Neoplasms

All Conditions

Symptoms and General Pathology

Rare Diseases

Neuroendocrine Tumors

Disease Progression

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Gastro-enteropancreatic Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Gastrointestinal Agents

Somatostatin

Octreotide

Lanreotide

Antineoplastic Agents, Hormonal

Hormones

Hormone Antagonists

Somatostatin analog (octreotide long-acting release (LAR) 30 mg or lanreotide 120 mg) will be given every four weeks for a duration of 18 months.

Somatostatin analog treatment (octreotide LAR 30 mg or lanreotide 120 mg) will be withdrawn for a duration of 18 months.

Somatostatin analog treatment every 4 weeks

Somatostatin analog

Marc U Peeters, MD

Timon Vandamme, MD

Wim Demey

Marijke Ulenaers

Karen Geboes

Willem Lybaert

Chris Verslype

Isabelle Sinapi

Timon Vandamme

Frank Van Fraeyenhove

Isabelle Maurissen

Ioannis Karfis

Ivan Borbath

Laurence Lousberg

Theo Van Voorthuizen

Loes Latten-Jansen

Wouter Dercksen

Heinz-Josef Klumpen

Annemiek Walenkamp

Wouter de Herder

Marc Peeters, MD

The SAUNA trial is a multi-national, multi-centre, open-label, randomised, controlled, pragmatic clinical trial in patients with advanced, non-functional gastroenteropancreatic (GEP) neuroendocrine tumours (NET) with progressive disease on first-line therapy with somatostatine analogues (SSA). Eligible patients will be divided into two substudies according to the second-line therapy of choice (peptide receptor radionuclide therapy (PRRT) or targeted therapy, at the discretion of the local investigator). Patients within each substudy will be randomised 1:1 between continuation or withdrawal from SSA at the start of second-line systemic therapy. Stratification will occur according to study site and according to the Ki67 value (below 10% (grade 1 and low grade 2) and equal to or above 10% (high grade 2)).

Continuing Somatostatin Analogues Upon Progression in Neuroendocrine Tumour pAtients

Continuing Somatostatin Analogues Upon Progression in Neuroendocrine Tumour pAtients - The SAUNA Trial

QoL measurement with 30-item Quality of Life Questionnaire (QLQ-C30)

QoL measurement with 21-item QoL questionnaire in the gut, pancreas and liver neuroendocrine tumours (QLQ-GINET21)

QoL measurement with EuroQol-5 Dimensions-5 Level questionnaire

Health technology assessment (HTA) analysis

Safety will be reported in terms of incidence and severity of (serious) adverse events

Erasmus Medical Center

ZonMw: The Netherlands Organisation for Health Research and Development

Belgium Health Care Knowledge Centre

University Hospital, Antwerp

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

Liver Extracts

1. Patients with cirrhosis without HCC in all liver function classes already receiving specific therapy for cirrhosis who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study
2. Patients with cirrhosis with multifocal HCC and clinical and/or radiological signs of persistence or recurrence of HCC in presence or absence of trombosis of the portal vein, with a single nodule of \>6 cm in size or multiple nodules of \>3 cm in size who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study

Octreotide-LAR intramuscular, dose of 30 mg every 28 days to increase up to 60 mg; lanreotide autogel 120 mg deep subcutaneous every 28 days for 3 months then uptitrated according with the protocol.

Octreotide-LAR, Lanreotide Autogel

Locoregional treatments

Annamaria Colao, MD, PhD

The hepatocellular carcinoma (HCC) represents more than 5% of all human malignancies, with more than 500,000 deaths per year (1). In Campania region, mortality for HCC is 2 times higher than in the rest of Italy because of a higher locally prevalence of hepatitis-C virus infection.

Development of HCC in liver cirrhosis is associated with increased DNA synthesis and regeneration of hepatocytes (2). Hepatocyte growth factor, the transforming growth factor-α, the fibroblast growth factor are well studied (3,4) while the insulin-like growth factor system (IGF-I, IGF-II and their binding proteins) has been less investigated. IGF-I and IGF-II modulate growth, metabolism and cell differentiation and have specific receptors in the liver (5). IGF-I levels in the upper normal range have been associated with an increased risk to develop prostate cancer (6), breast cancer (7) and colon cancer (8). Some data report increased expression of IGF-II in HCC (9,10) and others suggest a role of increased IGF-I bioavailability in HCC (11). We reported increased IGF-I/IGFBP-3 ratio in patients with HCC compared with those with cirrhosis with a similar liver function, so suggesting increased IGF-I bioavailability in HCC (12).

There is no currently medical treatment for patients with advanced HCC which has a very poor prognosis (survival \<6 months). Because of limited liver function, classical chemotherapy cannot be applied (13). In patients with HCC without cirrhosis, surgery is possible only in 5% while in those with cirrhosis first-line treatment is still questioned as survival is \<50% three years after operation. Patients suitable for local resection of HCC are only those with Child-Pugh's "hyper A" liver function class, who are a minority (14-16). Percutaneous resection treatments may treat approximately 70%-90% of tumors with maximal diameters of \<3 cm (15,17-19).

Somatostatin analogues are indicated in patients with neuroendocrine tumors expressing somatostatin receptors type 2 and 5 and has excellent safety profile. In advanced HCC, some studies demonstrated beneficial effects (20,21) while some others did not (22,23).

Only a few data are available on somatostatin receptor expression in HCC (24,25). Somatostatin analogues have also a clear-cut inhibitory effect on circulating IGF-I levels with a potential additional effect in delaying HCC progression.

Study objectives

1. To evaluate relationships between GH/IGF-I and IGF-II axis and development and progression of HCC;
2. To evaluate the expression of somatostatin receptor expression in biopsies of HCC by quantitative RT-PCR and immunohistochemistry and in vivo by octreoscan;
3. To evaluate the efficacy of octreotide-LAR or lanreotide-autogel as compared to placebo on clinical symptoms, liver function, biological markers and tumor dimensions by ultrasonography in advanced HCC patients;
4. To correlate the response to somatostatin analogues to somatostatin receptor expression in vitro and in vivo and suppression of the IGF-I and -II axis.

Study design

This is a pilot, open, prospective, monocentric study addressed to:

1. patients with liver cirrhosis and multifocal HCC with or without portal vein invasion;
2. patients with liver cirrhosis and single HCC nodule of \>6 cm in size with or without portal vein invasion \[principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)\];
3. patients with liver cirrhosis and more than 3 HCC nodules of \> 3 cm in size with or without portal vein invasion \[principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)\];
4. patients with cirrhosis without HCC.

Study protocol All enrolled subjects will be subjects to a baseline evaluation and a post-treatment evaluation according with the treatment protocol (see below).

A) Clinical study in vivo diagnostic routine analysis (clinical evaluation, ECG, chest X-ray, blood chemistry, analysis of liver function, α-FP assay, CEA, liver ultrasonography and angio-ultrasonography, abdominal CT scan or MRI); blood sampling for GH, IGF-I, IGF-II, IGFBP-3, ALS, insulin, IGFBP-1 and IGFBP-2; whole body scintigraphy with radiolabeled octreotide (octreoscan) liver biopsy in patients in good clinical condition according with good clinical practice procedures. Biopsy will be performed under ultrasonography guidance with a 19G or 21G needle after local subcutaneous anesthesia (lidocaine 2%). Abdominal ultrasonography will followed biopsy to exclude hemorrage. The tissue sample will be stores at -80° until analysis.

B) Morphological in vitro study the expression of somatostatin receptors will be performed by immunohistochemistry in sequential sections as well as by RT-PCR using specific primers for all receptors; the study includes an analysis of classical histology and immunohistochemical markers. The study includes positive and negative controls for an appropriate analysis of the results.

Study duration

The first study is a pilot study which expected number of patients fulfilling the inclusion criteria is 15 to address the issue of liver cirrhosis with HCC. The enrollment period will be of 12 months or shorter if the 15 patients are enrolled in a shorter time. The observational period is expected to be 3-12 months, according with previous studies. Treatment will be continued in all survivors even if the study will end after 12 months, according with previous studies. Subsequently, the study will proceed with a placebo-controlled randomized study according with the results obtained in the pilot study and will enroll 30-60 in case of patients with HCC without cirrhosis and 20-40 for patients with liver cirrhosis and HCC. All patients will be registered in dedicated CRF and data will be collected by investigators not involved in data analysis.

Withdrawal from the study

The causes of early study withdrawal will be recorded according with:

1. adverse events;
2. no treatment response or patients' clinical condition deterioration according with the investigator judgment;
3. major protocol violation;
4. patient's withdrawal of the consent.

Concomitant therapies All patients will continue all treatments as per investigator judgment. In case some therapy will be withdrawn this will be recorded in the CRF and analyzed as a potential beneficial effect of somatostatin analogues therapy.

Main outcome measures A) Efficacy parameters

For cirrhosis:

Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

For HCC:

Prolongation of the survival curve (\>6 months) Stabilization or reduction of tumor size Reduction or disappearance of portal vein thrombosis Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

Expected results

The expected results are:

1. Both cirrhotic and normal liver express somatostatin receptors. The different receptor pattern can suggest a role of this receptor subtype in HCC development. The correlation study can also give insight into any role of somatostatin receptors in differentiation, staging and prognosis of HCC.
2. Treatment with somatostatin analogues will prolong survival in advanced HCC patients. This should occur according with liver function before starting the treatment. We expect that patients having tumors with high expression of SS-2 receptors on their HCC will have the longest survival.

GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma

Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression

Ospedali dei Colli

Federico II University

Annamaria Colao

Nervous System Diseases

Gland and Hormone Related Diseases

Musculoskeletal Diseases

Adenoma

Pituitary Diseases

Acromegaly

Pituitary Neoplasms

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Bone Diseases

Bone Diseases, Endocrine

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Philippe BALTZINGER, MD

Saïd CHAYER, PhD, HDR

Ninon STAHL, MD

At present there are no recommendations regarding the possibility of discontinuing treatment in cases of recurrent acromegaly with good hormonal control. Discontinuation of treatment is therefore most often decided by the practitioner, on the basis of his experience and knowledge of the patient, the long-term course with somatostatin analogues being very little described.

Thus, although hormonal control is achieved in a majority of cases under medical treatment, we do not know if it is possible to stop treatment and in this case how the pathology evolves. It would appear that approximately 40% of patients defined as very good responders to somatostatin analogues may gradually space their injections.

Somatostatin Analogues in the Treatment of Relapsing GH Pituitary Adenomas After Surgery

Maintenance of Remission After Discontinuation of Somatostatin Analogues in the Treatment of Relapsing GH Pituitary Adenomas After Surgery

University Hospital, Strasbourg, France

Heart and Blood Diseases

Substance Related Disorders

Syndrome

Heart Diseases

Carcinoid Tumor

Malignant Carcinoid Syndrome

Serotonin Syndrome

Carcinoid Heart Disease

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Carcinoid Syndrome

Psychotropic Drugs

Amino Acids

Tryptophan

Lanreotide 120 mg q4w Telotristat Ethyl 250 mg TID

Telotristat Ethyl

120 mg Q4W deep subcutaneous injection in the superior external quadrant of the buttock or in the upper outer thigh

Juan Valle

Angela Lamarca

This is a randomized phase III clinical trial of Lanreotide combined with Telotristat ethyl or placebo for the first-line treatment in patients with advanced well differentiated small intestinal neuroendocrine tumours (siNET) with highly-functioning carcinoid syndrome to test whether telotristat ethyl plus lanreotide is more effective than placebo plus lanreotide in reducing the number of daily bowel movements.

In addition, the study allows evaluation of the biochemical response (5-HIAA and chromogranin-A), the reduction in the number of daily cutaneous flushing episodes, the improvement in abdominal pain/discomfort, health-related quality of life, improvement in gastro-intestinal and endocrine symptoms, changes in emotional functioning, the impact of discontinuation of telotristat ethyl/placebo on HRQOL and symptoms, and the safety and toxicity of the treatment.

Patients will enter into a screening/run-in period of 1 week to establish baseline characteristics and symptomatology. The baseline assessment of daily bowel movement, as assessed in an electronic diary, will be averaged over the run-in period.

Following the screening/run-in period, patients will be randomly assigned (1:1) to either the control arm or the experimental arm for 12 months. Randomization will be stratified according to the grade of tumour differentiation (grade 1 vs. grade 2) and by baseline number of bowel movements per day (4-6 versus \>6). A total of 94 patients will be randomly assigned (1:1) to either arm.

Upon randomization, all patients will enter the 12-month treatment period with lanreotide + telotristat ethyl/placebo (blinded). In the experimental arm, patients will receive the deep subcutaneous injection of lanreotide (120 mg) every 28 days and 250 mg orally three times daily (TID) of telotristat ethyl for 12 months. In the control arm, patients will receive the deep subcutaneous injection of lanreotide every 28 days (120 mg) and placebo orally TID for 12 months.

After completion of a minimum of 6 months on randomized blinded-treatment, the protocol allows for patients on treatment with telotristat ethyl/placebo to be unblinded in the event of "lack of symptom control". Unblinding due to "lack of symptom control" can happen at any time between 6 and 12 months of the blinded-treatment period. After unblinding, patient will interrupt protocol treatment and will be further treated as per clinician discretion.

All patients will be unblinded after a maximum of 12 months on randomized blinded-treatment.

After a follow-up of 12 months, patients will go off study except patients with carcinoid heart disease. Patients off study will be further treated as per clinician discretion.

Patients with carcinoid heart disease will continue open-label treatment on study (lanreotide + telotristat ethyl or lanreotide alone according to what they were receiving at unblinding at 12 months) for 4 additional years (open-label extension period). Patients with carcinoid heart disease who discontinue protocol treatment before 12 months will also enter the extension period for additional follow-up. Additional follow-up will last 4 years for these patients and will include 6-monthly cardiological assessments.

All efficacy analyses will be conducted in the Intention-to-treat population as primary analyses i.e. all 94 randomized patients will be analyzed in the arm they were allocated by randomization. Safety analyses will be performed on the Safety population i.e. on all patients who have received at least one dose of the study drugs.

The translational research projects include blood metabolite discovery and targeted assays to find new biomarker candidates of response to Telotristat.

Human biological material that will be collected for translational research purpose:

* whole blood, plasma and serum at baseline, 4 hours after first dose, 4 weeks, 12 weeks and at end of treatment visit with telotristat/placebo (due to end of study, disease progression or lack of benefit)
* archival tissue samples (formalin-fixed paraffin-embedded) will be retrieved for all patients at study entry. In addition, one EDTA blood tube of whole blood (10 ml) at baseline, 12 weeks and end of treatment (EOT visit) might be also collected for not yet pre-defined and further translational research.

Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3, together with the QLQ-GI.NET21 specific module designed for Neuroendocrine Tumours. The computer-adaptive testing (CAT) diarrhea scale will also be used. The baseline questionnaires must be completed during the screening period and before randomization. Subsequent questionnaires are completed at 4 weeks, 12 weeks, 24 weeks, 36 weeks and 52 weeks. Once a patient has stopped treatment, HRQoL data collection for that patient is required 1 month (28-35 days) after protocol treatment discontinuation.

Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome

Randomized Phase III Clinical Trial of Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome

The change from baseline in the number of bowel movements (BMs) per day

Intrapatient change from baseline in urine/serum/plasma 5-HIAA and chromogranin-A

Change from baseline in the number of daily cutaneous flushing episodes.

Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. Scale measures are: not at all; a little; quite a bit; very much.

Ipsen

European Organisation for Research and Treatment of Cancer - EORTC

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Continuing Somatostatin Analogues Upon Progression in Neuroendocrine Tumour pAtients	NCT05701241	Gastroenteropan...	Somatostatin an...	18 Years -	University Hospital, Antwerp
GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma	NCT00495846	Advanced Hepato...	Octreotide-LAR,... Locoregional tr...	18 Years - 75 Years	Federico II University
Somatostatin Analogues in the Treatment of Relapsing GH Pituitary Adenomas After Surgery	NCT05149495	Acromegaly		18 Years -	University Hospital, Strasbourg, France
Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome	NCT04065165	Small Intestina... Carcinoid Heart...	Telotristat Eth... Lanreotide	18 Years -	European Organisation for Research and Treatment of Cancer - EORTC
Somatostatin Analogues in the Treatment of Relapsing GH Pituitary Adenomas After Surgery	NCT05149495	Acromegaly		18 Years -	University Hospital, Strasbourg, France

Spots Global Cancer Trial Database for somatostatin analogues