Molecularly Targeted Umbrella Study in Luminal Advanced Breast Cancer

Study Overview
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Brief Summary
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This study is a prospective, single-center, open-label, umbrella-shaped phase II clinical study for patients with HR+/HER2- endocrine-resistant advanced breast cancer.

Detailed Description
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Seven precision treatment cohorts, which targeting NF1 mutation, gBRCA mutation,HER2 mutation, FDGFRb mutation PAM pathway mutations, CD8 and AR, as long as an epigenetic therapy cohort and a combined immunization cohort were initially set up based on gene expression profiles and molecular pathways. The main purpose is to screen valuable treatment cohorts and prepare for subsequent randomized controlled phase III clinical studies with larger sample size.

Official Title
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Precision Treatment of Luminal Advanced Breast Cancer Based on Molecular Subtyping

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: SHR7390
* Drug: Famitinib
* Drug: SHR3162
* Drug: Pyrotinib
* Drug: Capecitabine
* Drug: SHR1210
* Drug: Everolimus
* Drug: Nab paclitaxel
* Drug: SHR2554
* Drug: SHR3680
* Drug: SHR6390
* Drug: SHR1701
* Drug: SERD
* Drug: AI
* Drug: VEGFi


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females ≥18 years old; Histologically confirmed HR + / HER2- invasive breast cancer (specific definition: immunohistochemical detection of ER> 10% tumor cell positive is defined as ER positive, PR> 10% tumor cell positive is defined as PR positive, ER and / or PR Positive is defined as HR positive; HER2 0-1 + or HER2 is ++ but negative followed by FISH detection, no amplification, defined as HER2 negative); Locally advanced breast cancer (incapable of radical local treatment) or recurrent metastatic breast cancer; Patients with HR+/HER2- advanced breast cancer who were previously treated with CDK4 / 6 inhibitor except for Arm 5E-5F; Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) Has adequate bone marrow function: absolute neutrophil count > 1.5x10ˆ9 /L; platelet count > 75x10ˆ9 /L, hemoglobin > 9g/dL; Has adequate liver function: alanine aminotransferase (ALT) ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) ≤3×ULN, alkaline phosphatase (AKP) ≤3×ULN, total bilirubin (TBIL) ≤ 1.5×ULN. Has adequate kidney function: serum creatinine ≤1×ULN.Endogenous creatinine clearance> 50 ml / min (Cockcroft-Gault formula); Did not receive radiation, molecular targeted therapy or surgery within 3 weeks before the study began, and has recovered from the acute toxicity of previous treatment (if surgery, the wound has completely healed); no peripheral neuropathy or first degree peripheral neurotoxicity ; ECOG score ≤ 2 and life expectancy ≥ 3 months; Participants voluntarily joined the study, has signed informed consent before any trial related activities are conducted, has good compliance and has agreed to follow-up. Exclusion Criteria: Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded)within3 weeks prior to initiation of study treatment(bisphosphonates can be used for bone metastasis); Symptomatic, untreated, or actively progressing CNS metastases(glucocorticoids or mannitol needed to control symptoms); Significant cardiovascular disease(including congestive heart failure, angina pectoris, myocardial infarction or ventricular arrhythmia in the last 6 months); Grade ≥ 1 adverse reactions that are ongoing due to previous treatment. Exceptions to this are hair loss or the investigator's opinion should not be ruled out. Such cases should be clearly documented in the investigator's notes; Is pregnant or breast feeding; Malignant tumors in the past five years (except cured skin basal cell carcinoma and cervical carcinoma in situ).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NF1 mutated<br>If a patient were NF1 mutated, she would receive SHR7390(MEK1/2 inhibitor) and Faminitib. | Drug: SHR7390<br>* MEK1/2 inhibitor<br>Drug: Famitinib<br>* Multi-target tyrosine kinase inhibitor<br>|
| Experimental: gBRCA mutated<br>If a patient were gBRCA mutated, she would receive SHR3162 (PARP inhibitor)and SHR6390(CDK4/6 inhibitor) . | Drug: SHR3162<br>* PARP inhibitor<br>Drug: SHR6390<br>* CDK4/6 inhibitor<br>|
| Experimental: HER2 activated mutated<br>If a patient were HER2 activated mutated and had not previously used capecitabine, she would receive Pyrotinib and Capecitabine , while if the patient have previously used capecitabine, she would only use pyrotinib as a single agent. | Drug: Pyrotinib<br>* HER1 / HER2 receptor tyrosine kinase inhibitor<br>Drug: Capecitabine<br>* In Arm III, if the patient had not previously used capecitabine,she would receive pyrotinib and capecitabine, if the patients have previously used capecitabine, she would only used pyrotinib as a single agent.<br>|
| Experimental: PDGFRb mutated<br>If a patient were PDGFRb mutated, she would receive Faminitib. | Drug: Famitinib<br>* Multi-target tyrosine kinase inhibitor<br>|
| Experimental: CD8 ≥10%<br>In the arm which IHC showed CD8 ≥10%, this arm will be subdivided into 6 sub-arms, in which Arm 5A-4D, we choose the patients who had CDK4/6 inhibitor before while in Arm 5E, we choose the patients who secondarily resistant to adjuvant endocrine therapy , and in Arm 5FF, we choose the patients who is in stage IV without precious treatment or sensitively recurrence. A patient would receive SHR1210(PD-1 antibody) ,nab-paclitaxel and Faminitib in Arm-5A. A patient would receive SHR1210(PD-1 antibody) and VEGF inhibitor in Arm-5B. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) in Arm-5C. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) and SHR6390(CDK4/6 inhibitor) in Arm-5D. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and SERD in Arm-5E. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and AI in Arm-5F. | Drug: Famitinib<br>* Multi-target tyrosine kinase inhibitor<br>Drug: SHR1210<br>* PD-1 antibody<br>Drug: Nab paclitaxel<br>* Albumin bound paclitaxel<br>Drug: SHR6390<br>* CDK4/6 inhibitor<br>Drug: SHR1701<br>* anti-PD-L1/TGF-βRII bifunctional fusion protein<br>Drug: SERD<br>* Fulvestrant<br>Drug: AI<br>* aromatase inhibitor<br>Drug: VEGFi<br>* Bevacizumab<br>|
| Experimental: PAM pathway mutated<br>If a patient had any PAM pathway mutation, she would receive Everolimus(mTOR inhibitor) combined with nab-paclitaxel. | Drug: Everolimus<br>* mTOR inhibitor<br>Drug: Nab paclitaxel<br>* Albumin bound paclitaxel<br>|
| Experimental: AR≥10%<br>If a patient's IHC showed AR≥10% , she would receive SHR2554(EZH2 inhibitor) and SHR3680(AR inhibitor). | Drug: SHR2554<br>* EZH2 inhibitor<br>Drug: SHR3680<br>* AR inhibitor<br>|
| Experimental: Epigenetic Cohort<br>In this cohort, a patient would receive SHR2554(EZH2 inhibitor) and SHR3162 (PARP inhibitor). | Drug: SHR3162<br>* PARP inhibitor<br>Drug: SHR2554<br>* EZH2 inhibitor<br>|
| Experimental: Combined Immunity Cohort<br>In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with SHR1701(anti-PD-L1/TGF-βRII bifunctional fusion protein) . | Drug: SHR6390<br>* CDK4/6 inhibitor<br>Drug: SHR1701<br>* anti-PD-L1/TGF-βRII bifunctional fusion protein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CBR | the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the evaluable subjects | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years) | 
| 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 5 years) | 
| OS | time to death due to any cause | Randomization to death from any cause, through the end of study (approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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first-line therapy