Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double Blind, Randomized Placebo Controlled Clinical Trial Investigating the Efficacy and Safety of Somatuline Depot (Lanreotide) Injection in the Treatment of Carcinoid Syndrome
Brief Summary: The purpose of this study was to determine whether monthly deep subcutaneous (s.c.) injections of lanreotide Autogel (Somatuline Depot) were effective and safe in controlling diarrhoea and flushing by reducing the usage of s.c. short-acting octreotide as a rescue medication to control symptoms in subjects with carcinoid syndrome.


Options:
A: 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
B: Subjects were eligible for participation in the study if they met the following criteria:

1. At least 18 years of age at the time of first dosing.
2. Subjects must have given signed informed consent before any study related activities were conducted.
3. Subjects in the United States of America (USA) must have given written authorisation for the release of protected health information in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulations; subjects in other countries must have provided appropriate authorisation as needed by regulatory authorities in each country.
4. Subjects must have been willing to receive s.c. octreotide injections as rescue medication, as needed to control their symptoms, if any.
5. If female, the subject must not have been pregnant (confirmed by negative pregnancy test) and must have had the following documented via verbally given history:

   * At least 1 year postmenopausal (natural cessation of menses), or
   * Surgically sterile (if by tubal ligation, surgery must have been performed more than 3 months prior to entry into the study), or
   * If the subject was of childbearing potential and sexually active, she must have been using an acceptable form of contraception (oral, injected, transdermal or implanted contraceptives, diaphragm or barrier method with spermicidal and/or intrauterine device); local methods such as condoms or sponges/vaginal tablets were not acceptable forms of contraception.
6. Subjects with a histopathologically confirmed diagnosis of carcinoid tumour or, a carcinoid tumour of unknown location with liver metastases (documented biopsy), and a history of carcinoid syndrome (flushing and/or diarrhoea) who were either naïve to treatment with a somatostatin analogue (SSTa) or responsive (according to the opinion of the principal investigator) to conventional doses of Sandostatin LAR® Depot (LAR; ≤30 mg every 4 weeks) or to daily doses of ≤600 μg of s.c. octreotide.
7. Confirmation of positive somatostatin receptor (SSTR) status by somatostatin receptor scintigraphy (SRS; up to 6 months prior to study entry at the Screening Visit).
8. Absence of tumour progression documented by two sequential computed tomography (CT) scans or two sequential magnetic resonance imaging (MRI) scans (≥3 months apart); the last CT or MRI scan must have been performed within 6 months of study entry (Screening Visit).
9. Subjects previously treated with LAR, must have received their last dose of LAR at least 4 weeks prior to first dose of study treatment (no later than at the Screening Visit).
10. Be able to communicate and cooperate with the principal investigator and the staff and willing to comply with the study instructions.

Subjects were excluded from entering the study for the following reasons:

1. History of known allergy or hypersensitivity to investigational drug or any components of its formulation, or octreotide.
2. History of carcinoid syndrome refractory to treatment with conventional doses of SSTa.
3. Treatment with any other investigational drug within 30 days prior to study entry (Screening Visit) and/or at any time during the subject's participation in the study.
4. Treatment with interferon, chemotherapy and/or radiotherapy (a radiolabelled SSTa) and/or tumour debulking \<3 months prior to study entry (Screening Visit).
5. History of hepatic arterial embolisation, hepatic arterial chemoembolisation and/or selective internal radiation therapy (selective internal radiation \[SIR\] therapy \[SIRT\]; e.g. SIR Spheres) \<6 months prior to study entry (Screening Visit).
6. Short bowel syndrome.
7. Uncontrolled diabetes and/or hypertension.
8. Severe renal impairment (glomerular filtration rate \<30 mL/min/1.73 m2) and/or severe liver impairment as evidenced by serum total bilirubin \>1.5 mg/dL associated with bile duct blockage or with alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5.0 upper limit of normal (ULN).
9. Diagnosis of cardiac disease New York Heart Association (NYHA) functional classification \>Class I. (Subject has limitation of physical activity. Ordinary physical activity causes undue fatigue, palpitation, or dyspnoea).
10. Life expectancy less than 1 year.
11. Any malignancies except carcinoid tumour, basocellular carcinoma of the skin, in situ carcinoma of the cervix and ≥5 years disease free after curative cancer treatment.
12. Any serious medical condition that could jeopardise the safety of the subject and/or the efficacy assessments of the study.
13. Subject is being treated with a proton pump inhibitor (PPI) and has been at a stable dose (no change in dose or frequency of administration) for less than 4 weeks at study entry (Screening Visit).
C: Inclusion Criteria:

* Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin
* No history of and no active symptoms related to carcinoid syndrome
* In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment
* Radiological documented disease progression within 6 months prior to randomization
* Measurable disease
* WHO performance status ≤1
* Adequate bone marrow, liver and renal function

Exclusion Criteria:

* Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma
* Patients with pancreatic NET or NET of origins other than GI or Lung
* Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea)
* Patients with more than one line of prior chemotherapy
* Prior targeted therapy
* Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization
* Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus)
* Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
* Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
* Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy
* Patients who had any severe and/or uncontrolled medical conditions such as:

  * unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia
  * active or uncontrolled severe infection
  * liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)
* Chronic treatment with corticosteroids or other immunosuppressive agents
* Known history of HIV seropositivity
* Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria might apply.
D: Inclusion Criteria:

1. Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
2. Ki67 index ≤ 20% (to be centrally confirmed).
3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to randomization in the study.
4. Patients ≥18 years of age.
5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
6. Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see §Appendix 2, Section 1 and 2, RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to randomization in the study (to be centrally confirmed). The OctreoScan® should be one that was performed while the patient was on a fixed dose of Octreotide LAR. If a patient has had an OctreoScan® performed while Octreotide LAR treatment-naïve, the patient must have a repeat OctreoScan® performed after 3 months of Octreotide LAR treatments before entering the clinical study to prove that the index lesions or new lesions still meet the criteria for inclusion. It is acceptable to have patients temporarily switched to Octreotide s.c. (up to six weeks) in order to obtain an OctreoScan®, provided they return to the same fixed dose of Octreotide LAR prior to the scan.
7. The tumour uptake observed in each target lesion (for target/non-target/measurable lesions definition see §Appendix 2, Sections 1 and 2, RECIST Criteria, Version 1.1) using OctreoScan® must be ≥ normal liver uptake observed on planar imaging (to be centrally confirmed) (§Appendices 5 and 6).
8. Karnofsky Performance Score (KPS)\>=60.
9. Presence of at least 1 measurable site of disease.
10. \[Applicable only for France\] All patients included in the trial must be affiliated with a social security regime or be a beneficiary of the same in order to be included in the study.

Exclusion Criteria:

1. Either serum creatinine \>150 µmol/L (\>1.7 mg/dL), or creatinine clearance \<50 mL/min calculated by the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) \<50 mL/min (the measured creatinine clearance / GFR is required only as confirmatory exam).
2. Hb concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<2x109/L (2000/mm3); platelets \<75x109/L (75x103/mm3).
3. Total bilirubin \>3 x ULN.
4. Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. For female patients of childbearing potential (defined as \< 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in §Appendix 7.
7. Treatment with \>30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study.
8. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
9. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
10. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
11. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
12. Uncontrolled congestive heart failure (NYHA II, III, IV).
13. Uncontrolled diabetes mellitus as defined by a fasting blood glucose \>2 ULN.
14. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake on target lesions observed by OctreoScan® imaging during continued Octreotide LAR treatment is at least as high as normal liver uptake observed by planar imaging.
15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
16. Prior external beam radiation therapy to more than 25% of the bone marrow.
17. Current spontaneous urinary incontinence.
18. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
19. Patients who have not provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
20. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
21. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days are excluded from participation in this trial.

Answer: B