SNF Platform Study of HR+/ HER2-advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to establish a prospective, single-center platform research based on clinical subtypes to explore precision therapy in patients hormone-receptor-positive HER2-negative advanced breast cancer who had previously used CDK4/6 inhibitors.

Detailed Description
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Participants in this study were hormone-receptor-positive HER2-negative patients with advanced breast cancer who had previously used CDK4/6 inhibitors. Hormone receptor positive HER2 negative was defined as ER positive (IHC ER positive percentage > 10% or PR positive (IHC PR positive percentage > 10%) and HER2 negative (IHC-/+; Or IHC++ but FISH/CISH-). The Department of Pathology and the Key Laboratory of Breast Cancer of Fudan University Shanghai Cancer Center conducted digital pathological typing of the biopsy pathology of metastatic lesions of all participants . If the pathology of metastatic lesions could not be obtained, the digital pathological typing was performed according to the pathology of primary lesions. According to the digital pathological types of biopsy tissue and peripheral blood ctDNA, the patients were divided into four precise subtypes: SNF1, SNF2, SNF3, and SNF4. At the same time, the negative control group was randomly set by subtype stratification at 2:1. In different SNF types, patients were divided into 7 subcohorts according to the genetic PANEL results.

Official Title
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Precision Platform Study of HR+/ HER2-advanced Breast Cancer Based on SNF Typing (A Prospective, Open-label, Multi-center, Phase II Platform Study)

Conditions
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Breast Neoplasm, Breast Cancer, Hormone Receptor Positive Tumor, HER2-negative Breast Cancer, Advanced Breast Cancer

Intervention / Treatment
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* Drug: PIK3CA inhibitor
* Drug: AKT inhibitor
* Drug: Carrelizumab
* Drug: Famitinib
* Drug: Fluzoparib
* Drug: Dalpiciclib
* Drug: SHR-A1811
* Drug: TROP2 ADC
* Drug: Everolimus
* Drug: Aromatase Inhibitors or Fulvestrant
* Drug: Goserelin
* Drug: TPC
* Drug: RTK Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged ≥18 years; HR+/HER2- invasive breast cancer confirmed by histology (specific definition: ER >10% positive tumor cells by immunohistochemistry is defined as ER positive, PR >10% positive tumor cells is defined as PR positive, ER and/or PR positive is defined as HR positive; HER2 0-1+ or HER2 + but negative by FISH without amplification was defined as HER2 negative); Locally advanced breast cancer (unable to undergo radical local treatment) or recurrent metastatic breast cancer; HR+/HER2- advanced breast cancer patients who had previously received CDK4/6 inhibitor therapy; At least one measurable lesion according to RECIST 1.1 (conventional CT scan ≥20 mm, spiral CT scan ≥10 mm, measurable lesion has not received radiotherapy); The functions of the main organs are basically normal and meet the following conditions: I. Blood routine examination criteria shall meet: HB ≥90 g/L (no blood transfusion within 14 days); The ANC acuity 1.5 x 109 / L; PLT acuity 75 x 109 / L; Ii. Biochemical tests should meet the following criteria: TBIL ≤1.5×ULN (upper limit of normal value); ALT and AST ≤3×ULN; If liver metastases were present, ALT and AST≤ 5×ULN; Serum Cr ≤1×ULN, endogenous creatinine clearance > 50 ml/min (Cockcroft-Gault formula); They have not received radiotherapy, molecular targeted therapy, or surgery within 3 weeks before the start of the study, and have recovered from the acute toxicity of previous treatment (if surgery was performed, the wound has healed completely); No peripheral neuropathy or grade I peripheral neurotoxicity; ECOG score ≤2, and life expectancy ≥3 months; Fertile female subjects were required to use a medically approved contraceptive method during the study treatment period and for at least 3 months after the last use of the study drug; Subjects volunteered to join the study, signed informed consent, had good compliance, and cooperated with follow-up. Exclusion Criteria: Radiotherapy (except for palliative causes), chemotherapy, and immunotherapy were used in the first 3 weeks of treatment, except bisphosphonate (which can be used for bone metastasis); Uncontrolled central nervous system metastases (indicating symptomatic or symptomatic treatment with glucocorticoids or mannitol); A history of clinically important or uncontrolled heart disease, including congestive heart failure, angina pectoris, myocardial infarction, or ventricular arrhythmia within the last 6 months; Persistent grade 1 or higher adverse reactions caused by previous treatments. The exception to this is hair loss or something the researchers don't think should be ruled out. Such cases should be clearly documented in the investigator's notes; Underwent major surgery (except minor outpatient procedures, such as placement of vascular access) within 3 weeks of the first course of trial treatment; Pregnant or lactating patients; Malignancy (except basal cell carcinoma of the skin, which has been cured, and carcinoma in situ of the cervix) in the past 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: SNF1 1A: PIK3CA mutation<br>PIK3CA inhibitors +Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks. | Drug: PIK3CA inhibitor<br>* PIK3CA inhibitor<br>Drug: Aromatase Inhibitors or Fulvestrant<br>* Letrozole/Anastrozole/Exemestane or Fulvestrant<br>Drug: Goserelin<br>* For premenopause<br>|
| Experimental: SNF1 1B: AKT pathway mutation<br>AKT pathway inhibitors +Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks. | Drug: AKT inhibitor<br>* AKT inhibitor<br>Drug: Aromatase Inhibitors or Fulvestrant<br>* Letrozole/Anastrozole/Exemestane or Fulvestrant<br>Drug: Goserelin<br>* For premenopause<br>|
| Experimental: SNF1 1C: without above mutation<br>Everolimus 10mg po qd+Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks. | Drug: Everolimus<br>* mTOR inhibior<br>Drug: Aromatase Inhibitors or Fulvestrant<br>* Letrozole/Anastrozole/Exemestane or Fulvestrant<br>Drug: Goserelin<br>* For premenopause<br>|
| Experimental: SNF2 2: Stratification of CD8 expression<br>Treatment of physician' choice+Pd-1 mab (Carrelizumab 200mg Q2W)+Famitinib 15mg po qd for 4 weeks as a cycle | Drug: Carrelizumab<br>* Pd-1 mab<br>* Other names: SHR1210;Drug: Famitinib<br>* VEGFR inhibitor<br>|
| Experimental: SNF3 3: Stratification of BRCA/PALB2 expression<br>Fluzoparib SHR3162 100mg po qd+Dalpiciclib 125mg po qd for 4 weeks as a cycle | Drug: Fluzoparib<br>* PARP inhibitor<br>* Other names: SHR3162;Drug: Dalpiciclib<br>* CDK4/6 inhibitor<br>* Other names: SHR6390;|
| Experimental: SNF4 4A: HER2 low<br> | Drug: SHR-A1811<br>* HER2 ADC<br>|
| Experimental: SNF4 4A: HER2 zero<br> | Drug: TROP2 ADC<br>* TROP2 ADC<br>Drug: RTK Inhibitor<br>* Sorafenib, Apatinib, Famitinib<br>|
| Active Comparator: The control arm<br>Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin) | Drug: TPC<br>* Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1) | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the subjects | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 3 years | 
| Progression Free Survival (PFS) | time to progressive disease (according to RECIST1.1) | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 3 years)] | 
| Overall Survival (OS) | time to death due to any cause | Randomization to death from any cause, through the end of study (approximately 3 years) | 
| CTCAE scale (V5.0) | To evaluate the rate of adverse effects of patient by the standard CTCAE scale (V5.0) | up to One Year during follow-up |