Clinical trial NCT03293654
Conditions: Healthy Volunteers
Sponsor: mAbxience Research S.L.
Start date: 2017-12-07; Completion date: 2019-05-29
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1. arm 2: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1. arm 3: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
Interventions: intervention 1: MB02 intervention 2: US licenced Avastin® intervention 3: EU approved Avastin®
Intervention descriptions: intervention 1: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion. intervention 2: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion. intervention 3: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.

Protocol documents:
Prot_004.pdf: 
Protocol 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 
NCT Number: 
NCT03293654 
Protocol version 
date: 
Version 7.0, 25 March 2019 
 












Protocol 
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Covance Study: 8370738 
Sponsor Reference: MB02-A-02-17 
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RATIONALE FOR CHANGES FROM PROTOCOL VERSION 6.0 TO VERSION 7.0 
Amendment Version 7.0 for the Final Study Protocol, Version 6.0, dated 15 October 2018, 
has been to: 
• Update the Principal Investigator for one of the study sites. 
 
Details of the changes incorporated in this amendment are provided in the table overleaf.  
 










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SYNOPSIS 
Title of study: 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. 
Objectives: 
The primary objective of the study is: 
 
• 
To investigate and compare the pharmacokinetic (PK) profiles of MB02, US-licenced 
Avastin® (US Avastin®) and EU-approved Avastin® (EU Avastin®) to establish 
bioequivalence between the 3 study arms. 
The secondary objectives of the study are: 
 
• 
Evaluation and comparison of derived PK parameters not covered by the primary endpoints 
for MB02, US Avastin® and EU Avastin® 
• 
To compare the safety profile of MB02 and US Avastin® and EU Avastin® 
• 
To compare the immunogenicity of MB02, US Avastin® and EU Avastin® 
 
Study design: 
This will be a Phase 1, double-blind, randomised, parallel-group, single-dose, 3-arm study to 
investigate and compare the PK, safety and immunogenicity profile of MB02 with US and EU 
Avastin® in healthy male subjects. 
 
Potential subjects will be screened to assess their eligibility to enter the trial within 30 days prior to 
study drug administration. Subjects will be admitted to the Clinical Research Unit (CRU) on 
Day -1, and will be confined to the CRU until discharge on Day 8. On Day 1, subjects will receive a 
single 3 mg/kg intravenous (IV) dose of the study drug. Subjects will return on Days 10, 14, 21, 28, 
42, 56, 78 and 100 for nonresidential visits for the collection of pharmacokinetics (PK) and safety 
assessments. Immunogenicity samples will be collected on Days 14, 28, 56, and 78. 
Number of subjects: 
One hundred and fourteen (114) subjects will participate in the study.  
Diagnosis and main criteria for inclusion: 
Healthy male subjects of any race, in good health, between 18 and 55 years of age, inclusive, with a 
body mass index between 18.5 and 29.9 kg/m2, inclusive, and a body weight between 60 and 95 kg, 
inclusive. Subjects will have relevant clinical laboratory evaluations within normal ranges, and be 
able and willing to sign an informed consent form, and to abide by the study restrictions. See 
protocol for detailed inclusion criteria.  
Test products, dose, and mode of administration: 
3 mg/kg MB02, administered as a 90 minute IV infusion 
3 mg/kg US-licenced Avastin®, administered as a 90 minute IV infusion 
3 mg/kg EU-approved Avastin®, administered as a 90 minute IV infusion 
Duration of treatment: 
Planned Screening duration: up to 29 days. 
Planned study duration (Screening to final visit): maximum of 19 weeks.  


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Criteria for evaluation: 
Pharmacokinetics: 
Blood samples will be collected for the analysis of serum concentrations of bevacizumab. The 
primary PK endpoints for bevacizumab will be maximum observed serum concentration (Cmax) and 
area under the serum concentration-time curve (AUC) from time zero to infinity (AUC[0-∞]). The 
secondary PK endpoints for bevacizumab will include time of maximum observed serum 
concentration (tmax), clearance (CL), AUC calculated to the last observable concentration at time 
t (AUC[0-t]) and apparent serum terminal elimination half-life (t1/2). 
Safety: 
Safety endpoints for this study include adverse events (AEs), vital signs measurements, 12-lead 
electrocardiograms, clinical laboratory evaluations and physical examinations. 
Immunogenicity: 
Blood samples will be collected for the assessment of serum concentrations of anti-MB02 and 
anti-Avastin® antibodies  
Statistical methods: 
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. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.............................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
SPONSOR AGREEMENT ........................................................................................................4 
SPONSOR AGREEMENT ........................................................................................................5 
RATIONALE FOR CHANGES FROM PROTOCOL VERSION 6.0 TO VERSION 7.0 ......6 
STUDY IDENTIFICATION .....................................................................................................9 
SYNOPSIS ...............................................................................................................................11 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Overview ................................................................................................................17 
1.2 
Summary of Nonclinical Experience .....................................................................17 
1.3 
Summary of Clinical Experience ...........................................................................17 
1.3.1 
Safety ...........................................................................................................18 
1.3.2 
Pharmacokinetics .........................................................................................18 
1.3.3 
Immunogenicity ...........................................................................................18 
1.4 
Study Rationale ......................................................................................................18 
1.5 
Benefit-risk Assessment.........................................................................................19 
2 
OBJECTIVES ..................................................................................................................20 
2.1 
Primary Objective ..................................................................................................20 
2.2 
Secondary Objectives.............................................................................................20 
3 
ENDPOINTS ...................................................................................................................20 
3.1 
Primary Endpoints .................................................................................................20 
3.2 
Secondary Endpoints .............................................................................................20 
4 
INVESTIGATIONAL PLAN ..........................................................................................21 
4.1 
Study Design ..........................................................................................................21 
4.2 
Discussion of Study Design ...................................................................................21 
4.3 
Selection of Doses in the Study .............................................................................22 
5 
SELECTION OF STUDY POPULATION .....................................................................23 
5.1 
Inclusion Criteria ...................................................................................................23 
5.2 
Exclusion Criteria ..................................................................................................24 
5.3 
Subject Number and Identification ........................................................................25 
5.4 
Subject Withdrawal and Replacement ...................................................................26 
5.5 
Study Termination .................................................................................................26 
6 
STUDY TREATMENTS .................................................................................................27 
6.1 
Description, Storage, Packaging, and Labelling ....................................................27 
6.2 
Study Treatment Administration............................................................................27 
6.3 
Randomisation .......................................................................................................27 


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6.4 
Blinding..................................................................................................................27 
6.5 
Study Treatment Compliance ................................................................................28 
6.6 
Drug Accountability...............................................................................................28 
7 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................28 
7.1 
Concomitant Medications ......................................................................................28 
7.2 
Diet .........................................................................................................................29 
7.3 
Smoking .................................................................................................................29 
7.4 
Exercise ..................................................................................................................29 
7.5 
Blood Donation ......................................................................................................29 
7.6 
Contraception .........................................................................................................29 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................30 
8.1 
Pharmacokinetic Assessments ...............................................................................30 
8.1.1 
Pharmacokinetic Blood Sample Collection and Processing ........................30 
8.1.2 
Analytical Methodology ..............................................................................30 
8.2 
Immunogenicity Assessments ................................................................................31 
8.2.1 
Immunogenicity Blood Sample Collection and Processing .........................31 
8.2.2 
Analytical Methodology ..............................................................................31 
8.3 
Safety and Tolerability Assessments .....................................................................31 
8.3.1 
Adverse Events ............................................................................................31 
8.3.2 
Clinical Laboratory Evaluations ..................................................................31 
8.3.3 
Vital Signs ....................................................................................................32 
8.3.4 
12-Lead Electrocardiogram .........................................................................32 
8.3.5 
Physical Examination...................................................................................32 
9 
SAMPLE SIZE AND DATA ANALYSES .....................................................................32 
9.1 
Determination of Sample Size ...............................................................................32 
9.2 
Analysis Populations ..............................................................................................33 
9.2.1 
Pharmacokinetic Population ........................................................................33 
9.2.2 
Safety Population .........................................................................................33 
9.3 
Pharmacokinetic Analyses .....................................................................................33 
9.4 
Safety Analysis ......................................................................................................34 
9.4.1 
Medical Safety Monitoring ..........................................................................34 
9.5 
Interim Analysis .....................................................................................................34 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................34 
10.1 
Auditing .................................................................................................................34 
10.2 
Monitoring .............................................................................................................35 
11 DATA HANDLING AND RECORD KEEPING ...........................................................35 
11.1 
Data Handling ........................................................................................................35 
11.2 
Case Report Form ..................................................................................................35 
11.3 
Records ..................................................................................................................35 
12 ETHICAL AND REGULATORY CONSIDERATIONS ...............................................36 


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12.1 
Ethics Committee ...................................................................................................36 
12.2 
Regulatory Considerations .....................................................................................36 
12.3 
Informed Consent...................................................................................................36 
12.4 
Subject Confidentiality ..........................................................................................37 
12.5 
Protocol Amendments ............................................................................................37 
13 ADMINISTRATIVE ASPECTS .....................................................................................37 
13.1 
Disclosure ..............................................................................................................37 
13.2 
Reports and Publications........................................................................................37 
13.3 
Finances and Insurance ..........................................................................................37 
14 REFERENCES ................................................................................................................37 
15 APPENDICES .................................................................................................................39 
Appendix 1: Schedule of Assessments ..............................................................................40 
Appendix 2: Adverse Event Reporting ..............................................................................43 
Appendix 3: Clinical Laboratory Evaluations ...................................................................48 
Appendix 4: Total Blood Volume......................................................................................49 


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LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AUC 
area under the serum concentration-time curve 
AUC(0-∞) 
AUC from time zero to infinity 
AUC(0-t) 
AUC from time zero to the time of the last observable concentration 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum observed serum concentration 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
FIH 
first in human 
FOLFIRI 
leucovorin, fluorouracil and irinotecan 
FOLFOX 
leucovorin, fluorouracil and oxaliplatin 
GI 
gastrointestinal 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
INR 
international normalised ratio 
IUD 
intrauterine device 
IV 
intravenous 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RMP 
reference medicinal product 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
t1/2 
apparent serum terminal elimination half-life 
tmax 
time of maximum observed serum concentration 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
 


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1 
INTRODUCTION 
Please refer to the Investigator’s Brochure (IB)1 for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event 
(AE) profile of the investigational medicinal product (IMP). 
1.1 
Overview 
MB02 is a bevacizumab biosimilar product to the originator Reference Medicinal Product 
(RMP) Avastin®. MB02 is currently marketed in Argentina, and a first-in-human clinical 
study has been conducted in cancer patients. Avastin® is indicated for the treatment of 
multiple cancer types, administered alone or in combination with chemotherapy. 
Bevacizumab, the active substance of Avastin®, is a recombinant humanised monoclonal 
antibody that specifically binds to all isoforms of the human vascular endothelial growth 
factor (VEGF), neutralising its biological activity. By sequestering VEGF, bevacizumab 
inhibits angiogenesis, inhibiting tumour growth and progression, and sensitising tumour 
vasculature to chemotherapy-induced damage.  
 
1.2 
Summary of Nonclinical Experience 
A number of nonclinical in vitro and in vivo characterisation and efficacy studies have been 
conducted to demonstrate the similarity of MB02 with the RMP Avastin®. A full in vitro 
characterisation was undertaken, in accordance with European Medicines Agency (EMA) 
guidance on similar biological medicinal products containing monoclonal antibodies.2 MB02 
was shown to be identical to Avastin® in primary structure, and similar in protein 
conformation, posttranslational modification, and purity. MB02 and Avastin® also displayed 
similar mechanism of action, and similar affinity to FcRn receptors in vitro, which was 
indicative of a similar pharmacokinetic (PK) profile in vivo. Based upon these results, MB02 
and Avastin® were considered similar in terms of physicochemical, structural and biological 
properties. 
An in vivo toxicokinetic study has been conducted in cynomolgus monkeys. Twice-weekly 
intravenous (IV) doses of 50 mg/kg MB02 or Avastin®, infused over 30 minutes for 28 days, 
were well tolerated, and no clear differences were observed between MB02 and the RMP. 
Pharmacokinetic parameters derived during the toxicokinetic study demonstrated the 
similarity of MB02 to the RMP. Similar levels of accumulation were observed on Day 25 
between MB02 and Avastin ® (with mean accumulation ratios ranging from 3.7 to 4.2 and 3.0 
to 3.1, respectively). There was no appreciable difference in sex—related differences in 
exposure to MB02 and the RMP, and systemic exposure of MB02 and the RMP were similar 
on Days 1 and 25. 
1.3 
Summary of Clinical Experience 
MB02 has been marketed in Argentina since November 2016. A single first bioequivalence 
study has been conducted, comparing the PK, safety, efficacy and immunogenicity of 
5 mg/kg MB02 to 5 mg/kg Avastin® when administered in combination with leucovorin, 
fluorouracil and oxaliplatin (FOLFOX) or leucovorin, fluorouracil and irinotecan (FOLFIRI) 
chemotherapy regimens as first-line treatments in patients with metastatic colorectal cancer. 


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1.3.1 
Safety 
The safety population analysed in the bioequivalence study included 140 patients: 69 in the 
MB02 arm and 71 in the Avastin® arm. Almost all patients (96%) experienced at least one 
treatment emergent adverse event (TEAE). A total of 1258 TEAEs were reported, 605 in the 
MB02 arm of the trial. The most frequent TEAEs (with an incidence >10%) were 
gastrointestinal (GI) disorders, general disorders and administration site conditions, nervous 
system disorders, blood and lymphatic system disorders, metabolism and nutrition disorders, 
infections and infestations, and investigations. Fourteen patients had at least one TEAE 
leading to discontinuation from the study drug (8 in the MB02 arm). There was no obvious 
differential pattern relating to the type of AEs in either arm of the trial, regardless of 
relationship to treatment. 
Grade 3 or 4 TEAEs were reported at similar proportions in both arms of the study. Grade 3 
and 4 TEAEs were reported in 79 patients (40 in the MB02 arm). The distribution of Grade 3 
and 4 AEs remained relatively similar between the study arms, and the frequency of AEs 
observed appeared consistent with the known AE profile of bevacizumab and 
FOLFOX/FOLFIRI chemotherapy. 
The safety comparability exercise shows no signals of concern with regard to prior 
experience with regards to Avastin®, and no obvious differences in the safety profile in terms 
of nature, frequency and severity of the AEs reported. The safety profile for the bevacizumab 
biosimilar, MB02, was similar to the reference product, Avastin®, and was within the 
expectations given the underlying disease and concurrent use of chemotherapy. 
1.3.2 
Pharmacokinetics 
A total of 116 patients (55 in the MB02 arm and 61 in the Avastin® arm) were included in the 
PK population. Results from the PK analyses demonstrated that MB02 and Avastin® were 
bioequivalent in cancer patients, exhibiting similar serum concentration-time profiles, and 
ratios of geometric means for the area under the concentration-time curve (AUC) between 
time zero and 336 hours and AUC at steady state within the predefined margin of 80 to 
125%. Following the end the of dosing cycle, serum bevacizumab concentrations slowly 
declined in a biphasic manner until the last PK timepoint at 336 h postdose, with the start of 
the elimination phase occurring between 24 and 168 hours postdose. 
1.3.3 
Immunogenicity 
Measurement of anti-drug antibodies occurred in all patients dosed in the first-in-human 
study of MB02. Six patients tested positive for anti-drug antibodies (ADAs) at Screening 
(2 in the MB02 arm and 4 in the Avastin® arm). Following treatment, 2 de novo positive 
results for ADA were found, both in patients administered MB02. One patient was positive 
for ADA at Screening and after treatment in the Avastin® treatment arm; however, no boost in 
ADA titre was found post-treatment. In the 3 ADA-positive patients, no concerns were raised 
regarding the efficacy, safety or PK data relative to ADA-negative patients. 
1.4 
Study Rationale 
Previous nonclinical studies and an open-label bioequivalence study of MB02 have 
demonstrated that MB02 is bioequivalent to EU-approved Avastin®. This study will conduct 


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a comparison between MB02, EU Avastin® and US Avastin®, fulfilling the criteria for a 
PK bridging study to address regulatory requirements for biosimilars.3,4 
1.5 
Benefit-risk Assessment 
Healthy male subjects in the current study will not receive any health benefit (beyond that of 
an assessment of their medical status) from participating in the study. The risks of 
participation are primarily those associated with adverse reactions to the study treatments, 
although there may also be some discomfort from collection of blood samples and other study 
procedures. More information about the known and expected benefits, risks and reasonably 
anticipated AEs associated with MB02 may be found in the IB.1 


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2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is: 
•
To investigate and compare the PK profiles of MB02, US-licenced Avastin®
(US Avastin®) and EU-approved Avastin® (EU Avastin®) to establish bioequivalence
between the 3 study arms.
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
•
Evaluation and comparison of derived PK parameters not covered by the primary
endpoint for MB02, US Avastin® and EU Avastin®
•
To compare the safety profile of MB02 and US Avastin® and EU Avastin®
•
To compare the immunogenicity of MB02, US Avastin® and EU Avastin®
3 
ENDPOINTS 
3.1 
Primary Endpoints 
The PK outcome endpoints of MB02 and Avastin® derived from the serum 
concentration-time profile from Days 1 to 100 following IV administration are as follows: 
• area under the serum concentration‑ time curve from time zero to infinity (AUC[0-∞])
• maximum observed serum concentration (Cmax)
3.2 
Secondary Endpoints 
•
Evaluation of all other PK parameters for MB02, US-licenced Avastin® and
EU-approved Avastin®, including
o
Time of maximum observed serum concentration (tmax)
o
AUC from time zero to the time of the last observable concentration (AUC[0-t])
o
Clearance (CL)
o
Apparent serum terminal elimination half-life (t1/2)
•
The safety outcome measures for this study are as follows:
o
incidence and severity of AEs
o
incidence of laboratory abnormalities, based on haematology, clinical
chemistry, and urinalysis test results
o
12-lead electrocardiogram (ECG) parameters
o
vital sign measurements
o
physical examinations.


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•  The immunogenicity of MB02, US Avastin® and EU Avastin® 
o Determination of serum concentrations of anti-MB02 and anti-Avastin® 
antibodies. 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This will be a Phase 1, double-blind, randomised, parallel-group, single-dose 3-arm study to 
investigate and compare the PK, safety and immunogenicity profile of MB02 with US and 
EU Avastin® in healthy male subjects. A total of 114 subjects will be randomised to one of 
following 3 arms in a 1:1:1 ratio: 
• Arm 1: MB02 as a 90 minute IV infusion 
• Arm 2: Avastin® sourced from the US, as a 90 minute IV infusion 
• Arm 3: Avastin® sourced from the EU, as a 90 minute IV infusion. 
Thirty-eight subjects will be dosed in each arm. Potential subjects will be screened to assess 
their eligibility to enter the trial within 30 days prior to study drug administration. 
Subjects will be admitted to the Clinical Research Unit (CRU) on Day -1, and will be 
confined to the CRU until discharge on Day 8. On Day 1, subjects will receive a single 
3 mg/kg IV dose of the study drug. Subjects will return on Days 10, 14, 21, 28, 42, 56, 78 and 
100 for nonresidential visits for the collection of PK samples and safety assessments. 
Immunogenicity samples will be collected on Days 14, 28, 56, and 78. 
The total duration of trial participation for each subject (from Screening through to the final 
visit) is anticipated to be a maximum of 19 weeks. The end of the study is defined as the date 
of the last subject’s last assessment (planned or unplanned). 
A Schedule of Assessments is presented in Appendix 1. 
4.2 
Discussion of Study Design 
The clinical PK properties of MB02 have been investigated in a previous open-label study 
conducted in metastatic colorectal cancer patients, which demonstrated that MB02 was 
bioequivalent to the RMP, Avastin®. This study aims to compare PK, immunogenicity and 
safety of MB02 versus EU and US-sourced Avastin® in healthy volunteers. 
A single-dose, parallel-group design was chosen for this study due to the long half-life of 
bevacizumab of approximately 20 days, and the potential of ADA response, as recommended 
in EMA guidance 2,5 The study will be double-blinded as the secondary objective of 
comparing the safety profile of MB02 to Avastin® is considered subjective. The collection of 
serum samples through Day 1 to Day 100 will allow the PK parameters for MB02 and 
Avastin® to be adequately described. 
Assessment of PK in a single-dose study in healthy volunteers was expected to be the most 
sensitive setting possible to detect differences in PK between MB02 and Avastin®. The use of 


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healthy volunteers avoids factors that can confound the interpretation of PK, safety and 
tolerability results in patient studies, including varying tumour burden and complications 
arising from the disease state, comorbidities and concomitant therapies and medications. The 
selection of only male subjects avoids the documented influence of sex upon bevacizumab 
clearance.5 
4.3 
Selection of Doses in the Study 
Intravenous doses were chosen for this study as this is the intended clinical route of 
administration for MB02 and Avastin®. Therapeutic doses in the prescribing instructions for 
Avastin® range from 5 mg/kg every 2 weeks up to 15 mg/kg every 3 weeks. A lower dose level 
of 3 mg/kg for MB02 and Avastin® was chosen based upon the dosages used in previously 
published studies of bevacizumab PK6,7, and to balance considerations of safety in 
healthy volunteers and the need to capture the full PK profile. The results of the in vivo 
repeating dose toxicokinetic study demonstrated the similarity of MB02 to the RMP, with 
regards to the pharmacokinetic parameters, and further supported the safe administration of 
MB02 at doses <5 mg/kg in clinic. 


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5 
SELECTION OF STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects must satisfy all of the following criteria at the Screening visit unless otherwise 
stated: 
1. Males of any race, between 18 and 55 years of age, inclusive, at Screening. 
2. Body mass index between 18.5 and 29.9 kg/m2, inclusive, at Screening. 
3. Total body weight between 60 and 95 kg, inclusive, at Screening. 
4. 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). 
5. 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 to 1.3 
• Urine dipstick for proteinuria <2+ 
6. Systolic blood pressure ≥90 mmHg and ≤140 mmHg and diastolic blood pressure 
≥50 mmHg and ≤90 mmHg at Screening and Check-in. 
7. Subjects agree to use contraception as detailed in Section 7.6. 
8. 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. 


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5.2 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening visit unless otherwise stated: 
1. 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). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any current or recent history of active infections, including localised infections. 
4. 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. 
5. Presence of a nonhealing wound or fracture. 
6. Known history of clinically significant essential hypertension, orthostatic hypotension, 
fainting spells or blackouts for any reason, cardiac failure or history of 
thromboembolic conditions. 
7. 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. 
8. 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 
(Appendix 3, confirmed by repeat) at Screening or Check-in. 
9. History of bleeding disorders or protein C, protein S, and/or factor V Leiden 
deficiency. 
10. History of clinically significant haemorrhage, epistaxis, GI bleeding, haemorrhoids 
and/or haemoptysis. 
11. History of GI perforation, ulcers, gastro-oesophageal reflux, inflammatory bowel 
disease, diverticular disease, or any fistulae. 
12. 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. 
13. Positive hepatitis panel, positive human immunodeficiency test (Appendix 3). Subjects 
whose results are compatible with prior immunisation and not infection may be 
included at the discretion of the Investigator. 
14. 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. 
15. 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). 


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16. 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. 
17. 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). 
18. Have received a live or attenuated vaccine from 3 months prior to Screening, or have 
the intention to receive a vaccine during the study. 
19. Intend to travel to a region where a vaccination will be required due to endemic 
disease within 3 months of dosing. 
20. Previous treatment with an anti-VEGF antibody or any other protein or antibody 
targeting the VEGF receptor. 
21. Use of tobacco- or nicotine-containing products within 1 year prior to Check-in, or 
positive cotinine test upon Screening or Check-in. 
22. Receipt of blood products within 60 days prior to Check-in. 
23. Donation of blood from 90 days prior to Screening, plasma from 14 days prior to 
Screening, or platelets from 42 days prior to Screening. 
24. Poor peripheral venous access. 
25. History of abnormal peripheral sensation including paraesthesia and/or numbness in 
arms and/or legs. 
26. Have previously completed or withdrawn from this study or any other study 
investigating bevacizumab, and/or have previously received bevacizumab. 
27. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
Subjects may previously have been screened on a generic basis to determine their eligibility 
for inclusion in Phase 1 clinical studies conducted at the CRU. If generic Screening was 
performed within the specified study Screening window, selected study-specific procedures 
will be repeated either at an additional Screening visit or on admission to the CRU on Day -1. 
If generic Screening was performed outside the specified Screening window, all 
study-specific Screening assessments will be repeated either at an additional Screening visit 
or on admission to the CRU on Day -1. 
5.3 
Subject Number and Identification 
After signing the ICF, subjects will be assigned a unique Screening number by the study site. 
Subjects will be assigned a subject number upon randomisation at the time of the first dosing 
occasion. Replacement subjects (Section 5.4) will be assigned a subject number 
corresponding to the number of the subject he is replacing plus 1000 (eg, Subject 1101 
replaces Subject 101). 


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Subjects will be identified by subject numbers only on all study documentation. A list 
identifying the subjects by subject number and Screening number will be kept in the Site 
Master File. 
5.4 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn from dosing if any of the following criteria are met: 
• Change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the Investigator (or designee) 
• Noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• Any clinically relevant sign or symptom that in the opinion of the Investigator (or 
designee) warrants subject withdrawal. 
If a subject is withdrawn from dosing, the Sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). 
If a subject is withdrawn, efforts will be made to perform all Follow-up assessments, if 
possible (Appendix 1). Other procedures may be performed at Investigator’s (or designee’s) 
and/or Sponsor’s discretion. If the subject is in-house, these procedures should be performed 
before the subject is discharged from the clinic. The Investigator (or designee) may also 
request that the subject return for an additional Follow-up Visit. All withdrawn subjects will 
be followed until resolution of all their AEs or until the unresolved AEs are judged by the 
Investigator (or designee) to have stabilised. 
Subjects who are withdrawn for nondrug related reasons may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
5.5 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• Adverse events unknown to date (ie, not previously reported in any similar 
investigational study drug trial with respect to their nature, severity, and/or duration) 
• Increased frequency and/or severity and/or duration of known, anticipated, or 
previously reported AEs (this may also apply to AEs defined at Check-in as baseline 
signs and symptoms) 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of subjects 
• Cancellation of drug development. 


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6 
STUDY TREATMENTS 
6.1 
Description, Storage, Packaging, and Labelling 
The IMP (MB02 IV solution, 25 mg/mL), US, and EU Avastin® (bevacizumab IV solution, 
25 mg/mL) will be supplied by the Sponsor, along with batch/lot numbers and certificates of 
analysis. 
MB02 and Avastin® will be diluted to the required dose for administration with 100 mL of 
sodium chloride (9 mg/mL, 0.9%) solution for injection using aseptic technique.5 
6.2 
Study Treatment Administration 
Doses of MB02 and Avastin® will be administered as a slow IV infusion, (duration 
approximately 90 minutes). Subjects will be dosed in numerical order while supine. 
 In the event of a significant infusion reaction, the infusion will be slowed or stopped, 
depending on the symptoms/signs present. 
In the event of acute hypertension (increase by >20mmHg diastolic or >160/100 mmHg if 
previously within normal limits) during the infusion, the infusion will be stopped and may be 
resumed at a slower rate if blood pressure returns to the pretreatment range within one hour. 
 
If the infusion is slowed, the infusion should be completed at the slower rate, as tolerated. If 
the infusion is stopped, a single attempt to restart the infusions at a lower rate may be made 
after resolution of symptoms. Supportive care should be employed in accordance with the 
symptoms and signs. 
Any changes or stopping of infusions should be recorded in the subject’s eCRF alongside the 
AE which caused the slowing or stopping of the infusion. 
6.3 
Randomisation 
The randomisation code will be produced by the statistics department at Covance Early 
Clinical Biometrics using a computer-generated pseudo-random permutation procedure. 
Subjects will be randomly assigned to 1 of 3 treatment arms and stratified into 2 groups based 
on weight (≥60.0 to <77.5kg, and ≥77.5 to <95.0 kg respectively). Prior to the start of the 
trial, a copy of the master randomisation code will be supplied to the Covance CRU 
pharmacy staff, PAREXEL pharmacy staff, the analyst at Covance Laboratories Ltd. 
6.4 
Blinding 
The following controls will be employed to maintain the double blind status of the study: 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with a sealed randomisation code for 
each subject, containing coded details of the treatment. These individual sealed envelopes 
will be kept in a limited access area that is accessible 24 hours a day. If, in order to manage 
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unblind resides with the Investigator. Whenever possible, and providing it does not interfere 
with or delay any decision in the best interest of the subject, the Investigator will discuss the 
intended code-break with the Sponsor. If it becomes necessary to break the code during the 
study, the date, time and reason will be recorded in the subject's source data and on the 
individual envelope and will be witnessed by a second person. 
Where the subject experiences a suspected unexpected serious adverse reaction (SUSAR) the 
Sponsor pharmacovigilance team may be unblinded prior to notification of the relevant 
competent authorities and ethics committee in order to provide appropriate information. 
6.5 
Study Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
 
• All doses will be administered under the supervision of suitably qualified study site 
staff 
• At each dosing occasion, a predose and postdose inventory of MB02 and Avastin® 
will be performed. 
6.6 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the IMP and 
study drugs received. In addition, an accurate drug disposition record will be kept, specifying 
the amount dispensed to each subject and the date of dispensing. This drug accountability 
record will be available for inspection at any time. At the completion of the study, the 
original drug accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, retention samples allowing for 5 separate full characterisation 
assays to be performed will be retained at the Study Site. Any additional unused MB02 and 
Avastin® will be returned to the Sponsor or disposed of by the Study Site, per the Sponsor’s 
written instructions. 
7 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
7.1 
Concomitant Medications 
Subjects will refrain from use of any prescription and/or nonprescription 
medications/products during the study until the final visit, unless the Investigator (or 
designee) and/or Sponsor have given their prior consent. 
Paracetamol (up to 2 g/day for up to 3 consecutive days) is an acceptable concomitant 
medication if prescribed by the Investigator due to an AE. The administration of any other 
concomitant medications during the study is prohibited without prior approval of the 
Investigator (or designee), unless its use is deemed necessary in a medical emergency. Any 
medication taken by a subject during the course of the study and the reason for its use will be 
documented in the source data. 


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Premedication for infusions is not planned. However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the Investigator. 
7.2 
Diet 
While confined at the study site, subjects will receive a standardised diet at scheduled times 
that do not conflict with other study-related activities. Subjects will be fasted overnight (at 
least 8 hours) before collection of fasting blood samples for safety laboratory tests. 
On Day 1 the subjects will be fasted overnight (at least 8 hours) prior to dosing. Food will be 
allowed from 4 hours post end of infusion. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until discharge and from 36 hours before non-residential visits. 
Decaffeinated tea and coffee will be available with morning and evening meals whilst 
resident at the clinic. 
Consumption of alcohol will not be permitted from 48 hours prior to Check-in and 
non-residential visits. Alcohol intake will be limited to a maximum of 2 units/day on all other 
days, whilst not in the CRU, from Screening through the final visit. 
7.3 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 1 year 
prior to Check-in until the final visit. 
7.4 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in and 
7 days before non-residential visits and will otherwise maintain their normal level of physical 
activity during this time (ie, will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
7.5 
Blood Donation 
Subjects are required to refrain from donation of blood from 90 days prior to Screening, 
plasma from 14 days prior to Screening, or platelets from 42 days prior to Screening until 
90 days after the final visit. 
7.6 
Contraception 
Subjects with partners of childbearing potential must use a male barrier method of 
contraception (ie, male condom with spermicide) in addition to a second method of 
acceptable contraception. The acceptable methods of contraception include: 
• Intrauterine device (IUD; eg, Mirena) 
• Established use of oral, implanted, transdermal, or hormonal method of contraception 
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• Male sterilisation, with verbal confirmation of surgical success 
• Bilateral tubal ligation 
• Established use of progesterone only oral contraception, where inhibition of ovulation 
is not the primary mode of action 
• Diaphragm, cap, or sponge in conjunction with spermicide. 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active they must 
agree to use contraception as described above. 
Sexual intercourse with female partners who are pregnant or breastfeeding should be avoided 
unless condoms are used from the time of dosing until 120 days after dosing. Male subjects 
are required to refrain from donation of sperm from Check-in until 120 days after the dose of 
study drug. 
For subjects who are exclusively in same sex relationships, a barrier method of contraception 
(ie male condom) should be used from the time of dosing until 120 days after dosing. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The order of priority for scheduling procedures around a timepoint is (in descending order of 
priority): 
• 
Dosing 
• 
Blood samples 
• 
Any other procedures (ECGs will be scheduled before vital sign measurements). 
8.1 
Pharmacokinetic Assessments 
8.1.1 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples (approximately 1 x 3.5 mL for bevacizumab) will be collected by 
venepuncture or cannulation at the times indicated in the Schedule of Assessments in 
Appendix 1. Procedures for collection, processing, and shipping of PK samples will be 
detailed in a separate document. 
8.1.2 
Analytical Methodology 
Serum concentrations of bevacizumab will be determined using a validated analytical 
procedure. Specifics of the analytical method will be provided in a separate document. 


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8.2 
Immunogenicity Assessments 
8.2.1 
Immunogenicity Blood Sample Collection and Processing 
Blood samples (approximately 1 x 3.5 mL) will be collected by venepuncture or cannulation 
at the times indicated in the Schedule of Assessment in Appendix 1. Procedures for 
cannulation, processing and shipping of immunogenicity samples will be detailed in a 
separate document. 
8.2.2 
Analytical Methodology 
Serum concentrations of anti-MB02 and anti-Avastin® antibodies will be determined using a 
validated analytical procedure. Specifics of the analytical method will be provided in a 
separate document. 
8.3 
Safety and Tolerability Assessments 
8.3.1 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 2. 
The condition of each subject will be monitored from time of signing the ICF to final 
discharge from the study. In addition, subjects will be observed for any signs or symptoms 
and asked about their condition by open questioning, such as “How have you been feeling 
since you were last asked?”, at least once each day while resident at the study site and at each 
study visit. Subjects will also be encouraged to spontaneously report AEs occurring at any 
other time during the study. 
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with an 
Investigator’s (or designee’s) opinion of the relationship to drug administration. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution. This will be completed at the Investigator’s (or designee’s) discretion. 
8.3.2 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, haematology, urinalysis, coagulation, and serology) at the times indicated 
in the Schedule of Assessments in Appendix 1. Clinical laboratory evaluations are listed in 
Appendix 3. 
Subjects will be asked to provide urine samples for a drugs of abuse screen, cotinine test, and 
undergo an alcohol breath test at the times indicated in the Schedule of Assessments in 
Appendix 1. An Investigator (or designee) will perform a clinical assessment of all clinical 
laboratory data. 


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8.3.3 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, oral body temperature and pulse 
oximetry will be assessed at the times indicated in the Schedule of Assessments in 
Appendix 1. Vital signs may also be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of vital 
signs is required. 
All measurements will be performed singly, and repeated once if outside the relevant clinical 
reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
8.3.4 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 1. Single 
12-lead ECGs will be repeated once if either of the following criteria apply: 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) > 500 msec 
• QTcF change from the baseline (predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG. 
8.3.5 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at 
the timepoints specified in the Schedule of Assessments in Appendix 1. 
9 
SAMPLE SIZE AND DATA ANALYSES 
A detailed statistical analysis plan (SAP) describing full details of the planned analyses will 
be issued to the Sponsor for review and will be finalised prior to database lock. The following 
analyses represent an outline of the planned methodology. 
9.1 
Determination of Sample Size 
Up to 114 subjects will be enrolled in order that 108 complete the study. 
A sample size of 36 subjects per arm (108 subjects in total) will provide at least 90% power 
for all the pairwise comparisons for primary endpoints (AUC and Cmax) using a percent 
coefficient of variation (CV%) of 25% in both PK parameters for the similarity objective if 
the true ratio is equal to 1.05 or less. 
A conservative estimate of CV% was based on a prior MB02 study 8 and information from 
the public domain 9. Model-based simulations from a developed population PK literature 


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model, accounting for similarity between bevacizumab sources (EU/US), intrinsic PK 
altering factors (body weight, sex, serum albumin and alkaline phosphatase), between subject 
variability and residual variability, showed that a sample size of 90 subjects provided at least 
90% probability of concluding PK similarity for the all pairwise comparisons in terms of Cmax 
and AUC(0–∞). 
Simulations also showed that the probability of concluding PK similarity in terms of AUC(0-t) 
is almost the same as AUC(0–∞) 
A maximum of 5% loss of data due to premature discontinuation is expected therefore, the 
sample size is increased to 114 subjects in total, with 38 subjects per arm. 
9.2 
Analysis Populations 
9.2.1 
Pharmacokinetic Population 
The PK population will include all subjects who received the full dose of MB02 or Avastin®, 
did not have any major protocol deviations, and have evaluable PK data for at least one 
timepoint. 
Further details of subjects considered for exclusion from the PK population will be provided 
in the SAP, detailing major deviations (for statistical analyses) prior to database lock. 
9.2.2 
Safety Population 
The safety population will include all subjects exposed to MB02 or Avastin®, and have at 
least 1 postdose safety assessment. 
9.3 
Pharmacokinetic Analyses 
The primary PK parameter endpoints are Cmax and AUC0-∞ 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 
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criteria for all 3 pairwise comparisons; MB02 versus EU-approved Avastin®; MB02 versus 
US-licenced Avastin®; and EU-approved Avastin® versus US-licenced Avastin®. 
9.4 
Safety Analysis 
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 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). 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®, 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. 
9.4.1 
Medical Safety Monitoring 
It is the responsibility of the Investigator to oversee the safety of the subject at the clinical 
site. This safety monitoring will include careful assessment and appropriate reporting of AEs 
as noted above. 
 
A safety review committee comprising at minimum the Principal Investigator and Sponsor 
Medical Contact will review all available safety data monthly, or more frequently if 
indicated. In advance of each meeting, Covance will prepare blinded tables/listings based on 
a snapshot of data available in the eCRFs, including those for subject status, AEs, and 
laboratory results. 
 
9.5 
Interim Analysis 
No interim analyses are planned for this study. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Auditing 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures (SOPs) or per Sponsor request and as applicable according to the 
contract between Covance and the Sponsor. 
The study may be audited or reviewed by an independent quality assurance department, 
Ethics Committee (EC), and/or regulatory authority at any time. The Investigator will be 
given notice before an audit occurs. The study site will permit study-related monitoring, 
audits, EC review, and regulatory inspections by providing direct access to source 
data/documents. 


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Measures will be undertaken to protect the confidentiality of records that could identify 
subjects, respecting the privacy and confidentiality rules in accordance with applicable 
regulatory requirements. 
10.2 
Monitoring 
Covance will designate an independent Study Monitor who will be responsible for 
monitoring this clinical study. The Study Monitor will monitor the study conduct, eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the Study Monitor will visit the study site at suitable intervals and be in frequent 
contact through verbal and written communication. It is essential that the Study Monitor has 
access to all documents, related to the study and the individual participants, at any time these 
are requested. In turn, the Study Monitor will adhere to all requirements for subject 
confidentiality as outlined in the ICF. The Investigator and Investigator’s staff will be 
expected to cooperate with the Study Monitor, to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information. 
11 
DATA HANDLING AND RECORD KEEPING 
11.1 
Data Handling 
Covance will be responsible for data management of this study, including quality checking of 
the data. The study site will be responsible for data entry into the electronic data capture 
(EDC) system. A comprehensive validation check program will verify the data. 
Discrepancies will be generated automatically in the system at the point of entry or added 
manually for resolution by the study site staff. 
Covance will produce a Data Management Plan that describes the quality checking to be 
performed on the data. Laboratory data and other electronic data will be sent directly to 
Covance, using Covance standard procedures to handle and process the electronic transfer of 
these data. 
11.2 
Case Report Form 
Data from all parts of the trial will be captured on source paper or electronic data documents 
and then entered into the EDC system by staff at the trial site. Following data entry, the eCRF 
pages and the data entry will undergo quality control checks in accordance with Covance 
procedures. Any discrepancies will be resolved in the database. 
Following all data validation steps, the Principal Investigator (or designee) will electronically 
sign the completed electronic data prior to database lock. 
11.3 
Records 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the in the study site archive for at least 5 years after the end of the study. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 


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Final, Version 7.0, 25 March 2019 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
Ethics Committee 
Prior to the start of the study, the following documents will be reviewed and approved by the 
appropriate EC: 
• protocol 
• ICF 
The EC will be informed by the Investigator (or designee) of any changes to the approved 
protocol. 
The EC must provide written approval of any substantial protocol amendments likely to 
affect the safety of the subjects or the conduct of the study. The EC must be notified of 
nonsubstantial protocol amendments. 
The EC will be informed by the Investigator (or designee) of serious and unexpected AEs. 
The Investigator will provide the EC with progress reports at least annually and a report 
following completion, termination, or discontinuation of the Investigator’s participation in the 
study. 
12.2 
Regulatory Considerations 
The study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of Medical 
Sciences Ethical Guidelines 
• International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical 
Practice 
• Applicable local laws and regulations. 
The Investigator will be responsible for the overall conduct at the study site and adherence to 
the requirements of the ICH guidelines and all other applicable local regulations. 
12.3 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. 
Following discussion of the study with CRU personnel, subjects will sign 2 copies of the ICF 
in the presence of a suitably trained member of staff to indicate that they are freely giving 
their informed consent. One copy will be given to the subject, and the other will be 
maintained in the subject’s records. 


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12.4 
Subject Confidentiality 
The results from Screening and data collected during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by a unique 
subject identification number. 
Subject medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the ICF signed by the subject, unless permitted or required by 
law. 
12.5 
Protocol Amendments 
Substantial protocol amendments will be submitted to the EC and to regulatory authorities in 
accordance with local regulatory requirements. Approval must be obtained from the EC and 
regulatory authorities (as locally required) before implementation of any changes, except for 
changes necessary to eliminate an immediate hazard to subjects or any nonsubstantial 
changes, as defined by regulatory requirements. 
13 
ADMINISTRATIVE ASPECTS 
13.1 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
13.2 
Reports and Publications 
Any publication of the results, either in part or in total (eg, articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator or their representative, shall require prior 
notification and review, within a reasonable time frame, by the Sponsor, and cannot be made 
in violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property. 
13.3 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
14 
REFERENCES 
1. MB02– Investigator’s Brochure. (Version 6.0, 28 July 2017) 
2. EMA Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substance: clinical and nonclinical issues, 
CHMP/BMWP/42832/2005 Rev1 of 18 December 2014 (effective 1 July 2015) 
3. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference 
Product. US Dept of Health and Human Services; Food and Drug Administration; Centre 


Protocol 
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Covance Study: 8370738 
Sponsor Reference: MB02-A-02-17 
Final, Version 7.0, 25 March 2019 
Page 38 of 49 
for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and 
Research (CBER). December 2016. 
4. EMA Guideline on similar biological medicinal products. CHMP/437/04 Rev 1 of 
23 October 2014 (effective 30 April 2015). 
5. Genentech Inc (2016) Avastin® (bevacizumab) prescribing information. 
http://www.gene.com/download/pdf/avastin_prescribing.pdf. Accessed 29 June 2017. 
6. Willem Hettema et. al. A randomised, single-blind, Phase I trial (INVICTAN-1) assessing 
the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in 
healthy subjects. Expert Opin Investig Drugs. 2017, Aug;26(8):889-896 
7. N Tajima et. al. A phase 1 study comparing the proposed biosimilar BS-503a with 
bevacizumab in healthy male volunteers. Pharmacol Res Perspect. 2017, 20;5(2):e00286. 
8. mAbxience; Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus 
Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients (MB02-A-01-13). 
mAbxience SA, Madrid, Spain. 
9. Beverly Knight, Danielle Rassam, Shanmei Liao, Reginald Ewesuedo. A phase I 
pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with 
bevacizumab in healthy male volunteers. Cancer Chemother Pharmacol. 2016; 77: 839–
846. 
 
 


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Sponsor Reference: MB02-A-02-17 
Final, Version 7.0, 25 March 2019 
Page 39 of 49 
15 
APPENDICES 
 


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Appendix 1: Schedule of Assessments 


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Final, Version 7.0, 25 March 2019 
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Study Procedures 
Screening 
Day -1 
Day 1 
Day 
2 
Day 3 to Day 8 
Day 10 
Day 14 to Day 78 
Day 10
0 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
Xa 
 
 
 
 
 
 
Urinary drug screen 
and cotinine test 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
Height and body 
weightb 
X 
X 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 8 
 
 
 
Nonresidential visitg 
X 
 
 
 
 
X 
Day 14, 21, 28, 42, 
56, 78 
X 
Study drug 
administration: 
 
 
 
 
 
 
 
 
MB02 or Avastin® 
 
 
Day 1 (0 h) 
 
 
 
 
 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Blood samplinge 
 
 
Predose, 1.5f, 2, 
3, 4, 5, 6, 8, 12 h 
24 h 
Day 3, Day 4, Day 5, Day 6, 
Day 7 and Day 8  
X 
 
Day 14, Day 21, 
Day 28, Day 42, 
Day 56, Day 78  
X  
Immunogenicity: 
 
 
 
 
 
 
 
 
Blood sampling 
 
X 
 
 
 
 
Day 14, 28, 56, 78 
 
Safety and 
tolerability: 
 
 
 
 
 
 
 
 
Adverse event 
recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 


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Final, Version 7.0, 25 March 2019 
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Study Procedures 
Screening 
Day -1 
Day 1 
Day 
2 
Day 3 to Day 8 
Day 10 
Day 14 to Day 78 
Day 10
0 
Serious adverse 
event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Prior/concomitant 
medication 
monitoring 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Clinical laboratory 
evaluations 
X 
X 
 
 
 
 
Day 14, 21, 28, 42, 
56, 78 
X 
Supine blood 
pressure, pulse rate, 
respiratory ratee 
X 
X 
Predose, 0.5, 1, 
1.5hf, 2h 
X 
Day 5, Day 8 
X 
Day 21 
X 
Pulse oximetry 
X 
 
 
 
 
 
 
 
Oral body 
temperature 
X 
 
 
X 
 
X 
Day 21 
X 
12-lead ECG 
X 
X 
 
 
Day 3, Day 8 
 
 
X 
Physical 
examination 
Xc 
Xd 
 
 
 
 
 
Xd 
Abbreviations: ECG = electrocardiogram 
a Interim medical history 
b Height measured at Screening only 
c. Can be performed between the Screening visit and predose assessments 
d. Symptom-directed physical examination 
e. All times stated are post-start of infusion. 
f. 1.5 hour timepoint is immediately after end of infusion. 
g All nonresidential visits on Days 14 to 100 can be conducted within ±1 day of the planned date. 
 


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Sponsor Reference: MB02-A-02-17 
Final, Version 7.0, 25 March 2019 
Page 43 of 49 
Appendix 2: Adverse Event Reporting 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and/or unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
The causal relationship between an AE and the study drug will be defined as below: 
• Not Related: when the AE is definitely caused by the subject’s clinical state, or the 
study procedure/conditions 
• Unlikely Related: when the temporal association between the AE and the drug is 
such that the drug is not likely to have any reasonable association with the AE 
• Possibly Related: when the AE follows a reasonable temporal sequence from the 
time of drug administration but could have been produced by the subject’s clinical 
state or the study procedures/conditions 
• Probably Related: when the AE has a reasonable time relationship to study drug 
administration and is unlikely to be attributed to concurrent disease or other drugs or 
chemicals 
• Related: when the AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or hypothesised 
cause-effect relationship, and (if appropriate) reappears when the drug is reintroduced 
The severity of an AE or SAE will be recorded in the eCRF following the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, outlined 
below: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
•  Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
•  Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care activities of daily living 
•  Grade 4 Life-threatening consequences; urgent intervention indicated 
•  Grade 5 Death related to AE 
An AE that is assessed as severe (CTCAE Grade 3 or higher) should not be confused with a 
SAE. Severity is a category utilised for rating the intensity of an event; both AEs and SAEs 
can be assessed as severe. An event is defined as ‘serious’ when it meets one of the 
predefined outcomes, as described in the section “Serious Adverse Events”, outlined below. 


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Every reasonable effort will be made to follow-up subjects who have AEs. Any subject who 
has an ongoing AE at the final visit will be followed up, where possible, until resolution or 
until, in the opinion of the Investigator, the event is stabilised or determined to be chronic. 
Details of AE follow-up or resolution must be documented in the eCRF. This will be 
completed at the Investigator’s (or designee’s) discretion. 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator’s 
Brochure for an unapproved IMP). 
Follow-up of adverse events 
All investigators should follow-up subjects with AEs until the event is resolved or until, in 
the opinion of the Investigator, the event is stabilised or determined to be chronic. Details of 
AE follow-up or resolution must be documented in the eCRF. 
Subjects should be followed up until final discharge from the study, and any AEs that occur 
during this time should be reported according to the procedures outlined below. 
All subjects with unresolved AEs at the end of the study, except those who dropped out 
before randomisation or starting active treatment, must be included in a safety follow-up visit 
to check response of AEs. 
Follow-up can be waived in specific cases after consultation with the Sponsor. This 
permission must be documented per case and retained in the Sponsor File. 
Documentation and reporting of adverse events  
Adverse events should be reported and documented in accordance with the procedures 
outlined below; AEs will be recorded in the eCRF from the signing of the informed consent 
form (ICF) until final discharge from the study. The following data should be documented for 
each AE: 
• Description of the symptom event 
• Classification as ‘serious’ or ‘not serious’ 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken 
• Causal relationship 
• Outcome of event (unknown, recovered, recovering, not yet recovered, recovered with 
sequelae, death [with date and cause reported]). 
 


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Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose either: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgement, 
they may jeopardise the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. These events should be collected in the 
eCRF under the seriousness criteria “Important Medical Event”. 
Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
possibly related to the study treatment, will be reported to the Sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment which would not 
have been appropriate at the CRU. When in doubt as to whether hospitalisation occurred or 
was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a Clinical Assessment Form 
and added to the electronic Case Report Form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
The Investigator will complete an SAE report form and forward it by facsimile to the Sponsor 
Safety Department immediately (no more than 24 hours) after becoming aware of an SAE. 


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Final, Version 7.0, 25 March 2019 
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Full details for SAE reporting and contact information can be found in the Site Safety 
Instruction. 
All serious adverse reactions will be considered as SUSARs, and will follow the expedited 
SUSAR reporting process described below. The Investigator should not wait to receive 
additional information to fully document the event before notification of a SAE, though 
additional information may be requested. Where applicable, information from relevant 
laboratory results, hospital case records, and autopsy reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the Investigator at any 
time after cessation of study drug administration and linked by the Investigator to this study, 
should be reported to the Safety department within 24 hours. 
Other events subject to immediate notification (within 24 hours), include but are not limited 
to: 
• Pregnancy of female partner of a study subject 
• Infusion site reaction (grade 3 according to the CTCAE and higher or classified as 
serious to be reported) 
• Medication errors, namely overdose, leading to a suspected adverse reaction. 
 
Follow-up of serious adverse events 
All SAEs will be followed clinically until they are resolved or until a stable situation has been 
reached. Depending on the event, follow-up may require additional tests or medical 
procedures as indicated, and/or referral to a medical specialist. Follow-up information on 
SAEs should be reported until recovery or until a stable situation has been reached. 
The final outcome of the SAE should be reported in a final SAE report. 
Reporting of pregnancy 
Pregnancies of the female partner of a male subject should be reported to the Sponsor’s 
Safety Department. Pregnancies must be reported to pharmacovigilance by email/fax within 
24 hours after the event was known to the Investigator, using the pregnancy report form. 
The Investigator is encouraged to provide outcome information of the pregnancy of the 
female partner of a male subject, if this information is available to the Investigator and the 
female partner gives her permission. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (ie, spontaneous or therapeutic abortion, stillbirth, 
neonatal death, or congenital anomaly - including that in an aborted fetus), the Investigator 
should follow the procedures for reporting SAEs. In the case of a live “normal” birth, the 
Sponsor should be informed as soon as the information is available. All neonatal deaths that 
occur within 30 days of birth should be reported, without regard to causality, as SAEs. 
In addition, any infant death after 30 days from birth that the Investigator suspects to be 
related to in utero exposure to the investigational medicinal product(s) should also be 
reported. 


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Final, Version 7.0, 25 March 2019 
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Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related to 
the administration of the study drug at any dose that is not consistent with the applicable 
product information (eg, Investigators Brochure for an unauthorised investigational medicinal 
product or summary of product characteristics for an authorised product). 
All SUSARs will be the subject of expedited reporting. The Sponsor and/or delegate shall 
ensure that all relevant information about a SUSAR that is fatal or life-threatening is reported 
to the relevant competent authorities and EC within 7 days after knowledge by the Sponsor of 
such a case and that relevant follow-up information is communicated within an additional 8 
days. All other SUSARs will be reported to the relevant competent authorities and EC within 
15 days after knowledge by the Sponsor of such a case. All Investigators should follow-up 
SUSARs until the events are resolved or until, in the opinion of the Investigator, the events 
are stabilised or determined to be chronic. 
 
 
 


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Sponsor Reference: MB02-A-02-17 
Final, Version 7.0, 25 March 2019 
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Appendix 3: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Total cholesterol 
HDL cholesterol 
LDL cholesterol 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase 
Lactate dehydrogenase 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total protein 
Triglycerides 
Urea 
Uric acid 
Haematocrit 
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination  
Serologya: 
Urinary drug screenb: 
Coagulation 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
(anti-HBs) 
Hepatitis B core antibody 
(anti HBc) 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
 
Including but not limited to: 
Cotinine 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/cannabinoids 
Tricyclic antidepressants 
 
Alcohol breath test  
International normalised 
ratio 
Prothrombin time 
Activated partial 
thromboplastin time 
a  Only analysed at Screening 
b Only analysed at Screening and Check-in. 


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Appendix 4: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
9.7 
9 
87.3 
Serology 
3.5 
1 
3.5 
Bevacizumab 
pharmacokinetics 
3.5 
24 
84 
Immunogenicity 
3.5 
5 
17.5 
Total: 
192.3 
 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed the volume of a normal blood donation. 

SAP_005.pdf: 
Protocol 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 
NCT Number: 
NCT03293654 
Statistical 
Analysis Plan 
version date: 
Version 2.0, 05 June 2019 
 


Final Version 2: 05 June 2019 
 
Page 1 of 18 
 
STATISTICAL ANALYSIS PLAN 
A Randomised, Double-Blind, Three-Arm, Single Dose, Parallel Study to Compare the 
Pharmacokinetics, Safety, and Immunogenicity of MB02 (Bevacizumab Biosimilar Drug), 
US-licensed Avastin® and EU-approved Avastin® in Healthy Male Volunteers 
Statistical Analysis Plan Status: Final Version 2 
Statistical Analysis Plan Date: 05 June 2019 
Study Drug: MB02  
Sponsor Reference Number: MB02-A-02-17 
Covance Study Number: 8370738 
Clinical Phase 1 
 
 
Sponsor: 
 
mAbxience Research S.L. 
C/ Manuel Pombo Angulo, 28, 
3rd floor, 28050 
Madrid, 
Spain 
 
Study Sites: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
UK 
 
PAREXEL International  
Early Phase Clinical Unit  
Pharmaceutical Services  
St Mark's Hospital, Level 7  
Watford Road,  
Harrow, London  
HA1 3UJ, United Kingdom 
 
 
Sponsor Signatory: 
 
Medical Advisor 
 
Principal Investigators: 
Covance - 
 
 
PAREXEL - 
 
 
 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8370738 
 
Sponsor Reference: MB02-A-02-17 
 
Final Version 2: 05 June 2019 
 
Page 2 of 18 
 
1  STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
By signing this page when the Statistical Analysis Plan (SAP) is considered final, the signatories 
agree to the statistical, pharmacokinetic (PK), and immunogenicity analyses to be performed for 
this study, and to the basic format of the tables, figures, and listings (TFLs). Once the SAP has 
been signed, programming of the TFLs based upon this document can proceed. Any 
modifications to the SAP and TFLs made after signing may result in a work-scope change. 
 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8370738 
 
Sponsor Reference: MB02-A-02-17 
 
Final Version 2: 05 June 2019 
 
Page 3 of 18 
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................. 2 
2 
TABLE OF CONTENTS ............................................................................................... 3 
3 
ABBREVIATIONS........................................................................................................ 5 
4 
INTRODUCTION ......................................................................................................... 7 
5 
STUDY OBJECTIVES .................................................................................................. 7 
5.1 
Primary Objective.................................................................................................... 7 
5.2 
Secondary Objectives .............................................................................................. 7 
6 
STUDY DESIGN ........................................................................................................... 8 
7 
TREATMENTS ............................................................................................................. 8 
8 
SAMPLE SIZE JUSTIFICATION ................................................................................. 8 
9 
DEFINITION OF ANALYSIS POPULATIONS ............................................................ 9 
10 STATISTICAL METHODOLOGY ............................................................................... 9 
10.1 General .................................................................................................................... 9 
10.1.1 Definition of Baseline and Change from Baseline ......................................... 10 
10.1.2 Repeat and Unscheduled Readings ............................................................... 10 
10.2 Demographics and Subject Disposition .................................................................. 10 
10.3 Pharmacokinetic Assessment ................................................................................. 11 
10.3.1 Pharmacokinetic Analysis ............................................................................. 11 
10.3.2 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis ............................................................................. 12 
10.3.3 Criteria for Handling Concentrations Above the Limit of Quantification in 
Pharmacokinetic Analysis ............................................................................. 13 
10.3.4 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life .. 13 
10.3.5 Calculation of AUC ...................................................................................... 13 
10.3.6 Anomalous Values ....................................................................................... 14 
10.4 Presentation of Pharmacokinetic Data .................................................................... 14 
10.4.1 Presentation of Pharmacokinetic Serum Drug Concentration Data ................ 14 
10.4.2 Presentation of Pharmacokinetic Parameters ................................................. 14 
10.4.3 Pharmacokinetic Statistical Methodology ..................................................... 15 
10.5 Safety and Tolerability Assessments ...................................................................... 16 
10.5.1 Adverse Events ............................................................................................. 16 
10.5.2 Clinical Laboratory Parameters ..................................................................... 16 
10.5.3 Vital Signs .................................................................................................... 17 
10.5.4 Electrocardiogram ........................................................................................ 17 
10.5.5 Immunogenicity Safety Assessment.............................................................. 17 
10.5.6 Other Assessments ....................................................................................... 17 


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10.5.7 Safety and Tolerability Statistical Methodology ............................................ 18 
11 INTERIM ANALYSES ............................................................................................... 18 
12 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 18 
13 DATA PRESENTATION ............................................................................................ 18 
13.1 Insufficient Data for Presentation............................................................................ 18 
14 REFERENCES ............................................................................................................ 18 
 


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3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADA 
anti-drug antibody 
ADaM 
analysis data model 
AE 
adverse event 
AUC 
area under the serum concentration-time curve 
AUC(0-∞) 
AUC from time zero to infinity 
AUC(0-t) 
AUC from time zero to the time of the last observable concentration 
%AUCextrap 
percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI  
confidence interval 
CL 
total body clearance of drug after intravenous administration 
Cmax 
maximum observed serum concentration 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ICH 
International Council for Harmonisation 
IV 
intravenous  
kel 
Elimination rate constant of the terminal phase 
LLOQ 
lower limit of quantification 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
QTc 
QT correction; QT interval corrected for heart rate 
QTcF 
QTc calculated using the Fridericia correction  


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SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
 t1/2 
apparent serum terminal elimination half-life 
tmax 
time of maximum observed serum concentration 
Vz 
Volume of distribution during the terminal phase after intravenous 
administration 
 


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4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 6.0 dated 
15 October 2018). 
This SAP describes the planned analysis of the safety, tolerability, immunogenicity and PK data 
from this study. A detailed description of the planned TFLs to be presented in the Clinical Study 
Report (CSR) is provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical analyses of safety, 
tolerability, immunogenicity and PK. In general, the analyses are based on information from the 
protocol, unless they have been modified by agreement between mAbxience Research S.L. and 
Covance Early Clinical Biometrics. A limited amount of information concerning this study (e.g., 
objectives, study design) is given to help the reader’s interpretation. This SAP must be finalised 
prior to the lock of the clinical database for this study. When the SAP and TFL shells are agreed 
upon and finalised, they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between mAbxience Research S.L. and Covance Early Clinical Biometrics and identified in the 
CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Council for Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  STUDY OBJECTIVES 
5.1 
Primary Objective 
The primary objective of the study is: 
 To investigate and compare the PK profiles of MB02, US-licensed Avastin® (US 
Avastin®) and EU-approved Avastin® (EU Avastin®) to establish bioequivalence 
between the 3 study arms. 
 
5.2 
Secondary Objectives 
The secondary objectives of the study are: 
 Evaluation and comparison of derived PK parameters not covered by the primary 
endpoint for MB02, US Avastin® and EU Avastin®  
 To compare the safety profile of MB02, US Avastin® and EU Avastin® 
 To compare the immunogenicity of MB02, US Avastin® and EU Avastin® 


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6  STUDY DESIGN 
This will be a Phase 1, double-blind, randomised, parallel-group, single-dose, 3-arm study to 
investigate and compare the PK, safety and immunogenicity profile of MB02 with US and 
EU Avastin® in healthy male subjects. A total of 114 subjects will be randomised to one of the 
following 3 arms in a 1:1:1 ratio: 
 
 Arm 1: MB02 as a 90 minute IV infusion 
 Arm 2: Avastin® sourced from the US, as a 90 minute IV infusion 
 Arm 3: Avastin® sourced from the EU, as a 90 minute IV infusion. 
 
Thirty-eight subjects will be dosed in each arm.  
 
Subjects will be admitted to the Clinical Research Unit (CRU) on Day -1, and will be confined to 
the CRU until discharge on Day 8. On Day 1, subjects will receive a single 3 mg/kg IV dose of 
the study drug. Subjects will return on Days 10, 14, 21, 28, 42, 56, 78 and 100 for nonresidential 
visits for the collection of PK samples and safety assessments. Immunogenicity samples will be 
collected on Days 14, 28, 56, and 78. 
 
The total duration of trial participation for each subject (from Screening through to the final 
visit) is anticipated to be a maximum of 19 weeks. The end of the study is defined as the date of 
the last subject’s last assessment (planned or unplanned). 
 
7  TREATMENTS 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs. 
Study Treatment Name 
Abbreviation 
Treatment 
Order on TFLs 
3 mg/kg MB02 IV 
3 mg/kg MB02 
IV 
1 
3 mg/kg US-licensed Avastin®  IV 
3 mg/kg US 
Avastin® IV 
2 
3 mg/kg EU-approved Avastin® IV 
3 mg/kg EU 
Avastin® IV 
3 
 
8  SAMPLE SIZE JUSTIFICATION 
Up to 114 subjects will be enrolled in order that 108 complete the study. 
 
A sample size of 36 subjects per arm (108 subjects in total) will provide at least 90% power for 
all the pairwise comparisons for primary endpoints (AUC and Cmax) using a percent coefficient 


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of variation (CV%) of 25% in both PK parameters for the similarity objective if the true ratio is 
equal to 1.05 or less. 
 
A conservative estimate of CV% was based on a prior MB02 study3 and information from the 
public domain4. Model-based simulations from a developed population PK literature model, 
accounting for similarity between bevacizumab sources (EU/US), intrinsic PK altering factors 
(body weight, sex, serum albumin and alkaline phosphatase), between subject variability and 
residual variability, showed that a sample size of 90 subjects provided at least 90% probability of 
concluding PK similarity for the all pairwise comparisons in terms of Cmax and AUC(0-). 
 
Simulations also showed that the probability of concluding PK similarity in terms of AUC(0-t) 
is almost the same as AUC(0-).  
 
A maximum of 5% loss of data due to premature discontinuation is expected therefore, the 
sample size is increased to 114 subjects in total, with 38 subjects per arm. 
 
9  DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will include all subjects exposed to MB02 or Avastin® and have at least 
1 postdose safety assessment. 
The PK Population will include all subjects who received the full dose of MB02 or Avastin®, 
did not have any major protocol deviations, and have an evaluable PK serum concentration-time 
profile. This population will be used for the primary analysis of PK bioequivalence 
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Population will be consistent with the Safety Population.  
10  
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations (Safety/ 
PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, number of observations (N), and number of subjects 
(n). For log-normal data (e.g., the PK parameters: areas under the concentration-time curve 
[AUCs] and maximum observed concentration [Cmax]), the geometric mean and geometric 
coefficient of variation (CV%) will also be presented. For categorical data, frequency counts and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 


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withdrawal, with any subjects excluded from the relevant population highlighted. For the 
calculation of summary statistics and statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.4 or higher. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilised to ensure 
compliance with CDISC standards. 
It is planned that the Sponsor will create a secondary CSR containing only data from MB02 and 
EU-licensed Avastin therefore to support this all TFLs will be repeated with US-licensed Avastin 
removed. 
10.1.1 Definition of Baseline and Change from Baseline 
Baseline for each parameter is defined as the last value measured prior to dosing, including 
repeat (vital signs and electrocardiograms [ECGs]) and unscheduled (clinical laboratory 
parameters) readings (see Section 10.1.2 for definitions of repeat and unscheduled readings). 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading. 
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Unscheduled readings are labelled as ‘Unscheduled’ in the listings. Because unscheduled 
readings are not associated with any scheduled timepoint, they are excluded from all summaries 
(with the exception that they may be used as baseline, as stated in Section 10.1.1). 
10.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, body weight, height, and body mass index will be 
summarised and listed. Subject disposition will be summarised and listed. 


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10.3 Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Analysis 
Serum pharmacokinetic parameters  
The following PK parameters will, where possible, be determined from the serum bevacizumab 
concentration-time profiles obtained following single dosing (using non-compartmental 
procedures in Phoenix WinNonlin (Certara USA, Inc. Version 6.4, or later): 
Parameter 
Definition 
AUC(0-t) 
Area under the concentration-time curve from time 0 to the time of last quantifiable 
concentration 
AUC(0-) 
Area under the concentration-time curve from time 0 extrapolated to infinity 
%AUCextrap 
Percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity 
Cmax 
Maximum serum concentration observed 
tmax 
Time of observed maximum serum concentration 
t1/2 
Apparent serum terminal elimination half-life 
kel 
Elimination rate constant of the terminal phase 
CL 
Total body clearance of drug after intravenous administration 
Vz 
Volume of distribution during the terminal phase after intravenous administration 
Additional PK parameters may be determined where appropriate.  
PK parameters will be calculated for each subject using actual doses and actual sampling times 
after start of infusion. 
 
Serum concentrations are used as supplied by the analytical laboratory for PK analysis. The units 
of concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory. 
Cmax and tmax will be obtained directly from the serum concentration-time profiles.  If Cmax occurs 
at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax.  
t1/2 will be calculated according to the following formula: 
 
el
2
/1
k
)
2
ln(
 
t
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where kel will be calculated by least squares linear regression of the terminal portion of the 
log-transformed serum concentration-time curve. 
The start of the terminal elimination phase for each subject will be defined by visual inspection 
and will be the first point at which there is no systematic deviation from the log-linear decline in 
serum concentrations. 
AUC(0-t) and AUC(0-∞) will be calculated using the linear trapezoidal method when concentrations 
are increasing and the logarithmic trapezoidal method when concentrations are decreasing. 
The certificate of testing documents show that although the protein contents of each batch were 
within the specified range there is variability in the actual protein content between batches and 
treatments which has the potential to influence the study results, therefore protein corrected 
AUC(0-∞), AUC(0-t), and Cmax will also be derived for each individual by dividing each parameter 
by the actual protein content of the product batch that the individual received, according to the 
table below: 
Batch number 
Protein content (mg/mL) 
17A043 
27.2 
3240772 
24.0 
3155155 
23.2 
B8034H02 
23.0 
B8027H01 
24.2 
 
10.3.2 
Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
Concentration values that are below the limit of quantification (BLQ) will be set to zero, with 
defined exceptions as follows. 
 
 Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
 
 If there are late positive concentration values following 2 BLQ concentration values in 
the apparent terminal phase, these values will be evaluated. If these values are 


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considered to be anomalous, they will be set to missing. 
 
 If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
 
 If a predose concentration is missing on Day 1, these values may be set to zero. 
10.3.3 
Criteria for Handling Concentrations Above the Limit of Quantification in 
Pharmacokinetic Analysis 
Any samples with concentrations above the upper limit of quantification that could not be 
reanalysed to determine the exact concentration, will be set as the upper concentration limit of 
the assay for PK analysis.  The concentration and PK parameters will be flagged in the listings 
but excluded from the summary statistics and will be described in the CSR. 
10.3.4 
Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
Number of Data Points 
 At least three data points will be included in the regression analysis and preferably 
should not include Cmax. 
Goodness of Fit 
 When assessing terminal elimination phases, the R2 adjusted value will be used as a 
measure of the goodness of fit of the data points to the determined line.  
 
 Regression-based parameters (AUC(0-), t1/2, kel, CL and Vz) will only be calculated if the 
R2 adjusted value of the regression line is greater than or equal to 0.70. 
Period of Estimation 
 Time period used for the estimation of t1/2, where possible, would be recommended to 
be calculated over at least two half-lives.  
 
 Where an elimination half-life is estimated over a time period of less than two half-
lives, it will be flagged in the data listings at the discretion of the pharmacokineticist, 
and the robustness of the value should be discussed in the study report. 
 
10.3.5 
Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at least 
three consecutive serum concentrations above the lower limit of quantification (LLOQ), 
with at least one of these concentrations following Cmax. 
 
 For any partial AUC determination (i.e. AUC to common partial area interval), nominal 
time will generally be used for the end of the interval. Actual times for partial AUC 
intervals may be used at the discretion of the pharmacokineticist. 
 


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 AUC(0-) values where the percentage extrapolation is less than 20% will be reported. 
For AUC(0-) and AUC(0-) derived parameters, where the percentage extrapolation is 
between 20 to 30%, these will be flagged and included in the descriptive statistics. 
Where the percentage of AUC extrapolation is greater than 30%, AUC(0-) and AUC(0-) 
derived parameters will be listed but excluded from descriptive statistics. 
 
10.3.6 
Anomalous Values 
 Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
 
 On Day 1, positive predose value(s) greater than 5% of Cmax may be excluded from the 
summary statistics of PK tables and the PK and statistical analysis as appropriate if 
there is a valid scientific reason for doing so. 
 
10.4  
Presentation of Pharmacokinetic Data 
10.4.1 Presentation of Pharmacokinetic Serum Drug Concentration Data 
 
The following rules will be applied if there are values that are BLQ or if there are missing values 
(e.g., no result [NR]) in a serum concentration data series to be summarized. 
 For the calculation of summary statistics, BLQ values will be set to zero. 
 If an embedded BLQ value is considered anomalous within the concentration-time 
profile, this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than 3 values in the data series, only the min, max and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ is 
considered a value. 
 If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and 
max will be presented as zero, and the geometric mean and geometric CV% will be 
denoted as NC. 
 If the value of the arithmetic mean or median is BLQ, these values will be presented as 
zero and the geometric mean and geometric CV% will be denoted as NC. 
 
10.4.2 Presentation of Pharmacokinetic Parameters 
 
For the calculation of summary statistics of PK parameters, all NR and NC values in a data series 
will be set to missing. 
The AUC values will be set to NC if they have been calculated using fewer than 3 concentrations 
and/or three concentrations if the last is Cmax. 


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10.4.3 Pharmacokinetic Statistical Methodology 
Serum Bevacizumab Concentrations  
All investigational product serum concentration data and derived PK parameters will be 
summarised. Individual primary PK parameters will be presented graphically to display the PK 
of the treatments. 
 
Serum concentrations of bevacizumab will be listed by subject and summarised for each 
treatment arm and time-point. Descriptive statistics (number of patients, arithmetic mean, SD, 
CV%, minimum, maximum, median, geometric mean, and geometric CV%) will be calculated 
for serum concentrations. 
 
In the assessment of bioequivalence MB02 is the test treatment and US Avastin® and EU 
Avastin® are the reference treatments. MB02 will be considered to be bioequivalent to US 
Avastin® and EU Avastin® if the 90% confidence intervals (CIs) for the ratios of MB02 relative 
to US Avastin® and EU Avastin® are completely contained within the interval 0.8000 to 1.2500 
for AUC(0-∞) and Cmax5. The PK population will be used for the analysis. 
The PK parameters (AUC(0-∞), AUC(0-t), and Cmax) will be log-transformed (base e)6 prior to 
analysis and will be analysed using an ANCOVA model. The model will include treatment as a 
fixed effect and body weight as a covariate. An example of the SAS code that will be used 
(assuming TRTMNT coding is 1= MB02, 2= US Avastin® or EU Avastin®) is as follows: 
 
proc mixed data=xxx; 
 
class trtmnt; 
 
model l_pk = trtmnt weight/ ddfm=kr; 
 
estimate ‘Test - Ref’ trtmnt 1 -1 / cl alpha=0.1; 
 
lsmeans trtmnt; 
 
run; 
where l_pk is the log-transformed (base e) PK parameter. 
For these parameters, least square (LS) means and mean differences will be calculated for MB02 
versus US Avastin®, MB02 versus EU Avastin®, and EU Avastin® versus US Avastin®.  The 
residual variance from the model will be used to calculate 90% CI for the differences and these 
values will be back-transformed to give geometric LS means, a point estimate and 90% CI for 
the ratio of MB02 relative to US Avastin® and EU Avastin®. This procedure is equivalent to 
Schuirmann’s two one-sided tests7 at the 0.05 level of significance7. 
Between-subject coefficients of variation (CVB) will be calculated for AUC(0-∞), AUC(0-t), and 
Cmax based on the log-normal distribution using the following formula: 
CVB(%) = [exp(mse) – 1]½ x 100 
where mse is the residual error from the mixed model. 


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Residual plots will be produced to assess the adequacy of the model. 
Sensitivity Analysis 
An additional sensitivity analysis will also be performed using the same methodology as the 
primary analysis but will use the protein adjusted PK parameters as the response variables to 
assess the impact of the actual protein content on the study results. Analyses may be repeated for 
subgroups of subjects with or without ADA and de novo ADA formation and any influencing 
subject demographics as appropriate. 
10.5 Safety and Tolerability Assessments 
10.5.1 Adverse Events 
A baseline sign and symptom is defined as an adverse event (AE) that starts after the subject has 
provided written informed consent and that resolves prior to the first dosing occasion, or an AE 
that starts prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose. AEs will be graded by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 
All AEs will be listed. The TEAEs will be summarised by treatment arm, severity, and 
relationship to the study drug. The frequency of TEAEs (the number of TEAEs, the number of 
subjects experiencing a TEAE, and the percentage of subjects experiencing a TEAE) will be 
summarised by treatment arm, severity grade, and by Medical Dictionary for Regulatory 
Activities system organ class and preferred term. The percentage of subjects experiencing a 
TEAE will be compared among the treatments using a fisher's exact test. The summary and 
frequency TEAE tables will be presented for all causalities and for those TEAEs considered 
related to the study drug (those that have a relationship of possibly related, probably related, or 
related). Any severe or serious AEs will be tabulated. For any AEs that change severity ratings 
the AE will be included only once under the maximum severity rating in the summaries.    
Onset times postdose are calculated from the start of infusion. 
10.5.2 Clinical Laboratory Parameters 
Clinical chemistry, haematology, and coagulation data will be summarised by treatment arm. 
Changes from baseline will be calculated. In addition, all clinical chemistry, haematology, 
urinalysis, and coagulation data outside the clinical reference ranges will be listed by parameter 
and treatment arm. 
Values for any clinical chemistry, haematology, urinalysis, and coagulation values outside the 
clinical reference ranges will be flagged on the individual subject data listings. 
 
Serology data will be listed by subject.   


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10.5.3 Vital Signs 
Vital signs data (including supine blood pressure, supine pulse rate, respiration rate, and oral 
temperature) will be listed and summarised.   
 
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. 
The vital signs data will be summarised by treatment arm, together with changes from baseline.  
Figures of mean vital signs and mean change from baseline profiles will be presented by 
treatment arm.  
 
Pulse oximetry data will be listed by subject. 
10.5.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the QT interval calculated using the Fridericia correction (QTcF), the 
PR and QT intervals, the QRS duration, and heart rate.  
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
The ECG data will be summarised by treatment arm, together with changes from baseline. 
Figures of mean ECG data and mean change from baseline profiles will be presented by 
treatment arm.  
 
10.5.5 Immunogenicity Safety Assessment 
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 and 
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. A summary over all visits 
will also be presented by treatment, this will be performed separately including and excluding 
subjects who were positive at baseline. Drug clearance will be presented graphically and 
numerically by ADA/neutralising ADA status of a subject by treatment. This figure will use the 
PK population, all other immunogenicity data summaries will be based on the safety population. 
Select analyses may be repeated for subsets with or without ADA and de novo ADA formation 
as appropriate. 
 
10.5.6 Other Assessments 
All other safety assessments not detailed in this section will be listed but not summarised or 
statistically analysed. 
Medical history data will not be presented. 


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10.5.7 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
No interim statistical analyses are planned. 
12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
Protein adjusted primary PK parameters will be calculated and used for a sensitivity analysis. 
13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
3. mAbxience; Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus 
 Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients (MB02-A-01-13). 
 mAbxience SA, Madrid, Spain. 
4. Beverly Knight, Danielle Rassam, Shanmei Liao, Reginald Ewesuedo. A phase I 
pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with 
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