Comparing Efficacy and Safety Between Pertuzumab® and Perjeta® in Neoadjuvant Treatment of HER2+ Breast Cancer

Study Overview
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Brief Summary
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This study was a phase III, multicenter, triple-blind, equivalency clinical trial to determine the therapeutic efficacy and safety between Pertuzumab® (CinnaGen Co.) compared to originator pertuzumab in HER2-positive early breast cancer patients. Patients were stratified dynamically for random assignment to treatment with either Pertuzumab® (CinnaGen Co.) or originator pertuzumab, and received neoadjuvant TCHP regimen every 3- weeks.

Detailed Description
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This study was a phase III, multicenter, triple-blind , equivalency clinical trial to determine the therapeutic efficacy and safety between Pertuzumab® (CinnaGen Co.) compared to originator pertuzumab in HER2-positive early breast cancer patients. Patients stratified dynamically according to two factors: type of breast cancer (inflammatory, locally and operable) and estrogen/ progesterone receptor (ER/PR) (positive or negative) with 1:1 allocation ratio. Study drugs were administered intravenously on a 3-weekly schedule and were given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel (TCHP regimen). The primary endpoint was breast pCR (bpCR). Secondary efficacy endpoints included total pCR (tpCR); objective response rate (ORR) and rate of breast-conserving surgery (BCS) for patients for whom mastectomy was planned before treatment (T2-3). During this study, adverse events (AEs) were monitored continuously. As an adverse event of special interest (AESI), left ventricular ejection fraction (LVEF) decreased was monitored and assessed by echocardiography throughout the study. Immunogenicity was also assessed.

Official Title
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A Phase III, Randomized, Two-armed, Parallel, Triple-blind, Active-controlled, Equivalency Clinical Trial of Efficacy and Safety Pertuzumab® (CinnaGen Co.) Compared With Perjeta® (Originator Pertuzumab) in Neoadjuvant Treatment of HER2+ Breast Cancer

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Carboplatin
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients aged 18-70 years. Diagnosed with locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0), inflammatory (T4d, any N, M0) or operable (T2-3, N0-1, M0), invasive breast cancer. Primary tumor > 2 cm in diameter. HER2 positive breast cancer confirmed (Tumors must be IHC 3+ or FISH/CISH + for IHC 2+ tumors). Baseline LVEF ≥ 55% measured by echocardiography. Performance status ECOG ≤ 1 Signed informed consent. Exclusion Criteria: Metastatic disease (Stage IV) or bilateral breast cancer. Previous anticancer therapy or radiotherapy for any malignancy. Other malignancy, except for carcinoma in situ of the cervix or basal cell carcinoma. Received any investigational treatment within 4 weeks of study start. At least 4 weeks since major surgery. Uncontrolled hypertension (systolic > 150 and/or diastolic > 100), unstable angina, CHF of any NYHA classification, serious cardiac arrhythmia requiring treatment, history of myocardial infarction within 6 months of enrollment. Hematological, biochemical and organ dysfunction: Inadequate bone marrow function: Absolute Neutrophil Count (ANC) < 1500 cells/ µL, Platelet count < 100,000 cells/ µL and Hb < 9 g/dL). Impaired liver function: serum [total] bilirubin > 1.25 x ULN, AST/ALT > 1. 5 x ULN with ALP > 2.5 x ULN Inadequate renal function: serum creatinine > 1.5 x ULN. Dyspnea at rest or other diseases which require continuous oxygen therapy. Severe uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, metabolic, etc). Current chronic daily treatment with corticosteroids (dose of ≥10 mg Oral prednisolone, or equivalent [excluding inhaled steroids]) Subjects with known infection with HIV, HBV, and HCV. Known hypersensitivity to any of the study drugs or excipients. Pregnant and/or lactating women or subjects with reproductive potential not willing to use effective methods of contraception. Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol (e.g.: physical, psychological and mental problems)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCHP regimen (trastuzumab, pertuzumab® (CinnaGen Co.), carboplatin, and docetaxel)<br>Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; pertuzumab® (CinnaGen Co.) is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2. | Drug: Trastuzumab<br>* An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks<br>Drug: Pertuzumab<br>* An initial dose of 840 mg, followed by 420 mg every 3-weeks<br>Drug: Carboplatin<br>* A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks<br>Drug: Docetaxel<br>* 75 mg/m2 every 3-weeks<br>|
| Active Comparator: TCHP regimen (trastuzumab, Perjeta®, carboplatin, and docetaxel)<br>Study drugs are administered intravenously on a 3-weekly schedule and given consecutively on the same day in the following sequence: trastuzumab, followed by pertuzumab, carboplatin, and docetaxel. Trastuzumab is given at an initial dose of 8 mg/kg, followed by 6 mg/kg; Perjeta® is given at an initial dose of 840 mg, followed by 420 mg. Carboplatin is administered at a dose of AUC6 (area under the plasma concentration-time curve) and docetaxel is given at 75 mg/m2. | Drug: Trastuzumab<br>* An initial dose of 8 mg/kg, followed by 6 mg/kg every 3-weeks<br>Drug: Pertuzumab<br>* An initial dose of 840 mg, followed by 420 mg every 3-weeks<br>Drug: Carboplatin<br>* A dose of AUC6 (area under the plasma concentration-time curve) every 3-weeks<br>Drug: Docetaxel<br>* 75 mg/m2 every 3-weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast Pathological Complete Response (bpCR) | bpCR defined as the absence of invasive neoplastic cells in the breast at microscopic examination of the primary tumor at surgery following primary systemic therapy (ypT0/is) | 18-20 weeks after first intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Pathological Complete Response (tpCR) | tpCR defined as no invasive tumor residues in the breast and lymph nodes (ypT0/is ypN0) | 18-20 weeks after first intervention | 
| Objective response rate (ORR) | ORR defined as the proportion of patients who achieved a complete or partial response | 18-20 weeks after first intervention | 
| Rate of breast-conserving surgery (BCS) | Rate of BCS for patients for whom mastectomy was planned before treatment (T2-3) | 18-20 weeks after first intervention | 
| Adverse Events (AEs) | AEs were monitored continuously and all the reported events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 . The causality relation was assessed based on World Health Organization (WHO) criteria. | Throughout the study duration (from first visit to week 18-20) | 
| Abnormal laboratory data | The abnormality in selected laboratory data was considered as adverse event and was reported. | Throughout the study duration (from first visit to week 18-20) | 
| Decline in LVEF of ≥10% points from baseline to <50% | LVEF decrease was measured by echocardiography. | every 6 week (from first visit to week 18-20) | 
| Incidence of symptomatic left ventricular systolic dysfunction (LVSD) | symptoms of LVSD were monitored by physician and reported as AEs. | Throughout the study duration (from first visit to week 18-20) | 
| Immunogenicity | antidrug antibody [ADA] assessment | Every 3 weeks (from first intervention to week 18) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pertuzumab, HER2-positive Breast Cancer, Neoadjuvant treatment, Equivalency clinical trial