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 parameter endpoints are Cmax and AUC(0-∞) for bevacizumab. The secondary PK endpoints will include all other PK parameters for bevacizumab, including tmax, t1/2, CL and AUC(0-t). The serum PK parameters of 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 (CI) 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% 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 version 5.0. 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). Each AE will be coded using the Medical Dictionary for Regulatory Activities. 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 (NAB) before the dose of MB02, EU Avastin®, or US Avastin® (Day -1) and at scheduled postdose assessments will be presented by treatment arm. All safety data and immunogenicity data summaries will be based on the safety analysis population. Select analyses may be repeated for subsets with or without ADA and de novo ADA formation as appropriate.
Study Type
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
Early Phase Clinical Unit (EPCU) PAREXEL International GmbH
Berlin, Germany
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 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, 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 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, 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 and compare the tmax of MB02, US Avastin® and EU Avastin® .
Time frame: Predose, 1.5 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, 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 and compare the AUC\[0-t\] of MB02, US Avastin® and EU Avastin®.
Time frame: Predose, 1.5 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
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INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
TRIPLE
Enrollment
115
CL: Total Body Drug Clearance After IV Administration
To evaluate the CL of MB02, US Avastin® and EU Avastin®
Time frame: Predose, 1.5 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, 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 hours (end of infusion), 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 3-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
Immunogenicity: Number of Participants With Anti-bevacizumab Antibodies (Including Neutralizing Antibodies)
Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here. Rows for ADA and nAb are not mutually exclusive, i.e. a participant could be included in more than one Row.
Time frame: Day -1, Day 14, Day 28, Day 56, and Day 78
Number of Participants With Treatment-emergent Adverse Events (Safety)
Compare the incidence of Treatment-emergent Adverse Events (TEAEs) reported in each treatment arm. TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 22.0) and graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Time frame: Day 1 - Day 100