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Lanreotide

Somatuline Autogel® to treat Functioning Midgut NeuroEndocrine Tumours (NET)

Somatuline Autogel injection 120mg for first 3 months then 120, 90 or 60 mg administered via the deep subcutaneous route every 28 days

lanreotide acetate

Matthew Hickling, MD

Circulating tumour cells (CTCs) are detectable in the blood in around 50% of patients with functioning NeuroEndocrine Tumours (NET) arising in the midgut area (tumours which are secreting hormones and are located in the area in the middle of the digestive system) and their presence usually means that the prognosis for the patient is poor. CTCs have also been shown to be valuable as predictive markers following treatment and there is increasing interest in using CTCs as 'liquid biopsies' that can help to inform treatment decisions. CTC analysis has the benefit of being relatively non- invasive and quick compared with a conventional CT scan and is therefore an attractive method of monitoring the tumour throughout the treatment period.

The purpose of this study is to assess the clinical value that enumeration will have in predicting the clinical symptomatic response and progression free survival in patients receiving Somatuline Autogel for functioning midgut NETs over a one year period.

Circulating Tumour Cells in Somatuline Autogel Treated NeuroEndocrine Tumours Patients

A Phase IV, Multicentre, Open Label, Single Group Exploratory Study to Assess the Clinical Value of Enumeration of Circulating Tumour Cells (CTCs) to Predict Clinical Symptomatic Response and Progression Free Survival in Patients Receiving Deep Subcutaneous Administrations of Somatuline® (Lanreotide) Autogel® to Treat the Symptoms of Functioning Midgut NeuroEndocrine Tumours (NET)

This endpoint was assessed using 2 efficacy variables:

* CTCs, enumerated at baseline and Weeks 5, 17, 25, 53
* Clinical symptomatic response, assessed by the use of symptom reporting

Subjects recorded 24-hour symptom frequency and severity for 7 days prior to first treatment (baseline), throughout the study, and up to 28 days following final drug administration. Symptoms were recorded by answering predetermined questions on the interactive voice response system (IVRS).

Subjects were considered to have a clinical symptomatic response between baseline and last study visit if any 1 of the following criteria were fulfilled: the average number of episodes of diarrhoea decreased by at least 50%, the average number of episodes of flushing decreased by at least 50%, the mode severity of flushing decreased by at least 1 level. Clinical symptomatic response was assessed as a qualitative variable (Yes/No) and reported according to CTC presence at baseline and overall.

Subjects underwent Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans at baseline, Visit 8 (Week 25) and Visit 15 (Week 53). Progression was assessed by investigators using RECIST v1.1, and classified as a complete response, partial response, stable disease, progressive disease or non evaluable.

The time point responses at Week 25 and Week 53 were analysed by CTC presence at baseline and overall. The percentage of subjects within each response category are presented. Percentages are based on the number of subjects in the concerned population with available responses.

The effect of lanreotide Autogel on the symptoms of diarrhoea and flushing in subjects was assessed through subject reporting of symptoms every 24-hours for the 7 days prior to treatment (baseline), for the first 16 weeks and on days 11 to 17 after each subsequent injection interval. After the final study drug injection at Week 49, subjects provided 24-hour symptom frequency on days 11 to 28 (up to Week 53). Symptom frequency was recorded by answering predetermined questions on the IVRS.

Mean change from baseline in frequency (number of episodes) of diarrhoea and flushing are described at Visit 2 (average number of episodes in Week 1) and at Visit 14 (average number of episodes over days 11 to 17 after Week 49 injection and over days 11 to 28 after Week 49 injection) by CTC presence at baseline and overall. A negative change indicates an improvement in symptoms from baseline.

The effect of lanreotide Autogel on the mode severity of flushing was assessed through subject reporting of symptoms every 24-hours for the 7 days prior to treatment (baseline), for the first 16 weeks and on days 11 to 17 after each subsequent injection interval until Week 49. After the final study drug injection at Week 49, subjects provided 24-hour symptom severity on days 11 to 28 (up to Week 53). Symptom severity was recorded by answering predetermined questions on the IVRS using a three-point system (mild, moderate or severe). The mode (most frequent) intensity of flushing are reported at baseline and at Visit 14 (average number of episodes over days 11 to 17 after Week 49 injection and over days 11 to 28 after Week 49 injection). Percentages of subjects in each severity category are based on the number of subjects in the analysis set with available responses. Data is presented according to CTC presence at baseline and overall.

The effect of lanreotide Autogel treatment on QoL was assessed using the EORTC QLQ-C30 at baseline, Weeks 13 (Visit 5), 25 (Visit 8) and 53 (Visit 15/end of study). The 30 item scale is divided into 9 multi item scales (including 5 functional scales, 1 global health status/QoL scale and 3 general symptom scales) and 6 single items. Possible answers to the first 28 items (all items except the 2 concerning global quality of life) go from 1 (Not at all) to 4 (Very much). The answers for the 2 last questions (Q29- 30) go from 1 (Very poor) to 7 (Excellent). All of the scales and single-item measures range in score from 0 to 100. For multi-item scales, the raw score will be calculated by the addition of item responses divided by the number of items. Higher scores for global health and functional domains indicate a better QoL, while higher symptom scores indicate worse symptoms.

The mean change from baseline at each time point is reported for each of the category subscores.

The effect of lanreotide Autogel treatment on QoL was assessed using the EORTC QLQ-G.I.NET21 at baseline, Weeks 13 (Visit 5), 25 (Visit 8) and 53 (Visit 15/end of study). The QLQ-G.I.NET21 questionnaire contained 21 questions that used a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much) to evaluate 3 defined multi-item symptom scales (endocrine, gastrointestinal and treatment related side effects), 2 single item symptoms (bone/muscle pain and concern about weight loss), 2 psychosocial scales (social function and disease-related worries) and 2 other single items (sexuality and communication). Each individual subscore was transformed to range from 0 to 100. Higher scores indicate worse symptoms or more problems. The mean change from baseline at each time point is reported for each of the category subscores.

Subjects underwent CT or MRI scans at baseline and Week 53. Progression was assessed by investigators using RECIST v1.1. The best overall response to study treatment is the highest time point response achieved by the subject and was assessed as a complete response, partial response, stable disease, progressive disease or non evaluable. For analysis of PFS, event dates were assigned to the first time that progressive disease was noted or the date of death. In case of progressive disease followed by death, the first event was considered in the analysis. Censoring dates were defined in subjects with no progressive disease or death before end of study.

At one year (end of study), the mean percentage of subjects who were alive and progression free, as calculated using the Kaplan-Meier method, is reported by CTC presence and overall.

Ipsen

Treatment emergent adverse events are reported and defined as any adverse event that occurred from the first study drug injection until 28 days after the last study drug injection.

Subjects received deep subcutaneous injections of lanreotide Autogel for 1 year to treat the symptoms of functioning midgut NETs.

A washout period was required for subjects receiving either subcutaneous octreotide (at least 2 weeks) or 1 injection of long-acting somatostatin analogue (at least 6 weeks) prior to treatment in the study.

Initially subjects began treatment with a dose of lanreotide Autogel 120 mg every 28 days for 3 months. Thereafter, the dose administered was determined on an individual subject basis by the treating clinician. Subjects could remain on the 120 mg dose, or be titrated to either 60 mg or 90 mg lanreotide Autogel, administered every 28 days according to their symptomatic response.

Lanreotide Autogel

years

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Medical Director

Clinical symptomatic response as dependent variable and CTC presence at baseline as explanatory variable was used to perform the logistic regression analysis.

Clinical Symptomatic Response = Yes(2)

Clinical Symptomatic Response = No(3)

Subjects with a baseline presence of CTCs, determined by either or both baseline CTC blood samples having a CTC enumeration \>0.

Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

CTC Presence at Baseline

Subjects with no baseline presence of CTCs, determined by both baseline CTC blood samples having a CTC enumeration = 0.

Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

No CTC Presence at Baseline

Analysis was performed on the Intention-to-treat (ITT) population, defined as all enrolled subjects who received at least one injection of study medication. Only subjects with data available for analysis are presented.

Assessment of Clinical Symptomatic Response

Week 25: Complete Response

Week 25: Partial Response

Week 25: Stable Disease

Week 25: Progressive Disease

Week 25: Non evaluable

Week 53: Complete Response

Week 53: Partial Response

Week 53: Stable Disease

Week 53: Progressive Disease

Week 53: Non evaluable

Analysis was performed on subjects from the ITT population, defined as all enrolled subjects who received at least one injection of study medication. Only subjects with data available for analysis are presented.

Percentage of Subjects With Time Point Responses According to Response Evaluation Criteria in Solid Tumours (RECIST) Assessments at Weeks 25 and 53

Diarrhoea: Visit 2 (daily)

Diarrhoea: Visit 14 (days 11-17)

Diarrhoea: Visit 14 (days 11-28)

Flushing: Visit 2 (daily)

Flushing: Visit 14 (days 11-17)

Flushing: Visit 14 (days 11-28)

Subjects whose CTC status at baseline could not be evaluated as both CTC blood samples were missing. Baseline is defined as the 7 days preceding the first study treatment injection, or for subjects who required a washout period, these 7 days were during the washout period.

Missing CTC Status at Baseline

Analysis was performed on the ITT population, defined as all enrolled subjects who received at least one injection of study medication. Only subjects with data available for analysis at each time point are reported.

Mean Change From Baseline in Number of Episodes of Diarrhoea and Flushing

No flushing: Baseline

Mild: Baseline

Moderate: Baseline

Severe: Baseline

No flushing: Visit 14 (days 11-17)

Mild: Visit 14 (days 11-17)

Moderate: Visit 14 (days 11-17)

Severe: Visit 14 (days 11-17)

No flushing: Visit 14 (days 11-28)

Mild: Visit 14 (days 11-28)

Moderate: Visit 14 (days 11-28)

Severe: Visit 14 (days 11-28)

Analysis was performed on the ITT population, defined as all enrolled subjects who received at least one injection of study medication. Only subjects with data available for analysis are presented.

Mode Symptom Severity of Episodes of Flushing

Physical functioning: Visit 5

Physical functioning: Visit 8

Physical functioning: End of study

Role functioning: Visit 5

Role functioning: Visit 8

Role functioning: End of study

Emotional functioning: Visit 5

Emotional functioning: Visit 8

Emotional functioning: End of study

Cognitive functioning: Visit 5

Cognitive functioning: Visit 8

Cognitive functioning: End of study

Social functioning: Visit 5

Social functioning: Visit 8

Social functioning: End of study

Global QoL: Visit 5

Global QoL: Visit 8

Global QoL: End of study

Fatigue: Visit 5

Fatigue: Visit 8

Fatigue: End of study

Nausea and vomiting: Visit 5

Nausea and vomiting: Visit 8

Nausea and vomiting: End of study

Pain: Visit 5

Pain: Visit 8

Pain: End of study

Dyspnoea: Visit 5

Dyspnoea: Visit 8

Dyspnoea: End of study

Insomnia: Visit 5

Insomnia: Visit 8

Insomnia: End of study

Appetite loss: Visit 5

Appetite loss: Visit 8

Appetite loss: End of study

Constipation: Visit 5

Constipation: Visit 8

Constipation: End of study

Diarrhoea: Visit 5

Diarrhoea: Visit 8

Diarrhoea: End of study

Financial difficulties: Visit 5

Financial difficulties: Visit 8

Financial difficulties: End of study

Quality of Life (QoL) Questionnaire: European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30

Endocrine symptoms: Visit 5

Endocrine symptoms: Visit 8

Endocrine symptoms: End of study

Gastrointestinal symptoms: Visit 5

Gastrointestinal symptoms: Visit 8

Gastrointestinal symptoms: End of study

Treatment symptoms: Visit 5

Treatment symptoms: Visit 8

Treatment symptoms: End of study

Social function: Visit 5

Social function: Visit 8

Social function: End of study

Disease related worries: Visit 5

Disease related worries: Visit 8

Disease related worries: End of study

Muscle/Bone pain: Visit 5

Muscle/Bone pain: Visit 8

Muscle/Bone pain: End of study

Sexual function: Visit 5

Sexual function: Visit 8

Sexual function: End of study

Information/communication function: Visit 5

Information/communication function: Visit 8

Information/communication function: End of study

Body image: Visit 5

Body image: Visit 8

Body image: End of study

QoL Questionnaire: EORTC QLQ-G.I.NET21

Percentage of Subjects Alive and Progression Free at One Year

Subjects received deep subcutaneous injections of lanreotide Autogel for 1 year to treat the symptoms of functioning midgut NETs.

A washout period was required for subjects receiving either subcutaneous octreotide (at least 2 weeks) or 1 injection of long-acting somatostatin analogue (at least 6 weeks) prior to treatment in the study.

Initially subjects began treatment with a dose of lanreotide Autogel 120 milligrams (mg) every 28 days for 3 months. Thereafter, the dose administered was determined on an individual subject basis by the treating clinician. Subjects could remain on the 120 mg dose, or be titrated to either 60 mg or 90 mg lanreotide Autogel, administered every 28 days according to their symptomatic response.

Overall Study

Immune System Diseases

Hypersensitivity

Pancreatic Neuroendocrine Tumor

Gastrointestinal Agents

Octreotide

The patients enrolled in the study (see below), with a consistent clinical suspicion of a primary duodenal-pancreatic NET.

Patients will undergo MDCT, PET and EUS. Every attempt will be made to achieve a pre-operative cytologic diagnosis of any primary lesion by EUS-FNA. All diagnostic tests (MDCT, PET, EUS) should be performed during a two month time span, in this fixed order. The nuclear medicine doctor will be blinded of findings of MDCT. The gastroenterologist will be blinded about the findings of MDCT and PET until he has completed the diagnostic EUS. For ethical reasons, the findings of MDCT and PET will be disclosed to her/him, while the patient is still sedated in the operating room, just before the FNA. The minimal technical requirement for the techniques, the requested levels of clinical competence of the operators and the procedure for critical revision of radiological and cytological and histological specimens are detailed in the protocol. For PET any 68Ga -labeled-octreotide analogue will be allowed. Before EUS, an extended-esophagogastroduodenoscopy (until the Treitz) until will be performed.

Diagnostic work up

Lorenzo Camellini, MD

Gabriele Carlinfante, MD

Andrea Frasoldati, MD

Armando Froio, Biologist

Tiziana Cassetti, Biologist

The diagnostic work-up of patients suspected of having neuroendocrine tumours (NETs) has traditionally been a challenging issue. The last two decades have been marked by the application to use in the diagnosis of NETs of 3 newly available diagnostic techniques: endoscopic ultrasonography (EUS), multidetector CT (MDCT), and more recently, positron emission tomography using 68Ga-labelled octreotide analogues (PET). In a prospective study conducted at a single referral centre that compared PET with conventional somatostatin receptor scintigraphy and MDCT in diagnosis, staging and follow-up of patients affected by NET, PET detected more primary and secondary lesions than other methods. Recent studies investigated the clinical impact of PET in the management of patients affected by NET, previously studied by MDCT. The investigators recently reported the results of the investigation of 19 patients suspected of having primary pancreatic NET and studied by PET, MDCT and EUS. The investigators preliminary data suggest that PET may be slightly more sensitive than MDCT in detecting small (\<2cm) pancreatic lesions; accuracy of PET and EUS is probably similar. No prospective study has yet been devoted to evaluate the accuracy of PET in the diagnosis and staging of primary duodenal-pancreatic NETs. Furthermore, the clinical impact of the adjunct of PET to the traditional protocols of diagnosis and staging of these tumours waits to be thoroughly evaluated. Thus the appropriate place of PET in the diagnostic algorithm of patients suspected of having duodenal-pancreatic NET remains undefined.

The main aim of this project is to prospectively compare the accuracy of PET and MDCT in the diagnosis and staging of patients suspected of having duodenal-pancreatic NETs. The investigators hypothesised that PET is superior to MDCT in the diagnosis of these neoplasm (the dimension of the study sample is estimated in order to detect a 10% difference). The impact of PET on management plan of affected patients will also be evaluated. As a secondary endpoint of the study, the investigators will compare EUS, PET and MDCT in the diagnosis of primary duodenal-pancreatic NET. The study is designed as a multicentre, prospective, non-randomised clinical trial. All patients will undergo MDCT, PET and EUS in this fixed order.

68-Ga-labeled Octreotide Analogues PET in Duodenal-pancreatic Neuroendocrine Tumours

Accuracy and Clinical Impact of 68-Ga-labeled Octreotide Analogues PET in Diagnosis and Staging of Duodenal-pancreatic Neuroendocrine Tumours; Proposal of a Multicenter, Prospective Clinical Trial

Accuracy was computed as: (number of true positives + true negatives)/(number + true positives + true negatives + false positives + false negatives). Reference standard will be considered the diagnoses of primary NET, when supported by histology or by at least one year of follow up.

Accuracy was computed as: (number of true positives + true negatives)/(number + true positives + true negatives + false positives + false negatives). Accuracy of MDCT and PET in the diagnosis of primary duodenal-pancreatic NET will be calculated on a patient basis and they will be compared using McNemar test. Reference standard will be considered the diagnoses of primary NET, when supported by unambiguous cytology, histology or by at least one year of follow up.In cases of disagreement between cytological and histological findings, histology will be the gold standard.

Accuracy was calculated as above, but based on subjects matching criteria 1-7 of the list of clinical situations suggestive for NET (see below, inclusion criteria). Patients with a lesion suspicion of NET incidentally diagnosed during abdominal ultrasound or MDCT not performed for clinical suspicion of NET were excluded.

Number of patients with adverse events of each procedure: PET, MDCT, endoscopic ultrasonography-fine needle aspiration (EUS-FNA)

Sensitivity (Number of true positive results/number of true positive + false negative results) of the diagnostic tests in the diagnosis of primary duodenal-pancreatic NET. Sensitivity of each diagnostic test (MDCT, PET, EUS) will be calculated separately on patient (number of true affected patients/number of true affected + number of false non affected patients) and on lesion basis (number of true positive lesions/number of true positive + false positive lesions)with its 95% confidence interval based on normal approximation.Reference standard will be considered the diagnoses of primary NET, when supported by unambiguous cytology, histology or by at least one year of follow up.In cases of disagreement between cytological and histological findings, histology will be the gold standard.

Specificity (Number of true negative results/number of true negative + false positive results) of the diagnostic tests in the diagnosis of primary duodenal-pancreatic NET. Specificity of each diagnostic test (MDCT, PET, EUS) will be calculated separately on patient (number of true non affected patients/number of true non affected + number of false affected patients) and on lesion basis (number of true negative lesions/number of true negative positive + false positive lesions)with its 95% confidence interval based on normal approximation.Reference standard will be considered the diagnoses of primary NET, when supported by unambiguous cytology, histology or by at least one year of follow up.In cases of disagreement between cytological and histological findings, histology will be the gold standard.

Changes in management plan in consequence of PET results. Prior to receiving the results of the PET scans, the referring clinician will be required to explicit a management plan for the patient. Following the release of the PET results, a second management plan will be recorded, including any changes resulting from the PET findings. The number of patients with changes in their management plan will be recorded.

Median diameter (cm) and ranges of lesions diagnosed by each technique will be calculated.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Circulating Tumour Cells in Somatuline Autogel Treated NeuroEndocrine Tumours Patients	NCT02075606	NeuroEndocrine ...	lanreotide acet...	18 Years -	Ipsen
68-Ga-labeled Octreotide Analogues PET in Duodenal-pancreatic Neuroendocrine Tumours	NCT01673906	Neuroendocrine ...	Diagnostic work...	18 Years - 90 Years	Arcispedale Santa Maria Nuova-IRCCS
[18]F-FAZA PET Imaging Study in Patients With Cancer of the Head & Neck, Lung, Renal Cell, Brain, Lymphoma and Neuroendocrine Tumours	NCT00323076	Renal Cell Carc... Neuroendocrine ...	18F-FAZA PET Im...	16 Years -	AHS Cancer Control Alberta
Somatuline Predictive Factors in Acromegaly and NET	NCT01840449	Acromegaly Neuroendocrine ...	Somatuline Auto...	18 Years -	Ipsen
Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)	NCT04464122	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Somatostatin an...	18 Years - 80 Years	University of Roma La Sapienza
Somatuline Predictive Factors in Acromegaly and NET	NCT01840449	Acromegaly Neuroendocrine ...	Somatuline Auto...	18 Years -	Ipsen
A Retrospective Data Analysis of Therapy With PRRT Combined With Lanreotide Autogel® for Neuroendocrine Tumours	NCT02788578	Neuroendocrine ...		18 Years -	Ipsen
68-Ga-labeled Octreotide Analogues PET in Duodenal-pancreatic Neuroendocrine Tumours	NCT01673906	Neuroendocrine ...	Diagnostic work...	18 Years - 90 Years	Arcispedale Santa Maria Nuova-IRCCS
Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)	NCT04464122	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Somatostatin an...	18 Years - 80 Years	University of Roma La Sapienza
Open-Label Surufatinib in European Patients With NET	NCT04579679	Neuroendocrine ... Neuroendocrine ... Small Intestina...	Surufatinib	18 Years -	Hutchmed
A Retrospective Data Analysis of Therapy With PRRT Combined With Lanreotide Autogel® for Neuroendocrine Tumours	NCT02788578	Neuroendocrine ...		18 Years -	Ipsen
Efficacy and Safety of Lanreotide Autogel in Tumour Stabilization of Patients With Progressive Neuroendocrine Tumours	NCT00326469	Neuroendocrine ...	lanreotide (Aut...	18 Years -	Ipsen

Spots Global Cancer Trial Database for neuroendocrine tumours