Effect of Huaier Granule on Adjuvant Treatment for High-risk Early-stage Triple-negative Breast Cancer

Study Overview
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Brief Summary
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This is a prospective, multicenter, randomized, parallel controlled, open-label study. The primary purpose of this study is to evaluate the efficacy of Huaier Granule on postoperative adjuvant therapy of high-risk early-stage triple-negative invasive ductal carcinoma. The Secondary purposes are to evaluate the safety of long-term use of Huaier granules as postoperative adjuvant treatment of high-risk early-stage triple-negative invasive ductal carcinoma, and the changes of quality of life score after treatment with Huaier granule.

Detailed Description
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Triple-negative breast cancer（TNBC） accounts for 10% to 20% of breast cancer. TNBC is more likely to show lymph node involvement at diagnosis, and biologically more aggressive. Women with TNBC have a higher rate of distant recurrence at early-stage and a worse 5-year prognosis than women of other molecular types. Although PARP inhibitors and immune checkpoint inhibitors are showing promise to patients with advanced TNBC, however, these targeted therapies and immunotherapy for TNBC can not increase the clinical benefits of early-stage patients. As adjuvant therapy for hepatocellular carcinoma after curative liver resection, a multicentre study demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. Retrospective studies have shown that Huaier granules can improve the rates of disease-free survival（DFS） and overall survival（OS）, and reduce the incidence of adverse events among operable patients with TNBC. In this study, 1072 high-risk early-stage triple-negative invasive ductal carcinoma participants (536 cases in the observation group and 536 cases in the control group) from 30 research centers will be included. The block randomization was adopted, participants will be randomly divided into the experimental group (Huaier granule plus conventional treatment/visit) and control group (conventional treatment/visit only). All participants will be followed up for 5 years, including 2-year treatment follow-up and 3-year survival follow-up. During the treatment period, the participants will be followed up every 3 months, and the survival follow-up period will be followed up every 6 months.

Official Title
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Effect of Huaier Granule on Postoperative Adjuvant Treatment for High-risk Early-stage Triple-negative Invasive Ductal Carcinoma: a Prospective, Multicenter, Randomized, Controlled, Open-label Study

Conditions
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Carcinoma Breast, Triple-negative Breast Cancer, Invasive Ductal Carcinoma, Breast

Intervention / Treatment
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* Drug: Huaier Granule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged from 18 to 70. Histologically confirmed as breast invasive ductal carcinoma. Molecular typing of breast lesions is triple-negative breast cancer, when the patient had multicentric lesions at the same time, all invasive lesions were confirmed as triple-negative. Regional lymph node metastasis confirmed by postoperative pathology [except isolated tumor cells ( ITC )], or tumor response did not achieve pathological complete response (pCR) after neoadjuvant therapy [neoadjuvant chemotherapy completed at least four cycles, the breast has residual invasive cancer or axillary lymph node metastasis ( except isolated tumor cells ) .] There was no local recurrence and distant metastasis of the tumor. The time of randomization is during the postoperative adjuvant therapy or within 60 days after the end of the last postoperative adjuvant therapy. Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. Hepatic function and renal function: serum creatinine level ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) concentration / alanine aminotransferase (ALT) concentration≤ 2.5 × ULN，total serum bilirubin concentration≤ 1.5 × ULN. Blood routine: neutrophil count ≥ 1.5*109 / L, platelet count ≥ 100*109 / L, hemoglobin concentration ≥ 90 g / L (without transfusion). The participants volunteered to join the study with good compliance and signed an informed consent form. Exclusion Criteria: Bilateral breast cancer. Complicated with severe cardiopathy, hepatopathy, nephropathy, endocrine system diseases. According to the researchers' judgement, the comorbidities can cause unacceptable safety risks and affect participants' compliance with research programs. Suffering from malignant tumors other than breast cancer (except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix) in the past 5 years. Allergic to Huaier granule. Pregnant or lactating women, and those who planning a pregnancy during the study period. Participating in other clinical trials or participated in other clinical studies within 3 months. Patients with a poor compliance, or they are not appropriate for this study because of other reasons considered by the researchers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Huaier Granule + Conventional Treatment/visit<br>Huaier Granule: oral administration, 20g each time, 3 times a day. The starting time of Huaier granule: from the beginning of adjuvant therapy to the end of adjuvant therapy, and within 60 days after the end of adjuvant therapy is also acceptable. Conventional Treatment/visit：The postoperative adjuvant therapy and visit of TNBC are based on clinical routine. | Drug: Huaier Granule<br>* The subjects in the experimental group will be treated with Huaier Granule continuously for 2 years or until the disease progressed, intolerable toxicity, withdrawal of informed consent form or died for any reason.<br>* Other names: Z20000109（NMPA Approval Number）;|
| No Intervention: Conventional Treatment/visit<br>Conventional Treatment/visit：The postoperative adjuvant therapy and visit of TNBC are based on clinical routine. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year rates of disease-free survival | Disease-free survival (DFS)：The time from randomization until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, local recurrence, distant metastasis, death from any cause, contralateral invasive breast cancer, ipsilateral ductal carcinoma in situ, contralateral ductal carcinoma in situ, second primary invasive carcinoma (except breast cancer). 3-year rates of disease-free survival: The percentage of participants who have not occurred events described in the DFS definition within 3 years. | Start of treatment until 3-year follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year rates of overall survival | Overall survival (OS): The time from randomization until the date of death from any cause. 3-year rates of overall survival: The percentage of participants who have not died from any cause within 3 years. | Start of treatment until 3-year follow-up | 
| 3-year rates of invasive-disease-free survival | Invasive-disease-free survival (iDFS): The time from randomization until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, local recurrence, distant metastasis, death from any cause, contralateral invasive breast cancer, second primary invasive carcinoma (except breast cancer). 3-year rates of invasive-disease-free survival: The percentage of participants who have not occurred events described in the iDFS definition within 3 years. | Start of treatment until 3-year follow-up | 
| 5-year rates of disease-free survival | 5-year rates of disease-free survival: The percentage of participants who have not occurred events described in the DFS definition within 5 years. | Start of treatment until 5-year follow-up | 
| 5-year rates of overall survival | 5-year rates of overall survival: The percentage of participants who have not died from any cause within 5 years. | Start of treatment until 5-year follow-up | 
| 5-year rates of invasive-disease-free survival | 5-year rates of invasive-disease-free survival: The percentage of participants who have not occurred events described in the iDFS definition within 5 years. | Start of treatment until 5-year follow-up | 
| Changes in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire | Quality of Life (QOL) will be measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). The scope of each domain is 0 to 100. Higher scores in the functional and general health areas indicate better functional status and quality of life, and higher scores in the symptomatic areas indicate more symptoms or problems (poorer quality of life). | Up to 5 years since the start of treatment | 
| Incidence and severity of AE or SAE | AE: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAE: A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. | Start of treatment until 3 year after enrollment | 
| Incidence and severity of ADR，SUSAR or SADR | All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. A SADR is a serious ADR according to the above criteria of SAE. A SUSAR is an unexpected SADR. | Start of treatment until 3 year after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Huaier Granule, Triple-negative Breast Cancer, Invasive Ductal Carcinoma, Breast, Adjuvant Treatment