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

Sponsor

AryoGen Pharmed Co. (Industry)

Overall Status

Completed

CT.gov ID

NCT03425656

Collaborator

(none)

108

Enrollment

Locations

Arms

24.9

Actual Duration (Months)

5.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Malignant Neoplasm of Breast	Drug: Trastuzumab plus docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

108 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 9, 2016

Actual Primary Completion Date :

Mar 6, 2018

Actual Study Completion Date :

Aug 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trastuzumab (AryoTrust) 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 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)
Active Comparator: Trastuzumab (Herceptin) 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 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)

Arm

Intervention/Treatment

Experimental: Trastuzumab (AryoTrust)

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

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)

Active Comparator: Trastuzumab (Herceptin)

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

Outcome Measures

Primary Outcome Measures

pathologic Complete Response [week 23]
the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes

Secondary Outcome Measures

clinical Complete Response [week 21]
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
clinical Partial Response [week 21]
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters
clinical Stable Disease [week 21]
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
clinical Progressive Disease [within week 21]
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)
clinical Objective Response [week 21]
clinical Complete Response + clinical Partial Response
Breast conservation rate [week 23]
Patients who underwent lumpectomy
Adverse event assessment [up to week 26]
Adverse event
Immunogenicity [week 10, week 13, week 19, week 26]
antidrug antibody

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Shafa Hospital	Ahvaz	Iran, Islamic Republic of
2	Sheikh Mofid Clinic	Isfahan	Iran, Islamic Republic of
3	Payandeh Clinic	Kermanshah	Iran, Islamic Republic of
4	Javadol Aemeh Clinic	Kerman	Iran, Islamic Republic of
5	Park clinic	Kerman	Iran, Islamic Republic of
6	Imam Reza Hospital	Mashhad	Iran, Islamic Republic of
7	Tohid Hospital	Sanandaj	Iran, Islamic Republic of
8	Shahid Faqihi Hospital	Shiraz	Iran, Islamic Republic of
9	Baqiatallah Hospital	Tehran	Iran, Islamic Republic of
10	Booali Hospital	Tehran	Iran, Islamic Republic of
11	Firoozgar Hospital	Tehran	Iran, Islamic Republic of
12	Imam Khomeini hospital	Tehran	Iran, Islamic Republic of
13	Jahad Daneshgahi Clinic	Tehran	Iran, Islamic Republic of
14	Masood Clinic	Tehran	Iran, Islamic Republic of
15	Mehrad Hospital	Tehran	Iran, Islamic Republic of
16	Rasool Akram Hospital	Tehran	Iran, Islamic Republic of
17	Toos Hospital	Tehran	Iran, Islamic Republic of
18	Mortazavizadeh Clinic	Yazd	Iran, Islamic Republic of
19	Aliebne Abitaleb Hospital	Zahedan	Iran, Islamic Republic of