Comparing Efficacy and Safety of AryoGen Pharmed Biosimilar Trastuzumab (AryoTrust) Versus Herceptin® in Breast Cancer

Study Overview
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Brief Summary
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This is A Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel active controlled non-Inferiority clinical trial study to evaluate efficacy and safety of AryoTrust (Aryogen Trastuzumab in comparison to Herceptin® (Genentech/Roche) in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. The main objective is to verify the non-inferiority of AryoTrust (Aryogen trastuzumab) vs. Herceptin® (Genentech/Roche trastuzumab), both given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological complete response (pCR) as primary objective and objective response (cOR), clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), breast conservation rate as Secondary objectives of this study. Evaluating the safety and immunogenicity of AryoTrust vs. Herceptin®, are also the other secondary outcomes. This study has two arms and 108 subjects will participate with a 1:1 allocation and receive mentioned treatment randomly.

Detailed Description
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This is A Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel active controlled non-Inferiority clinical trial study to evaluate efficacy and safety of AryoTrust (Aryogen Trastuzumab) in comparison to Herceptin® (Genentech/Roche) in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. Patients who met the following criteria will be recruited. The inclusion criteria are: 18-70 years old female patients, Patients with newly diagnosed stage III (locally advanced) or in-operable stage II (due to sizes larger than 5 cm or high tumor to breast ratio) tumors are candidates for participation, Willing and able to sign an informed consent, Pathological diagnosis of adenocarcinoma of the breast, ECOG status of 0-1, With any ER/PR status, HER2 positive (Immunohistochemical (IHC) 3+ intensity, amplification of the HER2 gene on fluorescence in situ hybridization (FISH+ ) or HER2 positive results of Chromogenic in situ hybridization (CISH)). Exclusion criteria are: Clinical or radiologic evidence of metastatic disease, History of any other malignancy including previous breast cancer, second non-breast malignant disease, History of previous chemotherapy, Left ventricular ejection fraction [LVEF] <55% confirmed by echo cardiogram within 3 months before registration, Any prior myocardial infarction, History of documented congestive heart failure (CHF),Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant, Current use of medications for treatment of angina pectoris, Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg), A severe conduction abnormality (having pacemaker or diagnosed by the ECG) and any other significant cardiovascular disease, Hematologic abnormalities including baseline Absolute Neutrophil Count (ANC) of ≤1,500/µL or platelet count ≤ 100,000/µL, Liver dysfunction including (baseline) Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) ≥ 3 Upper Limit Normal (ULN), Alkaline phosphatase (ALP) ≥3 ͯ ULN, serum total, bilirubin > 1.5 ULN, Renal dysfunction, defined as serum creatinine ≥2.5 mg/dL, Pregnant, lactating women or women of childbearing potential who are not willing to use adequate contraception. The main objective is to verify the non-inferiority of AryoTrust (Aryogen Trastuzumab) vs. Herceptin® (Genentech/Roche Trastuzumab), both given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological, clinical response and immunogenicity assay in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. The primary objective of this study is to verify the non-inferiority of AryoTrust vs. Herceptin®, given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological complete response (pCR) rate. The secondary objectives are to evaluate non-significance between AryoTrust and Herceptin®, given concomitantly with docetaxel after Adriamycin plus cyclophosphamide in the neoadjuvant setting according to clinical objective response (cOR), clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), breast conservation rateEvaluating the safety and immunogenicity of AryoTrust vs. Herceptin®, are also the other secondary outcomes. This study has two arms and 108 subjects will participate with a 1:1 allocation and receive AryoTrust vs. Herceptin® randomly given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide For primary outcome analysis, Treatment differences in proportions will be calculated. A 95% two-sided confidence interval will be constructed and the upper bound to determine non-inferiority with a 2.5% significance level will be used.Frequency and proportions will be calculated for all secondary efficacy endpoints include clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), clinical objective response (cOR), breast conservation rate. All safety data will be analyzed descriptively by each treatment group. same protocol and procedures have been implemented by using same SOPs. Regular and strict monitoring visits have been provided to ensure all processes will be carried out in accordance with GCP. Probable variation of eligibility criteria and evaluation criteria are resolved through investigator meetings.

Official Title
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A Phase III, Randomized, Two-armed, Triple Blinded, Parallel, Active Controlled Non-Inferiority Clinical Trial of AryoTrust (AryoGen Trastuzumab) Efficacy and Safety in Comparison to Herceptin (Genentech) in HER2-Positive Breast Cancer

Conditions
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Malignant Neoplasm of Breast

Intervention / Treatment
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* Drug: Trastuzumab plus docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70 years old female patients Patients with newly diagnosed stage III (locally advanced) or inoperable stage II (due to sizes larger than 5 cm or high tumor to breast ratio) tumors are candidates for participation. Willing and able to sign an informed consent Pathological diagnosis of adenocarcinoma of the breast ECOG status of 0-1 With any ER/PR status HER2 positive (Immunohistochemical (IHC) 3+ intensity, amplification of the HER2 gene on fluorescence in situ hybridization (FISH+ ) or HER2 positive results of Chromogenic in situ hybridization (CISH+)). Exclusion Criteria: Clinical or radiologic evidence of metastatic disease History of any other malignancy including previous breast cancer, second non-breast malignant disease History of previous chemotherapy Left ventricular ejection fraction [LVEF] <55% confirmed by echo cardiogram within 3 months before registration, Any prior myocardial infarction, History of documented congestive heart failure (CHF),Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant, Current use of medications for treatment of angina pectoris, Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg), A severe conduction abnormality (having pacemaker or diagnosed by the ECG) and any other significant cardiovascular disease. Hematologic abnormalities including baseline Absolute Neutrophil Count (ANC) of ≤1,500/µL or platelet count ≤ 100,000/µL Liver dysfunction including : (baseline) Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) ≥ 3 Upper Limit Normal (ULN) Alkaline phosphatase (ALP) ≥3 ͯ ULN serum total bilirubin > 1.5 ULN Renal dysfunction, defined as serum creatinine ≥2.5 mg/dL Pregnant, lactating women or women of childbearing potential who are not willing to use adequate contraception

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: Trastuzumab (AryoTrust)<br>Trastuzumab (AryoTrust) is given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide | Drug: Trastuzumab plus docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide<br>* Trastuzumab (8 mg/kg IV loading dose at cycle 1, followed by 6 mg/kg at subsequent cycles) is given concomitantly with docetaxel (100 mg/m2 IV) for four 21-day cycles after four 14-day cycles of Doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV)<br>|
| Active Comparator: Trastuzumab (Herceptin)<br>Trastuzumab (Herceptin) is given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide | Drug: Trastuzumab plus docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide<br>* Trastuzumab (8 mg/kg IV loading dose at cycle 1, followed by 6 mg/kg at subsequent cycles) is given concomitantly with docetaxel (100 mg/m2 IV) for four 21-day cycles after four 14-day cycles of Doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pathologic Complete Response | the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes | week 23 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical Complete Response | Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm | week 21 | 
| clinical Partial Response | At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters | week 21 | 
| clinical Stable Disease | Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest diameters while on study | week 21 | 
| clinical Progressive Disease | At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) | within week 21 | 
| clinical Objective Response | clinical Complete Response + clinical Partial Response | week 21 | 
| Breast conservation rate | Patients who underwent lumpectomy | week 23 | 
| Adverse event assessment | Adverse event | up to week 26 | 
| Immunogenicity | antidrug antibody | week 10, week 13, week 19, week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, AryoTrust, Herceptin®, non-Inferiority