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FUSCC Refractory TNBC Umbrella (FUTURE) (FUTURE)

Primary Purpose

Triple-negative Breast Cancer

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Pyrotinib with Capecitabine

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

anti PD-1 with nab-paclitaxel

PARP inhibitor included therapy

BLIS with anti-VEGFR included therapy

MES with anti-VEGFR included therapy

mTOR inhibitor with nab-paclitaxel

About this trial

This is an interventional treatment trial for Triple-negative Breast Cancer focused on measuring TNBC, Molecular Subtype, Precision Treatment, Umbrella

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)FemaleDoes not accept 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

Sites / Locations

Fudan University Shanghai Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Arm Label

pyrotinib with capecitabine

AR inhibitor with CDK4/6 inhibitor

anti PD-1 with nab-paclitaxel

PARP inhibitor included therapy

BLIS with anti-VEGFR included therapy

MES with anti-VEGFR included therapy

mTOR inhibitor with nab-paclitaxel

Arm Description

If patients were LAR subtype with HER2 gene activated mutation

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;

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

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

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

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

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

Outcomes

Primary Outcome Measures

Objective Response Rate (ORR)

The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)

Secondary Outcome Measures

Disease Control Rate(DOR)

Complete remission or partial remission or stable disease (according to RECIST1.1)

Progression Free Survival(PFS)

time to progressive disease (according to RECIST1.1)

Overall Survival (OS)

time to death due to any cause

Full Information

NCT ID

NCT03805399

First Posted

January 8, 2019

Last Updated

August 8, 2022

Sponsor

Fudan University

1. Study Identification

Unique Protocol Identification Number

NCT03805399

Brief Title

FUSCC Refractory TNBC Umbrella (FUTURE)

Acronym

FUTURE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 18, 2018 (Actual)

Primary Completion Date

December 1, 2022 (Anticipated)

Study Completion Date

December 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Fudan University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Triple-negative Breast Cancer

Keywords

TNBC, Molecular Subtype, Precision Treatment, Umbrella

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

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).

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

pyrotinib with capecitabine

Arm Type

Experimental

Arm Description

If patients were LAR subtype with HER2 gene activated mutation

Arm Title

AR inhibitor with CDK4/6 inhibitor

Arm Type

Experimental

Arm Description

Arm Title

anti PD-1 with nab-paclitaxel

Arm Type

Experimental

Arm Description

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

Arm Title

PARP inhibitor included therapy

Arm Type

Experimental

Arm Description

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

Arm Title

BLIS with anti-VEGFR included therapy

Arm Type

Experimental

Arm Description

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

Arm Title

MES with anti-VEGFR included therapy

Arm Type

Experimental

Arm Description

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

Arm Title

mTOR inhibitor with nab-paclitaxel

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Pyrotinib with Capecitabine

Other Intervention Name(s)

SHR1258

Intervention Description

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

Intervention Name(s)

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

Other Intervention Name(s)

SHR3680 SHR6390

Intervention Description

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

Intervention Name(s)

anti PD-1 with nab-paclitaxel

Other Intervention Name(s)

SHR1210

Intervention Description

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

Intervention Name(s)

PARP inhibitor included therapy

Other Intervention Name(s)

SHR3162

Intervention Description

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

Intervention Name(s)

BLIS with anti-VEGFR included therapy

Other Intervention Name(s)

YN968D1

Intervention Description

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

Intervention Name(s)

MES with anti-VEGFR included therapy

Other Intervention Name(s)

YN968D1

Intervention Description

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

Intervention Name(s)

mTOR inhibitor with nab-paclitaxel

Other Intervention Name(s)

everolimus

Intervention Description

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).

Primary Outcome Measure Information:

Title

Objective Response Rate (ORR)

Description

The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)

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)

Secondary Outcome Measure Information:

Title

Disease Control Rate(DOR)

Description

Complete remission or partial remission or stable disease (according to RECIST1.1)

Time Frame

Baseline through end of study (approximately 3 years)

Title

Progression Free Survival(PFS)

Description

time to progressive disease (according to RECIST1.1)

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)

Title

Overall Survival (OS)

Description

time to death due to any cause

Time Frame

Randomization to death from any cause, through the end of study (approximately 3 years)

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Zhimin U Shao, Professor

Phone

86-021-64175590

Ext

88807

zhimingshao@yahoo.com

First Name & Middle Initial & Last Name or Official Title & Degree

Zhonghua U Wang,Professor

Phone

86-021-64175590

Ext

88603

zhonghuawang95@hotmail.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Zhimin U Shao, Professor

Organizational Affiliation

Fudan University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Fudan University Shanghai Cancer Center

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200032

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Zhimin Shao M.D.

Phone

86-021-64175590

Ext

88807

zhimingshao@yahoo.com

First Name & Middle Initial & Last Name & Degree

Yin Liu,Doctor

Phone

86-021-64175590

Ext

88603

liuyinfudan@163.com

12. IPD Sharing Statement

Citations:

PubMed Identifier

35105939

Citation

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.

Results Reference

derived

PubMed Identifier

32719455

Citation

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.

Results Reference

derived

Learn more about this trial

FUSCC Refractory TNBC Umbrella (FUTURE)

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