FUSCC Refractory TNBC Umbrella (FUTURE)

Study Overview
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Brief Summary
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This is a Phase Ib/II, open-label, multi-center umbrella study evaluating the efficacy and safety of multiple targeted treatment in patients with refractory metastatic TNBC.The specific grouping of patients' depends on FUSCC 500+ gene panel testing and IHC subtype staining.

Detailed Description
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This is a Phase Ib/II, open-label, multi-center,umbrella study evaluating the efficacy and safety of multiple targeted treatment in patients with metastatic TNBC who had disease progression during or following standard treatment with chemotherapy(anthracyclines,taxanes,platinums, vinorelbine,capecitabine,and gemcitabine included).300-400 patients will be screened and eligible participants will enter different treatment arms according to their molecular subtype (IHC staining) and FUSCC 500+ gene panel testing results. These tests would be done on their rebiopsy tumor specimen. Specifically, as to TNBC molecular subtyping,FUSCC data identified the genomic aberrations that drive each TNBC subtype by applying an integrative analysis combining somatic mutation, copy number aberrations (CNAs) and gene expression profiles, which classified TNBC patients into four subtypes, namely luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune suppressed (BLIS), and mesenchymal-like (MES). Then, FUSCC conducted a IHC subtyping model to replace complex genomic sequencing, which have been validated in FUSCC cohort.FUSCC 500+ gene panel was developed combining public database(TCGA, METABRIC, 560WES, MSKCC-IMPACT ect.) and FUSCC private TNBC database.New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Official Title
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Precision Treatment of Refractory Triple Negative Breast Cancer Based on Molecular Subtyping --FUSCC-TNBC- Umbrella Trial

Conditions
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Triple-negative Breast Cancer

Intervention / Treatment
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* Drug: Pyrotinib with Capecitabine
* Drug: AR inhibitor combined with everolimus(B1) or CDK4/6 inhibitor(B2),or EZH2 inhibitor (B4)
* Drug: anti PD-1 with nab-paclitaxel
* Drug: PARP inhibitor included therapy
* Drug: BLIS with anti-VEGFR included therapy
* Drug: MES with anti-VEGFR included therapy
* Drug: mTOR inhibitor with nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG Performance Status of 0, 1, or 2 Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER, and PR expression) Radiologic/objective evidence of recurrence or disease progression after available standard chemotherapy regimens(anthracyclines,taxanes, platinums, vinorelbine,capacitabine, and gemcitabine included) for metastatic breast cancer(MBC) Availability of a representative tumor specimen that is suitable for rebiopsy, IHC staining and gene sequencing Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) have the cognitive ability to understand the protocol and be willing to participate and to be followed up. Exclusion Criteria: Symptomatic, untreated, or actively progressing CNS metastases Active or history of autoimmune disease or immune deficiency Significant cardiovascular disease History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death Treatment with chemotherapy, radiotherapy,immunotherapy or surgery (outpatient clinic surgery excluded)within3 weeks prior to initiation of study treatment. Pregnancy or breastfeeding, or intention of becoming pregnant during the study

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
Interventional Model Description: The refractory mTNBC participants will be classified into four subtypes based on immunohistochemistry tests namely luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune suppressed (BLIS), and mesenchymal (MES).Then according to gene sequencing outcomes, different subtypes would receive different targeted therapy (combined with chemotherapy in three treatment arms).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pyrotinib with capecitabine<br>If patients were LAR subtype with HER2 gene activated mutation | Drug: Pyrotinib with Capecitabine<br>* If patients were LAR subtype with HER2 gene activated mutation, she would receive pyrotinib(EGFR-TKI) 400mg qd and capecitabine 1000mg/m2 bid (d1-d14)<br>* Other names: SHR1258;|
| Experimental: AR inhibitor with CDK4/6 inhibitor<br>If patients were LAR subtype without HER2 gene activated mutation, but had PIK3CA mutation, enter into arm B1; If patients were LAR subtype without HER2 gene activated mutation or PIK3CA mutation, enter into arm B2;If B2 was closed, enter into B4; | Drug: AR inhibitor combined with everolimus(B1) or CDK4/6 inhibitor(B2),or EZH2 inhibitor (B4)<br>* B1: if patients were LAR subtype without HER2 gene activated mutation, but had PI3KCA mutation, she would receive everolimus 10mg qd combined with AR inhibitor SHR3680 240mg qd continuously ; B2: if patients were LAR subtype without HER2 gene activated mutation or PI3KCA mutation, she would receive AR inhibitor SHR3680 240mg qd combined with CDK4/6 inhibitor SHR6390 150mg qd (three week on one week off); B4: If patients were LAR subtype without HER2 gene activated mutation or PI3KCA mutation, she would receive AR inhibitor SHR3680 240mg qd combined with EZH2 inhibitor SHR2554 300mg bid continuously<br>* Other names: SHR3680 SHR6390;|
| Experimental: anti PD-1 with nab-paclitaxel<br>If patients were IM subtype(CD8 positive T cell more than 20%) | Drug: anti PD-1 with nab-paclitaxel<br>* If patients were IM subtype, she will receive PD-1 antibody SHR1210 200mg q2w and nab-paclitaxel 100mg qw (three week on one week off).<br>* Other names: SHR1210;|
| Experimental: PARP inhibitor included therapy<br>If patients were BLIS subtype and had a BRCA gene pathogenic mutation | Drug: PARP inhibitor included therapy<br>* If patients were BLIS subtype and had a BRCA gene pathogenic mutation, she will receive PARP inhibitor SHR3162 150mg bid and famitinib 20mg qd continuously .<br>* Other names: SHR3162;|
| Experimental: BLIS with anti-VEGFR included therapy<br>If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation | Drug: BLIS with anti-VEGFR included therapy<br>* If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation , she will receive: E2: apatinib 250mg qd continuously combined with VP-16 50mg qd (three week on one week off); E3: famitinib 20mg qd continuously combined with VP-16 50mg qd (three week on one week off); E4: BP102 10mg/kg d1,d15 combined with nab-paclitaxel 100mg d1,d8,d,15; q4w<br>* Other names: YN968D1;|
| Experimental: MES with anti-VEGFR included therapy<br>If patients were MES subtype and without PI3K/AKT pathway activation | Drug: MES with anti-VEGFR included therapy<br>* If patients were MES subtype and without PI3K/AKT pathway activation,she will receive famitinib 20mg qd continuously combined with VP-16 50mg qd (three week on one week off).<br>* Other names: YN968D1;|
| Experimental: mTOR inhibitor with nab-paclitaxel<br>If patients were MES subtype and had PI3K/AKT pathway activation | Drug: mTOR inhibitor with nab-paclitaxel<br>* If patients were MES subtype and had PI3K/AKT pathway activation, she will receive mTOR inhibitor 10mg qd continuously combined with nab-paclitaxel 100mg qw (three week on one week off).<br>* Other names: everolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective 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 |
| --- | --- | --- |
| Disease Control Rate(DOR) | Complete remission or partial remission or stable disease (according to RECIST1.1) | Baseline through 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Umbrella, TNBC, Molecular Subtype, Precision Treatment