Intestinal Microbiome Modulation With Antibiotics in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer

January 27, 2025 updated by: Samuel Aguiar Jr, AC Camargo Cancer Center

Phase II Trial for Intestinal Microbiome Modulation With Antibiotics in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer

Colorectal cancer is the second most common malignancy worldwide and one-third of these tumors are located in the rectum. The treatment may involve up to three modalities: radiotherapy, chemotherapy, and surgery. For several years, thanks mainly to Brazilian researchers, subgroups of patients have been selected for non-surgical treatment when chemoradiotherapy induces a complete clinical response. These treatment regimens have reached a plateau leading researchers to seek strategies that can increase response rates. Intestinal microbiota studies have shown that an overpopulation of certain anaerobic bacteria is generally associated with poorer treatment response. No study has attempted to intervene in the gut microbiota to increase the complete response rate in rectal cancer. The proposal of the investigators aims to modulate the intestinal microbiota through a phase 2 clinical trial, with the use of metronidazole as the intervention .

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This is a single-center, phase 2, single-arm clinical trial, compared with a historical control. The intervention consists of the oral administration of metronidazole at a daily dose of 1.500 mg, divided into three 500mg doses taken every 8 hours, during the first seven days of neoadjuvant radiotherapy. Adherence to metronidazole will be monitored by evaluating records on the patient´s daily card, designed by the researchers, and questioning during medical visits. Adverse events related to metronidazole use are uncommon and mainly include gastrointestinal disturbances. Infrequent reactions occur in less than 0,01% of patients. All adverse effects will be carefully monitored by the study team. Patients may discontinue the medication for any following reasons: disease progression, death, adverse event, leading to permanent discontinuation of chemoradiotherapy, medication intolerance, withdrawal of consent by the patient (or legal representative), or the need for new systemic oncological therapy or surgery. The primary objective of the study is to determine the effectiveness of antimicrobial therapy at the start of neoadjuvant treatment in patients with locally advanced rectal adenocarcinoma. The secondary objectives are to evaluate changes in the intestinal bacterial profile through intestinal analyses (16S RNA analysis) in pre- and post-treatment fecal samples, to measure the organ preservation rate, to determine the rate of complete pathological response among operated patients, to monitor the toxicity of neoadjuvant treatment and to calculate the 3-year locoregional recurrence-free survival rate. The primary outcome will be a complete clinical response to neoadjuvant treatment, defined by the absence of detectable residual disease through the following methods: digital rectal examination, rectal endoscopy, and magnetic resonance image. The standard neoadjuvant treatment regimen consists of long-course radiotherapy, with 4.500 cGy fractionated into 25 applications of 180 cGy, and a boost to the primary tumor up to a total dose of 54 Gy, concomitant with fluoropyrimidine. The current practice is to perform the entire neoadjuvant treatment before surgery, which consists of chemoradiotherapy followed by chemotherapy with fluoropyrimidine and oxaliplatin for up to 6 cycles (TNT consolidation), or starting with chemotherapy followed by chemoradiotherapy (TNT induction). The primary outcome will be evaluated between 7 and 10 days after the completion of chemotherapy in TNT consolidation or between 10-12 weeks after the radiotherapy in TNT induction. For patients who were candidates for rectal amputation and achieved complete clinical response after the neoadjuvant treatment, an organ preservation strategy (Watch Wait - WW) will be recommended as the first option. For patients with mid-rectal tumors, where surgery involves sphincter preservation, total mesorectal excision surgery with sphincter preservation will be offered as the first treatment option, regardless of the response pattern. In cases of complete clinical response, the WW strategy will be offered as an alternative to patients who refuse surgery. For the evaluation of adverse events, patients will be seen before the start of the study, within 7 days of the start of chemoradiotherapy, and at the end of the study, during the evaluation of the primary outcome, with a complete clinical examination and routine laboratory tests. Patients who experience intolerable grade 2 or 3 toxicity will have their treatment dose reduced and/ or interrupted, according to routine procedures. All adverse effects will be graded and assessed to determine if they are treatment-related. Since this is a Brazilian-approved drug that is widely used commercially, the investigators do not expect to observe severe adverse events. However, if there is intolerance, dose reduction will not be allowed, but the investigators will recommend discontinuation. Adverse events will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Whenever possible, each adverse event must be evaluated to determine: its severity, its relationship to each study drug, its duration, and actions taken. The investigators will collect pre- and post-intervention stool samples from all patients included in the study to investigate the secondary outcome, which consists of evaluating changes in the intestinal bacteria profile through intestinal analyses (16S RNA analysis) in pre- and post-treatment fecal samples.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Brazil
    • SP
      • São Paulo, SP, Brazil, 01509-010
        • Recruiting
        • A.C Camargo Cancer Center
        • Contact:
        • Principal Investigator:
          • Samuel Aguiar Jr, MD, PhD
        • Sub-Investigator:
          • Virgilio S Silva, MD, PhD
        • Sub-Investigator:
          • Renata T Mayumi, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients over 18 years old with middle and lower rectal adenocarcinoma, classified as locally advanced or where the tumor´s location necessitates rectal amputation surgery;
  • Tumors located below the peritoneal reflection, as determined by MRI, will be defined as middle and lower rectum;
  • Patients eligible for rectal amputation will be those with tumor whose distal margin is less than 2,0cm from the pectineal line, as determined by rectoscopy, or less than 2,0cm from the anorectal ring by palpation or MRI.
  • Patients with middle rectum cancer candidates for radiotherapy as part of neoadjuvant treatment will be included according to the following criteria: mesorectal fascia compromised by direct extension of the primary tumor or by an affected lymph node; cT4 tumors.

Exclusion Criteria:

  • Patients without performance status for total neoadjuvant treatment;
  • Histologies other than adenocarcinoma;
  • Adenocarcinomas with a microsatellite instability phenotype, as determined by immunohistochemistry;
  • Patients with middle rectal tumors who are not indicated for radiotherapy in the neoadjuvant treatment regimen, according to the institutional protocol (tumors cT3N0, with free mesorectal fascia; cT1-3 N+, with free mesorectal fascia).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Antibiotic in neoadjuvant treatment of locally advanced rectal adenocarcinoma
This study investigates the administration of an oral antibiotic, metronidazole, during the first seven days of radiotherapy for patients with locally advanced rectal adenocarcinoma undergoing total neoadjuvant treatment. Metronidazole is a safe medication with a very low risk of adverse effects and is commonly used to treat infections caused by anaerobic bacteria present in the intestinal microbiota. Additionally, certain genera of anaerobic bacteria are known to be associated with a poorer response to treatment.
Drug: Metronidazole
This intervention involves administering the oral antibiotic metronidazole during the first seven days of radiotherapy for patients with locally advanced rectal adenocarcinoma who are undergoing total neoadjuvant treatment. Metronidazole is considered a safe medication, with a very low risk of adverse effects. It is commonly used to treat infections caused by anaerobic bacteria that are part of the intestinal microbiota. Additionally, it is well established that certain genera of anaerobic bacteria are linked to a poorer response to treatment.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Complete clinical response in total neoadjuvant treatment of rectal adenocarcinoma
Time Frame: Between 7 -10 days after TNT consolidation and 10 - 12 weeks after TNT induction
Absence of residual disease detectable by clinical examination, rectal endoscopy, nuclear magnetic resonance imaging.
Between 7 -10 days after TNT consolidation and 10 - 12 weeks after TNT induction

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Evaluate changes in the intestinal bacteria profile.
Time Frame: Up to 7 days before starting intervention with metronidazole and up to 7 days after the end of intervention with metronidazole.
Intestinal analysis (RNA-16S analysis) on fecal samples before and after treatment.
Up to 7 days before starting intervention with metronidazole and up to 7 days after the end of intervention with metronidazole.
Organ preservation rate.
Time Frame: 6 to 12 weeks after the end of treatment.
Organ preservation rate after neoadjuvant treatment.
6 to 12 weeks after the end of treatment.
Complete pathological response rate among operated patients
Time Frame: 10 days after surgery.
Complete pathological response (pCR) in surgical pathological examination result.
10 days after surgery.
Toxicity of neoadjuvant treatment.
Time Frame: Through treatment completion, an average of 6 months.
Evaluation of neoadjuvant treatment toxicity using CTCAE 5.0.
Through treatment completion, an average of 6 months.
Locoregional recurrence-free survival.
Time Frame: 3 years after the end of treatment.
Evaluation of local or locoregional recurrence by magnetic resonance imaging (MRI).
3 years after the end of treatment.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
AC Camargo Cancer Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Conselho Nacional de Desenvolvimento Científico e Tecnólogico - CNPQ

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Samuel Aguiar Jr, MD, PhD, A.C. Camargo Cancer Center
  • Study Chair: Virgilio S Silva, MD, PhD, A.C. Camargo Cancer Center
  • Study Chair: Renata T Mayumi, MD, A.C. Camargo Cancer Center
  • Study Chair: Bruna E Catin Kupper, BSN, PhD, A.C. Camargo Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 22, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 31, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 30, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 13, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 24, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 25, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 27, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CEP3589/24

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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