Metronidazole as Preoperative Therapy in CRC / FusoMetro-001

Preoperative Treatment With Metronidazole to Evaluate the Efficacy in Reducing Fusobacterium Nucleatum Tumor Colonization in Patients With Colorectal Cancer (CRC): a Proof-of-concept Trial

The proposed proof-of concept trial aims at determining the effectiveness of metronidazole in decreasing the Fusobacterium nucleatum load in tissues and possibly on its detrimental effects on tumor cells and tumor microenvironment.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Metronidazole Oral

Detailed Description

Colorectal cancer (CRC) is among the most frequent tumor types and is a leading cause of cancer-related death worldwide. Surgery represents the first therapeutic option, whereas advanced cases are usually treated by established chemotherapy protocols, yet with variable response rates.

Mechanisms underlying unresponsiveness are still largely unclear. Recently, the gut microbiota, consisting of trillions of microorganisms, which populate the gastrointestinal tract, has also been implicated in chemo-resistance.

Defined bacterial species have been reported to be associated with CRC. In particular, Fusobacterium nucleatum (F.n.), a commensal bacterium of the oral cavity, is enriched in CRC tissues and its abundance appears to be associated with reduced patient survival.

In experimental models F.n. promotes CRC cell proliferation and reduces tumor responsiveness to 5-fluorouracil (5-FU). Furthermore, it suppresses tumor infiltration by immune cells associated with improved prognosis.

Administration of metronidazole effectively reduces F.n. load and overall tumor growth in animal models.

However, its efficacy in reducing F.n. loads in human CRC has not been verified so far.

The proposed proof-of concept trial aims at determining the effectiveness of metronidazole in decreasing the F.n. load in tissues and possibly on its detrimental effects on tumor cells and tumor microenvironment.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sara De Dosso, MD; Phone Number: +41 91 811 93 02; Email: sara.dedosso@eoc.ch
• Study Contact Backup: Name: Luigi Tortola, PhD; Phone Number: +41 91 811 96 68; Email: luigi.tortola@eoc.ch

Study Locations

• Switzerland
  • Ticino
    • Bellinzona, Ticino, Switzerland, 6500
      • Recruiting
      • Oncology Institute of Southern Switzerland
      • Contact: Sara De Dosso, MD; Phone Number: +41 91 811 93 02; Email: sara.dedosso@eoc.ch
      • Contact: Luigi Tortola, PhD; Phone Number: +41 91 811 96 68; Email: luigi.tortola@eoc.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent according to ICH/GCP regulations before registration.
• Age ≥ 18 years old
• Untreated, primary colorectal adenocarcinoma (> 15 cm from the anal verge)
• Colonoscopy with endoscopic biopsy for disease confirmation and correlative studies.
• Candidates for surgical resection prior to administration of any therapy.

Exclusion Criteria:

• Insufficient material on the tissue biopsy to be left in the archives of the Cantonal Institute of Pathology for further evaluations/analyses
• Known prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives
• Oral or parenteral antibiotic therapy within the six weeks prior to enrolment
• Emergency surgery (planned within less than 14 days), where no opportunity to administer preoperative oral antibiotics exists
• Other malignant disease within 5 years prior to study enrollment, except basocellular or squamous skin cancer and carcinoma in situ cervices uteri
• Any previous anticancer treatment prior resection
• Women who are pregnant or breast feeding
• Fertile women or men who do not use safe contraception during the study period
• Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.),
• Inability to consent and follow the procedures of the study e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
• Participation in another study with investigational drug within the 30 days preceding and during the present study,
• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment, affect patient compliance or place the patient at high risk from treatment-related complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metronidazole treated arm; Administration of Metronidazole for 10 days prior to surgery in CRC patients	Drug: Metronidazole Oral; Metronidazole will be administered per os at 500 mg x 3/day, for 10 days prior to surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of metronidazole on F.n. loads in CRC tissues.	F.n. load assessed by qRT-PCR analysis in excised tumor tissues upon antibiotic treatment, as compared to corresponding diagnostic biopsies prior to treatment.	12 (+ 3) days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Potential effects of metronidazole on the expression of immune cell markers in CRC tissue samples	Expression of multiple immune cell markers will be assessed in tissue samples by immunohistochemistry and immunofluorescence. Number of positive cells/mm2 will be evaluated.	12 (+ 3) days after surgery
Potential effects of metronidazole on the expression of autophagy markers in CRC tissue samples	Expression of multiple autophagy signaling elements will be assessed in tissue samples by immunohistochemistry and immunofluorescence. Number of positive cells/mm2 will be evaluated.	12 (+ 3) days after surgery
Potential effects of metronidazole on microbiome	Differences in community diversity and/or abundance of specific bacterial taxa between the tumor-associated microbiome prior to or after antibiotic treatment.	12 (+ 3) days after surgery
Potential effects of metronidazole on the intestinal metabolic profile	Measurement of changes in the biosynthesis pathways of intestinal bacteria by comparing the gut metabolic profile before and after antibiotic treatment. Fold changes in the abundance of bacterial metabolites will be evaluated.	12 (+ 3) days after surgery

Collaborators and Investigators

• Sponsor: Oncology Institute of Southern Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 26, 2023
• First Submitted That Met QC Criteria: February 17, 2023
• First Posted (Actual): February 28, 2023

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: FusoMetro-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No