Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients
Brief Summary: This randomized phase III trial studies octreotide acetate and recombinant interferon alfa-2b to see how well it works compared to octreotide acetate and bevacizumab in treating patients with high-risk neuroendocrine tumors that have spread to other places in the body (metastatic) or spread from where it started to nearby tissue or lymph nodes (locally advanced). Octreotide acetate and recombinant interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving octreotide acetate together with recombinant interferon alfa-2b is more effective than giving octreotide acetate together with bevacizumab in treating patients with neuroendocrine tumor.


Options:
A: Inclusion Criteria:

* Provision of written informed consent prior to any study related procedures
* Inoperable, Gastro-Entero-Pancreatic-Neuroendocrine Tumour G1 or G2 (Proliferation Index, Ki67-Index: 0 to ≤20%) confirmed by pathological/histological assessment
* Progressive disease within 12 months before inclusion (RECIST 1.1: increase of \>20% tumour load; by Computer Tomography (CT) or Magnetic Resonance Imaging (MRI)
* Measurable disease according to RECIST 1.1.
* Metastatic disease confirmed by CT/MRI.
* Functioning or non-functioning NET (G1, G2).
* Positive Octreo-Scan (≥ Grade 2 Krenning scale) or positive DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-TATE (Tyr3-Thre8-Octreotide or DOTA-Tyr3-octreotate)/TOC (Tyr3-octreotide) -PET (Positron-Emission-Tomography) -CT within 12 months prior to screening

Exclusion Criteria:

* Has the diagnosis of Insulinoma
* Has a diagnosis of a multiple endocrine neoplasia (MEN)
B: Inclusion Criteria:

1. Adequately understand the study and voluntarily sign the Informed Consent Form;
2. Be at least 18 years old;
3. Based on central pathology review results，patients have a confirmed histologically pathology diagnosis of low- or intermediate grade (G1 or G2) advanced (unresectable or distant metastatic) extrapancreatic NETs with origins including, but not limited to, the lung, thymus, the gastrointestinal tract (stomach, duodenum, liver, jejunum, ileum, colon, cecum, appendix, rectum) and unknown origin etc. For Gastrointestinal neuroendocrine tumors (GI-NETs), G1 is defined as \< 2 mitoses /10 high-power field［HPF］and/or \<3% Ki-67 index; G2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index; for NETs originating from the lung and thymus gland, G1 is defined as \<2 mitoses/10 HPF and no necrosis; G2 is defined as 2-10/10 HPF and/or foci of necrosis. NETs from origin other than GI-NET, lung and thymus, or from unknown origins should be graded according to the GI-NET grading criteria. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade should be used to assign classification.
4. Have previously progressed on no more than two types of systemic anti-tumor therapy, including long-acting somatostatin analogs (SSAs), interferon, PRRT(peptide receptor radionuclide therapy), mTOR inhibitors or chemotherapy(chemotherapies were considered as one kind of regimen, regardless of medications and cycles); patients who are unable or unwilling to receive such treatments are also eligible;
5. Patients must have radiological documentation of progression of disease within 12 months prior to randomization.
6. Have measurable lesions (according to RECIST 1.1);
7. Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL;
8. Serum total bilirubin \<1.5 times the upper limit of normal (ULN);
9. Patients who do not have liver metastasis, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the ULN; and who do have liver metastasis, with ALT and AST ≤ 5 times ULN.
10. Serum creatinine \<1.5 times ULN and creatinine clearance ≥60 ml/min;
11. International Normalized Ratio (INR) ≤1.5 ULN and activated partial thromboplastin time (APTT) ≤1.5 ULN.
12. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale;
13. Have expected survival of more than 12 weeks;
14. Male or females patients with reproductive potential must agree to use an effective contraceptive method, for example, double-barrier device, condom, oral or injected birth control medication or intrauterine device, during the study and within 90 days after study treatment discontinuation. All female patients are considered to be fertile, unless the patient had natural menopause or artificial menopause or sterilization (such as hysterectomy, bilateral oophorectomy or ovarian irradiation).

Exclusion Criteria:

1. High grade (G3) neuroendocrine cancer, adenocarcinoid, pancreatic islet cell carcinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma;
2. Neuroendocrine tumors with pancreatic origins
3. Functional NETs which need to be treated with long acting SSAs to control disease related syndromes, such as insulinoma, gastrinoma, glucagonoma, somatostatinoma, ACTHoma, VIPoma, accompanied by carcinoid syndrome, Zollinger-Ellison syndrome or other active symptoms;
4. Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
5. Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
6. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceed the normal range with clinical significance;
7. Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg;
8. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal conditions that may cause bleeding or perforation by investigator's discretion;
9. History or presence of a serious hemorrhage (\>30 ml within 3 months), hemoptysis (\>5 ml blood within 4 weeks) or a thromboembolic event (including transient ischemic attack) within 12 months;
10. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure according to the New York Heart Association (NYHA) classification ≥ 2; ventricular arrhythmias which needs drug treatment; LVEF (LVEF) \<50%;
11. Mean corrected QT interval (QTc) ≥ 480 msec;
12. Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection;
13. Anti-tumor therapy received within 4 weeks prior to the initiation of the investigational treatment, including, but not limited to, chemotherapy, radical radiotherapy, targeted therapy, immunotherapy and anti-tumor Chinese medicine treatment, hepatic chemoembolization, cryoablation and radiofrequency ablation ;
14. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
15. Drugs containing St John's wort taken within 3 weeks prior to the first study treatment, or other strong inducers with CYP3A4 or strong inhibitors taken within two weeks prior to the first study treatment (see appendix 3);
16. Any clinically significant active infection, including, but not limited to, human immunodeficiency virus (HIV) infection;
17. History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×104/ml); known Hepatitis C virus infection with HCV RNA positive (copies ≥1×103/m); or liver cirrhosis, etc.
18. Surgery (except biopsy) within 28 days prior to the initiation of investigational treatment or unhealed surgical incision;
19. Brain metastases and/or spinal cord compression not treated by surgery and/or radiotherapy, and with no clinical imaging evidence of disease stability;
20. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for hair loss);
21. Received investigational treatments in other clinical studies within 4 weeks prior to enrollment;
22. Women who are pregnant or lactating;
23. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions are inappropriate for the use of the investigational product or affect interpretation of study results.
C: Inclusion Criteria:

* Patient must have unresectable metastatic or locally advanced, low- or intermediate-grade neuroendocrine carcinoma

  * NOTE: pathology report must state one of the following: carcinoid, low-grade or well-differentiated neuroendocrine carcinoma, atypical carcinoid, intermediate-grade or moderately differentiated neuroendocrine carcinoma; patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, or goblet cell carcinoid are not eligible; patient must not have osseous metastasis as only site of disease; patients with medullary thyroid carcinoma or islet cell carcinoma are not eligible; if pathology report states only neuroendocrine carcinoma, pathology subtype must be reconfirmed
  * Occasionally, it is not possible to establish tumor grade on fine-needle aspiration (FNA) cytology material; if a new biopsy is needed, a core needle biopsy should be obtained whenever possible
* Patient must have high risk disease as defined by at least one of the following:

  * Progressive disease
  * Refractory carcinoid syndrome while receiving octreotide (defined by \> 2 flushing episodes/day or \> 4 bowel movements/day)
  * Atypical histology and more than 6 lesions
  * Metastatic colorectal carcinoid; patients with metastatic cecal or appendiceal carcinoid tumor are not eligible unless the tumors fit into one of the other high-risk categories (a, b, or c above)
  * Metastatic gastric carcinoid
* Patient must have measurable disease; CT or magnetic resonance imaging (MRI) used for tumor measurement must have been completed within 28 days prior to registration; X-rays, scans or other tests for assessment of non-measurable disease must have been performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form; these scans also must be submitted for central radiology review
* Institutions are required to submit CT/MRI scans and archived tissue for pathology review; furthermore, institutions are required to seek additional patient consent for submission of octreotide scans, and submission of blood and use of archived tissue for correlative studies
* If patient consents to the submission of octreotide scans, the patient must also be registered to Registration Step 2
* Patient may have had up to one prior regimen of cytotoxic chemotherapy; at least 28 days must have elapsed since completion of prior therapy, and patient must have recovered from all effects
* Patient may have had prior hepatic artery embolization; at least 28 days must have elapsed since embolization and there must be residual measurable disease; chemoembolization will be considered as one prior chemotherapy regimen
* Patient must not have received prior interferon, bevacizumab or any other therapy targeting VEGF or VEGF receptors
* Patient may have received prior therapy targeting stem cell factor receptor (c-kit), abelson murine leukemia viral oncogene homolog 1 (abl), platelet-derived growth factor receptor (PDGFR), mammalian target of rapamycin (mTOR), and somatostatin receptors (not counted toward prior cytotoxic chemotherapy)
* Prior radiation is allowed; there must be measurable disease; if prior therapies include peptide receptor radiotherapy, the target lesion(s) must have shown disease progression; at least 28 days must have elapsed since completion of prior therapy, and patient must have recovered from all effects
* Patients must have recovered from any prior surgery; one week must have elapsed from the time of a minor surgery and 4 weeks from major surgery
* At least 21 days must have elapsed since any prior octreotide LAR depot treatment
* Patient must have a Zubrod performance status of 0-2
* Absolute neutrophil count (ANC) \> 1,500/mcl
* Hemoglobin \> 8 g/dl
* Platelets \> 100,000/mcl
* Serum bilirubin \< 1.5 x institutional upper limit of normal (IULN)
* Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =\< 2.5 x IULN
* Serum creatinine \< 1.5 mg/dL
* Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein must be obtained and the level must be \< 1,000 mg for patient enrollment; these results must be obtained within 28 days prior to registration

  * Note: 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 not on anticoagulation must have prothrombin time (PT) and partial thromboplastin time (PTT) =\< 1.1 x lULN obtained within 28 days prior to registration; patients on full-dose anticoagulation (warfarin or low molecular weight heparin) are eligible provided that both of the following criteria are met:

  * The patient has an in-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
  * The patient has no active bleeding or pathological condition that carries a high risk of bleeding such as varices
* Patient must not have history or evidence of clinically significant peripheral vascular disease such as non-healing peripheral ulcers or claudication
* Patient must not have a history of primary brain tumor or metastatic cancer to the brain; brain imaging studies are not required for eligibility if the patient has no neurological signs or symptoms; if brain imaging studies are performed, they must be negative for disease
* Patient must not have a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration
* Patient must not have history within the past 5 years or presence of bleeding diathesis or coagulopathy that results in spontaneous bleeding (in the absence of trauma) requiring packed red blood cells (pRBC) transfusion
* Patient must not have a serious (requiring active medical therapy with medication or medical device under the supervision of a physician) non-healing wound, ulcer, or bone fracture
* Patient must not have recent history (within 6 months prior to registration) of these arterial thromboembolic events: transient ischemic attack, cerebrovascular accident, unstable angina, myocardial infarction, or New York Heart Association grade II or higher congestive heart failure
* Patients with a history of hypertension must be well-controlled (blood pressure \< 150/90), on a stable regimen of antihypertensive therapy
* Patient must not have hemoglobinopathies (e.g., Thalassemia) or any other cause of hemolytic anemia
* Patient must not plan to use any other concurrent chemotherapy, immunotherapy, hepatic artery embolization, hepatic artery chemoembolization, radiofrequency ablation, other tumor ablative procedure or radiotherapy while on protocol treatment
* Patient must not be pregnant or nursing because bevacizumab may be harmful to the developing fetus and newborn; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout protocol treatment and for up to 6 months following discontinuation of bevacizumab
* No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years
* All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
* At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional re view board approval for this study has been entered into the data base
* REGISTRATION STEP 2 - SPECT SUBSTUDY
* Patient must have registered to the main study
* Patient must have consented to the submission of octreotide scans
* An octreotide scan obtained within 28 days prior to Registration Step 1 must be available for submission
D: Inclusion criteria:

* Advanced (unresectable or metastatic) carcinoid tumor
* Confirmed low-grade or intermediate-grade neuroendocrine carcinoma
* Documented progression of disease within 12 months prior to randomization.
* Measurable disease determined by triphasic computer tomography (CT) scan or magnetic resonance imaging (MRI).

Exclusion criteria:

* Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma.
* Hepatic artery embolization within the last 6 months or cryoablation of hepatic metastasis within 2 months of enrollment.
* Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (sirolimus, temsirolimus, everolimus)
* Intolerance or hypersensitivity to octreotide, everolimus, or other rapamycins.
* Severe or uncontrolled medical conditions
* Chronic treatment with corticosteroids or other immunosuppressive agent.
* Other primary cancer within 3 years.

Other protocol-defined inclusion/exclusion criteria applied

Answer: C