A Phase I Study Comparing Pharmacokinetics and Safety of Bevacizumab

Study Overview
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Brief Summary
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The aim of the Clinical study is to evaluate the pharmacokinetic and safety profile of a new formulation of Bevacizumab (Zutrab®, Argentinian origin) when compared to two already marketed formulations of Bevacizumab Avastin® (reference product) and Cizumab® (Indian origin), to establish similarity.

Detailed Description
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Three-way bridge phase 1 trial. It is conducted in healthy, male adult subjects, it is single-dose, double-blind, parallel groups, randomized and balanced. Blood samples are collected for up to 90 days, to determine serum drug concentration and anti-drug antibodies. Safety and tolerability are also assessed.

Official Title
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A Double-blind, Randomized, Balanced, Parallel Group, Phase I Study Comparing Pharmacokinetics and Safety of Bevacizumab

Conditions
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Pharmacokinetics, Safety Issues

Intervention / Treatment
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* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study subjects must be willing and able to provide written informed consent Subjects of study, volunteers, adults, healthy. Study subjects whose safety and complementary laboratory tests are within normal values or which, in the Investigator's opinion, do not have clinical relevance: blood count, erythrosedimentation, hepatogram, urea, creatinine, glucose, coagulogram, serology for HIV, hepatitis B , hepatitis C, complete urinalysis, detection of drugs of abuse in urine and electrocardiogram. Sample taken for immunogenicity Body mass index between 19 and 27 kg / m2 at the screening visit. Subjects of study preferably non-smokers. Men with a partner of childbearing age must agree that their partner uses an adequate contraceptive method before entering the study and for at least 3 months after the end of the study. It is understood as a contraceptive method suitable to any hormonal contraceptive method or intrauterine device (which should be established before the start of the study) and the use of a spermicide as a barrier method. The use of a barrier method alone or sexual abstinence is not considered adequate. Subjects must agree not to donate sperm during the study and for 4 months after treatment. Exclusion Criteria: History of pulmonary, gastrointestinal, hepatic, renal, hematological, endocrine-metabolic, neurological or psychiatric illnesses (depressive disorders, in particular) at the time of taking the anamnesis and the physical examination during the first visit of the Protocol of Clinical research. History of gastrointestinal surgeries (except uncomplicated appendectomy, at least 3 months old). History of major surgery, surgical biopsy and / or history of significant trauma within 1 month of the screening visit. Specifically, pre-existing gastrointestinal conditions such as abdominal fistulas, gastrointestinal perforation within 6 months of the screening visit. Specifically, preexisting gastrointestinal conditions such as acute or subacute intestinal occlusion. Specifically, history of inflammatory bowel disease. History of hemorrhagic diseases and / or coagulopathies and / or thromboembolic events. History of heart and vascular diseases: specifically myocardial infarction, unstable angina, cerebrovascular accident, uncontrolled arterial hypertension and cardiac arrhythmias. Background or current history of alcohol or drug abuse. Blood donation within 3 months prior to selection. Administration of any other drug under investigation or participation in a clinical research trial within 3 months prior to the planned participation in this Clinical Research Protocol. History of clinically significant diseases or disorders that, in the opinion of the Investigator, may impede the participation of the study subject for safety reasons or that may influence the results of the same as well as the ability of the study subject to participate in the Clinical Research Protocol. History of hypersensitivity to bevacizumab and / or any of the excipients. Study subjects who present contraindications to therapy Study subjects who have received (2 weeks before) or are receiving aspirin or clopidogrel The study subjects must have suspended any pharmacological treatments at least 2 weeks before the initiation of this Clinical Research Protocol. Non-cooperative study subjects Study subjects employed by the Researcher or the Clinical-Pharmacokinetic Research Unit, with direct participation in the Clinical Research Protocol or other clinical protocols under the Direction of the Researcher or the Clinical-Pharmacokinetic Research Unit Physical findings and laboratory analyses: Cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, endocrine-metabolic, neurological disease or psychiatric disorder (depressive disorders, in particular) Evidence of ulcers, unhealed wounds or bone fractures. Clinically significant abnormalities in any laboratory analysis, and electrocardiogram Positive serology for HIV, hepatitis B, hepatitis C

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zutrab® (Bevacizumab Richmond)<br>a single 1 mg/kg IV dose of Bevacizumab | Biological: Bevacizumab<br>* Single-dose infusion<br>|
| Active Comparator: Avastin®<br>a single 1 mg/kg IV dose of Bevacizumab | Biological: Bevacizumab<br>* Single-dose infusion<br>|
| Active Comparator: Cizumab®<br>a single 1 mg/kg IV dose of Bevacizumab | Biological: Bevacizumab<br>* Single-dose infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Serum Concentration of Bevacizumab (Cmax) | Cmax will be obtained directly from the serum concentration-time curve | 0, 0.33, 0.5, 1, 1.5 hours during infusion, 0.33, 0.66, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512 hours post-infusion | 
| Area Under the Serum Concentration-time Curve of Bevacizumab (ABC0-t) | Area under the serum concentration-time curve from time zero to the last experimental point, will be calculated by the trapezoidal rule | Day 1 to Day 63 | 
| Area Under the Serum Concentration- Time Curve ob Bevacizumab (ABC0-∞) | Area under the serum concentration- time curve from time zero to infinity | Day 1 to Day 63 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach the Peak Serum Concentration (Tmax) | Time to reach the peak serum concentration, which will be obtained directly from the serum concentration curve- time | Day 1 to Day 63 | 
| Terminal Elimination Rate Constant (λz) | Terminal elimination rate constant will be calculated by linear regression analysis of the semi-logarithmic curve | Day 1 to Day 63 | 
| Elimination Half Life (T1/2) | To assess pharmacokinetic parameters | Day 1 to Day 63 | 
| Systemic Clearance (CL) | To assess pharmacokinetic parameters | Day 1 to Day 63 | 
| Distribution Volume | To assess pharmacokinetic parameters | Day 1 to Day 63 | 
| Number of Participants With Positive Anti-bevacizumab Serum Antibodies Detection | To assess the immunogenic potential of the products under investigation, samples were taken for the determination of anti-bevacizumab serum antibodies for each randomized volunteer subject. | Screening and end of study (Day 63) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bevacizumab, Biosimilar, Antineoplastic Agents, Bioequivalence, Immunogenicity, safety, healthy male volunteers