Gut Microbiome and Its Immune Modulation in Locally Advanced Rectal Cancer

Efficacy and Safety of GEN-001 (Lactococcus Lactis) Plus Total Neoadjuvant Therapy and Dynamic Change of Gut Microbiome in Locally Advanced Rectal Cancer : Exploratory, Pilot, Prospective, Longitudinal Study

To investigate dynamic change of gut microbiomes and metabolites, and their effects on immune modulation. To evaluate the efficacy and safety of TNT with GEN-001 (Lactococcus lactis) and identify predictive biomarkers for pathologic response in patients with locally advanced rectal cancer (LARC).

Study Overview

• Status: Not yet recruiting
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Drug: GEN-001

Detailed Description

The multimodality strategy, neoadjuvant chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT) followed by surgery, has been widely used to improve local control and overall survival in locally advanced rectal cancer (LARC). TNT is a recently promising strategy incorporating systemic chemotherapy following short-course radiotherapy before surgery in LARC, and showed superior rates of pathologic complete response (pCR) compared with the concurrent CRT followed by surgery and adjuvant chemotherapy (CRT-A). However, issues regarding neoadjuvant therapy-related toxicity as well as disease progression during TNT have been raised, which need to identify biomarkers for prediction of treatment responses and safety in patients with LARC.

Growing evidence suggests that gut microbiomes interact with tumor microenvironment and are related with inflammation and immunomodulation. The association between gut microbiomes and responses of chemotherapy or immunotherapy has been previously reported. The administration of certain beneficial microbiome can be one of the strategies to treat gut dysbiosis in cancer patients, restoring microbial diversity and changing the composition of microbiome. GEN-001, Lactobacillus lactis is a live, purified facultative anaerobic gram-positive probiotic lactic acid bacterial strain. The preclinical studies showed the potential therapeutic effects of GEN-001 as an anti-cancer treatment through the activation of immune cells, including CD4 or CD8 T-cells and natural killer cells, and synergistic effects with oxaliplatin chemotherapy. Therefore, the investigators plan to investigate dynamics of gut microbiomes and metabolites, and their effects on immune modulation. Additionally investigators plan to evaluate the efficacy and safety of TNT with GEN-001 and identify predictive biomarkers for pathologic response in patients with LARC.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Soohyeon Lee, M.D., Ph.D.; Phone Number: +82-2-920-5690; Email: soohyeon_lee@korea.ac.kr
• Study Contact Backup: Name: Jwa Hoon Kim, M.D.; Phone Number: +82-2-2199-3804; Email: jhoonkim@korea.ac.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 19 years
2. Locally advanced rectal cancer, histologically confirmed; clinically T3/4, clinically N+, enlarged lateral lymph nodes, extramural vascular invasion (+), or mesorectal fascia (+)
3. Patients who schedule to receive total neoadjuvant therapy, including short-course radiotherapy (25 Gy in 5 fractions), followed by FOLFOX chemotherapy (5-fluorouracil, leucovorin, and oxaliplatin)
4. Patients with ability to swallow and retain oral medication and no clinically significant gastrointestinal abnormalities that may alter absorprtion
5. Patients with ability to collect their blood and stool samples

Exclusion Criteria:

1. Rectal cancer, other histologic type than adenocarcinoma (such as squamous cell carcinoma)
2. Patients who schedule to receive concurrent chemoradiotherapy or short-course radiotherapy alone followed by surgery and adjuvant chemotherapy
3. Patients who need emergent surgery or colostomy due to obstruction or bleeding
4. Prior use of proton pump inhibitors or H2 blockers, probiotics, immunosuppressive agents, and antibiotics within 4 weeks
5. Patients have concurrent medication that may interact with fluoropyrimidine or oxaliplatin (i.e. flucytosine, phenytoin, or warfarin)
6. Known prior history of severe adverse events during fluoropyrimidine or deficiency of dihydropyrimidine dehydrogenase (DPD)
7. Known prior severe hypersensitivity to platinum
8. Patients who have an active infection requiring antibiotics, antifungal, or antiviral agents
9. Prior solid organ or allogenic stem cell transplantation

11. Patients who have clinically significant medical disease

• Cardiovascular disease <6 months prior to enrollment (myocardial infarction, unstable angina, coronary artery bypass surgery or percutaneous coronary intervention)
• Cerebral vascular accident/stroke (<6 months prior to enrollment)
• Congestive heart failure (≥New York Heart Association (NYHA) Classification Class II)
• Uncontrolled hypertension by standard therapy: systolic blood pressure >160 mmHg or diastolic blood pressure > 100 mmHg
• Serious cardiac arrhythmia requiring medication 12. Pregnant women 13. Patients who have psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: TNT plus GEN-001; Total neoadjuvant therapy (TNT) includes short-course radiotherapy (25 Gy/5fx), followed by systemic chemotherapy with FOLFOX regimen for 3-6 months. GEN-001 is orally administered once daily during total TNT periods and surgery will be performed 1 month after systemic chemotherapy.	Drug: GEN-001; GEN-001, Lactobacillus lactis is a live, purified facultative anaerobic gram-positive probiotic lactic acid bacterial strain. GEN-001 is orally administered once daily during total TNT periods.; Other Names: Lactococcus lactis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dynamic change of gut microbiome: a-diversity index	16s rRNA sequencing	up to 30 weeks
Dynamic change of gut microbiome: b-diversity index	16s rRNA sequencing	up to 30 weeks
Immune modulation in blood	Cytotoxic T cells or regulatory T cells using flowcytometry	up to 30 weeks
Immune modulation in tissue	CD4 or CD8 tumor-infiltrating lymphocytes using immunohistochemistry	up to 30 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy and safety of TNT plus GEN-001	Achieving pathologic complete response	up to 30 weeks
Identify predictive biomarkers for pathologic responders	Prediction for pathologic complete response	up to 30 weeks

Collaborators and Investigators

• Sponsor: Korean Cancer Study Group

Study record dates

Study Major Dates

• Study Start (Anticipated): December 15, 2021
• Primary Completion (Anticipated): August 30, 2023
• Study Completion (Anticipated): January 30, 2024

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: October 3, 2021
• First Posted (Actual): October 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 3, 2021
• Last Verified: October 1, 2021

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; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: 2021AN0403

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