The Effect of Probiotics ATG-F4 in Cancer Patients

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.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer; Colon Cancer
• Intervention / Treatment: Drug: LT-002 (Lactobacillus reuteri ATG-F4

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hyewon Ryu, Professor; Phone Number: 82 + 42 280 6834; Email: ryhw001@naver.com
• Study Contact Backup: Name: Sora Kang, clinical professor; Email: sorakang0515@gmail.com

Study Locations

• Korea, Republic of
  • Daejeon, Korea, Republic of, 35015
    • Recruiting
    • Chungnam National University Hospital
    • Contact: Sora Kang, Clinical professor; Phone Number: +82 42-280-6834; Email: sorakang0515@gmail.com
    • Principal Investigator: Hyewon Ryu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• 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: LT-002 (Lactobacillus reuteri ATG-F4) arm; 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.	Drug: LT-002 (Lactobacillus reuteri ATG-F4; The group that will be consuming probiotics for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Body weight (Kg)	Body weight measured by Bio-electrical Impedance Analysis	baseline, 4 weeks, 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lean body mass	Lean body mass measured by Bio-electrical Impedance Analysis	baseline, 4 weeks, 8 weeks
Body mass index	kg/m^2	baseline, 4 weeks, 8 weeks
C-reactive protein	C-reactive protein (mg/dL) measured by laboratory analysis	baseline, 4 weeks, 8 weeks
Interleukin-6	Interleukin-6 (pg/mL) measured by laboratory analysis	baseline, 4 weeks, 8 weeks
Neutrophil to lymphocyte ratio	Absolute neutrophil count and lymphocyte count will be combined to report Neutrophil to lymphocyte ratio	baseline, 4 weeks, 8 weeks
Platelet to lymphocyte ratio	Platelet and lymphocyte count will be combined to report Neutrophil to lymphocyte ratio	baseline, 4 weeks, 8 weeks
Progression-free survival	Progression free survival (from initiation of chemotherapy to disease-progression or death, whenever occured first)	Up to 24 weeks, by 3 months
Overall survival	Overall survival (from diagnosis to death)	Up to 24 seeks, by 3 months
effects of probiotics to Quality of life	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.	baseline, 4 weeks, 8 weeks
Chemotherapy toxicity	Chemotherapy toxicity Survey	baseline, 4 weeks, 8 weeks
Changes in gut microbiome profiles	Changes in gut microbiome profiles, using 16s RNA analysis.	baseline, 4 weeks, 8 weeks
Hand grip strength	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.	baseline, 4 weeks, 8 weeks
Mid calf circumference	Mid calf circumference will be measured to estimate the lean body mass of participants.	baseline, 4 weeks, 8 weeks

Collaborators and Investigators

• Sponsor: Chungnam National University Hospital
• Collaborators: AtoGen Co. Ltd
• Investigators: Principal Investigator: Hyewon Ryu, Professor, Department of Hematology Oncology

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2024
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 18, 2024
• First Submitted That Met QC Criteria: May 24, 2024
• First Posted (Actual): May 31, 2024

Study Record Updates

• Last Update Posted (Actual): May 31, 2024
• Last Update Submitted That Met QC Criteria: May 24, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: probiotics; colon cancer; pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Colonic Neoplasms
• Other Study ID Numbers: CNUH 2023-08-012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Due to the organization's policy, personal information of participants cannot be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No