A Randomised, Double Blind, Three-Arm, Single Dose, Parallel Study To Compare the Pharmacokinetics, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar Drug), US Licenced Avastin® and EU Approved Avastin® in Healthy Male Volunteers
Overview
- Phase
- Phase 1
- Intervention
- MB02 (Bevacizumab Biosimilar)
- Conditions
- Healthy Volunteers
- Sponsor
- mAbxience Research S.L.
- Enrollment
- 115
- Locations
- 1
- Primary Endpoint
- Cmax: Maximum Observed Serum Concentration
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Males of any race, between 18 and 55 years of age, inclusive, at Screening.
- •Body mass index between 18.5 and 29.9 kg/m2, inclusive, at Screening and Check-in.
- •Total body weight between 60 and 95 kg, inclusive, at Screening and Check-in.
- •In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations (congenital nonhaemolytic hyperbilirubinemia \[eg, Gilbert's syndrome\] is acceptable) at Screening or Check-in as assessed by the Investigator (or designee).
- •Relevant clinical laboratory evaluations of haematology, coagulation, urinalysis and clinical chemistry within the following ranges at Screening and Check in. A single repeat test will be allowed at each timepoint.
- •Absolute neutrophil count ≥1.5 × 109 L
- •Platelet count ≥100 × 109 L
- •Haemoglobin \>10 g/dl
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN
- •Alkaline phosphatase (ALP) ≤1.5 × ULN
Exclusion Criteria
- •Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee).
- •History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee).
- •Any current or recent history of active infections, including localised infections. (Within 2 months prior Screening Visit for any serious infection which requires hospitalization or intravenous anti-infective, and within 14 days prior Screening Visit for any active infection which requires oral treatment).
- •History of, or planned surgery, including suturing, dental surgery or wound dehiscence within 30 days of dosing, or within 30 days of the last study visit.
- •Presence of a nonhealing wound or fracture.
- •Known history of clinically significant essential hypertension, orthostatic hypotension, fainting spells or blackouts for any reason, cardiac failure or history of thromboembolic conditions.
- •Medically significant dental disease or dental neglect, with signs and/or symptoms of local or systemic infection that would likely require a dental procedure during the course of the study.
- •Clinically relevant history of alcoholism, addiction or drug/chemical abuse prior to Check-in, and/or positive urinary test for alcohol or drugs of abuse at Screening or Check in.
- •History of bleeding disorders or protein C, protein S, and/or factor V Leiden deficiency.
- •History of clinically significant haemorrhage, epistaxis, GI bleeding, haemorrhoids and/or haemoptysis.
Arms & Interventions
MB02 (Bevacizumab Biosimilar)
Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Intervention: MB02 (Bevacizumab Biosimilar)
EU approved Avastin®
Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Intervention: EU approved Avastin®
US licenced Avastin®
Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Intervention: US licenced Avastin®
Outcomes
Primary Outcomes
Cmax: Maximum Observed Serum Concentration
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.
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.
AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity
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.
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.
Secondary Outcomes
- Tmax: Time of Maximum Observed Serum Concentration(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.)
- Number of Participants With Treatment-emergent Adverse Events (Safety)(Day 1 - Day 100)
- CL: Total Body Drug Clearance After IV Administration(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.(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(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)(Day -1, Day 14, Day 28, Day 56, and Day 78)