Comparing Efficacy and Safety of Stivant (AryoGen Bevacizumab) Versus Avastin in Metastatic Colorectal Cancer

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

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. This trial was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen Pharmed) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic colorectal cancer (mCRC). Patients who met the following criteria could be recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75 years, 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 (ECOG) performance status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function, 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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Bevacizumab + FOLFIRI-3

Detailed Description

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. This trial was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic colorectal cancer (mCRC). Patients who met the following criteria could be recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75 years, 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 (ECOG) performance status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function, 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 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), 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, Clinically significant peripheral vascular disease, Uncontrolled diabetes; Serious active or uncontrolled infection, Inability to comply with study and/or follow-up procedures. The primary endpoint is progression-free survival and overall survival, Objective Response rate, time of treatment failures, adverse events and immunogenicity will be assessed as secondary outcomes.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Ahvaz, Iran, Islamic Republic of
    • Shafa Hospital
  • Hamadān, Iran, Islamic Republic of
    • Shahid Beheshti Hospital
  • Isfahan, Iran, Islamic Republic of
    • Saba Clinic
  • Isfahan, Iran, Islamic Republic of
    • Sheikh Mofid
  • Kermanshah, Iran, Islamic Republic of
    • Payandeh Clinic
  • Kermanshah, Iran, Islamic Republic of
    • Shazad Clinic
  • Mashhad, Iran, Islamic Republic of
    • Imam Reza Hospital
  • Mashhad, Iran, Islamic Republic of
    • Qaem Hospital
  • Rasht, Iran, Islamic Republic of
    • Razi Hospital
  • Rasht, Iran, Islamic Republic of
    • Rasool Hospital
  • Shiraz, Iran, Islamic Republic of
    • Namazi Hospital
  • Tehran, Iran, Islamic Republic of
    • Shariati Hospital
  • Tehran, Iran, Islamic Republic of
    • Firoozgar Hospital
  • Tehran, Iran, Islamic Republic of
    • Imam Khomeini Hospital
  • Tehran, Iran, Islamic Republic of
    • Masih Daneshvari Hospital
  • Tehran, Iran, Islamic Republic of
    • Sina Hospital
  • Tehran, Iran, Islamic Republic of
    • Imam Reza Hospital (501 Artesh)
  • Tehran, Iran, Islamic Republic of
    • Masoud Internal Clinic
  • Tehran, Iran, Islamic Republic of
    • Safa najafi clinic
  • Tehran, Iran, Islamic Republic of
    • Taleqani Hospital
  • Yazd, Iran, Islamic Republic of
    • Mortazavizadeh Clinic
  • Yazd, Iran, Islamic Republic of
    • Seyedshohada Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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:

  • Absolute neutrophil count (ANC) greater than/equal to 1,500/mm3;
  • Platelets greater than/equal to 100,000/ mm3;
  • Hemoglobin greater than/equal to 9 gm/dl (may be transfused to maintain or exceed this level);
  • Total bilirubin less than/equal to 1.5 within institutional upper limit of normal (IULN);
  • 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;
• 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 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 therapeutic use of heparin or low molecular weight heparin is not 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;
• Clinically significant peripheral vascular disease;
• Uncontrolled diabetes; Serious active or uncontrolled infection
• Inability to comply with study and/or follow-up procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab); Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.	Drug: Bevacizumab + FOLFIRI-3; Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists 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 on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.; Other Names: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil
Active Comparator: Bevacizumab + FOLFIRI-3 (Roche Bevacizumab); Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.	Drug: Bevacizumab + FOLFIRI-3; Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists 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 on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.; Other Names: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	PFS was measured from the start of chemotherapy to the date of disease progression or to the date of death if no progression whichever came first, assessed up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival OS was defined as the time from date of randomization to date of death due to any cause	Up to 12 months
Objective Response Rate	Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.	Up to 12 months
Time to Treatment Failure	Time to treatment failure was defined 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 cells,; The tumor either became larger (disease progression) or stayed the same size after treatment,; Death due to any cause,; Discontinuation of treatment	Up to 12 months
Incidence of the Adverse Events	Safety was 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 5.0, 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	Up to 12 months
Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)	Anti-drug antibody assessment	Up to 12 months

Collaborators and Investigators

• Sponsor: AryoGen Pharmed Co.
• Investigators: Principal Investigator: Hamid Rezvani, M.D, Shahid Beheshti University of Medical Sciences

Publications and helpful links

General Publications

• Rezvani H, Mortazavizadeh SM, Allahyari A, Nekuee A, Najafi SN, Vahidfar M, Ghadyani M, Khosravi A, Qarib S, Sadeghi A, Esfandbod M, Rajaeinejad M, Rezvani A, Hajiqolami A, Payandeh M, Shazad B, Anjidani N, Meskinimood S, Alikhasi A, Karbalaeian M, Salari S. Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial. Clin Ther. 2020 May;42(5):848-859. doi: 10.1016/j.clinthera.2020.03.009. Epub 2020 Apr 22.

Helpful Links

• This protocol is registered according to program in Iran Registry of Clinical Trial (IRCT) with IRCT2015072517994N2 code
• Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2016
• Primary Completion (Actual): July 30, 2018
• Study Completion (Actual): July 30, 2018

Study Registration Dates

• First Submitted: September 18, 2017
• First Submitted That Met QC Criteria: September 18, 2017
• First Posted (Actual): September 20, 2017

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: December 30, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Bevacizumab; Leucovorin; Irinotecan
• Other Study ID Numbers: BEV.ARY.HR.94 (III)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No