FUSCC Refractory TNBC Umbrella (FUTURE)

NCT ID: NCT03805399

Last Updated: 2022-08-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-18
• Study Completion Date: 2022-12-01

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.

Conditions

Triple-negative Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

pyrotinib with capecitabine

If patients were LAR subtype with HER2 gene activated mutation

Group Type: EXPERIMENTAL

Pyrotinib with Capecitabine

Intervention Type: 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)

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;

Group Type: EXPERIMENTAL

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

Intervention Type: 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

anti PD-1 with nab-paclitaxel

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

Group Type: EXPERIMENTAL

anti PD-1 with nab-paclitaxel

Intervention Type: 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).

PARP inhibitor included therapy

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

Group Type: EXPERIMENTAL

PARP inhibitor included therapy

Intervention Type: 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 .

BLIS with anti-VEGFR included therapy

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

Group Type: EXPERIMENTAL

BLIS with anti-VEGFR included therapy

Intervention Type: 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

MES with anti-VEGFR included therapy

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

Group Type: EXPERIMENTAL

MES with anti-VEGFR included therapy

Intervention Type: 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).

mTOR inhibitor with nab-paclitaxel

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

Group Type: EXPERIMENTAL

mTOR inhibitor with nab-paclitaxel

Intervention Type: 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).

Interventions

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)

Intervention Type: 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

Intervention Type: 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).

Intervention Type: 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 .

Intervention Type: 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

Intervention Type: 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).

Intervention Type: 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).

Intervention Type: DRUG

Other Intervention Names

SHR1258; SHR3680 SHR6390; SHR1210; SHR3162; YN968D1; YN968D1; everolimus

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Zhimin Shao

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhimin U Shao, Professor

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhimin U Shao, Professor

Role: CONTACT

zhimingshao@yahoo.com

86-021-64175590 ext. 88807

Zhonghua U Wang,Professor

Role: CONTACT

zhonghuawang95@hotmail.com

86-021-64175590 ext. 88603

Facility Contacts

Zhimin Shao M.D.

Role: primary

zhimingshao@yahoo.com

86-021-64175590 ext. 88807

Yin Liu,Doctor

Role: backup

liuyinfudan@163.com

86-021-64175590 ext. 88603

References

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.

Reference Type: DERIVED

PMID: 38290515 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35105939 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32719455 (View on PubMed)

Other Identifiers

1807188-16

Identifier Type: -

Identifier Source: org_study_id