Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized, Placebo-controlled, Parallel Group, Multicenter, Double-blind Study to Evaluate the Efficacy and Safety of Telotristat Etiprate (LX1606) in Patients With Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog (SSA) Therapy
Brief Summary: The primary objective of the study is to confirm that at least 1 or more doses of telotristat etiprate compared to placebo is effective in reducing the number of daily bowel movements (BMs) from baseline averaged over the 12-week double-blind portion (Treatment Period) of the trial in patients not adequately controlled by current SSA therapy.


Options:
A: 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).
B: 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
C: Inclusion Criteria:

* Histopathologically-confirmed, well-differentiated metastatic neuroendocrine tumor
* Documented history of carcinoid syndrome and currently experiencing ≥4 bowel movements per day during the Run-in period
* Currently receiving stable-dose somatostatin analog (SSA) therapy
* Minimum dose of long-acting release (LAR) or depot SSA therapy

  * Octreotide LAR at 30 mg every 4 weeks
  * Lanreotide Depot at 120 mg every 4 weeks
  * Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose
* Ability and willingness to provide written informed consent

Exclusion Criteria:

* Presence of diarrhea attributed to any condition(s) other than carcinoid syndrome
* Karnofsky Performance status ≤60%
* Treatment with any tumor directed therapy, including interferon, chemotherapy, mechanistic target of rapamycin (mTOR) inhibitors \<4 weeks prior to Screening, or hepatic embolization, radiotherapy, radiolabelled SSA, and/or tumor debulking \<12 weeks prior to Screening
* History of short bowel syndrome (SBS)
* Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study
* Previous exposure to telotristat etiprate
D: Inclusion Criteria:

* Endocrine tumour in the intestine or pancreas and with locally advanced or metastatic disease
* No hormone related symptoms
* Well or moderately differentiated tumour confirmed by histology
* Tumour lesions which are measurable by a CT or MRI scan

Exclusion Criteria:

* Previously treated with a somatostatin analogue unless more than 6 months ago and given for no more than 15 days
* Treated within the last 6 months with interferon, chemoembolisation or chemotherapy or at any time with a radionuclide
* Had a previous cancer except basal cell carcinoma and/or in situ carcinoma of the cervix/uterus and/or patients treated with curative intent and free from disease for 5 years
* Pregnant or lactating
* Females must use adequate contraception during the study

Answer: C