Probiotics for Prevention of Pyrotinib/Neratinib-Induced Diarrhea in Breast Cancer Patients

Not Applicable

Not yet recruiting

• Conditions: HER2-positive Breast Cancer; Diarrhea Caused by Drug; Neratinib; Pyrotinib

• Registration Number: NCT06892093
• Lead Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Brief Summary

This study aims to evaluate the efficacy and safety of probiotics for the prevention of diarrhea in patients with breast cancer receiving tyrosine kinase inhibitors (TKIs), specifically Pyrotinib or Neratinib.

Study Design: This is a prospective, randomized controlled clinical trial. Participants will be randomly assigned to either a probiotics intervention group or a placebo-controlled group. Both groups will be permitted to use loperamide as needed for diarrhea management.

Primary Objective: To evaluate the efficacy of probiotics in reducing the incidence and severity of diarrhea in patients receiving TKIs.

Secondary Objectives: This study will also investigate the effects of probiotics on gut microbiota composition and their potential impact on drug efficacy.

Study Duration: Patient enrollment is expected to take place from January 2025 to June 2027 at Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Both the intervention and control groups will receive treatment for 12 weeks, followed by a 4-week post-intervention observation period, making the total study duration 16 weeks.

Eligibility Criteria: Participants must be diagnosed with HER2-positive breast cancer and scheduled to receive Pyrotinib or Neratinib. Exclusion criteria include patients with severe gastrointestinal disorders or recent probiotic consumption.

Detailed Description

Breast cancer patients treated with tyrosine kinase inhibitors (TKIs), such as Pyrotinib and Neratinib, often experience severe diarrhea, leading to treatment interruptions, dose reductions, or discontinuation. Emerging evidence highlights the role of gut microbiota in drug metabolism and gastrointestinal toxicity. Probiotics have been proposed as a potential intervention to modulate gut microbiota and mitigate diarrhea; however, their efficacy in preventing TKI-induced diarrhea remains inconclusive.

This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy and safety of probiotics in preventing diarrhea in HER2-positive breast cancer patients receiving TKIs. The study will also explore the impact of probiotics on gut microbiota composition and potential microbiome-mediated mechanisms that may enhance treatment adherence and therapeutic outcomes.

Metagenomic sequencing and targeted metabolomics will be performed on stool and blood samples to investigate gut microbial composition and metabolic changes. Additional analyses will assess the association between gut-derived metabolites and immune cell activation, aiming to elucidate potential interactions among gut microbiota, metabolites, and immune responses.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-11
• Study First Submitted QC: 2025-03-18
• Study First Posted: 2025-03-24
• Study Start: 2025-05
• Last Update Submitted: 2025-05-12
• Last Update Posted: 2025-05-13
• Primary Completion: 2027-06
• Study Completion: 2027-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 308

Inclusion Criteria

Participants must meet all of the following criteria:

1. Female patients aged ≥18 years, diagnosed with HER2-positive breast cancer.
2. Eligible for pan-HER TKI therapy, including Pyrotinib or Neratinib, based on clinical guidelines.
3. ECOG performance status ≤ 2, with an expected survival of at least 3 months.
4. Left ventricular ejection fraction (LVEF) ≥ 50%.
5. Resolution of prior treatment-related toxicity to Grade ≤1 (CTCAE v5.0), with AST and ALT ≤ 2.5 times the upper normal limit, and total bilirubin ≤ 1.5 times the upper normal limit.
6. Adequate bone marrow function, defined as white blood cell count ≥ 3.0 × 10⁹/L, neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, hemoglobin ≥ 90 g/L, and serum creatinine ≤ 1.5 times the upper normal limit.
7. No persistent gastrointestinal symptoms (e.g., hematochezia, chronic constipation, or abdominal pain).
8. No evidence of structural gastrointestinal abnormalities based on gastroscopy or other relevant examinations.

Exclusion Criteria

Patients will be excluded if they meet any of the following criteria:

1. Conditions that impair swallowing or drug absorption.
2. Presence of other gastrointestinal diseases, including but not limited to inflammatory bowel disease or gastrointestinal tumors.
3. Severe cardiovascular disease or conditions incompatible with chemotherapy, including but not limited to life-threatening arrhythmias, advanced atrioventricular block, unstable angina, clinically significant pericardial disease, myocardial fibrosis, or uncontrolled hypertension.
4. Known hypersensitivity to any active ingredient or component of the investigational drug.
5. Prior radiotherapy, chemotherapy, endocrine therapy, or investigational drug trials within 4 weeks before enrollment, or history of chronic use of constipation-inducing medications within 6 months before enrollment.
6. Pregnant or lactating women or those unwilling to adopt effective contraception during the study period.
7. Any condition, at the investigator's discretion, that may compromise patient safety, interfere with study participation, or affect the interpretation of study results.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Occurrence of Grade 3 or Higher Diarrhea	Up to 12 weeks	The incidence of grade 3 or higher diarrhea during the treatment period, assessed using the Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Name	Time	Method
Occurrence of Grade 2 or Higher Diarrhea	Up to 12 weeks	The incidence of grade 2 or higher diarrhea during the treatment period, assessed using CTCAE.
Duration of Diarrhea	Up to 12 weeks	The total duration of diarrhea episodes and the duration of each diarrhea episode experienced by participants during the treatment period.
Hospitalization Rate Due to Diarrhea	Up to 12 weeks	The percentage of participants who require hospitalization due to severe diarrhea.
Loperamide Use	Up to 12 weeks	The frequency and dosage of loperamide use for diarrhea management.
Change from Baseline in Overall Quality of Life Assessed by EORTC QLQ-C30	Baseline, Weeks 2, 4, 8, 12, and 16 (End of Study)	Changes in quality of life assessed using the EORTC QLQ-C30 questionnaire. The tool evaluates overall health status and functioning, including physical, role, emotional, cognitive, and social domains. Higher scores in functional and global health scales indicate better quality of life, while higher scores in symptom scales indicate greater symptom burden.
Change from Baseline in Diarrhea-Related Quality of Life Assessed by FACT-D	Baseline, Weeks 2, 4, 8, 12, and 16 (End of Study)	Changes in diarrhea-related quality of life assessed using the FACT-D subscale of the Functional Assessment of Cancer Therapy system. This tool specifically evaluates the severity and impact of diarrhea symptoms on patients' daily life and well-being. Higher scores indicate fewer symptoms and better diarrhea-related quality of life.
Incidence of Treatment-Related Adverse Events (AEs)	Up to 16 weeks	The incidence of treatment-related adverse events (AEs) among participants receiving probiotics plus Pyrotinib/Neratinib versus the control group. Adverse events, including nausea, allergic reactions, and other related symptoms, will be recorded throughout the treatment period and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).
Incidence of Serious Adverse Events (SAEs)	Up to 16 weeks	The incidence of serious adverse events (SAEs) associated with probiotics or Pyrotinib/Neratinib treatment. Serious adverse events, including severe allergic reactions, life-threatening complications, or hospitalizations, will be recorded and analyzed to assess potential safety concerns.
Treatment Discontinuation Rate Due to Adverse Events	Up to 16 weeks	The proportion of participants who discontinue treatment due to adverse events or side effects. The study will evaluate whether the addition of probiotics contributes to safety concerns leading to early termination of therapy.

Trial Locations

Locations (1)

Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; 🇨🇳 Guangzhou, Guangdong, China