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
Phase: PHASE3
Conditions: HER2-positive Breast Cancer
Sponsor: Cinnagen

Clinical Trial Protocol
CinnaGen Co.
Protocol of Pertuzumab study (produced by CinnaGen Co.) compared with
Perjeta® (Pertuzumab, the reference drug, produced by Genentech)
Title
A Phase III, randomized, two armed, parallel, triple-blind, active controlled, equivalency
clinical trial to determine the therapeutic efficacy and safety between Pertuzumab®
(Manufactured by CinnaGen Co.) compared with active control group treated by Perjeta®
(Pertuzumab, the reference drug, Manufactured by Genentech) in neoadjuvant treatment of
HER 2 positive Breast Cancer patients
NCT Number: NCT04957212
Date: 18 January 2020
Page 0 of 78
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Clinical Trial Protocol
CinnaGen Co.
Confidentiality
The information in the following document is the property of CinnaGen Research and Production Company. The
content of this document should not be disclosed to anyone except to investigators, responsible persons, regulatory
officers and ethics committee staff without written permission from CinnaGen Co., if needed to obtain informed
consent from those persons to whom the products may be administered.
Page 1 of 78
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Clinical Trial Protocol
CinnaGen Co.
Table of Contents
Title.........................................................................................................................................................0
Abbreviations..........................................................................................................................................7
Administrative Information ....................................................................................................................9
Roles and Responsibilities:...................................................................................................................10
Sponsor .................................................................................................................................................10
Sponsor Representatives for Monitoring of the Study..........................................................................11
External Organization for Monitoring of the Study..............................................................................12
Principal Investigator............................................................................................................................13
Co-investigators....................................................................................................................................14
Statistical Consultants...........................................................................................................................15
Steering Committee and Scientific Advice...........................................................................................16
Trial Centers and Co-Investigators .......................................................................................................17
Introduction...........................................................................................................................................25
Background and Rationals for the Study ..............................................................................................25
Rationale for the Study .........................................................................................................................30
Objectives .............................................................................................................................................31
Primary Objectives................................................................................................................................31
Secondary Objetcives............................................................................................................................31
Study Design.........................................................................................................................................32
Procedures.............................................................................................................................................32
Study Sites ............................................................................................................................................32
Study Population Criteria......................................................................................................................33
Inclusion Critera: ..................................................................................................................................33
Exclusion Criteria: ................................................................................................................................33
Interventions .........................................................................................................................................35
Endpoints ..............................................................................................................................................39
Primary Endpoints ................................................................................................................................39
Secondary Endpoints ............................................................................................................................39
Safety Endpoints...................................................................................................................................40
End of Study Policy ..............................................................................................................................41
Timeline of the Study............................................................................................................................42
Description of Study Visits...................................................................................................................43
Visit 0: Screening, eligibility criteria evaluation (Day -1 to -14) .........................................................43
Visit 1 (Day 0, patient allocation).........................................................................................................44
Visit 2 (week 3).....................................................................................................................................45
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Visit 3 (week 6).....................................................................................................................................45
Visit 4 (week 9).....................................................................................................................................46
Visit 5 (week 12)...................................................................................................................................46
Visit 6 (week 15)...................................................................................................................................47
Visit 7 (week 18)...................................................................................................................................47
Surgery visit (week 18-20)....................................................................................................................47
Sample Size...........................................................................................................................................48
Recruitment...........................................................................................................................................48
Randomization......................................................................................................................................48
Blinding ................................................................................................................................................48
Data Collection Methods ......................................................................................................................49
Data Management.................................................................................................................................49
Data Monitoring....................................................................................................................................49
Statistical Analysis................................................................................................................................50
Statistical Methods................................................................................................................................51
Missing Data.........................................................................................................................................51
Covariate Adjustment ...........................................................................................................................51
Patient Characteristics and Baseline Comparisons ...............................................................................51
Primary Endpoint Analysis...................................................................................................................52
Secondary Endpoint Analysis...............................................................................................................52
Safety Endpoint Analysis......................................................................................................................52
Immunogenicity Analysis.....................................................................................................................52
Monitoring ............................................................................................................................................54
Site Initiation Visit (SIV)......................................................................................................................54
Site Monitoring Visit ............................................................................................................................54
Study Close-Out....................................................................................................................................55
Adverse Events .....................................................................................................................................56
AEs Classification Based on Severity:..................................................................................................56
AE classification based on its relation with the treatment (Causality assessment):..............................57
AEs Recording......................................................................................................................................59
AE Reporting Responsibilities..............................................................................................................59
Principle Investigator Responsibilities..................................................................................................59
Sponsor Responsibilities.......................................................................................................................59
Follow-up..............................................................................................................................................60
Withdrawal of patients..........................................................................................................................61
Ethics and Dissemination......................................................................................................................62
Research Ethics Approval.....................................................................................................................62
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Consent .................................................................................................................................................62
Confidentiality ......................................................................................................................................63
Amendment...........................................................................................................................................63
Declaration of Interests.........................................................................................................................63
Funding Organization ...........................................................................................................................63
Access to Data.......................................................................................................................................64
Ancillary and Post-Trial Care ...............................................................................................................64
Dissemination Policy ............................................................................................................................64
Appendixes ...........................................................................................................................................65
Appendix 1: Informed Consent Form...................................................................................................66
Appendix 2: Classification of Breast Cancer........................................................................................71
Appendix 3: RECIST 1.1......................................................................................................................72
Appendix 4: Discontinution Algorithm of Trastuzumab and Pertuzumab based on heart function.....73
Appendix 5: Carboplatin Dosing ..........................................................................................................74
Appendix 6: Heart Evaluation Questionnaire.......................................................................................75
References.............................................................................................................................................76
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Confidential Information
Confidential information in this document is provided for you as sponsor, external inspector
and sponsor, in order to review by you, your colleagues and ethics committee (IRB/IEC) and
Food and Drug administration office. You by accepting this document will be committed to
not disclosing the information of this document to anyone without written permission from
CinnaGen Co. and main principal investigator, if needed to obtain informed consent from those
persons to whom the products may be administered. By signing the below part, investigator is
committed to adhere to all the conditions in protocol and also is committed to get approval
from CinnaGen Co. for each change in protocol before getting approval from ethics committee.
This study will be conducted in accordance with Good Clinical Practices (GCPs), the
Declaration of Helsinki, local, ethical, and legal requirements.
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Name of Principal Investigator: Dr. Behrooz Najafi
Affiliation: Hematology and Oncology Specialist, Guilan university of Medicaal Sciences
Signature:
Date:
External Party Monitoring: CRO Trial
Signature:
Date
Sponsor Representative: Dr. Araz Sabzvari
Signature:
Date
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Abbreviations
ANC
ADR
AE
ALT
ALP
AUC
AST
BUN
CRF
CISH
cCR
cPR
cPD
CRA
CRR
cSD
CTA
CBC
CRO
CIOMS
Cr
ECOG
ECG
ER
FISH
GFR
GCP
hCG
HER2
IHC
IRB/IEC
ICH
IFDA
IRCT
LVEF
LVSD
MRI
MI
NYHA
NSAID
tpCR
bpCR
Plt
PI
Page 7 of 78
Absolute Neutrophil Count
Adverse Drug Reaction
Adverse Event
Alanine Aminotransferase
Alkaline Phosphatase
Area Under the Curve
Aspartate Aminotransferase
Blood Urea Nitrogen
Case Report Form
Chromogenic In Situ Hybridization
clinical Complete Response
clinical Partial Response
Clinical Progressive Disease
Clinical Research Associate
Clinical Response Rate
clinical Stable Disease
Clinical Trial Authorization
Complete Blood Count
Contract Research Organization
Council for International Organizations of Medical Sciences
Creatinine
Eastern Cooperative Oncology Group
Electrocardiogram
Estrogen Receptor
Fluorescence In Situ Hybridization
Glomerular Filtration Rate
Good Clinical Practices
human Chorionic Gonadotropin
Human Epidermal growth factor Receptor 2
Immunohistochemistry
Institutional Review Board/ Independent Ethics Committee
International Conference on Harmonization
Iranian Food & Drug Administration
Iranian Registry of Clinical Trial
Left Ventricular Ejection Fraction
Left Ventricular Systolic Dysfunction
Magnetic Resonance Imaging
Myocardial Infarction
New York Heart Association
Nonsteroidal Anti-Inflammatory Drug
Total Pathological Complete Response
Breast Pathological Complete Response
Platelet
Principal Investigator
Confidential

Clinical Trial Protocol
CinnaGen Co.
PR
SAE
SAE/R
SOP
SUSARs
ULN
Page 8 of 78
Progesterone Receptor
Serious Adverse Event
Serious Adverse Event/Reaction
Standard Operating Procedure
Suspected Unexpected Serious Adverse Reactions
Upper Limit of Normal
Confidential

Clinical Trial Protocol
CinnaGen Co.
Administrative Information
Title
A Phase III, randomized, two armed, parallel, triple-blind, active controlled, equivalency
clinical trial to determine the therapeutic efficacy and safety between Pertuzumab®
(Manufactured by CinnaGen Co.) compared with active control group treated by Perjeta®
(Pertuzumab, the reference drug, Manufactured by Genentech) in neoadjuvant treatment of
HER 2 positive Breast Cancer patients
Study Registeration:
This protocol is registered according to the program in Iran Registration Clinical Trial (IRCT).
IRCT registration number: IRCT20150303021315N11
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Roles and Responsibilities:
Sponsor
Name: Dr. Araz Sabzvari, representative from CinnaGen Co.
Roles:

Preparing final draft of study protocol

Providing electronic CRF

Obtaining necessary licenses from foreign organizations for conducting the trial

Providing standard operating procedure (SOP) for principal investigators

Providing quality controlled medications in order to use during the study and transferring
the medications to the centers of the study

Providing financial aids for all anticipated activities in protocol by having agreement with
principal investigator

Providing any insurance or indemnity to cover the liability of the investigator and sponsor

Providing protocol training and other necessary trainings for all the trial personnel

Recruiting staff for monitoring the trial

Responsibility of all trial costs for patients

Monitoring the trial sites in order to check the progress of trial and reporting of protocol
deviation

Not disclosing protocol information and all the data without written permission of main
principal investigator

Providing financial aids for all anticipated activities in protocol by having agreement with
principal investigator
Address:
Central Office: 3rd Sq., Simindasht Industrial Area, Karaj, Alborz, I.R.IRAN. Zip Code:
3165933155
Email: cinnagen@cinnagen.com
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Sponsor Representatives for Monitoring of the Study
Name: Somayeh Amini, Pharm D
Medical Manager
Address: Orchid Pharmed Company, No 2, First of Derakhti St, Dadman Blvd, Shahrak Gharb
District, Tehran.
Name: Nasim Anjidani, Pharm D
Clinical trial Manager
Address: No 74. 5th Floor, Hafezi St, Farahzadi Blvd, Shahrak Gharb District, Tehran.
Name: Mr. Siavash Bakhshian
Clinical Trial Supervisor
Address: No 74. 5th Floor, Hafezi St, Farahzadi Blvd, Shahrak Gharb District, Tehran.
Name: Mrs. Samaneh Salehi
Clinical Trial Coordinator
Address: No 74. 5th Floor, Hafezi St, Farahzadi Blvd, Shahrak Gharb District, Tehran.
Roles:

Visiting study sites to review the process of the protocol and ensure that the study is
conducted in accordance with the protocol and GCP principles (at least one or two of these
persons will attend each visit).

Check the site's facilities for the performance and continuation of the clinical trials and take
the necessary measures to provide them (to ensure that enough drugs are available to
continue the study, to ensure that enough CRF and consent forms are provided and other
requirements for the performance of the study).

Persistent training of site personnel for protocol performance.

Checking eCRFs and matching them with source data and filling out the query for
noncompliance and reminding them to correct them.

Provide reports of non-compliances and facilities required by the site and submit it to the
company's managers.
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External Organization for Monitoring of the Study
Name:Trial CRO
CRO representative: Dr. Hamed Hosseini, Tehran University of Medical Sciences
Contact address: Tehran University of Medical Sciences, Institute of Research and Research
Centers, Keshavarz Blvd., North Kargar St., Tehran
Name: Selective represenatative of CRO Trial
Contact address: Tehran University of Medical Sciences, Institute of Research and Research
Centers, Keshavarz Blvd., North Kargar St., Tehran, Iran.
Roles:

Conducting a 70% monitoring in all of the sites participating in the study according to GCP
Guidelines

Supervision over the study and Data Management

Performing Statistical analysis and preparing the project report at the end of trial with
coordination and supervision of main principal investigator

Cooperation with the sponsor to perform monthly monitoring

Cooperation with the sponsor for answering the methodology queries

Regular visiting to all study sites
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Principal Investigator
Name: Dr. Behrooz Najafi, Hematology and Oncology Specialist, Faculty member of Guilan
University of Medical Sciences
Roles:

Conducting the study according to the agreed protocol by IFDA and ethics committee

Setting up a team for this purpose

Organizing training session for their recruited team members wherever necessary

Confirmation and supervision of suitable place for patient admission

Confirmation and supervision of suitable place for drug storage in the trial

Cooperation with monitors during the conduct of the study

None disclosing protocol information and all the data without written permission of
CinnaGen Co. (if needed to obtain informed consent from those persons to whom the
products may be administered.)
Address:
Razi hospital: Razi Educational and Treatment Center, Sardar Jangal St, Rasht, Guilan
Golsar hospital: No 142 St, Somayeh Blvd, Rasht, Golsar
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Co-investigators
Roles:

Conducting the study according to approved protocol by principal investigator, IFDA
and ethics committee

Setting up a team for conducting the trial in trial site

Organizing training sessions for their team members whenever necessary

Provision suitable venues for patients’ admission

Provision of suitable storage for IMP in the trial

Cooperation with Monitors during the conduct of the study

Recording all of the possible protocol deviation

All medical documents related to the trial should be kept in investigator site till the
end of trial and 5 years after finishing the study

None disclosing protocol information and all the data without written permission of
CinnaGen Co. (if needed to obtain informed consent from those persons to whom the
products may be administered.)
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Statistical Consultants
Name: Ramin Shahpari
Address: Orchid Pharmed Company, No 2, Derakhti St, Dadman Blvd, Shahrak Gharb
District, Tehran
Name: Dr. Ali Akhlaghi
Adress: No. 1547, Tehran University of Medical Sciences, North Kargar St, Tehran
Roles:

Supervision on data entry in database

Analysis of the results
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Steering Committee and Scientific Advice
Roles:

Coordination between investigators

Supervision and assessing reports provided by sponsor and CRO

Approving the protocol and protocol amendments and provided reports to IFDA and
committees on behalf of other investigators

Make the right decision in order to deal with the situations which affects balance of risk-
benefit for participants in the study either individual or general. Regarding safety profile,
this decision includes determining the causality between drug and adverse events

Taking the right decision for continuing the study and excluding the participant who is not
eligible for study anymore

Make the right decision for decoding

Holding periodic meeting (if necessary).
Members:

Dr. Behrooz Najafi

Dr. Safa Najjar Najafi

Dr. Hamed Hosseini

Representative of Iranian Food and Drug Administration
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Trial Centers and Co-Investigators

Mehrad Hospital
Address: Miremad St, Motahari Ave, Tehran
Tel: 021-88747401
Co-investigator:
Dr. Jahangir Rafat- Faculty member of Tehran University of Medical Sciences

Jahad Daneshgahi center
Address: No 45, West Nazar St., Abourayhan St., Enghelab Ave, Tehran

Dr. Safa Najar Najafi clinic
Address: No 17, Pardis St., Mollasadra St., Tehran
Tel: 021- 66404050
Co-investigator for these two sites:
Dr. Safa Najar Najafi, Faculty member of Tehran Univeristy of Medical Sciences

Bou Ali Hospital
Address: First of Damavand St., Emam Hossein Sq., Tehran
Tel: 021- 33348035
Co-investigators:
Dr. Arash Jenabian- Faculty member of Azad University of Tehran
Dr. Abdolali Shahrasbi- Faculty member of Azad University of Tehran

Sina Hospital
Address: Hasan Abad Sq, Emam Khomeini St, Tehran
Tel: 021- 66348500
Co-investigator:
Dr. Mohsen Esfandbod- Faculty member of Tehran University of Medical Sciences

Masoud Clinic
Address: No 144, 19th St, Above Ale Ahmad highway, North Kargar Ave, Tehran
Tel: 021- 88747401
Co-investigator:
Dr. Masoud Iravani- Faculty member of Tehran University of Medical Science

Imam Khomeini Hospital
Address: Hematology and oncology center, Valiasr hospital, Imam Khomeini Therapeutic
Complex, Keshavarz blvd., Tehran
Co-investigators:
Dr. Reza Safaeinodehi- Faculty member of Tehran University of Medical Sciences
Dr. Farhad Shahi- Faculty member of Tehran University of Medical Sciences
Dr. Mohsen Esfandbod- Faculty member of Tehran University of Medical Sciences
Dr. Mirzania- Faculty member of Tehran University of Medical Sciences
Dr. Senobar Sedighi- Faculty member of Tehran University of Medical Sciences
Dr. Amir Hossein Emami- Faculty member of Tehran University of Medical Sciences
Dr. Ramezan Ali Sharifian- Faculty member of Tehran University of Medical Sciences
Dr. Farahnaz Vafaie zadeh- Faculty member of Tehran University of Medical Sciences
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
Masih Daneshvari Hospital
Address: Darabad St, Shahid Bahonar (Niavaran) Ave, Tehran
Tel: 021- 27123000
Co-investigator:
Dr. Adnan Khosravi- Faculty member of Shahid Beheshti University of Medical Sciences

Taleghani Hospital
Address: Department of Hematology and Oncology, 4th Floor, Taleghani Hospital, Shahid
Beheshti University of Medical Sciences
Tel: 021- 22937031
Co-investigator:
Dr. Hamid Attarian- Faculty member of Shahid Beheshti University of Medical Sciences
Dr. Mojtaba Ghadiani- Faculty member of Shahid Beheshti University of Medical Sciences
Dr. Sina Salari- Faculty member of Shahid Beheshti University of Medical Sciences
Dr. Hamid Rezvani- Faculty member of Shahid Beheshti University of Medical Sciences

Firouzgar Hospital
Address: Behafarin St, Karimkhan Zand Ave, Valiasr Sq, Tehran
Tel: 021- 88937902
Co-investigators:
Dr. Mohsen Razavi- Faculty member of Iran University of Medical Sciences
Dr. Saeed Salimi- Faculty member of Iran University of Medical Sciences

Rasool Akram Hospital
Address: Niayesh St., Satarkhan St., Rasool Akram Hospital, Tehran
Tel: 021- 66515000
Co-investigator:
Dr. Nafiseh Ansarinejad- Faculty member of Iran University of Medical Sciences

Imam Reza Hospital
Address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi
Tel: 051- 85430311
Co-investigator:
Dr. Abolghasem Allahyari- Faculty member of Mashad Medical University

Dr. Mohammadreza Mortazavi Zadeh Clinic
Address: No 25, Shahid haj Mohammadi Alley, Yazd
Tel: 0351- 37250044
Co-investigator:
Dr. Mohammadreza Mortazavi Zadeh- Faculty member of Yazd Medical University

Dr. Mehrdad Payandeh Clinic
Address: No 101, Fakhr Razi Alley, Shahrdari square, Modares St., Kermanshah
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Tel: 0833-7282400
Co-investigator:
Dr. Mehrdad Payandeh- Faculty member of Kermanshah University of Medical Sciences

Namazi Hospital of Shiraz
Address: Namazi Sq, Zand St, Namazi Hospital, Shiraz, Fars
Tel: 06136474332
Co-investigator:
Dr. Mani Ramzi- Faculty member of Shiraz University of Medical Sciences
Dr. Alireza Rezvani- Faculty member of Shiraz University of Medical Sciences
Dr. Mehdi Dehghani- Faculty member of Shiraz University of Medical Sciences

Shahid Faghihi of Hospital
Address: Karim Khan Zand St., Shiraz, Iran.
Tel: 06132304905
Co-investigator:
Dr. Shirin Haghighatju, Shiraz University of Medical Sciences.

Shahid Bahonar Hospital
Address: West Gharani St, Kerman
Tel: 03432235011
Co-investigator:
Dr. Behjat Kalantari, Faculty member of Kerman University of Medical Sciences
Dr. Vahid Moazed, Faculty member of Kerman University of Medical Sciences

Shafa Hospital of Ahwaz
Address: Golestan St., Ahwaz, Khoozestan, Iran
Tel: 06113367543
Co-investigator:
Dr. Mehran Hosseinzadeh, Faculty member of Ahwaz University of Medical Sciences
Dr. Ahmad Ahmad Zadeh Deilami, Faculty member of Ahwaz University of Medical Sciences

Razi Hospital of Rasht
Address: Sardar Jangal St, Rasht, Gilan
Tel: 01333541001
Co-investigator:
Dr. Behrouz Najafi- Faculty member of Rasht University of Medical Sciences
Dr. Sirous Gharib- Faculty member of Rasht University of Medical Sciences
Dr. Mehdi Mirblouk- Faculty member of Rasht University of Medical Sciences
Dr. Hossein Mirpour- Faculty member of Rasht University of Medical Sciences

Shams Hospital of Tabriz
Address: Between Abresan and Abbasi 4-way road, Tabriz
Tel: 04136583030
Co-investigator:
Dr. Babak Nejati- Faculty member of Tabriz University of Medical Sciences
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Dr. Ali Esfahani- Faculty member of Tabriz University of Medical Sciences
Dr. Alireza Nikanfar- Faculty member of Tabriz University of Medical Sciences
Dr. Seyed Hadi Chavoushi- Faculty member of Tabriz University of Medical Sciences

Seyedolshohada Hospital of Isfahan
Address: Saba Building, First of Mohammadabad St, Amadgah Ave, Isfahan

Sheikh Mofid Clinic of Isfahn
Address: Second intersection, Sheikh Mofid St, Feyz Ave, Isfahan
Tel: 0312240219
Co-investigator:
Dr. Fariborz Makarian- Faculty member of Isfahan University of Medical Sciences
Dr. Valiollah Mehrzad- Faculty member of Isfahan University of Medical Sciences
Dr. Alireza Sadeghi- Faculty member of Isfahan University of Medical Sciences
Dr. Seyed Amir Abbas Nekouie- Faculty member of Isfahan University of Medical Sciences

Sajad Hospital of Tehran
Address: next to Chehelsotoun St, Dr. Fatemi Sq, Tehran
Tel: 021- 88957170
Co-investigator:
Dr. Safa Najar Najafi, Faculty member of Tehran Jahad Daneshgahi of Tehran

Jam Hospital of Tehran
Address: Fajr St, Motahari Ave, Tehran
Tel: 021- 88820091
Co-investigator:
Dr. Arash Jenabian- Faculty member of Azad University of Tehran

Tehran Hospital
Address: Karimkhan Zand St, Haft-e-Tir Sq, Tehran
Tel: 021- 88821021
Co-investigator:
Dr. Abdolali Shahrasbi- Faculty member of Azad University of Tehran

Iranmehr Hospital of Tehran
Address: Before gholhak 2 way roads, Shariati St
Tel: 021- 22009071
Co-investigator:
Dr. Adnan Khosravi- Faculty member of Shahid Beheshti University of Medical Sciences

Dr. Behrouz Najafi Clinic
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Address: Next to Golsar Pharmay, Golsar Intersection, Rasht
Tel: 013- 33115049
Co-investigator:
Dr. Behrouz Najafi- Faculty member of Guilan University of Medical Sciences

Besat Clinic
Address: Enghelab St, Rasht
Tel: 01333261451
Co-investigator:
Dr. Hossein Mirpour- Faculty member of Guilan University of Medical Sciences
Dr. Siroos Gharib- Faculty member of Guilan University of Medical Sciences

Dr. Mehdi Mirblouk Clinic
Address: 8-Floor-Bousar Physican Building-Golsar intersection, Rasht
Tel: 013-32113588
Co-investigator:
Dr. Mehdi Mirblouk- Faculty member of Guilan Uinversity of Medical Sciences

Baghiatallah Hospital
Address: Mollasadra St, VAnak Square, Tehran
Tel: 021- 88050435
Co-investigator:
Dr. Mojtaba Ghadiani- Faculty member of Shahid Beheshti University of Medical Sciences

Resalat Hospital of Tehran
Address: Abouzar Ghaffari St, Resalat Highway, Seyyedkhandan Bridge, Tehran
Tel: 021- 22869647
Co-investigator:
Dr. Amir Hossein Emami, Faculty member of Tehran University of Medical Sciences

Toos Hospital of Tehran
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Address: Motahari St, Valiasr square, Tehran
Tel: 021- 88714891
Co-investigator:
Dr. Mohsen Razavi- Faculty member of Iran University of Medical Sciences

Ghaem Hospital of Mashhad
Address: Ahmad Abad St, Dr. Shariati square, Mashhad
Tel: 051- 38400000
Co-investigator:
Dr. Alireza Bari- Faculty member of Mashad University of Medical Sciences

Sanabd Clinic of Mashahd
Address: Between sanabad 43 and 45, Sanabad, Mashad
Tel: 051- 38430606
Co-investigator:
Dr. Hossein Rahimi, Faculty member of Mashad University of Medical Sciences

Dr. Allahyari Clinic
Address: No. 173, Next to Asia insurance, Chamran St, Mashad
Tel: 051- 38583050
Co-investigator:
Dr. Abolghasem Allahyari- Faculty member of Mashad University of Medical Sciences

Amir Hospital of Shiraz
Address: Farhang Shahr, Amir Hospital of Shiraz, Shiraz
Tel: 071- 36323731
Co-investigator:
Dr. Alireza Rezvani, Faculty member of Shiraz University of Medical Sciences

Dr. Behjat Kalantari Clinic
Address: Park Clinic building, Park Neshat, Kerman
Tel: 034- 32265003
Co-investigator:
Dr. Behjat Kalantari- Faculty member of Kerman University of Medical Sciences
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
Javadolaemeh Clinic
Address: No 25, North Abouzar St, Kerman
Tel: 034- 3210025
Co-investigator:
Dr. Vahid Moazed- Faculty member of Kerman University of Medical Sciences

Dr. Majid Baghaee Hospital of Ahwaz
Address: End of Golestan Road, Ahvaz
Tel: 061- 33750000
Co-investigator:
Dr. Mehran Hosseinzadeh- Faculty member of Ahwaz University of Medical Sciences

Arvand Hospital of Ahwaz
Address: Ghanavati St, Shariati Ave, Ahvaz
Tel: 06132933347
Co-investigator:
Dr. Ali Ehsanpour- Faculty member of Ahwaz University of Medical Sciences

Saba Clinic Isfahan
Address: Saba Building, First of Mohammadabad alley, Amadgah Ave, Isfahan
Tel: 031- 32240219
Co-investigator:
Dr. Mohsen Khani- Faculty member of Esfahan University of Medical Sciences

Milad Hospital of Isfahan
Address: Bakhshi St, Janbazan Blvd, Simin 3 way road, Isfahan
Tel: 031- 37774001
Co-investigator:
Dr. Fariborz Makarian- Faculty member of Isfahan University of Medical Sciences
Dr. Valiollah Mehrzad- Faculty member of Isfahan University of Medical Sciences

Naft Hospital of Tehran
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Address: Sakhaee St, Hafez Ave, Tehran
Tel: 021- 54175000

Ebne Sina hospital
Address: Kashani Blvd, Second Sadeghieh Sq, Tehran
Tel: 021- 47909000
Co-investigator:
Dr. Behrouz Gharib- Faculty member of Qom University of Medical Sciences
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Introduction
Background and Rationals for the Study
Breast cancer
Breast cancer is a disease in which certain cells in the breast become abnormal and divide
uncontrollably to form a tumor. Breast cancer is the second most commonly diagnosed cancer
in women. About one in eight women in the United States will develop invasive breast cancer
in her lifetime. Researchers estimate that more than 230,000 new cases of invasive breast
cancer will be diagnosed in U.S. women in 2015 (1).
Some genes and the proteins can determine how a breast cancer behaves and how it might
respond to a specific treatment. Human epidermal growth factor receptor 2 (HER2) is one of
the such genes that can play a role in the development of breast cancer (2). The amplification
of the HER2 gene leads to overexpression of the receptor, which is linked to the development
of many types of human cancers including breast, ovarian and those of the gastrointestinal tract
(3).
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25% to 30% of breast
cancers, suggesting a role for overexpression in tumorigenesis. This overexpression is most
commonly the result of gene amplification. Several lines of evidence support the role of HER2
overexpression in the pathogenesis and poor clinical outcome of human tumors. A number of
these studies have shown that breast cancers that overexpress HER2 have a more aggressive
course and higher relapse and mortality rates (4).
Knowledge of HER2 status is a prerequisite when considering a patient's eligibility for
Herceptin (trastuzumab) therapy. Accurate assessment of HER2 status is essential to ensure
that all patients who may benefit from Herceptin are correctly identified. There are several
assays available to determine HER2 status: the most common in routine clinical practice are
immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (5).
Treatment
According to the studies, the most common and prevalent type of breast cancer would be breast
cancers with positive esterogen/progestrone receptors. Endocrine treatment for breast cancers
with positive non metastatic hormonal receptor includes tamoxifen and aromatase inhibitors
(anastrazole, letrozole and exemestane). (6, 7)
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Two target therapy method for breast cancer treatment include HER2 pathway and
angiogenesis pathway. Studies shows that although prescription of Bevacizumab with
angiogenesis inhibitor mechanism pathway can increase clinical complete response in patients
with breast cancer, but still hasn’t been approved the usefulness of the drug in increasing
survival (8-10).
Several murine monoclonal antibodies against the extracellular domain of the HER2 protein
were found to inhibit the proliferation of human cancer cells that overexpressed HER2, both in
vitro and in vivo (11). In 1980, one monoclonal antibody was made against HER2 and named
Trastuzumab. In 1998, trastuzumab (Herceptin®; Genentech Inc. South San Francisco, CA) as
a humanized monoclonal antibody directed against the extracellular domain of HER2 was
approved as adjuvant treatment for breast cancer and treatment of metastatic breast cancer (12).
In a study which has been done by Buzdar et al, the efficacy level of Trastuzumab was assessed
along with chemotherapy regimen. Clinical complete response in Trastuzumab arm was 65.2%
comparing to 26.3% in non-Trastuzumab chemotherapy regimen arm. The 3 years’ survival
rate was 100% in Trastuzumab arm comparing to 85.3% in non-Trastuzumab chemotherapy
regimen arm (4).
In a meta-analysis study, which was done in 2012 and included 12000 patients, efficacy of
Trastuzumab chemotherapy regimen was assessed by non-Trastuzumab chemotherapy regimen
and confirmed prescription of Trastuzumab increases overall survival in 12 months. Although
prescription of Trastuzumab less than 6 months, showed level of increment of overall survival
(13).
Pertuzumab
Recently, new treatments with HER2 targeting have been developed and Pertuzumab as a
monoclonal humanized antibody which connect to different epitope of HER2 external receptor
(subgroup II) is one of them (14). Pertuzumab prevents HER2 dimerization with other HER
receptors, especially HER3 (15).
Like Trastuzumab, Pertuzumab also induce antibody-dependent cellular cytotoxicity (ADCC)
pathway. Since Pertuzumab and Trastuzumab attach to different epitopes of HER2 and have
complementary effect, concurrent prescription of these two drugs causes more inhibition in
HER2 signaling and anti tumor activity comparing to single use of them (16, 17). Efficacy of
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Trastuzumab-Pertuzumab regimen in patients with HER2+ breast cancer patients has been
shown in phase II trials (18-20).
In 2012, phase III clinical trial of Trastuzumab and Pertuzumab (CLEOPATRA) has been
assessed safety and efficacy of Docetaxel and Trastuzumab plus Pertuzumab comparing to
placebo as fist line treatment in HER2+ metastatic breast cancer patients. In this study, 808
patients in 204 centers were treated and the median of Progressive Free Survival (PFS) in
Pertuzumab arm showed 6.1 months’ increment compared to placebo arm. Furthermore, in this
study, the ratio of treatment reponse in Pertuzumab arm showed 10.8% improvement compared
to the placebo arm and reached to 80.2% (21).
Study on assessing safety and efficacy of neoadjuvant Pertuzumab and Trastuzumab in women
with locally advanced breast cancer or HER2+ inflammation (NeoSphere study) caused
accelerated approval in using this medication in neoadjuvant treatment. This phase II study
conducted with 4 arms to assess effect of Docetaxel, Trastuzumab and Pertuzumab in different
regimen. (19).
In 2013, another study with the aim of assessing the heart complications in neoadjuvant therapy
combination of Trastuzumab and Pertuzumab for HER2+ breast cancer patients were done and
checked the chemotherapy regimen with or without Antracycline. In this study, 225 patients
were assessed and according to the results, heart complications did not show statistical
significance difference between 3 treatment arm and the most treatment response (66.2%) was
related to Docetaxel, Trastuzumab and Pertuzumab and carboplatin (22).
Pharmacological propertis
Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the
extracellular dimerization domain (subdomain II) of the human epidermal growth factor
receptor 2 protein (HER2), and thereby, blocks ligand-dependent heterodimerisation of HER2
with other HER family members, including EGFR, HER3 and HER4. As a result, pertuzumab
inhibits ligand-initiated intracellular signalling through two major signal pathways, mitogen-
activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these
signalling pathways can result in cell growth arrest and apoptosis, respectively. In addition,
pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).
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While pertuzumab alone inhibited the proliferation of human tumour cells, the combination of
pertuzumab and trastuzumab significantly augmented antitumour activity in HER2-
overexpressing xenograft models (21).
Adverse events
>10%:
Central nervous system: Fatigue (26% to 36%), headache (11% to 21%), decreased left
ventricular ejection fraction (8% to 16%), insomnia (8% to 13%), dizziness (3% to 13%)
Dermatologic: Alopecia (52% to 65%), skin rash (11% to 34%), pruritus (4% to 14%), palmar-
plantar erythrodysesthesia (11%), xeroderma (9% to 11%)
Gastrointestinal: Diarrhea (46% to 67%), nausea (39% to 53%), vomiting (13% to 36%),
decreased appetite (11% to 29%), mucositis (20% to 28%), constipation (23%), stomatitis (17%
to 19%; grades 3/4: <1%), dysgeusia (13% to 18%)
Hematologic & oncologic: Neutropenia (47% to 53%; grades 3/4: 43% to 49%), anemia (3%
to 23%; grades 3/4: 2% to 4%), leukopenia (9% to 16%; grades 3/4: 5% to 12%), febrile
neutropenia (8% to 14%; grades 3/4: 9% to 13%)
Hypersensitivity: Hypersensitivity (1% to 11%)
Neuromuscular & skeletal: Asthenia (15% to 26%), myalgia (11% to 22%), arthralgia (10% to
12%)
Respiratory: Upper respiratory tract infection (4% to 17%), epistaxis (11%)
Miscellaneous: Fever (9% to 19%), infusion reactions (13%)
1% to 10%:
Cardiovascular: Left ventricular dysfunction (3% to 4%), peripheral edema (3% to 4%)
Central nervous system: Peripheral sensory neuropathy (8%; grades 3/4: <1%), peripheral
neuropathy (1%)
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Dermatologic: Nail disease (7%), paronychia (1% to 7%)
Gastrointestinal: Dyspepsia (8%)
Hematologic & oncologic: Thrombocytopenia (1%)
Hepatic: Increased serum alanine aminotransferase (3%)
Ophthalmic: Increased lacrimation (4% to 5%)
Respiratory: Dyspnea (8%), nasopharyngitis (7%), oropharyngeal pain (7%), cough (5%)
<1%, postmarketing, and/or case reports: Left systolic heart failure, pleural effusion, sepsis,
tumor lysis syndrome
Contraindications:
Any known sensitivity to Pertuzumab or each of compounds (23)
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Rationale for the Study
Different studies showed enhanced anti tumor activity of Pertuzumab along with trastuzumab
in breast cancer patients. Due to high price of this antibody and due to not availability of this
drug in Iran’s drug list, the CinnaGen Co.decided to produce this drug. This study has been
designed as a neoadjuvant treatment in patients with HER2+ breast cancer and patients
randomized in 2 gropus receiving Pertuzumab (manufactured by CinnaGen Co.) and Perjeta
(Refrence drug, manufactured by Genentech). Patients in this study will receive Docetaxel,
Trastuzumab and Pertuzumab and carboplatin regimen every 3 weeks for 6 periods in the form
of IV.
The most important objectives of this study would be efficacy and safety comparison of
Pertuzumab (manufactured by CinnaGen Co.) and Perjeta manufactured by Genentech in
neoadjuvant setting for HER2+ breast cancer patients.
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Objectives
Pertuzumab (manufactured by CinnaGen Co.) and Perjeta (manufactured by Genentech) are
equivalence in neoadjuvant setting treatment of patients with HER2+ breast cancer.
Primary Objectives
Primary objective of this study is to evaluate equivalence of Pertuzumab (Manufactured by
CinnaGen Co.) compared to the Perjeta® (Reference drug, Genentech), when added to
Carboplatin+Docetaxel+Trastuzumab regimen, based on the pathological complete response
(pCR) in neoadjuvant treatment setting in HER2+ breast cancer patients
Secondary Objetcives
Clinical Response Rate
Total Pathological complete response (tpCR) in breast and axillary lymph nodes
Breast conserving surgery rate
Safety
Immunogenicity
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Study Design
Procedures
Phase III clinical trial, randomized, 2 arms, triple blind, parallel, with active control in order
to assess equivalency with 1: 1 ratio
Study Sites
This study will be done from Jan 2018 till Oct 2019 on patients in below centers. All the sites
will use the same protocol and procedures. The methods are standardized as much as possible
in order to reduce differences and all the staff will be trained accordingly. The name and city
of study cenetrs is as below:
1- Razi Hospital-Guilan
2- Golsar Hospital-Guilan
3- Mehrad Hospital-Tehran
4- Imam Khomeini Hospital-Tehran
5- Sina Hospital-Tehran
6- Firouzgar Hospital-Tehran
7- Masoud Clinic-Tehran
8- Dr. Safa Najar Najafi clinic-Tehran
9- Imam Reza Hospital-Mashad
10- Dr. Mehrdad Payandeh Clinic-Kermanshah
11- Dr. Mortazavizadeh Clininc-Yazd
12- Namazi Hospital-Shiraz
13- Shafa Hospital-Ahwaz
14- Shahid Bahonar Hospital-Kerman
15- Jahad Daneshgahi center-Tehran
16- Rasool Akram Hospital-Tehran
17- Taleghani Hospital-Tehran
18- Faghihi Hospital-Tehran
19- Shams Hospital-Tabriz
20- Seyedolshohada Hospital-Isfahan
21- Bou Ali Hospital-Tehran
22- Masih Daneshvari Hospital-Tehran
23- Sheikh Mofid clinic-Isfahan
24- Ghaem Hospital-Mashhad
25- Sanabd Clinic-Mashhad
26- Arvand Hospital-Ahwaz
27- Saba Clinic-Isfahan
28- Naft Hospital-Tehran
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Study Population Criteria
Inclusion Critera:

Female patients aged 18 - 70

Operable (T2-3, N0-1, M0), locally advanced (T2-3, N2 or N3, M0; T4a-c, any N, M0),
or inflammatory (T4d, any N, M0) breast cancer

Primary tumor diameter should be more than 2 centimeters

Positive HER2 status approved by immunohistochemistry (IHC 3+ or IHC 2+ verified
by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization
(CISH))

Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1

LVEF ≥55% at baseline assessed by echocardiography

Able and willing to sign an informed consent
Exclusion Criteria:

Metastatic (stage IV) or bilateral breast cancer

Previous systemic or local anticancer therapy (chemotherapy or radiotherapy) for any
type of cancer

Any other malignancy except for carcinoma in situ of the cervix, basal cell carcinoma,
or squamous cell carcinoma of the skin

Use of another research drug in the four weeks before the start of the study

Major surgery four weeks before the start of the study

Uncontrolled hypertension (systolic blood pressure more than 150 mmHg or/and
diastolic blood pressure more than 100 mmHg), unstable angina, Congestive heart
failure with any class based on the NYHA classification, serious arrhythmia which
needs treatment, or history of MI 6 months prior to enrollment
 Bone marrow malfunction:
ANC < 1500/µL
Plt < 100,000/µL
Hb < 9 g/dL
 Liver malfunction:
ALT/AST>1.5, ALP>2.5 ULN
Total serum Blirubin>1.25 ULN

Kidney malfunction:
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Serum Creatinine >1.5 ULN

Shortness of breath during rest or any other disease that requires continuous oxygen
therapy

Any severe uncontrolled systemic disease (cardiovascular, pulmonary, metabolic,
etc.)

Chronic treatment with corticosteroids with a daily dose of ≥ 10 mg oral prednisolone
or equivalent of other types (other than inhaled corticosteroid drugs)

Patients with HIV, HBV, and HCV infections

Hypersensitivity to any of the studied drugs or excipients

Pregnancy, lactating or fertile women who do not want to use contraceptive methods
(contraceptives should be taken in to consideration up to six months after the last dose
of the drug)

Unwillingness or inability to fulfill the requirements of the protocol, including any
kind of condition (physical, mental or social) that affects one's ability to fulfill the
requirements of the protocol
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Interventions
All of the participants in the study, will receive the below regimens. In order to increase patient’
compliance and safety, study drug wil be injected by a trained nurse.
In the test drug arm (group 1), Pertuzumab (manufactured by CinnaGen Co.) and in the control
arm Perjeta® (Reference drug) will be administered.
All of the patients will receive Trastuzumab, Pertuzumab, Carboplatin and Docetaxel as follow:
Duration of each cycle: 21 days
Number of cycles: 6 cycles
Drugs
Trastuzumab
Pertuzumab
Carboplatin
Docetaxel
Dose and route of administration
8 mg/kg IV loading dose (at cycle
1), followed by 6 mg/kg at
subsequent cycles
Change in dosage during the
treatment is not allowed.
Fixed dose of 840 mg IV infusion
in first cycle, followed by fixed IV
infusion of 420 mg in next cycles
Changing in dosage during the
treatment is not allowed.
AUC* = 6 mg/mL x min
IV infusion
75mg/m2, IV infusion,
Increasing dosage of Docetaxel is
not allowed.
Adminstration
Days
IV infusion in 250ml NS over
Day 1
90 minutes for first dose
IV infusion in 250 mL NS
over 30 min on all subsequent
doses if no adverse reactions.
DO NOT mix with D5W, and
DO NOT infuse as an IV
push or bolus.
Dilute into a 250 mL normal
Day 1
saline. Dose in first cycle in
over 60 min and in second till
6th cycle during 30- 60 min,
IV infusion
DO NOT mix with D5W, and
DO NOT infuse as an IV
push or bolus.
Dilute into a 250 mL 5%
Day 1
Dextrose and administered as
a 30-minute IV infusion.
Infusion of carboplatin
should start 30-60 min after
completion of Pertuzumb
administration.
Dilute into a 250 mL NS till
Day 1
the final concentration of 0.3-
0.74 mg/mL and then
administered as a 60-minute
IV infusion.
In case of variation more than 10% in weight, dose should be calculated for all drugs again.
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AUC* or area under curve with regards to renal activity and by using Clavert formula can be converted to required
dose in milligram.
According to Clavert formula, final dose (milligram) would be multiplication of target AUC in GFR+25. In case
of using creatinine, final limit of GFR in this calculation would be 125 ml/min.
Carboplatin Dose (mg) = Target AUC * (GFR + 25)
Pre treatment Consideration
Prevention of nausea
Recommened to be premedicated with a serotonin antagonist (8-16 mg Ondansetron with 1-2
mg Granisetron), Neurokinin inhibitor (125 mg Aperpitant) and Dexametasone (8mg) in the
day of chemotherapy.
Diarrhea
It is recommened to use Loperamide (4mg and then 2 mg every 4 hours up to 16 mg daily) till
12 hours after cessation of diarrhea.
Prevention of infusion related recations
Dexamethasone 8 mg PO bid for 3 days, starting one day prior to each Docetaxel
administration. Pre treatment usually is not used for Pertuzumab and carboplatin, however in
the case of flu-like side effects within 24 hours after Trastuzumab administration; it is
recommened to use Acetaminophen or NSAID.
Dose Adjust in Hepatic or Renal impairment
Docetaxel should not be administered to patients with bilirubin more than ULN or with
transaminase more than 1.5 times ULN and alkaline phosphatase more than 2.5 times ULN.
Each dose of Carboplatin should be caculated according to kidney activity and based on the
Calvert formula.
Cardiac issue
Cardiotoxicity has been observed by Trastuzumab and Pertuzumb, So LVEF should be
measured before the treatment.
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Prevention of Thrombocytopenia
It is necessary to administer amyloid growth factor 24-72 hours after each chemotherapy cycle.
Dose adjustment:
Myelotoxicity:
In the case of ANC>1000 cell and Platelet>100000, complete dose of chemotherapy regimen
drugs should be administered. In case, count of cell or platelet are less than specified amount,
chemotheraoy should be postponed for 1 week.
ANC<1000 and two times of one
week delay
More than 1 week delay due to
Dose adjustment of Docetaxel by
75% dose
Dose adjustment of Docetaxel by
thrombocytopenia
and
Platelet 75% dose
<50000
In case of Febrile Neutropenia (ANC<500, Fever>38.3 required treatment by IV antibiotic with or
without hospitalization), dose of chemotherapy drugs should be adjusted.
In case of febrile neutropenia
Antibiotic treatment according to NCCN
and ESMO guideline
Episode 1
Docetaxel dose reduced by 75% and
Carboplatin dose reduce to 5 AUC
Episode 2
Docetaxel dose reduced by 60% and
Carboplatin dose reduce to 4 AUC
Hepatic toxicity:
Docetaxel dose can be reduced to 60 mg/m2 in patients with significant change of liver factors
(increase of Transaminase>1.5 ULN and increase of Alkaline phosphatase>2.5 ULN) and it
cannot be level up to 75 mg/m2 in next cycles. In case of Transaminase increase to more than
3.5 ULN and increase of alkaline phosphatase to more than 6 ULN, it is not recommended to
use Docetaxel.
Docetaxel dose
100%
ALP
< 2.5 ULN
AST +/or ALT
< 1.5 ULN and
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75%
Not recommended
2.5-6 ULN
6-10 ULN
1.5-3.5 ULN and
> 3.5 ULN and
Cardiotoxicity:
In case of left ventricular ejection fraction (LVEF) reduced to less than 45% or decrease of
10% or more than from baseline amount to 45-49%, administration of Trastuzumab or
Pertuzumab should be stopped for at least one cycle until recovering to normal condition
(Appendix 4).
Infusion-related reactions:
In case of infusion realted reactions, the rate of infusion should be decreased or discontinued
in order to have supportive therapy. In case of severe adverse events or anaphylactic shock, the
administration of drug should be discontinued.
Dermatological, mucosal and neurotoxicity:
In case of severe or cumulative cutaneous reactions, grade 3 or 4 stomatitis or moderate
neurosensory signs and/or symptoms, Reduce dose to 60 mg/m2, if reactions persist at 60
mg/m2, therapy should be discontinued.
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Endpoints
Endpoints will be evaluated during 20 weeks after study start.
Primary Endpoints

Pathologic Complete Response (pCR):
pCR Defined as the absence of invasive neoplastic cells at microscopic examination of the
primary tumor at surgery (ypT0/is)
Secondary Endpoints

Clinical Response Rate (CRR) according to RECIST 1.1 (Appendix 3):
Sum of patients who had clinical complete response (cCR) or clinical partial response (cPR)
before surgery.
Clinical Complete Response (cCR): 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 (cPR): At least a 30% decrease in the sum of diameters of
target lesions, taking as reference the baseline sum diameters.
Clinical Progressive Disease (cPD): At least a 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 Stable Disease (cSD): Neither sufficient shrinkage to qualify for PR nor
sufficient increase to qualify for PD, taking as reference the smallest sum diameters
while on study.

Total Pathological complete response (tpCR) in breast and axillary lymph nodes:
Defined as the absence of invasive neoplastic cells at microscopic examination of the
primary tumor at surgery in breast and axillary lymph nodes, without considering in situ
involvement (ypT0/is ypN0)

Conserving surgery rate in patients who are mastectomoy candidate (T2-3)

Adverse Drug Reaction (Safety)
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Safety Endpoints
Adverse events (AEs) and Adverse drug reactions (ADRs) including:

Incidence of Left Ventricular Systolic Dysfunctionn (LVSD)

10% or more reduction of LVEF compared to the baseline limit to less than 50%

Other adverse drug reactions

Abnormal lab test

Vital sign assessment

Immunogenicity
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End of Study Policy
This decision is under authorization of DSMB committee and should be confirmed by IFDA
and ethical committee of Tehran Univeristy of Medical Sciences and Guilan Univeristy of
Medical Sciences.
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Timeline of the Study
Duration of study
Screening
Interventions
End of
study
Visits
Weeks
Eligibility evaluation
Informed consent form
Medical history
Physical examination and vital sign
ECG
Laboratory
Pregnancy (β-hCG)
Echocardiography
Metastasis
HER2  وER/PR
MRI*)Tumor assessment)
Concomitant drug record
Adverse events
Randomization
Drug intervention
Heart evaluation questionnaire **
Immunogenicity
Surgery and pathological sampling
Visit 0                 Visit 1
Day -1 to -14            Day 0
X
X
X
X
X
X
X
X
X
X
X
X
X
X                         X
X                         X
X
X
X
X
Visit 2            Visit 3
Week 3             Week
6
X
X
X
X
X
X
X                    X
X                    X
X                    X
X                    X
X
X
Visit 4         Visit 5      Visit 6       Visit 7
Week 9        Week      Week          Week
12
15
18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X                 X              X
X                 X              X
X
X
X
X
Surgery
Week 18-
20
X
*In case of patient early drop out due to any reason before completion of the treatment period, MRI should be done.
** Refer to Appendix 6
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Description of Study Visits
Visit 0: Screening, eligibility criteria evaluation (Day -1 to -14)
1. Eligibility criteria evaluations
2. Explaining protocol, preparing informed consent form (ICF), asking for reading and
understanding and then asking for signing of ICF
3. Medical history including underlying disease and recent surgery
4. Pysical examination, vital signs, height, weight
5. Electrocardiogram test
6. Laboratory test including: CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, P, Mg,
Cl, albumin, glucose, LDH ،INR ،PTT/aPTT, urine analysis, HBV, HCV, HIV tests.
7. ECOG evaluations
8. Pregnancy test (β-hCG)
9. Echocardiography for LVEF
10. Assessing of non-metastatic in suspicious patients by bone scan،CT scan of thorax,
abdomen, pelvic and if needed brain MRI.
11. Assessment of HER2 and ER/PR receptors
12. Assessment of basis tumor specifications. In this evaluation, size of tumor, grade of
tumour, inflammation, locally advanced, capability of surgery is determined by surgeon
to be conservative. MRI should be done in this visit under physician decision.
13. Record concomitant drugs and observed adverse events
14. In screeing visit, the first step is determining ER/PR, MRI, and type of breast cancer
43

Visit 1 (Day 0, patient allocation)
When the investigator is ensured about the eligibility, patients allocated to one of the below
groups:
Group 1: Pertuzumab (manufactured by CinnaGen Co.)
Drug: Pertuzumab vial (840 mg dose)(Initial dose), IV infusion every 3 weeks for 6 cycles.
Group 2: Perjeta® (Manufacutured by Genentech)
Drug: Pertuzumab vial (840 mg dose)(Initial dose), IV infusion every 3 weeks for 6 cycles
After randomization, each patient will receive a randomization code. Patient will receive the
treatment based on her group and will received these interventions:
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pysical examination, vital signs, height, weight
3. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
4. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
5. Heart evaluation questionnaire
6. Concomitant drugs, adverse events record
7. AE of previous visit will be checked and results will be recorded, if applicable.
8. Determination of lab visit time, one day prior to next chemotherapy cycle
9. Information about the next visit time
10. Record of information in CRF
44

Visit 2 (week 3)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pysical examination, vital signs, height, weight
3. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
4. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
5. Heart evaluation questionnaire
6. Concomitant drugs, adverse events record
7. AE of previous visit will be checked and results will be recorded, if applicable.
8. Determination of lab visit time, one day prior to next chemotherapy cycle
9. Information about the next visit time
10. Record of information in CRF
Visit 3 (week 6)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pregnancy test (β-hCG)
3. Pysical examination, vital signs, height, weight
4. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
5. Echocardiography for LVEF evaluation
6. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
7. Heart evaluation questionnaire
8. Concomitant drugs, adverse events record
9. AE of previous visit will be checked and results will be recorded, if applicable.
10. Determination of lab visit time,one day prior to next chemotherapy cycle
11. Information about the next visit time
12. Record of information in CRF
45

Visit 4 (week 9)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pysical examination, vital signs, height, weight
3. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
4. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
5. Heart evaluation questionnaire
6. Concomitant drugs, adverse events record
7. AE of previous visit will be checked and results will be recorded, if applicable.
8. Determination of lab visit time, one day prior to next chemotherapy cycle
9. Information about the next visit time
10. Record of information in CRF
Visit 5 (week 12)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pysical examination, vital signs, height, weight
3. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
4. Echocardiography for LVEF evaluation
5. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
6. Heart evaluation questionnaire
7. Concomitant drugs, adverse events record
8. AE of previous visit will be checked and results will be recorded, if applicable.
9. Determination of lab visit time, one day prior to next chemotherapy cycle
10. Information about the next visit time
11. Record of information in CRF
46

Visit 6 (week 15)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pregnancy test (β-hCG)
3. Pysical examination, vital signs, height, weight
4. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
5. Chemotherapy regimen drugs (Trastuzumab, Pertuzumab, Carboplatin, Docetaxel)
6. Heart evaluation questionnaire
7. Concomitant drugs, adverse events record
8. AE of previous visit will be checked and results will be recorded, if applicable.
9. Determination of lab visit time, one day prior to next chemotherapy cycle
10. Information about the next visit time
11. Record of information in CRF
Visit 7 (week 18)
1. Laboratory tests (CBC diff, BUN, Cr, ALT, AST, Bilirubin, Na, K, Ca, Mg, P, Cl,
albumin, glucose, LDH) before administration of chemotherapy regimen in order to
diagnose any hematologic changes and patient ability for receiving next cycle will be
evaluated. Moreover sampling for immunogenicity will be done.
2. Pysical examination, vital signs, height, weight
3. MRI by decision of investigator (in case of early withdrawal) can be done in this visit
4. Echocardiography for LVEF evaluation
5. Concomitant drugs, adverse events record
6. Follow up of AEs and record
7. Record of information in CRF
Surgery visit (week 18-20)
Surgery and pathological sampling should be done 2 weeks later than visit 7 (week 18-20)
47

Sample Size
Using an equivalence margin of 0.2, a sample size of 96 subjects in each one of both
Pertuzumab (CinnaGen Co.) and Perjeta® (Genentech Co.) groups achieves 80% power to
detect bioequivalence for the difference between groups. The actual difference is considered
zero. The PCR efficacy for Perjeta® group is 0.66 (22, 24, 25). Two-way independent T-test
with 5% significance level will be used to analyze the results. Considering 10% dropout, final
sample size is considered 107 in each group.
Recruitment
This study has two arms and 214 patients will be enrolled (107 patients in each arm)
1) Group 1: Patients who receive Pertuzumab (Manufactured by CinnaGen Co.) every 3
weeks with Trastuzumab, Carboplatin, Docetaxel
2) Group 2: Patients who receive Perjeta® (Manufactured by Genentech) every 3 weeks with
Trastuzumab, Carboplatin, Docetaxel
Randomization
Patients will be dynamically randomized to different groups during the study using
Minimization method (with a 90% random component). The two main variables on which the
balance is performed will be as follows:
1- ER/PR: ER/PR+, ER/PR-
2- Type of breast cancer: operable, locally advanced, inflammatory
At the beginning of the study, each patient will receive a unique code in order to be recognized
during the study. The assigned code consists of 4 letters (corresponding to the first two letters
of the first name and the first two letters of the surname), three digits (center code), the first
three letters of the generic drug name (which is PER-) and 3 digits (corresponding to
randomization code). For example: ABCD001PER-001.
Each Pertuzumab package which will be used for a patient's treatment during the study and
will be recognized by a unique 3-digit code similar to the randomization code (this number
includes two English letters and a number which will be unique for each subjetcs).
Blinding
48

Both Pertuzumab drugs in this study are not identifiable by patients and treatment group. Since
the administration route of this drug is IV infusion, patients’ blinding in medication groups
would be possible. Furthermore, persons who are doing the data analysis are not aware of
patients’ grouping.
Patients’ groups and type of their medications will not disclose to investigators and will be in
the stamped pocket and will be provided to investigator of each site. Persons who are doing
analysis are not aware of grouping.
Data Collection Methods
Data collection will be electronic-based and the data will be recorded in eCRF. Adequate
attention will be given to collect accurate and valid data. Investigators are responsible for
completing the eCRF in study centers. The sites will be equipped with personal computers or
tablets. Only the investigator or the person assigned by the investigator will have access to the
database for data entry.
Data Management
The principal investigator, investigators, and other personnel assigned by the investigators will
be responsible for eCRF data entry. Each investigator will be given a specific username and
password. The PI and investigators must not disclose the data obtained from the study. All of
the Investigators are responsible for keeping the study data safe. Sending and receiving the
patients' information must be done considering safety and security procedures. Trial CRO is
responsible for planning a monitoring which will be conducted by qualified personnel in order
to check the eCRF for discrepancies with the patients’ source documents. The monitors or
auditors are not able to change eCRF data. However, they can make queries for blatant mistakes
in data entry and the investigator is responsible for rectifying such mistakes or answering to
the queries. The history of modification in eCRF data will be recorded meticulously and can
be observed by the monitors or auditors.
Data Monitoring
The objectives of the data quality control are:

To ensure the existence of the patients and the respect of ethics (including signed
patient informed consent)
49


To detect the issues (including systematic errors) as early as possible for appropriate
measures to be taken

To ensure the validity of the data
To meet these objectives, quality control should be applied via the following activities:
The schedule of site quality control evaluation, performed by the monitoring team must be
explained to the investigators at the time of site initiation visit and agreed upon. QC will be
performed in study sites by the monitoring team who are in charge of planning for action plans
to improve study site quality.
QC of the study site will be carried out during two main monitoring visits (30% and 70% of
study completion) and several periodic monitoring visits throughout the study.
In every monitoring visit the following items will be evaluated according to a pre-prepared
check list and the quality control report will be completed.

eCRF forms will be assessed in terms of completeness, the quality of data entry and
accordance with source data.

Informed consent forms signed by the patient and the physician for all the patients
who have gone through the screening visit

Evaluation of key variables regarding the wrong and missing data
Statistical Analysis
Statistical analysis of data will be conducted by the study statistical consultant. Additionally,
the available data will be evaluated separately by the Trial CRO representative and the results
will be compared. The final analysis will be assessed by the Steering Committee prior to
submission to the Food and Drug Administration.
It should also be noted that in order to prevent any bias in the analysis, all the results will be
reviewed in joint meetings with Trial CRO on behalf of Dr. Hamed Hosseini and approved by
the Trial CRO team.
50

Statistical Methods
The primary endpoints will be analysed for Per-protocol population. Moreover, primary
endpoints and secondary endpoints in intention-to-treat/FAS population will be assessed and
for comparison of primary endpoints, sensisitivity anlysis will be applied.
All adverse events analysis was conducted based on the Saftey population
1. Per-protocol population: All randomized patients who treated with trial drugs and does not
have a major violation with protocol.
2. Intention- to – treat population: All randomized patients who were allocated to treatment
groups and received at least one dose of study drug. The patients were analyzed based on their
treatment group which was randomized.
3. Safety population: All patients who randomly received at least one dose of the drugs. The
patients were analyzed based on the randomized received drugs.
Missing Data
Graphical methods (standard tables and figures) will be used to recognize potential outliers.
Then, the analyses will be conducted including/excluding outliers. Finally, the results of the
two model will be compared considering the effect of outliers.
Both pre-protocol and FAS/ITT populations (with and without imputation) will be reported for
the primary endpoint analysis. In case there is no final answer, the worst-case scenario “NO
PCR” will be applied. Then, the results will be comaprd and if there was any significant
differences, the reason will be evaluated.
Covariate Adjustment
Since the randomization method in this study is Minimization, the results of patients who will
be randomly assigned to one of the treatment groups at the beginning of the study will be
compared with that of other patients who will assigned to their treatment group using
Minimization method during the study.
Patient Characteristics and Baseline Comparisons
Descriptive statistics of thew data will be presented in the study. For categorical variables,
number and percentage of patients in each category, and for continuous variables, mean,
standard deviation, and quartiles will be calculated.
51

Primary Endpoint Analysis
Primary endpoint (pCR) analysis, will be conducted using a two-sided 95% confidence interval
with equivalence margin of 0.2. Equivalence of Pertuzumab (CinnaGen Co.) and Perjeta® will
be concluded if the resulted 95% confidence interval for the difference will be within the
predetermined range (-0.2, 0.2)
Secondary Endpoint Analysis
The clinical response rate and tpCR in both treatment groups will be calculated and compared
using the ratio test.
The conserving surgery rate in both treatment groups will be calculated and their comparison
will be done using the ratio test.
Safety Endpoint Analysis
All adverse events data will be descriptively analyzed.
Adverse events: The number and percentage of adverse events caused by treatment will be
classified by organ system class and preferred term will be applied. Laboratory data of
hematology and biochemistry will be graphically displayed to show the trend of changes
between treatment groups.
Frequency of abnormal parameters will be reported in each visit. Furthermore, clinical
significant items will be determined in the study. Change in vital sign parameters will be
determined in each visit and change from Normal to Abnormal for physical evaluation will be
evaluated.
Immunogenicity Analysis
Samples for immunogenicity assessment (antidrug antibody [ADA] and neutralizing antibody
[nAb]) will be collected prior Pertuzumab administration in all visits. All patients in each
treatment arm will be assessed for ADA formation to Pertuzumab. In Institute Pasteur, with
validated kit, ADA formation will be detected and characterized. These tests will be done in 3
following steps:

A screening assay to detect anti-Pertuzumab antibodies;

A confirmatory assay for the samples that were positive in previous step

A titration assay to determine antibody titers
52

53

Monitoring
The purpose of monitoring is to assuring conducting the trial according to protocol and GCP
standards.
Monitor should prepare a written report for each visit to sponsor and PI. This report should
include monitor’s name, date of visit, center name, summary of visit, important findings,
deviations, final conclusion, and CAPA.
Site Initiation Visit (SIV)
SIV will be performed to ensure that the facility and medications required for the trial are
available in the study site and the investigators and staff involved in the study are aware of
study objectives and GCP principles.
In the SIV, the role of the monitor, CRA, project manager, and the auditor will be defined
clearly. After the introduction of the roles and responsibilities, staff will be taught the protocol
details including timelines, sample size, eligibility criteria, protocol conformity, deviation, and
reporting. The training should be documented. The eCRF details, ICD process, source
documentation, randomization and serious adverse event reporting will be discussed and
documented as well.
Site Monitoring Visit
Site monitoring visit will be performed to ensure the conduct of the study according to
approved protocol and GCP principles.
Before the trial starts, monitoring visits will be planned for each study site and will be
confirmed by the PI and other investigators through email or letter. The monitoring visits
during the study will be scheduled in order to visit when the planned recruitment of patients
will be in its 30% and 70% progress. Sponsor is responsible for the 30% monitoring visit and
“Trial” CRO is in charge of the 70% visit. In each visit, study elements will be monitored
including source data, consent forms, trial medicinal products accountability, adverse events,
protocol compliance, team qualification, and training. The monitoring report will be prepared
and reported to both PI and sponsor preferably in an arranged meeting.
54

Study Close-Out
Study close-out visit will be performed to ensure the proper documentation of the data and
return of the medicinal product and the equipments related to the trial.
After the last visit of the last participant, site close-out will be scheduled in a meeting and
in the presence of the investigator. The site close-out visit will start with a brief meeting
with the investigator and a decision will be made regarding the disposal of the remaining
investigational medicinal product. The study documents will be archived at the trial site.
A copy all safety reports will remain with the investigator and one copy will be rendered
to the sponsor. There will be a brief closure meeting with the investigator at the site and
the site close-out report will be prepared after the visit.
55

Adverse Events
Adverse Event will be considered any medical event presented by the subjects involved in the
study, which do not necessarily have a causal relation with the treatment in study. It will be
reported as an adverse effect any symptom, sign (including any abnormal laboratory
determination) or temporary disease associated to the use if the drug in study, whether they are
or not etiologically related to it. The medical conditions present before the beginning of the
study will only be considered as adverse events if they worsen during the study and cannot be
attributable to the natural evolution of the disease.
Adverse drug reaction (ADR)—The World Health Organization defines an ADR as “any
response to a drug which is noxious and unintended, and which occurs at doses normally used
in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of
physiological function.”
AEs will be considered a Serious Adverse Event (SAE) if the event:
Results in death;
Implies a death risk;
Requires hospitalization;
Extends prior hospitalization;
Results in persistent or significant incapacity;
Produces a congenital anomaly or malformation, or
Requires medical or surgical intervention to avoid a permanent damage.
AEs Classification Based on Severity:
AEs will be classified according to its severity in relation to the guidelines established in the
Common Terminology Criteria for Adverse Events (CTCAE, version 5.0, published on
November 27, 2017). Grade refers to the severity of the AE. The CTCAE displays Grades 1
through 5 with unique clinical descriptions of severity for each AE based on this general
guideline:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting
ageappropriate instrumental ADL*.
56

Grade 3: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care
ADL**.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
* A Semi-colon indicates ‘or’ within the description of the grade.
* Activities of Daily Living (ADL)
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet,
taking medications, and not bedridden.
AE classification based on its relation with the treatment (Causality assessment):
In order to establish the relation between the AE or the DAR and the treatment in study,
the following definitions will be considered:
Certain: a clinical event including alterations in the laboratory tests manifesting with
a reasonable temporal sequence related to the administration of the drug and cannot be
explained by the current disease, or by other drugs or substances. The response to the
drug suppression (released; dechallenge) should be clinically plausible. The event
should be final from a pharmacological point of view, using, if necessary, a conclusive
re-exposure procedure.
Probable/Likely: a clinical event, including alterations in the laboratory tests
manifesting with a reasonable temporal sequence related to the administration of the
drug, which is unlikely to be attributed to the current disease, or other drugs and
substances, and which when releasing the drug (dechallenge) a clinically reasonable
response appears. No information on re-exposure (rechallenge) is required to assign
this definition.
Possible: a clinical event, including alteration in the laboratory tests manifesting with
a reasonable temporal sequence related to the administration of the drug, but can also
be explained by the concurrent disease, or by other drugs and substances. The
information regarding the release of the drug may be missing or unclear.
57

Unlikely: a clinical event, including alterations in the laboratory tests manifesting with
an improbable temporal sequence related to the administration of the drug, and can be
explained in a more plausible way by the concurrent disease, or by other drugs or
substances.
Conditional/Unclassified: a clinical event, including alterations in the laboratory tests,
notified as an adverse reaction, of which it is essential to obtain more data in order to
make a proper evaluation, or the additional data are under examination.
Non evaluable/Unclassifiable: a notification that suggests an adverse reaction, but
cannot be judged because the information is insufficient or contradictory and cannot be
verified or completed in its data.
58

AEs Recording
All the undesirable and unexpected AEs that follow the administration of the drug will be
accurately recorded in the medical record of the patient and in the corresponding section of the
CRF. The event description should be recorded, as well as the temporal sequence regarding to
the administration of the drug, its duration, the procedures performed for the diagnosis if
appropriate, the results of the repeated exposure and the qualification made by the Researcher
as regards its severity and its relation to the administered drug.
AE Reporting Responsibilities
Principle Investigator Responsibilities
The investigator must report any SAE/R, which results in death or is life-threatening, to the
sponsor and IEC within the maximum of 24 hours by fax, email or etc.
The investigator must immediately and not later than seven calendar days report those
SAE/Rs which are not life-threatening or do not result in death but may put subjects in
danger or require intervention (medical or surgical) to prevent life-threatening outcomes.
These SAE/R need to be reported to the sponsor and IEC as soon as possible but not later
than seven calendar days of having taken notice of the SAE/R.
The investigator should report to the sponsor and IEC all predictable adverse events of
investigational medicinal product including for example injection site reactions, in case of
patient withdrawal from study or adverse event with a greater frequency than expected.
Sponsor Responsibilities
SUSARs which result in death, or are life-threatening; need to be reported by the sponsor
as soon as possible but not later than seven calendar days, to IEC and IFDA, using CIOMS
form (Suspect Adverse Reaction Report Form). A follow-up report is to be submitted within
15 calendar days.
The sponsor must report SUSARs which are not life-threatening or do not result in death,
but may put subjects in danger or require intervention (medical or surgical) to prevent life-
threatening outcomes, as soon as possible but not later than 15 calendar days, to IEC and
IFDA, using CIOMS form (Suspect Adverse Reaction Report Form). The follow-up report
considering the relation between the investigational medicinal product and an adverse event
is to be submitted as soon as possible.
59

All the reports and follow-up results of SAE/R need to be reported to IFDA within maximum
15 calendar days after sponsor awareness of SAE/R.
If the severity or frequency of predictable adverse events, for example, injection site
reactions, results in patient withdrawal from the study, or in case of higher incidence than
expected, the sponsor must report it to IFDA within maximum 15 calendar days.
The sponsor must report all the information regarding the SAE and serious ADR that are
reported during the course of the study and recommendations of investigators related to
increasing of study risk for subjects to Food and Drug Administration of Iran within 15
calendar days.
The sponsor must report to IFDA all recommendations from investigators about possible
increased risk of adverse events or participants, within maximum 15 calendar days.
Follow-up
The Investigator should take all appropriate measures to ensure the safety of the patients,
notably he/she should follow up the outcome of any Adverse Events (clinical signs,
laboratory values or other, etc.) until the return to normal or consolidation of the patient's
condition;
In case of any Serious Adverse Event, the patient must be followed up until clinical recovery
is complete and laboratory results have returned to normal, or until progression has been
stabilized. This may imply that follow-up will continue after the patient has left the study
and that additional investigations may be requested by the Monitoring Team
In case of any SAE brought to the attention of the Investigator at any time after cessation of
Investigational Product and considered by him/her to be caused by the Investigational
Product with a reasonable possibility, this should be reported to the Monitoring Team.
60

Withdrawal of patients
Participants may be withdrawn from the study for any of the following reasons:
Withdrawal of consent by the patient
Noncompliance, including refusal of study medical requirements, refusal of procedures as
stated in the study protocol, or use of prohibited medications
In the case of suspected pregnancy, a pregnancy test for Beta hCG will be requested, and
if the test is positive, the patient will be excluded from the study
Any hematologic, hepatic or renal AEs which needs cessation of study treatment
The occurrence of an undesirable event that causes the investigator to consider the
patient's exclusion from the study
Not possible to follow the patient's condition (Loss to follow-up)
In case patients’ treatment need to be changed or use of prohibited drug according the
protocol
Progress od disease based on the RECIST criteria
In case patients recive less than half of the study doses (less than 3 cycle)
The reason(s) for withdrawal should be stated clearly in the eCRF.
Patient Admission Criteria
Since all injections during the study are performed under the supervision of the nurse/nurses
who have been trained, we will ensure that patients who are present at all injection days and
whose injections are approved in the CRF, has an admission to the treatment.
61

Ethics and Dissemination
Research Ethics Approval

Ethics committee approval is mandatory for start of this study

No patient will be recruited to this study without a signed informed consent.

Patients will be informed that they can leave the study anytime they desire with no need for
any explanation.

To ensure the confidentiality in case a form is lost, the name and surname of the patients
will not appear on any forms.

Adverse effect report forms will be evaluated after every visit. The research team is
responsible for dealing with the immediate aftermath of any adverse event regardless of the
event being directly related to the medication that is being studied.

Before initiation of the trial, it will be reviewed with IFDA. The protocol, CRF, information
for patients and informed consent form will be submitted to the ethics committee of Tehran
university of medical sciences and Isfahan University of medical sciences, for review and
approval according to international regulatory guidelines
Consent
The investigator will thoroughly explain the purpose of the study to patient. The patient will
be provided with an information sheet and will be given sufficient time and opportunity to
inquire about the details of the study and to decide whether or not to participate in the study,
e.g. to give permission to use their data for investigative purposes, knowing their information
will remain confidential. The informed consent form should be signed and dated by the patient
and the person with whom they discuss the information regarding the consent form. The
investigator will explain that the patient is completely free to refuse to give permission for
his/her data to be used or to withdraw from the trial at any time and for any reason. Similarly,
the investigator and/or sponsor will be free to withdraw the patient at any time for
administrative reasons. Any other requirements necessary for the protection of the human rights
of the patient will also be explained, according to GCP guidelines, declaration of Helsinki and
local regulation for clinical trials.
62

Confidentiality
All study-related information will be stored securely at the study site.
To ensure confidentiality, randomization codes will be used on all the reports, gathered data,
information regarding the study progress and administrative forms.
All records that contain names or other personal identifiers, such as subject identification form
and informed consent forms, will be stored separately from study records.
All local databases will be secured with password-protected access systems.
Forms, lists, logbooks, appointment books, and any other lists which link participant’s
randomization code to other identifying information will be stored in a separate, locked file in
an area with limited access.
All laboratory and other test results will be kept strictly confidential. All counseling and blood
sampling will be conducted in private rooms, and study staff will be required to preserve the
confidentiality of all participants.
Amendment
Any modifications to the protocol which may impact on the conduct of the study, the potential
benefit of the patient or may affect patient safety, including changes to study objectives, study
design, patient population, sample size, study procedures, or significant administrative aspects
will require a formal amendment to the protocol. Such amendment will be agreed upon by
Principal Investigator and sposnor and should be approved by IFDA and the Ethics Committee
prior to implementation. Administrative changes to the protocol are minor corrections and/or
clarifications that have no effect on the way the study is to be conducted. These administrative
changes will be agreed upon by Principal Investigator and sponsor and will be documented in
a memorandum.
Declaration of Interests
The presence or absence of any kind of financial and or nonfinancial relationship between the
sponsor and principal investigator and investigators (with the exemption of this study contract)
should be officially declared to IFDA as a written conflict of interest letter.
Funding Organization
63

All expenses of this study including patients’ treatment and medicines, study conduct and
performing and research related injuries compensation will be provided by Sponsor.
Access to Data
Only Principal investigator will have access to full dataset.
Ancillary and Post-Trial Care
Ancillary care (related to trial) will be provided by investigators under sponsor support for
participants.
Dissemination Policy
No other publication is allowed before the primary publication. Any subsequent presentation
or publication (including the sub-studies) by a study team member must be approved by the
steering committee and chief Investigator and the primary publication should be cited. The
final decision to publish any manuscript/ abstract/ presentation will be made by principal
Investigator and the sponsor after prior notice to the Trial CRO for their review and comments.
64

Appendixes
65

Appendix 1: Informed Consent Form
Informed Consent Form
A Phase III, randomized, two armed, parallel, triple-blind, active controlled, equivalency
clinical trial to determine the therapeutic efficacy and safety between Pertuzumab®
(Manufactured by CinnaGen Co.) compared with active control group treated by Perjeta®
(Pertuzumab, the reference drug, Manufactured by Genentech) in neoadjuvant treatment of
HER 2 positive Breast Cancer patients
Mrs./Miss ………………………………
We invite you to participate in the above-mentioned clinical study. Information about this research is
provided in this sheet, and you are free to join this research or not.
You do not have to make an immediate decision and you are given a deadline to announce your opinion
after consulting the research team and anyone you desire, about participation and your involvement in
this research is entirely voluntarily. Before signing this consent, make sure that you understand all the
information
in
this
form
and
all
of
your
questions
are
answered.
Investigator:
1) I know that purposes of this research are evaluation of the efficacy and safety of Pertuzumab
(Manufactured by CinnaGen Co.) compared to Perjeta® (Manufactured by Genentech)
2) I know that my participation in this study is voluntary and I am not obligated to participate in this
research. I was assured that if I were not willing to participate in this research, I would not be
deprived of routine diagnostic and therapeutic care and my therapeutic relationship with the health
center and my physician will not get affected.
3) I know that even after agreeing to participate in the research, I can resign freely at any time after
informing the researcher, without giving any reason and my withdrawal from the research will not
deprive me of the usual treatment services.
4) This is how my participation is in this study:
Whenever the physician diagnosed that I need to receive Pertuzumab to improve my clinical
conditions, and I consented to receive it, treatment regimen according to the study protocol of will
66

be started and I will allocated in one of the treatment group (one of the treatment group receive
Pertuzumab (Manufactured by CinnaGen Co.) and the next group will receive Perjeta®
(Manufactured by Genentech)). During the study, I have to go to trial site in order to get my treatment
drugs, laboratory test and other interventions of visits. The activity of visits of study include:
Duration of study is 18-20 weeks with pathological sampling test after surgery. With considering
screening visit, I will have 8 visits (each visit is about 15 min without considering time of drug
administration) in this study. The difference between screening and first visit (treatment visit) is
maximum 2 weeks and the difference between other visits is 3 weeks. In screening visit, my health
condition, medical history, height, weight and vital sign will be evaluated by physician. In addition,
one blood sampling (3-5 mm) for general and specific laboratory test (CBC diff,. BUN, Cr, Bilirubin,
ALP, AST, ALT, NA, K, Mg, Ca, P, Cl, Albumin, Glucose, LDH, INR, PTT/aPTT, HIV, HCV,
HBs-Ag, assessment of antibody formation against drug, Unrine analysis, and pregnancy test if it is
required) will be drawn. Other evaluation include Echocardiography, MRI, and ECG. If all of my
lab results, imaging and clinical examination were confirmed by physician and I passed all eligibility
criteria of the study, I can enrolled in the study after signing this consent form. During the study I
will receive these drugs: in each treatment visits I will receive Carboplatin, Docetaxel, Trastuzumab
and one of the Pertuzumab drugs. I know that my allocation to each treatment group will be
randomly. My physician informed me that this blinding of the treatment is scientific and is to
evaluate the efficacy of the drugs. My physician informed me that all of the treatments and
interventions will be based on the routine treatment procedure and I do not need to have any extra
visit of clinic. Regardless of treatment group, I will receive all of the required interventions and
whenever participating in this study will considered not safe for me, I can discontinue the study and
will receive appropriate treatment after my quit. I know that all of the drugs of this study between
two treatment arms are similar and the only difference is related to Pertuzumab group.
In my next visits (visit 1-6), in each one of them, my health condition will be assessed by physician
(investigator). In each visit and before drug administration (every 3 weeks), one blood sampling will
be drawn in specified laboratory and these test include: CBC diff,. BUN, Cr, Bilirubin, ALP, AST,
ALT, NA, K, Mg, Ca, P, Cl, Albumin, Glucose, LDH, assessment of antibody formation against
drug (this test will be done with other lab test and there is no need to give extra blood sample).
In every 6 weeks interval (visit 3, 5, 7), echocardiography test is planned for me. In addition, in first
visit and last visit (visit 7) or any other visit that physician consider necessary, MRI test is planned
for me and there will be laboratory test in last visit which includes similar laboratory test with
previous visits.
In addition, in each visit, questions related to my health condition, other used drugs will be asked. I
know that laboratory and imaging test can be repeated based on the physician discretion.
I am assured that if in any time of the study, I had progress, I can discontinue the study and another
treatment will start for me based on the physician discretion. In addition, if I received less than 3
67

doses of pertuzumab (less than 3 cycle of 6 cycle) due to my condition, I will be withdrawan form
the study and new treatment based on the physician decision will be started for me.
By considering my health condition, I accept that during the study duration and 6 months after that, I
will not try to be pregnant and if there is a chance that I became pregnant or had delay in my
menstrual period, I will forthwith inform my physician (To be sure about pregnancy, there is
pregnancy test in screening, visit 3 and 6)
5) The possible benefits of my participation in this study are as follows:
Pertuzumab is one of the novel drug which has FDA and EMA approval for breast cancer indication.
The efficacy of Pertuzumab in breast cancer before and after surgery is confirmed and addition of this
drug to chemotherapy regimen can increase significantly clinical response without increasing AE
frequency. By participating in this study, I can receive pertuzumab while this drug is not easily
accessable in my country and I do not need to pay any cost for this drug. In addition, I will be examined
and evaluated by the physicians with greater precision and sensitivity regarding my condition and the
side effects of drugs. Also, the effects of my treatment will be carefully evaluated
6) The possible harms and adverse events of my participation in this research are as follows:
It is possible to experience these adverse events after participation in this study, including diarrhea,
cardia issue, hematologic issue, dermatologic issue, gastrointestinal issue, or reduce of white blood
cells, alopecia, nausea, vomiting (most commonly related to chemotherapy regimen drugs and not
necessarily related to Pertuzumab). The mentioned adverse events, can be occurred in both treatment
groups and can be observed by other chemotherapy regimen too. I have to remember that these adverse
events are temporary and after cessation of the tretamnet, all of these adverse events will be disappear
after specific time. In addition, if any AEs were occurred, I or my family should inform the physician as
soon as possible. This AE can be not related to the investigational drug of the study, but should be
reported to the physician of the study.
7) In the case of unwillingness to participate in the research, the usual services (therapeutic,
diagnostic, etc.) for me will be provided. My treatment will be based on the physician decision in
case of unwillingness to participate in the research
8) I know that the researchers of this study will keep all of my information confidential and are only
allowed to publish the overall and collective results of this research without mentioning my name
and my profile.
9) I know that the Ethical Committee in my study is allowed to have access to my information to
monitor my rights.
68

10) I know that I should not pay any costs of the trial drugs and tests including Chemotherapy regimen
drugs, Trastuzumab drugs, Pertuzumab drugs, Pegagen drugs, laboratory test, MRI,
Echocardiography, ECG, pathology test
11) Physician of the study and Mr. Siavash Bakhshian (sponsor representative) has been introduced to
me for answering my questions, and I was told that during the study any time a health problem
occurred to me or if I had a question regarding participation in this research, I can share with him
and ask for guidance.
12) I know that if during and after the research any physical and mental problems arose because of my
participation in this research, it will be the responsibility of the physician to treat the complications
and the related damages.
13) I know that if I have a problem or objection to executors of the research or the research process, I
can contact the ethic Committee of the Tehran University of Medical Sciences at the address of:
Room 605, 6th Floor, Central headquarters of Tehran University of Medical Sciences, Qods Street,
Keshavarz Blvd., Tehran, Iran. Telephone: 009821-81633626 or ethic committee of Guilan reseach
center at the address of: Research and technology building, west beheshti blv, Rasht, Guilan and
present my problem either verbally or in writing.
14) This form of information and informed consent is provided in two copies and will be signed by the
physician and me. A signed copy will be given to me and a signed copy will be given to the
physician.
This section should be completed by patient
I have read and understood the explanations mentioned above, and based on that, I declare my
informed consent to participate in this research.
Participant signature:
69

This section should be completed by investigator (physician) of the study
I consider myself bound to comply with the obligations of the executor in the above provisions, and I
undertake to work on the rights and safety of people participating in this research.
Investigator signature:
70

Appendix 2: Classification of Breast Cancer
Tumor
classification
T2
T2
T3
T2
T3
T3
T4a
T4b
T4c
T4d
T4a
T4b
T4c
T4d
T4a
T4b
T4c
T4d
T2
T3
T4a
T4b
T4c
T4d
Lymph Node
classification
N0
N1
N0
N2
N1
N2
N0
N0
N0
N0
N1
N1
N1
N1
N2
N2
N2
N2
N3
N3
N3
N3
N3
N3
Anatomic Staging
IIA
IIB
IIB
IIIA
IIIA
IIIA
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIB
IIIC
IIIC
IIIC
IIIC
IIIC
IIIC
Breast Cancer type
Operable (Early Stage)
Operable (Early Stage)
Operable (Early Stage)
Locally Advanced
Operable (Early Stage)
Locally Advanced
Locally Advanced
Locally Advanced
Locally Advanced
Inflammatory
Locally Advanced
Locally Advanced
Locally Advanced
Inflammatory
Locally Advanced
Locally Advanced
Locally Advanced
Inflammatory
Locally Advanced
Locally Advanced
Locally Advanced
Locally Advanced
Locally Advanced
Inflammatory
71

Appendix 3: RECIST 1.1
New response evaluation criteria in solid tumours: Revised RECIST
guideline (version 1.1)
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether
target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters.
Progressive Disease (PD): At least a 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).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for
PD, taking as reference the smallest sum diameters while on study.
Evaluation of non-target lesions
Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour marker
level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker
level above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the
appearance
of
one
or
more
new
lesions
is
also
considered
progression).
72

Appendix 4: Discontinution Algorithm of Trastuzumab and Pertuzumab based on heart function
73

Appendix 5: Carboplatin Dosing
Carboplatin Dose (mg) = Target AUC * (GFR + 25)
AUC* = 6 mg/mL x min
AUC* or area under curve based on the kidney function and Calvert Formula, calculated to
required dose of patient according to mg. According to Calvert Formula, the final dose (mg)
is multiplication of AUC and GFR+25. In case of application of Serum Creatinine, the
maximum limit of GFR will be 125 mL/min.
The below table is based on the above formula and is for easy of application.
GFR
20.0-22.4
Dose
270 mg
GFR
54.1-63.2
Dose
500 mg
22.4- 27.4
300 mg
63.2-74.0
560 mg
27.4-32.4
330 mg
74.0-85.7
630 mg
32.4-38.2
360 mg
85.7-98.9
700 mg
38.2-45.7
400 mg
98.9-114.8
790 mg
45.7-54.1
450 mg
114.8-132.2
890 mg
74

Appendix 6: Heart Evaluation Questionnaire
In each visit and before any drug interventions, patient’s heart condition should be evaluated
based on this questionnaire. Please record the result of this evaluation in related part of eCRF.

Have you recently experienced shortness of breath with physical activity or walking?

Have you recently feel palpitation while you are in rest or in activity?

Have you experienced cough or shortness of breath while you are resting in lying
down position?

Have you recently felt swelling in your hands and feet, or tightness of shoes or a ring?
75

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