Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Randomized, Double-Blinded Evaluation of Oral Everolimus (RAD001) Plus Bevacizumab vs. Oral Placebo Plus Bevacizumab in the Treatment of Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Brief Summary: This randomized phase II trial studies how well bevacizumab with or without everolimus works in treating patients with recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and everolimus may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether bevacizumab is more effective when given together with or without everolimus in treating ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer.


Options:
A: Inclusion Critera

1. Female ≥ 18 years of age
2. Histologically proven diagnosis of:

   a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent Stage I to II endometrial and other uterine cancers, after at least one prior line of standard therapy, requiring further treatment with platinum-based chemotherapy ii. Advanced Stage III to IV endometrial and other uterine cancers requiring treatment with platinum-based chemotherapy

   b. Ovarian Cancer: Platinum-sensitive or platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer treated with at least one prior line of platinum-based chemotherapy and requiring further treatment.(Part 1/Phase Ib, Part 2/Phase 2a)

   Platinum-sensitive is defined as cancer progression ≥ 6 months after platinum- based chemotherapy. Platinum-resistant is defined as cancer progression \< 6 months after platinum-based chemotherapy.

   Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified.

   Phase III/Part 3:

(1) Platinum-resistant (progression within 6 months after last platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer that meets one of the following criteria: i. Subject has received at least two prior lines of systemic therapy including a bevacizumab-containing regimen as standard of care ii. Subject has received at least two prior lines of systemic therapy, has not received a prior bevacizumab-containing regimen and is not eligible for a bevacizumab containing regimen based on Investigator's assessment (2) Platinum-refractory (progression during first-line platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer after at least one prior line of systemic therapy (3) For groups 1-2 above: Subjects with positive deleterious or suspected deleterious, germline or somatic BRCA mutated status must have received a PARP inhibitor as a prior line of therapy.

c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy after at least one prior line of standard therapy, requiring further treatment. Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma

3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment.

4. Life expectancy of ≥ 3 months at the time of enrollment.

5. Able to take orally administered study medication.

6. Have adequate baseline function and performance status within 28 days of enrollment:

1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3
2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is \> 1.5 x ULN, creatinine clearance must be \> 50 mL/min.
3. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
4. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT \< 1.2 x ULN
5. ECOG performance ≤ 2

   7. Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment.

   8. Provide written informed consent and authorization permitting release of Protected Health Information.

   9. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion Criteria

1. Serious, non-healing wound, ulcer or bone fracture.
2. Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to C1D1 (a major surgical procedure is defined as requiring general anesthesia).
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4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
5. History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor; seizures not controlled with standard medical therapy; and history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within 6 months of enrollment.

   a. Subjects with metastatic CNS tumors may participate in this study if the subject is \> 28 days from therapy completion (including radiation and/or surgery), is clinically stable at the time of study enrollment, and is not receiving corticosteroid therapy.
6. Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection and demonstrate \< 1000 mg protein per 24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be \<1.0 to allow participation in the study.
7. Clinically significant cardiovascular disease including uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix E); serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease.
8. Women who are pregnant or nursing.
9. (Intentionally left blank)
10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
11. Hemoptysis within 3 months prior to enrollment.
12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there is an emergent or life-threatening medical condition that required it.
15. Known history of human immunodeficiency virus infection (HIV).
16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection).
17. Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
18. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject at risk of side effects on an anti-angiogenesis product.
19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
20. Intra-abdominal abscess within the last 3 months of enrollment.
21. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP \>160 mm Hg or diastolic BP \> 90 mm Hg pressure.
22. QTc \> 470 msec on screening ECG per Fridericia's formula.
23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
24. Concurrent use of concomitant medications that prolong the QT/QTc interval.
25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) \< 50%.
26. History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818.
27. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
28. Treatment with an investigational agent within 28 days of enrollment.
29. Known recreational substance abuse.
30. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment.
31. Known hypersensitivity to AL3818 or components of the formulation.
B: Inclusion Criteria:

1. Pathologically and radiologically confirmed stage IV or postoperative recurrence ovarian cancer.
2. Age of 18-70, Karnofsky score higher than 80.
3. No severe functional damage of major organ, normal liver and kidney function.
4. Peritoneal adhesion. (1) peritoneal adhesions diagnosed by microlaparoscopy or abdominal operations, and classification according to Nair criteria is performed. (1) must be met. (2) Peritoneal adhesion symptoms, intermittent abdominal pain, abdominal distension, nausea and vomiting, hard to pass stools or gas; (3) Peritoneal adhesion signs，abdominal distension, abdominal tenderness, reduced or absent bowel sounds; (4) B ultrasound or CT or MRI show peritoneal adhesion or adhesion-related complications.

Exclusion Criteria:

1. Complete intestinal obstruction and suitable for surgery.
2. Patients known to be allergic to bevacizumab or any of the components of the drug.
3. Other ongoing anti-tumor treatment.
4. Heart disease with significant clinical symptoms, such as: congestive heart failure, coronary heart disease with symptom, arrhythmia hardly be controlled by drugs, myocardial infarction in 6 months, or heart failure
5. Active wound infection and a history of uncontrolled psychiatric illness.

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C: For additional information, please contact the BMS oncology clinical trial information service at 855-216-0126 or email MyCancerStudyConnect@emergingmed.com. Please visit www.BMSStudyConnect.com for more information on clinical trial participation.

Inclusion Criteria:

* Life expectancy at least 3 months
* Diagnosis of a solid tumor which is unresectable in which no approved effective therapy exists or for subjects who are intolerable to such therapy. The initial enrollment will focus on non-small cell lung, gastric/esophageal adenocarcinoma, soft tissue sarcoma, transitional cell carcinoma, and pancreatic cancer including ampulla of Vater tumors
* Adequate tumor sample
* Adequate recovery (baseline or Grade 1) from recent therapy. At least 1 week must have elapsed from the time of a minor surgery, and at least 8 weeks for major surgery or radiation therapy

Exclusion Criteria:

* Subjects with known brain metastasis.
* Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI

Medical History and Concurrent Diseases:

* History of thrombo-embolic disease within the last six months requiring therapeutic anticoagulation
* Subjects with history of poor wound healing or non healing ulcers
* Uncontrolled or significant cardiovascular disease

Allergies and Adverse Drug Reactions:

* History of allergy to brivanib its drug class, or related compounds

Prohibited Treatments and/or Therapies:

* Exposure to any investigational drug within 4 weeks of enrollment
* Other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiotherapy, standard or investigational. Subjects may continue to receive hormone replacement therapy
* Prior exposure to brivanib
D: 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

Answer: D