FUSCC Refractory TNBC Umbrella (FUTURE)

Sponsor

Fudan University (Other)

Overall Status

Recruiting

CT.gov ID

NCT03805399

Collaborator

(none)

140

Enrollment

Location

Arms

49.4

Anticipated Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Triple-negative Breast Cancer	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	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention 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).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)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 18, 2018

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: pyrotinib with capecitabine If patients were LAR subtype with HER2 gene activated mutation	Drug: Pyrotinib with Capecitabine 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) Other Names: SHR1258
Experimental: AR inhibitor with CDK4/6 inhibitor 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) 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 Other Names: SHR3680 SHR6390
Experimental: anti PD-1 with nab-paclitaxel If patients were IM subtype(CD8 positive T cell more than 20%)	Drug: anti PD-1 with nab-paclitaxel 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). Other Names: SHR1210
Experimental: PARP inhibitor included therapy If patients were BLIS subtype and had a BRCA gene pathogenic mutation	Drug: PARP inhibitor included therapy 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 . Other Names: SHR3162
Experimental: BLIS with anti-VEGFR included therapy If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation	Drug: BLIS with anti-VEGFR included therapy 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 Other Names: YN968D1
Experimental: MES with anti-VEGFR included therapy If patients were MES subtype and without PI3K/AKT pathway activation	Drug: MES with anti-VEGFR included therapy 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). Other Names: YN968D1
Experimental: mTOR inhibitor with nab-paclitaxel If patients were MES subtype and had PI3K/AKT pathway activation	Drug: mTOR inhibitor with nab-paclitaxel 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). Other Names: everolimus

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [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)]
The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)

Secondary Outcome Measures

Disease Control Rate(DOR) [Baseline through end of study (approximately 3 years)]
Complete remission or partial remission or stable disease (according to RECIST1.1)
Progression Free Survival(PFS) [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)]
time to progressive disease (according to RECIST1.1)
Overall Survival (OS) [Randomization to death from any cause, through the end of study (approximately 3 years)]
time to death due to any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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