Comparative Efficacy of Xiaopi Granules and Decoction in Triple-negative Breast Cancer: a Randomized Controlled Trial

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical trial is to compare the efficacy of xiaopi granules and decoction in improving the pathological complete response (pCR) of neoadjuvant chemotherapy of triple-negative breast cancer. The main objective aims to answer whether Xiaopi granules combined with neoadjuvant Chemotherapy could improve the pCR rate of triple-negative breast cancer. The secondary outcome included genomics of plasma extracellular vesicles, plasma metabolites and metabolomics, urine metabolomics, fecal intestinal flora tests, pathological tissue genomics, functional assessment of cancer therapy breast (FACT-B), and adverse events. Participants enrolled in this study will be randomized to xiaopi granules plus neoadjuvant chemotherapy, or xiaopi decoction plus neoadjuvant chemotherapy, or placebo plus neoadjuvant chemotherapy alone. Researchers will compare the pathological complete response between xiaopi granules and decoction group, and to determine their effects in chemosensitizing triple-negative breast cancer.

Detailed Description
-----------------
Background: Triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage, and onset of resistance to chemotherapy. Neoadjuvant chemotherapy is commonly used to improve the surgical pathological complete response rate (pCR) in stage II-III triple-negative breast cancer. However, chemotherapy can lead to immune escape and drug resistance in breast cancer cells, while the toxic side effects significantly affect patients' quality of life. The combination of Chinese herbal medicine and chemotherapy can improve survival rates while alleviating chemotherapy-related adverse events. Xiaopi Granules were developed by Professor Lin Yi, a renowned Traditional Chinese Medicine doctor in the field of breast diseases. The investigators' preliminary research has confirmed that Xiaopi Granules can inhibit tumor progression by targeting TAMs/CXCL1 signaling to suppress chemotherapy-induced autophagy, as well as inhibit the formation of tumor stem cells and pre-metastatic niches. Chinese medicine granules not only have several advantages compared to decoction, such as reliable drug quality and convenient administration but also have the characteristics of individualized prescription. However, whether their efficacy is comparable to that of the decoction granules still requires exploration. The investigators aimed to compare the efficacy of xiaopi granules and decoction in improving the pathological complete response of neoadjuvant chemotherapy of triple-negative breast cancer. Hypothesis: Xiaopi granules can improve the pathological complete response of neoadjuvant chemotherapy of triple-negative breast cancer. Patients and methods: Ninety patients with TNBC will be enrolled in this study and randomized to xiaopi granules plus neoadjuvant chemotherapy, xiaopi decoction plus neoadjuvant chemotherapy, or placebo plus neoadjuvant chemotherapy. The primary aim is the rate of pathological complete response (pCR, defined as the absence of invasive cells in breast and lymph nodes). The secondary outcome included genomics of plasma extracellular vesicles, plasma metabolites and metabolomics, urine metabolomics, fecal intestinal flora tests, pathological tissue genomics, functional assessment of cancer Therapy-Breast(FACT-B), and safety( AE and SAE). The neoadjuvant chemotherapy is carried out based on the National Comprehensive Cancer Network (NCCN) guidelines. Different treatments and doses are set according to the standard recommendations outlined in the guidelines. In addition to receiving neoadjuvant chemotherapy, the participants will be subjected to Xiaopi granules or decoction orally at a dosage of 18g per bag, twice daily, for a total of 8 days per treatment course. The duration of the treatment course will align with that of the chemotherapy regimen. A placebo is a look-alike substance that contains no active drug.

Official Title
-----------------
Comparative Efficacy of Xiaopi Granules and Decoction in Improving Pathological Complete Response of Neoadjuvant Chemotherapy of Triple-negative Breast Cancer: a Randomized, Double-blind, Controlled Trial

Conditions
-----------------
Triple Negative Breast Neoplasms

Intervention / Treatment
-----------------
* Drug: Xiaopi granules
* Drug: Xiaopi decoction
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Females aged ≥18 and ≤75 years Pathological diagnosis of triple-negative breast cancer with stage II-III Not having received any previous treatment for breast cancer Having at least one measurable tumor No distant metastases ECOG score 0-2 Neoadjuvant chemotherapy or combination immunotherapy Agree to participate in this clinical study and sign the informed consent form Exclusion Criteria: Pregnant and breastfeeding, with fertility requirements during the study period Combined other malignant tumors Combination of serious diseases of the heart, brain, liver, kidney, and hematopoietic system, liver function impairment, and diabetes mellitus Active hepatitis B virus or hepatitis C virus infection, or human immunodeficiency virus (HIV) infection Presence of factors affecting the administration and absorption of the drug Allergy to the drug components of this regimen A history of psychotropic substance abuse or drug use The patient has other life-threatening diseases Participating in other drug trials

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Xiaopi granules plus neoadjuvant chemotherapy<br>Xiaopi granules have a dosage of 18 g per bag, 18 g per administration, twice daily, for a total of 8 days per treatment course. The duration of the treatment course will align with that of the chemotherapy regimen. The neoadjuvant chemotherapy is developed based on the National Comprehensive Cancer Network (NCCN) guidelines. Different treatments and doses are according to the standard recommendations outlined in the guidelines. Treatment options may include AC-T, ECT, EC, TC, AC, TAC, TP, etc. | Drug: Xiaopi granules<br>* Xiaopi granules (18 g/ bag), 18 g/ time, 2 times/day, 8 days/course.<br>* Other names: Xiaopi formula;|
| Experimental: Xiaopi decoction plus neoadjuvant chemotherapy<br>Xiaopi decoction has a dosage of 18 g per bag, 18 g per administration, twice daily, for a total of 8 days per treatment course. The duration of the treatment course will align with that of the chemotherapy regimen. The neoadjuvant chemotherapy is developed based on the National Comprehensive Cancer Network (NCCN) guidelines. Different treatments and doses are according to the standard recommendations outlined in the guidelines. Treatment options may include AC-T, ECT, EC, TC, AC, TAC, TP, etc. | Drug: Xiaopi decoction<br>* Xiaopi decoction (18 g/ bag), 18 g/ time, 2 times/day, 8 days/course.<br>* Other names: Xiaopi formula;|
| Placebo Comparator: Placebo plus neoadjuvant chemotherapy<br>The placebo is a look-alike substance that contains no active drug and has a placebo inspection report. The dosage of 18g per bag, 18g per administration, twice daily, for a total of 8 days per treatment course. The duration of the treatment course will align with that of the chemotherapy regimen. The neoadjuvant chemotherapy is developed based on the National Comprehensive Cancer Network (NCCN) guidelines. Different treatments and doses are according to the standard recommendations outlined in the guidelines. Treatment options may include AC-T, ECT, EC, TC, AC, TAC, TP, etc. | Drug: Placebo<br>* The placebo does not contain any active pharmaceutical ingredients .<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response | Defined as the absence of invasive cells in breast and lymph nodes. | Through study completion,an average of 6 moths | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | The RECIST 1.1 version is used as the standard for evaluating the clinical efficacy of solid tumors. | Through study completion, an average of 6 moths | 
| Genomics of plasma extracellular vesicles | Extracellular vesicles were isolated from the plasma of breast cancer patients using a differential ultracentrifugation method. High-throughput whole transcriptome sequencing was conducted to identify differentially expressed genes in the isolated extracellular vesicles. The primary experimental procedures for transcriptome sequencing analysis include RNA quantification and qualification, library preparation for transcriptome sequencing, clustering and sequencing, and data analysis. . Analysis of whole transcriptome microarray data was performed using BioConductor software based on the statistical R programming language. | Through study completion, an average of 6 moths | 
| Plasma Genomic Tests | Utilize the Ultimate U3000 HPLC (Thermo Fisher Scientific) coupled to Q Exactive Plus mass spec- trometer (Thermo Fisher Scientific) to detect differences in metabolites within the blood of different medication intervention treatment groups before and after medication.All data were acquired and analyzed with the Xcalibur 4.0 software (Thermo Fisher Scientific). | Through study completion, an average of 6 moths | 
| Urine Metabolomics Tests | Utilize the Vanquish ultra-high-performance liquid chromatography-mass spectrometry system (Thermo Fisher Scientific) to detect variations in metabolites within the urine of different medication intervention treatment groups before and after medication.All data were acquired and analyzed with the Xcalibur 4.0 software (Thermo Fisher Scientific). | Through study completion, an average of 6 moths | 
| Fecal Intestinal Flora Tests | Laboratory testing for differences in faecal intestinal flora testing before and after the patient's medication. | Through study completion, an average of 6 moths | 
| Pathological Tissue Genomics Tests | Using whole exome sequencing (WES) to perform high-throughput sequencing of the exonic regions in pathological tissues, thereby detecting mutations, insertions, or deletions within genes. Furthermore, utilize the Genome Analysis Toolkit (GATK) software package to analyze the genomic sequencing data. | Through study completion, an average of 6 moths | 
| Functional Assessment of Cancer Therapy-Breast | Utilize the FACT-B questionnaire to evaluate the quality of life of breast cancer patients in different medication intervention treatment groups before and after treatment. This questionnaire comprehensively assesses patients' performance in social interactions, emotional experiences, daily functioning, and physical condition, which indirectly reflects their overall quality of life. | Through study completion, an average of 6 moths | 
| Safety assessments | Evaluate to adverse events and serious adverse events. | Through study completion, an average of 6 moths |