Inetetamab Combined With Pyrotinib and Chemotherapy in the Treatment of HER2 Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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HER2-targeted therapy after the failure of trastuzumab treatment has become a new difficulty and challenge. Inetetamab, a new antibody to optimize the ADCC effect, has become one of the second-line treatment options after trastuzumab fails, showing good survival benefits. Pyrotinib, another second-line HER2 targeted drug, is a typical representative of TKI drugs, which not only has a strong HER2 antagonistic effect but also can synergize with monoclonal antibodies to amplify the ADCC effect. Pyrotinib and Inetetamab showed excellent anti-tumor efficacy and good safety in TKI and optimized ADCC respectively. we plan to carry out a phase II single-arm clinical study to evaluate the efficacy and safety of Inetetamab combined with Pyrotinib and chemotherapy in the treatment of her positive metastatic breast cancer.

Detailed Description
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Trastuzumab is the first target drug for HER2 positive metastatic breast cancer, which can significantly improve the survival of patients with HER2 positive metastatic breast cancer and become the first-line standard treatment. However, the selection of second-line targeted drugs after the failure of trastuzumab treatment has become a new difficulty and challenge. Studies have shown that the ADCC effect is one of the main mechanisms of the anti-tumor effect of trastuzumab. Therefore, Inetetamab, a new antibody to optimize the ADCC effect, has become one of the second-line treatment options after trastuzumab fails, showing good survival benefits. Pyrotinib, another second-line HER2 targeted drug, is a typical representative of TKI drugs, which not only has a strong HER2 antagonistic effect but also can synergize with monoclonal antibodies to amplify the ADCC effect. As two important class 1.1 innovative drugs in China, Pyrotinib and Inetetamab showed excellent anti-tumor efficacy and good safety in TKI and optimized ADCC respectively. Considering that the current guidelines recommend the combination of multiple anti-HER2 targeted drugs, and basic research also shows that Pyrotinib and Inetetamab have a synergistic effect, we plan to carry out a phase II single-arm clinical study to evaluate the efficacy and safety of Inetetamab combined with Pyrotinib and chemotherapy in the treatment of her positive metastatic breast cancer, so as to provide better results for patients with HER2 positive metastatic breast cancer Treatment options!

Official Title
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A Phase II Single-arm Clinical Trial of Inetetamab Combined With Pyrotinib and Chemotherapy in the Treatment of HER2 Positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Inetetamab
* Drug: Pyrotinib
* Drug: Capecitabine
* Drug: Gemcitabine
* Drug: Vinorelbine
* Drug: Carboplatin
* Drug: Albumin paclitaxel
* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following conditions: Adult female patients (age 18-70 years) with metastatic breast cancer confirmed by pathology or imaging; Pathological diagnosis of HER-2 was positive (definition: immunohistochemical results were + + + or in situ hybridization results were positive); Received trastuzumab treatment in the past; the patients have received 1-3 treatments for metastatic breast cancer in the past; According to RECIST 1.1, patients with at least one target lesion or simple bone metastasis can be evaluated; ECoG score of physical status was less than 2, and the expected survival time was not less than 3 months; Prior treatment-related toxicity should be reduced to NCI CTCAE (version 5.0) ≤ 1 degree (except for hair loss or other toxicity which is considered as no risk to patient's safety according to the investigator's judgment) 8）LVEF≥50%； 9) Sufficient functional reserve of bone marrow White blood cell count (WBC) ≥ 3.0 × 10 ^ 9 / L, Neutrophil count (ANC) ≥ 1.5 × 10 ^ 9 / L, Platelet count (PLT) ≥ 100 × 10 ^ 9 / L 10) Previous treatment-related toxicity should be relieved as NCI CTCAE (version 5.0) ≤ 1 degree, total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN), alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln), serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 ml / min; 11) Be able to understand the research process, volunteer to participate in the study, and sign informed consent. Exclusion Criteria: Subjects were not allowed to participate in the study if they had any of the following conditions: No trastuzumab treatment was received; Have received more than 3 therapeutic regimens for metastatic breast cancer; No treatment for metastatic breast cancer was received; Patients who are known to be allergic to active or other components of the study drug. They received radiotherapy, chemotherapy, endocrine therapy within 4 weeks before enrollment, or were participating in any clinical trials of intervention drugs; Pregnant or lactating women, women of childbearing age who refused to take effective contraceptive measures during the study period. Any other situation in which the researcher considers that the patient is not suitable for the study may interfere with the concomitant diseases or conditions involved in the study, or there are any serious medical barriers that may affect the safety of the subjects (e.g., uncontrollable heart disease, hypertension, active or uncontrollable infection, active hepatitis B virus infection)

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

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Interventional Model Description: In order to improve the curative effect and prolong the survival rate, we added Inetetamab to the current second-line treatment regimen of Pyrotinib combined with chemotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inetetamab Combined With Pyrotinib and Chemotherapy<br>Inetetamab: 8mg/kg for the first dose, 6mg/kg for the following doses, every 3 weeks for one cycle. Pyrotinib: 400mg, oral, every day. Chemotherapy: the choice of physicians，as the following regimens: Capecitabine, 1000 mg/m2, d1-d14, 3-week cycle Gemcitabine, 1000 mg/m2, D1, D8, 3-week cycle Vinorelbine, 25-30 mg/m2, D1, D8, 3-week cycle Carboplatin, AUC = 6, 3-week cycle Albumin paclitaxel, 100 mg/m2, weekly Eribulin, 1.4 mg/m2, D1, D8, 3-week cycle | Drug: Inetetamab<br>* Inetetamab: 8mg/kg for the first dose, 6mg/kg for the following doses, every 3 weeks for one cycle.<br>Drug: Pyrotinib<br>* Pyrotinib: 400mg, oral, every day.<br>Drug: Capecitabine<br>* Capecitabine, 1000 mg/m2, d1-d14, 3-week cycle<br>* Other names: xeloda or other names;Drug: Gemcitabine<br>* Gemcitabine, 1000 mg/m2, D1, D8, 3-week cycle<br>* Other names: Gemzar or other names;Drug: Vinorelbine<br>* Vinorelbine, 25-30 mg/m2, D1, D8, 3-week cycle<br>* Other names: Navelbine or other names;Drug: Carboplatin<br>* Carboplatin, AUC = 6, 3-week cycle<br>* Other names: Paraplatin or other names;Drug: Albumin paclitaxel<br>* Albumin paclitaxel, 100 mg/m2, weekly<br>* Other names: Abraxane or other names;Drug: Eribulin<br>* Eribulin, 1.4 mg/m2, D1, D8, 3-week cycle<br>* Other names: Halaven;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate，ORR | Objective response rate assessed at 18 weeks after enrollment，that is about 6 cycles of treatment | 18 weeks after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival，PFS | The time from the beginning of treatment to the progression or death of the patient | 2 years | 
| overall survival，OS | The time from the beginning of treatment to the death of the patient | 4 years | 
| Clinical Benefit Rate，CBR | Clinical Benefit Rate assessed at 24 weeks after enrollment，that is about 8 cycles of treatment | 24 weeks after enrollment | 
| the rate of adverse events | The probability and severity of adverse reactions were analyzed up to 24 weeks after enrollment | up to 24 weeks after enrollment | 
| Quality of life scale score，QoL | The quality of life score of patients during treatment was analyzed（FACT-B）. Performance Status Rating (PSR) was demonstrated for the FACT-B total score, which is the result of the following subscale scores: SWB (the Social / family Well-Being subscale) , EWB (the Emotional Well-Being subscale), AC (Additional Concerns subscale), PWB (the Physical Well-Being subscale), FWB (the Functional Well-Being subscale) | 1 year | 
| Exploration of biomarkers | Objective to explore the correlation between biomarkers and the ORR. The biomarkers will be test by nest-generation sequence, which include 520 genes and tumor mutation burden, like ERBB2/TP53/PIK3CA/ERBB4/CCND1 and so on. | the first week after the enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 positive metastatic breast cancer, Inetetamab, Pyrotinib