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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Bevacizumab + FOLFIRI-3


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)<br>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks. | Drug: Bevacizumab + FOLFIRI-3<br>* 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.<br>* Other names: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil;|
| Active Comparator: Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)<br>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks. | Drug: Bevacizumab + FOLFIRI-3<br>* 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.<br>* Other names: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil;|

What is the study measuring?
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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 |