SNF Platform Study of HR+/ HER2-advanced Breast Cancer

Precision Platform Study of HR+/ HER2-advanced Breast Cancer Based on SNF Typing (A Prospective, Open-label, Multi-center, Phase II Platform Study)

The purpose of this study is to establish a prospective, multi-center platform research based on clinical subtypes to explore precision therapy in patients hormone-receptor-positive HER2-negative advanced breast cancer who had previously used CDK4/6 inhibitors.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Advanced Breast Cancer; Breast Neoplasm; HER2-negative Breast Cancer; Hormone Receptor Positive Tumor
• Intervention / Treatment: Drug: Fluzoparib; Drug: PIK3CA inhibitor; Drug: Aromatase Inhibitors or Fulvestrant; Drug: Goserelin; Drug: AKT inhibitor; Drug: Everolimus; Drug: Carrelizumab; Drug: Famitinib; Drug: Dalpiciclib; Drug: SHR-A1811; Drug: TPC; Drug: Apatinib; Drug: SHR-A1921; Drug: bevacizumab; Drug: SHR-A2009; Drug: SHR-A2102; Drug: SHR-1167; Drug: SHR-6209; Drug: Sorafenib

Detailed Description

Participants in this study were hormone-receptor-positive HER2-negative patients with advanced breast cancer who had previously used CDK4/6 inhibitors. Hormone receptor positive HER2 negative was defined as ER positive (IHC ER positive percentage > 10% or PR positive (IHC PR positive percentage > 10%) and HER2 negative (IHC-/+; Or IHC++ but FISH/CISH-).

The Department of Pathology and the Key Laboratory of Breast Cancer of Fudan University Shanghai Cancer Center conducted digital pathological typing of the biopsy pathology of metastatic lesions of all participants . If the pathology of metastatic lesions could not be obtained, the digital pathological typing was performed according to the pathology of primary lesions. According to the digital pathological types of biopsy tissue and peripheral blood ctDNA, the patients were divided into four precise subtypes: SNF1, SNF2, SNF3, and SNF4. At the same time, the negative control group was randomly set by subtype stratification at 2:1. In different SNF types, patients were divided into 7 subcohorts according to the genetic PANEL results.

• Study Type: Interventional
• Enrollment (Estimated): 620
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhimin Shao, M.D; Phone Number: 88807 +86-021-64175590; Email: zhimingshao@yahoo.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Breast cancer institute of Fudan University Cancer Hospital
      • Sub-Investigator: Ying Zhou
      • Contact: Zhi-Ming Shao, MD; Phone Number: 86-21-641755901105; Email: zhimingshao@yahoo.com
      • Contact: Lei Fan, MD; Phone Number: 86-21-641755901105; Email: cmchen@medmail.com.cn
      • Principal Investigator: Zhi-Ming Shao, MD
      • Sub-Investigator: Lei Fan, MD
      • Sub-Investigator: Wenjuan Zhang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female aged ≥18 years;
2. HR+/HER2- invasive breast cancer confirmed by histology (specific definition: ER >10% positive tumor cells by immunohistochemistry is defined as ER positive, PR >10% positive tumor cells is defined as PR positive, ER and/or PR positive is defined as HR positive; HER2 0-1+ or HER2 + but negative by FISH without amplification was defined as HER2 negative);
3. Locally advanced breast cancer (unable to undergo radical local treatment) or recurrent metastatic breast cancer;
4. HR+/HER2- advanced breast cancer patients who had previously received CDK4/6 inhibitor therapy;
5. At least one measurable lesion according to RECIST 1.1 (conventional CT scan ≥20 mm, spiral CT scan ≥10 mm, measurable lesion has not received radiotherapy);

6. The functions of the main organs are basically normal and meet the following conditions:

   I. Blood routine examination criteria shall meet: HB ≥90 g/L (no blood transfusion within 14 days); The ANC acuity 1.5 x 109 / L; PLT acuity 75 x 109 / L; Ii. Biochemical tests should meet the following criteria: TBIL ≤1.5×ULN (upper limit of normal value); ALT and AST ≤3×ULN; If liver metastases were present, ALT and AST≤ 5×ULN; Serum Cr ≤1×ULN, endogenous creatinine clearance > 50 ml/min (Cockcroft-Gault formula);

7. They have not received radiotherapy, molecular targeted therapy, or surgery within 3 weeks before the start of the study, and have recovered from the acute toxicity of previous treatment (if surgery was performed, the wound has healed completely); No peripheral neuropathy or grade I peripheral neurotoxicity;
8. ECOG score ≤2, and life expectancy ≥3 months;
9. Fertile female subjects were required to use a medically approved contraceptive method during the study treatment period and for at least 3 months after the last use of the study drug;
10. Subjects volunteered to join the study, signed informed consent, had good compliance, and cooperated with follow-up.

Exclusion Criteria:

1. Radiotherapy (except for palliative causes), chemotherapy, and immunotherapy were used in the first 3 weeks of treatment, except bisphosphonate (which can be used for bone metastasis);
2. Uncontrolled central nervous system metastases (indicating symptomatic or symptomatic treatment with glucocorticoids or mannitol);
3. A history of clinically important or uncontrolled heart disease, including congestive heart failure, angina pectoris, myocardial infarction, or ventricular arrhythmia within the last 6 months;
4. Persistent grade 1 or higher adverse reactions caused by previous treatments. The exception to this is hair loss or something the researchers don't think should be ruled out. Such cases should be clearly documented in the investigator's notes;
5. Underwent major surgery (except minor outpatient procedures, such as placement of vascular access) within 3 weeks of the first course of trial treatment;
6. Pregnant or lactating patients; Malignancy (except basal cell carcinoma of the skin, which has been cured, and carcinoma in situ of the cervix) in the past 5 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

26

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SNF1 1A: PIK3CA mutation; PIK3CA inhibitors +Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks.	Drug: PIK3CA inhibitor; PIK3CA inhibitor; Drug: Aromatase Inhibitors or Fulvestrant; Letrozole/Anastrozole/Exemestane or Fulvestrant; Drug: Goserelin; For premenopause
Experimental: SNF1 1B: AKT pathway mutation; AKT pathway inhibitors +Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks.	Drug: Aromatase Inhibitors or Fulvestrant; Letrozole/Anastrozole/Exemestane or Fulvestrant; Drug: Goserelin; For premenopause; Drug: AKT inhibitor; AKT inhibitor
Experimental: SNF1 1C: without above mutation; Everolimus 10mg po qd+Aromatase inhibitors(Letrozole/Anastrozole/Exemestane, po, qd, specific dose (letrozole 2.5mg/ day; Anastrozole 1mg/ day, Exemestane 25mg/ day);Or fulvestrant, 500mg ,im, qm, followed by 500mg im 2 weeks after the first dose; Premenopausal: Goserelin 3.6mg IM every 4 weeks.	Drug: Aromatase Inhibitors or Fulvestrant; Letrozole/Anastrozole/Exemestane or Fulvestrant; Drug: Goserelin; For premenopause; Drug: Everolimus; mTOR inhibior
Active Comparator: The control arm; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)	Drug: TPC; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)
Experimental: SNF2 2A; Treatment of physician' choice+Pd-1 mab (Carrelizumab 200mg Q2W)+Famitinib 15mg po qd for 4 weeks as a cycle	Drug: Carrelizumab; Pd-1 mab; Other Names: SHR1210; Drug: Famitinib; VEGFR inhibitor; Drug: TPC; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)
Experimental: SNF3 3A: Stratification of BRCA/PALB2 expression; Fluzoparib SHR3162 100mg po qd+Dalpiciclib 125mg po qd for 4 weeks as a cycle	Drug: Fluzoparib; PARP inhibitor; Other Names: SHR3162; Drug: Dalpiciclib; CDK4/6 inhibitor; Other Names: SHR6390
Experimental: SNF4 4A: HER2 low; SHR-A1811	Drug: SHR-A1811; HER2 ADC
Experimental: SNF3 3B: Fluzoparib SHR3162 100 mg qd+Treatment of physician' choice	Drug: Fluzoparib; PARP inhibitor; Other Names: SHR3162; Drug: TPC; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)
Experimental: SNF4 4B: Apatinib 250mg qd+Treatment of physician' choice	Drug: TPC; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin); Drug: Apatinib; Apatinib 250mg po qd
Experimental: SNF1 1D: without above mutation; Everolimus 10mg po qd+Treatment of physician' choice	Drug: Everolimus; mTOR inhibior; Drug: TPC; Treatment of Physicians' Choice (albumin-paclitaxel, capecitabine, vinorelbine, and irbribulin)
Experimental: SNF1 1E: HER2 LOW; Everolimus 10mg po qd+SHR-A1811	Drug: Everolimus; mTOR inhibior; Drug: SHR-A1811; HER2 ADC
Experimental: SNF1 1F: HER2 zero; Everolimus 10mg po qd+SHR-A1921	Drug: Everolimus; mTOR inhibior; Drug: SHR-A1921; TROP2 ADC
Experimental: SNF2 2B: HER2 zero; SHR-A1921+Pd-1 mab (Carrelizumab 200mg Q2W)+bevacizumab 7.5mg po ivgt t for 3 weeks as a cycle	Drug: Carrelizumab; Pd-1 mab; Other Names: SHR1210; Drug: SHR-A1921; TROP2 ADC; Drug: bevacizumab; bevacizumab
Experimental: SNF2 2C: HER3 -ADC+Pd-1 mab (Carrelizumab 200mg Q2W)+Famitinib for 3 weeks as a cycle	Drug: Carrelizumab; Pd-1 mab; Other Names: SHR1210; Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A2009; HER3 ADC
Experimental: SNF2 2D: Nectin4-ADC+Pd-1 mab (Carrelizumab 200mg Q2W)+Famitinib for 3 weeks as a cycle	Drug: Carrelizumab; Pd-1 mab; Other Names: SHR1210; Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A2102; NECTIN4 ADC
Experimental: SNF2 2E: HER2 low; SHR-A1811+Pd-1 mab (Carrelizumab 200mg Q2W)+Famitinib for 3 weeks as a cycle	Drug: Carrelizumab; Pd-1 mab; Other Names: SHR1210; Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A1811; HER2 ADC
Experimental: SNF3 3C: CDK4i（SHR-6209 PR2D+PARP1i（SHR-1167 PR2D）	Drug: SHR-1167; PARP1i; Drug: SHR-6209; CDK4i
Experimental: SNF3 3D: PARP1i（SHR-1167 PR2D)+Famitinib 5mg po qd for 4 weeks as a cycle	Drug: Famitinib; VEGFR inhibitor; Drug: SHR-1167; PARP1i
Experimental: SNF3 3E: HER2 low; PARP1i（SHR-1167 PR2D)+SHR-A1811 for 3 weeks as a cycle	Drug: SHR-A1811; HER2 ADC; Drug: SHR-1167; PARP1i
Experimental: SNF3 3F: HER2 zero; PARP1i（SHR-1167 PR2D)+SHR-A1921 for 3 weeks as a cycle	Drug: SHR-A1921; TROP2 ADC; Drug: SHR-1167; PARP1i
Experimental: SNF4 4C; Famitinib 20mg po qd	Drug: Famitinib; VEGFR inhibitor
Experimental: SNF4 4D; Sorafenib 0.4g bid	Drug: Sorafenib; RTK Inhibitor
Experimental: SNF4 4E; Apatinib 500mg qd	Drug: Apatinib; Apatinib 250mg po qd
Experimental: SNF4 4F: HER2 low; Famitinib+SHR-A1811 for 3 weeks as a cycle	Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A1811; HER2 ADC
Experimental: SNF4 4G; Famitinib+HER3-ADC for 3 weeks as a cycle	Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A2009; HER3 ADC
Experimental: SNF4 4H; Famitinib+Nectin4-ADC for 3 weeks as a cycle	Drug: Famitinib; VEGFR inhibitor; Drug: SHR-A2102; NECTIN4 ADC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1)	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 Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate (CBR)	the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the subjects	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
Progression Free Survival (PFS)	time to progressive disease (according to RECIST1.1)	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)]
Overall Survival (OS)	time to death due to any cause	Randomization to death from any cause, through the end of study (approximately 3 years)
CTCAE scale (V5.0)	To evaluate the rate of adverse effects of patient by the standard CTCAE scale (V5.0)	up to One Year during follow-up
Exploration of translational research markers	The collected subjects' tumor tissues, paracancerous tissues, blood, and fecal samples will be used for discovering exploratory biomarkers. The relationships between discovered biomarkers and subjects' disease status and treatment responses will also be investigated.	up to One Year during follow-up

Collaborators and Investigators

• Sponsor: Fudan University
• Collaborators: Chongqing University Cancer Hospital; Sun Yat-sen University; Peking University Cancer Hospital & Institute; First Affiliated Hospital Xi'an Jiaotong University; Ningbo Medical Center Lihuili Hospital; The First Hospital of Jilin University; Fujian Medical University Union Hospital; First Hospital of China Medical University; Shanghai First Maternity and Infant Hospital; Shanghai 6th People's Hospital; Affiliated Hospital of Nantong University; The Affiliated Hospital of Nantong University; Liaoning Cancer Hospital & Institute; Northern Jiangsu People's Hospital; Nanchang People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 25, 2022
• First Posted (Actual): October 26, 2022

Study Record Updates

• Last Update Posted (Actual): October 4, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; MTOR Inhibitors; Sorafenib; Fulvestrant; Goserelin; Bevacizumab; Everolimus; Apatinib; Aromatase Inhibitors; Fluzoparib
• Other Study ID Numbers: BCTOP-L-M05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No