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Efficacy of Everolimus Combined With First-line Endocrine Therapy for HR+/HER2- SNF1-subtype Advanced Breast Cancer

Primary Purpose

Breast Cancer, Advanced Breast Cancer

Status
Not yet recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Everolimus 10 mg
CDK4/6 Inhibitor SHR6390
Aromatase inhibitor and Fulvestrant combined with CDK4/6 inhibitors
Sponsored by
Fudan University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring luminal breast cancer, advanced breast cancer

Eligibility Criteria

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

Inclusion Criteria: Patients need to meet all of the following conditions Patients must be ≥18 and ≤ 75 years of age; Pathologically confirmed breast cancer is HR+/HER2- breast cancer (IHC ER >10%, or/and PR>10%, HER 0 OR +, if HER2++, FISH negative); SNF1 subtype definition: SNF1 subtype confirmed by digital pathology of H&E sections; Locally advanced breast cancer (radical local therapy is not possible) or metastatic breast cancer (without using adjuvant CDK4/6 inhibitors in the past, or one year after adjuvant CDK4/6 inhibitor therapy has ended); No prior therapy (chemotherapy, targeted therapy, etc.) for advanced or metastatic breast cancer; Patients with at least one measurable lesion that has not previously received radiation therapy and can be evaluated repeatedly according to RECIST 1.1; The functions of the main organs are basically normal, and the following conditions are met: Blood routine examination standards should meet: HB≥90g/L (no blood transfusion within 14 days); ANC≥1.5×109/L; PLT≥75×109/L; Biochemical examination shall meet the following standards: TBIL≤1.5×ULN (upper limit of normal value); ALT and AST≤3 x ULN; In case of liver metastasis, ALT and AST≤5×ULN; Serum Cr ≤1.5×ULN, endogenous creatinine clearance > 50ml/min (Cockcroft-Gault formula); ECOG performance status 0 or 1; The expected survival is more than 3 months; Fertile female is required to use a medically approved contraceptive during study treatment and for at least 3 months after the last use of the study drug; Patients voluntarily join the study, sign the informed consent, have good compliance, and cooperate with follow-up. Exclusion Criteria: Patients with any of the following conditions were excluded from the study Patients with central nervous system metastasis out of control (symptoms need to use glucocorticoids or mannitol). A history of clinically significant or uncontrolled heart disease, including congestive heart failure, angina pectoris, myocardial infarction within the last 6 months, or ventricular arrhythmia; Radiotherapy, chemotherapy, surgery, other targeted therapy and immunotherapy for advanced HR+/HER2- breast cancer within 4 weeks prior to first administration of drugs used in this study. Pregnant or lactating patients; Other malignancies within the previous 3 years, excluding cured skin basal cell carcinoma and cervical carcinoma in situ; Significant comorbid medical conditions, including mental illnesses that the investigator or sponsor believes would adversely affect the patient's participation in the study; Allergic physique, or known allergic history of the drug components of this program; Or allergic to other monoclonal antibodies; The investigator does not consider the patient suitable for participation in any other circumstances of the study.

Sites / Locations

  • Fudan University Shanghai Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm-A

Arm-B

Arm Description

Everolimus + CDK4/6 inhibitor+ Endocrine therapy group: Everolimus, 10mg po. qd; Dalpiciclib 125mg po. qd. for 3 weeks, followed by 1 week off, 4 weeks as a cycle. Aromatase inhibitors (Letrozole/Anastrozole/Exemestane), po. qd. at specific doses (Letrozole 2.5mg/day; Anastrozole 1mg/day, Exemestane 25mg/day); Or Fluvestrant, 500mg im. q28d, (Extra 500mg given after 2 weeks of first dose); Premenopause participants: Goserelin 3.6mg, subcutaneously, once every 4 weeks.

CDK4/6 inhibitor+ Endocrine therapy group: Dalpiciclib 125mg po. qd. for 3 weeks, followed by 1 week off, 4 weeks as a cycle. Aromatase inhibitors (Letrozole/Anastrozole/Exemestane), po. qd. at specific doses (Letrozole 2.5mg/day; Anastrozole 1mg/day, Exemestane 25mg/day); Or Fluvestrant, 500mg im. q28d, (Extra 500mg given after 2 weeks of first dose); Premenopause participants: Goserelin 3.6mg, subcutaneously, once every 4 weeks.

Outcomes

Primary Outcome Measures

Progression Free Survival (PFS)
The interval from randomization until the first occurrence of disease progression (according to RECIST 1.1) or death from any cause, which ever occurs first.

Secondary Outcome Measures

Clinical Benefit Rate (CBR)
CBR is the total percentage of participants who achieved a complete response, partial response, or had stable disease for 6 months or more.
Objective Response Rate (ORR)
ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR) based on BICR and investigator assessment using RECIST 1.1.
Overall Survival (OS)
OS is defined as the time from randomisation until the date of death due to any cause.
Safety and tolerability
Number of adverse events according to NCI-CTCAE Version 5.0 per each treatment arm.

Full Information

First Posted
July 9, 2023
Last Updated
July 14, 2023
Sponsor
Fudan University
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1. Study Identification

Unique Protocol Identification Number
NCT05949541
Brief Title
Efficacy of Everolimus Combined With First-line Endocrine Therapy for HR+/HER2- SNF1-subtype Advanced Breast Cancer
Official Title
Study of Efficacy of Everolimus Combined With First-line Endocrine Therapy for HR+/HER2- (Open, Randomized, Phase II )
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 2023 (Anticipated)
Primary Completion Date
July 2026 (Anticipated)
Study Completion Date
January 2028 (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
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This is a randomized, controlled, open-label, phase II study to explore the efficacy and safety of Everolimus in combination with standard first-line endocrine therapy for the HR+/ HER2-SNF1 subtype of advanced breast cancer. The study was used to explore the efficacy of Everolimus in combination with standard endocrine therapy.
Detailed Description
A total of 584 patients with luminal breast cancer who received surgery in the breast surgery Department of the Affiliated Cancer Hospital of Fudan University were collected in the early stage. All patients could be divided into four categories, namely SNF1 (classical luminal type), SNF2 (immune-mediated type), SNF1 (proliferative type), and SNF4 (receptor tyrosine kinase-driven type), through clustering by the SNF algorithm. SNF1 (classical luminal type): The transcriptional component type is dominated by PAM50 LumA, with high PIK3CA mutation and low TP53 mutation. By combining artificial intelligence based on H&E pathological sections with deep learning methodology, molecular typing can be effectively distinguished. Prior to enrollment, the patient's primary lesion or metastasis was classified by molecular classification based on the H&E section combined with digital pathology, and SNF1 was confirmed to be considered for subsequent enrollment. Receivers will be randomly assigned 1:1 to either Everolimus plus Standard Endocrine therapy (study group) or Standard Endocrine therapy (control group). Treatment will continue until disease progression, intolerable toxicity, informed withdrawal, or death from any cause.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Advanced Breast Cancer
Keywords
luminal breast cancer, advanced breast cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
265 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm-A
Arm Type
Experimental
Arm Description
Everolimus + CDK4/6 inhibitor+ Endocrine therapy group: Everolimus, 10mg po. qd; Dalpiciclib 125mg po. qd. for 3 weeks, followed by 1 week off, 4 weeks as a cycle. Aromatase inhibitors (Letrozole/Anastrozole/Exemestane), po. qd. at specific doses (Letrozole 2.5mg/day; Anastrozole 1mg/day, Exemestane 25mg/day); Or Fluvestrant, 500mg im. q28d, (Extra 500mg given after 2 weeks of first dose); Premenopause participants: Goserelin 3.6mg, subcutaneously, once every 4 weeks.
Arm Title
Arm-B
Arm Type
Active Comparator
Arm Description
CDK4/6 inhibitor+ Endocrine therapy group: Dalpiciclib 125mg po. qd. for 3 weeks, followed by 1 week off, 4 weeks as a cycle. Aromatase inhibitors (Letrozole/Anastrozole/Exemestane), po. qd. at specific doses (Letrozole 2.5mg/day; Anastrozole 1mg/day, Exemestane 25mg/day); Or Fluvestrant, 500mg im. q28d, (Extra 500mg given after 2 weeks of first dose); Premenopause participants: Goserelin 3.6mg, subcutaneously, once every 4 weeks.
Intervention Type
Drug
Intervention Name(s)
Everolimus 10 mg
Other Intervention Name(s)
Afinitor
Intervention Description
Everolimus is a kind of mTOR inhibitor which has been approved to use in several kinds of cancers, especially in metastatic breast cancer.
Intervention Type
Drug
Intervention Name(s)
CDK4/6 Inhibitor SHR6390
Other Intervention Name(s)
Dalpiciclib
Intervention Description
Dalpiciclib (SHR6390) is a kind of CDK4/6 inhibitor that has demonstrated tolerability and preliminary clinical activity in patients with heavily pretreated hormone receptor-positive, HER2-negative advanced breast cancer.
Intervention Type
Drug
Intervention Name(s)
Aromatase inhibitor and Fulvestrant combined with CDK4/6 inhibitors
Other Intervention Name(s)
Endocrine therapy
Intervention Description
Endocrine therapy combined with CDK4/6 inhibitors is the standard first-line therapy for advanced luminal breast cancer. Investigators choose endocrine therapy including Letrozole, Anastrozole, Exemestane, and Fulvestrant. Postmenopausal participants should use Goserelin.
Primary Outcome Measure Information:
Title
Progression Free Survival (PFS)
Description
The interval from randomization until the first occurrence of disease progression (according to RECIST 1.1) or death from any cause, which ever occurs first.
Time Frame
Approximately 5 years
Secondary Outcome Measure Information:
Title
Clinical Benefit Rate (CBR)
Description
CBR is the total percentage of participants who achieved a complete response, partial response, or had stable disease for 6 months or more.
Time Frame
Approximately 5 years
Title
Objective Response Rate (ORR)
Description
ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR) based on BICR and investigator assessment using RECIST 1.1.
Time Frame
Approximately 5 years
Title
Overall Survival (OS)
Description
OS is defined as the time from randomisation until the date of death due to any cause.
Time Frame
Approximately 5 years
Title
Safety and tolerability
Description
Number of adverse events according to NCI-CTCAE Version 5.0 per each treatment arm.
Time Frame
Approximately 5 years

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients need to meet all of the following conditions Patients must be ≥18 and ≤ 75 years of age; Pathologically confirmed breast cancer is HR+/HER2- breast cancer (IHC ER >10%, or/and PR>10%, HER 0 OR +, if HER2++, FISH negative); SNF1 subtype definition: SNF1 subtype confirmed by digital pathology of H&E sections; Locally advanced breast cancer (radical local therapy is not possible) or metastatic breast cancer (without using adjuvant CDK4/6 inhibitors in the past, or one year after adjuvant CDK4/6 inhibitor therapy has ended); No prior therapy (chemotherapy, targeted therapy, etc.) for advanced or metastatic breast cancer; Patients with at least one measurable lesion that has not previously received radiation therapy and can be evaluated repeatedly according to RECIST 1.1; The functions of the main organs are basically normal, and the following conditions are met: Blood routine examination standards should meet: HB≥90g/L (no blood transfusion within 14 days); ANC≥1.5×109/L; PLT≥75×109/L; Biochemical examination shall meet the following standards: TBIL≤1.5×ULN (upper limit of normal value); ALT and AST≤3 x ULN; In case of liver metastasis, ALT and AST≤5×ULN; Serum Cr ≤1.5×ULN, endogenous creatinine clearance > 50ml/min (Cockcroft-Gault formula); ECOG performance status 0 or 1; The expected survival is more than 3 months; Fertile female is required to use a medically approved contraceptive during study treatment and for at least 3 months after the last use of the study drug; Patients voluntarily join the study, sign the informed consent, have good compliance, and cooperate with follow-up. Exclusion Criteria: Patients with any of the following conditions were excluded from the study Patients with central nervous system metastasis out of control (symptoms need to use glucocorticoids or mannitol). A history of clinically significant or uncontrolled heart disease, including congestive heart failure, angina pectoris, myocardial infarction within the last 6 months, or ventricular arrhythmia; Radiotherapy, chemotherapy, surgery, other targeted therapy and immunotherapy for advanced HR+/HER2- breast cancer within 4 weeks prior to first administration of drugs used in this study. Pregnant or lactating patients; Other malignancies within the previous 3 years, excluding cured skin basal cell carcinoma and cervical carcinoma in situ; Significant comorbid medical conditions, including mental illnesses that the investigator or sponsor believes would adversely affect the patient's participation in the study; Allergic physique, or known allergic history of the drug components of this program; Or allergic to other monoclonal antibodies; The investigator does not consider the patient suitable for participation in any other circumstances of the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhimin Shao, MD, PhD
Phone
+86-021-64175590
Ext
88807
Email
zhimingshao@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
Min He, MD, PhD
Phone
+86-021-64175590
Ext
6671
Email
min1.he@shca.org.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhimin Shao, MD,PhD
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
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhimin Shao Shao, MD,PhD
Phone
86-021-64175590
Email
zhimingshao@yahoo.com

12. IPD Sharing Statement

Learn more about this trial

Efficacy of Everolimus Combined With First-line Endocrine Therapy for HR+/HER2- SNF1-subtype Advanced Breast Cancer

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