No concurrent requirements for IV hydration or nutritional support
* No active or ongoing infection
* No psychiatric illness or social situation that would preclude study compliance
* No other concurrent uncontrolled illness
* No other invasive malignancy with the past 5 years except nonmelanoma skin cancer
* More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
* More than 3 weeks since prior hormonal therapy
* More than 4 weeks since prior radiotherapy and recovered
* No prior sorafenib
* No prior anticancer therapy that contraindicates study therapy
* No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort)
* No concurrent combination antiretroviral therapy for HIV-positive patients
* No concurrent therapeutic anticoagulation therapy
* Concurrent prophylactic low-dose warfarin allowed for maintenance of venous or arterial access devices
* No other concurrent anticancer therapies
* No other concurrent investigational agents
* Not pregnant or nursing
C: Inclusion Criteria:

* Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report
* Patients must have measurable disease or detectable (non-measurable) disease:

  * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI
  * Detectable disease in a patient is defined as one who does not have measurable disease but has at least one of the following conditions:

    * Baseline values of CA-125 at least 2 x upper limit of normal (ULN)
    * Ascites and/or pleural effusion attributed to tumor
    * Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
* Patients in the measurable disease cohort must have at least one ?target lesion? to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as ?non-target? lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
* Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG phase III protocol or Rare Tumor Protocol for the same patient population
* Patients who have had one prior treatment must have a GOG performance status of 0, 1, or 2; patients who have had two or three prior treatments must have a GOG performance status of 0 or 1
* Patients should be free of active infection requiring parenteral antibiotics (with the exception of uncomplicated urinary tract infection \[UTI\])
* Recovery from effects of recent surgery, radiotherapy, or chemotherapy

  * Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration
  * Any other prior therapy directed at the malignant tumor, including biological and immunologic agents, must be discontinued at least 3 weeks prior to registration (including small molecules and murine monoclonal antibodies); chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor (VEGF) receptor fusion protein (including VEGF Trap, aflibercept) must be discontinued for at least 12 weeks prior to registration; no investigational therapy within 30 days prior to the first date of study treatment
* Prior therapy:

  * Patients 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, 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, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen
  * Patients are allowed to receive, but are not required to receive, biologic (non-cytotoxic) therapy as part of their primary treatment regimen; patients must have NOT received any non-cytotoxic therapy for management of recurrent or persistent disease
  * Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy
  * For the purposes of this study, poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitors will be considered ?cytotoxic,? and prior treatment with PARP inhibitors for primary or recurrent disease WILL be allowed (either alone or in combination with chemotherapy)
* Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
* Platelets greater than or equal to 100,000/mcl
* Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)
* Bilirubin less than or equal to 1.5 x ULN
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) less than or equal to 3 x ULN
* Alkaline phosphatase less than or equal to 2.5 x ULN
* Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of deep vein thrombosis including pulmonary embolism)
* Partial thromboplastin time (PTT) less than or equal to 1.5 times the upper limit of normal
* Fasting serum cholesterol less than or equal to 300 mg/dL OR less than or equal to 7.75 mmol/L AND
* Fasting triglycerides less than or equal to 300 mg/dL or 3.42 mmol/L
* Urine protein creatinine (UPC) ratio must be \< 1.0 gm; if UPC ratio \>= 1, collection of 24-hour urine measurement of urine protein is recommended; UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion?a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
* Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception
* Patients must have signed an approved informed consent and authorization permitting the release of personal health information
* Patients must meet pre-entry requirements
* 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 within 6 months prior to registration
  * New York Heart Association (NYHA) class II or greater congestive heart failure
  * Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate
  * Patients who have received prior treatment with an anthracycline (including doxorubicin and or liposomal doxorubicin) and have an ejection fraction \< 50%
  * Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater peripheral vascular disease (at least brief \[\< 24 hours (hrs)\] episodes of ischemia managed non-surgically and without permanent deficit)

Exclusion Criteria:

* Patients who have received prior everolimus or any other mammalian target of rapamycin (mTOR) inhibitor
* Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies, are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
* Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years 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 OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years 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 the patient remains free of recurrent or metastatic disease
* 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 prior to the first date of study treatment
* 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 prior to the first date of study treatment
* Known hypersensitivity to murine or chimeric antibodies
* Major surgery within 28 days prior to the first date of study treatment
* Patients with clinical symptoms or signs of gastrointestinal obstruction and patients 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 can consult the Study Chair or Study Co-Chairs for uncertainty in this regard
* Patients who are pregnant or nursing
* Patients with active hepatitis B or C

  * Laboratory confirmation to exclude hepatitis B and C is required in any patient considered at high risk for hepatitis B or C; risk factors can include:

    * You currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece
    * Known or suspected past hepatitis B infection
    * Known or suspected past hepatitis C infection (including past interferon ?curative? treatment)
    * Blood transfusion(s) prior to 1990
    * Current or prior IV drug use
    * Current or prior dialysis
    * Household contact with hepatitis B or hepatitis C infected person(s)
    * Current or prior high-risk sexual activity
    * Body piercing or tattoos
    * Mother known to have hepatitis B
    * History suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain
D: Inclusion Criteria:

* Female aged ≥ 18 years at inclusion
* Histologically confirmed diagnosis of ovarian Sex cord-stromal tumors including the following cell types: granulosa cell tumours (adults and juveniles types), granulosa cell-theca cell tumour, Sertoli-Leydig cell tumours, malignant steroid cell tumours, gynandroblastoma, unclassified SCST and mixed tumours
* Documented relapse of SCST defined by progression of disease (radiologic, clinic or biological progression)
* At least one measurable site of disease as defined by RECIST 1.1

  * Tumours within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence \> 90 days following completion of radiotherapy.
* Patients must have been pre-treated with at least 1 prior line of platinum-based chemotherapy
* Adequate bone marrow, liver and renal functions including the following:

  * Absolute neutrophil count ≥ 1.5 G/L, platelet count ≥ 100 G/L, and hemoglobin ≥ 9 g/dL. Prior transfusion is authorized to keep haemoglobin level to ≥9g/dL
  * AST/ALT ≤ 3 x upper limit of normal (ULN) (or ≤ 5.0 ULN if liver metastasis) and total bilirubin ≤ 1.5 ULN
  * Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥ 50 mL/min according to Cockcroft formula (or to MDRD formula for patients older than 65 years-old).
* Adequate coagulation panel:

  * PT ≤ 1.2 ULN
  * aPTT ≤ 1.5 ULN
  * INR ≤ 1.5 ULN
* Adequate neurologic function: only neuropathy (sensory and motor) grade ≤ 1 (CTCAE v4.3) are allowed
* ECOG Performance status of 0, 1, or 2 (Appendix 5)
* Life expectancy ≥ 4 months
* Satisfactory cardiac function
* Ability to understand and sign informed consent and willingness to comply with the study procedures before study entry
* Women of childbearing potential\* are required to have a negative serum pregnancy test within 7 days prior to study treatment initiation (i.e. Cycle 1 Day 1) and are willing to use adequate contraceptive method during the whole study period and for up to 6 months after the last treatment intake

  \*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
  * ≥ 50 years old and naturally amenorrheic for ≥ 1 year
  * Permanent premature ovarian failure confirmed by a specialist gynaecologist

    * Previous bilateral salpingo-oophorectomy or hysterectomy
    * XY genotype, Turner's syndrome, or uterine agenesis
    * Female patient who do not meet at least of the above criteria are defined as women of childbearing potential
* Covered by a medical insurance (in country where applicable)

Exclusion Criteria:

* Prior systemic therapy with bevacizumab
* Active peripheral neuropathy ≥ grade 3 (NCI-CTCAE v4.3)
* Prior history of other malignancies other than ovarian SCST (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the subjects has been free of the disease for at least 3 years or 5 years for breast cancer
* No resolution of specific toxicities related to any prior anti-cancer therapy to grade ≤1, excluding alopecia, according to the NCI-CTCAE v.4.3
* History or evidence of thrombotic or hemorrhagic disorders, including cerebro-vascular accident/stroke or transient ischemic attack or sub-arachnoids' haemorrhage within 6 months prior to first dose of study drugs
* Uncontrolled arterial hypertension (systolic ≥ 150 mmHg or diastolic ≥ 100 mmHg) despite optimal antihypertensive therapy or clinically significant cardiovascular disease including one of the following:

  * Myocardial infarction or instable angina within 6 months prior to first dose of study drugs
  * NYHA grade ≥ II congestive heart failure
  * Serious cardiac arrhythmia requiring medication
  * Peripheral vascular disease ≥ grade 3
* History of bowel obstruction, including sub-occlusive syndrome and history of abdominal fistula, gastro-intestinal perforation or intra-abdominal abscess during the year prior to inclusion
* Prior treatments:

  * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study inclusion or anticipation of need for major surgical procedure during the course of the study
  * Current or recent treatment with another investigational drug within 30 days of first study treatment dosing or within 6 weeks in case of prior nitrozo-urea and or mitomycin C treatment. In case of hormonotherapy , patients will be eligible if hormonotherapy is discontinued within at least 1 week before treatment initiation
  * Current or recent (within 10 days prior to randomization) chronic use of aspirin\> 325 mg/day or use of any other inhibitor of platelet aggregation
  * Chronic treatment (i.e. \> 15 days) with non steroids anti-inflammatory agents unless a washout period of 15 days was observed before the inclusion.
  * Intake of granulocyte growth factor within 3 weeks before study entry
* Presence of hematuria and proteinuria ≥ 2+ (urine dipstick). Patients with ≥ 2+ proteinuria on dipstick at screening should undergo a 24-hour urine collection and will be eligible only if 24-h proteinuria ≤ 1 g
* Untreated evolutive brain metastases
* Active bacteria or fungal infection (grade ≥2, CTC AE V4.3)
* Known HIV1, HIV2 or chronic hepatitis B or C infection
* Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies
* Any contraindications to paclitaxel treatment: for example severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil) or to any of the excipients (Ethanol Citric acid) (refer to Taxol® SPC for further details)

Answer: D