Neoplasms

All Conditions

Rare Diseases

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Small Intestinal Adenocarcinoma

Antineoplastic Agents

All Drugs and Chemicals

Oxaliplatin

Fluorouracil

Capecitabine

Antimetabolites

Mono- or bichemotherapy: fluoropyrimidine with or without Oxaliplatin (choice by physician/patient or by randomisation)

Bichemotherapy: fluoropyrimidine with oxaliplatin

Monotherapy: 12 cycles of 5FU or 8 cycles of Capecitabine. The choice of fluoropyrimidine must be specified prior to randomisation.

Fluoropyrimidine

Bichemotherapy: Oxaliplatine combined with Fluoropyrimidine.

Ine De Bruyne

Micheline Stempin

Kristel Van Varenbergh

Koen Hendrickx, Dr

Marie Ferrier

Marc Van den Eynde, Prof

Maude Piron

Catherine Loly, Dr

Marc Peeters, Prof

An open-label, randomised, controlled, multi-centre, trial with disease free survival as the primary end point. The worldwide collaboration is referred to as GLOBAL BALLAD and consists of a number of individual parallel prospective studies addressing the same objectives with similar designs brought together under the framework of the International Rare Cancer Initiative. This protocol is for BALLAD BELGIUM, which is the component of GLOBAL BALLAD.

The utility of adjuvant chemotherapy in the management of Small Bowel Adenocarcinoma (SBA) remains unproven and awaits the results of a large, global, prospective, phase III, randomised, controlled trial. Across the 830 million population of North America and Europe, there are approximately 3,000 patients with R0 resected and potentially cured SBA every year who would be potentially eligible for such an adjuvant chemotherapy trial.

Given the absence of good-quality and evidence-based data, it has been agreed that a trial considering adjuvant chemotherapy versus no chemotherapy was appropriate for patients with stage I-IV SBA in whom the oncologist and patient feel that the benefit of adjuvant chemotherapy is uncertain. For those patients with stage I-IV SBA who, with their oncologists, feel that the potential benefit of adjuvant chemotherapy is certain (and hence are not willing to accept randomisation to the 'no chemotherapy' arm), a randomisation between single agent fluoropyrimidine versus doublet fluoropyrimidine and oxaliplatin chemotherapy will be offered. Tumour stage will be used as a stratification factor. Those patients who do not consent to be randomised will be offered registration to allow collection of demographic, clinicopathological, epidemiological and survival data, thereby making optimal use of the rare patient population available. In addition, archival Formalin Fixed Paraffin Embedded (FFPE) tissue and contemporaneous venous blood samples will be collected from every registered patient to allow molecular profiling and future translational research. A questionnaire about underlying risk factors (e.g. Crohn's disease, coeliac disease, Lynch syndrome etc) will be completed along with the other collected data on all registered patients.

The trial hypotheses are that:

1. Adjuvant chemotherapy results in an improved outcome (DFS and OS) over observation alone after potentially curative R0 surgery for stage I, II, III and IV SBA
2. Adjuvant fluoropyrimidine and oxaliplatin chemotherapy results in an improved outcome (DFS and OS) over fluropyrimidine alone after potentially curative R0 surgery for stage I, II, III and IV SBA.

A Trial to Evaluate the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma

BALLAD BELGIUM: A Trial to Evaluate the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma

This is defined as time from randomisation to the first occurrence of the following events:

* Disease relapse (confirmed by imaging)
* Incidence of a new primary (confirmed by imaging and histology/cytology)
* Death from any cause

The patient's survival status is determined at each follow-up visit. After the mandated clinic visits survival status data will come from responsible cancer centres, cancer registries and national databases and include long-term passive follow-up data.

Toxicity will be assessed using CTCAE version 4.0. Only toxicities that are at least grade 2 will be recorded on the CRF

This will be completed at 9, 12, 18 and 24 months post randomisation for all arms of the trial. Minimum and maximum values do not apply for this scale.

This will be completed at 9, 12, 18, 24, 30, 36, 48, 60 72 and 84 months post randomisation for all arms of the trial. Minimum and maximum values do not apply for this scale.

The aim is to establish a biobank of SBA tissue and blood with complete and comprehensive trial quality follow-up data which may act as the foundation for many future collaborative research projects and for combined projects with other funded tissue collections.

Kom Op Tegen Kanker

Cancer Research UK

Belgian Group of Digestive Oncology

Dan Høgdall, MD PhD

Jakob HV Schou, MD

Elizaveta M Tabaksblat, MD PhD

Carsten P Hansen, MD DMSc

Dan Hogdall, MD PhD

Small bowel adenocarcinoma is a rare malignancy, and there is limited knowledge about its optimal clinical management and molecular background. The SBAMOL study is an observational biomarker study that aims to identify prognostic and predictive biomarkers. This effort is intended to lay the groundwork for personalized medicine tailored to this specific patient group.

Small bowel adenocarcinoma (SBA), an orphan cancer, has annual diagnoses of 12,070 in the USA and 100 in Denmark. Despite its rarity, patient management should prioritize evidence-based care, but large trials are not feasible, leading to data scarcity and suboptimal care. As a result, SBA is treated like colorectal cancer, yet its prognosis is worse, indicating this parallel approach is insufficient. The grasp on SBAs molecular landscape is limited compared to prevalent cancers. Scant mutational profiling studies, suggest SBA is a heterogeneous disease where subsets resemble other gastrointestinal cancers. This underscores the potential for personalized treatments, including targeted therapies and immunotherapies. Comprehensive molecular characterization, using DNA, RNA, and T-cell receptor characteristics, can provide much-needed strategic direction for patient care and future trials. Capitalizing on this, the investigators propose a comprehensive molecular characterization aiming to develop consensus molecular subtypes that can direct future trials and SBA therapeutic strategies.

The investigators hypothesize that a consensus molecular profiling approach can identify subgroups of SBA with distinct molecular, cellular, and histological characteristics, that will benefit from tailored treatment strategies using chemotherapy, targeted therapy, and immunotherapy.

To explore this hypothesis, the investigators will: (WP1) perform molecular and immunological characterization of tumor tissues from SBA patients (n=200) to establish consensus molecular subtypes of SBA and define their biological attributes; (WP2) ascertain therapeutic avenues tailored to each subtype and devise a molecular algorithm to prospectively categorize individual tumors in real-time, laying the groundwork for molecularly-driven management.

Formalin-Fixed, Paraffin-Embedded or fresh frozen tissue for DNA, RNA and geospatial analyses

Molecularly Redefining Small Bowel Adenocarcinoma to Accelerate Precision Patient Care

Due to Danish ethical regulations, data can only be shared upon appropriate ethical amendment

Due to the scarce knowledge of the biological background of SBA. The primary endpoint of the study is to present a comprehensive descriptive molecular characterisation of patients with SBA.

DNA aberrations will associated with disease free, progression free and overall survival. Analysis will be performed using the Oncomine comprehensive plus gene panel. Potential aberrations indicative of targeted treatments will be explored and reported.

mRNA aberrations will associated with disease free, progression free and overall survival. Analysis will be performed using high-throughput sequencing. Potential aberrations indicative of targeted treatments will be explored and reported.

T-cell receptor clonality and diversity will associated with disease free, progression free and overall survival. Analysis will be performed using a high-throughput t-cell receptor sequencing.

Aarhus University Hospital

Rigshospitalet, Denmark

University of Copenhagen

Copenhagen University Hospital at Herlev

MD PhD

observation alone

LV5FU2

FOLFOX

Martina SCHNEIDER

Côme LEPAGE

The utility of adjuvant chemotherapy in the management of Small Bowel Adenocarcinoma (SBA) remains unproven and awaits the results of a large, global, prospective, phase III, randomised, controlled trial. Across the 830 million population of North America and Europe, there are approximately 3,000 patients with stage I-III SBA every year who would be potentially eligible for such an adjuvant chemotherapy trial.

Given the absence of good-quality and evidence-based data, it has been agreed that a trial considering adjuvant chemotherapy versus no chemotherapy was appropriate for patients with stage I-III SBA in whom the oncologist and patient feel that the benefit of adjuvant chemotherapy is uncertain. For those patients with stage I-III SBA who, with their oncologists, feel that the potential benefit of adjuvant chemotherapy is certain (and hence are not willing to accept randomisation to the 'no chemotherapy' arm), a randomisation between single agent fluoropyrimidine versus doublet fluoropyrimidine and oxaliplatin chemotherapy will be offered. Tumour stage will be used as a stratification factor. Those patients who do not consent to be randomised will be offered registration to allow collection of demographic, clinicopathological and survival data, thereby making optimal use of the rare patient population available. In addition, archival Formalin Fixed Paraffin Embedded (FFPE) tissue and contemporaneous venous blood samples will be collected from every registered patient to allow molecular profiling and future translational research. A questionnaire about underlying risk factors (e.g. Crohn's disease, coeliac disease, Lynch syndrome etc) will be completed along with the other collected data on all registered patients.

Phase III Trial Investigating the Potential Benefit of Adjvant Chemotherapy for Small Bowel Adenocarcinoma

PRODIGE 33 - BALLAD - Phase III Trial Investigating the Potential Benefit of Adjvant Chemotherapy for Small Bowel Adenocarcinoma

Centre Hospitalier Universitaire Dijon

Sabine HELFEN

Despite the fact that small intestine makes up 75% of the length of the digestive tract and 90% of its mucosal surface area, small bowel adenocarcinoma (SBA) is rare. SBA is not equally dispatched along the small bowel, a predisposing disease is frequently associated. All these data suggest particular carcinogenesis pathway. SBA carries poor prognosis at all stages and no standard treatment have proved efficacy. So far, no data are available for targeted therapy. From the literature and a previous study of our group some biologic data showed that SBA carcinogenesis is closer to colorectal than gastric carcinogenesis. Nevertheless, some differences arise (ie: low Adenomatous Polyposis Coli mutation rate or frequent DNA mismatch repair deficiency). Even if some trends are founded the prognostic value of molecular alteration and phenotype variation according to small bowel segment, or predisposing disease could not been demonstrate due to small sample size.

BIONADEGE study is a planned biologic ancillary study of the NADEGE cohort that enrolled 366 patients with SBA from 2009 to 2012 in France. The tumour blocks and clinical data of 187 patients have been collected. The main objective is to assess the prognostic value for recurrence free survival (RFS) in non-metastatic patients and overall survival (OS) in metastatic patients of molecular alteration in a set of 46 genes and abnormal protein expression potentially implicated in carcinogenesis. The mains secondary objectives are: 1) to identify potential mutation targetable in small intestine tumours and protein expression, 2) to state the frequency of molecular alteration according to the tumour location, stage or predisposing disease and established clinico-biologic correlation. Tissue microarrays will be performed and several potential prognostic markers will be assessed. Sequencing on tumour DNA will investigate the presence of 740 hot spot somatic mutations in 46 genes involved.The abnormal protein expression or the genetic alterations with an expected frequency superior to 10% will be assessed as potential prognostic factor to RFS and OS.

These evaluations on a large cohort could allow comparison between pathways and will offer better knowledge of tumour molecular phenotype and prognosis will give rational for targeted therapy trials The predisposing diseases for SBA involved several different carcinogenesis pathways. Finally, a molecular classification of SBA will be attempt.

The NADEGE cohort involves 75 centres and had enrolled 365 patients. Among them 232 patients had a resection of the primary tumour in 58 centres. This will is be the largest series in the world of SBA for biological study. The patients enrolled in the NADEGE cohort were aware of the biologic study and their authorisation to perform is already collected.

Baseline clinical data of patients enrolled in NADEGE cohort are already available and were presented in a poster discussion session at the European Society for Medical Oncology congress 2013. In all the cohort the primary location was duodenum in 51% of the patients, and a predisposing disease was reported in 18.8% of the patient mainly Crohn disease in 8% and Lynch syndrome in 6% of the patients. The follow-up is ongoing. The analyses of 3-years recurrence-free survival is planned in 2015 and the analysis of 5-years overall survival in 2017.

Today 187 tumour sample are collected and archived in the pathology department of Saint Antoine hospital (Paris). Among these 187 tumours the tumour stage are: stage 0: 4, stage I: 10, stage II: 34, stage III: 63, undetermined stage non-metastatic: 30 (thus 141 non-metastatic tumours) and stage IV: 48, and the primary are: duodenum: 128, jejunum: 31, ileon: 27, undetermined: 3. The chemotherapy performed was FOLFOX in 80% of the cases.

Work Package 1: Database (team 1) The clinical data of NADEGE cohort are collected with an e-crf. The initial descriptive data are already monitored by the GERCOR team. The results have been already presented. BIONADEGE is a planned ancillary study of the NADEGE cohort. The complementary queries for the purpose of BIONADEGE will be addressed by the team 1 to the NADEGE investigator. The follow-up data for progression (metastatic patients), recurrence (non-metastatic patient) and death (all patients) will be obtained every 6 months. Follow-up data will be collected until 2019 in order to obtain 5-years follow-up for all the patients.

Work Package 2: Anatomopathology (team 2) All the tumour samples are already bank in the pathology laboratory of Saint Antoine hospital. Slides from representative tumour area will be selected and send to Paris Descartes university to allow DNA extraction. Tissue microarrays (TMA) for immunohistochemistry validation studies will be performed. Several potential prognostic markers will be assessed as MismatchRepair (MMR) protein, P53, beta-catenin, c-myc protein. Other predictive markers for chemotherapy as hENT1, O6-methylguanine DNA methyltransferase (MGMT) and for targeted therapy as Proto-oncogene tyrosine-protein kinase (ROS1), hepatocyte growth factor receptor c-Met (HGFR), Alk, Human Epidermal Growth Factor Receptor-2 (HER-2) and Programmed cell death 1 (PD-1) will also be assessed. The cases overexpressing HER-2 and HGFR protein by immunohistochemistry will be tested by Fluorescent In Situ Hybridisation (FISH).

Work Package 3: Biochemistry (team 3) DNA will be extracted from tumour block in the university unit S1147 according to the following protocol. Using a 1.0-mm punch, paraffin embedded tissues from all cases will be sampled from representative areas that will contain more than 50% of tumour cells. DNA will be thereafter extracted from each sample following the manufacturer's recommendation. The team3 will use a competitive allele specific taqman probe designed on Kras wild type allele (Hs.00000174-rf - Life Technologies) on serial dilution of each DNA sample in order to quantify amplifiable DNA. Only samples with more than 10 ng of amplifiable DNA will be retained for the sequencing. DNA from each sample will be amplified. The presence of more than 740 hot spot somatic mutations in the 46 genes will be investigate. Data analysis, including alignment to the hg19 human reference genome and variant calling, will be done using the Software of Life Technologies. Alignments will be visually verified and annotated with the software of Integrative Biosoftware. A sequence variation will be considered as a potential mutation if (i) the coverage is superior to 200×, (ii) the allelic frequency is superior to 10%, (iii) the strand bias is from 0.2 to 0.8, (iv) the variation is not reported in the 1000 genomes database, (v) the variation is a missense or a non-sense variation. All these selected variations will be controlled using the Sanger sequencing technics using amplified fragments of less than 150 bp centred on the potential mutation.

Phenotyping of Small Bowel Adenocarcinoma

University of Paris 5 - Rene Descartes

Centre Hospitalier Universitaire de Besancon

GERCOR - Multidisciplinary Oncology Cooperative Group

Assistance Publique - Hôpitaux de Paris

Symptoms and General Pathology

Diseases and Abnormalities at or Before Birth

Digestive System Diseases

Nutritional and Metabolic Diseases

Syndrome

Lynch Syndrome II

Colorectal Neoplasms

Colorectal Neoplasms, Hereditary Nonpolyposis

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Neoplastic Syndromes, Hereditary

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

Video capsule endoscopy

Giulia Martina Cavestro, MD PhD

Marta Puzzono, MD

Background Lynch syndrome is caused by a pathogenic variant in one of the four Mismatch Repair genes (MMR): MLH1, MSH2/Epcam, MSH6, or PMS2. These pathogenic variants confer a higher risk of developing colorectal and other cancers, including small bowel cancer. The risk of developing a small bowel adenocarcinoma is about 100 times higher compared to individuals without Lynch syndrome, and the lifetime risk of small bowel cancer is estimated at 4,2%.

The diagnosis of a small bowel cancer depends on videocapsule endoscopy (VCE). This device is swalled so that it can record images of the small bowel, which are then stored on a wearable device for about 8 hours. The capsule is then expelled in the feces while the images are transferred to a computer to be analysed. To date, there is conflicting evidence on the efficacy of small bowel cancer screening with VCE

Rationale: this registry study will collect prospective data from patients with LS undergoing VCE

Aim: evaluate the incidence of neoplastic and pre-neoplastic lesions in patients with LS during a VCE-based small bowel cancer screening study

Design: this is a multicentric, observational study that analyzes data from diagnostic techniques already approved. Patients will not undergo diagnostic procedures beyond what would be recommended by clinical practice.

Background Lynch syndrome (LS) is caused by a pathogenic germline defect in one of the mismatch repair genes (MMR), namely MLH1, MSH2/Epcam, MSH6, or PMS2. Such pathogenic defects confer a higher risk of developing not only colorectal cancer but also small bowel cancer (SBC). Patients with LS have a lifetime risk of SMB of 4.2%, with a relative risk of \>100, compared to the general population. Moreover, patients with LS may develop SBC at a younger age, compared to SBC in individuals without LS.

The diagnostic standard for SBC is video capsule endoscopy (VCE). This consists in swallowing a pill with a camera inside. The VCE will record the images through the gastrointestinal tract and send them via Bluetooth to a wearable device for roughly 8 hours The capsule is then expelled with feces while the images are stored in a computer for later revision. Today, the data on the efficacy of a screening program for SBC in patients with LS is controversial.

Rationale This register study will collect prospective data on the VCEs done on patients with LS

Objective To estimate the incidence of neoplasia and preneoplastic lesions of the small bowel in patients with LS via VCE

Design Multicentric observational study with the use of approved diagnostic devices. It will not modify the current standard of care. The study design will not mandate obligatory studies of further procedures besides those that are clinically approved.

Population At least 10 subjects/year by each center (400 patients by study completion)

Controindications to VCE

* Stenosis, obstructions, fistulas (suspected or known)
* Cardiac defibrillators or cardiac pace-makers.
* Dysphagia
* Inability to provide written informed consent.
* Pregnancy (suspected or known).

Risks of VCE VCE retention is the most dreaded adverse events. The risk may vary between 1.5 and 21%.

Allergic reactions may be possible due to the use of sticky electrodes on the skin.

Study duration 10 years from January 2016.

Confounders To date, not known.

Data management All results will remain confidential. Clinical data may become available at scientific meetings or in published articles, but patient anonymity will always be maintained

Statistics The incidence of neoplastic and preneoplastic lesions of the subjects included in the study will be estimated. The sample size was established on the basis of feasibility (10 subjects enrolled each year for each center in 10 years = 400 patients in total). The expected incidence of small bowel injury is approximately 5%. With 400 subjects it is possible to estimate the incidence with an accuracy of 2% estimated with a 95% confidence interval.

Descriptive statistical variables (mean, standard deviation, median, etc.) will be evaluated on the collected data.

Any relationships between these variables will be evaluated using inferential statistics (t-test, chi-squared, logistic regression analysis, multivariate analysis, etc.). Any relationship with a p-value less than 0.05 will be considered significant.

Ethics The investigators declare that the study will be conducted in accordance with the ethical principles deriving from the Declaration of Helsinki and the current legislation on Observational Studies.

Informed consent. All subjects will be informed of the purpose of the study, of the confidentiality of the personal data, and of the fact that this data may be subject to review, for study-related reasons, by authorized person other than the physician.

It will be emphasized that participation is entirely voluntary and that the patient can refuse further participation in the protocol at any time without affecting the patient's subsequent care. Informed consent will be obtained for all subjects included in the study prior to their inclusion in the present study, in accordance with national and local regulations.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial to Evaluate the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma	NCT04257461	Small Bowel Ade...	Fluoropyrimidin... Oxaliplatin	18 Years -	Belgian Group of Digestive Oncology
Molecularly Redefining Small Bowel Adenocarcinoma to Accelerate Precision Patient Care	NCT06234306	Small Bowel Ade...		18 Years -	Copenhagen University Hospital at Herlev
A Trial to Evaluate the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma	NCT04257461	Small Bowel Ade...	Fluoropyrimidin... Oxaliplatin	18 Years -	Belgian Group of Digestive Oncology
Phase III Trial Investigating the Potential Benefit of Adjvant Chemotherapy for Small Bowel Adenocarcinoma	NCT02502370	Small Bowel Ade... Adjuvant Chemot...	observation alo... LV5FU2 FOLFOX	18 Years -	Centre Hospitalier Universitaire Dijon
Phenotyping of Small Bowel Adenocarcinoma	NCT02976090	Small Bowel Ade...		18 Years -	Assistance Publique - Hôpitaux de Paris
Phenotyping of Small Bowel Adenocarcinoma	NCT02976090	Small Bowel Ade...		18 Years -	Assistance Publique - Hôpitaux de Paris
Molecularly Redefining Small Bowel Adenocarcinoma to Accelerate Precision Patient Care	NCT06234306	Small Bowel Ade...		18 Years -	Copenhagen University Hospital at Herlev
Videocapsule Endoscopy in Lynch Syndrome	NCT05704010	Lynch Syndrome Lynch Syndrome ... Lynch Syndrome ... MLH1 Gene Mutat... MSH2 Gene Mutat... MSH6 Gene Mutat... PMS2 Gene Mutat... Small Bowel Ade...	Video capsule e...	18 Years -	San Raffaele University

Spots Global Cancer Trial Database for small bowel adenocarcinoma