Combination Followed by Maintenance Chemotherapy Versus CDK4/6 Inhibitor Combined With Endocrine Therapy for HR Low/HER2-negative Advanced Breast Cancer: a Prospective, Randomized, Open-label Phase Ⅱ Clinical Trial

Study Overview
=================
Brief Summary
-----------------
To observe the differences in the efficacy of Combination followed by maintenance chemotherapy versus CDK4/6 inhibitor combined with endocrine therapy in HR low expression /HER2 negative advanced breast cancer, and to provide new evidence for the best treatment of HR low expression /HER2 negative advanced breast cancer, and to explore the efficacy and safety of combined/maintenance chemotherapy.

Detailed Description
-----------------
To observe the differences in the efficacy of Combination followed by maintenance chemotherapy versus CDK4/6 inhibitor combined with endocrine therapy in HR low expression /HER2 negative advanced breast cancer, and to provide new evidence for the best treatment of HR low expression /HER2 negative advanced breast cancer, and to explore the efficacy and safety of combined/maintenance chemotherapy.

Official Title
-----------------
Combination Followed by Maintenance Chemotherapy Versus CDK4/6 Inhibitor Combined With Endocrine Therapy for HR Low/HER2-negative Advanced Breast Cancer: a Prospective, Randomized, Open-label Phase Ⅱ Clinical Trial

Conditions
-----------------
Treatment, Advanced Breast Cancer, HR Low/HER2 Negative

Intervention / Treatment
-----------------
* Drug: Experimental: chemotheyapy
* Drug: Active Comparator: endocrine therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age ≥18 years old; Invasive breast cancer with metastatic disease confirmed by histological or cytological examination; Patients without pathologically or cytologically confirmed metastatic disease should have clear evidence of metastasis by physical examination or radiological studies; The most recent pathological report of biopsy confirmed HR low expression and HER2 negative. HR low expression was defined as 1-50% ER expression by immunohistochemistry (IHC); Or ER<1% and PR≥1%; Patients with ER expression of 1-10% or ER-/ PR-positive patients were eligible for inclusion after careful evaluation by the investigator, and those with a small tumor burden and candidates for endocrine therapy were eligible. HER2-negative definition: IHC 0 or 1+; If the IHC was 2+, it was confirmed negative by fluorescence in situ hybridization (FISH). at least one measurable lesion; No previous salvage chemotherapy for metastatic disease was required, and first-line endocrine therapy was allowed; no previous CDK4/6 inhibitor; For adjuvant CDK4/6i treatment, recurrence and metastasis were required more than 1 year after drug withdrawal. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, life expectancy is more than 12 weeks; Adequate function of major organs. All adverse events recovered to grade 1 or less before enrollment (NCI CTCAE version 5.0); patients without major organ dysfunction and heart disease; Women and men of childbearing potential must agree to use appropriate contraception before and during study participation. Exclusion Criteria: symptomatic, uncontrolled brain or leptomeningeal metastases; Patients who had received previous systemic radical treatment for brain metastases (radiotherapy or surgery), if stable disease had been maintained for at least 1 month as confirmed by imaging, and if systemic hormone therapy (dose 10mg/ day prednisone or other effective hormones) for more than 2 weeks without clinical symptoms. patients received radiotherapy, chemotherapy, major surgery, targeted therapy or immunotherapy within 2 weeks before enrollment; Patients received endocrine therapy within 1 week before enrollment. Chemotherapy with nitrosourea or mitomycin was administered within 6 weeks before enrollment. participated in other clinical trials of new drugs within 4 weeks before enrollment; there can not be controlled by drainage or pneumatic methods third space effusion; patients with other malignant tumors within the past 3 years, excluding radical cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma; suffering from serious or uncontrolled diseases, including but not limited to: 1) active viral infection, such as HIV or HBV active (HbsAg positive and HBV-DNA≥103, hepatitis C antibody positive); 2) history of severe cardiovascular disease: uncontrolled hypertension; Myocardial infarction, unstable arrhythmia, congestive heart failure, pericarditis, myocarditis, etc. Patients with NYHA class ⅲ-ⅳ cardiac dysfunction, or left ventricular ejection fraction (LVEF) 50% by echocardiography; 3) severe infection (e.g., intravenous antibiotic, antifungal, or antiviral therapy according to clinical practice) within 4 weeks prior to the first dose or unexplained fever during screening/before the first dose; 38.3°C (fever due to cancer, as judged by the investigator, was eligible); patients with a history of psychotropic drug abuse and unable to abstain or with mental disorders; Or accompanied by swallowing and absorption dysfunction; patients with other concomitant diseases that seriously endanger the safety of patients or affect the completion of the study according to the judgment of the investigators; patients with known history of allergy to the components of this regimen; A history of immunodeficiency, including testing positive for HIV, HCV or other acquired or congenital immunodeficiency disorders, or a history of organ transplantation; pregnant or lactating women; Patients deemed unsuitable for inclusion by the investigators.

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

Sexes Eligible for Study
-----------------
All

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>nab-paclitaxel 130mg/m2，day 1 and day 8 Capecitabine 2000mg/m2，from day1 to DAY 14 Vinorelbine 25mg/m2，day 1 and day 8 | Drug: Experimental: chemotheyapy<br>* nab-paclitaxel 130mg/m2，day 1 and day 8 + Capecitabine 2000mg/m2, followed by nab-paclitaxel 130mg/m2，day 1 and day 8 or Capecitabine from day1 to DAY 14 Vinorelbine 25mg/m2，day 1 and day 8 + Capecitabine 2000mg/m2，from day1 to DAY 14<br>* Other names: Vinorelbine 25mg/m2，day 1 and day 8 + Capecitabine 2000mg/m2，from day1 to DAY 14;|
| Active Comparator: B<br>palbociclib/Dalpiciclib Letrozole/Anastrozole/fulvestrant | Drug: Active Comparator: endocrine therapy<br>* palbociclib 125mg per day for 21days Dalpiciclib 150mg per day for 21days Letrozole 2.5mg per day Anastrozole 1mg per day fulvestrant 500mg per 28 days<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR by investigator using RECIST Guideline (Version 1.1) | ORR was defined as percentage of participants with best (confirmed) overall response (BOR) of either CR or PR assessed by the investigator according to RECIST version 1.1 | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | PFS was defined as the time from first dose to first documented disease progression (PD) or death from any cause, whichever occurred first | up to 1.5 years | 
| Adverse events | Proportion of participants experienced adverse events during the study period | up to 1.5 years | 
| OS | OS was defined as the time from first dose to death for any cause | up to 3 years |