Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial)

NCT04312360 | Completed Phase 2 DMC

• 2 other identifiers: REG-010-20192019-000131-51
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 2

Brief Summary

Clinical studies have shown that patients with right-sided colon cancer have reduced progression-free and overall survival compared to patients with left-sided colon cancer. At the same time, patients with right-sided colon adenomas have a higher risk of developing interval cancers after endoscopic mucosal resection. Dysbiosis and known bacterial drivers play a significant role in the carcinogenesis of colorectal cancer, and may contribute to the growth of adenomas. Clinical studies have found biofilm formation and positive staining for Fusobacterium nucleatum (FN) in almost all right-sided colon cancers and adenomas. The composition of bacteria also in the normal mucosa in these two groups of patients has been found to be different from healthy controls. Endoscopic preoperative antibiotic local treatment of the biofilm and tumors would theoretically result in decreased tumor mass, recovery of the mucosa, and a normalization of the immune response in the treated section of the colon. The oral administration of the antibiotic metronidazole in mice has shown to lower the tumor load (FN-positive xenograft tumors) and decrease in intratumoral abundance of the pro-carcinogenic bacteria, FN. The aim of this study is to investigate the effect of local antibiotic treatment with fosfomycin and metronidazole on tumor characteristics and the colonic biofilm in patients with right-sided colon cancer or right-sided colon adenomas. This is a clinical proof-of-concept intervention study, and the investigators are to our knowledge the first group to look into local antibiotic treatment of biofilm in patients with colon cancer or colon adenoma. It is based on a non-randomized trial design with an open label single group assignment. There are two tracks depending on the pathology of the tumor: 1) patients with right-sided colon cancer; 2a) patients with right-sided colon adenoma. The intervention is a therapeutic endoscopy where the antibiotics fosfomycin and metronidazole are sprayed throughout the right colon section from caecum to the right colon flexure (100ml of gel contains 800mg of fosfomycin and 200mg of metronidazole). Patients will be included prospectively from the surgical department of Herlev University Hospital and Zealand University Hospital once having received oral and written information, followed by signing the consent. There will be a retrospective cohort of patients with colon adenoma from 2018 (track 2b). The investigators will retrieve the archived adenoma tissue as control tissue. In Clinical Trial, Track 1 and Track 2a will be registered as two different arms that use the same intervention, but the results from each arm later on is going to be reported in separate publications.

Conditions

Right-sided Colon Cancer; Right-sided Colon Adenoma

Keywords

colon cancer; Endoscopy; endoscopic procedure; bacteria; colon adenoma; microbiota; fosfomycin; metronidazole; biofilm; mucosa

Outcome Measures

Primary Outcomes (4)

• Change in the bacterial biofilm depth adherent to the colonic epithelium

  A quantitative change in the bacterial biofilm adherent to the colonic epithelium of the resected colon adjusted for baseline level found before the intervention through fluorescence in situ (FISH) technique. The specific measurement variable is biofilm depth in μm. The method of aggregation will be means.

  10 - 30 months

• quantitative change in bacterial biomass adherent to the colonic epithelium

  A quantitative change in the bacterial biomass adherent to the colonic epithelium of the resected colon adjusted for baseline level found before the intervention through fluorescence in situ (FISH) technique. The specific measurement variable is biofilm mass in ng/cm\^2. The method of aggregation will be means.

  10 - 30 months

• Change in gene expression (Exploratory primary outcome 1)

  \- The determination of differences in translational markers present in the resected tumor tissue adjusted for the level seen at the baseline (the therapeutic colonoscopy) through a principal component analysis (PCA). The translational markers of interest are tumor markers, markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).

  10 - 30 months

• Change in bacterial composition (Exploratory primary outcome 2)

  \- The determination of a change in the bacterial composition adjusted for the bacteria found at baseline before the intervention through fluorescence in situ (FISH) technique and sequencing with Metagenome.

  10 - 30 months

Secondary Outcomes (17)

• Differences in the presence of known bacterial drivers for right-sided colon og adenoma cancer in track1

  10 - 30 months

• Differences in gene expression in the normal mucosa from preoperative in biopsies and the resected colon in track1

  10 - 30 months

• Differences in gene expression in the preoperative and operative blood samples in track1

  10 - 30 months

• The immunological assessment of tumor in track1

  10 - 30 months

• The pathological assessment of tumor in track1

  10 - 30 months

Study Arms (2)

intervention track 1

EXPERIMENTAL

14 patient with right-sided colon cancer receive intervention before the hemicolectomi. both arms of this study use the same intervention.

Drug: therapeutic endoscopy with metronidazole and fosfomycin disodium

intervention track 2a

EXPERIMENTAL

14 patient with right-sided colon adenoma receive intervention before the endoscopic mucosa resection. both arms of this study use the same intervention.

Drug: therapeutic endoscopy with metronidazole and fosfomycin disodium

Interventions

therapeutic endoscopy with metronidazole and fosfomycin disodium DRUG

therapeutic endoscopy where the two drugs: metronidazole and fosfomycin disodium are sprayed through out the right colon section (from caecum to right colon flexure). This intervention is going to be performed on patients in both track 1 and track 2a.

intervention track 1; intervention track 2a

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients above 18 years of age with either:
• right-sided colon cancer tumor with adenocarcinoma histologically verified scheduled for open or laparoscopic resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 1.
• Right-sided adenomas ≥2cm in diameter endoscopically verified scheduled for endoscopic mucosal resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 2a.
• ASA I,II or III
• The caecum must be reached by the endoscope.
• Male and female patients above 18 years of age who were operated for colon adenoma ≥2cm in diameter in the right hemicolon in 2018 at Department of Surgery, Zealand University Hospital. They will be matched 2:1 with the patients included in track 2a (cases) based on age and gender and pathology of the tumor.

You may not qualify if:

• Patients with previous allergic reaction to fosfomycin and/or metronidazole
• Patients with a non-passable tumor or patients where a part of the tumor is not visible during endoscopy (Track 1)
• Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection.
• Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)
• Patients with a history of inflammatory bowel disease (IBD)
• Patients under current treatment with warfarin (Marevan) and phenprocoumon (Marcoumar), or NOAK such as dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban (Lixiana®) or apixaban (Eliquis®)
• Patients under current treatment with Fenemal (Phenobarbital)
• Patients who previously have received a fecal transplantation
• Patients who have previously had colorectal cancer, and are now presenting with a secondary colon tumor.
• Patients with a current alcohol use disorder (AUD): defined as a patient who are currently drinking 8 or more drinks/week for women and 15 or more drinks/week for men.
• Predictable poor compliance (psychiatric disease, not speaking fluent Danish, mentally, impaired etc)
• Patients with an American Society of Anaesthesiologists physical status
• Classification (ASAscore) of IV.
• Patients unable to be sedated
• Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate)

Sponsors & Collaborators

• Zealand University Hospital: lead
• Costerton Biofilm Center: collaborator
• Reponex Pharmaceuticals A/S: collaborator
• Region Zealand: collaborator

Study Sites (2)

Department of Surgery, Herlev Hospital

Copenhagen, 2730, Denmark

Location

Department of Surgery, Zealand University Hospital

Køge, 4200, Denmark

Location

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

Metronidazole

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Astrid LB Bennedsen, M.D.

  Department of Surgery, Zealand University Hospital

  PRINCIPAL INVESTIGATOR

• Ismail Gögenur, DMSc, MD,

  Department of Surgery, Zealand University Hospital

  PRINCIPAL INVESTIGATOR

• Peter Vilmann, DMSc, MD

  Department of Surgery, Herlev Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The same intervention will apply to both arms of this study, the only difference is the patient group which receives the treatment. In Clinical Trial, Track 1 and Track 2a will be registered as two different arms, but the results from each arm later on is going to be reported in separate publications.

Study Record Dates

• First Submitted: September 9, 2019
• First Posted: March 18, 2020
• Study Start: January 16, 2020
• Primary Completion: April 13, 2022
• Study Completion: July 1, 2023
• Last Updated: September 7, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

DK (2)