A Pharmacokinetic Study Comparing MB02 And US And EU Avastin® In Healthy Male Volunteers

Study 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 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.

Official Title
-----------------
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

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: MB02
* Drug: US licenced Avastin®
* Drug: EU approved Avastin®


Participation Criteria
=================
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. Total body weight between 60 and 95 kg, inclusive, at Screening. 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 normal range at Screening and Check in as follows. 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 Total bilirubin <1.5 × ULN (<51.30 µmol/L in subjects with Gilbert's syndrome) Blood urea nitrogen ≤1.5 × ULN Creatinine < 132.63 µmol/L Serum albumin: >35 g/L Low density lipoprotein cholesterol ≤ ULN High density lipoprotein cholesterol ≥ lower limit of normal Creatine kinase (CK) < × 2 ULN International normalised ratio (INR) 0.8-1.3 Urine dipstick for proteinuria <2+ Systolic blood pressure ≥90 mmHg and ≤140 mmHg and diastolic blood pressure ≥50 mmHg and ≤90 mmHg at Screening and Check in. Subjects agree to use contraception as detailed in protocol. 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. 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. 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 alcohol breath test and/or urinary drug test screen at Screening or Check in. History of bleeding disorders or protein C, protein S, and/or factor V Leiden deficiency. History of clinically signifiant haemorrhage, epistaxis, GI bleeding, haemorrhoids and/or haemoptysis. History of GI perforation, ulcers, gastro oesophageal reflux, inflammatory bowel disease, diverticular disease, or any fistulae. Alcohol consumption of >24 units per week. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. Positive hepatitis panel, positive human immunodeficiency test. Subjects whose results are compatible with prior immunisation and not infection may be included at the discretion of the Investigator. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to Check-in, or within 5 half lives of the investigational drug used in the study. Use or intend to use slow-release medications/products considered to still be active within 30 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Use or intend use of any prescription medications/ nonprescription products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort, within 30 days prior to Check-in, unless deemed acceptable by the Investigator or designee. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant derived preparations within 7 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Have received a live or attenuated vaccine from 3 months prior to Screening, or have the intention to receive a vaccine during the study. Intend to travel to a region where a vaccination will be required due to endemic disease within 3 months of dosing. Previous treatment with an anti VEGF antibody or any other protein or antibody targeting the VEGF receptor. Use of tobacco- or nicotine-containing products within 5 years prior to Check-in, or positive cotinine test upon Screening or Check-in. Receipt of blood products within 60 days prior to Check-in. Donation of blood from 90 days prior to Screening, plasma from 14 days prior to Screening, or platelets from 42 days prior to Screening. Poor peripheral venous access. History of abnormal peripheral sensation including paraesthesia and/or numbness in arms and/or legs. Have previously completed or withdrawn from this study or any other study investigating bevacizumab, and/or have previously received bevacizumab. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MB02 (Bevacizumab Biosimilar)<br>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1. | Drug: MB02<br>* Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.<br>* Other names: MB02 (Bevacizumab Biosimilar);|
| Active Comparator: US licenced Avastin®<br>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1. | Drug: US licenced Avastin®<br>* Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.<br>* Other names: Bevacizumab (United States);|
| Active Comparator: EU approved Avastin®<br>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1. | Drug: EU approved Avastin®<br>* Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.<br>* Other names: Bevacizumab (European Union);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax: Time of Maximum Observed Serum Concentration | To evaluate the tmax of MB02, US Avastin® and EU Avastin® . | 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®. | 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. | 
| CL: Total Body Drug Clearance After IV Administration | To evaluate the CL of MB02, US Avastin® and EU Avastin® | 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® | 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. | 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. | Day 1 - Day 100 |