Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare the Pharmacokinetics (PK), safety and immunogenicity profile of MB02 with US and EU Avastin® in healthy male subjects. During the course of the study, the similarity in pharmacokinetics will be assessed by sampling the levels of drug in the blood, and by comparing these levels among the different administration arms. Safety, tolerability, and immunologic response to the administered drugs will also be evaluated throughout.
The primary PK parameters are Cmax and AUC(0-∞). The PK parameters for bevacizumab will be calculated using standard noncompartmental methods. An analysis of covariance model will be used to analyse the log-transformed primary PK parameters (AUC\[0-∞\].and Cmax) and AUC(0-t). The model will include a fixed effect for treatment and body weight as a covariate. All other PK parameters will not be subject to inferential statistical analysis. Estimates of geometric mean ratios together with the corresponding 90% confidence intervals will be derived for the comparisons of the PK parameters as follows: * MB02 versus EU Avastin® * MB02 versus US Avastin® * EU Avastin® versus US Avastin® PK similarity will be achieved if the 90% confidence intervals (CIs) for the biosimilar-to-reference ratios of PK endpoints (AUC\[0-∞\] and Cmax) fall within the predefined 0.80-1.25 acceptance similarity criteria for all 3 pairwise comparisons; MB02 versus EU-approved Avastin®; MB02 versus US-licenced Avastin®; and EU-approved Avastin® versus US-licenced Avastin®. All AEs will be listed and summarised using descriptive methodology. All observed or patient-reported AEs will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The incidence of AEs for each treatment will be presented by severity and by association with the study drugs as determined by the Investigator (or designee). All safety data will be listed and summarised as appropriate Immunogenicity data (overall anti-drug antibody \[ADA\] incidence and titers, and neutralising ADA results) will be listed. A summary of the number and percent of subjects testing positive for ADA or neutralising antibodies before the dose of MB02, EU Avastin®, or US Avastin® (Day 1) and at scheduled postdose assessments will be presented by treatment arm.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
PAREXEL International - Northwick Park Hospital
Harrow, United Kingdom
Covance Clinical Research Unit Limited
Leeds, United Kingdom
Cmax: Maximum Observed Serum Concentration
To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of Cmax) to establish bioequivalence between the 3 study arms. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric LS means ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity
To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of AUC\[0-∞\]) to establish bioequivalence between the 3 study arms. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric least square means (GLSM) ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
Tmax: Time of Maximum Observed Serum Concentration
To evaluate the tmax of MB02, US Avastin® and EU Avastin® .
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
AUC(0-t) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration;
To evaluate the AUC\[0-t\] of MB02, US Avastin® and EU Avastin®.
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
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Purpose
OTHER
Masking
TRIPLE
Enrollment
114
CL: Total Body Drug Clearance After IV Administration
To evaluate the CL of MB02, US Avastin® and EU Avastin®
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
t1/2: Apparent Serum Terminal Elimination Half-life
To evaluate the t1/2 of MB02, US Avastin® and EU Avastin®
Time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
Immunogenicity
Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here.
Time frame: Day -1, Day 14, 28, 56, and 78
Safety (Incidence of Treatment-related Adverse Events Using CTCAE v4.03)
Compare the incidence of TEAEs reported in each treatment arm.
Time frame: Day 1 - Day 100