A Phase I Study Comparing Pharmacokinetics and Safety of Bevacizumab

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

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Safety Issues
• Intervention / Treatment: Biological: Bevacizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425BAA
    • FP Clinical Pharma S.R.L.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Report the nature and incidence of adverse events and the eventual suspension or abandonment of the study or the participation of a study subject.	63 days

Collaborators and Investigators

• Sponsor: Laboratorios Richmond S.A.C.I.F.
• Collaborators: FP Clinical Pharma S.R.L.; Syngene International Limited
• Investigators: Principal Investigator: Ethel C Feleder, MD, FP Clinical Pharma S.R.L.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): September 11, 2019
• Study Completion (Actual): September 11, 2019

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: safety; Bevacizumab; Bioequivalence; Immunogenicity; Antineoplastic Agents; Biosimilar; healthy male volunteers
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 0221

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No