A Phase III, Randomized, Two-armed, Triple Blinded, Parallel, Active Controlled Non-Inferiority Clinical Trial of Stivant (AryoGen Trastuzumab) Efficacy and Safety in Comparison to Avastin in Metastatic Colorectal Cancer
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer
Sponsor: AryoGen Pharmed Co.

Stivant (Bevacizumab of AryoGen Pharmed) against Avastin® in metastatic colorectal cancer 
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Study Protocol 
Title:  
 
A Phase III, randomized, two-armed, double-blind (patient and assessor blinded), parallel, 
active controlled non-inferiority clinical trial to evaluate the efficacy and safety of 
bevacizumab (AryoGen Pharmed) plus FOLFIRI-3 in comparison with bevacizumab 
(Avastin®) plus FOLFIRI-3 as a first line therapy in patients with metastatic colorectal cancer 
(mCRC). 
 
Version: 6.4 
 
Date: 3 April 2017 
 
CONFIDENTIAL 
The information contained in this document is the property of AryoGen pharmed. The content 
of this document may not be disclosed to others than the investigator(s) and duly staff, 
applicable EC and regulatory authorities without written approval from AryoGen pharmed Co, 
except to the extent necessary to obtain informed consent from those persons to whom the 
medication may be administered.  
 
 

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Contents 
 
Contents ...................................................................................................................... 2 
Confidential Information ............................................................................................... 5 
Abbreviations ............................................................................................................... 6 
Administrative information ............................................................................................ 8 
Title ......................................................................................................................... 8 
Trial registration ....................................................................................................... 8 
Protocol version ........................................................................................................ 8 
Funding .................................................................................................................... 8 
Roles and Responsibilities .......................................................................................... 9 
Sponsor ................................................................................................................ 9 
Chief investigator: ................................................................................................ 12 
Principal investigators ........................................................................................... 12 
Statistical adviser .................................................................................................. 17 
Scientific steering committee ................................................................................. 18 
Introduction ................................................................................................................ 19 
Background and rationale .......................................................................................... 19 
Objectives ................................................................................................................... 23 
Primary objective(s) ................................................................................................. 23 
Secondary objective(s) .............................................................................................. 23 
Trial Design ............................................................................................................. 23 
Methods ...................................................................................................................... 24 
Study setting ............................................................................................................ 24 
Eligibility criteria ......................................................................................................... 26 
Inclusion criteria ...................................................................................................... 26 
Exclusion criteria ..................................................................................................... 27 
Interventions ............................................................................................................... 29 
Suggested dose alterations for toxicity ........................................................................ 31 
Outcomes .................................................................................................................... 32 
Primary outcomes .................................................................................................... 32 
Secondary outcomes ................................................................................................. 32 
Safety outcomes ....................................................................................................... 32 

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Immunogenicity ....................................................................................................... 32 
Termination policy ................................................................................................... 33 
Participant timelines ..................................................................................................... 34 
Sample size ................................................................................................................. 37 
Recruitment ................................................................................................................ 37 
Randomization ............................................................................................................ 37 
Allocation (concealment process) .................................................................................. 38 
Blinding ...................................................................................................................... 38 
Treatment compliance .................................................................................................. 38 
Treatment discontinuation ............................................................................................ 38 
Data management ........................................................................................................ 40 
Data collection methods ............................................................................................ 40 
Data management ..................................................................................................... 40 
Data monitoring ....................................................................................................... 41 
Statistical methods ....................................................................................................... 41 
Statistical analysis ........................................................................................................ 43 
Monitoring .................................................................................................................. 44 
Site initiation visit .................................................................................................... 44 
Site monitoring visit ................................................................................................. 44 
Study closeout ......................................................................................................... 45 
Adverse events ......................................................................................................... 45 
Auditing ..................................................................................................................... 53 
Ethics and dissemination .............................................................................................. 53 
Research ethics approval ........................................................................................... 53 
Consent ................................................................................................................... 54 
Confidentiality ......................................................................................................... 54 
Amendment ............................................................................................................. 54 
Declaration of interests ............................................................................................. 55 
Funding organization/Sponsor ................................................................................... 55 
Access to data .......................................................................................................... 55 
Ancillary and post-trial care ...................................................................................... 55 
Dissemination policy ................................................................................................ 55 
Appendices ................................................................................................................. 56 

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Appendix 1: Informed consent form ........................................................................... 56 
Appendix 2: RECIST ................................................................................................ 59 
Evaluation Criteria for Target Lesions .................................................................... 59 
Evaluation Criteria for Non-Target Lesions ............................................................. 59 
Appendix 3: Reference ............................................................................................. 61 
 
 

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Confidential Information 
 
The confidential information in the following document is provided to you as an investigator, 
auditor, and sponsor for review by you, your staff and an ethics committee and food and drug 
administration. By accepting this document, you agree that the information contained herein 
will not be disclosed to others without written authorization from AryoGen Pharmed Co., 
except to the extent necessary to obtain informed consent from those persons to whom the 
products may be administered. By signing below, the investigator agrees to adhere to the 
protocol as outlined and agrees that any changes to the protocol must be approved by AryoGen 
Pharmed Co., prior to seeking approval from the Independent Ethics Committee (IEC). 
This study will be conducted in accordance with Good Clinical Practices (GCPs), the 
Declaration of Helsinki, local, ethical, and legal requirements. 
Chief Investigator: Dr. Hamid Rezvani 
Affiliation: Hematology and oncology Center, Taleghani Hospital, Shahid Beheshti university 
of medical sciences, Tehran, Iran. 
Signature: 
Date: ……/………. /……… 
 
Sponsor representative: Dr. Araz Sabzvari 
Signature: 
Date: ……/………. /… …… 
 
Contract Research Organization representative: Dr. Hamed Hosseini 
Signature: 
Date: ……/………. /……… 
 
 

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Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline phosphatase  
CEA 
Carcinoembryonic Antigen 
CRC 
Colorectal Cancer 
CRO  
Contract Research Organization 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiography 
EGFR  
Epidermal growth-factor receptor  
FAP 
Familial Adenomatous Polyposis  
FOLFIRI 
5-fluorouracil, leucovorin and irinotecan  
GOT 
Glutamic Oxaloacetic Transaminase 
GPT 
Glutamic Pyruvic Transaminase 
HCT 
Hematocrit 
Hgb 
Hemoglobin 
HNPCC 
Hereditary nonpolyposis colorectal cancer 
IBD 
Inflammatory Bowel Disease 
ICD 
Informed Consent Document 
ICF 
Informed Consent Form 
IFDA 
Iran Food and Drug Administration 
IRCT 
Iranian Registry of Clinical Trial 
LDH 
Lactate Dehydrogenases 

Stivant (Bevacizumab of AryoGen Pharmed) against Avastin® in metastatic colorectal cancer 
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LFT 
Liver Function Test 
mCRC 
Metastatic Colorectal Cancer 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PI 
Principle Investigator 
RFT 
Renal Function Test 
VEGF 
Vascular Endothelial Growth Factor 

 
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Administrative information 
Title 
A Phase III, randomized, two-armed, double-blind (patient and assessor blinded), parallel, 
active controlled non-Inferiority clinical trial to evaluate the efficacy and safety of 
bevacizumab (AryoGen pharmed) plus FOLFIRI-3 in comparison with bevacizumab 
(Avastin®) plus FOLFIRI-3 as a first line therapy in patients with metastatic colorectal cancer 
(mCRC). 
Trial registration 
It is planned to register this protocol to Iranian Registry of Clinical Trial (IRCT) http://IRCT.ir 
Registration code in IRCT: IRCT2015072517994N2 
Ethics committee code has been received in 1395/05/02 from Shahid Beheshti university of 
medical sciences with the number of IR.SBMU.REC.1395.4. with letter number of 
1395/ص/25912. 
Ethics committee code has been received in 1395/06/03 from Ahwaz Jondi-Shapur university 
of medical sciences with the number of IR.AJUMS.REC.1395.351. with letter number of 
پ/8/20/د/3787  
Clinical Trial Authorization (CTA) from food and drug administration of Iran with the number 
of 665/111592 in 1395/07/13. 
Protocol version 
Version: 6.4   Date: 96.01.14 
Funding 
Bevacizumab (AryoGen pharmed) will be manufactured by AryoGen pharmed and 
bevacizumab (Avastin®) will be provided by AryoGen pharmed. All trial costs will be provided 
by Aryogen pharmed. 
 

 
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Roles and Responsibilities 
Sponsor 
 AryoGen pharmed Company 
Contact address: AryoGen pharmed, No. 140, Corner of Tajbakhsh St., 24th Km Tehran-Karaj 
Makhsous Road, Alborz, Iran 
Tel: +98 26 36106480-4 
Fax: +98 26 36104644 
Zip Code: 3164819711 
 
Sponsor representative: Dr. Araz Sabzvari  
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone:  00982143473600                     
Role: 
• Preparing final draft of study protocol 
• Obtaining necessary approvals from external organizations for the conduct of study  
• Providing standard operational procedures (SOP) for principle investigators in 
participating centers 
• Providing quality controlled drugs to be used in the trial and delivery to participating 
centers 
• Funding provision for all activities foreseen in study protocol via signing contracts with 
principal investigator 
• Providing compensation for patients who may be adversely affected by participating in 
the trial 
• Providing insurance coverage for all study participants 
• Providing necessary training for staff 
• Recruiting necessary workforce to conduct monitoring of the trial 
• All expenses will be the responsibility of the sponsor. 

 
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• Audit of study sites to review the process of conducting the study and report the cases 
of violations from the protocol. 
 
Representatives of the sponsor to conduct an audit to monitor the quality of the study: 
Name: Dr. Nasim Anjidani, Pharmacist, Medical Manager 
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone: 00982143473200                Email: Anjidani.s@orchidpharmed.com     
Name: Mr. Siavash Bakhshian, Clinical Trial Manager 
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone: 00982143473170                Email: Bakhshian.s@orchidpharmed.com     
Name: Mrs. Elham Farhangara, Clinical Trial Coordinator 
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone: 00982143473162                 Email: Farhangara.e@orchidpharmed.com 
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 met, and other 
requirements for the performance of the study). 
• Persistent training of site personnel for protocol performance. 
• Checking CRFs and matching them with source data and filling out the query for 
noncompliance and reminding them to correct them. 

 
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• Provide reports of non-compliances and facilities required by the site and submit it to 
the company's managers. 
Representative of the sponsor for external monitoring on quality control of the study: 
Name: CRO Trial  
Name: 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, Iran. 
Telephone: 00982188963546 
Signature: 
Name: Dr. Mansour Shamsipour, Tehran university of medical sciences 
Contact address: Tehran university of medical sciences, Institute of Research and Research 
Centers, Keshavarz Blvd., North Kargar St., Tehran, Iran. 
Telephone: 00982188963546 
Signature: 
Roles: 
• Preparing a randomization file 
• Conducting a 70% monitoring in all of the sites participating in the study according to 
GCP Guidelines, 126 patients were diagnosed in patient recruitment centers. 
• Supervision over the study and Data Management 
• Performing Statistical analysis and Preparing or approving the project either in middle 
or the end of the study  
• Cooperation with company to perform Monitoring visits 
• Cooperation for answering the methodology queries 
• Regular visiting of all patient sites of Tehran 

 
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Chief investigator:  
Name: Dr. Hamid Rezvani, Professor of Hematology and Oncology  
 
Role: 
✓ Conducting the study according to the agreed protocol  
✓ Setting up a team for this purpose 
✓ All clinical examinations  
✓ Responsible for conducting trial according to ICH-GCP in sites.  
✓ Organizing training events for their existing and newly recruited team members 
wherever necessary 
✓ Provision of suitable storage and delivery for drugs used in the trial 
✓ Cooperation with monitors during the conduct of the study 
✓ No part of this trial could be published without the prior agreement with sponsor.  
(This agreement must be signed by PI and sponsor before the study initiation.) 
✓ Responsible to provide training for staff at the study site 
✓ Patients care 
✓ Notification of AEs and ADRs to sponsor and regulatory according to the protocol 
schedule and regulatory requirements. 
 
Contact address: Hematology and oncology Center, Fourth floor, Taleghani Hospital, Shahid 
Beheshti university of medical sciences, Tehran, Iran. 
Signature: 
 
Principal investigators 
Roles: 
• Conducting the study according to the agreed protocol 
• Setting up a team for this purpose 
• Organizing training events for their existing and newly recruited team members 
whenever necessary 
• Provision of suitable venues for patient’s admission 
• Provision of suitable storage for drugs used in the trial 

 
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• Cooperation with monitors during the conduct of the study 
• All medical documents related to the trial should be sent to AryoGen pharmed 
Company at the end of the trial. A copy may be kept by principle investigator 
• No part of this trial could be published without the prior agreement of AryoGen 
Pharmed Company. 
In all of these centers, patient recruitment is performed. 
 
 
Researcher name and address: 
• Taleghani Hospital 
Contact address:  Hematology and oncology center, Fourth floor, Shahid Beheshti 
university of medical sciences, Shahid Arabi St., Yaman St., Chamran highway, 
Tehran, Iran. 
Telephone: 00982122432560 
- Dr. Mojtaba Ghadyani, Shahid Beheshti university of medical sciences 
- Dr. Sina Salari, Shahid Beheshti university of medical sciences 
 
• Emam Khomeini Hospital 
Contact address: Hematology and oncology center, Valiasr hospital, Imam Khomeini 
Therapeutic Complex, Keshavarz blvd., Tehran, Iran. 
Telephone: 00982166581593 
             - Dr. Farhad Shahi, Tehran university of medical sciences 
 
• Shariati Hospital 
Contact address: East Jalal al Ahmad highway, Tehran, Iran. 
           Telephone: 00982184901000 
- Dr. Davood Babakhani, Tehran university of medical sciences. 
- Dr. Mohammad Vaezi, Tehran university of medical sciences. 
 
 

 
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• Sina Hospital 
Contact address: Hasan Abad Square, Emam Khomeini St., Tehran, Iran. 
           Telephone: 00982166348500 
- Dr. Mohsen Esfandbod, Tehran university of medical sciences. 
 
• Masih Daneshvari Hospital 
Contact address: Hematology and Oncology center, Darabad St., Shahid Bahonar 
(Niavaran) St., Tehran, Iran. 
Telephone: 00982127123000 
- Dr. Adnan Khosravi, Shahid Beheshti university of medical sciences. 
• Firoozgar Hospital 
Contact address: Beh Afarin St. Karim khan Zand St. Valiasr square, Tehran, Iran. 
Telephone: 00982182141600 
- Dr. Mohsen Razavi, Iran university of medical sciences. 
 
• Artesh 501 Hospital 
Contact address: Shahid Etemad Zadeh St. West Fatemi St., Tehran, Iran. 
Telephone: 00982186096350 
- Dr. Mohsen Rajaei Nejad, Artesh university of medical sciences. 
 
• Masoud Clinic 
Contact address: No. 144., 19th St., after Jalal Al Ahmad Highway, North Kargar St., 
Tehran, Iran. 
Telephone: 00982188336300 
- Dr. Masoud Iravani, Tehran university of medical sciences. 
 
• Dr. Safa Najar Najafi Clinic 
Contact address: No. 15., Pardis St. Molla sadra St., Tehran, Iran. 
Telephone: 00982188798525 
- Dr. Safa Najar Najafi, Tehran university of medical sciences. 
 
 

 
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• Isfahan Sheikh Mofid Clinic 
Contact address: Sheikh Mofid St., Feiz St., Isfahan, Iran. 
Telephone: 00983136631677 
- Dr. Valiollah Mehrzad, Isfahan university of medical sciences 
- Dr. Amir Abas Nekoyi, Isfahan university of medical sciences 
- Dr. Ali Haji Gholami, Isfahan university of medical sciences 
- Dr. Alireza Sadeghi, Isfahan university of medical sciences 
 
• Saba Clinic 
Contact address: Saba Building, Mohammad Abad alley, Opposite Venus hotel, 
Amadgah St., Isfahan, Iran. 
Telephone: 00983132220455 
- Dr. Mohsen Khani, Isfahan university of medical sciences. 
 
• Mashhad Emam Reza Hospital 
Contact address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi. 
Telephone: 00985138543031 
- Dr. Abolghasem Allahyari, Mashhad university of medical sciences. 
 
• Mashhad Ghaem Hospital 
Contact address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi, Iran. 
Telephone: 00985138400000 
- Dr. Rahimi, Mashhad university of medical sciences. 
 
• Dr. Mehrdad Payandeh Clinic 
Contact address: No 101, Fakhr Razi Alley, Shahrdari square, Modares St., 
Kermanshah, Iran.  
Telephone: 00988337282400 
- Dr. Mehrdad Payandeh, Kermanshah university of medical sciences. 

 
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• Dr. Babak Shazad Clinic  
Contact address: Third floor, Mahdieh Building, Javanshir St., Kermanshah, Iran.  
Telephone: 00988337238018 
- Dr. Babak Shazad, Kermanshah university of medical sciences. 
 
• Yazd Seyedshohada Hospital 
Contact address: Emam Khomeini St., Yazd, Iran.  
Telephone: 00983536210010 
- Dr. Mohammad Reza Mortazavi Zadeh, Yazd university of medical sciences. 
- Dr. Mohammad Reza Vahidfar, Yazd university of medical sciences 
 
• Dr. Mohammadreza Mortazavi Zadeh Clinic 
Contact address: No 25, Shahid haj Mohammadi Alley, Yazd, Iran.  
Telephone: 00983537250044 
- Dr. Mohammadreza Mortazavi Zadeh, Yazd university of medical sciences.  
 
• Shiraz Namazi Hospital 
Contact address: Namazi square, Zand St., Shiraz, Fars, Iran.  
Telephone: 00987136474332 
- Dr. Mani Ramzi, Shiraz university of medical sciences.  
- Dr. Alireza Rezvani, Shiraz university of medical sciences. 
 
• Ahwaz Shafa Hospital 
Contact address: Golestan St., Ahwaz, Khoozestan, Iran.  
Telephone: 00986133743281 
- Dr. Mehran Hosseinzadeh, Ahwaz university of medical sciences. 
- Dr. Mohammad Segholeslami, Ahwaz university of medical sciences. 
- Dr. Ahmad Ahmad Zadeh Deilami, Ahwaz university of medical sciences. 
 
• Rasht Razi Hospital 
Contact address: Sardar Jangal St., Rasht, Guilan, Iran.  

 
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Telephone: 0098133550028 
- Dr. Sirus Gharib, Rasht university of medical sciences. 
 
• Rasht Rasoul Hospital 
Contact address: Guil square, Rasht, Iran.  
Telephone: 00981333665652 
- Dr. Mehdi Mirbolouk, Rasht university of medical sciences. 
 
• Hamedan Shahid Beheshti Hospital 
Contact address: Eram BLVD., Ghaem square, Hamedan, Iran. 
Telephone: 00988138380283 
- Dr. Mohammad Abasi, Hamedan university of medical sciences. 
 
Statistical adviser 
- Name: Ramin Shahpari 
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone: 00982143473270 
- Name: Ameneh Valujerdi 
Contact address: Orchid Pharmed Company, No 42, Attar St, Tehran, Iran. 
Telephone: 00982143473271 
- Name: Dr. Ali Akhlaghi 
Contact address: Number 1547, Tehran university of medical sciences research center, 
Keshavarz Blvd., North Kargar street, Tehran, Iran. 
Telephone: 00982188963546 
Role: evaluating and analysis of trial data 
 

 
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Scientific steering committee 
- Name: Dr. Hamid Rezvani, Oncologist, Shahid Beheshti University of medical sciences. 
Contact address: Oncology and hematology center, Fourth floor, Taleghani hospital, Shahid 
Beheshti University of medical sciences, Shahid Arabi St., Yaman St., Chamran highway, 
Tehran, Iran. 
Telephone: 00982122937031 
 
- Name: Dr. Sina Salari, Oncologist, Shahid Beheshti university of medical sciences. 
Contact address: Oncology and hematology center, Fourth floor, Taleghani hospital, Shahid 
Beheshti University of medical sciences, Shahid Arabi St., Yaman St., Chamran highway, 
Tehran, Iran. 
Telephone: 00982122937031 
Roles: 
1- Establishing coordination among researchers in study centers. 
2- Monitor and review the reports provided by the sponsor and CRO. 
3- Signing of the protocol and protocol amendments and reports submitted to the Food 
and Drug Administration of Iran and ethics committees on behalf of other professors. 
4- Adopting a proper decision to address the conditions in which the profit-risk balance 
for participants in the study, either individually or in general, conflicts. With regard to 
safety information, these decisions may include the identification of the relationship 
between the drug and the unwanted event observed, the adoption of appropriate 
strategies for the continuation of study and the departure of the person who is no longer 
eligible for the study. 
5- Make the right decision to decode the drug. 
6- Investigator meeting at least once a month (every two weeks, the report of study and 
patient’s status is fully described to Dr. Rezvani and his consultant, Dr. Salari.). 
 
 
 

 
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Introduction 
Background and rationale 
Epidemiology  
Colorectal carcinoma is a common malignancy and a major cause of morbidity and mortality 
throughout the world. It accounts for over 9% of all cancer incidences. It is the third most 
common cancer worldwide and the fourth most common, cause of death (The third most 
commonly diagnosed cancer in males and the second in females). (1). CRC is the third leading 
cause of cancer worldwide and accounts for 10% of all new cancer diagnoses. 20% of patients 
will have metastatic disease at presentation and a further 30% of those diagnosed with early 
stage CRC will develop metastatic disease. (4).  Colorectal cancer survival is highly dependent 
upon stage of disease at diagnosis, and typically ranges from a 90% 5-year survival rate for 
cancers detected at the localized stage; 70% for regional; to 10% for people diagnosed for 
distant metastatic cancer. In general, the earlier the stage at diagnosis associated with the higher 
the chance of survival. Survival is extremely limited in stage IV colon carcinoma. The most 
common site of metastasis is the liver. The second most common site of metastasis is the lung, 
occurring in approximately 20% of patients with colorectal carcinoma. The patients with stage 
IV disease (mCRC) cannot be cured surgically; newer chemotherapeutic regimens have 
significantly improved response and tumor shrinkage. (1, 2, 3) 
Etiology  
Approximately 5 to 10% of colorectal cancers are a consequence of recognized hereditary 
conditions. The most common inherited conditions are familial adenomatous polyposis (FAP) 
and hereditary non-polyposis, colorectal cancer (HNPCC), also called Lynch syndrome. Genes 
responsible for these forms of inherited colorectal cancer have been identified. HNPCC is 
associated with mutations in genes in the DNA repair pathway, namely the MLH1 and MSH2 
genes, which are the responsible mutations in individuals with HNPCC. FAP is caused by 
mutations in the tumor suppressor gene APC. (5) 
Treatment 
Current standard of care first-line treatments for mCRC include FOLFOX and FOLFIRI. Since 
2004, targeted therapies alone or in combination with standard chemotherapies have provided 
more treatment options and better results. These include the VEGF monoclonal antibody and 

 
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the EGFR monoclonal antibodies. Today the standard treatment of mCRC in the first-line 
setting combines chemotherapy regimens with antibody therapy. As chemotherapy backbones 
infusional 5-fluorouracil (5-FU) and leucovorin (LV) or capecitabine with either irinotecan 
(FOLFIRI/CAPIRI) or oxaliplatin (FOLFOX/CAPOX) are administered. Additionally, the 
monoclonal antibodies cetuximab and bevacizumab have shown activity and were approved in 
combination with FOLFOX/CAPOX and/or FOLFIRI/CAPIRI for first-line chemotherapy in 
mCRC. (6, 7) 
The first drug of choice for patients with mCRC was the fluoropyrimidine 5- fluorouracil (5-
FU). Bolus FU led to modest response rates of approximately 12% and a median survival of 
approximately 11 months. Combining FU with leucovorin (LV) improves clinical outcomes. 
Researches have showed that irinotecan or oxaliplatin plus FU/LV known as IFL and 
FOLFOX, respectively, significantly improve outcomes. (8) In the other hand, in the study 
performed by Bidard et al, FOLFIRI3 has shown promising results in second-line PFS vs. 
FOLFIRI and other various irinotecan-based regimens for mCRC patients previously exposed 
to oxaliplatin (9). Another study by Kim et al, has shown, FOLFIRI-3-bevacizumab is associated 
with an acceptable toxicity and induced promising objective response. (10) 
Bevacizumab  
Angiogenesis is critical to both the growth of the primary tumor and metastases. Poor prognosis 
and an increased relapse rate are often correlated with increased blood vessel density in the 
primary tumor in mCRC. One of the most important stimulators of angiogenesis is VEGF. The 
potential of VEGF as an anticancer target was supported by the demonstration that a murine 
anti-VEGF monoclonal antibody can inhibit the growth of human tumor xenografts 
Subsequently, a recombinant humanized monoclonal antibody against VEGF, Bevacizumab 
(Avastin®), has been examined as an antiangiogenic cancer therapy. (11) 
In addition to its direct antiangiogenic effects, bevacizumab may also improve the delivery of 
chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure in 
tumors. 
 In mCRC patients, initial studies of Bevacizumab showed improvements in tumor response 
rate and progression-free survival (PFS) when added to fluorouracil and leucovorin. 
Subsequent randomized trials showed Bevacizumab to prolong median overall survival (OS; 

 
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20.3 versus 15.6 months) in combination with FOLFOX and to improve response rates and 
PFS times with the addition of Bevacizumab to FOLFIRI or FOLFOX in patients with 
untreated MCRC. (11, 12) 
The pivotal trial of bevacizumab in mCRC patients demonstrated the benefit of adding the 
agent to irinotecan with bolus 5-FU and LV (IFL) in first-line treatment. Given the similar 
efficacy profiles of these latter two regimens, along with evidence for the superiority of 
FOLFIRI–bevacizumab over modified IFL–bevacizumab, it was assumed that FOLFOX and 
FOLFIRI could be used interchangeably with bevacizumab as first-line treatment. (13)  
Treatment with bevacizumab in combination with FOLFIRI for the first-line regimen resulted 
in an overall response rate of 53.1%. In terms of survival, patients treated with bevacizumab 
plus FOLFIRI had a median PFS of 11.1 months. Addition of bevacizumab to each of the 
chemotherapy regimens resulted in improved PFS of 11.2 months in the FOLFIRI arm (vs. 7.6 
months for FOLFIRI alone) and 8.3 months in the mIFL arm (vs. 5.9 months for mIFL alone). 
Further support for the use of bevacizumab in combination with FOLFIRI comes from a single-
arm phase II trial in which 43 patients had a median PFS of 12.5 months and 1-year survival 
rate of 95%. Two observational studies, BRiTE and BEAT, were designed to evaluate the 
safety and efficacy of bevacizumab in large, less-selected, community-based patient 
populations. Patients treated with bevacizumab plus FOLFIRI achieved a median PFS of 10.9 
months (95% CI: 9.7–11.8) in the BRiTE study and 11.6 months in the BEAT study. In the 
BEAT study, the median OS for patients receiving bevacizumab plus FOLFIRI was 23.7 
months compared with 22.7 months for the total patient population. Antiangiogenic therapy 
with bevacizumab plus FOLFIRI is an effective and well-tolerated regimen for the first-line 
treatment of metastatic CRC, and appears to be equally effective in clinical trials and 
community-based settings. Available data suggest that bevacizumab, combined with FOLFIRI 
or any fluoropyrimidine- containing chemotherapy regimen, should be considered as the 
therapy of choice for the treatment of patients with metastatic CRC. (14) 
Bevacizumab common adverse events: 
Lethargy, weakness, mild fever, chills, mild headache, rhinitis, tinnitus, sore throats, 
paresthesia, gingivitis, swelling or ulcers in the lips and mouth, nausea, vomiting and decreased 
appetite, skin reactions (including erythrodysesthesia, rash), tachycardia and bradycardia, 
restlessness, chest pain and dyspnea, decreased urine volume, painful urination, dark stools, 
venous thromboembolic complications, hypertension, bleeding events, Gastrointestinal 

 
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perforation, arterial thromboembolism complications, wound healing problems, fistula or 
abdominal abscess, proteinuria. 
 
Rationale:  
Bevacizumab is effective in various types of cancer and already this drug is used in treatment 
of patients of metastatic colorectal cancer, non-small cell carcinoma. This drug (Avastin®) was 
produced by Genentech Company a member of the Roche Groups in the USA. Because 
Bevacizumab is so expensive, production of this drug in our country with the same quality is 
very important. So, the purpose of this study is comparing the efficacy and safety 
characteristics of bevacizumab (AryoGen pharmed ®) in comparison with bevacizumab 
(Avastin®) to irinotecan plus leucovorin/continuous 5-fluorouracil [FOLFIRI -3] in patients 
with metastatic colorectal cancer (mCRC). 
 
 

 
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Objectives 
The evaluation of non-inferiority of efficacy and safety of bevacizumab (AryoGen pharmed) 
in comparison with bevacizumab (Avastin®) plus FOLFIRI-3 (irinotecan plus leucovorin/5-
fluorouracil as continuous infusion) and immunogenicity assay in patients with metastatic 
colorectal cancer (mCRC). 
Primary objective(s) 
To determine the non-inferiority of the efficacy of bevacizumab (AryoGen pharmed) versus 
bevacizumab (Avastin®) in progression free survival (PFS) when added to FOLFIRI- 3 
(irinotecan plus leucovorin/ 5-fluorouracil as continuous infusion) in patients with metastatic 
colorectal cancer (mCRC).  
Secondary objective(s) 
The secondary purposes of this study are to establish the overall survival, tumor response rate, 
time to treatment failure (TTF) and to assess the safety and immunogenicity in bevacizumab 
(AryoGen pharmed) group in comparison with bevacizumab (Avastin®) group. 
Trial Design 
This is a, Phase III, randomized, two arms, double blind (patient and assessor blinded), parallel 
active non-inferiority controlled clinical trial with a 2:1 allocation. 
 
 
 

 
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Methods 
Study setting 
This trial will be initiated from October 2016 and 126 patients with metastatic colorectal cancer 
will be recruited from below centers. All centers implement same protocol and procedures. 
Procedures will standardize as completely as possible and variation of evaluation criteria and 
schemes will be reduced by investigator meetings, training of personnel in advance of the trial, 
and by careful monitoring during the trial. 
1- Taleghani Hospital 
Contact address:  Hematology and oncology center, Fourth floor, Shahid Beheshti 
university of medical sciences, Shahid Arabi St., Yaman St., Chamran highway, 
Tehran, Iran. 
2- Emam Khomeini Hospital 
Contact address: Hematology and oncology center, Valiasr hospital, Imam Khomeini  
3- Shariati Hospital 
Contact address: East Jalal al Ahmad highway, Tehran, Iran. 
4- Sina Hospital 
Contact address: Hasan Abad Square, Emam Khomeini St., Tehran, Iran. 
5- Masih Daneshvari Hospital 
Contact address: Hematology and Oncology center, Darabad St., Shahid Bahonar  
6- Firoozgar Hospital 
Contact address: Beh Afarin St. Karim khan Zand St. Valiasr square, Tehran, Iran. 
7- Artesh 501 Hospital 
Contact address: Shahid Etemad Zadeh St. West Fatemi St., Tehran, Iran. 
8- Masoud Clinic 
Contact address: No. 144., 19th St., after Jalal Al Ahmad Highway, North Kargar St., 
Tehran, Iran. 
9- Dr. Safa Najar Najafi Clinic 
Contact address: No. 15., Pardis St. Molla sadra St., Tehran, Iran. 
10- Isfahan Sheikh Mofid Clinic 
Contact address: Sheikh Mofid St., Feiz St., Isfahan, Iran. 
11- Saba Clinic 

 
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Contact address: Saba Building, Mohammad Abad alley, Opposite Venus hotel, 
Amadgah St., Isfahan, Iran. 
12- Mashhad Emam Reza Hospital 
Contact address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi. 
13- Mashhad Ghaem Hospital 
Contact address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi, Iran. 
14- Dr. Mehrdad Payandeh Clinic  
Contact address: No 101, Fakhr Razi Alley, Shahrdari square, Modares St., 
Kermanshah, Iran.  
15- Dr. Babak Shazad Clinic  
Contact address: Third floor, Mahdieh Building, Javanshir St., Kermanshah, Iran.  
16- Yazd Seyedshohada Hospital 
Contact address: Emam Khomeini St., Yazd, Iran.  
17- Dr. Mohammadreza Mortazavi Zadeh Clinic  
Contact address: No 25, Shahid haj Mohammadi Alley, Yazd, Iran.  
18- Shiraz Namazi Hospital 
Contact address: Namazi square, Zand St., Shiraz, Fars, Iran.  
19- Ahwaz Shafa Hospital 
Contact address: Golestan St., Ahwaz, Khoozestan, Iran.  
20- Rasht Razi Hospital 
Contact address: Sardar Jangal St., Rasht, Guilan, Iran.  
21- Rasht Rasoul Hospital 
Contact address: Guil square., Rasht, Iran.  
22- Hamedan Shahid Beheshti Hospital 
Contact address: Eram BLVD., Ghaem square, Hamedan, Iran. 
 
 
 
 

 
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Eligibility criteria 
Inclusion criteria 
This study will include participants who: 
- 
Are male or female aged 18-75 years at the time of signing the informed consent form. 
- 
Have been diagnosed as mCRC verified histologically 
- 
Having one or more bi-dimensionally measurable lesions as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria, 
- 
Was not felt to be amenable to curative resection 
- 
With an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
- 
Life expectancy of longer than 3 months (clinical assessment) 
- 
Adequate organ and marrow function as defined below:  
o  Absolute neutrophil count (ANC) greater than/equal to 1,500/mm3;  
o Platelets greater than/equal to 100,000/ mm3;  
o Hemoglobin greater than/equal to 9 gm/dl (may be transfused to maintain or 
exceed this level);  
o Total bilirubin less than/equal to 1.5 within institutional upper limit of normal 
(IULN);  
o Aspartate aminotransferase (AST or SGOT)/alanine aminotransferase (ALT or 
SGPT) less than/equal to 2.5 times IULN, or less than/equal to 5 times IULN if 
known liver metastases;  
o Serum creatinine less than/equal to 1.5 times IULN Patients must have an 
International Normalized Ratio (INR) less than/equal to 1.5 and a Partial 
Thromboplastin Time (PTT) less than/equal to 1.5 IULN 
 

 
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- 
May have received adjuvant therapy for primary colorectal cancer provided that at least 
6 months have elapsed from the time the adjuvant therapy was concluded and recurrent 
disease was documented 
- 
Patients with history of hypertension must be well-controlled (blood pressure less 
than/equal to 150/100), on a stable regimen of anti-hypertensive therapy. 
 
Exclusion criteria 
- 
Prior systemic targeted therapy for mCRC 
- 
Radiotherapy or surgery for mCRC less than 4 weeks before random assignment. 
- 
Undergone major surgical procedures or open biopsy within 28 days before the 
initiation of study treatment 
- 
Experienced significant traumatic injury, within 28 days before study entry 
- 
Currently using or had recently used therapeutic anticoagulants, thrombolytic therapy, 
chronic, daily treatment with aspirin (higher than 325 mg/daily). (Patients may have 
prophylactic use of low molecular weight heparin; however prophylactic use of heparin 
with low molecular weight is acceptable) 
- 
Proteinuria exceeding 500mg/24 h 
- 
History or presence of central nervous system metastases 
- 
Female patients who are pregnant or lactating 
- 
Patients with a history of allergic reactions attributed to compounds of similar chemical 
or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin 
- 
Serious non-healing wound, ulcer, or active bone fracture 
- 
Myocardial infarction within 6 months before of study enrollment; 
- 
 History of stroke within 6 months before of study enrollment;  
- 
Unstable symptomatic arrhythmia requiring medication  

 
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- 
 Clinically significant peripheral vascular disease;  
- 
Uncontrolled diabetes; Serious active or uncontrolled infection 
- 
Inability to comply with study and/or follow-up procedures 
 
 

 
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Interventions 
 
Arms 
Assigned Interventions  
 
 
 
 
Intervention (Arm A): 
 
FOLFIRI -3+bevacizumab (AryoGen 
pharmed) 
Drug: 
FOLFIRI -3: 
In this group FOLFIRI-3 regimen consist of 
irinotecan 100 mg/m2 over 1 hour at day 1, 
leucovorin 400 mg/m2 at day 1 followed by a 46 
hour 5-FU continuous infusion (2000 mg/m2)  
and irinotecan 100 mg/m2 over 1 hour at day 3 will 
administer.  
Drug:  
Bevacizumab (AryoGen pharmed):    
5 mg/kg will administer at day 1 every 2 weeks. 
Initially it will administer as a 90 min infusion. If 
the first infusion is well tolerated, the second will 
deliver as a 60 min infusion; if the 60-min infusion 
is well tolerated; all subsequent infusions will 
deliver over 30 min.  
 

 
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Active Comparator (Arm B) 
FOLFIRI -3 + Bevacizumab (Avastin®) 
Drug: 
FOLFIRI-3: 
In this group FOLFIRI-3 regimen consist of 
irinotecan 100 mg/m2 over 1 hour at day 1, 
leucovorin 400 mg/m2 at day 1 followed by a 46 
hour 5-FU continuous infusion (2000 mg/m2) and 
irinotecan 100 mg/m2 over 1 hour at day 3 will 
administer.  
 Drug:  
Bevacizumab (Avastin®):  
5 mg/kg will administer at day 1 every 2 weeks. 
Initially it will administer as a 90 min infusion. If 
the first infusion is well tolerated, the second will 
deliver as a 60 min infusion; if the 60-min infusion 
is well tolerated; all subsequent infusions will 
deliver over 30 min 
 
Induction treatment was administrated every 2 weeks for a maximum of 26 cycles, until disease 
progression, unacceptable toxicities, surgical intervention, or withdrawal of consent. 
The response was defined according to Response Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1). Radiological response assessment was validated in a blinded fashion 
by an independent radiologist.  
 
 

 
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Suggested dose alterations for toxicity 
❖ Diarrhea   
Patients who develop diarrhea within 24 hours of treatment should be closely monitored and 
supportive care measures (e.g., fluid and electrolyte replacement, loperamide, antibiotics, etc.) 
provided as needed. Do not retreat until resolution of diarrhea for at least 24 hours without anti-
diarrheal medication 
For patients who develop abdominal cramps and/or diarrhea within 24 hours of treatment, 
administer atropine (0.5 mg IV) and premedicate with atropine during later cycles. 
Reduce irinotecan dose by 20 % for patients with grade 2 or worse diarrhea during a prior 
treatment cycle  
❖ Myelotoxicity  
Delay treatment until absolute neutrophil count is >1500 cells/microL and the platelet count is 
>100,000/microL. United States Prescribing Information suggests irinotecan dose reduction by 
25% for grade 3 or worse hematologic toxicity during a prior cycle. A different approach is 
used by some clinicians. If treatment is delayed for two weeks or delayed for one week on two 
separate occasions, the day 1 FU bolus is eliminated. With the second occurrence, reduce the 
FU infusion dose by 20 percent and reduce irinotecan dose to 150 mg/m2  
Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for 
dihydropyrimidine dehydrogenase deficiency 
❖ Other toxicity 
Hold treatment until less than or equal to grade 1, if grade 2; hold treatment until less than or 
equal to grade 2, if grade 3 or 4. Withhold FU for grade 2 or worse diarrhea, and restart at a 
lower dose after complete resolution.  
Reduce irinotecan dose by 20% for patients with grade 3 or worse other non-hematologic 
toxicities during a prior treatment cycle.   
For grade 3 mucositis; prophylactic ice chips may be beneficial 
If there is a change in body weight of at least 10 percent, doses should be recalculated. 

 
Bevacizumab (AryoGen pharmed) against Avastin® in metastatic colorectal cancer 
 
 
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Outcomes 
Primary outcomes 
The primary end point is progression-free survival (PFS). 
PFS is defined as the time from the date of randomization to the first date of documentation 
progression (per investigator assessment) or death as a result of any cause. 
Secondary outcomes 
- 
Overall survival OS is defining as the time from date of randomization to date of death 
due to any cause. 
- 
Objective Response rate (Tumor response was defined as partial and complete 
responses, according to the RECIST criteria). 
- 
Monitoring of side effects  
- 
Time of treatment failures define as the time from the date of randomization to the date 
of each of the following, 
- The treatment modalities did not destroy or modify the cancer cell. 
- 
The tumor either became larger (disease progression) or stayed the same size after 
treatment,  
- 
Death from any cause 
- 
Discontinuation of treatment 
Safety outcomes 
Safety will be assessed on the basis of reports of adverse events, laboratory-test results, and 
vital sign measurements. Adverse events were categorized according to the Common Toxicity 
Criteria of the National Cancer Institute, version .0, in which a grade of 1 indicates mild adverse 
events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade 
of 4 life-threatening adverse events.  
Immunogenicity 
Samples for immunogenicity assessment (antidrug antibody [ADA]) will be collected 
at the beginning of the first bevacizumab administration (visit 1), (visit 3), (visit 5), 
(visit 7), (visit 9), (visit 11), (visit 13), (visit 15), (visit17), (visit 19), (visit 21), (visit 

 
Bevacizumab (AryoGen pharmed) against Avastin® in metastatic colorectal cancer 
 
 
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23) and (visit 25). All patients in each treatment arm were considered evaluable for 
ADA response to bevacizumab. The evaluation of both arms immunogenicity used 
tiered strategies to detect, confirm, and characterize ADA responses. Each tiered 
strategy included the following elements:  
• 
A screening assay to detect anti-bevacizumab antibodies; 
• 
A confirmatory assay to assess the specificity of screen positive samples by competition 
with excess bevacizumab; 
• 
A titration assay to determine anti-bevacizumab antibody titers for confirmed positive 
samples. 
Serial dilutions of all confirmed positives were performed in order to estimate the magnitude 
of a positive response. The highest dilution that produced a signal above the screening assay 
cut point multiplied by the assay minimum required dilution (1:10) was deemed the end-point 
titer and was expressed as a dilution factor (reciprocal of the dilution). Any potential effects of 
ADAs on the efficacy (clinical index for efficacy) and safety (administration-related reactions 
[ARRs]) of bevacizumab were explored using descriptive statistics. 
 
Termination policy 
This decision is the responsibility of the scientific steering committee and must be approved 
by the Food and Drug Administration of Iran, the Ethics Committee of Shahid Beheshti 
University of Medical Sciences and the Ethics Committee of Ahwaz Jondi Shapur University 
of Medical Sciences. 
  
 
 
 
 
 
 

 
Bevacizumab (AryoGen pharmed) against Avastin® in metastatic colorectal cancer 
 
 
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Participant timelines 
 
 
Study Period for 52 weeks 
Screening Allocation 
Post Allocation/intervention 
Time point 
Visit0 
Visit1 
Visit2 Visit3 Visit4 Visit5 Visit6 Visit7 Visit8 
Day 
 -7 to -1 
days 
0 day 
2nd  
week 
4th     
week 
6th  
week 
8th  
week 
10th 
week 
12th  
week 
14th 
week 
Informed 
consent 
× 
 
 
 
 
 
 
 
 
Medical history 
× 
 
 
 
 
 
 
 
 
Eligibility 
criteria 
× 
 
 
 
 
 
 
 
 
Physical 
examination 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Random 
allocation 
 
× 
 
 
 
 
 
 
 
FOLFIRI- 3 
 
× 
× 
× 
× 
× 
× 
× 
× 
Bevacizumab 
 
× 
× 
× 
× 
× 
× 
× 
× 
LAB data (CBC, 
LFT.BUN/CR, 
U/A) 
 
× 
× 
× 
× 
× 
× 
× 
× 
β-HCG* 
× 
 
 
 
 
 
 
 
 
CEA  
× 
 
 
 
 
 
× 
 
 
Imaging (CT to 
evaluate 
metastatic status) 
× 
 
 
 
 
 
× 
 
 
Concomitant 
medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Adverse event 
 
× 
× 
× 
× 
× 
× 
× 
× 
Immunogenicity 
sampling 
 
× 
 
× 
 
× 
 
× 
 
 
*Only in Women 
 
 
 
 
 
 

 
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*Only in Women 
 
 
 
 
 
 
 
 
 
 
 
 
Study Period for 52 weeks 
Post Allocation / intervention 
Time point 
Visit 
9   
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
Visit 
16 
Visit 
17 
Day 
16th 
week 
18th 
week 
20th 
week 
22nd 
week 
24th 
week 
26th  
week 
28th  
week 
30th  
week 
32nd  
week 
Informed consent 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
Physical examination 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Random allocation 
 
 
 
 
 
 
 
 
 
FOLFIRI 3 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Bevacizumab 
× 
× 
× 
× 
× 
× 
× 
× 
× 
LAB data (CBC, LFT.BUN/CR, 
U/A) 
× 
× 
× 
× 
× 
× 
× 
× 
× 
β-HCG* 
 
 
 
 
 
 
 
 
 
CEA  
 
 
 
× 
 
 
 
 
 
Imaging (CT to evaluate 
metastatic status) 
 
 
 
× 
 
 
 
 
 
Concomitant medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Adverse event 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Immunogenicity sampling 
× 
 
× 
 
× 
 
× 
 
× 

 
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Study Period for 52 weeks 
Post Allocation / intervention 
Close- 
out 
Time point 
Visit 
18 
Visit 
19 
Visit 
20 
Visit 
21 
Visit 
22 
Visit 
23 
Visit 
24 
Visit 
25 
Visit 
26 
Visit  
27 
Day 
34th   
week 
36th   
week 
38th   
week 
40th   
week 
42nd  
 
week 
44th   
week 
46th  
 
week 
48th   
week 
50th   
week 
52nd 
week 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Physical examination 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Random allocation 
 
 
 
 
 
 
 
 
 
 
FOLFIRI 3 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Bevacizumab 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
LAB data (CBC, 
LFT.BUN/CR, U/A) 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
β-HCG* 
 
 
 
 
 
 
 
 
 
 
CEA  
× 
 
 
 
 
 
 
 
 
× 
Imaging (CT to 
evaluate metastatic 
status) 
× 
 
 
 
 
 
 
 
 
× 
Concomitant 
medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Adverse Event 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Immunogenicity 
sampling 
 
× 
 
× 
 
× 
 
× 
 
 
 
*Only in Women 
 
 
 
 
 
 
 
 
 

 
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Sample size 
The primary endpoint (PFS) was assumed to be 10.7 months in both groups. By defining a 2-
month shorter PFS with bevacizumab (AryoGen pharmed) than with bevacizumab (Avastin®) 
as the acceptance limit for non-inferiority, a non-inferiority margin of (δ = −2 month) was 
selected. With 2:1 allocation, total sample sizes of 114, achieve 80% power to detect non-
inferiority margin. The significance level of the test was targeted at 0.05 and standard deviation 
selected 4 months. Considering 10% losses to follow up, final sample size is 126 patients.  
Recruitment 
This study has two arms with 2:1 allocation and 126 patients will participate: 
1. Group I: subjects will receive bevacizumab (produced by AryoGen Pharmed) IV infusion 
plus FOLFIRI-3 from 1st to 26th visit. 
2. Group II: subjects will receive Avastin® (the reference drug, produced by Genentech/Roche) 
IV infusion plus FOLFIRI-3 from 1st to 26th visit. 
Randomization 
The randomization plan of the patients will be carried out using an on-line system 
(http://www.randomization.com). Using permuted block randomization (length of each block 
is 6) will be made, for a total of 126 patients (with 2:1 allocation ratio). Once the randomization 
has been made, each patient is given a code with which he will be identified throughout the 
study. The assigned code will be denoted by 4 initials (corresponding to the 2 first letter of the 
first name, the 2 first letter of the first surname) and 3 numbers (center code). Moreover, the 
code described is followed by study unique identification consisting of first two letters of the 
generic name and study phase, respectively (which is BE3-) and 4 numbers (corresponding to 
the randomization number), e.g. ABCD001BE3-0001. The randomization number will be 
assigned in a consecutive way. Each Study's drug package for the course of a patient's 
treatment will have a 3-digit number similar to the randomization code (this number 
includes two English letters and one number, which is unique for each disease), so as long 
as the random code It's unique, each patient will have a unique drug package that will be 
completely identified with the randomized process. Regarding this, even if it is decoded 
for a patient, the type of drug used by other people will not be identified. Responsibility 
for creating random codes is the responsibility of CRO Trial on behalf of Dr. Hamid 
Hosseini). 

 
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Allocation (concealment process) 
Randomization process will not be exposed to those who are conducting the study and will be 
provided via telephone call for each consecutive eligible patient after the identification 
characteristics of each eligible patient have been recorded by the randomization center. Since 
the randomization code is unique, the next sequence is not predictable for site personnel. The 
allocation of randomization code will be performed after all inclusion criteria and none of 
exclusion criteria were met and signing the informed consent was done.  
 
Blinding 
Both Bevacizumab products are indistinguishable for patients and health care providers. Since 
the route of administration is infusion, it will be possible to make patients blind about the 
treatment group which they have been allocated to.  
 
Treatment compliance 
Patient education will be done to reduce the lack of adherence to treatment in each visit. Each 
patient has a reminder call before the visit. 
 
Treatment discontinuation 
The reasons for discontinuation of the drug should be clearly stated in the CRF. Study 
participants may be excluded from the study for the following reasons: 
• Patient dissatisfaction 
• Failure to adhere to treatment includes refusing to study drug requirements, refusing 
to perform the procedures listed in the study protocol or using drugs that are 
prohibited for the patient. 
• Pregnancy or suspected pregnancy 
• The occurrence of any blood, hepatic or renal complications requiring treatment 
discontinuation. 
• The onset of any side effect that the investigator considers necessary for the patient to 
leave the study 

 
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• Failure to follow the patient 
• If the patient needs treatment changes. 
 
 

 
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Data management 
Data collection methods 
Data collection will be electronic-based and the data will be recorded in eCRF. Adequate heed 
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.” Trial CRO” and sponsor is responsible to set up a regular monitoring scheme by 
qualified staff. 
Data management 
The chief investigator, principal 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 chief investigator and principal 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 and sponsor is responsible for planning a monitoring which 
will be conducted by qualified personnel in order to check the eCRF for discrepancies with the 
patient 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. 
 

 
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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) 
• 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 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 methods 
1.1 Analysis principles 
All tests of the effect of treatment on outcomes will be conducted on a per protocol basis. The 
intent-to-treat (ITT) patient population includes all patients who signed the informed consent 
form and underwent random assignment, and the per protocol set (PPS) population will be 
defined as the ITT population excluding patients who violated protocols to a considerable 
extent, including major protocol inclusion/exclusion criteria or treatment protocols. The safety 
population will be defined as all patients receiving at least one dose of study drugs.  
Missing data & Outliers 
All data collected on the CRF will be listed. Outliers will be identified by examining standard 
plots. Cases that visually “stand out” will be assessed for possible influence on results and 
conclusions by comparing results from analyses with and without the outlier(s).  
 

 
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1.2 Center considerations  
Study center will not be adjusted for in the main analyses of the primary and secondary 
outcomes. Descriptive report of centers will be reported. 
 
1.3 Multiple comparisons and multiplicity 
There are not any planned multiple comparisons. 
 
1.4 Covariate Adjustment 
The primary statistical analyses for outcome variables will be unadjusted.  
 

 
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Statistical analysis 
1.1 Trial profile 
All patients who provide informed consent will be accounted for in the final statistical report. 
A CONSORT style flow diagram will illustrate patient progression through the trial from initial 
screening for eligibility to completion of the final primary outcome assessment. Number 
(percentage) by treatment group will be given for patients in the PPS population, reasons for 
study withdrawal, and major protocol deviations and violations. 
 
1.2 Patient characteristics and baseline comparisons 
Demographic and other baseline characteristics will be summarized by assigned treatment 
group. Categorical variables will be summarized by frequencies and percentages. Percentages 
will be calculated according to the number of patients for whom data are available. Where 
values are missing, the denominator, which will be less than the number of patients assigned 
to the treatment group, will be reported either in the body or a footnote in the summary table. 
Continuous variables will be summarized by mean and standard deviation or quartiles. The 
following baseline demographic and clinical characteristics will be presented by treatment 
group: gender, age at randomization, ECOG performance status (0, 1, 2), Primary tumor site 
(Colorectal, Colon, Rectal), Stage at first diagnosis (Local regional, Metastatic), Number of 
metastatic sites (0, 1, 2, 3, >=4), Alkaline phosphatase (Abnormal, Normal), Prior adjuvant 
therapy (Yes, No). 
 
1.3 Analysis of the primary outcome 
2 Main approach for analysis is per protocol also ITT analysis will have done. 
PFS is the primary study end point, and is defined as the time from random assignment to the 
first documentation of PD (per investigator assessment), or death from any cause. Patients 
undergoing curative metastasectomy will be censored at the time for surgery. For the primary 
endpoint of PFS, the HR for bevacizumab (AryoGen pharmed) to bevacizumab (Avastin®) and 
its 95 % CI will be calculated to show the non-inferiority of bevacizumab (AryoGen pharmed) 
to bevacizumab (Avastin®), respectively. PFS will be estimated using the Kaplan–Meier 

 
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method. The 95 % CI for the median PFS will be calculated using the method of Brookmeyer 
and Crowley (Brookmeyer and Crowley 1982). The Cox proportional hazards model will be 
used to estimate and construct confidence intervals for the HR. 
2.1 Analysis of secondary outcomes 
Secondary efficacy endpoints are overall survival (OS), response rate (RR) and time to 
treatment failure. 
OS and time to treatment failure will be estimated using the Kaplan–Meier method and the 95 
% CI for the median of these outcomes will be calculated using the method of Brookmeyer and 
Crowley (Brookmeyer and Crowley 1982). The Cox proportional hazards model will be used 
to estimate and construct confidence intervals for the HR. To determine the magnitude of the 
treatment effects for ORR, proportion and frequency in two groups will be calculated. 
 
2.2 Analysis of safety outcomes 
Adverse events will be reported as incidence. For each SAE, data by treatment group will be 
summarized using frequencies and percentages. SAEs will be classified according to body 
system with reference to the Medical Dictionary for Regulatory Activities (MedDRA) central 
coding dictionary, version 18.  
 Monitoring 
Site initiation visit 
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 initiation visit 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 

 
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for each study site and will be confirmed by the respective PI 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. 
Study closeout 
Study closeout visit will be performed to ensure the proper documentation of the data 
and return of the medicinal product and the equipment’s 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 PI. The site close-out visit will start with a brief meeting with the PI and 
a decision will be made regarding the disposal of the remaining investigational 
medicinal product. The study documents will be available at the trial site. A copy all 
safety reports will remain with the PI 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. 
Adverse events 
Safety will be assessed on the basis of reports of adverse events, laboratory-test results, and 
vital sign measurements. Adverse events will be categorized according to the Common 
Toxicity Criteria of the National Cancer Institute, version 4.0, in which grade 1-4 corresponds 
to mild, moderate, serious and life-threatening adverse events. 
Any adverse event should be recorded. If the adverse effect is serious enough to require medical 
attention, it should be reported as soon as possible within a few days.  
Scientific steering committee should be informed and it will take decisions on whether or not 
blinding should be removed and the patient should be excluded from the study. 
In case of fatal or severe event requiring hospital admission, reporting should be prompt at the 
same day to the responsible officer in AryoGen pharmed Company by fax.  
Studies show that this drug has some side effects: 
• venous thromboembolic events  
• hypertension 
• bleeding 
• arterial thromboembolic events 

 
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• gastrointestinal perforations 
• wound healing complications 
• fistula/intra-abdominal abscess 
• proteinuria 
Adverse Event (AE) will be described as any medical event occurring in patients who 
participate in the trial and do not necessarily have a causal relation with the treatment in study. 
Clinical manifestations which will be reported as an adverse effect include any symptom, sign 
(as any abnormal laboratory determination) or temporary disease associated to the use of the 
drug in study, whether they are or not etiologically related to it.  
The medical conditions which 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) will be defined as the harmful response to a drug and that is 
produced with the doses regularly used in the human being for the prophylaxis, diagnosis, 
treatment of diseases or to modify a physiological function [15]. 
It will be considered a Serious Adverse Event (SAE) any event that: 
- 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. 
Record and report of AE: 
All the AE and ADRs will be recorded in the medical record of the patient and in the 
appropriate section of the CRF, and will be classified based on their severity and relation with 

 
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the treatment in study according to the Researcher's criteria and following the guidelines 
presented below.  
AE classification based on its severity: 
AE 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 age 
appropriate instrumental ADL*. 
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 in study: 
In order to establish the relation between the AE or the ADR and the treatment in study, the 
following definitions will be considered: 

 
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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. 
 
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.  
Unassessable/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. 
 
 
 
 
 

 
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WHO-UMC Causality Categories 
Causality term 
Assessment criteria* 
Certain 
• Event or laboratory test abnormality, with plausible time 
relationship to drug intake  
• Cannot be explained by disease or other drugs  
• Response to withdrawal plausible (pharmacologically, 
pathologically)  
• Event definitive pharmacologically or phenomenological 
(i.e. an objective and specific medical disorder or a recognized 
pharmacological phenomenon)  
• Rechallenge satisfactory, if necessary 
Probable/ Likely 
• Event or laboratory test abnormality, with reasonable time 
relationship to drug intake  
• Unlikely to be attributed to disease or other drugs  
• Response to withdrawal clinically reasonable  
• Rechallenge not required 
Possible 
• Event or laboratory test abnormality, with reasonable time 
relationship to drug intake  
• Could also be explained by disease or other drugs  
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug 
intake that makes a relationship improbable (but not 
impossible)  
• Disease or other drugs provide plausible explanations 

 
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Conditional/ Unclassified 
• Event or laboratory test abnormality  
• More data for proper assessment needed, or  
• Additional data under examination 
Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction  
• Cannot be judged because information is insufficient or 
contradictory  
• Data cannot be supplemented or verified 
*All points should be reasonably complied with 
 
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 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. 

 
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- 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.  
- 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.  
 
 
 

 
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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 Serious Adverse Event 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.  
 
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 
• 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) 
• A patient that does not receive a chemotherapy regimen for two consecutive cycles 
The reason(s) for withdrawal should be stated clearly in the eCRF. 
 
 

 
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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. 
Auditing 
Regular auditing will be carried out to ensure strict adherence to the study protocol. the auditor 
will be determined and introduced to regulatory authorities by the sponsor. 
The Audit reports will be prepared for the sponsor and the results will be reported to chief 
investigator as well. 
Auditors will be responsible for: 
- 
Regular visits to the study centers to inspect the sufficiency of existing structures 
and processes  
- 
Identifying training needs of study site staff 
- 
Making necessary arrangements to set up training courses 
- 
Monitoring adherence to all procedures foreseen in the study protocol  
- 
Preparing written report from each visit 
- 
Certifying the quality and reliability of the monitoring visits during the study 
- 
Certifying the quality and reliability of the study conduction by investigators and 
staff 
- 
Certifying the quality and veracity of the data to be reported to legal bodies 
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 Shahid Beheshti university of medical sciences and Ahvaz Jondi Shapur 

 
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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 the 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. 
 
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 chief 
Investigator and AryoGen Pharmed Company, and should be approved by the Ethics 
Committee prior to implementation and notified to the health authorities in accordance with 

 
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local regulations. 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 chief Investigator and AryoGen Pharmed Company 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 chief investigator and principal investigators (with the exemption of this study 
contract) should be officially declared to IFDA as a written conflict of interest letter. 
 
Funding organization/Sponsor 
Covering all expenses of the study including the physicians’ contract, laboratory costs, 
providing 126 patients with their medication and insurance will be the responsibility of 
AryoGen Pharmed pharmaceutical company. 
 
Access to data 
Chief investigator, sponsor and CRO Trial will have access to full dataset. In addition, ethic 
committee and regulatory organizations can access to data, if needed. 
Ancillary and post-trial care 
Ancillary care (related to trial) will be provided by principal investigator 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 chief 
Investigator and the sponsor after prior notice to the “steering committee for their review and 
comments.  
 
 

 
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Appendices 
 
Appendix 1: Informed consent form 
Informed consent form for participation in the clinical trial design: Comparison of the efficacy 
and safety of bevacizumab of AryoGen Pharmed company with Avastin® (manufactured by 
ROCHE Company) in patients with metastatic colorectal cancer. 
Mrs./Mr.…………………………. 
I hereby invite you to participate in the above-mentioned research. Research information is 
provided in this service sheet and you are free to participate or not in this research. You do not 
have to make an immediate decision and you can ask your questions from the research team to 
decide on it and consult with anyone you want. Before signing this consent, make sure you 
understand all the information in this form and all your questions have been answered. 
Researcher……………………....
 
1- I know that the purpose of this study is to compare the efficacy and safety of 
bevacizumab of AryoGen Pharmed Company with Avastin® (manufactured by ROCHE 
Company) in patients with metastatic colorectal cancer. 
2- I know that my participation in this research is totally voluntary and I do not have to 
participate in this research. I was assured that if I did not want to participate in this 
study, I would not be deprived of routine diagnostic and therapeutic care and my 
therapeutic relationship with the treatment center and the physician will not get 
affected. 
3- I know that my cooperation in this study is that, after signing informed consent and 
being placed randomly in one of the groups of bevacizumab will be treated according 
to the following protocol: 
       Patients are randomized in to the two groups A and B (AryoGen pharmed bevacizumab          or 
Avastin®) and will be treated according to the following protocol:  
Bevacizumab 5 mg/kg will administer at day 1 every 2 weeks. Initially it will administer as a 
90 min infusion. If the first infusion is well tolerated, the second will deliver as a 60 min 
infusion; if the 60-min infusion is well tolerated; all subsequent infusions will deliver over 30 
min. 
 

 
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FOLFIRI-3: 
      FOLFIRI-3 regimen consist of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 
mg/m2 at day 1 over 2 hours, followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) 
and irinotecan 100 mg/m2 over 1 hour at day 3 will administer. 
      These treatment cycles will be repeated every 2 weeks for 26 cycles. Also during 6 months 
to 1 year therapeutic evaluations will be done.  
      Before starting treatment, the full detail of the study, drug administration and its possible 
side effects have been described to me. 
4- The possible benefits of my participation in this research are as follows: 
By participating in this research, the cost of my medication will be free of charge, and 
during this study, I will be examined more carefully and precisely regarding side effects 
of medications by physicians. By participating in this study, I can help improve the 
patient's treatment process and make cheaper drugs being available for patients like me. 
5- The possible harms and adverse events of participation in this study are as follows: 
Possible damages include side effects of medications. According to the fact that one of 
the study groups receives Avastin® (manufactured by Roche) is a common drug that is 
commonly used in many countries, including Iran, adverse events are the same as 
mentioned in the pharmacy books. In the other group receiving bevacizumab of 
AryoGen pharmed, the side effects are similar to that of the previous one and have not 
been seen more than the usual treatment. 
6- I know that the researchers of this clinical trial keep all of my information, confidential 
and are only allowed to publish the general and cumulative results of this research 
without mentioning my name and profile. 
7- I know that the Ethics Committee can have access to my information for monitoring 
my rights. 
8- Dr. Hamid Reza Rezvani was introduced to me for answering my questions and I was 
told that whenever a problem or question related to participation in the above-
mentioned research came to me, I can ask him. His address and phone number are given 
to me as follows: 
Address: Taleghani Hospital, Shahid Beheshti university of medical sciences, Shahid 
Arabi St., Yaman St., Chamran highway, Tehran, Iran. 
Telephone: 00982122432560-9 

 
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9- I know that if during the research any physical or mental problem arose for me 
regarding my participation in this research, it would be the responsibility of the 
researcher to treat side effects and compensate the costs and expenses.  
10- I know that if for any reason, the clinical trial is terminated sooner or suspended, my 
research organization or researcher will be notified me of this matter and they ensured 
me that appropriate treatment and follow up will be done for me. 
11- I know that if I become hospitalized due to participation in this study, or a disability or 
any other unpleasant consequence occur for me in this study, that if I did not attend this 
study, it would not happen for me, the relevant compensation is AryoGen pharmed 
company responsibility and I am insured by the AryoGen pharmed company due to the 
adverse events occur for me because of my participation in the study. 
I know that if I have a problem or objection to executers of the research or the research 
process, I can contact the Ethics Committee of Shahid Beheshti University of Medical 
Sciences at the address of: Shahid Beheshti university of medical sciences, Shahid 
Arabi St., Yaman St., Chamran highway, Tehran, Iran and present my problem either 
verbally or in writing. 
12- This form of information and informed consent is provided in two copies and will be 
signed by the researcher and me. A signed copy will be given to me and a signed copy 
will be given to the researcher. 
 
I read and understood the above-mentioned tips, and based on that, I declare my informed 
consent to participate in this research. 
Participant signature: 
 
 
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. 
Researcher signature: 
 
 
. 

 
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Appendix 2: RECIST 
RECIST 
In the terminology of RECIST, “lesion” is generally used instead of “tumour.”  And the 
lesion would be divided in to two categories, target lesion and non-target lesion.  Target 
lesions are lesions that have been specifically measured. Non-target lesions are lesions whose 
presences have been noted, but whose measurements have not been taken. 
Evaluation Criteria for Target Lesions 
At the beginning of an evaluation, certain lesions are measured in order to provide bases for 
comparison. Response assessment and evaluation criteria for target lesions are as follows: 
Complete Response, or CR – Signifies that all target lesions have disappeared during the 
course of treatment. 
Partial Response, or PR – Signifies that decreases of at least 30% have been noted in the 
lesion that has the largest diameter, or LD. 
Stable Disease, or SD – Signifies that there has been no significant decrease or increase in 
the size of target lesions, based on the smallest sum LD. 
Progressive Disease, or PD – Signifies that there has been an increase of at least 20% in the 
sum of the LD of targeted lesions. 
Evaluation Criteria for Non-Target Lesions 
The criteria for non-target lesions are similar to those of target lesions: 
▪ 
Complete Response, or CR – Signifies the disappearance of all non-target lesions. 
▪ 
Stable Disease, or no CR/no PD – Signifies the continued presence of one or more non-
target lesions. 

 
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▪ 
Partial Response, or PD – Signifies that appearance of at least one new lesion, or the 
increasing size of at least one existing non-target lesion. 
 
 
 
 

 
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Fatima A. Haggar, M.P.H.,1,2 and Robin P. Boushey, M.D., Ph.D.1 CLINICS IN 
COLON AND RECTAL SURGERY/VOLUME 22, NUMBER 4 2009 
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Schwartz’s principle of surgery- chapter 29. nine editions  
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ABC of colorectal cancer Epidemiology Peter Boyle, J S Langman BMJ VOLUME 
321 30 SEPTEMBER 2000 
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 Treatment of metastatic colorectal cancer: focus on panitumumab, Rebecca Y Tay 
Rachel Wong, Eliza A Hawkes, cancer management and research 2015:7 189-198 
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Mutation of a mutL homolog in hereditary colon cancer. Papadopoulos N, 
Nicolaides NC, Wei YF, et al Science 1994; 263(5153):1625–162 
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 Precision medicine in colorectal cancer: the molecular profile alters treatment 
strategies, Nguyen H. Tran, Ludmila L. Cavalcante, Sam J. Lubner, Daniel L. 
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A. Deming.THR.adv.med onco. 2015, Vol. 7(5) 252–262  
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FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment 
for patients with metastatic colorectal cancer–subgroup analysis of patients with 
KRAS: mutated tumours in the randomised German AIO study KRK-0306 S. 
Stintzing1, L. Fischer von Weikersthal2, T. Decker3, U. Vehling-Kaiser4, E. 
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1693–1699, 2012 
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A meta-analysis of randomized controlled trials comparing chemotherapy plus 
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the GERCOR OPTIMOX1 study, F.-C. Bidard C. Tournigand, T. Andre, M. 
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Goebel, C. Louvet & A. de Gramont, Annals of Oncology 20: 1042–1047, 2009  

 
Bevacizumab (AryoGen pharmed) against Avastin® in metastatic colorectal cancer 
 
 
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with    bevacizumab: clinical outcomes in first-line metastatic colorectal 
cancers according to plasma angiopoietin-2 levels. Stefano Kim, Erion Dobi, 
Marine Jary, Franck Monnien, Elsa Curtit, Thierry NGuyen, Zaher Lakkis, 
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biomedcentral.com/articles/10.1186/1471-2407-13-611 
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Cancer Initially Treated with FOLFOX–Bevacizumab or FOLFIRI–Bevacizumab: 
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HURWITZ, MARK KOZLOFF,e HALUK TEZCAN,f NANCY ROACH,g 
YONG MUN,h SUSAN FISH,h E. DAWN FLICK,h DARSHAN DALAL,h 
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Phase IV Study of Bevacizumab in Combination with Infusional Fluorouracil, 
Leucovorin and Irinotecan (FOLFIRI) in First-Line Metastatic Colorectal Cancer, 
Alberto Sobrero a Stephen Ackland b Stephen Clarke c Ramón Perez-Carrión d 
Silvana Chiara e John Gapski f Paul Mainwaring g Bernd Langer, Oncology 2009; 
77:113–119