Well-differentiated gastrointestinal neuroendocrine tumors (GINETs) tend to be slow growing, but treatment of advanced disease remains a challenge. Somatostatin analogues (SSAs) are considered standard therapy for carcinoid syndrome. SSAs delay tumor progression in advanced well-differentiated gastroenteropancreatic NETs. Cytotoxic chemotherapy and interferon play a limited role in the treatment of nonpancreatic GINETs. There is no standard approach to treatment of patients with disease progression. Identification of systemic agents with antitumor activity in advanced disease remains an unmet medical need. Enrollment to clinical trials is encouraged; potential therapeutic targets include the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways.
Key points
- •
Low- and intermediate-grade neuroendocrine tumors are an indolent group of malignancies that can cause symptoms from hormone hypersecretion and/or tumor mass.
- •
Somatostatin analogues are the mainstay of therapy for the control of symptoms associated with carcinoid syndrome.
- •
Systemic treatment of advanced disease remains a challenge; only somatostatin analogues have proven antitumor activity in advanced gastrointestinal neuroendocrine tumors.
- •
Gastrointestinal neuroendocrine tumors represent an active area of research. Clinical trials with peptide receptor radionuclide therapy, inhibitors of the mammalian target of rapamycin and vascular endothelial growth factor signaling pathways, immunotherapy, and other therapeutic approaches are ongoing.
- •
Improved understanding of the underlying molecular biology may lead to additional treatment advances.
Introduction
Neuroendocrine tumors (NETs) are a relatively rare, heterogeneous group of neoplasms arising nearly anywhere in the body with an annual incidence of 5 cases per 100,000 people in the United States. The updated World Health Organization classification system of gastroenteropancreatic NETs emphasizes the tumor site of origin, clinical syndrome, and degree of differentiation when categorizing these malignancies. Well-differentiated NETs (formerly known as carcinoid tumors) arising from the tubular gastrointestinal tract tend to be indolent and slow growing, in contrast to poorly differentiated neuroendocrine carcinomas (NECs), which are more aggressive and associated with a poor prognosis. The treatment of well-differentiated NETs depends on the presence of symptoms and the tumor site of origin. Pancreatic NETs are distinguished from nonpancreatic gastrointestinal NETs (GINETs) given evidence suggesting a differential response to therapy and differences in the molecular underpinnings of each disease.
Somatostatin analogues (SSAs) continue to play a key role in controlling hormone-mediated symptoms. In addition, clinical trials completed in the last decade have definitively demonstrated the antitumor properties of these agents in patients with advanced disease. Based on an improved understanding of the mechanisms underlying NET tumor progression, several novel therapeutic targets have been identified, including the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. Therapeutic clinical trials of novel agents are ongoing, but none has been definitively validated in GINETs. As a result, the systemic treatment of unresectable disease remains a challenge, and there is a significant unmet medical need for additional systemic treatments.
Introduction
Neuroendocrine tumors (NETs) are a relatively rare, heterogeneous group of neoplasms arising nearly anywhere in the body with an annual incidence of 5 cases per 100,000 people in the United States. The updated World Health Organization classification system of gastroenteropancreatic NETs emphasizes the tumor site of origin, clinical syndrome, and degree of differentiation when categorizing these malignancies. Well-differentiated NETs (formerly known as carcinoid tumors) arising from the tubular gastrointestinal tract tend to be indolent and slow growing, in contrast to poorly differentiated neuroendocrine carcinomas (NECs), which are more aggressive and associated with a poor prognosis. The treatment of well-differentiated NETs depends on the presence of symptoms and the tumor site of origin. Pancreatic NETs are distinguished from nonpancreatic gastrointestinal NETs (GINETs) given evidence suggesting a differential response to therapy and differences in the molecular underpinnings of each disease.
Somatostatin analogues (SSAs) continue to play a key role in controlling hormone-mediated symptoms. In addition, clinical trials completed in the last decade have definitively demonstrated the antitumor properties of these agents in patients with advanced disease. Based on an improved understanding of the mechanisms underlying NET tumor progression, several novel therapeutic targets have been identified, including the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. Therapeutic clinical trials of novel agents are ongoing, but none has been definitively validated in GINETs. As a result, the systemic treatment of unresectable disease remains a challenge, and there is a significant unmet medical need for additional systemic treatments.
Systemic therapy for the control of symptoms from hormone hypersecretion
Somatostatin Analogues
GINETs can be classified as functional or nonfunctional. Nonfunctional tumors do not secrete hormones and present with symptoms from tumor mass and growth, such as obstruction, abdominal pain, and bleeding. Functional tumors can secrete several biologically active hormones and peptides, including serotonin, histamine, amines, and prostaglandins. Carcinoid syndrome is an uncommon, but potentially dramatic manifestation of functional GINETs, affecting approximately 20% of patients with advanced well-differentiated tumors of the jejunum or ileum. The symptoms are intermittent, attributable to hormonal hypersecretion, and may include flushing, diarrhea, rhinorrhea, wheezing, and ultimately can result in right-sided valvular heart disease. Most GINETs are associated with carcinoid syndrome only after they have metastasized to the liver, as hormones produced by tumor cells (most commonly serotonin) can be released directly into the systemic circulation, thus bypassing hepatic metabolism.
For patients with hormone-mediated symptoms from a GINET, therapy with a somatostatin analogue (SSA) is appropriate. Somatostatin is a small, 14-amino acid peptide that inhibits the secretion and synthesis of many gastrointestinal (GI) hormones. Effects of native somatostatin include inhibition of endocrine and exocrine secretion, gastric and intestinal motility, gallbladder contraction, angiogenesis, and cell proliferation. Somatostatin’s effects are mediated through 5 high-affinity G-protein coupled receptors. Most GINETs express a receptor for somatostatin, and somatostatin analogues have been shown to be highly effective at controlling the debilitating symptoms of NETs. The 2 synthetic SSAs that are used clinically, octreotide and lanreotide, have significantly longer half-lives than native somatastatin, which has a half-life of approximately 1 to 2 minutes. These analogues have high affinity for somatostatin receptor 2 and 5, in particular. The antisecretory effect of somatostatin has made SSA essential for managing GINETs.
Approximately 50% to 90% of patients experience improvement in hormone-mediated symptoms (carcinoid syndrome) as a result of SSA therapy. Octreotide has been approved by the US Food and Drug Administration (FDA) for this indication. Lanreotide autogel is also a long-acting SSA. Its receptor binding profile is similar to that of octreotide, but it is administered as a depot deep subcutaneous injection (every 4 weeks). Both octreotide LAR (long-acting release) and lanreotide afford an approximately 70% symptomatic response rate overall. Although there is no standard protocol preoperative administration of octreotide can reduce the incidence of carcinoid crisis and is recommended for patients with a history of carcinoid syndrome who undergo surgical procedures or related interventions. It remains unclear whether the use of SSA therapy per se can inhibit or reverse the progression of carcinoid heart disease.
Additional SSAs with broader receptor binding profiles are currently in development. Pasireotide has increased affinity for receptor subtypes 1, 3, and 5 compared with other somatostatin analogues, which preferentially target receptor subtype 2. In 1 study, pasireotide 600 to 900 μg subcutaneously twice daily controlled the symptoms of diarrhea and flushing in 27% of patients who had refractory symptoms despite octreotide LAR. However, a phase III study that compared pasireotide with octreotide LAR in patients with inadequate symptom control despite maximum doses of somatostatin analogues was terminated early because of futility with regard to incremental impact on symptom control. However, as discussed later, there is still interest in the potential antitumor activity of pasireotide.
Tryptophan Hydroxylase Inhibitors
Some patients with carcinoid syndrome have residual symptoms despite the use of somatostatin analogues, so there has been interest in developing alternative strategies for reducing serotonin-mediated resulting from functional tumors. Telotristat is an oral small-molecule inhibitor of the enzyme tryptophan hydroxylase, which catalyzes the conversion of tryptophan to 5-hydroxytryptophan, the rate-limiting step in the synthesis of serotonin. Telotristat is designed to inhibit peripheral serotonin synthesis without altering brain serotonin levels. The TELESTAR randomized phase III trial enrolled patients with refractory diarrhea despite being on a stable dose of SSA. Recently released results suggest that telotristat reduces the average number of bowel movements in patients with NET compared with placebo. Several other clinical trials are ongoing to assess the usefulness of telotristat and other novel formulations of somatostatin analogues ( Table 1 ) to treat patients with refractory symptoms.
| Study ID | Phase | Study Arms | Outcome | Condition | Sponsor |
|---|---|---|---|---|---|
| Telotristat Etiprate for Carcinoid Syndrome Therapy (TELECAST) a | III randomized | Telotristat vs placebo b | Incidence of treatment-emergent adverse events and urine 5-HIAA levels | Well-differentiated NETs with a history of carcinoid syndrome refractory to stable somatostatin analogue therapy | Lexicon Pharmaceuticals |
| TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) a | III randomized | Telotristat vs placebo; both in addition to somatostatin analogue b | Incidence of adverse events and number of bowel movements | Well-differentiated NETs with a history of carcinoid syndrome refractory to stable somatostatin analogue therapy | Lexicon Pharmaceuticals |
| An Efficacy and Safety Study of Somatuline Depot (Lanreotide) Injection to Treat Carcinoid Syndrome (ELECT) a | III randomized | Lanreotide depot vs placebo b | Use of rescue octreotide to control symptoms | Carcinoid (including unknown primary) with carcinoid syndrome (flushing ± diarrhea); treatment naive or responsive to octreotide | Beaufour Ipsen International SNC |
| Telotristat Etiprate – Expanded Treatment for Patients With Carcinoid Syndrome Symptoms (TELEPATH) | III | Telotristat | Long-term extension study of adverse events | Patients with well-differentiated NETs with a history of carcinoid syndrome who are participating in other trials of telotristat | Lexicon Pharmaceuticals |
| Phase II Study of Subcutaneous Injection Depot of Octreotide in Patients With Acromegaly and Neuroendocrine Tumors | II | Two doses of CAM2029 (octreotide FluidCrystal injection depot) | Pharmacokinetic study with secondary outcomes of adverse events and symptom relief | Acromegaly or a functional, well-differentiated NET, with carcinoid symptoms despite octreotide LAR | Camurus AB |
a Enrollment completed, results not yet published.
Interferon
Before SSAs were widely available, interferon was shown to reduce the symptoms of carcinoid syndrome in roughly 30% to 70% of patients (with some studies suggesting a superior effect on flushing compared with diarrhea). However, routine use of interferon for symptom control is limited by its relatively unfavorable side-effect profile (including fatigue, depression, myelosuppression, weight loss, flulike syndrome, and thyroid abnormalities). Instead, interferon alpha is typically reserved for patients with advanced GINETs with inadequate symptom control on SSAs or patients who are intolerant of SSAs.
Systemic therapy for the control of tumor growth
Somatostatin Analogues
In addition to controlling symptoms, SSAs have also been shown to inhibit the growth of well-differentiated GI and pancreatic NETs. Somatostatin inhibits the production of growth factors and hormones that promote tumor growth through paracrine and autocrine pathways, blocking tumor cell proliferation, invasion, and tumor angiogenesis, along with induction of apoptosis. Somatostatin seems to directly inhibit tumor growth and metastatic spread through the 5 somatostatin receptor subtypes, which are expressed by both tumor cells and endothelial cells in the tumor microenvironment.
The results of the PROMID (Placebo controlled, double blind, prospective, Randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine MIDgut tumors) trial demonstrated that octreotide slows progression of midgut NETs compared with placebo in treatment-naive patients. Use of octreotide LAR 30 mg monthly improved median time to tumor progression from 6 months in the placebo group to 14.3 months in the treatment group. Both functional and nonfunctional tumors seemed to benefit. In 2014, results from the Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) study were published. Treatment with extended-release lanreotide treatment resulted in prolonged progression-free survival (PFS) compared with placebo (median PFS, 18 months v NR [versus not reached]) in metastatic, nonfunctional, well-differentiated, and moderately differentiated GI and pancreatic NETs. As a result, lanreotide was approved by the FDA for tumor control in GINETs and pancreatic NETs. The most common side effect was mild diarrhea in 26% of patients, followed by abdominal pain and gallstones. Serious side effects were rare.
An exploratory post hoc data analysis of the negative phase III study originally designed to evaluate the effect of pasireotide on carcinoid symptoms demonstrated that pasireotide LAR increased PFS by 5 months, suggesting potential antitumor activity. A follow-up phase II clinical trial in treatment-naive patients with metastatic grade 1 or 2 NETs demonstrated a median PFS of 11 months with pasireotide LAR. There was a high incidence of hyperglycemia (14% grade 3 hyperglycemia), raising concerns about the suitability of pasireotide as a first-line agent. Another prospective open-label phase II clinical trial (COOPERATE-2) examined the effects of pasireotide in combination with everolimus compared with everolimus alone in advanced, progressive pancreatic NETs. The addition of pasireotide did not seem to improve tumor control. See Table 2 for a list of ongoing clinical trials with pasireotide and other somatostatin analogues.
| Study ID | Phase | Outcome | Population | Sponsors |
|---|---|---|---|---|
| Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in a Novartis-sponsored Study | IV | Number of patients receiving pasireotide; adverse events | Patients who completed a previous Novartis-sponsored Pasireotide study | Novartis Pharmaceuticals Corporation |
| A Study Evaluating Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno-Pancreatic Neuroendocrine Tumors (REMINET) a | II/III randomized | PFS at 6 mo | Advanced well-differentiated duodenopancreatic NETs; patients who progressed after first-line treatment with either chemotherapy or biotherapy | Federation Francophone de Cancerologie Digestive |
| Study of Pasireotide Long Acting Release (LAR) in Patients With Metastatic Neuroendocrine Tumors (NETs) b | II | PFS | Locally unresectable or metastatic carcinoid or pancreatic NETs | H. Lee Moffitt Cancer Center and Research Institute at University of South Florida; Novartis Pharmaceuticals Corporation |
| Study of Pasireotide in Patients With Rare Tumors of Neuroendocrine Origin b | II | Change in primary tumor biomarkers | Rare tumors of neuroendocrine origin (including pancreatic neuroendocrine) | Novartis Pharmaceuticals Corporation |
| Combination of Lanreotide Autogel 120 mg and Temozolomide in Progressive GEP-NET (SONNET) | II | Disease control rate at 6 mo | Low- or intermediate- grade gastroenteropancreatic NET | Ipsen |
| Safety and Tolerability of Pasireotide LAR in Combination With Everolimus in Advanced Metastatic NETs (COOPERATE-1) c | I | Safety and tolerability | Grade 1 or 2 advanced pulmonary or gastroenteropancreatic NETs | Novartis Pharmaceuticals Corporation |
| Dose Escalation Study of Pasireotide (SOM230) in Patients With Advanced Neuroendocrine Tumors (NETs) b | I | Pharmacokinetic/safety study | Well-differentiated or moderately differentiated NETs | Novartis Pharmaceuticals Corporation |
a Randomized, placebo-controlled trial.
b Enrollment completed, trial ongoing.
Interferon
Interferon receptors are expressed by GINETs. After binding to its receptor, interferon initiates a signal transduction cascade and exerts antitumor effects through a variety of mechanisms, including stimulation of T cells, induction of cell cycle arrest, and/or inhibition of angiogenesis. Several studies have been conducted comparing SSAs with or without interferon alpha. The results of 1 small study suggested prolonged 5-year survival in the combination group, but this difference was not statistically significant. Another 3-arm trial compared lanreotide alone, interferon alone, or combination therapy; tumor progression rates were essentially identical in all arms. A third randomized trial of 109 patients compared octreotide alone or in combination with interferon and demonstrated a nonsignificant increase in survival with the combination. Response rates across all arms were generally low. Taken together, the data preclude making definitive conclusions about the antitumor effects of interferon. Thus, the role for interferon remains controversial in GINETs and its use is typically reserved for SSA-refractory disease.
Everolimus
Small-molecule tyrosine inhibitors are a class of targeted therapies that hold promise for the treatment of GINETs. mTOR is a serine-threonine kinase that regulates cell growth, proliferation, and survival signaling in response to metabolic factors. mTOR mediates downstream signaling in several growth factor pathways active in NETs, including the VEGF and insulinlike growth factor signaling pathways. In addition, mTOR regulates angiogenesis by controlling the production of hypoxia inducible factor. Overactivation of the mTOR pathway by hyperphosphorylation has been demonstrated in some well-differentiated NETs, and inhibition of the mTOR pathway has antiproliferative effects in NET cell lines in vitro. As a result, there has been interest in developing inhibitors of mTOR as a novel treatment mechanism for advanced GINETs.
Everolimus (also known as RAD001) is an oral mTOR inhibitor that is already FDA-approved for the treatment of panNETs based on improvements in PFS. Treatment with everolimus showed a trend toward improved PFS in the randomized phase III RADIANT-2 study of 429 patients with advanced nonpancreatic NETs, a history of carcinoid syndrome, and radiologic disease procession. An investigator-initiated exploratory analysis that corrected for randomization imbalances found that everolimus plus octreotide reduced the risk of progression by 38% compared with octreotide alone, but the drug has not yet been approved by the FDA for this indication. There were also discordances between the central and investigator (local) radiologic review, highlighting the challenges associated with interpreting cross-sectional imaging of highly vascular GINETs and resulting in significant censoring for the final analysis, thus reducing the total number of events and the statistical power for the primary end point. There was no significant difference in overall survival between the 2 groups. However, patients who were randomized to placebo were permitted to cross over into the active treatment group, confounding interpretation of the survival data.
A follow-up phase III study in 279 patients with advanced, progressive low-grade or intermediate-grade, nonfunctional NETs of GI or lung origin has been completed (RADIANT-4). Patients were randomized to either everolimus 10 mg daily or placebo. Recently reported results suggest that everolimus extends PFS in these patients, but the drug is not yet approved for this indication. Several other clinical trials are ongoing in patients with low-grade or intermediate-grade GINETs ( Table 3 ).
| Study ID | Phase | Study Arms | Population | Sponsors |
|---|---|---|---|---|
| mTOR inhibitors | ||||
| Everolimus Roll-over Protocol for Patients Who Have Completed a Previous Novartis-sponsored Everolimus Study | IV | Everolimus | Patients receiving everolimus in a Novartis-sponsored, Oncology Clinical Development & Medical Affairs study | Novartis Pharmaceuticals Corporation |
| Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin) (RADIANT-4) c | III randomized | Everolimus vs placebo b | Advanced, well-differentiated gastrointestinal or lung NETs | Novartis Pharmaceuticals Corporation |
| Phase II Study of Everolimus Combined With Octreotide LAR to Treat Advanced GI NET (EVERLAR) a | II | Everolimus and octreotide LAR combination | Advanced, nonfunctioning, well-differentiated GINETs | Grupo Espanol de Tumores Neuroendocrinos |
| Study of Everolimus Treatment in Newly-diagnosed Patients With Advanced Gastrointestinal Neuroendocrine Tumors | II | Everolimus | Well-differentiated or moderately differentiated advanced (metastatic or unresectable) gastrointestinal or pancreatic NETs | Hellenic Cooperative Oncology Group |
| RAMSETE: RAD001 in Advanced and Metastatic Silent Neuro-endocrine Tumors in Europe (RAMSETE/CDE16) a | II | Everolimus | Progressive, low- or intermediate-grade, nonfunctional, nonpancreatic NET | Novartis Pharmaceuticals Corporation |
| Safety and Tolerability of Pasireotide LAR in Combination With Everolimus in Advanced Metastatic NETs (COOPERATE-1) c | I | Pasireotide in combination with everolimus | Grade 1 or 2 advanced pulmonary or gastroenteropancreatic NET | Novartis Pharmaceuticals Corporation |
| Pasireotide in Combination With RAD001 in Patients With Advanced Neuroendocrine Tumors a | I | Pasireotide in combination with Everolimus | Low-grade or intermediate-grade locally unresectable or metastatic NETs | Dana-Farber Cancer Institute; Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital; Massachusetts General Hospital; Novartis |
| Cixutumumab, Everolimus, and Depot Octreotide Acetate in Patients With Advanced Low- to Intermediate-Grade Neuroendocrine Carcinoma a | I | Combination of cixutumumab, everolimus, and octreotide | Low- or intermediate-grade neuroendocrine carcinoma | M.D. Anderson Cancer Center at University of Texas; National Cancer Institute |
| VEGF inhibitors | ||||
| Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors (A021202) | II randomized | Pazopanib vs placebo b | Progressive low- or intermediate-grade neuroendocrine carcinoma (foregut, midgut, hindgut origin; nonpancreatic) | National Cancer Institute; Alliance for Clinical Trials |
| A Study of Sunitinib vs Placebo in Combination With Lanreotide in Patients With Progressive Advanced/Metastatic Midgut Carcinoid Tumors (SUNLAND) | II randomized | Lanreotide plus either sunitinib or placebo b | Midgut low- or intermediate-grade NETs | Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) Pfizer Ipsen |
| Pazopanib as Single Agent in Advanced NETs a | II | Pazopanib | Pancreatic islet cell tumors, well-differentiated GINETs, pulmonary carcinoids, and well-differentiated thymic carcinoids | Grupo Espanol de Tumores Neuroendocrinos |
| A Study of Axitinib in Advanced Carcinoid Tumors a | II | Axitinib | Well-differentiated and moderately differentiated NETs of the aerodigestive tract, as well as rare primary sites (renal, ovarian, thymic, hepatic) | H. Lee Moffitt Cancer Center; National Comprehensive Cancer Network Pfizer |
| Ziv-Aflibercept for Advanced Progressive Carcinoid Tumors a | II | Ziv-aflibercept plus octreotide | Well-differentiated or moderately differentiated neuroendocrine tumors | Dana-Farber Cancer Institute |
| Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors | II | Nintedanib | Low- or intermediate-grade NETs of nonpancreatic origin; patients on stable dose of octreotide | Roswell Park Cancer Institute; National Cancer Institute |
| A Study of Famitinib in Patients With Advanced or Metastatic Gastroenteropancreatic Neuroendocrine Tumor | II | Famitinib | Metastatic low- or intermediate-grade gastroenteropancreatic NET | Jiangsu HengRui Medicine Co., Ltd; Cancer Institute and Hospital, Chinese Academy of Medical Sciences |
| Cabozantinib in Advanced Pancreatic Neuroendocrine and Carcinoid Tumors | II | Cabozantinib (XL184) | Carcinoid or pancreatic NET; patients with pancreatic NET must have had previous VEGF inhibitor treatment | Massachusetts General Hospital |
| Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors d | II | Regorafenib | Advanced metastatic, progressing carcinoid, or pancreatic islet cell cancers | University of Southern California; National Cancer Institute (NCI) |
| Other | ||||
| YF476 in Patients With Type II Gastric Carcinoids Associated With Zollinger-Ellison Syndrome | II | YF476 (gastrin antagonist) | Patients with Zollinger-Ellison syndrome and type II gastric carcinoids or their precancerous cells | National Institute of Diabetes and Digestive and Kidney Diseases |
| A Phase 2 Study of Fosbretabulin in Subjects With Gastrointestinal Neuroendocrine Tumors With Elevated Biomarkers | II | Fosbretabulin tromethamine | Well-differentiated, low- to intermediate-grade GINETs with increased levels of biomarkers and progressive disease | OXiGENE |
| Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers | II | Carfilzomib (proteasome inhibitor) | Advanced (unresectable or metastatic) well-differentiated or moderately differentiated NETs including typical carcinoid and pNETs | SCRI Development Innovations, LLC; Onyx Pharmaceuticals |
| A Pilot Study of Metformin Treatment in Patients With Well-differentiated Neuroendocrine Tumors (MetNet) | II | Metformin | Metastatic well-differentiated NET grade 1 or 2 | Instituto do Cancer do Estado de São Paulo |
| Recombinant Anti-tumor and Anti-virus Protein for Injection to Treat Advanced Neuroendocrine Tumors d | II | Novaferon | Low- or intermediate-grade advanced (unresectable or metastatic) NETs | The Affiliated Hospital of the Chinese Academy of Military Medical Sciences |
| LEE011 in Neuroendocrine Tumors of Foregut Origin d | II | LEE011 (CDK4/6 inhibitor) | Well-differentiated foregut NETs | M.D. Anderson Cancer Center; Novartis Pharmaceuticals Corporation |
| A Study to Determine Safety, Pharmacokinetics and Pharmacodynamics of Intravenous TKM 080301 in Neuroendocrine Tumors (NET) and Adrenocortical Carcinoma (ACC) Patients a | I/II | TKM-080301 (small interfering RNA directed against poliolike kinase 1) | Refractory NETs or adrenocortical carcinomas | Tekmira Pharmaceuticals Corporation |
| Biological Study of Resveratrol’s Effects on Notch-1 Signaling in Subjects With Low Grade Gastrointestinal Tumors a | I | Resveratrol | Low-grade GINETs | University of Wisconsin Paul P. Carbone Comprehensive Cancer Center |
Related posts:
Neuroendocrine Tumors—Current and Future Clinical Advances
Surgical Treatment of Small Bowel Neuroendocrine Tumors
Role of Somatostatin Analogues in the Treatment of Neuroendocrine Tumors
Neuroendocrine Tumors—Current and Future Clinical Advances
Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors
Surgical Management of Pancreatic Neuroendocrine Tumors
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
