Precision Treatment of Refractory Triple Negative Breast Cancer Based on Molecular Subtyping --FUSCC-TNBC- Umbrella Trial
Overview
- Phase
- Phase 1
- Intervention
- Pyrotinib with Capecitabine
- Conditions
- Triple-negative Breast Cancer
- Sponsor
- Fudan University
- Enrollment
- 140
- Locations
- 1
- Primary Endpoint
- Objective Response Rate (ORR)
- Last Updated
- 3 years ago
Overview
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.
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.
Investigators
Zhimin Shao
Professor
Fudan University
Eligibility Criteria
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
Arms & Interventions
pyrotinib with capecitabine
If patients were LAR subtype with HER2 gene activated mutation
Intervention: Pyrotinib with Capecitabine
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;
Intervention: AR inhibitor combined with everolimus(B1) or CDK4/6 inhibitor(B2),or EZH2 inhibitor (B4)
anti PD-1 with nab-paclitaxel
If patients were IM subtype(CD8 positive T cell more than 20%)
Intervention: anti PD-1 with nab-paclitaxel
PARP inhibitor included therapy
If patients were BLIS subtype and had a BRCA gene pathogenic mutation
Intervention: PARP inhibitor included therapy
BLIS with anti-VEGFR included therapy
If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation
Intervention: BLIS with anti-VEGFR included therapy
MES with anti-VEGFR included therapy
If patients were MES subtype and without PI3K/AKT pathway activation
Intervention: MES with anti-VEGFR included therapy
mTOR inhibitor with nab-paclitaxel
If patients were MES subtype and had PI3K/AKT pathway activation
Intervention: mTOR inhibitor with nab-paclitaxel
Outcomes
Primary Outcomes
Objective Response Rate (ORR)
Time Frame: 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 Outcomes
- Disease Control Rate(DOR)(Baseline through end of study (approximately 3 years))
- 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))
- Overall Survival (OS)(Randomization to death from any cause, through the end of study (approximately 3 years))