TIP6. Metronidazole to optimize the microbiome of patients with rectal adenocarcinoma undergoing neoadjuvant therapy: protocol for the phase II MONARCH trial

Friday, March 6, 2026

3:51 PM - 3:55 PM MST

Location: Pan-Tumor HUB Zone

Co-Author(s)

Taylor Neilson, MD

Surgical Oncology T32 Research Fellow
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, USA.
Houston, Texas, United States
NB

Neal Bhutiani, MD PhD

Assistant Professor
University of Louisville
Louisville, Kentucky, United States
JR

Jaganmurugan Ramamurthy, MD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
NG

Norman Galbraith, MD PhD

University of Glasgow
Glasagow, Scotland, United Kingdom
IH

Ian Hu, MD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
AD

Arvind Dasari, MD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Michael J. Overman, MD

Professor
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
SK

Scott Kopetz, MD

Professor
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
WQ

Wei Qiao, PhD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
PS

Pranoti Sahasrabhojane, PhD

Clinical Studies Supervisor
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
VO

Vivian Orellana, MS

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Brian K. Bednarski, MD (he/him/his)

Associate Professor
MD Anderson Cancer Center
Houston, Texas, United States
Montserrat Guraieb-Trueba, MD

Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Ramy Behman, MD, PhD

Assistant Professor
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
AD

Ashish V. Damania, PhD

Associate Data Scientist, Genomic Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
NA

Nadim Ajami, PhD

Director of Scientific Research for PRIME TR
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
YW

Yan Wang, MS

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
MX

Mingxuan Xu, MS

Clinical protocol Admin manager
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
GC

George J. Chang, MD, MSc, MHCM

Professor
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Jennifer A. Wargo, MD, MMSc

Surgical Oncology and Genomic Medicine
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
SB

Susan Bullman, PhD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
CJ

Christopher Johnston, PhD

The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
YY

Y. Nancy You, MD, MHSc

Professor
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Michael G. White, MD, MS

Assistant Professor, Director of Research
Department of Colon and Rectal Surgery, University of Texas MD Anderson Cancer Center
Houston, Texas, United States

Primary Presenter(s)

Laurence P. Diggs, MD (he/him/his)

Surgical Oncology Fellow
MD Anderson Cancer Center
Houton, Texas, United States

Background: Complete clinical response is reported in up to 50% receiving total neoadjuvant chemotherapy (TNT) including 5-fluorouracil (5-FU)-based chemotherapy and chemoradiation. Recent studies show that specific intratumoral bacteria are associated with reduced responsiveness to TNT. Importantly, these microbes are not constant or static components of tumors; their abundance and activity can be dynamically modulated by environmental stressors, chemotherapy, and antimicrobials. We aim to evaluate the efficacy of metronidazole (Flagyl), a routine antibiotic with activity against anaerobic bacteria including Fusobacterium nucleatum (F. nucleatum), to selectively target deleterious microbial populations and quantify our ability to clear F. nucleatum from rectal tumors.

Methods: This randomized, phase II study is enrolling treatment-naïve patients with locally advanced rectal cancers scheduled to receive TNT. P</span>atients are randomized 1:1 to receive standard of care TNT alone or TNT in combination with metronidazole. Metronidazole will be administered as a 7-day oral course initiated within the first two weeks of TNT or between the first and second cycles. Following therapy, patients with resectable tumors will undergo post-treatment sigmoidoscopy and biopsy (standard of care; if applicable) followed by proctectomy. Patients achieving complete clinical response who opt for watch and wait management will be followed according to standard protocols. A total of 78 patients will be randomized. The primary endpoint of the study is a ≥90% reduction in intratumoral anaerobic bacterial populations. Secondary endpoints include 2-year recurrence-free and overall survival. Rates of pathologic response will be quantified. Exploratory endpoints include spatial transcriptomic profiling before and after treatment to assess immune cell infiltration and its spatial relationship with intratumoral bacteria, with a particular focus on F. nucleatum.

Learning Objectives:

Understand the clinical need for improving response rates to total neoadjuvant therapy for rectal cancer.
Understand the role of the microbiome and specifically Fusobacterium Nucleatum in resistance to radiation and chemotherapy.
Understand how subtractive therapy using targeted antibiotics can help reduce the intratumoral anaerobes that may confer treatment resistance.