Clinical trial NCT06436976: The Effect of Probiotics ATG-F4 in Cancer Patients
Official title: The Effect of Probiotics ATG-F4 in Cancer Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pancreatic Cancer
Colon Cancer
Keywords: probiotics
pancreatic cancer
colon cancer
Lead sponsor: Chungnam National University Hospital
Sponsor class: OTHER
Collaborators: name: AtoGen Co. Ltd
First posted: 2024-05-31
Enrollment: 30
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Changes of Body weight (Kg)
timeFrame: baseline, 4 weeks, 8 weeks
Secondary outcomes:
measure: Lean body mass
timeFrame: baseline, 4 weeks, 8 weeks
measure: Body mass index
timeFrame: baseline, 4 weeks, 8 weeks
measure: C-reactive protein
timeFrame: baseline, 4 weeks, 8 weeks
measure: Interleukin-6
timeFrame: baseline, 4 weeks, 8 weeks
measure: Neutrophil to lymphocyte ratio
timeFrame: baseline, 4 weeks, 8 weeks
measure: Platelet to lymphocyte ratio
timeFrame: baseline, 4 weeks, 8 weeks
measure: Progression-free survival
timeFrame: Up to 24 weeks, by 3 months
measure: Overall survival
timeFrame: Up to 24 seeks, by 3 months
measure: effects of probiotics to Quality of life
timeFrame: baseline, 4 weeks, 8 weeks
measure: Chemotherapy toxicity
timeFrame: baseline, 4 weeks, 8 weeks
measure: Changes in gut microbiome profiles
timeFrame: baseline, 4 weeks, 8 weeks
measure: Hand grip strength
timeFrame: baseline, 4 weeks, 8 weeks
measure: Mid calf circumference
timeFrame: baseline, 4 weeks, 8 weeks
Other outcomes:
Locations:
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
Study officials:
affiliation: Department of Hematology Oncology
name: Hyewon Ryu, Professor
role: PRINCIPAL_INVESTIGATOR
References: