## Protocol Section
### Identification Module
**NCT ID:** NCT06436976

**Brief Title:** The Effect of Probiotics ATG-F4 in Cancer Patients

**Official Title:** The Effect of Probiotics ATG-F4 in Cancer Patients

#### Organization Study ID Info
**ID:** CNUH 2023-08-012
#### Organization
**Class:** OTHER
**Full Name:** Chungnam National University Hospital
### Status Module
#### Completion Date
**Date:** 2025-12-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-31

**Type:** ESTIMATED

**Last Update Submit Date:** 2024-05-24

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2024-12-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-03-01

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-31
**Type:** ESTIMATED
**Study First Submit Date:** 2024-02-18
**Study First Submit QC Date:** 2024-05-24
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** AtoGen Co. Ltd

#### Lead Sponsor

**Class:** OTHER

**Name:** Chungnam National University Hospital

#### Responsible Party

**Investigator Affiliation:** Chungnam National University Hospital

**Investigator Full Name:** Hyewon-Ryu

**Investigator Title:** Professor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** Patients with advanced colorectal cancer or pancreatic cancer who are receiving oxaliplatin-based chemotherapy will be included. The research participants in this study will consume probiotics along with safety and anti-cancer agent side effect-related questionnaires, blood, and fecal sample collection for up to 12 weeks from the date of registration. The total duration of participation for research subjects is 12 weeks.

**Detailed Description:** Chemotherapy is one of the cancer treatment methods, but some anticancer agents appear to influence the occurrence and progression of cachexia. Chemotherapy-Induced Cachexia refers to symptoms such as appetite loss, weight loss, muscle mass reduction, and fatigue caused by chemotherapy. While anticancer agents are used to eliminate or suppress tumor cells, most are administered intravenously, potentially causing damage not only to tumor cells but also to healthy cells and tissues. Cyclophosphamide, 5-fluorouracil (5-FU), and cisplatin induce negative nitrogen balance leading to weight loss, while cisplatin, irinotecan, adriamycin, and etoposide can cause muscle wasting through NF-κB activation. Additionally, muscle loss due to combination chemotherapy like FOLFIRI (5-fluorouracil, irinotecan, cisplatin) is associated with extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase activation. Furthermore, research approached from a metabolic perspective has shown clear differences between cancer-induced cachexia and chemotherapy-induced cachexia, highlighting the need to differentiate and study cachexia induced by anticancer agents separately from cancer cachexia. In conclusion, while anticancer agents are essential for the demise of cancer cells and the inhibition of tumor growth, the occurrence of cachexia due to chemotherapy-induced damage to normal cells through prolonged administration poses a challenge that needs to be addressed to maintain the overall health of patients.

On the other hand, the microbiome refers to the total sum of all microorganisms present in a specific environment, and the human microbiome specifically refers to the collection of commensal, symbiotic, and pathogenic microorganisms coexisting with the human body. Approximately 95% of all microbes reside in the gastrointestinal tract, including the colon, and they are also widely distributed in the respiratory, reproductive, oral, and skin systems. The gut microbiome is known to play a crucial role in nutrient absorption, immune system regulation, and prevention of infectious diseases within the body.

Several studies suggest that changes in the composition and function of the gut microbiome may contribute to the development and progression of cachexia in cancer patients undergoing chemotherapy. In experiments where gut microbiota from mice treated with chemotherapy were transplanted into germ-free mice, an increase in inflammation-related C-X-C motif chemokine ligand 1 (CXCL1) was observed in the germ-free mice, accompanied by a significant decrease in their movement and physical activity. This result indicates that chemotherapy induces changes in the gut microbiota, which in turn can impact the entire body.

Chemotherapy can induce dysbiosis, an imbalance in the microbial community structure, leading to a reduction in beneficial bacteria and overgrowth of harmful bacteria, which can trigger inflammation and impair intestinal barrier function. Ultimately, this can promote inflammatory responses, exacerbating muscle loss and weight loss in cancer patients. Moreover, it can also affect nutrient absorption and metabolism, leading to malnutrition and energy imbalance.

Additionally, gut microbial communities produce various metabolites, such as short-chain fatty acids (SCFAs), which play important roles in host metabolism and immune function regulation. Dysbiosis may affect intestinal protein synthesis and energy metabolism. Overall, the profound involvement of the gut microbiome and metabolites in chemotherapy-induced cachexia symptoms suggests that microbiome-based therapies could be an interesting development target for alleviating or treating chemotherapy-induced cachexia.

Probiotics are generally known to improve gastrointestinal conditions such as constipation and diarrhea, inhibit harmful bacteria in the gut, and prevent diseases through their regulatory effects on intestinal function. They are also known to have effects such as immune enhancement, improvement of vaginal health, and alleviation of allergies. In particular, there is ongoing global research aimed at developing probiotics as therapeutic agents for the microbiome, which constitutes the total microorganisms in the gut. Recently, with the FDA approval of microbiome therapy for clostridiosis difficile infection, research in this area has been increasing.

The test strain of Lactobacillus reuteri ATG-F4 used in this study has been confirmed to be safe based on preclinical research results. When administered to mice transplanted with tumors and then treated with anticancer agents, it was observed to improve weight loss, muscle mass reduction, and muscle strength decline. Additionally, it helped alleviate diarrhea symptoms and normalize gut microbiota. These effects were found to be associated with the suppression of inflammatory responses induced by anticancer agents. Based on previous studies, this trial was planned to analyze the impact of the investigational product LT-002 (Lactobacillus reuteri ATG-F4) on the safety and improvement of anticancer agent side effects in cancer patients.

### Conditions Module

**Conditions:**

- Pancreatic Cancer

- Colon Cancer

**Keywords:**

- probiotics

- pancreatic cancer

- colon cancer

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** SUPPORTIVE_CARE

#### Enrollment Info

**Count:** 30

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** The group that will be consuming probiotics (LT-002 (Lactobacillus reuteri ATG-F4)) for 12 weeks. The subjects will take a daily intake of 4 x 10\^10 colony forming unit (CFU) of LT-002.

**Intervention Names:**

- Drug: LT-002 (Lactobacillus reuteri ATG-F4

**Label:** LT-002 (Lactobacillus reuteri ATG-F4) arm

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- LT-002 (Lactobacillus reuteri ATG-F4) arm

**Description:** The group that will be consuming probiotics for 12 weeks.

**Name:** LT-002 (Lactobacillus reuteri ATG-F4

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Body weight measured by Bio-electrical Impedance Analysis

**Measure:** Changes of Body weight (Kg)

**Time Frame:** baseline, 4 weeks, 8 weeks

#### Secondary Outcomes

**Description:** Lean body mass measured by Bio-electrical Impedance Analysis

**Measure:** Lean body mass

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** kg/m\^2

**Measure:** Body mass index

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** C-reactive protein (mg/dL) measured by laboratory analysis

**Measure:** C-reactive protein

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Interleukin-6 (pg/mL) measured by laboratory analysis

**Measure:** Interleukin-6

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Absolute neutrophil count and lymphocyte count will be combined to report Neutrophil to lymphocyte ratio

**Measure:** Neutrophil to lymphocyte ratio

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Platelet and lymphocyte count will be combined to report Neutrophil to lymphocyte ratio

**Measure:** Platelet to lymphocyte ratio

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Progression free survival (from initiation of chemotherapy to disease-progression or death, whenever occured first)

**Measure:** Progression-free survival

**Time Frame:** Up to 24 weeks, by 3 months

**Description:** Overall survival (from diagnosis to death)

**Measure:** Overall survival

**Time Frame:** Up to 24 seeks, by 3 months

**Description:** The EORTC Quality of life questionnaire - C30 score consists of 30 items divided into three subdomains: overall quality of life, functional areas, and symptom areas. Higher scores in the overall quality of life and functional areas indicate a better quality of life, while lower scores in the symptom areas also indicate a better quality of life.

**Measure:** effects of probiotics to Quality of life

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Chemotherapy toxicity Survey

**Measure:** Chemotherapy toxicity

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Changes in gut microbiome profiles, using 16s RNA analysis.

**Measure:** Changes in gut microbiome profiles

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Hand grip strength measurement using Digital grip strength dynamometer, T.K.K 5401, Japan). Hand grip strength will be measured to estimate the physical performances of participants.

**Measure:** Hand grip strength

**Time Frame:** baseline, 4 weeks, 8 weeks

**Description:** Mid calf circumference will be measured to estimate the lean body mass of participants.

**Measure:** Mid calf circumference

**Time Frame:** baseline, 4 weeks, 8 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Patients diagnosed with advanced colorectal cancer or pancreatic cancer who are undergoing treatment with Oxaliplatin-based chemotherapy at Chungnam National University Hospital, including both newly diagnosed and recurrent cases.
* Aged 19 years or older.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 points.
* Expected life expectancy of at least 3 months.
* Ability to understand the requirements of the clinical trial and willingness to sign the informed consent form.

Exclusion Criteria:

* Presence of known brain metastases.
* Malignant bowel obstruction requiring surgical intervention.
* Uncontrolled, active infections, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or any psychiatric/social conditions that may limit compliance with the study requirements.
* Partial or complete intestinal obstruction.
* Pregnant or lactating women.
* Use of antibiotics, antifungals, or antiviral agents on more than one occasion within the past month.
* Consumption of probiotics products or fermented milk more than twice within the past month.
* Patients with neurological or psychiatric disorders.

**Minimum Age:** 19 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** ryhw001@naver.com

**Name:** Hyewon Ryu, Professor

**Phone:** 82 + 42 280 6834

**Role:** CONTACT

**Contact 2:**

**Email:** sorakang0515@gmail.com

**Name:** Sora Kang, clinical professor

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Daejeon

**Contacts:**

***Contact 1:***

- **Email:** sorakang0515@gmail.com

- **Name:** Sora Kang, Clinical professor

- **Phone:** +82 42-280-6834

- **Role:** CONTACT

***Contact 2:***

- **Name:** Hyewon Ryu

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Korea, Republic of

**Facility:** Chungnam National University Hospital

**Status:** RECRUITING

**Zip:** 35015

#### Overall Officials

**Official 1:**

**Affiliation:** Department of Hematology Oncology

**Name:** Hyewon Ryu, Professor

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Description:** Due to the organization's policy, personal information of participants cannot be shared.

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000004701

- Term: Endocrine Gland Neoplasms

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000010182

- Term: Pancreatic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000015179

- Term: Colorectal Neoplasms

- ID: D000007414

- Term: Intestinal Neoplasms

- ID: D000005770

- Term: Gastrointestinal Neoplasms

- ID: D000005767

- Term: Gastrointestinal Diseases

- ID: D000003108

- Term: Colonic Diseases

- ID: D000007410

- Term: Intestinal Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M13110

- Name: Pancreatic Neoplasms

- Relevance: HIGH

- As Found: Pancreatic Cancer

- ID: M6338

- Name: Colonic Neoplasms

- Relevance: HIGH

- As Found: Colon Cancer

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7863

- Name: Endocrine Gland Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M13102

- Name: Pancreatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17890

- Name: Colorectal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M10448

- Name: Intestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M6336

- Name: Colonic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10444

- Name: Intestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4387

- Name: Pancreatic Cancer

- Relevance: HIGH

- As Found: Pancreatic Cancer

### Condition Browse Module - Meshes

- ID: D000010190

- Term: Pancreatic Neoplasms

- ID: D000003110

- Term: Colonic Neoplasms

### Intervention Browse Module - Browse Branches

- Abbrev: Ot

- Name: Other Dietary Supplements

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: HB

- Name: Herbal and Botanical

### Intervention Browse Module - Browse Leaves

- ID: T355

- Name: Acidophilus

- Relevance: HIGH

- As Found: Students

- ID: T120

- Name: Cola

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
