Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Syndrome

Carcinoma

Adenoma

Colorectal Neoplasms

Colorectal Neoplasms, Hereditary Nonpolyposis

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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

Antineoplastic Agents

All Drugs and Chemicals

Herbal and Botanical

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Cola

Participants receive nivolumab intravenously IV over 60 minutes on day 1. Treatment repeats every 3 months for a total of 8 courses in the absence of disease progression or unacceptable toxicity.

Joanne Jeter, MD, MS

This phase II trial studies how well nivolumab works in preventing colon adenomas in participants with Lynch syndrome and a history of surgery to remove part of the colon. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To determine if maintenance therapy with nivolumab can decrease the incidence of colon adenomas in a population of patients with genetic predisposition to colorectal cancer and a history of hemicolectomy due to colon cancer or advanced colon adenoma.

SECONDARY OBJECTIVES:

I. To assess the safety of nivolumab maintenance therapy in this population. II. To obtain preliminary data on the short-term incidence of advanced colon adenomas (measuring greater than 10 mm or with high-grade dysplasia) and colon and non-colonic cancers in Lynch patients treated with maintenance nivolumab.

EXPLORATORY OBJECTIVES:

I. To determine biomarkers of immunologic activity associated with biologic activity of nivolumab in this population.

OUTLINE:

Participants receive nivolumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 3 months for a total of 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 3 months, every 6 months for 1 year, then every 12 weeks thereafter.

Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy

A Phase II Study of PD-1 Inhibition for the Prevention of Colon Adenomas in Patients With Lynch Syndrome and a History of Partial Colectomy

The associated confidence intervals will be reported and used to determine if the incidence rate is significantly different from that reported among Lynch patients not receiving nivolumab, 0.33.

The associated confidence interval will be reported and used to determine if the incidence rate is significantly different from 0.22, the reported incidence of high-risk adenomas among Lynch syndrome patients not receiving nivolumab.

The incidence rates of colon cancers in Lynch patients treated with nivolumab will be estimated with corresponding confidence intervals.

The incidence rates of non-colonic cancers in Lynch patients treated with nivolumab will be estimated with corresponding confidence intervals.

National Cancer Institute (NCI)

Joanne Jeter

Principal Investigator

Adenomatous Polyposis Coli

Rectal Diseases

APC, TP53, PIK3CA, KRAS APC, TP53, PIK3CA, MLH1 APC, TP53, PIK3CA, KRAS, and MLH1 APC, TP53, PIK3CA

co-occuring mutation

This is a pathogenic mutation profile of colorectal patients specifically in 5 genes, i.e. APC, TP53, PIK3CA, KRAS, and MLH1. Single nucleotide variants identified were synchronized with patients' characteristics.

Patogenic Mutation in 5 Genes

Genomic Landscape of APC, KRAS, TP53, PIK3CA, and MLH1 in Colorectal

grade, stage, lymphovascular invasion, tumor location

Dr Cipto Mangunkusumo General Hospital

Principal Investigator - Staff of Digestive Division - General Surgery Department

Hematinics

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Immunoglobulin G

Liver Extracts

Immunoglobulins, Intravenous

Tremelimumab

Ipilimumab

Immunologic Factors

Patients receive durvalumab IV over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Marwan Fakih, MD

This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. Establish the safety of durvalumab and tremelimumab following radioembolization with selective internal radiation (SIR)-Spheres in patients with microsatellite stable (MSS) metastatic colorectal cancer to the liver.

II. Determine the hepatic response rate of SIR-Spheres followed by durvalumab and tremelimumab in patients with MSS metastatic colorectal cancer to the liver.

SECONDARY OBJECTIVES:

I. Estimate the progression free survival (PFS) and overall survival (OS) of the overall treated population.

II. Describe the overall response rate of the treated population. III. Describe the extra-hepatic response in the treated population (abscopal responses).

TERTIARY OBJECTIVES:

I. Describe intra-tumor immune alterations following SIR-Spheres, and following durvalumab plus tremelimumab in comparison to baseline through serial hepatic metastases biopsies.

II. Describe the immune alterations in the blood following SIR-Spheres and following durvalumab plus tremelimumab.

OUTLINE:

Patients receive durvalumab intravenously (IV) over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver

A Pilot Feasibility Study of Durvalumab (MEDI4736) and Tremelimumab Following Radioembolization in Patients With Metastatic Microsatellite Stable (MSS) Colorectal Cancer to the Liver

Will be summarized using standard statistical summaries.

Will be summarized using a 90% exact Clopper-Pearson confidence interval

Toxicities observed will be summarized in terms of type and severity.

This will be reported for the overall population (safety analysis set) and will be described for liver only (time to hepatic progress or death) and for overall disease burden (progression free survival per se). Progression free survival will be estimated using the product-limit (Kaplan-Meier) method, with any loss to follow-up as censoring.

Overall survival will be estimated using the product-limit (Kaplan-Meier) method, with any loss to follow-up as censoring.

City of Hope Medical Center

Rare Diseases

Adenocarcinoma

Lynch Syndrome II

Small Intestinal Adenocarcinoma

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
Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy	NCT03631641	Colon Adenoma Colon Carcinoma Lynch Syndrome MLH1 Gene Mutat... MSH2 Gene Mutat...	Nivolumab	18 Years -	Ohio State University Comprehensive Cancer Center
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver	NCT03005002	Metastatic Carc... MLH1 Gene Mutat... MSH6 Gene Mutat... PMS2 Gene Mutat... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Durvalumab Laboratory Biom... Tremelimumab	19 Years -	City of Hope Medical Center
Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy	NCT03631641	Colon Adenoma Colon Carcinoma Lynch Syndrome MLH1 Gene Mutat... MSH2 Gene Mutat...	Nivolumab	18 Years -	Ohio State University Comprehensive Cancer Center
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
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 mlh1 gene mutation