A.Background

More than 90% of patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple pancreatic neuroendocrine tumors (pNETs). These tumors are the most common cause for premature death in MEN1.

While functioning pNETs must be treated to reduce or cure hormonal excess, the procedures for non-functioning pNETs are yet under discussion. Treatment ranges from watchful waiting to subtotal and total pancreatectomy. The latter may represent an "overtreatment", resulting in general complications and diabetic metabolic status.

The effect of somatostatin analogues (SAs) has shown promising results with regard to progression of non-functioning duodeno-pancreatic NETs. Treatment with SAs is highly safe and effective, resulting in long-time suppression of tumor growth.

B. Aim

In this study of MEN1 patients with non-functioning pNETs, the benefits of somatostatin analogs" (SAs; group 1) compared to "no treatment" (group 2) will be analyzed with regard to progression (tumor growth; development of new [functioning and non-functioning] neuroendocrine tumors and regional/distant metastasis).

C. Implementation

Patients will either receive Somatostatin Analogs (SAs) or no treatment. The observation period will be 60 months. The increase of tumor size and development of new tumors or metastasis will be monitored.

1. Introduction

   1.1 Background

   Due to the genetic background of the disease, every single neuroendocrine cell of the pancreas is a potential progenitor of neuroendocrine tumors (NETs). More than 90% of patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple pancreatic neuroendocrine tumors (pNETs) "viewable" by transgastric endosonography and/or cross sectional and/or functional imaging. These tumors are the most common cause for premature death in MEN1 (1, 2).

   While functioning pNETs are to be treated to reduce or cure hormonal excess, the strategies of addressing non-functioning (NF) pNETs are under discussion. Treatment ranges from "watchful waiting" to subtotal or total pancreatectomy (3-6). The latter may prove to be an "overtreatment" resulting in diabetic metabolic status and subsequently in general long-term complications.

   Somatostatin analogs (SAs) have shown promising results with regard to progression-free survival in patients with metastatic NETs of the midgut (9-11).

   As shown recently in a retrospective study of 40 patients with early-stage MEN1 duodeno-pancreatic NETs, treatment with SAs was safe and effective, resulting in long-time suppression of tumor and hormonal activity and 10% objective response. The authors suggest to start therapy with SAs early on in patients with MEN1-related NETs (12). Apart from this clinical study, there is one case report on SAs for MEN-1-related insulinoma (13).

   MEN1 is an orphan disease (ORPHA652).

2. Rationale and objectives

   In this prospective, randomized observation study, the benefits of subcutaneous application of somatostatin analogs (SAs) every 28 days (group 1) will be compared to no treatment (group 2). It has not been proven if the beneficial effects of SAs shown in advanced disease are also applicable to patients with early stage (≤20mm) pancreatic neuroendocrine tumors in MEN1. "Watch and wait" without medical treatment is the standard approach for MEN1 patients in this early stage of pancreatic disease. We hypothesize that SAs can decelerate tumor progression (according to our outcome parameters).

3. Study design

3.1 Design

Prospective, randomized, controlled, observation trial

3.2 Study population

Patients with proven MEN 1 (see eligibility criteria) will be recruited after discussing her/his individual clinical situation in the interdisciplinary tumor board.

The listed examinations and tests will be carried out in each patient before the first day of study participation:

• Medical history and physical examination
• Height and weight
• Biochemical parameters (chromogranin A [CgA] level)

3.3 Description of study days

The patients will be evaluated in six-monthly intervals biochemically and radiologically (according to the protocol below).

3.4 Withdrawal and replacement of subjects

Patients will be withdrawn under the following circumstances:

• At their own request
• If the investigators feel it would not be in the best interests of the patient to continue.

In all cases, the reasons why study subjects were withdrawn will be recorded in detail in the case report forms (CRFs) and in the subjects' medical records. Should the study be discontinued prematurely, all study materials (completed, partially completed and empty CRFs) will be retained.

4 Methods of evaluation

Functional imaging (DOTA-conjugated peptide PET-CT or MRI) will be performed and venous blood samples will be drawn as baseline evaluation for general laboratory tests and Chromogranin A (CgA).

4.1 Imaging modalities

DOTA-conjugated peptide PET-CT or MRI will be acquired on baseline and after 12, 24, 36, 48 and 60 months

Radiological interim assessments will be performed by MRI at 6, 18, 30, 42 and 54 months.

4.2 Laboratory parameters

A venous blood sample will be drawn at each assessment (baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 months). CgA will be determined in each sample, general laboratory tests will be made yearly (starting from baseline).

4.3 Adverse events (AE)

An AE is any event during a clinical study, including intercurrent illness or accident, which impairs the well-being of the patient; it may also take the form of an abnormal laboratory value. The term AE does not imply a causal relationship with the study therapy.

All subjects experiencing AEs - whether considered associated with the study therapy or not - will be monitored until symptoms subside and any abnormal laboratory values have returned to baseline, or until there is a satisfactory explanation for the changes observed, or until death, in which case a full pathologist's report will be supplied, if possible. All findings must be reported on an "AE" page in the "case report form (CRF)".

All AEs are divided into the categories "serious" and "non-serious". This determines the procedure that must be used to report/document the AE (see below).

4.3.1 Definition of serious and non-serious adverse events

A serious AE is:

• Any event that is fatal or life-threatening
• Any event that is permanently disabling
• Any event that requires hospitalization AEs that do not fall into these categories are defined as non-serious.

4.3.2 Reporting /documentation of adverse events AEs will be collected by spontaneous reporting.

4.3.3 Assessment of severity

Regardless of the classification of an AE as serious or non-serious (see above), its severity must be assessed as mild, moderate or severe, according to medical criteria alone:

Mild = does not interfere with routine activities, considered as acceptable

Moderate = interferes with routine activities

Severe = impossible to perform routine activities, considered as unacceptable

Further categories: Requires treatment, requires discontinuation of study, or has residual effect.

It should be noted that a severe AE need not be serious in nature and that a serious AE need not, by definition, be severe.

Regardless of severity, all serious AEs must be reported as above.

4.4 Data handling procedures A CRF will be completed for each patient. Trained personnel will check the entries and any errors or inconsistencies will be clarified immediately. The results of the pre-study screening examination will be documented in the study master file.

4.5 Biometric methods

4.5.1 Biometric methods

1. Descriptive analysis
2. After analysis for data distribution, parametric or non-parametric statistical tests will be applied

4.5.2 Biometric methods - adverse events/safety investigations

All AEs will be properly listed and an appropriate method will be used to summarize the data.

5 Ethical and legal aspects The study will be performed in accordance with the guidelines of the Declaration of Helsinki (1964), including current revisions.

5.1 Informed consent of the patient Before being admitted to the clinical investigation, patients must have consented to participate after the nature, scope and possible consequences of the clinical study have been made understandable to them in writing.

Patients must give a written consent. Their consent will be confirmed by the signature of one investigator.

5.2 Acknowledgment/approval of the study Before the start of the study, the study protocol will be submitted to the Ethics Committee of the Medical University of Vienna and, if necessary, to the responsible Ethics Committees of the participating centers.

5.3 Confidentiality

All subjects' names will be kept secret in the investigators' files. Subjects will be identified throughout documentation and evaluation by the number allotted to them at the beginning of the study. The subjects will be informed that all study findings will be stored and handled in strictest confidence.

6 Documentation and use of study findings

6.1 Documentation of study findings All findings collected during the study will be entered on the CRFs. CRFs will be completed immediately after the final examination.

6.2 Use of study findings The findings of this study will be published by the investigators in a scientific journal and presented at scientific meetings. The manuscript will be circulated to all co-investigators before submission.

7 Protocol amendments If any modifications become necessary or desirable, these will be documented in writing; major changes will require the approval of all investigators and the Ethics Committee.

Inclusion Criteria:

• Verified MEN1 syndrome by molecular genetics (known mutation)
• Non-functioning pNET
• Largest ("leading") pancreatic tumor with ≤20 mm in diameter and (if present) one small tumor <15 mm in diameter as reference lesion
• G1 or G2 (Ki-67 ≤ 10%) according to endoscopic ultrasound/fine-needle aspiration (EUS/FNA) acquired by 19-gauge needle
• Functional imaging: Ga68-DOTA-conjugated peptide positron emission tomography (PET) computed tomography (CT) or preferably Ga68-DOTA-conjugated peptide magnetic resonance imaging (MRI)
• Tumor(s) limited to the pancreas (N0, M0)

Exclusion Criteria:

• Functioning tumor - hormone excess
• Neuroendocrine carcinoma (G3)
• Metastatic disease (N1, M1)