Comparing the Efficacy of Nab-PH+Pyrrolitinib and TCbHP in the Neoadjuvant Treatment of HER2 Positive BC

Study Overview
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Brief Summary
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At present, the incidence rate of breast cancer has exceeded that of lung cancer, becoming the largest cancer in the world. HER2 overexpression breast cancer accounts for about 20% 30% of all breast cancer patients. HER2 is an important prognostic indicator and therapeutic target for breast cancer. Targeted therapy for HER2 protein is the core treatment of this type of breast cancer. Previous studies have confirmed that TKI drugs can reverse the resistance of large molecule monoclonal antibodies to a certain extent; Moreover, due to the complementarity of therapeutic targets, monoclonal antibodies are associated with TKI Drugs have synergistic effects. TCbHP is one of the preferred neoadjuvant chemotherapy schemes recommended by NCCN guidelines for HER2 positive breast cancer, but its incidence of adverse reactions such as vomiting, diarrhea, anemia, thrombocytopenia is significantly higher than that of the scheme without platinum. In the GeparOcto study and Geparsixto study, based on anthracycline+purple shirt+double target, the addition of carboplatin did not further improve the PCR rate of HER2 positive breast cancer neoadjuvant therapy. GeparSepto research showed that compared to the solvent based paclitaxel group, albumin paclitaxel increased the pCR rate by 8.2% and the IDFS by 7.3%. In the CA024 study, compared to docetaxel, albumin paclitaxel also significantly increased ORR and PFS. In the study by Lavasani SM et al., the neoadjuvant therapy of albumin paclitaxel combined with topiramate achieved a PCR rate of 64%. Therefore, we assume that the new adjuvant treatment scheme of Nab PH+pyrrolitinib can not be inferior to the efficacy of TCbHP, and has a lower incidence of adverse reactions, which may become a new adjuvant treatment option for HER2 positive breast cancer patients.

Detailed Description
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At present, the incidence rate of breast cancer has exceeded that of lung cancer, becoming the largest cancer in the world. HER2 overexpression breast cancer accounts for about 20% 30% of all breast cancer patients. HER2 is an important prognostic indicator and therapeutic target for breast cancer. Targeted therapy for HER2 protein is the core treatment of this type of breast cancer. Previous studies have confirmed that TKI drugs can reverse the resistance of large molecule monoclonal antibodies to a certain extent; Moreover, due to the complementarity of therapeutic targets, monoclonal antibodies are associated with TKI Drugs have synergistic effects. TCbHP is one of the preferred neoadjuvant chemotherapy schemes recommended by NCCN guidelines for HER2 positive breast cancer, but its incidence of adverse reactions such as vomiting, diarrhea, anemia, thrombocytopenia is significantly higher than that of the scheme without platinum. In the GeparOcto study and Geparsixto study, based on anthracycline+purple shirt+double target, the addition of carboplatin did not further improve the PCR rate of HER2 positive breast cancer neoadjuvant therapy. GeparSepto research showed that compared to the solvent based paclitaxel group, albumin paclitaxel increased the pCR rate by 8.2% and the IDFS by 7.3%. In the CA024 study, compared to docetaxel, albumin paclitaxel also significantly increased ORR and PFS. In the study by Lavasani SM et al., the neoadjuvant therapy of albumin paclitaxel combined with topiramate achieved a PCR rate of 64%. Therefore, we assume that the new adjuvant treatment scheme of Nab PH+pyrrolitinib can not be inferior to the efficacy of TCbHP, and has a lower incidence of adverse reactions, which may become a new adjuvant treatment option for HER2 positive breast cancer patients. This study aims to explore the efficacy and safety of TCbHP * 6 and Nab-PH+pyrrolitinib * 6 as two new adjuvant treatment regimens in HER2 positive patients through a randomized controlled trial.

Official Title
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A Non Inferior, Randomized Controlled Phase II Clinical Study Comparing the Efficacy of Nab-PH+Pyrrolitinib and TCbHP in the Neoadjuvant Treatment of HER2 Positive Breast Cancer

Conditions
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Breast Cancer, HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Albumin paclitaxel+trastuzumab+pyrrolitinib
* Drug: Docetaxel+Carboplatin+trastuzumab+Parstuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-65 years old, ECOG 0-1 point. Clinical T2-T4d, or T1c with axillary LN+. HER2+, invasive breast cancer confirmed by histopathology;(HER2 positive expression means that there is at least one case of tumor cell immunohistochemical staining intensity of 3+or positive confirmed by fluorescence in situ hybridization [FISH] in the pathological test/review of the primary focus conducted by the Pathology Department of the Research Center Hospital). Having clinically measurable lesions: measurable lesions displayed on ultrasound, mammography, or MR (optional) within the first month of randomization. Organ and bone marrow function tests within one month before chemotherapy indicate no contraindications to chemotherapy:Absolute value of neutrophil count ≥ 2.0 × 109/L; Hemoglobin ≥ 90g/L; Platelet count ≥ 100 × 109/L;Total bilirubin<1.5 ULN (upper limit of normal value); Creatinine<1.5 × ULN; AST/ALT < 1.5 × ULN. Cardiac ultrasound: Left ventricular ejection fraction (LVEF ≥ 55%). Women of childbearing age tested negative for serum pregnancy test 14 days before randomization. Sign an informed consent form. Exclusion Criteria: Stage IV (metastatic) breast cancer. Has received chemotherapy, endocrine therapy, targeted therapy, reflex therapy, etc. for this disease. The patient has a second primary malignant tumor, except for fully treated skin cancer. The patient had undergone major surgical procedures unrelated to breast cancer within 4 weeks before enrollment, or the patient has not fully recovered from such surgical procedures. Serious heart disease or discomfort, including but not limited to the following diseases:Confirmed history of heart failure or systolic dysfunction (LVEF<50%); High risk uncontrolled arrhythmias, such as atrial tachycardia, resting heart rate>100 bpm, significant ventricular arrhythmias (such as ventricular tachycardia), or higher-level atrioventricular block; Angina pectoris requiring treatment with anti angina drugs; Clinically significant heart valve disease; ECG shows transmural myocardial infarction; Poor control of hypertension (systolic blood pressure>180 mmHg and/or diastolic blood pressure>100 mmHg). Due to serious and uncontrollable other medical diseases, researchers believe that there are contraindications to chemotherapy. Individuals with a known history of allergies to the drug components of this protocol; Having a history of immunodeficiency, including HIV testing positive, or suffering from other acquired or congenital immunodeficiency diseases, or having a history of organ transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients who meet the inclusion criteria were randomly divided into TCbHP group and Nab-PH+pyrrolitinib group in a 1:1 ratio.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nab-PH+pyrrolitinib regimen group<br>Drug dose of Nab PH+pyrrolitinib scheme: albumin paclitaxel 260mg/m 2+trastuzumab (initial loading dose 8 mg/kg, sequential maintenance dose 6 mg/kg)+pyrrolitinib (400mg, QD), one cycle every 21 days. | Drug: Albumin paclitaxel+trastuzumab+pyrrolitinib<br>* Albumin paclitaxel 260mg/m 2+trastuzumab (initial loading dose 8 mg/kg, sequential maintenance dose 6 mg/kg)+pyrrolitinib (400mg, QD), one cycle every 21 days.<br>* Other names: Nab-PH+pyrrolitinib regimen;|
| Placebo Comparator: TCbHP regimen group<br>The drug dose of TCbHP protocol: docetaxel 75 mg/m2+carboplatin (AUC=6)+trastuzumab (initial load dose 8 mg/kg, sequential maintenance dose 6 mg/kg)+patuzumab (initial load dose 840mg, sequential maintenance dose 420 mg), one cycle every 21 days. | Drug: Docetaxel+Carboplatin+trastuzumab+Parstuzumab<br>* Docetaxel 75 mg/m2+carboplatin (AUC=6)+trastuzumab (initial loading dose 8 mg/kg, sequential maintenance dose 6 mg/kg)+patuzumab (initial loading dose 840mg, sequential maintenance dose 420 mg), one cycle every 21 days<br>* Other names: TCbHP regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate (pCR rate) | After neoadjuvant chemotherapy and surgery, the resected specimen (breast + axilla) was free of any invasive cancer (ie, ypT0/is, ypN0) | immediately after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) | EFS was defined as the time from randomization to any of the following events: disease progression during neoadjuvant therapy, local or distant recurrence, second primary malignancy (breast or other cancer), or death from any cause. | 5-10 years after surgery | 
| DFS | Disease-free Survival,From the date of surgery to the first local, regional, contralateral or distant recurrence, and death from any cause | 5-10 years after surgery | 
| Distant Disease Free Survival (DDFS) | DDFS is defined as the time from surgery to distant recurrence or death from any cause | 5-10 years after surgery | 
| Objective Response Rate (ORR) | ORR is defined as the number of target lesion responders as assessed by MRI | Preoperative | 
| number of adverse events | Evaluate the nature, incidence and severity of chemotherapy adverse events according to CTCAE 5.0 | during each cycle of chemotherapy (21 days as 1 cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive Breast Cancer, pathologic complete response, Pyrrolitinib, Disease-free survival