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

Study 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.

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

Conditions
-----------------
Healthy Volunteers, Male, Japanese

Intervention / Treatment
-----------------
* Drug: MB02 (Bevacizumab Biosimilar)
* Drug: EU approved Avastin®


Participation Criteria
=================
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 Hemoglobin >10 g/dl Adequate liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN Alkaline phosphatase (ALP) ≤1.5 × ULN Total bilirubin <1.5 × ULN Serum albumin: >3.5 g/dL Low density lipoprotein cholesterol ≤139 mg/dL High density lipoprotein cholesterol ≥ 40 mg/dL Creatine kinase (CK) <2 ULN at D-1 Adequate coagulation: • International normalised ratio (INR) 0.8 to 1.3 Adequate renal function: Blood urea nitrogen: ≤1.5 × ULN Creatinine: <1.5 mg/dL Urine dipstick for proteinuria <2+. All intermittent medications should have been stopped at least 30 days prior to admission to the clinical research center. Subjects agree to use contraception. Ability and willingness to abstain from alcoholic beverages (alcohol) 48 hours prior to admission to the clinical research center. 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. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 60 days prior to Check-in, or within 5 half lives of the investigational drug used in the study. Subjects considered unsuitable for inclusion by the investigator (e.g., inability to understand and comply with the study requirements or presence of any condition which, in the opinion of the investigator, would not allow safe participation in the study). Strenuous exercise within seven days prior to admission to the clinical research center. Significant or acute illness within 15 days prior to drug administration that may impact safety assessments per the judgement of the investigator. Unsuitable veins for infusion and/or venepuncture. 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. 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. 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). 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. Use of tobacco- or nicotine-containing products within 1 year prior to Check-in, or positive cotinine test upon Screening or Check-in. Receipt of blood products within 60 days prior to Check-in. Person who performed blood sampling more than 400 mL within 90 days before administration of investigational drug, more than 200 mL blood within 30 days, or blood donation of blood plasma / platelet component within 14 days. History of abnormal peripheral sensation including paraesthesia and/or numbness in arms and/or legs. Have previously received Bevacizumab either under present study or under any other circumstances.

Ages Eligible for Study
-----------------
Minimum Age: 20 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 (Bevacizumab Biosimilar)<br>* Solution for intravenous infusion, single dose of 3mg/kg, administered as 90- minute infusion<br>|
| 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>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Serum Concentration-time Curve From Time Zero to Infinity [AUC(0-∞)] | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) | To evaluate and compare the Cmax of MB02 and EU Avastin® in Japanese population. | 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) | To evaluate and compare the AUClast of MB02 and EU Avastin® in Japanese population. | 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. | 
| Time of Maximum Observed Serum Concentration (Tmax) | To evaluate and compare the tmax of MB02 and EU Avastin® in Japanese population. | 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) | To evaluate and compare the t1/2 of MB02 and EU Avastin® in Japanese population. | 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) | To evaluate and compare the CL of MB02 and EU Avastin® in Japanese population. | 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) | To evaluate and compare the Vz of MB02 and EU Avastin® in Japanese population. | 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) | Compare the incidence of TEAEs reported in each treatment arm using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. | Day 1 - Day 70 | 
| Incidence of ADA Including Nab (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, 50 and 70. |