Gut Microbiome and Its Immune Modulation in Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: GEN-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 19 years Locally advanced rectal cancer, histologically confirmed; clinically T3/4, clinically N+, enlarged lateral lymph nodes, extramural vascular invasion (+), or mesorectal fascia (+) 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) Patients with ability to swallow and retain oral medication and no clinically significant gastrointestinal abnormalities that may alter absorprtion Patients with ability to collect their blood and stool samples Exclusion Criteria: Rectal cancer, other histologic type than adenocarcinoma (such as squamous cell carcinoma) Patients who schedule to receive concurrent chemoradiotherapy or short-course radiotherapy alone followed by surgery and adjuvant chemotherapy Patients who need emergent surgery or colostomy due to obstruction or bleeding Prior use of proton pump inhibitors or H2 blockers, probiotics, immunosuppressive agents, and antibiotics within 4 weeks Patients have concurrent medication that may interact with fluoropyrimidine or oxaliplatin (i.e. flucytosine, phenytoin, or warfarin) Known prior history of severe adverse events during fluoropyrimidine or deficiency of dihydropyrimidine dehydrogenase (DPD) Known prior severe hypersensitivity to platinum Patients who have an active infection requiring antibiotics, antifungal, or antiviral agents 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

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNT plus GEN-001<br>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<br>* 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.<br>* Other names: Lactococcus lactis;|

What is the study measuring?
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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 |