Disitamab Vedotin (RC48) in Hormone Receptor Positive, HER2-low Metastatic Breast Cancer (the Rosy Trial)

Study Overview
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Brief Summary
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Hormone receptor positive, HER2-low expression metastatic breast cancer is the main type of breast cancer, accounting for about 50% - 60%. However, this type of patients lack ideal therapeutic drugs after the failure of first-line standard endocrine therapy, and the median overall survival time is only 30 months. Therefore, finding more efficient and safe therapeutic drugs for these patients has become a big clinical challenge at present. Disitamab Vedotin (DV), as a new class I Antibody-Drug Conjugates drug, can achieve high efficiency and precise tumor killing effect with low toxicity. According to previous study with same sample size, DV also showed good efficacy in metastatic breast cancer with Hormone receptor positive and HER2- low expression as a posterior line treatment.Therefore, we intend to explore the efficacy and safety of DV in the treatment of HER2-low expressioin /Hormone receptor positive metastatic breast cancer patients with endocrine resistance through a scientifically designed, randomized, phase III clinical study.

Official Title
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Disitamab Vedotin or Endocrine Therapy for Patients With Metastatic Breast Cancer With Hormone Receptor-positive and HER2-low-expression

Conditions
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HR Positive/HER2 Low Expression Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Disitamab vedotin
* Other: Endocrine therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult female patients (aged 18-70 years, including 18 and 70 years) with metastatic breast cancer confirmed by pathology or imaging are not suitable for surgical resection or radiotherapy for the purpose of cure; Pathological examination confirmed that ER and / or PR were positive, and HER-2 was low expression (ER expression: immunohistochemical staining of tumor cells ≥ 10%; PR expression: immunohistochemical staining of tumor cells ≥ 10%; HER2-low: immunohistochemical staining of 2 + and FISH is not expanded, IHC 1 +); Patients who have received endocrine therapy ; According to the efficacy evaluation criteria for solid tumors (RECIST) version 1.1, there is at least one evaluable target lesion or only osteolytic bone metastasis; Patients with stable brain metastasis or asymptomatic brain metastasis; ECOG physical condition score ≤ 2 points, and the estimated survival time is not less than 3 months; Prior treatment-related toxicity must be relieved to ≤ 1 degree (according to NCI CTCAE 5.0) before enrollment (except for hair loss or other toxicity that is considered as no risk to the safety of patients according to the judgment of the researcher); Adequate bone marrow functional reserve: a. WBC ≥ 3.0 × 10 ^ 9 ／ L, b. Neutrophil count (ANC) ≥ 1.5 × 10 ^ 9 ／ L, c. Platelet count (PLT) ≥ 70 × 10^9／L; Liver, kidney and heart function tests were basically normal within one week before enrollment (based on the normal values of laboratories in each research center): A. total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN), B. alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln), C. serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 ml / min; d. left ventricular ejection fraction (LVEF) ≥ 55%, e. QTcF(Fridericia correction) ≤ 470 ms; Patients understand the research process, voluntarily participate in the research, and sign the informed consent form. Exclusion Criteria: Patients who had received chemotherapy, radiotherapy, immunotherapy, and endocrine therapy for breast cancer within 2 weeks before enrollment.; Patients who had performed major surgery within 2 weeks before enrollment. Severe heart disease or discomfort within 12 months, including, but not limited to, the following: unstable angina pectoris, myocardial infarction, cerebral hemorrhage and cerebral infarction (except for silent lacunar cerebral infarction without treatment); Have active autoimmune diseases (such as corticosteroids or immunosuppressive drugs) requiring systemic treatment in the past 2 years, excluding those with adrenal insufficiency requiring corticosteroid replacement therapy; Have a clear history of neurological or mental disorders, including epilepsy or dementia; According to the judgment of the researchers, there are some accompanying diseases that seriously endanger the safety of patients or affect patients to complete the study. Those who have been known to have allergic history to Disitamab Vedotin or similar drugs; According to the estimation of the investigator , the patient's compliance with the clinical study is insufficient or the researcher believes that there are other factors that are not suitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients were randomly assigned to disitamab vedotin or endocrine therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disitamab Vedotin<br>Disitamab Vedotin, 2mg/kg, every 2 weeks | Drug: Disitamab vedotin<br>* Disitamab Vedotin 2mg/kg was injected every 2 weeks,<br>* Other names: RC48;|
| Active Comparator: Endocrine therapy<br>Doctors choose endocrine therapy independently | Other: Endocrine therapy<br>* Doctors choose endocrine therapy independently<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | The interval from the date of randomization to the first imaging confirmed progression of disease or death from any cause. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The time interval from the date of randomization to death due to any cause. | 36 months | 
| Objective response rate (ORR) | According to recist1.1 standard, the proportion of patients whose best remission was CR or PR accounted for the total number of evaluable patients. | 12 months | 
| Disease Control Rate (DCR) | According to recist1.1 standard, the proportion of patients whose best remission was CR or PR or SD accounted for the total number of evaluable patients. | 12 months | 
| Clinical Benefit Rate (CBR) | According to recist1.1 standard, the proportion of patients whose best remission was CR or PR or SD ≥ 24 weeks accounted for the total number of evaluable patients. | 12 months | 
| Quality of life assessed by EORTC-C30 | Quality of life will be collected using the following questionnaire: EORTC-C30 | 12 months | 
| Psychological condition assessed by GAD-7 |  | 12 months | 
| Pittsburgh Sleep Scale |  | 12 months | 
| Incidence of adverse events(AE) | From the date of enrollment to one year, the incidence of adverse events in the fulvestrant combined with pyrotinib group was compared with that of capecitabine combined with pyrotinib group. | from the date of enrollment to one year | 
| Biomarkers and treatment sensitivity analysis | Cox univariate and multivariate analysis will be used to explore the correlation between endocrine and HER2 pathway related biomarkers and treatment sensitivity（The biomarkers to be analyzed included 324 tumor related genes included in the FoundationOne CDx, and ER/PR/HER2/ki67 in IHC） | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADC, HR positive, HRE2 low expression, metastatic breast cancer