Clinical trial NCT03425656: Comparing Efficacy and Safety of AryoGen Pharmed Biosimilar Trastuzumab (AryoTrust) Versus Herceptin® in Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malignant Neoplasm of Breast
Keywords: breast cancer
AryoTrust
Herceptin®
non-Inferiority
Lead sponsor: AryoGen Pharmed Co.
Sponsor class: INDUSTRY
First posted: 2018-02-07
Enrollment: 108
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Pathologic Complete Response
timeFrame: week 23
Secondary outcomes:
measure: Clinical Objective Response
timeFrame: week 21
measure: Breast Conservation Rate
timeFrame: week 23
measure: Safety Assessment by Evaluation of Adverse Events (AEs) and Abnormal Laboratory Results
timeFrame: up to week 26
measure: The Number of Participants With Anti-drug Antibodies Against Trastuzumab (AryoTrust)
timeFrame: week 10, week 13, week 19, week 26
Other outcomes:
Locations:
city: Ahvaz
country: Iran, Islamic Republic of
facility: Shafa Hospital
city: Isfahan
country: Iran, Islamic Republic of
facility: Sheikh Mofid Clinic
city: Kermanshah
country: Iran, Islamic Republic of
facility: Payandeh Clinic
city: Kerman
country: Iran, Islamic Republic of
facility: Javadol Aemeh Clinic
city: Kerman
country: Iran, Islamic Republic of
facility: Park clinic
city: Mashhad
country: Iran, Islamic Republic of
facility: Imam Reza Hospital
city: Sanandaj
country: Iran, Islamic Republic of
facility: Tohid Hospital
city: Shiraz
country: Iran, Islamic Republic of
facility: Shahid Faqihi Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Baqiatallah Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Booali Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Firoozgar Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Imam Khomeini hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Jahad Daneshgahi Clinic
city: Tehran
country: Iran, Islamic Republic of
facility: Masood Clinic
city: Tehran
country: Iran, Islamic Republic of
facility: Mehrad Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Rasool Akram Hospital
city: Tehran
country: Iran, Islamic Republic of
facility: Toos Hospital
city: Yazd
country: Iran, Islamic Republic of
facility: Mortazavizadeh Clinic
city: Zahedan
country: Iran, Islamic Republic of
facility: Aliebne Abitaleb Hospital
Study officials:
affiliation: Tehran University of Medical Sciences
name: Reza Safaei, M.D
role: PRINCIPAL_INVESTIGATOR
References: