Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial)
Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial)
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.
Background Dysbiosis and known bacterial drivers play a significant role in the
 carcinogenesis of colorectal cancer. Among bacterial drivers, Fusobacterium nucleatum (FN)
 and the formation of biofilm on the surface of the colonic epithelium are considered
 pro-carcinogenic. The increased permeability of the mucosal layer and the invading bacteria
 in the colonic crypts and submucosal space result in genetic and epigenetic changes along
 with immune responses that are all important oncogenic factors. Clinical studies have found
 biofilm formation and positive staining for FN in almost all right-sided colon cancers and
 adenomas. Two studies compared the bacterial growth in normal mucosa from patients with and
 without adenoma. They found a different composition of bacteria in the normal mucosa from
 patients with adenomas in terms of richness, diversity and bacterial strains, thus indicating
 that the bacterial composition in the gut could contribute to the growth of adenomas and
 subsequently, adenocarcinomas.

 Endoscopic preoperative local antibiotic treatment of the biofilm and tumors would
 theoretically result in decreased tumor mass, recovery of the mucosal layer, and a
 normalization of the immune response in the treated section of the colon. The oral
 administration of the antibiotic metronidazole in mice has already been shown to decrease
 tumor growth (FN-positive xenograft tumors) as well as a decrease in intratumoral FN
 abundance.

 Investigational Medicinal Products In this study a gel containing the antibiotics fosfomycin
 and metronidazole will be sprayed endoscopically on the mucosa of the right hemicolon. The
 gel will be prepared on site by combining solutions of fosfomycin and metronidazole with a
 gel-forming gum.

 Study objectives 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.

 Study design This study is a clinical proof-of-concept intervention study. 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: track 1, patients with right-sided colon cancer;
 track 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 in a gel-forming mixture. Patients will
 be included from the surgical department of Herlev Hospital and Zealand University Hospital.
 There will be a retrospective cohort of patient with colon adenoma, track 2b.

 Effect parameters For patients with right-sided colonic carcinomas and/or adenomas, the
 investigators hypothesize that endoscopic, preoperative antibiotic treatment in the right
 colon with a gel-forming spray containing fosfomycin and metronidazole will result in
 normalization of the colonic epithelium and immune response as well as a reduction in colonic
 biofilm formation often seen in these patients.

 Trial structure and responsibilities The principal investigator (Astrid Bennedsen) is
 responsible for the preparation of the protocol, the Case Report Forms (CRFs), coordinating
 any meetings of the safety data monitoring committee as well as implementing decisions in the
 daily operations of the trial. Along with a team of co-investigators, the principal
 investigator will do the screening, recruitment, data collection and writing of the CRFs. The
 safety data monitoring committee consists of three members and will be impartial. They will
 overview the progress and the safety of the trial. The meetings of the safety data monitoring
 committee will take place every six months, but an extra meeting will be held in case of any
 severe adverse events or any other serious incidents during the trial. The trial will be
 monitored by a local GCP unit. The funding source had no role in the design of this study and
 will not have any role during its execution, analyses, interpretation of the data, or
 decision to submit results.

 Stopping rules In case of serious side effects or adverse events, the data will be monitored
 and the trial stopped if there is any evidence of lack of safety regarding the intervention
 and the study drugs. Included are unexpected complications in relation to colon cancer
 surgery.

 Study course This study has two tracks depending on the pathology of the colon tumor. When
 colon cancer is suspected, patients are referred to a colonoscopy during which biopsies are
 taken to confirm pathology indicating adenocarcinoma or benign pathology. There is a
 retrospective track 2b, where the investigators will retrieve FFPE adenoma tissue from up to
 28 random patients operated with endoscopic mucosal resection in 2018. The trial drugs will
 be accounted for - both per site and per patient.

 Selection and enrollment of participants Consecutive patients with endoscopically diagnosed
 right-sided colon adenomas or right-sided colon cancer tumors will be eligible for inclusion
 in the study. The investigators plan to include 14 patients with colon cancer (track 1) and
 14 patients with colon adenoma (track 2a).

 Also, 28 patients with colon adenoma will be included retrospectively (track 2b). The
 investigators will retrieve FFPE tissue from the resected mucosa bearing adenoma. They have
 had endoscopic mucosal resection performed in 2018 at Department of Surgery, Zealand
 University Hospital.

 Recruitment of patients will be done consecutively according to the Research Ethics
 Committee's recommendations. Patients who are eligible for inclusion will receive both oral
 and written information about the study. At the end of the enrolment meeting the patient may
 sign the informed consent if they wish, and may also be given the time needed for
 consideration (at least 24 hours). The informed consent will be written in accordance with
 the Danish law. Patients will be informed if any changes in the study occur, as this might
 influence the patient's willingness to participate or the safety of the participating
 patients. The approved document will be updated accordingly.

 A completed test person

 A completed test person is defined as:

 -  Track 1: a patient who received the therapeutic endoscopy and had preoperative blood
 samples drawn on the operation day. Other than the interview on the day of the
 out-patient clinic visit (approximately postoperative day 14) there is no further
 study-related physical follow-up of the patient.

 -  Track 2a: a patient who received the therapeutic endoscopy and had preoperative blood
 samples drawn on the operation day. Other than the telephone interview on postoperative
 day 14 there is no further study-related physical follow-up on the patients.

 Dropout procedure Dropout and withdrawals may happen at any point from the written consent
 till the preoperative blood sample on the operation day, and will not have any influence on
 the treatment of the patient.

 Participating patients can withdraw from the study at any time for any reason. The patients
 will be informed of this right in accordance with the Helsinki Declaration.

 The investigator can withdraw patients if the investigator feels the safety of the patient is
 compromised by the participation in the study. In that case, the investigator must inform the
 patient about the reason for withdrawal.

 Patients who withdraw their consent will receive standard treatment. The reason, if stated,
 for the withdrawal will be noted in the CRFs. The number of dropouts and withdrawals will be
 reported. No further data will be collected from the patients withdrawing from the study;
 however, the previously collected data will be part of the final data analysis unless the
 patient specifically requests all data to be deleted.

 Study interventions and procedures Intervention This is a non-randomized trial with an open
 label single group assignment. The intervention is a single therapeutic endoscopy during
 which patient´s right colon section will be sprayed with a predetermined volume of two
 component solutions, one containing fosfomycin and metronidazole, the other containing a gum
 that forms a gel on mixing with the former. During administration, the two components will be
 delivered through a dual channel colono-videoscope. The gel will form on the bowel wall and
 adhere to the mucosa.

 Track 1: patients with colon cancer Preoperative procedures - blood samples On the day of the
 therapeutic endoscopy study, blood samples are drawn. Blood samples are analyzed for
 hemoglobin (Hb), leucocytes and differential counts, c-reactive protein (CRP), thrombocytes,
 albumin, creatinine, estimated glomerular filtration rate (eGFR), transaminases in order to
 have baseline information on the patients and to be able to adjust for these variables in the
 multivariate analyses. Blood samples will also be analyzed for tumor-specific markers:
 carcinoembryonic antigen (CEA). Samples are also analyzed by means of the nCounter® PanCancer
 Immune Profiling Panel (nanoString).

 Preoperative procedures - therapeutic endoscopy At least 24 hours after the patient has given
 informed consent to participating in the study, the patient will be given a bowel
 preparation. After 48-72 hours the therapeutic endoscopy will take place. The bowel
 preparation procedure will follow the different sites standard guidelines of bowel
 preparation using Picoprep. The patient will be offered to be sedated before the endoscopy.
 Pictures of the colon will be taken during the endoscopy.

 Before spraying the right hemicolon, biopsies will be taken from the central and peripheral
 part of the tumor, and biopsies from the macroscopically normal mucosa in the proximal colon
 at least 10 cm orally and anally from the tumor.

 The proximal colon will be sprayed with a predetermined volume of the study medication
 through a double spray catheter from the ileum to the right flexure using a Video
 Colonoscope. The study medication contains fosfomycin and metronidazole, which are mixed in
 situ with the gel-forming components formulated on behalf of Reponex Pharmaceuticals A/S.

 Preoperative procedures - pathology Some biopsies taken during the therapeutic endoscopy will
 all be directly fixed in Phosphate-buffered (PBS-buffered) formalin and embedded in paraffin
 before microscopic assessment and further molecular biological or immunologic tests are
 performed. One biopsy from the healthy mucosa, one biopsy from the tumor center and one
 biopsy from the tumor periphery will be frozen immediately following the local protocol.

 Operation On the day of surgery, blood samples will be taken again. They will be analyzed
 using the same methods as the preoperative blood samples. Inclusion in the study does not
 interfere with the standard surgical protocol for patients with right-sided colon cancer.

 Postoperative procedures - pathology The resected colon section will be sent unfixed to the
 Pathological Department at the site, where the initial macroscopic assessment is performed:
 measuring of the tumor, lymph node assessment etc. One tissue sample from the healthy mucosa,
 one tissue sample from the tumor center and one tissue sample from the tumor periphery will
 be frozen immediately following the local protocol. The hemicolon will then be
 formalin-fixed. The paraffin-embedded tumor samples will be cut according to the standard
 protocol before microscopic assessment and further molecular biological or immunologic tests
 are performed. The histological assessment will follow the standard protocol.

 Discharge The discharge criteria are the same for patients included in the study as for other
 patients on the ward. Discharge is expected to take place on the 3rd postoperative day if no
 complications arise. A prolonged hospital stay will be defined as 10 days after surgery.

 Postoperative out-patient visit - follow-up Patients will be seen after their postoperative
 out-patient visit. The investigators will assess the patient's wellbeing and to ensure that
 any side effects or adverse reactions to the medicine in the trial are registered.

 Follow-up Patients will be contacted by telephone 12 months after surgery. There is no
 further study-related physical follow-up on patients, as it has no influence on the
 endpoints. The investigators will however, read the patient's hospital files after 12 months
 to see whether the therapeutic endoscopy has changed the clinical course of the patient, i.e.
 if staging and oncological treatment are changed because of the procedure. The patients are
 receiving the standard post-operative program with ambulatory follow-up according to the
 Danish Colorectal Cancer Group (DCCG) recommendations.

 Track 2: patients with adenomatous polyps of the colon Preoperative procedures - blood
 samples On the day of the therapeutic endoscopy, study blood samples are drawn. They will be
 analyzed by the same methods as the preoperative blood samples in Track 1.

 Preoperative procedures - therapeutic endoscopy The bowel preparation procedure and sedation
 are the same as in Track 1. Pictures of the tumor will be taken during the endoscopy.

 Before spraying the right hemicolon, biopsies from the macroscopically normal mucosa will be
 taken at least 10 cm orally and anally from the polyp.

 The spraying procedure is the same as in Track 1.

 Preoperative procedures - pathology Three of the four biopsies of the normal mucosa taken
 during the therapeutic endoscopy will all be directly fixed in PBS-buffered formalin and
 embedded in paraffin before microscopic assessment and further molecular biological or
 immunologic tests are performed. One biopsy of the normal mucosa will be frozen immediately
 following the local protocol.

 Resection On the day of resection, blood samples will be taken again. They will be analyzed
 by the same methods as the preoperative blood samples. During the endoscopic mucosal
 resection, biopsies from the healthy colon will be taken: two biopsies 10 cm orally and two
 biopsies 10 cm anally from the polyp.

 Postoperative procedures - pathology Three of the four biopsies of the normal mucosa taken
 during the operation will all be fixed directly in PBS buffered formalin. One biopsy of the
 normal mucosa will be frozen immediately following the local protocol. The resected mucosa
 with the adenoma will be send non-fixed to the Pathological Department at the site, where the
 initial macroscopic assessment is performed, measurement of the polyp in three dimensions.
 The mucosa and the biopsies will be fixed with formalin, and will be cut according to the
 standard protocol and paraffin embedded before microscopic assessment and further molecular
 biological or immunologic tests are performed. The histological assessment will follow the
 standard protocol.

 Follow-up On postoperative day 14+/-2, an investigator will call the patient to assess the
 patient's wellbeing and to ensure that any side events or adverse reactions to the medicine
 in the trial are registered. The Follow-up is as in Track 1.

 Archived FFPE tissue from patients with colon adenoma FPPE tissue blocks from colon adenomas
 will be retrieved from the archive of Department of Pathology, Zealand University Hospital.
 The tissue blocks will be cut according to standard protocol. They will be analyzed as the
 tissue from the resected mucosa of the patients included in track 2a.

 Pathology procedures for both tracks The paraffin blocks will be sectioned in series. In each
 step, the section 1 is stained with standard hematoxylin and eosin (H&E), section 3 is
 stained immunohistochemically for CD8 and CD3 (following the local immunoscore protocol), and
 section 5 will be stained for CD68 (macrophages). Sections 7, 9 and 11 will be analyzed for
 bacterial biofilm using a general bacterial PNA FISH probe. Section 13 will be prepared for
 PanCancer IO 360TM Gene Expression Panel (nanoString) analysis following the nanoString
 protocol. The remaining sections (2, 4, 6, 8, 10 and 12) remain unstained, and will be kept
 at -80°C.

 Microbiology procedures for both tracks In this study tissue samples will be analyzed for
 bacteria and biofilm using Fluorescence in situ hybridization and Metagenome sequencing.
 These analyzes will be performed at Costerton Biofilm Center.

 Safety assessments In this study, patients are administered the study drugs in a standard
 single dose of 800 mg of fosfomycin and 200 mg of metronidazole. The general dosage guideline
 for adults treated with fosfomycin infusions is 6 g*3 per day (in patients with renal
 insufficiency and a creatinine clearance of 10 ml/min the suggested dose is 1 g*2 per day).
 The general dosage guideline for treatment with metronidazole is 1500 mg as a single
 infusion.

 Blood samples The drawing of blood samples will result in some discomfort and may risk
 bruising at the site. A total of 8.5mL will be drawn at the sites: Zealand University
 Hospital, Roskilde, and Herlev Hospital (3.0 mL Gel + LiHep Tubes + 3.0 mL EDTA Tubes + 2.5
 mL PAXgene Blood RNA Tubes). A total of 11.5 mL will be drawn at the site: Zealand University
 Hospital, Køge (3.0 mL Gel + LiHep Tubes + 3.0 mL Gel + LiHep Tubes + 3.0 mL EDTA Tubes + 2.5
 mL PAXgene Blood RNA Tubes).

 Therapeutic endoscopy:

 In this study a full colonoscopy is necessary to deliver the study medication to the mucosa
 of the right hemicolon. Also, to assess the effect of the local antibiotic treatment it is
 necessary to take biopsies from the healthy mucosa, and if the patient is included in track
 1, also the colon cancer tumor. Forty-eight-72 hours before a colonoscopy the patient needs
 to be given a bowel preparation (15). There are risks associated with a colonoscopy:
 intestinal bleeding, bowel perforation, localized infection, adverse reaction to the
 sedatives and generalized bowel infection. Of these, intestinal bleeding and iatrogenic bowel
 perforation are the most prominent adverse events associated with a significant mortality
 rate and the need for surgical intervention. The risk of accidental bowel perforation has
 been estimated to 0.85/1000, and the risk of bleeding has been estimated to 1.64/1000 (16).
 However, the complications are less common with colonoscopies that do not involve
 polypectomy, such as this study. The colonoscopy will be performed by a trained specialist
 surgeon in the out-patient clinic. Patients unable to be sedated due to known allergies or
 comorbidities have already been excluded from study participation.

 Adverse events During and after administration of fosfomycin and metronidazole any adverse
 events or intercurrent illnesses will be reported. Patients who have known allergy to
 fosfomycin and or metronidazole are excluded from study participation. Treatment with
 metronidazole is known to give rise to Antabuse (disulfiram)-like reactions in patients who
 continue to drink alcohol. Patients who are currently heavy drinkers are excluded from study
 participation. Patients will be orally instructed not to drink alcohol from the day before
 the therapeutic endoscopy during the enrollment meeting. This information is included in the
 Patient information. A summary of the product characteristics of fosfomycin and metronidazole
 will function as reference documents in evaluation of adverse effects. The investigators will
 monitor adverse events from the day of the intervention until postoperative day 14
 (approximately 19 days in total). Safety of the intervention will be measured by adverse
 events.

 All serious adverse events (SAE) will be registered and reported to the sponsor by
 investigator within 24 hour after the event has been recorded. All adverse events will be
 reported to the Danish Medicines Agency and the local Ethics Committee in an annual report
 with a report on patient safety of the trial. All serious adverse reactions (SAR) will be
 reported in an annual report together with a report on patient safety to the Danish Medicines
 Agency. All SAR will be judged through the product summary if they are a possible suspected
 unexpected serious adverse reaction (SUSAR). The investigators are responsible for reporting
 all lethal or life-threatening SUSAR to the Danish Medicines Agency and the regional Ethical
 Committee as soon as possible and no later than 7 days after knowledge of such reaction has
 been received. No later than after 8 days after the reporting, will the Danish Medicines
 Agency be informed of the follow-up. All other SUSAR will be reported to the Danish Medicines
 Agency and the regional Ethics Committee no later than 15 days after knowledge has been
 received by the sponsor and the investigators. The patient will in these situations be
 followed until the reaction has terminated either via the outpatient clinic at the hospital
 or via contact with the sponsor or the investigators.

 Statistical considerations The investigators plan to include 14 consecutive patients with
 right-sided colon adenoma and 14 consecutive patients with right-sided colon cancer tumor.
 The trial will end by the last visit of the last patient. The retrospective cohort of 28
 patients with colon adenoma (track 2b) will be matched 2:1 with the prospective 14 patients
 with right-sided colon adenoma (track 2a). The investigators estimate a dropout rate of 15%.
 Therefore inclusion will stop by the 24th fully evaluable patient. 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. the investigators expect this number of patients to be sufficient to provide
 the necessary experience in implementing the technique and form a basis for future studies,
 including their sample size calculation.

 Data will be analyzed using non-parametric statistics or parametric statistics depending on
 the distribution of the data. P-values <0.05 are considered significant. Correction for
 multiple comparisons will be performed if needed. Descriptive statistics will be used for
 baseline characteristics. Both a principal intention-to-treat analysis and a per-protocol
 analysis will be performed, along with a standard sensitivity analysis. The effect of any
 missing data will be assessed with sensitivity analyses. Missing data will be addressed with
 a creation of clinically responsible imputations. The investigators will focus on molecular
 signatures discovery using supervised analyses (statistical tests like t-test or Wilcoxon
 test) and unsupervised analyses like PCA (principal component analysis) and ICA (independent
 component analysis). Statistics will be performed in collaboration with biostatistician
 Nicolas Derian.

 Patients included in track 2a, who are diagnosed with cancer after the postoperative
 pathological assessment of the polyp, will be included in the intention-to-treat analysis.

 Data collection and quality assessment In accordance with Danish law on personal data, the
 investigators will seek approval for this trial from the Danish Data Protection Agency. Data
 handling will be in accordance with the act on processing of sensitive personal information,
 the General Data Protection Regulation (GDPR) and the Data Protection Act. The investigators
 will also seek approval for the trial from The Research Ethics Committee and the Danish
 Medicines Agency.

 Data from each patient will be recorded continuously and written in forms (CRF) prepared
 before the trial begins. During the recruitment meeting, the investigators will use a paper
 work sheet for baseline data and inclusion/exclusion criteria. During the therapeutic
 endoscopy, the investigators will use paper work sheets for data collection; afterwards data
 will be entered into an electronic database using the Easytrial platform. All other data will
 be recorded directly to the electronic Easytrial database. The paper work sheets will be
 stored identifiable in a locked cabinet at the respective research sites. All collected data
 will have source documentation.

 Data will be stored as personally identifiable for 10 years, after which they are deleted the
 1st of February 2029. Data will be stored in compliance with GDPR and at Teamsite (secure
 data storage).

 If a patient withdraws from the study, the collected data will be anonymized. If the patient
 requests the collected data to be deleted, this will be done.

 Good Clinical Practice and quality assessment This trial is performed in accordance with the
 Danish Medicines Act §88 section 2 and the order on good clinical practice number 744 of 29th
 of June 2006. The trial will be monitored by a Good Clinical Practice (GCP) unit, Capital
 Region of Denmark. The existing procedures for quality assurance and control in intervention
 studies will be followed through a scheduled monitoring agreement at the beginning, mid-term
 and at the end of the project. At auditing, monitoring and/or inspection from the Danish
 Medicines Agency, GCP-unit or from other relevant authorities, these will all be allowed
 relevant access to the data and information stored.

 Ethical considerations The study is performed in accordance with the Helsinki Declaration and
 Danish law 593 of 14th June 2011 on the Research Ethics Committee's practices regarding
 health research trials. The project has been approved by the department management, the
 Danish Data Protection Agency (REG-010-2019), the Regional Research Ethics Committee (number
 SJ-753), and the Danish Medicines Agency (2019-000131-51). The study is registered at the
 EudraCT (number 2019-000131-51) and will be registered at www.clinicaltrials.gov. The trial
 will be monitored by the local GCP Unit. Any modification of the protocol which may impact on
 the conduct of the study, potential benefit of the patient or may affect patient safety,
 including changes of study objectives, study design, patient population, sample sizes, study
 procedures, or significant administrative aspects will require a formal amendment to the
 protocol. An amendment will be agreed upon by the study group and will need the approval of
 the Ethics Committee as well as other authorities prior to implementation, if suited.

 The study will be conducted in the Surgical Department, Herlev Hospital, and Zealand
 University Hospital. It will contribute to the clarification of whether local antibiotic
 treatment of the colon tumor and the surrounding normal mucosa has a place in the treatment
 of colon cancer and colon adenomas.

 Study patients are included after they have received oral and written information and after
 written consent has been obtained. At any time, the patients can withdraw their consent
 without impairing their relationship to the investigator or the doctors involved and without
 prejudicing their treatment at the Department. All patients can require further information
 about the project from the clinically responsible doctor.

 The patients will be informed of any additional health information found in the study.

 Funding and insurance DMSc Ismail Gögenur (sponsor), MD Hans Raskov (investigator), MD Mahdi
 Alamili (investigator) and MD Astrid Bennedsen (principal investigator) initiated this
 project. The investigators and the sponsor have no financial interests or conflicts of
 interest in this study. Reponex Pharmaceuticals A/S (Slotsmarken 12, 1.th.DK-2970 Hørsholm)
 will distribute the trial drugs and colonoscopes to the participating departments as well as
 cover salary expenses for MD Hans Raskov and MD Astrid Bennedsen and the running costs of the
 trial. The funding source had no role in the design of this study and will not have any role
 during its execution, analyses, interpretation of the data, or decision to submit results.

 Information about external funding is included in the written information for the patients.

 Insurance Patients are covered by the already existing insurance for hospitalized patients in
 the Surgical Department, Herlev Hospital and Zealand University Hospital (Patient Insurance
 Scheme).

 Publication of research findings Positive, negative and inconclusive research results will be
 published in international peer-reviewed journals. The Research Ethics Committee and the
 Danish Medicines Agency will be informed within 90 days when the last patient has had the
 last visit, and a final report will be reported within 12 months in the EUDRA database.

 No later than 12 months after trial termination, an article including the obtained results
 will be submitted for publication in an internationally recognized peer-reviewed journal with
 high impact. The investigators expect to get three publications from the study; a feasibility
 publication with a detailed description of the methods, a publication of the results of the
 intervention on patients with colon cancer and a publication on patients with colon adenoma.
 Authorship eligibility will be based on the guidelines of the International Committee of
 Medical Journal Editors (ICMJE).
Inclusion Criteria:

 Inclusion criteria for track 1 and 2a:

 -  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.

 Inclusion criteria for retrospective controls (track 2b):

 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.

 Exclusion Criteria:

 Exclusion criteria for track 1 and track 2a

 1. Patients with previous allergic reaction to fosfomycin and/or metronidazole

 2. Patients under current antibiotic treatment or patient who had the last dose of
 antibiotics 30 days prior to inclusion.

 3. Patients with a non-passable tumor or patients where a part of the tumor is not
 visible during endoscopy (Track 1)

 4. Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection.

 5. Patients with a history of familial adenomatous polyposis (FAP) or hereditary
 nonpolyposis colorectal cancer (HNPCC)

 6. Patients with a history of inflammatory bowel disease (IBD)

 7. Patients under current treatment with warfarin (Marevan) and phenprocoumon
 (Marcoumar), or NOAK such as dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban
 (Lixiana®) or apixaban (Eliquis®)

 8. Patients under current treatment with Fenemal (Phenobarbital)

 9. Patients who previously have received a fecal transplantation

 10. Patients who have previously had colorectal cancer, and are now presenting with a
 secondary colon tumor.

 11. 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.

 12. Predictable poor compliance (psychiatric disease, not speaking fluent Danish,
 mentally, impaired etc)

 13. Patients with an American Society of Anaesthesiologists physical status

 14. Classification (ASAscore) of IV.

 15. Patients unable to be sedated

 16. Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy
 test to participate)

 17. Fertile women who do not use safe contraception during the study period

 18. Following contraceptive methods are acceptable when used consistently and in
 accordance, with both the product label and the instructions of the physician are:

 -  Oral contraceptive, either combined or progestogen alone

 -  Injectable progestogen

 -  Implants of levonorgestrel

 -  Estrogenic vaginal ring

 -  Percutaneous contraceptive patches

 -  Intrauterine device or intrauterine system with a documented failure rate < 1%
 per year

 -  Male partner sterilization (vasectomy with documented azoospermia) prior to
 female patient ́s entry into the study, and this male is the sole partner for
 that patient.

 -  Double barrier method: condom with spermicidal agent
 (foam/gel/film/cream/suppository), condom and occlusive cap (diaphragm or
 cervical/vault cap) with vaginal spermicidal agent
 (foam/gel/film/cream/suppository).

 Exclusion criteria for retrospective controls (track 2b):

 -  Patients under the age of 18 years during the resection for colon adenoma

 -  Patients who were under antibiotic treatment during the EMR or patients who had the
 last dose of antibiotics 30 days prior to EMR

 -  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 who previously have received a fecal transplantation

 -  Patients who have previously had colorectal cancer

 -  Patients registered in "Vævsanvendelsesregistret"

 -  Patients with insufficient tissue samples