Metronidazole as Preoperative Therapy in CRC / FusoMetro-001

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05748145
• Other study ID #: FusoMetro-001
• Status: Recruiting
• Phase: Phase 2
• Start date: September 11, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2024
• Source: Oncology Institute of Southern Switzerland
• Contact: Sara De Dosso, MD
• Phone: +41 91 811 93 02
• Email: sara.dedosso[@]eoc.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• Metronidazole Oral
Metronidazole will be administered per os at 500 mg x 3/day, for 10 days prior to surgery.

Locations

Country	Name	City	State
Switzerland	Oncology Institute of Southern Switzerland	Bellinzona	Ticino

Sponsors (1)

Lead Sponsor	Collaborator
Oncology Institute of Southern Switzerland

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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