A Randomised, Double Blind, Two-Arm, Single Dose, Parallel Phase I Study To Compare the Pharmacokinetics, Safety and Immunogenicity of MB02 (a Proposed Bevacizumab Biosimilar Drug) and EU Approved Avastin® in Japanese Healthy Male Volunteers
Overview
- Phase
- Phase 1
- Intervention
- MB02 (Bevacizumab Biosimilar)
- Conditions
- Healthy Volunteers
- Sponsor
- mAbxience Research S.L.
- Enrollment
- 49
- Locations
- 1
- Primary Endpoint
- Area Under the Serum Concentration-time Curve From Time Zero to Infinity [AUC(0-∞)]
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
A Randomised, Double Blind, Two-Arm, Single Dose, Parallel Phase I Study To Compare the Pharmacokinetics, Safety and Immunogenicity of MB02 (a Proposed Bevacizumab Biosimilar Drug) and EU Approved Avastin® in Japanese Healthy Male Volunteers.
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 endpoint is AUC(0-∞) for bevacizumab. The secondary PK endpoints will include all other PK parameters for bevacizumab, including Cmax, tmax, t1/2, CL and AUClast. 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 AUClast. 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® A mixed effects model with treatment arm as fixed effect will be used to compare natural-logarithmic transformed PK parameters (AUC\[0-∞+, AUClast and Cmax) between the two treatment arms (MB02 vs EU-approved Avastin®) PK similarity between arms will be concluded if the 90% confidence intervals (CIs) for the geometric mean test/reference ratio of AUC(0-∞) fell within the predefined 0.80-1.25 bioequivalence interval. 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 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® (Day -1) and at scheduled post-dose 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
- •Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions. Subjects must have signed an informed consent before any study-related procedure or evaluation is performed.
- •Healthy Japanese males aged ≥20 to ≤55 years, inclusive, at Screening.
- •Subjects with Body mass index (BMI) between ≥18.5 to ≤28 kg/m2 and total body weight between ≥50 and ≤100 kg, at Screening
- •Subject must have no clinically relevant abnormalities identified by a detailed medical history.
- •Systolic blood pressure ≤140 mm Hg and diastolic blood pressure ≤90 mm Hg.
- •Computerized (12-lead) electrocardiogram (ECG) recording without signs of clinically relevant pathology.
- •All other values for hematology, coagulation and for biochemistry and urinalysis tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the Investigator, according to the following laboratory values:
- •Adequate bone marrow function
- •Absolute neutrophil count ≥1.5 × 109 L
- •Platelet count ≥100 × 109 L
Exclusion Criteria
- •History of relevant allergy/hypersensitivity (including allergy to drug or its excipients).
- •Previous treatment with an anti VEGF antibody like bevacizumab or any other protein or antibody targeting the VEGF receptor.
- •History of bleeding disorders or protein C, protein S, and/or factor V Leiden deficiency.
- •Known history of clinically significant essential hypertension (subjects under any antihypertensive treatment included), orthostatic hypotension, fainting spells or blackouts for any reason, cardiac failure or history of thromboembolic conditions.
- •History of GI perforation, ulcers, gastro oesophageal reflux, inflammatory bowel disease, diverticular disease, diverticular disease, any fistulae, pulmonary hemorrhage (hemoptysis) or reversible posterior leukoencephalopathy syndrome.
- •Any out-of-range laboratory values considered clinically significant by the investigator.
- •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).
- •Any current or recent history of active infections, including localized 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). A negative result for human immunodeficiency virus (HIV), Hepatitis B (Hep B), and hepatitis C (Hep C) is required for participation. If subject shows positive Hepatitis B test, but results are compatible with prior immunisation and not infection may be included at the discretion of the Investigator.
- •Clinically relevant history of alcoholism, addiction or drug/chemical abuse prior to Check-in, and/or positive urinary drug test screen and/or positive breath alcohol test at Screening or Check in. Average intake of more than 24 units of alcohol / wk. (1 unit of alcohol equals \~250mL of beer, 100mL of wine or 35mL of spirits). Positive urine drug screen (opiates, methadone, cocaine, amphetamines (including ecstasy or methamphetamines), cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and phencyclidine).
- •Treatment with non-topical medications within 7 days prior to study drug administration, with the exception of hormonal contraceptives, multivitamins, vitamin C, food supplements and a limited amount of acetaminophen, which may be used throughout the study.
Arms & Interventions
MB02 (Bevacizumab Biosimilar)
Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Intervention: MB02 (Bevacizumab Biosimilar)
EU approved Avastin®
Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Intervention: EU approved Avastin®
Outcomes
Primary Outcomes
Area Under the Serum Concentration-time Curve From Time Zero to Infinity [AUC(0-∞)]
Time Frame: Predose, 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 38, Day 50, Day 62, and Day 70.
To compare the pharmacokinetic (PK) profiles of MB02 and EU Avastin® (in terms of AUC(0-∞)\]) in Japanese population to establish bioequivalence between the 2 study drugs.
Secondary Outcomes
- Maximum Observed Serum Concentration (Cmax)(Predose, 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 38, Day 50, Day 62, and Day 70.)
- Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration (AUClast)(Predose, 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 38, Day 50, Day 62, and Day 70.)
- Incidence of Treatment-related Adverse Events (Safety)(Day 1 - Day 70)
- Incidence of ADA Including Nab (Immunogenicity)(Day -1, Day 14, 28, 50 and 70.)
- Time of Maximum Observed Serum Concentration (Tmax)(Predose, 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 38, Day 50, Day 62, and Day 70.)
- Apparent Serum Terminal Elimination Half Life (t1/2)(Predose, 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 38, Day 50, Day 62, and Day 70.)
- Total Body Clearance (CL)(Predose, 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 38, Day 50, Day 62, and Day 70.)
- Volume of Distribution (Vz)(Predose, 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 38, Day 50, Day 62, and Day 70.)