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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| pyrotinib with capecitabine | Experimental | If patients were LAR subtype with HER2 gene activated mutation |
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| AR inhibitor with CDK4/6 inhibitor | Experimental | 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; |
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| anti PD-1 with nab-paclitaxel | Experimental | If patients were IM subtype(CD8 positive T cell more than 20%) |
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| PARP inhibitor included therapy | Experimental | If patients were BLIS subtype and had a BRCA gene pathogenic mutation |
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| BLIS with anti-VEGFR included therapy | Experimental | If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pyrotinib with Capecitabine | Drug | 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) |
| 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) |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Zhimin U Shao, Professor | Contact | 86-021-64175590 | 88807 | zhimingshao@yahoo.com |
| Zhonghua U Wang,Professor | Contact | 86-021-64175590 | 88603 | zhonghuawang95@hotmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Zhimin U Shao, Professor | Fudan University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fudan University Shanghai Cancer Center | Recruiting | Shanghai | Shanghai Municipality | 200032 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38290515 | Derived | Liu CC, Chen L, Cai YW, Chen YF, Liu YM, Zhou YJ, Shao ZM, Yu KD. Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer. Cell Rep Med. 2024 Feb 20;5(2):101396. doi: 10.1016/j.xcrm.2024.101396. Epub 2024 Jan 29. | |
| 35105939 | Derived | Xiao Y, Ma D, Yang YS, Yang F, Ding JH, Gong Y, Jiang L, Ge LP, Wu SY, Yu Q, Zhang Q, Bertucci F, Sun Q, Hu X, Li DQ, Shao ZM, Jiang YZ. Comprehensive metabolomics expands precision medicine for triple-negative breast cancer. Cell Res. 2022 May;32(5):477-490. doi: 10.1038/s41422-022-00614-0. Epub 2022 Feb 1. |
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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).
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| MES with anti-VEGFR included therapy | Experimental | If patients were MES subtype and without PI3K/AKT pathway activation |
|
| mTOR inhibitor with nab-paclitaxel | Experimental | If patients were MES subtype and had PI3K/AKT pathway activation |
|
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| AR inhibitor combined with everolimus(B1) or CDK4/6 inhibitor(B2),or EZH2 inhibitor (B4) | Drug | 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 |
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| anti PD-1 with nab-paclitaxel | Drug | 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). |
|
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| PARP inhibitor included therapy | Drug | 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 . |
|
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| BLIS with anti-VEGFR included therapy | Drug | 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 |
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| MES with anti-VEGFR included therapy | Drug | 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). |
|
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| mTOR inhibitor with nab-paclitaxel | Drug | 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). |
|
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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) |
| 32719455 | Derived | Jiang YZ, Liu Y, Xiao Y, Hu X, Jiang L, Zuo WJ, Ma D, Ding J, Zhu X, Zou J, Verschraegen C, Stover DG, Kaklamani V, Wang ZH, Shao ZM. Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial. Cell Res. 2021 Feb;31(2):178-186. doi: 10.1038/s41422-020-0375-9. Epub 2020 Jul 27. |
| ID | Term |
|---|---|
| D064726 | Triple Negative Breast Neoplasms |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| C000622954 | pyrotinib |
| D000069287 | Capecitabine |
| C520255 | 130-nm albumin-bound paclitaxel |
| C000631724 | camrelizumab |
| C000722917 | fluzoparib |
| C553458 | apatinib |
| D020123 | Sirolimus |
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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