FUSCC Refractory TNBC Umbrella (FUTURE)

Fudan University

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Triple-negative Breast Cancer

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

Study type: Interventional

Funder types: Other

Identifiers

NCT03805399

1807188-16

Details and patient eligibility

About

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.

Full 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.

Enrollment: 140 estimated patients

Sex: Female

Ages: 18 to 75 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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140 participants in 7 patient groups

pyrotinib with capecitabine

Experimental group

Description:

If patients were LAR subtype with HER2 gene activated mutation

Treatment:

Drug: Pyrotinib with Capecitabine

AR inhibitor with CDK4/6 inhibitor

Experimental group

Description:

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;

Treatment:

Drug: AR inhibitor combined with everolimus(B1) or CDK4/6 inhibitor(B2),or EZH2 inhibitor (B4)

anti PD-1 with nab-paclitaxel

Experimental group

Description:

If patients were IM subtype(CD8 positive T cell more than 20%)

Treatment:

Drug: anti PD-1 with nab-paclitaxel

PARP inhibitor included therapy

Experimental group

Description:

If patients were BLIS subtype and had a BRCA gene pathogenic mutation

Treatment:

Drug: PARP inhibitor included therapy

BLIS with anti-VEGFR included therapy

Experimental group

Description:

If patients were BLIS subtype and did not have a BRCA gene pathogenic mutation

Treatment:

Drug: BLIS with anti-VEGFR included therapy

MES with anti-VEGFR included therapy

Experimental group

Description:

If patients were MES subtype and without PI3K/AKT pathway activation

Treatment:

Drug: MES with anti-VEGFR included therapy

mTOR inhibitor with nab-paclitaxel

Experimental group

Description:

If patients were MES subtype and had PI3K/AKT pathway activation

Treatment:

Drug: mTOR inhibitor with nab-paclitaxel