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Gut Microbiome and Its Immune Modulation in Locally Advanced Rectal Cancer

Primary Purpose

Locally Advanced Rectal Cancer

Status

Not yet recruiting

Phase

Not Applicable

Locations

Study Type

Interventional

Intervention

GEN-001

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Cancer

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TNT plus GEN-001

Arm Description

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.

Outcomes

Primary Outcome Measures

Dynamic change of gut microbiome: a-diversity index

16s rRNA sequencing

Dynamic change of gut microbiome: b-diversity index

16s rRNA sequencing

Immune modulation in blood

Cytotoxic T cells or regulatory T cells using flowcytometry

Immune modulation in tissue

CD4 or CD8 tumor-infiltrating lymphocytes using immunohistochemistry

Secondary Outcome Measures

Efficacy and safety of TNT plus GEN-001

Achieving pathologic complete response

Identify predictive biomarkers for pathologic responders

Prediction for pathologic complete response

Full Information

NCT ID

NCT05079503

First Posted

September 14, 2021

Last Updated

October 3, 2021

Sponsor

Korean Cancer Study Group

1. Study Identification

Unique Protocol Identification Number

NCT05079503

Brief Title

Gut Microbiome and Its Immune Modulation in Locally Advanced Rectal Cancer

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Not yet recruiting

Study Start Date

December 15, 2021 (Anticipated)

Primary Completion Date

August 30, 2023 (Anticipated)

Study Completion Date

January 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Korean Cancer Study Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Locally Advanced Rectal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Model Description

Single arm study

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

TNT plus GEN-001

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

GEN-001

Other Intervention Name(s)

Lactococcus lactis

Intervention Description

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.

Primary Outcome Measure Information:

Title

Dynamic change of gut microbiome: a-diversity index

Description

16s rRNA sequencing

Time Frame

up to 30 weeks

Title

Dynamic change of gut microbiome: b-diversity index

Description

16s rRNA sequencing

Time Frame

up to 30 weeks

Title

Immune modulation in blood

Description

Cytotoxic T cells or regulatory T cells using flowcytometry

Time Frame

up to 30 weeks

Title

Immune modulation in tissue

Description

CD4 or CD8 tumor-infiltrating lymphocytes using immunohistochemistry

Time Frame

up to 30 weeks

Secondary Outcome Measure Information:

Title

Efficacy and safety of TNT plus GEN-001

Description

Achieving pathologic complete response

Time Frame

up to 30 weeks

Title

Identify predictive biomarkers for pathologic responders

Description

Prediction for pathologic complete response

Time Frame

up to 30 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

19 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Soohyeon Lee, M.D., Ph.D.

Phone

+82-2-920-5690

soohyeon_lee@korea.ac.kr

First Name & Middle Initial & Last Name or Official Title & Degree

Jwa Hoon Kim, M.D.

Phone

+82-2-2199-3804

jhoonkim@korea.ac.kr

12. IPD Sharing Statement

Plan to Share IPD

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Gut Microbiome and Its Immune Modulation in Locally Advanced Rectal Cancer

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