Molecularly Targeted Umbrella Study in Luminal Advanced Breast Cancer

NCT ID: NCT04355858

Last Updated: 2022-07-26

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 319 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-01
• Study Completion Date: 2025-04-01

Brief Summary

This study is a prospective, single-center, open-label, umbrella-shaped phase II clinical study for patients with HR+/HER2- endocrine-resistant advanced breast cancer.

Detailed Description

Seven precision treatment cohorts, which targeting NF1 mutation, gBRCA mutation,HER2 mutation, FDGFRb mutation PAM pathway mutations, CD8 and AR, as long as an epigenetic therapy cohort and a combined immunization cohort were initially set up based on gene expression profiles and molecular pathways. The main purpose is to screen valuable treatment cohorts and prepare for subsequent randomized controlled phase III clinical studies with larger sample size.

Conditions

Breast Cancer; Metastatic Cancer

Study Design

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

Study Groups

NF1 mutated

If a patient were NF1 mutated, she would receive SHR7390(MEK1/2 inhibitor) and Faminitib.

Group Type: EXPERIMENTAL

SHR7390

Intervention Type: DRUG

MEK1/2 inhibitor

Famitinib

Intervention Type: DRUG

Multi-target tyrosine kinase inhibitor

gBRCA mutated

If a patient were gBRCA mutated, she would receive SHR3162 (PARP inhibitor)and SHR6390(CDK4/6 inhibitor) .

Group Type: EXPERIMENTAL

SHR3162

Intervention Type: DRUG

PARP inhibitor

SHR6390

Intervention Type: DRUG

CDK4/6 inhibitor

HER2 activated mutated

If a patient were HER2 activated mutated and had not previously used capecitabine, she would receive Pyrotinib and Capecitabine , while if the patient have previously used capecitabine, she would only use pyrotinib as a single agent.

Group Type: EXPERIMENTAL

Pyrotinib

Intervention Type: DRUG

HER1 / HER2 receptor tyrosine kinase inhibitor

Capecitabine

Intervention Type: DRUG

In Arm III, if the patient had not previously used capecitabine,she would receive pyrotinib and capecitabine, if the patients have previously used capecitabine, she would only used pyrotinib as a single agent.

PDGFRb mutated

If a patient were PDGFRb mutated, she would receive Faminitib.

Group Type: EXPERIMENTAL

Famitinib

Intervention Type: DRUG

Multi-target tyrosine kinase inhibitor

CD8 ≥10%

In the arm which IHC showed CD8 ≥10%, this arm will be subdivided into 6 sub-arms, in which Arm 5A-4D, we choose the patients who had CDK4/6 inhibitor before while in Arm 5E, we choose the patients who secondarily resistant to adjuvant endocrine therapy , and in Arm 5FF, we choose the patients who is in stage IV without precious treatment or sensitively recurrence. A patient would receive SHR1210(PD-1 antibody) ,nab-paclitaxel and Faminitib in Arm-5A. A patient would receive SHR1210(PD-1 antibody) and VEGF inhibitor in Arm-5B. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) in Arm-5C. A patient would receive SHR1701(PD-L1/TGF-βRII inhibitor) and SHR6390(CDK4/6 inhibitor) in Arm-5D. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and SERD in Arm-5E. A patient would receive SHR1210(PD-1 antibody) and SHR6390(CDK4/6 inhibitor) and AI in Arm-5F.

Group Type: EXPERIMENTAL

Famitinib

Intervention Type: DRUG

Multi-target tyrosine kinase inhibitor

SHR1210

Intervention Type: DRUG

PD-1 antibody

Nab paclitaxel

Intervention Type: DRUG

Albumin bound paclitaxel

SHR6390

Intervention Type: DRUG

CDK4/6 inhibitor

SHR1701

Intervention Type: DRUG

anti-PD-L1/TGF-βRII bifunctional fusion protein

SERD

Intervention Type: DRUG

Fulvestrant

AI

Intervention Type: DRUG

aromatase inhibitor

VEGFi

Intervention Type: DRUG

Bevacizumab

PAM pathway mutated

If a patient had any PAM pathway mutation, she would receive Everolimus(mTOR inhibitor) combined with nab-paclitaxel.

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

mTOR inhibitor

Nab paclitaxel

Intervention Type: DRUG

Albumin bound paclitaxel

AR≥10%

If a patient's IHC showed AR≥10% , she would receive SHR2554(EZH2 inhibitor) and SHR3680(AR inhibitor).

Group Type: EXPERIMENTAL

SHR2554

Intervention Type: DRUG

EZH2 inhibitor

SHR3680

Intervention Type: DRUG

AR inhibitor

Epigenetic Cohort

In this cohort, a patient would receive SHR2554(EZH2 inhibitor) and SHR3162 (PARP inhibitor).

Group Type: EXPERIMENTAL

SHR3162

Intervention Type: DRUG

PARP inhibitor

SHR2554

Intervention Type: DRUG

EZH2 inhibitor

Combined Immunity Cohort

In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with SHR1701(anti-PD-L1/TGF-βRII bifunctional fusion protein) .

Group Type: EXPERIMENTAL

SHR6390

Intervention Type: DRUG

CDK4/6 inhibitor

SHR1701

Intervention Type: DRUG

anti-PD-L1/TGF-βRII bifunctional fusion protein

Interventions

SHR7390

MEK1/2 inhibitor

Intervention Type: DRUG

Famitinib

Multi-target tyrosine kinase inhibitor

Intervention Type: DRUG

SHR3162

PARP inhibitor

Intervention Type: DRUG

Pyrotinib

HER1 / HER2 receptor tyrosine kinase inhibitor

Intervention Type: DRUG

Capecitabine

In Arm III, if the patient had not previously used capecitabine,she would receive pyrotinib and capecitabine, if the patients have previously used capecitabine, she would only used pyrotinib as a single agent.

Intervention Type: DRUG

SHR1210

PD-1 antibody

Intervention Type: DRUG

Everolimus

mTOR inhibitor

Intervention Type: DRUG

Nab paclitaxel

Albumin bound paclitaxel

Intervention Type: DRUG

SHR2554

EZH2 inhibitor

Intervention Type: DRUG

SHR3680

AR inhibitor

Intervention Type: DRUG

SHR6390

CDK4/6 inhibitor

Intervention Type: DRUG

SHR1701

anti-PD-L1/TGF-βRII bifunctional fusion protein

Intervention Type: DRUG

SERD

Fulvestrant

Intervention Type: DRUG

AI

aromatase inhibitor

Intervention Type: DRUG

VEGFi

Bevacizumab

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Females ≥18 years old;
• Histologically confirmed HR + / HER2- invasive breast cancer (specific definition: immunohistochemical detection of ER> 10% tumor cell positive is defined as ER positive, PR> 10% tumor cell positive is defined as PR positive, ER and / or PR Positive is defined as HR positive; HER2 0-1 + or HER2 is ++ but negative followed by FISH detection, no amplification, defined as HER2 negative);
• Locally advanced breast cancer (incapable of radical local treatment) or recurrent metastatic breast cancer;
• Patients with HR+/HER2- advanced breast cancer who were previously treated with CDK4 / 6 inhibitor except for Arm 5E-5F;
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
• Has adequate bone marrow function: absolute neutrophil count > 1.5x10ˆ9 /L; platelet count > 75x10ˆ9 /L, hemoglobin > 9g/dL;
• Has adequate liver function: alanine aminotransferase (ALT) ≤1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) ≤3×ULN, alkaline phosphatase (AKP) ≤3×ULN, total bilirubin (TBIL) ≤ 1.5×ULN.
• Has adequate kidney function: serum creatinine ≤1×ULN.Endogenous creatinine clearance> 50 ml / min (Cockcroft-Gault formula);
• Did not receive radiation, molecular targeted therapy or surgery within 3 weeks before the study began, and has recovered from the acute toxicity of previous treatment (if surgery, the wound has completely healed); no peripheral neuropathy or first degree peripheral neurotoxicity ;
• ECOG score ≤ 2 and life expectancy ≥ 3 months;
• Participants voluntarily joined the study, has signed informed consent before any trial related activities are conducted, has good compliance and has agreed to follow-up.

Exclusion Criteria

• Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded)within3 weeks prior to initiation of study treatment(bisphosphonates can be used for bone metastasis);
• Symptomatic, untreated, or actively progressing CNS metastases(glucocorticoids or mannitol needed to control symptoms);
• Significant cardiovascular disease(including congestive heart failure, angina pectoris, myocardial infarction or ventricular arrhythmia in the last 6 months);
• Grade ≥ 1 adverse reactions that are ongoing due to previous treatment. Exceptions to this are hair loss or the investigator's opinion should not be ruled out. Such cases should be clearly documented in the investigator's notes;
• Is pregnant or breast feeding;
• Malignant tumors in the past five years (except cured skin basal cell carcinoma and cervical carcinoma in situ).

• 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, Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhi-Ming Shao

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

Cancer Hospital Affiliated to Fudan University

Shanghai, Shanghai Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Zhi-Ming Shao

Role: CONTACT

zhimingshao@yahoo.com

86-021-64175590 ext. 8888

Zhong-Hua Wang

Role: CONTACT

zhonghuawang95@hotmail.com

+86 021-64175590

Facility Contacts

Zhimin Shao, MD, PhD

Role: primary

zhimingshao@yahoo.com

+86-021-64175590 ext. 8888

References

Chen MK. Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer. FEBS J. 2021 May;288(9):2884-2887. doi: 10.1111/febs.15730. Epub 2021 Feb 11.

Reference Type: DERIVED

PMID: 33570247 (View on PubMed)

Other Identifiers

SCHBCC-N029

Identifier Type: -

Identifier Source: org_study_id