Refractory Carcinoid Syndrome Research Articles

What Is Carcinoid Syndrome? A Critical Appraisal of Its Proposed Mediators.

Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and improved overall survival of patients with NEN over recent decades, patients are increasingly suffering from chronic and refractory CS symptoms. At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. This systematic review is the first to critically appraise the available evidence for the various hormonal mediators considered to play a causative role in CS. Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.

P-290 Treatment sequences and locoregional therapies for patients with carcinoid and refractory carcinoid syndrome. A multicentric cohort analysis

P-290 Treatment sequences and locoregional therapies for patients with carcinoid and refractory carcinoid syndrome. A multicentric cohort analysis

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

High-Dose Somatostatin Analogs for the Treatment of Neuroendocrine Neoplasms: where are we Now?

Neuroendocrine tumors (NET) represent a complex and heterogeneous group of malignancies arising from the diffuse endocrine cells and other cells derived from the neural crest. Advanced disease is observed at diagnosis in more than one-third of patients. Somatostatin analogs (SSA) are the cornerstone in advanced well-differentiated NET treatment. Unfortunately, most patients will eventually develop resistance to SSA treatment by different mechanisms that are not fully understood. In some cases of refractory carcinoid syndrome or progressive disease, the increase of SSA dose may help to reach out a symptomatic and/or tumor growth control. The clinical evidence behind above-label SSA administration is limited and should be individualized and discussed patient by patient. Some questions regarding high-dose SSA use are unsolved, such as the optimal dose to use, the frequency of administration, or the need of deepen molecular understanding that could help to adequately select patients for this approach.

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

BackgroundPreclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET).Aim(s)To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin.Patients and methodsSingle-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days.ResultsFrom 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2–9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases.ConclusionMetformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

Systemic Therapy for Neuroendocrine Neoplasms

AbstractNeuroendocrine neoplasms (NENs) are heterogeneous malignancies which are becoming more common. Systemic treatment is considered for patients with advanced disease, and treatment decisions are often driven by the histological grade of the tumor and the site of primary. Somatostatin analogues are the first-line option of choice for gastroenteropancreatic NENs but subsequent options may include the targeted agents everolimus and sunitinib as well as peptide receptor radionuclide therapy. Telotristat is a new option for the treatment of refractory carcinoid syndrome diarrhea. Chemotherapy is infrequently used for Grade 1 to 2 NENs (except for the combination of capecitabine and temozolomide) but is the mainstay of therapy for Grade 3 neuroendocrine carcinomas. Bronchial NENs are graded differently and there are few proven options for systemic treatment. Optimal integration of available systemic therapies, the timely recognition of tumor heterogeneity, and the use of nuclear medicine are areas of ongoing research. Finally, the patient experience is impacted by factors such as delayed diagnosis and symptoms of carcinoid syndrome. Clinicians need to account for patient priorities and disease characteristics to individualize therapy choices for patients with advanced NEN.

Oral Ondansetron Offers Effective Antidiarrheal Activity for Carcinoid Syndrome Refractory to Somatostatin Analogs.

Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome. We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit. A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months). Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit. Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders.

Liver Transplantation in a Young Patient with Severe and Refractory Carcinoid Syndrome

Objective: To report the role of liver transplantation in the management of refractory carcinoid syndrome. Methods: We describe the clinical course, biochemical, radiographic, and histopathologic features of a patient with severe refractory carcinoid syndrome due to a metastatic well-differentiated enterochromaffin cell neuroendocrine tumor of the jejunum. We also review and summarize the literature on liver transplantation in this setting. Results: An 18-year-old patient presented with a 3-year history of progressive palpitations, flushing, abdominal pain, and diarrhea. Initial imaging studies demonstrated multiple cystic liver lesions; biochemistry confirmed elevated 24-hour urinary 5-hydroxy-indolacetic acid (5-HIAA) levels. She was managed with somatostatin analogues followed by a partial small-bowel resection. Five sessions of liver embolization and escalating somatostatin analogues failed to control her symptoms or normalize urinary 5-HIAA levels. Cross-sectional imaging detected disease only in the...

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors

There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors (NETs). Key phase 3 studies include the CLARINET trial, which evaluated lanreotide in patients with nonfunctioning enteropancreatic NETs; the RADIANT-2 and RADIANT-4 studies, which evaluated everolimus in functioning and nonfunctioning NETs of the gastrointestinal tract and lungs; the TELESTAR study, which evaluated telotristat ethyl in patients with refractory carcinoid syndrome; and the NETTER-1 trial, which evaluated Lu-DOTATATE in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and postoperative surveillance) are summarized in this article. Surgical guidelines are described in a companion article.

Refractory carcinoid syndrome: a review of treatment options.

Carcinoid syndrome (CSy) is a constellation of symptoms that may commonly present in patients with well differentiated neuroendocrine tumors (NETs), with somatostatin analogs (SSAs) being the first-line option for symptom management. However, symptomatic progression eventually occurs and in this scenario of a refractory CSy; several treatment options have been studied such as dose escalation of SSA, interferon and liver-directed therapies. Nevertheless, recent phase III trials have contributed to the understanding and management of this condition. We performed a comprehensive review of interventional studies examining refractory CSy to provide the evidence for current treatment options and propose a treatment sequence.

78IN - Treatment Landscape and Ongoing Clinical Trials in Neuroendocrine Tumors

ABSTRACT Therapy in neuroendocrine tumors (NET) is guided by the presence of hormone-related syndromes, somatostatin receptor status, histology (ki67), aggressiveness and extrahepatic spread. Therapy aims at syndrome and tumor control. Surgery is the only option toward a cure. Loco-regional therapies (e.g. embolisation, radiofrequency ablation) may reduce tumor load and improve clinical syndromes. Somatostatin analogs (SSA) and interferon-alpha are established therapies for carcinoid syndrome (CS). An oral serotonin synthesis inhibitor is evaluated in refractory CS (TELESTAR). Other medical therapies (PPI; diazoxide) are used for syndrome control depending on the tumor type. Antiproliferative therapy options include SSA, novel targeted drugs and systemic chemotherapy. Large placebo-controlled trials provide evidence of the antiproliferative efficacy of SSA (octreotide and lanreotide) in midgut NET and enteropancreatic NET, respectively. Similarly, the novel molecular-targeted therapies, the multiple tyrosine kinase inhibitor (TKI) sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus have been evaluated in placebo-controlled trials, and approved in progressive pancreatic NET. Novel TKIs and combinations of everolimus with SSA or bevacizumab are currently explored in clinical trials to improve response rates or overcome drug resistance. Everolimus and sunitinib (RADIANT-4; Sunland study) are under evaluation in non-pancreatic NET, as well as high dose octreotide vs. Lu-DOTATATE in midgut NET (NETTER-1). Systemic chemotherapy has very limited if any value in slowly growing advanced NET (“carcinoids of different sites”), but is established therapy (streptozotocin/ 5-FU) in pancreatic NET. Future studies will have to establish in which line targeted drugs will be used, especially in pancreatic NET (SEQTOR trial). Molecular markers to preselect patients for specific therapies still need to be identified. Systemic chemotherapy is standard therapy in neuroendocrine carcinoma (NEC G3; first line cisplatin or carboplatin/ etoposide; second-line options include FOLFOX, FOLFIRI or temozolomide +/- capecitabine), however response rates are overall short-lasting (median 4-6 months).

Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in nonpancreatic neuroendocrine tumors (NET).

e15004 Background: Clinical activity of everolimus, an allosteric TORC1-selective inhibitor, has been established in pancreatic NET. CC-223 is an ATP-competitive inhibitor of the mTOR kinase, inhibiting both TORC1 and TORC2 complexes. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with non-pancreatic NET and selected other tumors were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated. Preliminary results from the NET cohort (n=23) are reported here. Subjects with non-pancreatic tumors of gut origin with progression within 12 months and receiving ongoing treatment with somatostatin analogs (SSA) were eligible. The majority of tumors were of midgut origin with liver metastases; 9 subjects had refractory carcinoid syndrome despite SSA use. The most common (&gt; 20%) related adverse events (all grades) were stomatitis, diarrhea, fatigue, anorexia, nausea and rash. In addition, related serious adverse events included one case of transient dehydration/renal insufficiency (1). CC-223 dose reduction to 30 or 15 mg was required in 57% of subjects, usually during cycle 1 or 2, but thereafter treatment was well tolerated. Inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers was confirmed in blood cells. Reduction in glucose uptake (&gt; 25% change in SUV) on PET imaging at day 15 was observed in 54% (7/13) subjects. All evaluable subjects (n=10) reported stable disease (SD) with treatment ongoing at up to 9 cycles (median 6; range 4 – 9). Although not prospectively collected, 6 subjects with refractory carcinoid syndrome reported complete resolution of flushing (5) or improvement in diarrhea (1). Symptom improvement generally occurred within the first week of dosing and persisted despite dose reduction in 5 subjects. Conclusions: Encouraging signals of biomarker and clinical activity were observed in NET including prolonged SD and symptomatic improvement in subjects with refractory carcinoid syndrome. Due to the frequency of early dose reductions, the NET cohort will be explored further at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.

Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database.

4142 Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n=82) and 23% of pNET pts (n=15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n=40), colorectal (n=4), and unknown (n=34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n=53, 65%), tumor progression (n=21, 25%), high urine 5-HIAA (n=1, 1%) and unknown (n=7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n=5, 33%), tumor progression (n=9, 60%), and unknown (n=1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n=5, 33%), 30mg every 2 weeks (n=4, 27%), and 60 mg every 4 weeks (n=4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.

Systemic Treatment in Unresectable Metastatic Well-Differentiated Carcinoid Tumors

This study aimed to develop expert consensus for the use of systemic treatments for unresectable metastatic well-differentiated (grade 1-2) carcinoid tumors using the RAND/UCLA modified Delphi process. After a comprehensive literature review, 404 patient scenarios addressing the use of systemic treatments for carcinoid tumors were constructed. A multidisciplinary panel of 10 physicians assessed the scenarios as appropriate, inappropriate, or uncertain (on a 1-9 scale) or as an area of disagreement before and after an extended discussion of the evidence. Experts were medical and surgical oncologists, interventional radiologists, and gastroenterologists. Among rated scenarios, disagreement decreased from 14% before the meeting to 4% after. Consensus statements about midgut carcinoids included the following: (1) Somatostatin analogs are appropriate as first-line therapy for all patients; (2) In patients with uncontrolled secretory symptoms, it is appropriate to increase the dose/frequency of octreotide long-acting repeatable up to 60 mg every 4 weeks or up to 40 mg every 3 weeks as second-line therapy for refractory carcinoid syndrome. Other options may also be appropriate. Consensus was similar for non-midgut carcinoids. The Delphi process provided a structured methodological approach to assist clinician experts in reaching consensus on the appropriateness of specific medical therapies for the treatment of advanced carcinoid tumors.

Above-label doses of octreotide-LAR in patients with metastatic small-intestinal carcinoid tumors.

e14579 Background: Octreotide LAR is indicated for treatment of the malignant carcinoid syndrome, and has been studied at doses of 10-30mg intramuscularly every 4 weeks. It has also been proven to delay time to progression of metastatic midgut carcinoid tumors at a dose of 30mg every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximal labeled dose. We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of ‘above-label’ dosing and outcomes. Methods: A retrospective chart-review was performed using a database of patients with metastatic small-bowel carcinoid tumors treated at the Moffitt Cancer Center between the years 2000 and 2010. Data included the maximal dose of octreotide LAR administered, reasons for change in dose or frequency (above the labeled dose of 30mg every 4 weeks), and clinical responses to dose change. Results: 337 patients were considered evaluable, among whom 99 patients (27%) underwent at least one increase in dose or frequency of octreotide-LAR above the standard labeled dose. The most common maximal doses were 40mg every 4 weeks (37 patients), 60mg every 4 weeks (34 patients), and 30mg every 3 weeks (17 patients). The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients) and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 62% experienced improvement in diarrhea and 56% experienced improvement in flushing. Conclusions: In clinical practice, octreotide LAR is commonly prescribed in doses or schedules above the labled dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from the change. Prospective data is needed to evaluate this strategy.

Medical treatment consensus in unresectable midgut gastrointestinal neuroendocrine tumors.

e14610 Background: Neuroendocrine tumors (NETs) comprise mostly carcinoid or pancreatic NETs and are rare with symptoms that may be difficult to control. Current treatment guidelines lack some specificity. We summarize an expert panel consensus on medical treatment of well-differentiated unresectable midgut NETs. Methods: Consensus statements were developed via RAND/UCLA Delphi process, which involved a diverse group of physician experts (e.g., by specialty, geography, practice) developing comprehensive clinical patient scenarios and rating the scenarios on the appropriateness of various medical therapies before and after a face-to-face meeting. Experts and moderator were blinded to funding source. Scenarios were rated on a 1-9 scale and were labeled as appropriate, inappropriate, or uncertain. Scenarios with &gt;2 ratings in 1-3 and &gt;2 in 7-9 range were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists (age: 38-63 years) were from the northeast, midwest, south, and west regions. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean 15.5 years (range: 6-33). Panelists rated 202 scenarios. The proportion for which there was disagreement decreased from 11.7% (23 scenarios) before the meeting to 4.5% (9) after. Post-meeting, 49% (99 scenarios) were rated inappropriate, 29.7% (60) were uncertain, and 16.8% (34) were appropriate. Consensus statements from the scenarios included: 1) it is appropriate to use somatostatin analogs (SA) as 1st-line therapy in all patients, 2) it is appropriate to increase the dose/frequency of octreotide-LAR as 2nd-line therapy in patients with uncontrolled symptoms up to 60 mg every 4 weeks or up to 40 mg every 3 or 4 weeks for refractory carcinoid syndrome. Other treatment options may also be appropriate in 2nd-line. Conclusions: Treatment consensus obtained in this study is concordant with NCCN recommendations. The Delphi process allowed quantification of ratings in a systematic and reliable way while improving consensus in a group of physicians on the appropriateness of medical therapies in midgut NETs.

Relief of bowel-related symptoms with telotristat etiprate in octreotide refractory carcinoid syndrome: Preliminary results of a double-blind, placebo-controlled multicenter study.

4085 Background: Diarrhea associated with carcinoid syndrome has been attributed to tumor production of serotonin. Telotristat etiprate, (LX1032, LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study explored the safety, tolerability, and efficacy of telotristat etiprate in carcinoid patients with octreotide-refractory diarrhea. Methods: Carcinoid patients with ≥4 bowel movements (BMs)/day on octreotide were randomized 3:1 to receive telotristat etiprate or placebo as double-blind treatment. Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA), BM frequency, and self-reported bowel-related symptoms. Subjects were asked “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain or discomfort?” Responses (yes or no) were analyzed as categorical variables. Results: 16 patients enrolled in the 4 escalating dose cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on placebo. Median age: 62 yrs; mean 6.3 BMs/day (range, 4-10). AEs included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. In treated subjects, adequate relief was reported as: Week 1 - 6/18 (33.3%), Week 2 - 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 - 6/13 (46.0%). No placebo subjects reported improvement at any timepoint. Biochemical response (≥50%reduction in u5-HIAA) and BM response (≥30% reduction in daily BMs for 2 weeks) were associated with reporting of adequate relief. For evaluable telotristat etiprate-treated patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) experienced a clinical (BM) response; no placebo subjects achieved either biochemical or clinical response. Conclusions: Treatment with telotristat etiprate was associated with decreases in u5-HIAA and BM frequency, and with self-reported relief of bowel related symptoms. Treatment in an extension phase with open-label telotristat etiprate is ongoing.

Relief of bowel-related symptoms with telotristat etiprate in octreotide refractory carcinoid syndrome: Preliminary results of a placebo-controlled, multicenter study.

312 Background: Diarrhea associated with carcinoid syndrome (CS) has been attributed to tumor production of serotonin. Telotristat etiprate, (LX1032, LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study explored the safety, tolerability, and efficacy of telotristat etiprate in carcinoid patients with octreotide-refractory diarrhea. Methods: Carcinoid patients with &gt;4 bowel movements (BM)/day on octreotide were randomized 3:1 to receive telotristat etiprate or placebo. Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA) secretion, BM frequency, and self-reported relief of bowel-related symptoms. Subjects were asked “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain or discomfort?” Responses (yes or no) were analyzed as categorical variables. Results: 16 patients enrolled in the 4 escalating dose cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on placebo. Median age was 62 yrs with a mean 6.2 BMs/day (range 4-10). AEs included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. In treated subjects, adequate relief was reported as follows: Week 1 – 6/18 (33.3%), Week 2 – 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 – 6/12 (50.0%). No placebo subjects reported improvement at any timepoint. Biochemical response (&gt;50%reduction in u5-HIAA) and BM response (&gt;30% reduction in daily BM for 2 weeks) were associated with reporting of adequate relief. For evaluable telotristat etiprate-treated patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) experienced a clinical (BM) response; no placebo subjects achieved either biochemical or clinical response. Conclusions: Treatment with telotristat etiprate was associated with decreases in u5-HIAA and BM frequency, and with self-reported relief of bowel related symptoms. Treatment in an extension phase with open-label telotristat etiprate is ongoing.

The new somatostatin analog SOM230 in the treatment of acromegaly

Most GH-secreting pituitary adenomas predominantly express sst2 and sst5, while sst1 and sst3 are moderately and sst4 almost not expressed. The clinically available SS-analogs octreotide and lanreotide display a high, low and moderate affinity to sst2, sst1+3 and sst5 respectively. Saveanu et al. reported that due to the heterogeneous expression of sst2 and sst5 subtypes in GH-secreting adenomas, a bispecific analog, such as BIM-23244 that can activate both receptors, and may achieve a better control of GH hypersecretion of acromegalic tumors. Bruns et al synthesized SOM230, a new cyclic hexapeptide somatostatin (SRIF) analog which binds with nanomolar affinity to sst1, 2, 3 and 5 receptors. In short term (1h) rat experiments, SOM230 and SMS 201–995 inhibit GH release with similar potency, but the effect of SOM230 was longer lasting, due to its increased metabolic stability. The plasma half-life of SOM230 in rats is 23h, as compared to 2h for SMS 201–995. The improved metabolic stability of SOM230 was confirmed in monkeys and humans. Continuous treatment of rats with SOM230 at 10µg/kg/h, decreased IGF-1 plasma levels on day 2 by 90% while under SMS 201–995 treatment plasma IGF-1 levels decreased only by 49%. After a 2-week infusion of somatostatin analogues in rats the suppression of GH and IGF-1 levels by SOM230 was still pronounced, while the response to SMS 201–995 was largely lost. Similar results were obtained in dogs and monkeys. Normalization of GH values was obtained recently in a first clinical study in acromegalic patients acutely treated with SOM230. Most importantly, SOM230 reduced plasma GH level in a patient unresponsive to octreotide and this patient showed a high expression of sst5. Similarly, sst5 receptors were found to be heavily expressed in ACTH secreting pituitary cells from Cushing's patients (Hofland et al.,) and SOM230 is shown strongly inhibiting ACTH release in vitro, in contrast to octreotide. In conclusion, SOM230 might be more efficacious than octreotide in established indications and has the potential for the treatment of additional endocrine indications, such as Cushing's disease, as well as non-endocrine indications, due to its multiligand binding properties. Studies evaluating effects of SOM230 in patients with Cushing's disease and somatostatin refractory carcinoid syndrome are ongoing.