Multicenter, Double-Blind, Randomized, Parallel-Group Study to Assess the Efficacy and Safety of MYL-1402O Compared With Avastin®, in the First-line Treatment of Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: NSCLC Stage IV
Sponsor: Mylan Pharmaceuticals Inc

 
Protocol MYL-1402O-3001 
Page 1 of 154 
19 February 2019 
 
Confidential 
CLINICAL STUDY PROTOCOL 
MYL-1402O-3001 
Multicenter, Double-Blind, Randomized, Parallel-Group Study to Assess the 
Efficacy and Safety of MYL-1402O Compared with Avastin®, in the First-line 
Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung 
Cancer 
 
Sponsor: 
Mylan GmbH 
Thurgauerstrasse, 40 
CH-8050 Zürich, Switzerland 
Sponsor 
Contacts: 
Catherine E Micales, MT  
Global Clinical Operations 
Mylan 
1000 Mylan Boulevard 
Canonsburg, PA 15317 USA 
Tel: +1 (724) 485 6596 
catherine.micales@mylan.com 
Dr. Eduardo Pennella, MD 
Global Clinical Development  
Mylan 
1000 Mylan Boulevard 
Canonsburg, PA 15317 USA 
Tel: +1 (724) 514 2369 
eduardo.pennella@mylan.com 
 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Mylan GmbH. The concepts and 
information contained in this document or generated during the study are considered proprietary and may not be 
disclosed in whole or in part without the expressed, written consent of Mylan GmbH. 
The study will be conducted according to the International Conference on Harmonisation, harmonised tripartite 
guideline E6 (R2): Good Clinical Practice 
 
 
 
 

 
Protocol MYL-1402O-3001 
Page 4 of 154 
19 February 2019 
 
Confidential 
Declaration of Principal Investigator 
I have read and understood all sections of the protocol (MYL-1402O-3001) entitled 
“Multicenter, Double-Blind, Randomized, Parallel-Group Study to Assess the Efficacy and 
Safety of MYL-1402O Compared With Avastin®, in the First-line Treatment of Patients with 
Stage IV Non-Squamous Non-Small Cell Lung Cancer”. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 19 February 2019, the International 
Conference on Harmonisation, harmonised tripartite guideline E6 (R2): Good Clinical 
Practice and all applicable government regulations. I will not make changes to the protocol 
before consulting with Mylan GmbH or implement protocol changes without independent 
ethics committee approval except to eliminate an immediate risk to patients. I agree to 
administer interventional treatment only to patients under my personal supervision or the 
supervision of a sub investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Mylan GmbH. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
Date 
 
 
 

 
Protocol MYL-1402O-3001 
Page 5 of 154 
19 February 2019 
 
Confidential 
Document History 
Version, Date 
Summary of Changes 
Version 3.0, 
February 19, 
2019 
• Update the definition of primary endpoint “The primary efficacy 
endpoint Overall Response Rate (ORR) will be based on best 
tumor responses as assessed by an independent review at any 
time point during the first 18 weeks, and assessed according to 
RECIST 1.1 
• 
ORR based on confirmed tumor responses will be evaluated as 
sensitivity analysis 
Version 2.0, 
April 04, 2018 
• Change in Study Design including Removal of the Survival Period 
from the study; every subject will be part of the study till 42 
weeks (Period 2), beyond which they can receive treatment under 
the extended period. During the Extended Period AEs related only 
to treatment (as described in the protocol, will be collected. AEs 
related to disease progression, will not be collected.  
• Change in sample Size; verbatim “It is estimated that 
approximately 864 screened patients will yield approximately 
640 patients for 1:1 randomization for having at least 628 
evaluable patients, taking into account the attrition rate of 2%.” 
• Change in the Statistical consideration in the primary endpoint as 
per the FDA and EMA feedback. Details of Meta-analysis 
included. 
• End of Study modified to study Closure; “Study closure will occur 
when either all patients have discontinued the study, or 42 weeks 
from the date the last patient was randomized to treatment OR at 
the administrative closure of the study. Patients on treatment at 
study closure will be advised by the PI and/or their associated 
primary health care provider on alternate therapies as per standard 
for the country. All treatment provided under the auspices of this 
protocol will cease at study closure.” 
• Preferred method for Urine Protein evaluation changed from 
UPCR to Urine dipstick; “Inclusion Criteria: Urine protein (via 
dipstick): 0 or 1+. Patients with ≥ 2+ can be included only if a 24-
hour urine specimen yields <2g of protein.” 
• Dose Modification Table, as recommended in the Avastin PI 2017 
is included. 
• Editorial changes throughout the document for harmonization of 
the text. 
• Administrative changes for study conduct 

 
Protocol MYL-1402O-3001 
Page 6 of 154 
19 February 2019 
 
Confidential 
Version 1.0,  
March 09, 2016 
Not Applicable- First Version 
 
 

 
Protocol MYL-1402O-3001 
Page 7 of 154 
19 February 2019 
 
Confidential 
 
Table of Contents 
Table of Contents .......................................................................................................................7 
List of Tables ............................................................................................................................12 
List of Figures ..........................................................................................................................12 
Protocol Synopsis.....................................................................................................................13 
List of Abbreviations................................................................................................................31 
Definition of Terms ..................................................................................................................34 
1 
Introduction ......................................................................................................................41 
2 
Study Objectives...............................................................................................................46 
2.1 
Primary Objective(s) ...............................................................................................46 
2.2 
Secondary Objective(s) ...........................................................................................46 
3 
Study Design ....................................................................................................................47 
3.1 
Endpoints ................................................................................................................47 
3.1.1 
Primary Endpoints ...................................................................................47 
3.1.2 
Secondary Endpoints ...............................................................................47 
3.1.3 
Pharmacokinetic Endpoints .....................................................................47 
3.1.4 
Safety Endpoints ......................................................................................47 
3.2 
Description of the Type/ Design of Study ...............................................................48 
3.3 
Randomization and Blinding ..................................................................................50 
3.3.1 
Randomization .........................................................................................50 
3.3.2 
Blinding ...................................................................................................50 
3.4 
Expected Duration of Subject Participation and Study Periods ..............................51 
3.5 
Stopping Rules or Discontinuation Criteria ............................................................53 
3.6 
Accountability procedures for the investigational product(s) .................................54 
3.7 
Maintenance and Breaking of Randomization Codes .............................................56 
4 
Selection and Withdrawal of Subjects ..............................................................................57 
4.1 
Subject Inclusion Criteria .......................................................................................57 
4.2 
Subject Exclusion Criteria ......................................................................................59 

 
Protocol MYL-1402O-3001 
Page 8 of 154 
19 February 2019 
 
Confidential 
4.3 
Withdrawal of Consent ...........................................................................................63 
4.3.1 
Efforts to Mitigate Missing Data .............................................................63 
5 
Study Treatments ..............................................................................................................65 
5.1 
Investigational Medicinal Product (Test and Reference) ........................................65 
5.2 
Treatment Administration .......................................................................................65 
5.2.1 
Bevacizumab (MYL-1402O or Avastin) ..................................................66 
5.2.2 
Carboplatin...............................................................................................67 
5.2.3 
Paclitaxel Premedications ........................................................................67 
5.2.4 
Paclitaxel ..................................................................................................67 
5.2.5 
Treatment Adjustments ............................................................................68 
5.2.5.1 
Adjustments for Bevacizumab (MYL-1402O or Avastin) .......................68 
5.2.5.2 
Adjustments for Carboplatin ....................................................................75 
5.2.5.3 
Adjustments for Paclitaxel .......................................................................77 
5.3 
Management of Overdose and Medication Errors ..................................................80 
5.4 
Prior and Concomitant Therapy ..............................................................................80 
5.4.1 
Permitted Medications and Procedures....................................................81 
5.4.2 
Prohibited Medications and Procedures ..................................................81 
5.5 
Treatment Compliance ............................................................................................82 
6 
Study Procedures and Assessments ..................................................................................84 
6.1 
Informed Consent....................................................................................................84 
6.2 
Screening.................................................................................................................84 
6.3 
Randomization ........................................................................................................86 
6.4 
Baseline ...................................................................................................................86 
6.5 
Treatment Period 1 ..................................................................................................87 
6.6 
Treatment Period 2 ..................................................................................................91 
6.7 
Extended Treatment Period .....................................................................................93 
6.8 
Safety Follow-Up Visit/End of Treatment Visit ......................................................94 
6.9 
Study Closure ..........................................................................................................95 
6.10 Unscheduled Visits ..................................................................................................95 
6.11 Assessment of Efficacy ...........................................................................................95 
6.11.1 
Tumor Response (RECIST) .....................................................................95 

 
Protocol MYL-1402O-3001 
Page 9 of 154 
19 February 2019 
 
Confidential 
6.11.1.1 Progressive Disease .................................................................................97 
6.11.2 
Survival ....................................................................................................97 
6.12 Safety and Tolerability Assessments .......................................................................98 
6.12.1 
Definitions of Adverse Events .................................................................98 
6.12.2 
Collection, Evaluation and Documentation of Adverse Events .............100 
6.12.2.1 Collection ...............................................................................................101 
6.12.2.2 Evaluation ..............................................................................................101 
6.12.2.3 Treatment of Adverse Events .................................................................106 
6.12.2.4 Emergency Unblinding ..........................................................................106 
6.12.2.5 Adverse Events of Special Interest ........................................................106 
6.12.2.6 Notification to Sponsor or Designee ......................................................107 
6.12.2.7 Follow-Up of Adverse Events................................................................108 
6.12.2.8 Notification and Submission to Regulatory Authorities and Ethics 
Committees ............................................................................................109 
6.12.3 
Pregnancy...............................................................................................109 
6.12.4 
Physical Examination ............................................................................ 110 
6.12.5 
Eastern Cooperative Oncology Group (ECOG) Performance Status .... 110 
6.13 Safety Monitoring ................................................................................................. 111 
6.14 Laboratory Analyses ............................................................................................. 111 
6.15 Sample Collections ............................................................................................... 112 
6.15.1 
Immunogenicity Blood Sampling .......................................................... 113 
6.15.2 
Pharmacokinetic Blood Sampling ......................................................... 114 
6.15.3 
Safety Blood Sampling .......................................................................... 116 
7 
Statistical and Analytical Plan ........................................................................................ 117 
7.1 
Efficacy Endpoints ................................................................................................ 117 
7.1.1 
Primary Efficacy Endpoints ................................................................... 117 
7.1.2 
Secondary Efficacy Endpoints ............................................................... 117 
7.2 
Pharmacokinetic Endpoints .................................................................................. 117 
7.3 
Safety Endpoints ................................................................................................... 118 
7.4 
Sample Size Calculations ...................................................................................... 118 
7.4.1 
FDA Regulatory Requirements .............................................................. 118 
7.4.2 
EU/EMA Regulatory Requirements ...................................................... 119 
7.4.3 
Study Sample Size Determination .........................................................120 

 
Protocol MYL-1402O-3001 
Page 10 of 154 
19 February 2019 
 
Confidential 
7.5 
Analysis Sets .........................................................................................................120 
7.6 
Description of Subgroups to be Analyzed ............................................................121 
7.7 
Statistical Analysis Methodology .........................................................................121 
7.7.1 
Analysis of Primary Efficacy Endpoint .................................................122 
7.7.1.1 
Efficacy Endpoint Analysis to Meet the FDA Requirements ................122 
7.7.1.2 
Efficacy Endpoint Analysis to Meet the EMA Requirements ...............123 
7.7.2 
Analyses of Secondary Efficacy Endpoints ...........................................123 
7.7.3 
Population Pharmacokinetic Analyses ...................................................124 
7.7.4 
Safety Analyses ......................................................................................125 
7.7.5 
Immunogenicity Analysis ......................................................................126 
7.7.6 
Other Analyses .......................................................................................126 
7.7.7 
Interim Analyses ....................................................................................126 
7.8 
Data Quality Assurance.........................................................................................127 
7.8.1 
Data Management ..................................................................................128 
8 
Ethics ..............................................................................................................................129 
8.1 
Independent Ethics Committee or Institutional Review Board ............................129 
8.2 
Ethical Conduct of the Study ................................................................................129 
8.3 
Patient Information and Consent ..........................................................................129 
9 
Principal Investigator’s Obligations ...............................................................................131 
9.1 
Confidentiality ......................................................................................................131 
9.2 
Financial Disclosure and Obligations ...................................................................131 
9.3 
Investigator Documentation ..................................................................................131 
9.4 
Study Conduct .......................................................................................................132 
9.5 
Adherence to Protocol...........................................................................................132 
9.6 
Adverse Events and Study Report Requirements .................................................132 
9.7 
Investigator’s Final Report ...................................................................................132 
9.8 
Records Retention .................................................................................................133 
9.8.1 
Publications ............................................................................................133 
10 Study Management .........................................................................................................134 
10.1 Monitoring ............................................................................................................134 
10.1.1 
External Steering Committee .................................................................134 

 
Protocol MYL-1402O-3001 
Page 11 of 154 
19 February 2019 
 
Confidential 
10.1.2 
Data and Safety Monitoring Board ........................................................134 
10.1.3 
Monitoring of the Study .........................................................................134 
10.1.4 
Inspection of Records ............................................................................134 
10.2 Management of Protocol Amendments and Deviations........................................135 
10.2.1 
Modification of the Protocol ..................................................................135 
10.2.2 
Protocol Deviations................................................................................135 
10.3 Study Termination .................................................................................................135 
10.4 Interim and Final Clinical Study Report ...............................................................136 
11 Reference List.................................................................................................................137 
12 Appendices .....................................................................................................................140 
12.1 Appendix A: Tumor Assessment According to RECIST Criteria Version 1.1 
(Eisenhauer 2009) .........................................................................................140 
12.2 1Appendix B  Eastern Cooperative Oncology Group Performance Status ..........144 
12.3 Appendix C  Bone Marrow ...................................................................................145 
12.4 Appendix D  Creatinine Clearance Calculations using Cockcroft and Gault 
Formula .........................................................................................................146 
12.5 Appendix E  Calculation of Paclitaxel Dose using Montseller Formula and based 
on Body Surface Area ...................................................................................147 
12.6 Appendix F: Bioanalytical Blood Sampling Collection Summary for 
Immunogenicity, Pharmacokinetics, and Safety Samples .............................148 
12.7 Appendix G: Initial Disease Diagnosis .................................................................151 
 
 
 

 
Protocol MYL-1402O-3001 
Page 12 of 154 
19 February 2019 
 
Confidential 
List of Tables 
Table 1-1 
Study Schedule of Events ............................................................................... 37 
Table 5-1 
Dose Modifications for Adverse Reactions .................................................... 69 
Table 5-2 
Carboplatin Dose Adjustments ....................................................................... 76 
Table 5-3 
Maximum AUC-based Carboplatin Dose ....................................................... 76 
Table 6-1 
Clinical Severity of Events ........................................................................... 102 
Table 6-2 
Action Taken for an Adverse Event Associated with Investigational Medicinal 
Product (MYL-1402O or Avastin) ................................................................ 103 
Table 6-3 
Action Taken for an Adverse Event Associated with Chemotherapy ........... 103 
Table 6-4 
Causality Assessment Categories .................................................................. 105 
Table 6-5 
Laboratory Tests .............................................................................................112 
Table 7-1 
Meta-Analysis ................................................................................................118 
Table 12-1 
Overall Responses for Target and Non-Target Lesions With and Without the 
Appearance of New Lesions ......................................................................... 142 
Table 12-2 
Best Overall Response at 18 weeks with Confirmed Assessment at subsequent 
Time Point ..................................................................................................... 143 
Table 12-3 
Distribution of Bone Marrow (by Weighing Cadaveric Bones) ................... 145 
Table 12-4 
Summary of Blood Sampling by Time Point ................................................ 149 
Table 12-5 
Definitions for T, N, and M Descriptors ....................................................... 151 
Table 12-6 
Lung Cancer Stage Grouping (Eighth Edition) ............................................ 152 
 
List of Figures 
Figure 1 
Definitions Aligned with Study Design .......................................................... 36 
Figure 3-1 
Study Design ................................................................................................... 49 
 

 
Protocol MYL-1402O-3001 
Page 13 of 154 
19 February 2019 
 
Confidential 
Protocol Synopsis 
Protocol Title 
Multicenter, Double-Blind, Randomized, Parallel-Group Study to 
Assess the Efficacy and Safety of MYL-1402O Compared with 
Avastin®, in the First-line Treatment of Patients with Stage IV 
Non-Squamous Non-Small Cell Lung Cancer 
Protocol Number 
MYL-1402O-3001 
Version 
3.0 
Protocol Date 
19 February 
2019 
Revision Date 
19 February 2019 
EudraCT no. 
2015-005141-32 
Product 
Bevacizumab (MYL 1402O [test product] or Avastin [reference 
product]) 
Study Type 
Confirmatory Safety and Efficacy Study 
Study Sites: 
This study will be conducted at approximately 190 study centers 
across the globe. 
Study 
Population: 
Patients with stage IV unresectable, recurrent or metastatic 
non-squamous non-small cell lung cancer (nsNSCLC) eligible to 
receive first-line treatment with bevacizumab in combination with 
carboplatin and paclitaxel 
Rationale: 
MYL-1402O is a monoclonal antibody currently being developed 
by Mylan GmbH, as a proposed biosimilar to European Union- and 
US-licensed Avastin (hereafter referred to as Avastin), which is 
approved as first-line treatment in combination with carboplatin 
and paclitaxel (CP) for patients with Stage IV unresectable, 
recurrent or metastatic nsNSCLC. This randomized equivalence 
study is designed to meet the global regulatory requirement for 
approval of a biosimilar product. For this study, both MYL-1402O 
and Avastin are considered investigational medicinal products 
(IMP). 
Objectives: 
Primary Objective: 
Compare the overall response rate (ORR) of MYL-1402O with that 
of Avastin, in combination with CP chemotherapy during the first 
18 weeks of first-line treatment in patients with Stage IV nsNSCLC 

 
Protocol MYL-1402O-3001 
Page 14 of 154 
19 February 2019 
 
Confidential 
Secondary Objectives: 
• Assess the safety profile of MYL-1402O as compared with 
that of Avastin when administered in combination with CP 
as first-line treatment for Stage IV nsNSCLC and when 
administered alone in the maintenance setting 
• Assess other efficacy parameters at 18 weeks and 42 weeks: 
Disease Control Rate (DCR), Duration of Response (DOR), 
Progression-Free survival (PFS), and Overall Survival (OS) 
rate of MYL-1402O as compared to Avastin when 
administered in combination with CP as first-line treatment 
for Stage IV nsNSCLC 
• Assess the potential immunogenicity at Week 18 and 42 of 
treatment of MYL-1402O as compared with that of Avastin 
• Compare the pharmacokinetic (PK) profile of MYL-1402O 
and Avastin using a population PK (Pop PK) approach 
Study Design: 
This is a multicenter, randomized, double-blind, 2-arm, parallel 
group, equivalence study that consists of the following periods: 
Screening/Baseline Period: In this period, which has a duration of 
up to 4 weeks (or ≤28 days prior to first dose [Day 0 of Cycle 1]), 
tumor imaging assessments must be performed no more than 28 
days prior to first dose (Day 0 of Cycle 1). The time between 
randomization (≤3 days prior to Day 0 of Cycle 1) and the first 
dose (Day 0 of Cycle 1) must be included in the 28-day window for 
tumor imaging assessment. Patients will be randomly assigned in a 
1:1 ratio to one of the two treatment groups (MYL-1402O or 
Avastin) within 3 days before the start of Period 1 (first dose of 
bevacizumab plus CP on Day 0 of Cycle 1). Baseline assessments 
must be performed within 24 hours of Day 0 of Cycle 1 to confirm 
that the patient has remained eligible for treatment, except for 
baseline labs which could be drawn before randomization and up to 
7 days prior to Day 0 of Cycle 1. 
Period 1: Patients will begin Period 1 receiving bevacizumab 
combination therapy (MYL1402O or Avastin, plus CP) on Day 0 of 
Cycle 1 for up to 6 cycles of therapy. Each cycle will consist of 
3 weeks (21 days ± 3 days) and a cycle will start with the 
administration of bevacizumab (as either MYL-1402O or Avastin). 
In this period, tumor assessments should be performed every 
6 weeks after Day 0 of Cycle 1 (the first dose of bevacizumab, 

 
Protocol MYL-1402O-3001 
Page 15 of 154 
19 February 2019 
 
Confidential 
either MYL-1402O or Avastin) and continuing every 6 weeks 
(window of ±3 days) through Week 18. 
Tumor assessments must be done consistently throughout the study 
as follows: employing a CT scan of thorax and abdomen and using 
the same technique - CT or MRI, slice interval, contrast agent. 
Period 1 will include 3 assessments at the pre-specified time points 
regardless of delays in treatment cycles. 
A blinded interim analysis with aim of a sample size re-estimation 
will be performed after at least 30% of the patients have completed 
week 18. The blinded interim analysis will be used to estimate the 
ORR at Week 18 and determine if any adjustments are required to 
the sample size. 
Period 2: A patient is eligible to continue into Period 2 if he/she 
has a response of stable disease or better (i.e., complete response 
[CR] or partial response [PR]) by RECIST 1.1 criteria at the 
Period 1 Week 18 tumor assessment. Eligible patients will continue 
to receive bevacizumab (either MYL-1402O or Avastin) every 3 
weeks as monotherapy. 
In this period, tumor assessments will occur every 12 weeks (+/- 3 
days) after the end of Period 1 (Week 18), at pre-specified time 
points (i.e., Week 30 and Week 42), regardless of delays of the 
cycles of treatment, until PD or discontinuation of interventional 
therapy (for any reason), or withdrawal of consent. The Week 42 
efficacy assessments will be used to evaluate the secondary 
endpoints. Patients will be assessed for tumor response using the 
same type of radiographic examinations used in Period 1 (e.g., CT 
or MRI of the thorax and abdomen, contrast agent, slice intervals) 
for ongoing evaluation of tumors. 
If a patient is discontinued from treatment prior to completion of 
Period 2 due to an Adverse Event, tumor assessment will be 
performed as per schedule until week 42. Patients started on a new 
anticancer treatment (surgery, radiotherapy or systemic treatment) 
or disease progression (PD), will be followed for OS till week 42. 
Extended Treatment Period: During the Extended Treatment 
Period, bevacizumab monotherapy given every 3 weeks will be 
provided to patients who at Week 42 have maintained stable 
disease or better response (CR or PR) by RECIST 1.1 criteria.  
During the Extended Treatment Period a patient will receive 
bevacizumab monotherapy (either MYL-1402O or Avastin) until 
PD or discontinuation of treatment or termination of study. Safety 

 
Protocol MYL-1402O-3001 
Page 16 of 154 
19 February 2019 
 
Confidential 
assessments will be made after each cycle of therapy and will be , 
focused only on treatment related AEs. This extended treatment 
period is aimed to keep providing treatment if patients are having 
benefit. 
Safety Follow-Up Visit: The Safety Follow-Up Visit is designed to 
capture safety assessments for any patient(s) that completed Period 
2 or discontinued the IMP at any time during the study for any 
reason (e.g., PD, treatment intolerance to bevacizumab).  
Safety follow-up visit will occur at 28 days (± 7 days) after the last 
dose of bevacizumab during an office visit.  
The End of Treatment Visit should occur after the last dose of any 
interventional therapy, mainly to capture the reason for 
discontinuation of the first-line treatment. The End of Treatment 
(EOT) Visit may occur at the same time as the safety follow-up 
visit. 
Patients who discontinue treatment prior to completion of Period 2, 
must have a Safety Follow Up Visit and End of Treatment Visit and 
will be followed up for survival status until Week 42. 
Study Closure: Study closure will occur when either all patients 
have discontinued the study, or 42 weeks from the date the last 
patient was randomized to treatment OR at administrative closure 
of study. Patients on study treatment at study closure will be 
advised by the PI and/or their associated primary health care 
provider on alternate therapies as per standard for the country. All 
treatment provided under the auspices of this protocol will cease at 
study closure.  
Estimated Study 
Duration: 
The estimated maximum planned study participation per patient is 
approximately 47 weeks. 

 
Protocol MYL-1402O-3001 
Page 17 of 154 
19 February 2019 
 
Confidential 
Sample Size: 
It is estimated that 864 screened patients will yield approximately 
640 patients for 1:1 randomization;. resulting in 628 evaluable 
patients (taking into account an attrition rate of 2%). 
Patients will be stratified by gender (male or female), smoking 
status (smoker or <100 cigarettes in entire lifetime), and number of 
metastasis sites (one or multiple sites). 
To meet the different regulatory requirements, the primary endpoint 
of ORR will be analyzed using the risk ratio and risk difference. As 
the EMA-based approach using the risk difference requires a 
slightly larger sample size; the planned sample size for this study 
will be based on the EMA requirement: a sample size of 
628 patients (314 per treatment group) provides at least 80% power 
for testing equivalence of MYL-1402O and Avastin at 1-sided 
2.5% level of significance, for the primary endpoint ORR at 
Week 18 (from the independent review). This sample size will 
assume that the ORR at Week 18 will be 38% for both 
MYL-1402O and Avastin. 
A blinded interim analysis for primary endpoint will be done after 
at least 30% of the population have either discontinued or 
completed 18 weeks on the study to assess the estimated overall 
ORR. The sample size will be increased up to a sample size of 670 
in case the estimated overall ORR is ≤ 36% or ≥40%. 
This blinded sample size re-estimation (BSSR) may have an effect 
on the actual type I error. When the magnitude of the Type I error 
increase was investigated by performing simulations for the 
situation with and without BSSR; results from the simulations 
suggest that the impact of a BSSR on the actual type I error is 
small. 

 
Protocol MYL-1402O-3001 
Page 18 of 154 
19 February 2019 
 
Confidential 
Inclusion 
Criteria: 
A patient is eligible for inclusion in the study if he or she meets all 
of the following criteria: 
1. Has demonstrated the ability to understand verbal and/or 
written instructions, to provide written informed consent, and is 
capable and agreeable to comply with protocol requirements. 
2. Male or female at least 18 years of age at the time of signing an 
informed consent form (ICF). 
3. Has a documented imaging diagnosis of Stage IV unresectable, 
recurrent or metastatic nsNSCLC. 
4. Has documented histologic or cytologic diagnosis of advanced 
nsNSCLC with negative or unknown sensitizing epidermal 
growth factor receptor (EGFR) mutation, and negative or 
unknown echinoderm microtubule-associated 
protein-like 4-anaplastic lymphoma kinase (EML4-ALK) 
rearrangement. 
5. Has measurable disease with at least one measurable lesion as 
defined by Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1; Section 12.1 [Appendix A]). All target (up to 
5 lesions) and nontarget lesions (other measurable not included 
in target, nonmeasurable, nonevaluable, or evaluable lesions) 
should be included in the assessment or evaluation of disease 
response as defined by RECIST 1.1 (Eisenhauer et al 2009). 
NOTE: If in the staging assessment, bone metastases are 
discovered and are localized outside of the thorax and 
abdominal region, each non target metastasis or as multiple non 
target bone metastases should be included in the tumor response 
assessments and followed by X-ray, CT scan, or MRI as 
appropriate. 
6. Has a performance status of 0 or 1 on the Eastern Cooperative 
Oncology Group (ECOG) scale. 
7. Has at least 6 months of expected survival. 
8. Has not received any prior systemic therapy for first-line 
treatment of advanced lung cancer, except adjuvant 
chemotherapy, and remained disease-free for at least 12 months 

 
Protocol MYL-1402O-3001 
Page 19 of 154 
19 February 2019 
 
Confidential 
from time of surgery, and at least 6 months from last dose of 
chemotherapy. 
9. May have had prior radiation therapy provided <25% of bone 
marrow is involved (Section 12.3 [Appendix C]), except for 
previous mediastinal irradiation that is not allowed. 
a. Prior radiation therapy must have been completed at least 
2 weeks prior to Day 0 of Cycle 1 
b. Patient must have recovered from acute toxicities 
associated with radiation therapy. Radiation-related 
toxicities must have resolved to Grade 1 according to the 
National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE; version 4.03) grade prior to 
Day 0 of Cycle 1. 
10. May have brain metastasis provided the metastasis has been 
treated and is considered stable. 
Treated, stable brain metastasis is defined as: 
a. Metastasis having no evidence of progressive disease (PD) 
or hemorrhage after treatment. 
b. No ongoing requirement for dexamethasone, as ascertained 
by clinical examination and post-treatment brain imaging 
(computed tomography [CT] scan or magnetic resonance 
imaging [MRI]) at baseline. 
c. Anticonvulsants are allowed, provided the dose regimen 
has been unchanged (stable) for at least 2 weeks prior to 
patient signing informed consent. 
d. Treatment for brain metastasis may include whole brain 
radiotherapy, radiosurgery (Gamma Knife®, linear particle 
accelerator, or equivalent), or a combination thereof, as 
deemed appropriate by the treating physician. All brain 
metastasis treatments must be completed at least 14 days 
prior to Day 0 of Cycle 1. 
11. Has adequate organ functions based on the following: 
a. Bone marrow reserve: 
i. 
White blood cell count ≥3 × 103/µL; 

 
Protocol MYL-1402O-3001 
Page 20 of 154 
19 February 2019 
 
Confidential 
ii. 
Absolute neutrophil count (segmented and bands) 
≥1.5 × 103/µL; 
iii. 
Platelet count ≥100 × 103/µL; 
iv. 
Hemoglobin ≥9.0 g/dL with at least 2 weeks without 
transfusions before Day 0 of Cycle 1. 
b. Hepatic: 
i. 
Total bilirubin ≤1.5 × upper limit of normal (ULN); 
except if elevation is due to Gilbert’s Syndrome with 
transitory elevations of indirect bilirubin. 
ii. 
Alkaline phosphatase, alanine transaminase, and/or 
aspartate transaminase ≤3 × ULN. Significant levels of 
alanine transaminase or aspartate transaminase should 
be further assessed for viral hepatitis, if not related with 
liver metastases. (Note: Isolated alkaline phosphatase 
elevation beyond 3 × ULN due to bone metastasis is 
allowed). 
c. Renal: 
i. 
Calculated creatinine clearance ≥45 mL/min based on 
the original, weight-based Cockcroft and Gault formula 
(Cockcroft and Gault 1976; Section 12.4 [Appendix D]) 
ii. 
Urine protein (via dipstick): 0 or 1+. Patients with ≥ 2+ 
can be included only if a 24-hour urine specimen yields 
<2g of protein 
12. If capable of reproduction, patients and their partners must use 
contraceptive methods during the full duration of the study and 
for 6 months after discontinuation of study. 
a. A patient who is capable of reproduction must be willing to 
practice birth control by using 2 different highly effective 
double barrier methods of contraception, or abstinence from 
sexual intercourse for the duration of the study. 
i. 
In particular a female patient of childbearing potential 
must use a method that results in less than 1% failure 
rate per year when used consistently and correctly such 
as implants, injectables, combined oral contraceptives, 

 
Protocol MYL-1402O-3001 
Page 21 of 154 
19 February 2019 
 
Confidential 
intrauterine devices, sexual abstinence, or vasectomized 
partner. 
ii. 
A male patient of reproductive potential (defined as a 
male that has not had a vasectomy) must use a condom 
with spermicide and their female partner to use another 
highly effective form of contraception. 

 
Protocol MYL-1402O-3001 
Page 22 of 154 
19 February 2019 
 
Confidential 
Exclusion 
Criteria: 
A patient who meets any of the following criteria will be excluded 
from the study: 
1. Is pregnant or breast-feeding. 
2. Has documented histology/cytology confirming any of the 
following: 
a. Squamous non-small cell lung cancer. (Note: In the event of 
mixed tumor histology/cytology or predominant cell type 
other than non-squamous, eligibility will be determined 
based on the predominant cell type, which must be non-
squamous.) 
b. A patient with any small cell type or large cell 
neuroendocrine histology. 
3. Has a recent (within 6 months prior to Day 0 of Cycle 1) 
cardiac condition as defined by the New York Heart 
Association Class II, III, or IV (AHA 1994). 
4. Has a recent (within 6 months prior to Day 0 of Cycle 1) 
history of a significant vascular event (such as aortic aneurysm 
requiring surgical repair or a recent peripheral arterial 
thrombosis) and/or history of significant and unstable vascular 
disease. 
5. Has a history of stroke or transient ischemic attack within 
6 months prior to Day 0 of Cycle 1, or has a long-term history 
of more than one of the following vascular thromboembolic 
events: 
a. Cerebrovascular accidents 
b. Transient ischemic attacks 
c. Myocardial infarctions 
d. Venous thromboembolic reactions, including pulmonary 
embolism 
6. Is receiving anticoagulant therapy that: 
a. Is not considered ‘stable’, defined as dosage not maintained 
for at least 3 months prior to Day 0 of Cycle 1. 

 
Protocol MYL-1402O-3001 
Page 23 of 154 
19 February 2019 
 
Confidential 
b. Is not within the targeted international normalized ratio at 
the time of consent signing. 
7. Has a current diagnosis, history, or risk of hemorrhage in the 
central nervous system (CNS), including the following: 
a. Patient with CNS metastasis treated by neurosurgical 
resection or brain biopsy performed within 8 weeks prior to 
Day 0 of Cycle 1. 
b. Patient should be off corticosteroids for at least 1 week 
(7 days) at the time of the post-treatment (for CNS 
metastasis) brain CT/MRI. 
8. Has any prior history of hypertensive crisis and/or hypertensive 
encephalopathy, or has a current diagnosis or recent history of 
inadequately controlled hypertension (defined as systolic blood 
pressure >150 mm Hg and/or diastolic >100 mm Hg, while on 
antihypertensive medications). 
9. Has a recent history of any of the following: 
a. A major surgical procedure, open biopsy, open pleurodesis, 
or significant traumatic injury within 28 days prior to Day 0 
of Cycle 1. 
b. Documented history of conditions that may need surgery 
during the study or within 6 months of signing informed 
consent. 
c. Has had either a core biopsy or other minor surgical 
procedure within 7 days prior to Day 0 of Cycle 1. (Note: 
Placement of a vascular access device, or a closed 
pleurodesis, thoracentesis, or mediastinoscopy are 
allowed). 
10. Has a history of any of the following: 
a. Hemoptysis (approximately >2.5 mL or a half teaspoon) 
within 3 months prior to Day 0 of Cycle 1. 
b. A thoracic, central, mediastinal tumor located within 2cm 
of carina invading or abutting major blood vessels (based 
on radiologist assessment) and associated bleeding risk as 
per PI judgement. 

 
Protocol MYL-1402O-3001 
Page 24 of 154 
19 February 2019 
 
Confidential 
c. A lung tumor with cavitation, if more than 50% of the 
diameter of the lesion is cavitated, and/or involving the 
central bronchus or vessel. 
- 
Major blood vessels are defined as:  
• Aorta 
• Superior and inferior vena cava 
• Main pulmonary artery 
• Intrapericardial portions of the right and left pulmonary 
arteries and pulmonary veins 
- 
Central location is defined as:  
• Distance of less than or equal to 2 cm from carina 
EC 10 will be evaluated on a case by case basis taking into 
consideration the above criteria in discussion with the site 
radiologist, PI and the medical monitor. 
11. Has a history of gastrointestinal fistula, perforation, or abscess. 
12. Has a current diagnosis or history of a nonhealing wound, 
active ulcer, or untreated bone fracture. 
13. Has prior history of another active malignancy within the last 
5 years, other than adequately treated superficial basal cell, 
superficial/skin squamous cell carcinoma, or carcinomas in 
situ. 
14. Has a known hypersensitivity to any component of carboplatin, 
paclitaxel, bevacizumab, Chinese hamster ovary cell products, 
or other recombinant human or humanized antibodies. 
15. Has received treatment with any other investigational drug 
prior to day 0 of cycle 1, within the last 30 days or 5 half-lives 
(if available); whichever is longer. 
16. Has previously received treatment with the following: 
a. Paclitaxel. 

 
Protocol MYL-1402O-3001 
Page 25 of 154 
19 February 2019 
 
Confidential 
b. Bevacizumab (Note: Prior intravitreal administration of 
bevacizumab does not preclude study participation). 
c. Anthracycline. (Note: May be allowed on a case by case 
basis after consulting with the medical monitor to rule out 
an increased risk of cardiac failure). 
17. Has documented or known current alcohol/drug abuse that 
precludes his/her ability to adhere to the protocol. 
18. Has any of the following concomitant treatments or conditions: 
a. Concomitant vaccination that contains an attenuated virus, 
for instance Yellow Fever vaccine. 
b. Has a known history of active or latent tuberculosis. 
c. Has a concomitant systemic disorder (e.g., active infection 
including known human immunodeficiency virus, viral 
hepatitis B or C) that, in the opinion of the principal 
investigator (PI; or designee), would compromise the 
patient's safety (for instance potential drug interactions, or 
ability to adhere to the protocol). 
d. Has any other concomitant condition that precludes the 
participation in the study through increased risk to the 
patient and/or potential to impact the PI’s (or designee’s) 
ability to administer this protocol. 

 
Protocol MYL-1402O-3001 
Page 26 of 154 
19 February 2019 
 
Confidential 
Efficacy 
Assessments: 
Efficacy assessments will consist of independently reviewed tumor 
assessments (at least a CT scan or MRI of the thorax and abdomen) 
using RECIST 1.1 criteria, but treatment decisions will be based on 
the Investigator's assessment. Tumor response (CR, PR, stable 
disease, or PD) will be evaluated using the international criteria 
proposed by the RECIST 1.1 committee.  
In Period 1, tumor assessments will occur every 6 weeks following 
first dose of bevacizumab (Week 6, Week 12, and Week 18).  
Tumor assessments will occur every 12 weeks in Period 2 
(Week 30 and Week 42). Progression-free survival and OS will also 
be assessed at 18 weeks and at 42 weeks. 
Pharmacokinetic 
Assessments: 
For PK analysis, scheduled samples will be collected from each 
randomized patient at the following time points: baseline (if 
possible, within 1 hour prior to first dose of bevacizumab), pre 
dose (if possible within 1 hour prior infusion) at Cycles 2 through 
6; post dose (immediately after infusion, < 15 minutes) at Cycles 1, 
2, 4, and 6.  
Additional samples from all patients in any cycle (Cycles 1 to 6): 
1 sample between Days 3 and 8 (inclusive) in any cycle, and 
1 sample between Days 10 and 18 (inclusive) in any cycle; pre 
dose at Cycles 704 and 708 (Period 2); and an additional sample 
collected at Safety Follow-Up Visit/EOT visit. In case of a 
hypersensitivity reaction, an unscheduled blood sample will be 
collected for drug concentration along with one immunogenicity 
sample as quickly/soon as possible after the event occurs. 
(Note: Post dose samples need to be taken from a different 
venipuncture location or catheter than the infusion one or should 
be taken after flushing the line). 
Immunogenicity 
Assessments: 
For immunogenicity analysis, scheduled samples will be obtained 
on all patients at the following time points: baseline (6 × 5 mL) 
prior to Cycle 1 for analytical method optimization and validation; 
prior to administration of bevacizumab (4 × 5 mL) during Period 1 
at Cycles 2, 4, 6, during Period 2 at Cycles 704 and 708, for 
antidrug (bevacizumab) antibody, and supplemental 
immunogenicity testing; and at Safety follow-up visit (4 × 5 mL). 
An unscheduled blood sample will be collected with a drug 
concentration sample if a hypersensitivity reaction occurs, as 
quickly/soon as possible after the event occurs. 
(Note: Immunogenicity samples are expected to be taken at the 
same time as the PK samples). 

 
Protocol MYL-1402O-3001 
Page 27 of 154 
19 February 2019 
 
Confidential 
Safety 
Assessments: 
Safety assessments will include the following: causality, incidence, 
nature, and severity of AEs (CTCAE [version 4.03] severity 
grading to be used) including adverse drug reactions, the ECOG 
performance status, clinical laboratory evaluations, detection of 
antibodies to bevacizumab, vital signs, and physical examinations. 
Treatment-emergent AEs will be coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA). Safety 
laboratory blood samples will be collected at Screening and prior 
to each administration of bevacizumab at each cycle of 
interventional therapy (Period 1: Cycle 1 through Cycle 6, 
Period 2: Cycles 704 and 708); and at Safety follow-up visit. In 
addition, women with childbearing potential must have a negative 
serum pregnancy test within 7 days prior to Day 0 of Cycle 1. 

 
Protocol MYL-1402O-3001 
Page 28 of 154 
19 February 2019 
 
Confidential 
Study Drug,  
Dosage and Route 
of 
Administration: 
Interventional therapy (bevacizumab and/or CP) is given on the 
first day of a cycle (21 days [± 3 days]). 
IMP Name: Bevacizumab (MYL-1402O [test product] or Avastin 
[reference product]) 
Dose, route, and frequency: The dose of bevacizumab is 
15 mg/kg administered every 21 days (± 3 days). The first dose is 
to be administered by continuous intravenous (i.v.) infusion over 
90 minutes (± 15 minutes). If the first infusion is tolerated without 
infusion-associated AEs (fever and/or chills), the second infusion 
may be delivered over 60 minutes (± 10 minutes). If the 60-minute 
infusion is well tolerated, subsequent infusions may be delivered 
over 30 minutes (± 10 minutes) every 21 days (± 3 days). During 
Period 1, bevacizumab combination therapy will be given with 
bevacizumab infusions sequentially followed by carboplatin 
infusions, paclitaxel pre-medications, and then paclitaxel on the 
first day of each cycle for up to 6 cycles and then in subsequent 
cycles, bevacizumab monotherapy may be used. 
Chemotherapy Name: Carboplatin 
Dose, route, and frequency: An area under the curve (AUC) dose 
of AUC 6 by continuous i.v. infusion over 30 minutes (+/- 15 
minutes) (after the administration of bevacizumab) every 21 days 
up to 6 cycles. NOTE: Carboplatin must be administered at AUC 6 
at Cycle 1. Thereafter (subsequent cycles); the minimal dose level 
of carboplatin allowed by this protocol is AUC 5.  
Chemotherapy Name: Paclitaxel 
Dose, route, and frequency: 200 mg/m2 dose by continuous 
i.v. infusion over 3 hours (± 30 minutes) (after the administration 
of carboplatin and paclitaxel pre-medication) every 21 days up to 
6 cycles. In countries where the initial dose is 175 mg/m2, PIs are 
allowed to initiate dosing at 175 mg/m2. For a patient that 
demonstrates tolerance of the 175 mg/m2 dose in Cycle 1, the PI 
may increase the dose to 200 mg/m2 in Cycle 2. The dose at 
subsequent cycles will be determined by the PI and tolerance of the 
individual patient. Dosing will be documented by the PI. If dose 
adjustment is needed, the minimum dose level of paclitaxel 
allowed by this protocol is 160 mg/m2. 
If a lower dose of paclitaxel or carboplatin is required, then the PI 
must discuss dosing with the medical monitor and receive approval 
from the sponsor. 

 
Protocol MYL-1402O-3001 
Page 29 of 154 
19 February 2019 
 
Confidential 
Statistical 
Methods: 
The primary efficacy endpoint will be ORR, based on  best tumor 
responses as assessed by an independent review at any time point 
during the first 18 Weeks.  
Since FDA and EMA use different approaches to determine 
equivalence based on the ORR, two primary analysis for the ORR 
will be done: 
Per FDA requirement, the ORRs for both MYL-1402O and Avastin 
will be calculated and the ratio of the ORRs will be used to 
determine if MYL-1402O is equivalent to Avastin. A 2-sided 90% 
CI for the ratio of the ORRs during the first Week 18 will be 
calculated with no adjustment for covariates. This analysis will be 
conducted in the intent-to-treat population.  
Per EMA requirement, the difference in the ORRs during the first 
18 Weeks will be evaluated using an unstratified 
Cochran-Mantel-Haenszel (CMH) test. A 2-sided 95% CI for the 
difference in ORRs at Week 18 will be calculated. This analysis 
will be conducted in the intent-to-treat population 
As sensitivity analysis, ORR based on best tumor response 
confirmed at  a second time point   by an independent review and 
ORRs as assessed by investigators will also be presented and 
analyzed using the same methods as  the primary efficacy endpoint. 
The secondary efficacy endpoints are DCR, PFS, OS, and DOR. 
DCR (Rate of CR + PR + SD) will be evaluated as a ratio and the 
90% CI will be estimated using logarithmic transformation with no 
adjustment for covariates. The difference in the disease control 
rates between treatment groups will be estimated using an 
unstratified CMH test and an asymptotic 2-sided 95% CI. 
Efficacy data at Week 18 for the entire ITT population will be 
submitted during initial submission. 
PFS and OS for the secondary efficacy endpoints will be evaluated 
using Kaplan-Meier plots. Survival rates at Weeks18, 30, and 42 
will be presented along with estimates of the relative risk and 
associated 95% CI at each time point. In addition, a Cox regression 
model will be used to estimate the hazard ratio of PFS and OS and 
the corresponding 95% CI for the treatment effect. 
DOR for the secondary efficacy endpoints will be evaluated using 
the same statistical analysis methods for the secondary efficacy 
endpoints of PFS and OS. 

 
Protocol MYL-1402O-3001 
Page 30 of 154 
19 February 2019 
 
Confidential 
Summary statistics of observed PK concentrations will be 
presented for all patients by treatment group. It is not intended that 
the study is powered for this secondary endpoint to demonstrate 
bioequivalence, but comparability of the results will be evaluated. 
Pharmacokinetic concentrations and covariate data will be 
analyzed by PopPK methods for all patients with evaluable PK 
data. Empiric Bayesian estimates of PK model parameters will be 
obtained for all patients. Pharmacokinetic parameters and exposure 
estimates (AUC, maximum concentration, minimum concentration, 
clearance, volume, and terminal elimination half-life) will be 
compared between treatment arms. Also, statistics of observed 
immunogenicity will be presented and analyzed. 
Treatment-emergent AEs and serious AEs will be descriptively 
summarized by system organ class, preferred term, and treatment 
group, as well as by severity and relationship to the IMP. 
Treatment-emergent AEs will be coded using the latest version of 
MedDRA. 
Descriptive summaries of observed values and change from 
baseline will be presented for clinical laboratory evaluations 
(hematology and biochemistry) by treatment group. The 
ECOG status and vital signs will be summarized for each visit. 
The number and percent of patients whose test results are positive 
for anti-bevacizumab antibodies will be provided for each 
treatment group. 
The descriptive statistics will include frequency and percentage of 
patients in each category for categorical variable, and the number 
of patients, arithmetic mean, standard deviation or standard error, 
median, first quartile, third quartile, minimum, and maximum for 
continuous variables. 
Date of Protocol: 
19 February 2019 

 
Protocol MYL-1402O-3001 
Page 31 of 154 
19 February 2019 
 
Confidential 
 
List of Abbreviations 
Abbreviation 
Definition 
AC 
alternative contact 
ADA 
anti-drug antibody 
AE 
adverse event 
AUC 
area under the curve 
BP 
blood pressure 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
parameters of clearance 
Cmin 
minimum concentration  
Cmax 
maximum concentration  
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CP 
carboplatin and paclitaxel 
CR 
complete response  
CRF 
case report form 
CrCl 
creatine clearance  
CT  
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor  
EMA 
European Medicines Agency 
EML4-ALK  
echinoderm microtubule-associated protein-like 4-anaplastic 
lymphoma kinase  
EOS 
end of study 
EOT 
end of treatment 
FDA 
United States Food and Drug Administration 

 
Protocol MYL-1402O-3001 
Page 32 of 154 
19 February 2019 
 
Confidential 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
Gastrointestinal 
HR 
hazard ratio 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
Ig 
Immunoglobulin 
IgG 
immunoglobulin G class 
INR 
international normalized ratio 
IMP 
investigational medicinal product 
IRB 
institutional review board 
ITT 
intent to treat 
i.v. 
Intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging  
NCI  
National Cancer Institute  
NSCLC 
non-small cell lung cancer  
nsNSCLC 
non-squamous non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival  
p 
p-value 
PD 
progressive disease  
PFS 
progression-free survival  
PI 
principal investigator 
PK 
Pharmacokinetic 
PopPK 
population pharmacokinetic(s) 
PP 
per protocol 
PPD 
Pharmaceutical Product Development  
PR 
partial response 

 
Protocol MYL-1402O-3001 
Page 33 of 154 
19 February 2019 
 
Confidential 
PRES 
posterior reversible encephalopathy syndrome 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
standard deviation 
SE 
standard error 
SmPC 
summary of product characteristics 
SS 
safety set 
SST 
serum separator tube 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
ULN 
upper limit of normal 
UPCR 
urine protein-to-creatinine ratio 
Vc 
volume of the central compartment 
VEGFR 
vascular endothelial growth factor receptor 
Vp 
volume of the peripheral compartment 
VEGF 
vascular endothelial growth factor 
 
 
 

 
Protocol MYL-1402O-3001 
Page 34 of 154 
19 February 2019 
 
Confidential 
Definition of Terms  
Protocol Term  
Definition 
Baseline  
Study related assessments conducted within 24 hours prior to first 
dose of bevacizumab (either MYL-1402O or Avastin) combination 
therapy (plus carboplatin and paclitaxel) to confirm that the patient has 
remained eligible for treatment during the Screening Period. 
Baseline Failure 
Any patient that meets initial eligibility requirements, is randomized to 
treatment, however does not receive first dose of bevacizumab and is 
deemed ineligible for continuation in the MYL-1402O-3001 study. 
Bevacizumab 
Combination 
Therapy 
Treatment administration of MYL-1402O or Avastin 15 mg/kg 
intravenous (i.v.) infusion plus carboplatin and paclitaxel every 
21 days.  
Bevacizumab 
Monotherapy 
Treatment with bevacizumab 15 mg/kg i.v. infusion (either 
MYL-1402O or Avastin) every 21 days until disease progression or 
treatment discontinuation.  
Chemotherapy 
Treatment with carboplatin and paclitaxel. Both are considered 
non-investigational medicinal products for this study. 
Early Terminator 
A patient that enters Period 1 and is terminated from the study prior to 
completing Week 18 assessments in Period 1 due to adverse event, 
progressive disease, withdrawal of consent, or discontinuation from 
interventional therapy. 
End of Treatment 
Visit 
A visit that occurs after last dose of all interventional therapy. Mainly 
to capture reason for ending first line therapy. The safety follow-up 
visit and the end of treatment visit may or may not occur on the same 
day. 
Interventional 
therapy 
Treatment with bevacizumab (investigational medicinal products: 
MYL-1402O [test product] or Avastin [reference product]) and 
chemotherapy (carboplatin, paclitaxel). 
Investigational 
Medicinal Product 
Blinded Bevacizumab (MYL-1402O [test product] or Avastin 
[reference product]) 
Period 1 
Period of study from Day 0 of Cycle 1 through Week 18. During this 
period, tumor assessments are done every 6 weeks (±3 days) following 
Day 0 of Cycle 1 through Week 18 (overall response rate is assessed at 
Week 18).  
Period 1 Completer 
A patient that completes Period 1 through Week 18 tumor assessment. 

 
Protocol MYL-1402O-3001 
Page 35 of 154 
19 February 2019 
 
Confidential 
Protocol Term  
Definition 
Period 2 
Period of study following Week 18 through Week 42. During this 
period tumor assessments are done every 12 weeks (±3 days) 
following Week 18 (end of Period 1) through Week 42. 
Period 2 Completer 
A patient that has remained on the study per protocol through Week 42 
tumor assessment (Period 2). 
Period 2 Terminator 
A patient that starts Period 2 and is terminated from the study prior to 
completing Week 42 tumor assessment due to adverse event, 
progressive disease, withdrawal of consent, or discontinuation from 
interventional therapy. 
Randomization 
Random assignment of patient to treatment (either MYL-1402O or 
Avastin); this may be up to 3 days prior to Day 0 of Cycle 1. 
Reference Product 
Avastin is the reference product of bevacizumab 
Safety Follow-up 
Visit  
A visit that occurs at 28 days (±7 days) after last dose of bevacizumab. 
Safety follow-up and end of treatment visits may or may not occur on 
the same day. 
Screen Failure 
A patient that has provided signed informed consent (via informed 
consent form) and that either through screening or occurrence of any 
event prior to randomization, is deemed ineligible for study 
participation. Within the 28-day Screening Period window, a patient 
that fails to meet initial inclusion/exclusion criteria should be 
re-evaluated once before being classified as a screen failure. 
Screening 
Assessment of eligibility of a patient to participate in the study during 
the period from patient signing informed consent up to randomization. 
Screening/Baseline 
Period 
Period up to 4 weeks (≤28 days) prior to first dose of bevacizumab 
(Day 0 of Cycle 1); includes baseline and randomization. 
Study Closure 
Study closure will occur when either all patients have discontinued the 
study, OR 42 weeks from the date the last patient was randomized OR 
upon the administrative closure of study. 
All treatment provided under the auspices of this protocol will cease at 
study closure 
Test Product 
MYL-1402O is the test product, proposed biosimilar of bevacizumab 

 
Protocol MYL-1402O-3001 
Page 36 of 154 
19 February 2019 
 
Confidential 
Figure 1 
Definitions Aligned with Study Design 
 
 

 
Protocol MYL-1402O-3001 
Page 37 of 154 
19 February 2019 
 
Confidential 
Table 1-1 
Study Schedule of Events 
 
 
Screening 
Random-
ization 
Baselinea 
 
-----------------Period 1b----------------- 
 
-----------Period 2c---------  
Safety 
Follow-
Up Visit 
d,e  
 
21 Day Cycles 
21 Day Cycles 
 
Cycle Number 
 
 
 
 
1 
2 
3 
4 
5 
6 
701 
702 
703 
70x 
28 Day  
F/U / 
EOT f, g 
Week Number  
 
 
 
 
W1 W4 W7 W10 W13 W16 W19 
W22 
W25 
Wx 
 
Day Number  
 ≤28 Days of 
Day 0 
≤3 Days 
of Day 0 
≤24 Hrs of 
Day 0 
Day 
0 
Day 
21 
Day 
42 
Day 
63 
Day 
84 
Day 
105 
Day 
126 
Day 
147 
Day 
168 
Day 
X 
 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenth 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteriai 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationj 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Interval historyl 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BSA calculationm 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Prior and concomitant 
medications/treatments 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs (with CTCAE grading)n  
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor assessment, at least a 
CT Scan of thorax and 
abdomen (RECIST1.1)o  
 
Xo 
 
 
 
 
Xo 
 
Xo 
 
Xo 
 
 
Xo 
Xo 

 
Protocol MYL-1402O-3001 
Page 38 of 154 
19 February 2019 
 
Confidential 
 
Abbreviations: AE=adverse events; BSA=body surface area; CT=computerized tomography; CrCl=creatinine clearance; CTCAE=Common Terminology Criteria for Adverse 
Events; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; F/U1=follow-up visit 1; F/U2=follow-up visit 2; hrs=hours; IMP=investigational medicinal product; 
INR=international normalized ratio; MRI=magnetic resonance imaging; PK=pharmacokinetics; RECIST=Response Evaluation Criteria in Solid Tumors; W=week. 
a 
Baseline (≤24 hours prior to first dose of bevacizumab [Day 0 of Cycle 1] and Randomization (≤3 days prior to first dose of bevacizumab [Day 0 of Cycle 1] assessments 
are shown in same column. If safety blood lab assessments are more than 7 days prior to baseline, then a new set of safety blood samples will be collected for safety 
assessments. 
b 
During Period 1, a treatment cycle is planned every 21 days until progressive disease, withdrawal of consent, or discontinuation from interventional therapy. Tumor 
assessments will still be conducted every 6 weeks (window of ±3 days). Week 18 efficacy assessments will be used to evaluate the primary and secondary endpoints, 
regardless of treatment at the time of Week 18 assessment. 
c 
During Period 2, a treatment cycle is planned every 21 days until progressive disease, withdrawal of consent, or discontinuation from interventional therapy. Tumor 
assessments will still be conducted every 12 weeks (Period 2: Week 30 and Week 42;). 
Brain image (MRI or CT 
scan) and bone X Rays 
(as required)p 
 
X 
 
 
 
 
Xp 
 
Xp 
 
Xp 
 
 
Xp 
Xp 
Survival informationr 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
IMP and/or Chemo Admin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP/chemo or IMP alone q 
 
 
 
 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
 
Laboratory/diagnostic tests  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
 
X 
 
Xa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calculated CrCl 
 
X 
 
Xa 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Immunogenicitys 
 
 
 
Xs 
 
Xs 
 
Xs 
 
Xs 
 
 
 
Xs 
Xs 
PKt 
 
 
 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
 
 
 
Xt 
Xt 
Urine dipstick 
(and 24 hour urine protein, if 
indicated) u 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (if indicated)v  
Xv 
 
Xv 
 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Prothrombin time or INR  
(if indicated)w 
 
X 
 
Xa 
 
X w 
X w 
X w 
X w 
X w 
X w 
X w 
X w 
X w 
X w 
Unscheduled visitsx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol MYL-1402O-3001 
Page 39 of 154 
19 February 2019 
 
Confidential 
d 
For patients that will continue into the extended period (after confirmation via tumor assessment per RECIST 1.1 of SD or better post Wk 42) a visit should be conducted 
28 days (± 7 days) post the last dose of IMP in Period 2. At this visit it will be important to collect the required labs inclusive of PK samples,  
e 
For patients that are discontinued from bevacizumab (for any reason) a safety follow-up visit ,must be conducted 28 days (± 7 days) after discontinuation from 
bevacizumab Of note: Depending on a patients’ circumstance - the safety follow-up visit and EOT may or may not occur at the same time point. If there is confusion 
about a combined visit, please contact your Mylan representative.  
f 
End of treatment (EOT) will occur after discontinuation of interventional therapy. The end of treatment visit may occur at the safety follow-up visit (Safety Follow-Up 
visit) or as soon as possible after the decision was made to terminate interventional therapy 
g 
If the patient continues to receive the study treatment in Extended Period, then only related AEs will be collected. 
h 
Informed consent must be provided by the patient prior to any protocol related procedures or tests. 
i 
The inclusion and exclusion criteria will be checked during the Screening Period and will be rechecked prior to randomization and prior to first dose of bevacizumab 
(Day 0 of Cycle 1) to confirm eligibility. During the Screening Period, an additional check of each patient’s eligibility for the study will be conducted by the Independent 
image vendor. This check will confirm: measurability of the lesions (per RECIST definition) and followed by the Medical Monitor confirmation of patient eligibility per 
the protocol inclusion/exclusion criteria. 
Serologic testing for hepatitis (Hepatitis A, Hepatitis B, or Hepatitis C virus) is required ONLY if alanine transaminase or aspartate transaminase values are elevated ≥ 
ULN (in the absence of liver metastasis) at screening. In case screening visit lab values are within ULN and baseline visit lab values are ≥ ULN, only clinically 
significant values (in the absence of liver metastasis) will need to be investigated further prior to dosing, but a sporadic rise of either of these do not need serology testing 
for viral hepatitis at baseline. 
j  
Physical examination is to be conducted on the first day of each cycle. 
k 
Randomization may occur up to 3 days prior to Day 0 of Cycle 1. 
l 
Evaluation of any change (new, increase, or decrease) in signs/symptoms and/or medical conditions since the previous visit 
m 
BSA will include assessing patient height and weight. (The dose does not need to be modified, if the change in weight is <10% from the prior calculation) 
n 
All AEs will be collected from signing of the informed consent through the Safety Follow-Up visit.. 
o 
Tumor assessment per RECIST 1.1 will be conducted on CT scans or MRIs every 6 weeks during Period 1 (first 18 weeks of treatment) at Weeks 6, 12, and 18. During 
Period 1, the timing is critically important and is independent of the treatment cycles, every effort should be done to accomplish this timing without affecting patient 
safety. During Period 2 (Cycle 704 and Cycle 708), tumor assessments are to occur every 12 weeks thereafter until progression. A window of ±3 days is permitted for all 
tumor assessments.  
No centralized tumor assessment will be conducted during the extended treatment period. Sites however will be expected to conduct regular tumor assessments to assure 
treatment efficacy on patients in the extended treatment period. PIs will assume the responsibility to continue to treat patients under the auspices of treatment benefit and 
safety management as per standard of care. Sites must record Progressive Disease tumor measurements as per RECIST 1.1 for patients in the extended treatment period. 
p 
 
Brain image (MRI or CT scan) and/or bone scan (e.g., X-ray) if indicated should occur with tumor assessments. NOTE: If in the screening / staging assessment, 
should bone metastasis be discovered and are localized outside of the thorax and abdominal region, each non target bone metastasis (or as multiple nontarget) 
should be included in the tumor response assessments. These lesions should be followed by X-ray, CT scan, or MRI as appropriate. During the study, bone 
scans may be used to confirm complete response or progression of disease.  

 
Protocol MYL-1402O-3001 
Page 40 of 154 
19 February 2019 
 
Confidential 
q 
On Day 0 of Cycle 1 (Period 1), patients will receive bevacizumab combination therapy: bevacizumab (either MYL-1402O [test product] or Avastin [reference product]) 
infusion followed by sequential infusions of carboplatin and paclitaxel (requires premedication). A cycle will last 21 days, including the first day of infusions. Patients 
may switch to bevacizumab monotherapy (either MYL-1402O or Avastin), provided the patient has stable disease or better (complete response or partial response) and 
either did not tolerate chemotherapy after Cycle 1 or has completed Week 18 assessments and is starting Period 2. Bevacizumab monotherapy may continue into the 
Extended Treatment period provided the patient’s disease is deemed, at minimum - stable at week 42.  
r 
Survival information will not be collected past week 42 unless there is a specific country level requirement.  
s 
For immunogenicity evaluation, an unscheduled blood sample will be collected with a drug concentration sample if a hypersensitivity reaction occurs, as quickly/soon as 
possible after the event occurs. Scheduled samples will be obtained on all patients at the following time points: baseline (6 × 5 mL) that is prior to Cycle 1 for analytical 
method optimization and validation; prior to administration of bevacizumab (4 × 5 mL) during Period 1 at Cycles 2, 4, 6, during Period 2 at Cycles 704 and 708), for 
antidrug (bevacizumab) antibody, and supplemental immunogenicity testing; and at safety follow-up visit (4 × 5 mL). 
t 
For PK, an unscheduled drug concentration blood sample will be collected with one immunogenicity sample if a hypersensitivity reaction occurs, as quickly/soon as 
possible after the event occurs. Scheduled samples will be collected from each randomized patient at the following time points: baseline ( if possible within 1 hour prior 
to first dose of bevacizumab), predose (if possible within 1 hour prior infusion) at Cycles 2 through 6; postdose (immediately after infusion, < 15 minutes) at Cycles 1, 2, 
4, and 6 , additional samples from all patients in any cycle (Cycles 1 to 6): 1 sample between Days 3 and 8 (inclusive) in any cycle, and 1 sample between Days 10 and 
18 (inclusive) in any cycle; predose at Cycles 704 and 708 (Period 2); and an additional sample collected at safety follow-up visit. When PK sample is concomitant with 
immunogenicity samples it should be taken at the same time, after dose using a different site or after flushing the line. 
u 
Urine protein will be done via a dipstick. However; should urine protein via dipstick be quantified at ≥ 2+ a 24 hour urine protein must be done. Patients will be 
considered eligible provided the 24 hour protein specimen yields <2g of protein. 
v 
Pregnancy test will be conducted, if indicated. Women with childbearing potential must have a negative serum pregnancy test during screening and one urine test within 
7 days prior to Day 0 of Cycle 1. Prior to each cycle of therapy, the women with childbearing potential must have a negative urine test. 
w 
For all patients at screening and subsequent cycles, the patient who is receiving an anticoagulant therapy (i.e.,warfarin), prothrombin time and/or international normalized 
ratio should be determined, if indicated . 
x 
Assessments performed during unscheduled visits should be guided by the reason for the visit and per the principal investigator’s discretion. For example, when there is 
suspicion of progressive disease, assessments should include an unscheduled computerize d tomography (CT) or magnetic resonance imaging (MRI). 

 
Protocol MYL-1402O-3001 
Page 41 of 154 
19 February 2019 
 
Confidential 
1 Introduction 
Lung cancer is the most prevalent cancer worldwide and the leading cause of cancer-related 
mortality (DHHS, 1999). In 2012, lung cancer caused an estimated 1.6 million deaths and 
was the most common cause of cancer deaths in men and the second most common cause of 
cancer deaths in women (Globocan 2012). Most cases of lung cancer are of the non-small 
cell lung cancer (NSCLC) type, which has a poor prognosis especially when it is 
locally-advanced or metastatic (Soria et al. 2013). Despite the latest improvements in the 
treatment of lung cancer, 5-year survival still remains low, ranging from 10% to 20% 
worldwide (DHHS, 1999). 
Vascular endothelial growth factor (VEGF) is a glycosylated angiogenic cytokine that is the 
key driver of vasculogenesis and angiogenesis in a variety of settings, especially in diseases 
such as cancer. Vascular endothelial growth factor is a mitogen, and specifically acts on 
endothelial cells to increase vascular permeability, induce angiogenesis, vasculogenesis, 
endothelial cell growth and cell migration, and inhibit apoptosis. 
Bevacizumab (Avastin®, Genentech/Roche) is a recombinant humanized monoclonal 
antibody of the immunoglobulin (Ig) G1 class that selectively binds to VEGF. The binding of 
bevacizumab to VEGF inhibits the binding of VEGF to its receptors on the surface of 
endothelial cells, Flt-1 (also known as VEGF receptor-1 [VEGFR-1]) and kinase insert 
domain receptor (also known as VEGF receptor-2 [VEGFR-2]). Neutralizing the biological 
activity of VEGF inhibits the formation of new tumor vasculature, causes regression in 
newly-formed tumor vasculature, and normalizes the remaining tumor vasculature, thereby 
inhibiting tumor growth. 
The pharmacokinetic (PK) parameters of bevacizumab are similar to those of other IgG 
antibodies and can be predicted by 2-compartment linear pharmacokinetics with a 
distribution half-life of 1.44 days and terminal elimination half-life of 19.9 days 
(Lu et al. 2008). Accumulation to steady-state would therefore be expected to occur during 
Cycle 5 (100 days) of a regimen with dosing every 21 days. The effect of other chemotherapy 
agents on bevacizumab PK parameters has been minimal. Body weight and gender are the 
most significant covariates of bevacizumab clearance (CL) with males having 26% faster CL 
than females (Lu et al. 2008). 
In the Phase 3 study Eastern Cooperative Oncology Group (ECOG) 4599, patients were 
randomly assigned to either bevacizumab plus carboplatin and paclitaxel (CP) or CP alone 
(Sandler et al. 2006). Patients who received 6 cycles of bevacizumab plus CP and were 

 
Protocol MYL-1402O-3001 
Page 42 of 154 
19 February 2019 
 
Confidential 
without disease progression (PD) continued on single-agent bevacizumab until PD. The 
median progression-free survival (PFS) time was significantly improved in the bevacizumab 
plus CP group (6.2 months versus 4.5 months in the CP group) with a hazard ratio (HR) for 
PD of 0.66 (95% confidence interval [CI], 0.57 to 0.77; p-value [p] <0.001). The overall 
response rate (ORR) was 35% (133/381) for patients on bevacizumab plus CP and 
15% (59/392) for patients on CP (p<0.001). Median overall survival (OS) was also 
significantly improved for patients on the bevacizumab plus CP group (12.3 months versus 
10.3 months for patients receiving CP) with HR of 0.79 (95% CI: 0.67 to 0.92; p = 0.003). 
One- and 2-year survival rates were 51% and 23%, respectively, for the bevacizumab plus CP 
regimen, compared with 44% and 15%, respectively, for the CP regimen. In Study 
ECOG 4599, the addition of bevacizumab resulted in modest changes to the expected toxicity 
profiles of chemotherapy alone (Genentech 2009). Similar to other bevacizumab studies, a 
number of safety signals (e.g., epistaxis, hypertension, proteinuria) were identified; the 
majority of these events were of low grade and did not require discontinuation of 
bevacizumab. The results of Study ECOG 4599 suggested that the addition of a third non-
cytotoxic agent and/or maintenance therapy with an agent of low toxicity could result in 
improved outcomes in patients with advanced NSCLC. Study ECOG 4599 also demonstrated 
that the treatment paradigm for patients with non-squamous NSCLC (nsNSCLC), that are 
eligible for treatment with bevacizumab, is different than the treatment paradigm for patients 
with squamous histology NSCLC based on a safety differences (NCCN 2015). 
The overall safety profile of Avastin is based on data from over 5700 patients with various 
malignancies, predominantly treated with Avastin in combination with chemotherapy in 
clinical trials (Roche 2017). The most frequently observed adverse reactions across clinical 
studies in patients receiving Avastin were hypertension, fatigue or asthenia, diarrhea, and 
abdominal pain. The most serious adverse reactions were gastrointestinal (GI) perforations, 
hemorrhage (including pulmonary hemorrhage/hemoptysis) which is more common in 
patients with NSCLC, and arterial thromboembolism. Major or massive pulmonary 
hemorrhage/hemoptysis, can occur suddenly and up to two-thirds of the serious pulmonary 
hemorrhages resulted in a fatal outcome (Roche 2017). Patients with predominantly 
squamous cell carcinoma, hemoptysis, or both have been excluded from more recent clinical 
studies due to a relationship between fatal hemoptysis and central lesions with squamous 
histology in lung cancer patients treated with bevacizumab (Johnson et al. 2004). 
Mylan GmbH is developing MYL-1402O as a proposed biosimilar product to Avastin. 
MYL-1402O has been extensively characterized using state-of-the-art physicochemical and 

 
Protocol MYL-1402O-3001 
Page 43 of 154 
19 February 2019 
 
Confidential 
functional tests. Critical quality attributes including peptide sequence, secondary and tertiary 
structure, and potency have been compared in side-by-side analyses with multiple batches of 
Avastin. These in vitro assays demonstrate that MYL-1402O is similar to Avastin in all 
critical quality attributes that might potentially affect the structure, safety, and efficacy. 
A biosimilar approach has been employed throughout the MYL-1402O development 
program, which depends on the demonstration of comparability to Avastin from the 
perspective of chemical, pharmaceutical, and biological attributes. Avastin, used throughout 
the comparability program, has been granted a marketing authorization in all major markets 
based on a complete quality, safety, and efficacy data set. 
MYL-1402O was well tolerated in single-dose and repeat-dose toxicity studies; and had a 
similar toxicological profile as Avastin in a repeat-dose toxicity study in Swiss albino mice. 
In repeat-dose studies, the no observed adverse effect level of MYL-1402O was found to be 
445 mg/kg body weight in Swiss albino mice (Study 9335) and 133.5 mg/kg body weight in 
New Zealand white rabbits (Study 9340). Similarly, results from 28-day repeat-dose 
toxicokinetic study (Study TOX 070-002) in cynomolgus monkeys showed that there were 
no notable differences in pathological toxic effects jn terms of serum concentrations or 
toxicokinetic parameters following treatments with MYL-1402O or Avastin (Investigator’s 
Brochure, V2.0, Mylan, Jan 2016). 
The PK and safety profile of MYL-1402O was further evaluated in the randomized, single-
blind MYL-1402O-1002 study, where 111 healthy male volunteers were randomly assigned 
to receive a single dose administration (1 mg/kg during a 90 minute intravenous [i.v.] 
infusion) of MYL-1402O, European Union-marketed Avastin or US-marketed Avastin. The 
90% CIs for the primary PK parameter, AUC0-inf, fell within the bioequivalence limits of 0.80 
to 1.25 for all 3 pairwise comparisons, MYL-1402O/US-Avastin®, MYL-1402O/EU- 
Avastin®, and EU-Avastin/US-Avastin, following a single, 1 mg/kg iv dose in healthy adult 
male volunteers.  
This study demonstrates that MYL-1402O is bioequivalent to US-Avastin® and 
EU-Avastin®, and that EU-Avastin® is bioequivalent to US-Avastin®. Safety and 
tolerability of MYL-1402O, US-Avastin® and EU-Avastin® were similar. There were no 
SAEs or discontinuations due to TEAEs. Generally, most TEAEs reported during the study 
were consistent with the clinical data of bevacizumab (Avastin®). The large majority of the 
reported TEAEs were of Grade 1 (mild) severity and none was higher than Grade 2 
(moderate). There were no clinically relevant findings with respect to clinical laboratory, 
vital signs, or physical examination. Overall, the local tolerability of MYL-1402O was good 

 
Protocol MYL-1402O-3001 
Page 44 of 154 
19 February 2019 
 
Confidential 
and was similar to that of US-Avastin® and EU-Avastin®. The immune response was 
comparable across the 3 treatments, transient in nature and with no correlation with any 
infusion-related adverse event or with the PK parameters. (Investigator’s Brochure, V3.0, 
Mylan, May 2017). 
Biocon Limited, development partner of Mylan GmbH, has completed a randomized 
double-blind active-controlled, parallel-design, comparative PK, efficacy, safety and 
immunogenicity study of MYL-1402O compared with Avastin both in combination with 
XELOX chemotherapy in metastatic colorectal cancer patients in India 
(BM100-CC-03-I-01). A total of 136 patients were randomized in Part 2. (MYL-1402O: 68; 
Avastin: 68). The primary end point of the study was to evaluate the single dose 
pharmacokinetic parameters. The 90% CIs were within the predefined bioequivalence range 
of 80.00%–125.00% (Cmax: 85.86% to 100.54%; and AUC0-t 87.56% to 104.79%), 
confirming bioequivalence of the two bevacizumab formulations. All primary and secondary 
single-dose PK parameters were comparable between MYL-1402O and Avastin. The PFS 
rate at 18 weeks was 61.76% in the MYL-1402O arm and 60.29% in the Avastin arm, 
indicating a high degree of comparability in the response to treatment. There was no 
statistically significant difference between the two arms (p =0.8604). The ORR and disease 
control rate (DCR) were also comparable between the two arms and did not have any 
statistically significant difference (p >0.05). The treatment with MYL-1402O was well-
tolerated in combination with XELOX chemotherapy and no new or unexpected safety 
signals were observed. The overall safety profile of Bmab-100 was comparable to that of 
Avastin. The study concluded that MYL-1402O is similar to Avastin with respect to 
pharmacokinetics, efficacy, safety, and immunogenicity. (Investigator’s Brochure, V3.0, 
Mylan, May 2017). 
In the clinical development program, MYL-1402O is being investigated in comparison with 
the EU-reference product Avastin and both treatments (MYL-1402O and Avastin) are being 
administered at a dose of 15 mg/kg bevacizumab by i.v. infusion once every 21 days until PD 
or treatment discontinuation according to the Avastin Summary of Product Characteristics 
(SmPC; Roche 2017). The current study is being conducted to compare the efficacy, safety, 
and immunogenicity between MYL-1402O and Avastin, when used as a first-line treatment 
of Stage IV nsNSCLC. For the purpose of this protocol (MYL-1402O-3001), EU-sourced 
Avastin (Roche 2017) will be referred to as Avastin. The first part of the study will evaluate 
both treatments in combination with CP, and the second part of the study will evaluate 

 
Protocol MYL-1402O-3001 
Page 45 of 154 
19 February 2019 
 
Confidential 
continued treatment with MYL-1402O or Avastin in those patients who have at least stable 
disease to first-line therapy, including continued safety and immunogenicity. 
Rationale of Study Design 
Some study design considerations were based on a Genentech-sponsored, randomized, 
Phase 2 study AVF0757g, where bevacizumab was added to the ECOG reference regimen 
established in Study ECOG 1594 with CP. This Phase 2 study identified a relationship 
between fatal hemoptysis and central lesions with squamous histology in lung cancer patients 
treated with bevacizumab (Johnson et al. 2004). Based on this safety data, the subsequent 
Phase 3 study excluded patients with predominantly squamous cell carcinoma, hemoptysis, 
or both. 
Interactions with the FDA and European Medicinal Agency indicated that the confirmatory 
efficacy and safety study should be conducted in a cancer indication with an ORR primary 
endpoint with a long term follow up to compare the safety profile and the immunogenicity. 
The demonstration of therapeutic equivalence in the nsNSCLC was expected to be applicable 
to other approved indications for Avastin, based on the fact that Avastin has the same 
mechanism of action in all indications and the dose used for NSCLC was highest amongst all 
indications. 
Thus, this confirmatory safety and efficacy study is a multicenter, double-blind, randomized, 
parallel-group study and is designed to develop MYL-1402O as a proposed biosimilar to the 
reference product, Avastin. 
As discussed in the introduction (Section 1), the dose of 15 mg/kg bevacizumab delivered by 
i.v. infusion once every 21 days until PD or treatment discontinuation has been chosen 
according to the EU-approved Avastin SmPC (Roche 2017). 

 
Protocol MYL-1402O-3001 
Page 46 of 154 
19 February 2019 
 
Confidential 
2 Study Objectives 
2.1 
Primary Objective(s) 
The primary objective of this study is to compare the ORR of MYL-1402O with that of 
Avastin, in combination with CP chemotherapy during the first 18 weeks of first-line 
treatment in patients diagnosed with Stage IV nsNSCLC. 
2.2 
Secondary Objective(s) 
The secondary objectives of this study are as follows: 
• Assess the safety profile of MYL-1402O as compared with that of Avastin when 
administered in combination with CP as first-line treatment for Stage IV nsNSCLC 
and when administered alone in the maintenance setting. 
• Assess other efficacy parameters at 18 weeks and 42 weeks: Disease Control Rate 
(DCR), Duration of Response (DR), Progression-Free survival (PFS), and Overall 
Survival (OS) rate of MYL-1402O as compared to Avastin when administered in 
combination with CP as first-line treatment for Stage IV nsNSCLC. 
• Assess the potential immunogenicity during 42 weeks of treatment of MYL-1402O as 
compared with that of Avastin. 
• Compare the PK profile of MYL-1402O and Avastin using a population PK (PopPK) 
approach. 
•  

 
Protocol MYL-1402O-3001 
Page 47 of 154 
19 February 2019 
 
Confidential 
3 Study Design 
3.1 
Endpoints 
3.1.1 
Primary Endpoints 
The primary efficacy endpoint is the ORR as assessed by an independent review during the 
first 18 Weeks, assessed according to RECIST 1.1. 
3.1.2 
Secondary Endpoints 
The secondary efficacy endpoints will consist of the following. 
• DCR (CR, PR, or stable disease) during the first 18 weeks 
• PFS, defined as the time from randomization to the first documentation of PD or to 
death due to any cause, whichever comes first; PFS rate will be calculated at 18 
weeks and 42 weeks, median PFS will be determined at 42 weeks. 
• OS, defined as the time from randomization to date of death due to any cause, OS 
rates will be calculated at 18 weeks and 42 weeks. 
• DOR, is defined as the time from start of the first documentation of objective tumor 
response (CR or PR) to the first documentation of tumor progression (i.e., PD) or to 
death due to any cause, whichever comes first. 
3.1.3 
Pharmacokinetic Endpoints 
The pharmacokinetics endpoints will be as follows: 
• PopPK measures of exposure of MYL-1402O and the reference product Avastin (e.g., 
AUC, Cmax, Cmin, CL, Vc, and the terminal elimination half-life). 
3.1.4 
Safety Endpoints 
The safety endpoints will be as follows: 
• Incidence, nature, and severity of AEs including adverse drug reactions graded 
according to CTCAE. 
• Detection of antibodies to bevacizumab. 

 
Protocol MYL-1402O-3001 
Page 48 of 154 
19 February 2019 
 
Confidential 
3.2 
Description of the Type/ Design of Study 
The study is a multicenter, randomized, double-blind, 2-arm, parallel-group, equivalence 
study to evaluate patients with Stage IV nsNSCLC when treated in first-line with 
bevacizumab (either MYL-1402O [test product] or Avastin [reference product]) in 
combination with CP and subsequently, with monotherapy of bevacizumab (either 
MYL-1402O or Avastin). 
The study is comprised of 4 periods: Screening/Baseline Period, Period 1, Period 2 and 
Extended Treatment Period. For Period 1 and Period 2, the length of the period is defined by 
the tumor assessments interval (every 6 weeks or every 12 weeks, respectively). 
The periods are shown in Figure 3-1 and are described in detail in Section 3.4. Assessments 
will be conducted per the Schedule of Events (Table 1-1). 
 

 
Protocol MYL-1402O-3001 
Page 49 of 154 
19 February 2019 
 
Confidential 
Figure 3-1 
Study Design 
 
 

 
Protocol MYL-1402O-3001 
Page 50 of 154 
19 February 2019 
Confidential 
 
3.3 
Randomization and Blinding 
3.3.1 
Randomization 
Patients who meet all of the inclusion and none of exclusion criteria and who are approved 
by the medical monitor will be considered eligible for entry into the study and will be 
randomly assigned to treatment in the study within 3 days prior to Day 0 of Cycle 1. 
Approximately 640 eligible patients (320 patients per group; Section 7.4) from 
approximately 120 sites worldwide will be randomly assigned to one of 2 treatment arms 
(MYL-1402O or Avastin). An interactive voice or web response system (IVRS/IWRS) will 
be used to administer the randomization schedule. Biostatistics will generate the 
randomization schedule using SAS software Version 9.3 or later (SAS Institute Inc, Cary, 
North Carolina) for IVRS/IWRS, which will link sequential patient randomization numbers 
to treatment kit numbers. The randomization schedule will be stratified by gender (male or 
female), smoking status (smoker or <100 cigarettes in entire lifetime), and number of 
metastasis sites (one site or multiple sites). It will also use an appropriate block size, which 
will not be revealed. 
3.3.2 
Blinding 
An unblinded pharmacist will be identified at each center; whose role will be limited to 
handling the blinded study treatment. Treatment allocation via the IVRS/IWRS will be 
provided only to the unblinded pharmacist (or authorized designee); and will be sent to the 
pre-specified fax/email accessible only to unblinded team members. 
The unblinded pharmacist will prepare infusion bags of MYL-1402O and Avastin and 
provide the infusion bags to the PI (or designee) in a blinded manner. Treatment assignment 
must NOT be disclosed to the PI (or designee), site or study personnel, or any sponsor 
representative except for the designated site monitor responsible for unblinded monitoring. 
The assessors (i.e., the PI and site personnel assessing safety and efficacy), the study patients 
as well as both the local and central radiologists must remain blinded throughout the study 
(Period 1 and Period 2). 
The sponsor plans to report results after all patients have completed Week 18 or discontinued 
the study. After Week 18, the study will continue as a blinded study for patients, PIs (or 

 
Protocol MYL-1402O-3001 
Page 51 of 154 
19 February 2019 
Confidential 
designees), vendors, blinded clinical research organization personnel, and blinded clinical 
team until completion. 
After all patients have completed Week 18 or discontinued the study, part of the sponsor 
clinical team will be unblinded to the randomization list, and the primary efficacy analysis 
will be performed. A clinical study report will be written to report the results of the primary 
efficacy analysis and all other efficacy and safety results up to that point in time, a second 
report will be written after all patients reach 42 weeks. 
3.4 
Expected Duration of Subject Participation and Study Periods 
The maximum planned study participation from Screening/Baseline Period through Safety 
Follow up Visit is approximately 47 weeks. 
Screening/Baseline Period: In this period, which has a duration of up to 4 weeks (or ≤28 
days prior to first dose [Day 0 of Cycle 1]), tumor imaging assessments must be performed 
no more than 28 days prior to first dose (Day 0 of Cycle 1). The time between randomization 
(≤3 days prior to Day 0 of Cycle 1) and the first dose (Day 0 of Cycle 1) must be included in 
the 28-day window for tumor imaging assessment. Patients will be randomly assigned in a 
1:1 ratio to one of the two treatment groups (MYL-1402O or Avastin) within 3 days before 
the start of Period 1 (first dose of bevacizumab plus CP on Day 0 of Cycle 1). Baseline 
assessments must be performed within 24 hours of Day 0 of Cycle 1 to confirm that the 
patient has remained eligible for treatment. 
Period 1: Patients will start Period 1 receiving bevacizumab combination therapy 
(MYL1402O or Avastin, plus CP) on Day 0 of Cycle 1 for up to 6 cycles of therapy. Each 
cycle will consist of 3 weeks (21 days ± 3 days) and a cycle will start with the administration 
of bevacizumab (as either MYL-1402O or Avastin). 
In this period, tumor assessments should be performed every 6 weeks after Day 0 of Cycle 1 
(the first dose of bevacizumab, either MYL-1402O or Avastin) and continuing every 6 weeks 
(window of ±3 days) through Week 18. 
Tumor assessments must be done consistently throughout the study, using at least a CT scan 
of thorax and abdomen and using the same technique - CT or MRI, slice interval, contrast 
agent. Period 1 will include 3 assessments at the pre-specified time points regardless of 
delays in treatment cycles. 
Period 2: A patient is eligible to continue into Period 2 if he/she has a stable disease or better 
response (i.e., complete response [CR] or partial response [PR]) by RECIST 1.1 criteria at 

 
Protocol MYL-1402O-3001 
Page 52 of 154 
19 February 2019 
Confidential 
the Period 1 Week 18 tumor assessment. The eligible patient will continue to receive 
bevacizumab (either MYL-1402O or Avastin) every 3 weeks as a monotherapy. 
In this period, tumor assessments should occur every 12 weeks after the end of Period 1 
(Week 18), at pre-specified time points (i.e., Week 30 and Week 42), regardless of delays of 
the cycles of treatment, until PD or discontinuation of interventional therapy (for any reason), 
or withdrawal of consent. The Week 42 efficacy assessments will be used to evaluate the 
secondary endpoints. Patients will be assessed for tumor response using the same type of 
radiographic examinations used in Period 1 (e.g., CT or MRI of the thorax and abdomen, 
contrast agent, slice intervals) for ongoing evaluation of tumors. 
If a patient is discontinued from treatment prior to completion of Period 2 due to an Adverse 
Event, tumor assessment will be performed as per schedule until week 42, patient is started 
on a new anticancer treatment (surgery, radiotherapy or systemic treatment) or disease 
progression (PD), and will be followed for OS till week 42. 
Extended Treatment Period: During the Extended Treatment Period, continued 
bevacizumab monotherapy may be provided to any patient that has maintained stable disease 
or better response (CR or PR) by RECIST 1.1 criteria at Week 42. 
During the Extended Treatment Period, a patient will receive bevacizumab monotherapy 
(either MYL-1402O or Avastin) until PD or discontinuation of treatment or termination of 
study. Safety assessments will be made for each cycle of therapy. 
Safety Follow-Up Visit: The Safety Follow-Up Visit is designed to capture safety 
assessments for any patient(s) that discontinue the IMP at any time during the study, for any 
reason (e.g., PD, treatment intolerance to bevacizumab). Safety follow-up visit will occur at 
28 days (± 7 days) after the last dose of bevacizumab during an office visit. The End of 
Treatment Visit should occur after the last dose of any interventional therapy, mainly to 
capture the reason for discontinuation of the first-line treatment. The End of Treatment 
(EOT) Visit may occur at the same time as the safety follow-up visit. 
Study Closure:  
Study closure will occur when one of the following is reached: 
1 All patients have discontinued from the study 
2 42 weeks from the date the last patient was randomized to treatment. 
3 Administrative closure of study.  

 
Protocol MYL-1402O-3001 
Page 53 of 154 
19 February 2019 
Confidential 
NOTE: Patients on study treatment at time of study closure will be advised by the PI and/or 
their associated primary health care provider on alternate therapies as per standard for the 
country. All treatment provided under the auspices of this protocol will cease at study 
closure.  
3.5 
Stopping Rules or Discontinuation Criteria 
Discontinuation from interventional therapy is terminology specific to patients who stop 
receiving interventional therapy under the auspices of the protocol. Patients can continue to 
participate in study evaluations and provide data (e.g., second line therapies, OS data 
collection points). 
It will be vitally important to capture in both the source document and the electronic case 
report form (eCRF) the reason a patient has decided or the PI decided to discontinue from 
interventional therapy. 
It is the patients’ right to consider whether they wish to continue to participate in 
study-related procedures and to have their data collected under the protocol (for instance, 
assessments related to the key primary endpoints) or other key assessments (such as safety, 
survival, disease response). 
Should a patient not wish to be followed (i.e., contacted by the investigative site, and/or 
participate in further assessments and/or have additional data collected), the patient must 
specifically sign a withdrawal of consent form. 
Treatment should be discontinued if any of the following reasons apply (but not limited to): 
• Progression of Disease  
• Severe infusion reactions to MYL-1402O or Avastin or carboplatin or paclitaxel 
• Pregnancy: If pregnancy occurs in a female patient, the patient will be discontinued from 
study and followed until the outcome of the pregnancy is known 
• Any other physical examination finding, change in vital signs, AE* or laboratory 
abnormality that in the opinion of the PI (or designee), would cause an excessive risk if 
the patient continues the study treatment 
• Unacceptable toxicity 

 
Protocol MYL-1402O-3001 
Page 54 of 154 
19 February 2019 
Confidential 
• In the PI’s (or designee’s) opinion it is in the patient’s best interest to discontinue 
treatment, e.g., due to changes in medical or social condition. 
• Patient withdrawal of consent 
• Patient indicates unwillingness to comply with study treatment or protocol requirements 
• Patient is lost to follow-up 
• Patient enters the study in violation of the protocol 
• Use of prohibited therapy (as defined in Section 5.4.2) 
• Non-compliance that in the opinion of the PI will compromise possible response to 
therapy 
• Administrative reasons, such as inability of the patient, the PI or the sponsor to continue 
the study. 
* Upon occurrence of a serious or intolerable AE, the PI (or designee) will confer with the 
sponsor. If a patient is discontinued because of an AE, the event will be followed until it is 
resolved. 
3.6 
Accountability procedures for the investigational product(s) 
Mylan GmbH will provide adequate supplies of interventional therapies (MYL-1402O, 
Avastin, carboplatin, and paclitaxel). Chemotherapy pre-medications and any other 
medications will be procured locally by the site. Sites will also provide the infusion supplies 
from their stock. For this protocol, carboplatin and paclitaxel are considered non-
investigational. 
MYL-1402O (test product) and Avastin (reference product) will be packaged, labelled and 
supplied centrally to all sites from the Mylan-approved packaging vendor. 
The CP chemotherapy will be administered sequentially after IP. This will also be packaged, 
labelled, and supplied centrally to all sites from the Mylan approved packaging vendor. 
MYL-1402O and Avastin vials are not blinded. Each vial will be labelled with a blinded label 
as per local language and regulatory requirement. Each individual vial will then be placed 
into a labelled carton. The carton will have a blinded label applied to it. Once the vial is 

 
Protocol MYL-1402O-3001 
Page 55 of 154 
19 February 2019 
Confidential 
placed into the carton and tamper sealed, it is then blinded. The dosage amount to be given to 
a patient will be determined based on a patient weight calculation and will be prepared for 
administration by the unblinded pharmacist as described in Section 3.3.2. 
The premedication and saline will be procured locally by the sites. 
All IMP must be protected from moisture, and kept in a refrigerator at 2°C to 8°C. 
Temperature monitoring in the form of an in-house management system is required that is, 
for example, alarmed if the refrigerator stops working. Regular refrigerator maintenance 
checks will be conducted. Quarantine management of supplies will be available on site if 
required within a refrigerator at 2°C to 8°C, for example, temperature variations at site or 
during distribution to site. Chemotherapy (i.e., carboplatin and paclitaxel) does not need to be 
refrigerated (see the package insert for each product for handling full details; 
Paraplatin 2010, Taxol 2011). 
Each shipment will come with a calibrated temperature monitor, which will require stopping 
upon receipt at site and the data will require to be downloaded and sent to the packaging 
vendor. Instruction on how to perform this activity will be provided in writing to each site as 
well as instruction on actions to be performed in IWRS and physically at site. 
An IWRS will be used for drug inventory and distribution management. There will be 
instructions provided to the site on what to do in the event of a temperature deviation, and 
how to manage the product in IWRS, and physically at the site. There will be return 
instructions put into place on how the IMP/chemotherapy needs to be returned back to the 
shipping depot if the site is not able to reconcile. Destruction of the IMP/chemotherapy must 
be pre-approved by the sponsor, if locally destroyed. If the site does destroy locally, a 
certificate of destruction will be required clearly linking which drug has been destroyed, 
using what method and when. 
The randomization list will be prepared by PPD and supplied to the packaging vendor who 
will use the randomization list to label supplies, and upload into IWRS. An approved third 
party courier will make the shipments and temperature monitor the shipments to the site. All 
updates will be made in the IWRS. 
Labelling text will be compliant with local regulatory requirements. Dispensation will be 
conducted via the IWRS and preparation by the unblinded pharmacist on site as described in 
Section 3.3.2. 

 
Protocol MYL-1402O-3001 
Page 56 of 154 
19 February 2019 
Confidential 
The label should include but not be limited to: Sponsor name/address, Dosage, Route of 
administration, Quantity, Name/strength, Packaging batch number/code, Trial reference or 
protocol number, Kit’s number, Directions for use, Statement ‘For Clinical Trial Use Only’, 
Storage conditions, Expiry/use by date 
The PI (or designee) will maintain accurate records of receipt of all test articles, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each patient in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
3.7 
Maintenance and Breaking of Randomization Codes 
A patient’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the patient depends on knowing the study treatment the patient received. In the 
extraordinary event that the blind needs to be broken because of a medical emergency, the PI 
may unblind an individual patient’s treatment allocation. As soon as possible, the PI should 
first contact the medical monitor to discuss the medical emergency and the reason for 
revealing the actual treatment received by that patient. The treatment assignment will be 
unblinded through IVRS/IWRS. Reasons for treatment unblinding must be clearly explained 
and justified in the eCRF. The date on which the code was broken together with the identity 
of the person responsible (i.e., medical monitor from the sponsor or PPD) must also be 
documented. 

 
Protocol MYL-1402O-3001 
Page 57 of 154 
19 February 2019 
Confidential 
4 Selection and Withdrawal of Subjects 
4.1 
Subject Inclusion Criteria 
A patient is eligible for inclusion in the study if he or she meets all of the following criteria: 
1. Has demonstrated the ability to understand verbal and/or written instructions, to provide 
written informed consent, and is capable and agreeable to comply with protocol 
requirements. 
2. Male or female at least 18 years of age at the time of signing an informed consent form 
(ICF). 
3. Has a documented imaging diagnosis of Stage IV unresectable, recurrent or metastatic 
nsNSCLC. 
4. Has documented histologic or cytologic diagnosis of advanced nsNSCLC with negative 
or unknown sensitizing epidermal growth factor receptor (EGFR) mutation, and negative 
or unknown echinoderm microtubule-associated protein-like 4-anaplastic lymphoma 
kinase (EML4-ALK) rearrangement. 
5. Has measurable disease with at least one measurable lesion as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1; Section 12.1 [Appendix A]). All target 
(up to 5 lesions) and nontarget lesions (other measurable not included in target, 
nonmeasurable, nonevaluable, or evaluable lesions) should be included in the assessment 
or evaluation of disease response as defined by RECIST 1.1 (Eisenhauer et al 2009). 
NOTE: If in the staging assessment, bone metastases are discovered and are localized 
outside of the thorax and abdominal region, each non target metastasis or as multiple non 
target bone metastases should be included in the tumor response assessments and 
followed by X-ray, CT scan, or MRI as appropriate. 
6. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
scale. 
7. Has at least 6 months of expected survival. 
8. Has not received any prior systemic therapy for first-line treatment of advanced lung 
cancer, except adjuvant chemotherapy, and remained disease-free for at least 12 months 
from time of surgery, and at least 6 months from last dose of chemotherapy. 
9. May have had prior radiation therapy provided <25% of bone marrow is involved 
(Section 12.3 [Appendix C]), except for previous mediastinal irradiation that is not 
allowed. 

 
Protocol MYL-1402O-3001 
Page 58 of 154 
19 February 2019 
Confidential 
a. Prior radiation therapy must have been completed at least 2 weeks prior to Day 0 of 
Cycle 1 
b. Patient must have recovered from acute toxicities associated with radiation therapy. 
Radiation-related toxicities must have resolved to Grade 1 according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 
4.03) grade prior to Day 0 of Cycle 1. 
10. May have brain metastasis provided the metastasis has been treated and is considered 
stable. 
Treated, stable brain metastasis is defined as: 
a. Metastasis having no evidence of progressive disease (PD) or hemorrhage after 
treatment. 
b. No ongoing requirement for dexamethasone, as ascertained by clinical examination 
and post-treatment brain imaging (computed tomography [CT] scan or magnetic 
resonance imaging [MRI]) at baseline. 
c. Anticonvulsants are allowed, provided the dose regimen has been unchanged (stable) 
for at least 2 weeks prior to patient signing informed consent. 
d. Treatment for brain metastasis may include whole brain radiotherapy, radiosurgery 
(Gamma Knife®, linear particle accelerator, or equivalent), or a combination thereof, 
as deemed appropriate by the treating physician. All brain metastasis treatments must 
be completed at least 14 days prior to Day 0 of Cycle 1. 
11. Has adequate organ functions based on the following: 
a. Bone marrow reserve: 
i. 
White blood cell count ≥3 × 103/µL; 
ii. 
Absolute neutrophil count (segmented and bands) ≥1.5 × 103/µL; 
iii. 
Platelet count ≥100 × 103/µL; 
iv. 
Hemoglobin ≥9.0 g/dL with at least 2 weeks without transfusions before Day 0 of 
Cycle 1. 
b. Hepatic: 
i. 
Total bilirubin ≤1.5 × upper limit of normal (ULN); except if elevation is due to 
Gilbert’s Syndrome with transitory elevations of indirect bilirubin. 
ii. 
Alkaline phosphatase, alanine transaminase, and/or aspartate transaminase 
≤3 × ULN. Significant levels of alanine transaminase or aspartate transaminase 

 
Protocol MYL-1402O-3001 
Page 59 of 154 
19 February 2019 
Confidential 
should be further assessed for viral hepatitis, if not related with liver metastases. 
(Note: Isolated alkaline phosphatase elevation beyond 3 × ULN due to bone 
metastasis is allowed). 
c. Renal: 
i. 
Calculated creatinine clearance ≥45 mL/min based on the original, weight-based 
Cockcroft and Gault formula (Cockcroft and Gault 1976; Section 12.4 
[Appendix D]) 
ii. 
Urine protein (via dipstick): 0 or 1+. Patients with ≥ 2+ can be included only if a 
24-hour urine specimen yields <2g of protein 
12. If capable of reproduction, patients and their partners must use contraceptive methods 
during the full duration of the study and for 6 months after discontinuation of study. 
a. A patient who is capable of reproduction must be willing to practice birth control by 
using 2 different highly effective double barrier methods of contraception, or 
abstinence from sexual intercourse for the duration of the study. 
i. 
In particular a female patient of childbearing potential must use a method that 
results in less than 1% failure rate per year when used consistently and correctly 
such as implants, injectables, combined oral contraceptives, intrauterine devices, 
sexual abstinence, or vasectomized partner. 
ii. 
A male patient of reproductive potential (defined as a male that has not had a 
vasectomy) must use a condom with spermicide and their female partner to use 
another highly effective form of contraception. 
4.2 
Subject Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Is pregnant or breast-feeding. 
2. Has documented histology/cytology confirming any of the following: 
a. Squamous non-small cell lung cancer. (Note: In the event of mixed tumor 
histology/cytology or predominant cell type other than non-squamous, eligibility will 
be determined based on the predominant cell type, which must be non-squamous.) 
b. A patient with any small cell type or large cell neuroendocrine histology. 

 
Protocol MYL-1402O-3001 
Page 60 of 154 
19 February 2019 
Confidential 
3. Has a recent (within 6 months prior to Day 0 of Cycle 1) cardiac condition as defined by 
the New York Heart Association Class II, III, or IV (AHA 1994). 
4. Has a recent (within 6 months prior to Day 0 of Cycle 1) history of a significant vascular 
event (such as aortic aneurysm requiring surgical repair or a recent peripheral arterial 
thrombosis) and/or history of significant and unstable vascular disease. 
5. Has a history of stroke or transient ischemic attack within 6 months prior to Day 0 of 
Cycle 1, or has a long-term history of more than one of the following vascular 
thromboembolic events: 
a. Cerebrovascular accidents 
b. Transient ischemic attacks 
c. Myocardial infarctions 
d. Venous thromboembolic reactions, including pulmonary embolism 
6. Is receiving anticoagulant therapy that: 
a. Is not considered ‘stable’, defined as dosage not maintained for at least 3 months 
prior to Day 0 of Cycle 1. 
b. Is not within the targeted international normalized ratio at the time of consent signing. 
7. Has a current diagnosis, history, or risk of hemorrhage in the central nervous system 
(CNS), including the following: 
a. Patient with CNS metastasis treated by neurosurgical resection or brain biopsy 
performed within 8 weeks prior to Day 0 of Cycle 1. 
b. Patient should be off corticosteroids for at least 1 week (7 days) at the time of the 
post-treatment (for CNS metastasis) brain CT/MRI. 
8. Has any prior history of hypertensive crisis and/or hypertensive encephalopathy, or has a 
current diagnosis or recent history of inadequately controlled hypertension (defined as 
systolic blood pressure >150 mm Hg and/or diastolic >100 mm Hg, while on 
antihypertensive medications). 
9. Has a recent history of any of the following: 
a. A major surgical procedure, open biopsy, open pleurodesis, or significant traumatic 
injury within 28 days prior to Day 0 of Cycle 1. 
b. Documented history of conditions that may need surgery during the study or within 
6 months of signing informed consent. 

 
Protocol MYL-1402O-3001 
Page 61 of 154 
19 February 2019 
Confidential 
c. Has had either a core biopsy or other minor surgical procedure within 7 days prior to 
Day 0 of Cycle 1. (Note: Placement of a vascular access device, or a closed 
pleurodesis, thoracentesis, or mediastinoscopy are allowed). 
10. Has a history of any of the following: 
a. Hemoptysis (approximately >2.5 mL or a half teaspoon) within 3 months prior to 
Day 0 of Cycle 1. 
b. A thoracic, central, mediastinal tumor located within 2cm of carina invading or 
abutting major blood vessels (based on radiologist assessment) and associated 
bleeding risk as per PI judgement. 
c. A lung tumor with cavitation, if more than 50% of the diameter of the lesion is 
cavitated, and/or involving the central bronchus or vessel. 
- 
Major blood vessels are defined as:  
• Aorta 
• Superior and inferior vena cava 
• Main pulmonary artery 
• Intrapericardial portions of the right and left pulmonary arteries and pulmonary 
veins 
- 
Central location is defined as:  
• Distance of less than or equal to 2 cm from carina 
EC 10 will be evaluated on a case by case basis taking into consideration the above 
criteria in discussion with the site radiologist, PI and the medical monitor. 

 
Protocol MYL-1402O-3001 
Page 62 of 154 
19 February 2019 
Confidential 
11. Has a history of gastrointestinal fistula, perforation, or abscess. 
12. Has a current diagnosis or history of a nonhealing wound, active ulcer, or untreated bone 
fracture. 
13. Has prior history of another active malignancy within the last 5 years, other than 
adequately treated superficial basal cell, superficial/skin squamous cell carcinoma, or 
carcinomas in situ. 
14. Has a known hypersensitivity to any component of carboplatin, paclitaxel, bevacizumab, 
Chinese hamster ovary cell products, or other recombinant human or humanized 
antibodies. 
15. Has received treatment with any other investigational drug prior to day 0 of cycle 1, 
within the last 30 days or 5 half-lives (if available); whichever is longer. 
16. Has previously received treatment with the following: 
a. Paclitaxel. 
b. Bevacizumab (Note: Prior intravitreal administration of bevacizumab does not 
preclude study participation). 
c. Anthracycline. (Note: May be allowed on a case by case basis after consulting with 
the medical monitor to rule out an increased risk of cardiac failure). 
17. Has documented or known current alcohol/drug abuse that precludes his/her ability to 
adhere to the protocol. 
18. Has any of the following concomitant treatments or conditions: 
a. Concomitant vaccination that contains an attenuated virus, for instance Yellow Fever 
vaccine. 
b. Has a known history of active or latent tuberculosis. 
c. Has a concomitant systemic disorder (e.g., active infection including known human 
immunodeficiency virus, viral hepatitis B or C) that, in the opinion of the principal 
investigator (PI; or designee), would compromise the patient's safety (for instance 
potential drug interactions, or ability to adhere to the protocol). 
d. Has any other concomitant condition that precludes the participation in the study 
through increased risk to the patient and/or potential to impact the PI’s (or designee’s) 
ability to administer this protocol. 

 
Protocol MYL-1402O-3001 
Page 63 of 154 
19 February 2019 
Confidential 
4.3 
Withdrawal of Consent  
Withdrawal of consent is a specific action whereby the patient verbally and/or in writing 
declares to the PI that they no longer wish to participate in the study and likewise no longer 
consents to collection of data associated with the study. In this regard, the patient is 
effectively withdrawing his/her consent from study participation. In the occurrence and 
specific instance of withdrawal of consent, there are a series of steps that the investigational 
site staff must engage with the patient. The purpose of these steps is to demonstrate 
prudence/due diligence in both acknowledging the patient’s request as well as appropriate 
management of the request. The reason a patient decides to withdraw consent or discontinue 
from interventional therapy should be captured both in the source documentation as well as 
the eCRF. 
All data generated up to the date whereby the patient makes this declaration is to be collected 
and monitored. This applies to medical/clinic-generated data, as well as any 
laboratory/blood/tissue analysis data. All patients who discontinue from interventional 
therapy or withdraw their consent from the study will undergo all safety and EOT 
assessments (Safety Follow-Up Visit, Section 6.8).  
Patients who withdraw early from the study prior to first dose of study drug (i.e., Baseline 
Failure) will not be replaced. 
4.3.1 
Efforts to Mitigate Missing Data 
Missing data and the impact on a clinical study can be extreme and serious. In the most 
extreme of cases, missing data could lead to a study having to be repeated due to loss of 
statistical power and/or significant bias impacting primary endpoints and overall protocol 
objectives. 
In order to better address missing data as a whole within the pharmaceutical industry, the US 
FDA convened a panel titled “Panel on Handling Missing Data in Clinical Trials – 
Committee of National Statistics – Division of Behavioral and Social Sciences and 
Education” in 2009 (FDA 2009). 
Based on discussions within the panel, a report titled “The Prevention and Treatment of 
Missing Data in Clinical Trials” – was generated which focuses on a number of approaches 
sponsor companies and PIs can utilize to mitigate missing data. 
Within this protocol, language that is specific to withdrawal of consent versus 
discontinuation from interventional therapy – is one approach to mitigate missing data. 

 
Protocol MYL-1402O-3001 
Page 64 of 154 
19 February 2019 
Confidential 
Additionally, patient education will be an important element to assure patients clearly 
understand the following: 
• Visit schedule associated with the study. 
• Amount of patient personal time/commitment to participate in the study. 
• The need to be communicative with the investigative site staff in the event a 
scheduled visit cannot be met. 
• Difference between withdrawal of consent versus discontinuation from interventional 
therapy. 
A variety of patient directed materials will be produced to assist patients in understanding the 
importance of their commitment to a clinical study as well as begin to explain the differences 
between withdrawal of consent versus discontinuation of interventional therapy. This basic 
reference will be available in the informed consent template. In addition, the use of patient 
directed materials (aside from the ICF) will be at the discretion of the site specific 
Institutional Review Board (IRB)/Ethics Committee. 
In the event a patient fails to return for final assessments, it will be important that the 
investigative site be prudent in attempts to contact the patient. If the patient cannot be 
contacted, the site will make attempts to contact the patient's Alternate Contact (AC). 
Contacting the patient or patient's AC can be done in a variety of methods via telephone, 
email, postal mail, and/or certified letter/messenger service. Attempts to contact the patient 
will be documented in the source document and only, after all attempts are exhausted, will 
the patient be deemed as “Lost to Follow Up”. 
It is vital to obtain follow-up data on any patient withdrawn because of an AE or SAE. In 
every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 

 
Protocol MYL-1402O-3001 
Page 65 of 154 
19 February 2019 
Confidential 
5 Study Treatments 
This protocol refers to bevacizumab as the IP, either as MYL-1402O (test product) and/or 
Avastin (reference product). In addition to IP, carboplatin (Section 5.2.2) and paclitaxel 
(Section 5.2.4) chemotherapy will be given to patients. All patients will receive standard 
premedication per the paclitaxel label (Taxol 2011) or local institutional protocols. 
For safety information Refer to IB, and Avastin SmPC (Investigator’s Brochure V3.0, Mylan, 
May 2017; Roche 2017). 
5.1 
Investigational Medicinal Product (Test and Reference) 
Both, MYL-1402O and Avastin are supplied at a concentration of 25 mg/mL as a sterile, 
concentrated solution for i.v. infusion, in preservative-free, single-use 100 mg/4 mL and 
400 mg/16 mL vials. 
The formulation and excipients used for MYL-1402O are identical to that of Avastin. These 
include trehalose dihydrate, sodium phosphate, polysorbate 20 and water for injections, per 
the Avastin EU-SmPC (Roche 2017). 
5.2 
Treatment Administration 
Patients will receive bevacizumab (as either MYL-1402O or Avastin) administered as an 
i.v. infusion, at a dose of 15 mg/kg of body weight given once every 21 days in combination 
with CP (bevacizumab combination therapy) and subsequently without CP (bevacizumab 
monotherapy). A cycle will start with administration of bevacizumab (MYL-1402O or 
Avastin; Section 5.2.1). In Period 1, bevacizumab will be followed by carboplatin 
(Section 5.2.2) and then paclitaxel (Section 5.2.4; and include pre-medications 
[Section 5.2.3]). 
Bevacizumab monotherapy will only include treatment with bevacizumab (MYL-1402O or 
Avastin; Section 5.2.1) and will not include any chemotherapy. 
Preparation for administration requires the use of appropriate aseptic technique. Parenteral 
drug products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. Reconstitution of MYL-1402O or 
Avastin is described in the study Procedure Manual. Any unused portion left in a vial is to be 
discarded, as the product contains no preservatives; additional information on the destruction 
of the interventional therapies is provided in the study Procedure Manual. Do not administer 
or mix with dextrose solution. 

 
Protocol MYL-1402O-3001 
Page 66 of 154 
19 February 2019 
Confidential 
The study treatment may only be administered by experienced and trained study team 
personnel. The body weight of the patient and the dose calculated by the trained study team 
member(s) must be documented in the source document (e.g., medical record) before the 
administration of treatment. Facilities and equipment for resuscitation must be immediately 
available: medications such as antihistamines, corticosteroids, and epinephrine and 
equipment such as electrocardiogram (ECG) monitors, and defibrillators. Hospitalization 
facilities should be accessible and within a short distance from the chemotherapy facility. 
5.2.1 
Bevacizumab (MYL-1402O or Avastin) 
Bevacizumab (MYL-1402O or Avastin) will be administered by i.v. infusion at a dose of 
15 mg/kg i.v. infusion every 21 days (± 3 days) for up to 6 treatment cycles (1 treatment 
cycle = 21 days based on bevacizumab administration) in combination with CP and then 
alone as a maintenance. 
Adjustments for bevacizumab (MYL-1402O or Avastin) are located in Section 5.2.5.1. 
In Period 1, the first dose of bevacizumab (either MYL-1402O or Avastin) will be 
administered over 90 minutes (±15 minutes). If the first infusion is tolerated without 
infusion-associated AEs (i.e., infusion reactions), then the second infusion (Cycle 2) may be 
delivered over 60 minutes (±10 minutes). If the 60-minute infusion (Cycle 3) is well 
tolerated, subsequent infusions (i.e., other cycles in Period 1) may be delivered over 
30 minutes (± 10 minutes). 
Patients will receive blinded bevacizumab (either MYL-1402O or Avastin) monotherapy, 
based on the randomization/blinded schema that was applied to Period 1. The length of 
bevacizumab infusion will be the same tolerated infusion length used in Period 1. 
Bevacizumab monotherapy will consist of bevacizumab (MYL-1402O or Avastin) 
administered alone by i.v. infusion at a dose of 15 mg/kg i.v. infusion every 21 days until PD 
or treatment discontinuation. Infusion may be delivered over 30 minutes (±10 minutes) if 
well tolerated during Period 1. 
The bevacizumab monotherapy may start if the patient has stable disease or better response 
(CR or PR), the PI or designee considers continued treatment with bevacizumab to be of 
benefit, and the following occurred: 
• The patient received at least one cycle of bevacizumab combination therapy (either 
MYL-1402O or Avastin, in combination with CP) and treatment with CP is 

 
Protocol MYL-1402O-3001 
Page 67 of 154 
19 February 2019 
Confidential 
terminated prior to receiving a total of 6 cycles of combination therapy due to 
intolerance of the CP therapy. 
• The patient received 6 cycles of bevacizumab combination therapy (either 
MYL-1402O or Avastin, in combination with CP) and continued treatment with 
bevacizumab monotherapy as planned. 
5.2.2 
Carboplatin 
Carboplatin will be prepared and administered in accordance with the package insert for the 
relevant registered product (Paraplatin 2010). 
Calculation of the carboplatin dose will be based on the creatinine clearance calculations 
using Cockcroft and Gault Formula (Section 12.4, Appendix D). For AUC 6, the maximum 
dose is 900 mg. 
Patients will receive carboplatin dose of AUC 6 by continuous i.v. infusion over 30 minutes 
every 21 days up to 6 cycles. If the infusion of bevacizumab (MYL-1402O or Avastin) is 
tolerated without infusion-associated AEs, then the infusion of carboplatin may be delivered 
over 30 minutes (±15 minutes) for the first infusion (Cycle 1). For subsequent infusion 
cycles, carboplatin may be delivered at 15 to 30 minutes. 
Adjustments for dosing are located in Section 5.2.5.2. NOTE: Carboplatin at AUC 6 is the 
required dose at cycle 1. For Subsequent cycles, Carboplatin dose may be lowered to 
AUC 5 ONLY after discussion with the medical monitor.  
5.2.3 
Paclitaxel Premedications 
All patients will receive standard premedication per the paclitaxel package insert 
(Taxol 2011) or local institutional protocols. 
5.2.4 
Paclitaxel 
Paclitaxel will be prepared and administered in accordance with the package insert for the 
relevant registered product (Taxol 2011). 
The calculation of the paclitaxel dose will use the Mosteller formula (Mostellar 1987) 
equation (Section 12.5, Appendix E), which is calculated based on the patient’s body surface 
area (BSA). 
After each administration of carboplatin, patients will receive a paclitaxel dose of 200 mg/m2 
by continuous i.v. infusion over 3 hours (± 30 minutes) every 21 days up to 6 cycles. If the 

 
Protocol MYL-1402O-3001 
Page 68 of 154 
19 February 2019 
Confidential 
infusion of paclitaxel is well tolerated in Cycle 1, then subsequent infusions of paclitaxel 
may be delivered over 60 to 120 minutes. 
In countries where the initial dose is 175 mg/m2 based on institutional protocol, PIs are 
allowed to initiate dosing at 175 mg/m2. For a patient that demonstrates tolerance of the 
175 mg/m2 dosing in Cycle 1, the PI may increase the dose to 200 mg/m2 in Cycle 2. The 
dose at subsequent cycles will be determined by the PI and tolerance of the individual 
patient. Dosing will be documented by the PI. If in the best interest of the patient, the PI does 
not increase the dose to 200 mg/m2, then the patient may remain at 175 mg/m2 for the 
remaining cycles of therapy. The minimum dose of paclitaxel allowed on this protocol is 
160 mg/m2. Any patient unable to tolerate the minimal dose level of paclitaxel will be 
discontinued from chemotherapy or the case will be discussed with the Medical Monitor if a 
lower dose is required by the Investigator and then needs approval by the sponsor. Dosing 
will be documented by the PI. 
For details on dosing adjustments, refer to Section 5.2.5.3. 
5.2.5 
Treatment Adjustments 
Treatment adjustments are recommendations per the product label. In the event the 
Investigator does not feel the recommendations are appropriate for a patient; then the 
Investigator MUST contact the Medical Monitor prior to dosing. It is critical to document 
any dose adjustments done which are not as per the recommendations of the product label, in 
the patient’s medical records.  
5.2.5.1 Adjustments for Bevacizumab (MYL-1402O or Avastin) 
Initial dose level of bevacizumab is 15 mg/kg (Roche 2017). 
There will be no modification of bevacizumab dose during this study; however, if the 
patient’s weight changes by ≥10% during the study, the dose of bevacizumab will be 
recalculated. 
If chemotherapy is held for a low ANC or thrombocytopenia, bevacizumab will also be held. 
During bevacizumab combination therapy, bevacizumab may be held for 1 cycle and the 
patient may only receive CP for that given cycle; the following cycle, patient should return to 
bevacizumab combination therapy or be switched to CP alone for the remaining cycles. 
Any patient who is delayed must be evaluated on a weekly basis until adequate 
non-hematologic parameters have been met, as described below. Treatment delays are to be 

 
Protocol MYL-1402O-3001 
Page 69 of 154 
19 February 2019 
Confidential 
kept to a minimum and every effort should be made to maintain the intended schedule. No 
treatment delays are permitted for other than documented toxicity, however a window of 
± 3 days is permissible without incurring a protocol violation for the next cycle to allow for 
holidays. 
Reasons for the withdrawal or discontinuation of patients from treatment or from the study 
are provided in Section 4.3. Clinical safety data indicate that the safety issues can be dose 
dependent (Roche 2017). 
Table 5-1 
Dose Modifications for Adverse Reactions 
Adverse Reaction 
Severity 
Dose Modification 
Gastrointestinal 
Perforation and 
fistulae 
Gastrointestinal perforation, any grade  
Tracheoesophageal fistula, any grade  
Fistula, Grade 4  
Fistula formation involving any internal 
organ 
Discontinue Avastin 
Wound Healing 
Complications 
Wound healing complications requiring 
medical intervention  
Necrotizing fasciitis 
Discontinue Avastin 
Hemorrhage 
Grade 3 or 4 
Discontinue Avastin 
 
Recent history of hemoptysis of 1/2 
teaspoon (2.5 mL) or more 
Withhold Avastin 
Thromboembolic 
Events 
Arterial thromboembolism, severe 
Discontinue Avastin 
 
Venous thromboembolism, Grade 4 
Discontinue Avastin 
Hypertension 
Hypertensive crisis 
Hypertensive encephalopathy 
Discontinue Avastin 
 
Hypertension, severe 
Withhold Avastin if not 
controlled with medical 
management; resume once 
controlled 
Posterior Reversible 
Encephalopathy 
Syndrome (PRES) 
Any 
Discontinue Avastin 
Renal Toxicity and 
Proteinuria 
Nephrotic syndrome 
Discontinue Avastin 

 
Protocol MYL-1402O-3001 
Page 70 of 154 
19 February 2019 
Confidential 
Adverse Reaction 
Severity 
Dose Modification 
 
Proteinuria greater than or equal to 2 grams 
per 24 hours in absence of nephrotic 
syndrome 
Withhold Avastin until 
proteinuria less than 2 
grams per 24 hours 
Infusion Reaction 
Severe infusion reaction 
Discontinue Avastin 
 
Clinically significant 
Interrupt infusion; resume 
at a decreased rate of 
infusion after symptoms 
resolve 
 
Mild, clinically insignificant 
Decrease infusion rate 
Congestive Heart 
Failure 
Any 
Discontinue Avastin 
5.2.5.1.1 Infusion-Related Reactions 
In clinical studies, infusion reactions with the first dose occurred in < 3% of patients and 
severe reactions occurred in 0.2% of patients. Infusion reactions reported across clinical 
studies and post-marketing experience include hypertension, hypertensive crises associated 
with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 
hypersensitivity, chest pain, headaches, rigors, and diaphoresis. 
In case of infusion reaction, decrease the rate of infusion for mild, clinically insignificant 
infusion reactions. Interrupt the infusion in patients with clinically significant infusion 
reactions and consider resuming at a slower rate following resolution. Discontinue in patients 
who develop a severe infusion reaction and administer appropriate medical therapy (e.g., 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen). 
(Roche 2017) 
5.2.5.1.2 Hypertension 
Hypertension is common in patients treated with bevacizumab, with an incidence of 20% to 
30% across studies. Initiation or increase of antihypertensive medications may be required, 
but in most cases, BP can be controlled with routine oral drugs. However, incidents of 
hypertensive crisis with encephalopathy or cardiovascular sequelae have been rarely 
reported. BP should be closely monitored during bevacizumab therapy and the goal of BP 
control should be consistent with general medical practice. 
Patients should have BP measured prior to each dose of bevacizumab; dosing rules based on 
degree of hypertension are as follows: 

 
Protocol MYL-1402O-3001 
Page 71 of 154 
19 February 2019 
Confidential 
• For controlled hypertension, defined as systolic <150 mm Hg and diastolic <90 
mm Hg, continue bevacizumab therapy. 
• For uncontrolled hypertension (systolic >150 mm Hg or diastolic >100 mm Hg) or 
symptomatic hypertension less than CTCAE Grade 4, hold bevacizumab treatment 
(and cytotoxic chemotherapy for up to 1 week if indicated), with antihypertensive 
therapy initiated, increased, or continued. During the period of combination 
chemotherapy with bevacizumab, if hypertension is controlled and symptomatic 
hypertension has resolved by 1 week after holding treatment, continue all therapy. 
• For patients with continued uncontrolled hypertension despite medication after a one 
week delay, treatment of bevacizumab will be withheld and patients will be treated 
with chemotherapy alone. 
• Bevacizumab will be permanently discontinued for patients with uncontrolled 
hypertension that has not resolved after three weeks of holding bevacizumab (i.e., the 
patient is discontinued from treatment if there is a maximum of 42 days from last 
infusion). 
• Finally, for any patient developing CTCAE grade 4 hypertension, bevacizumab will 
be discontinued and the patient will not be re-started on bevacizumab therapy. 
5.2.5.1.3 Proteinuria 
Proteinuria has been seen in all bevacizumab studies to date, ranging in severity from an 
asymptomatic increase in urine protein (incidence of about 20%) to rare instances of 
nephrotic syndrome (0.5% incidence). Pathologic findings on renal biopsies in 2 patients 
showed proliferative glomerulonephritis. National Cancer Institute (NCI) CTCAE grade 3 
proteinuria (> 3.5 g/24-hour urine) is uncommon. The safety of continuing bevacizumab in 
patients with moderate or severe proteinuria has not been adequately tested. 
If proteinuria is monitored by urine dipstick, patients with a 2+or greater urine dipstick 
reading should undergo further assessment with a 24-hour urine collection. If therapy is held 
for > 6 weeks from the last dose due to proteinuria, then bevacizumab will be discontinued 
and the patient will not be re-started on bevacizumab therapy. 
Data from a postmarketing safety study showed poor correlation between UPCR (Urine 
Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 
0.57)]. (Roche 2017) 

 
Protocol MYL-1402O-3001 
Page 72 of 154 
19 February 2019 
Confidential 
5.2.5.1.4 Nephrotic syndrome 
Bevacizumab will be discontinued and the patient will not be re-started on bevacizumab 
therapy. 
5.2.5.1.5 Hemorrhage 
Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC 
and 4% of patients with non-squamous NSCLC receiving Avastin with chemotherapy 
compared to none of the patients receiving chemotherapy alone. 
Do not administer Avastin to patients with recent history of hemoptysis of 1/2 teaspoon or 
more of red blood. Discontinue in patients who develop a Grade 3-4 hemorrhage. (Roche 
2017) 
5.2.5.1.6 Thromboembolic Events 
The risk of arterial thromboembolic events is increased with bevacizumab therapy, and such 
events included cerebral infarction, transient ischemic attack, myocardial infarction and other 
peripheral or visceral arterial thrombosis. Certain baseline characteristics, such as age and 
prior arterial ischemic events, appear to confer additional risk. Venous thromboembolic 
events reported in bevacizumab studies included lower extremity deep vein thrombosis, 
pulmonary embolism and rarely, mesenteric or portal vein thrombosis. 
Arterial Thrombosis: Patients with any grade arterial thromboembolic events (including 
cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial 
ischemia) will discontinue bevacizumab but may continue on chemotherapy. 
Venous Thrombosis: Bevacizumab treatment will be discontinued for symptomatic grade 4 
venous thrombosis. 
Bevacizumab treatment will be held for asymptomatic CTCAE grade 3 venous thrombosis. If 
the planned duration of full-dose anticoagulation is ≤2 weeks, bevacizumab should be held 
until the full-dose anticoagulation period is over. If the planned duration of full dose 
anticoagulation is >2 weeks, bevacizumab may be resumed during the period of full-dose 
anticoagulation if ALL of the following criteria are met: 
• The patient must have an in-range INR (usually between 2 and 3) on a stable dose of 
warfarin (or other anticoagulant) or on stable dose of heparin prior to restarting 
bevacizumab treatment. 

 
Protocol MYL-1402O-3001 
Page 73 of 154 
19 February 2019 
Confidential 
• The patient must not have pathological conditions that carry high risk of bleeding 
(e.g., tumor involving major vessels). 
• The patient must not have had hemorrhagic events while on study treatment. 
• The patient is benefiting from the bevacizumab therapy (no evidence of disease 
progression). 
5.2.5.1.7 Coagulopathy 
For CTCAE grade 3 or 4 coagulopathy, bevacizumab will be held until prothrombin time or 
partial thromboplastin time resolves to grade 1. If therapy is held for >6 weeks from the last 
dose, then bevacizumab will be discontinued and the patient will not be re-started on 
bevacizumab therapy. 
For patients with prothrombin time or partial thromboplastin time greater than therapeutic 
range while on therapeutic warfarin, bevacizumab will be held until prothrombin time or 
partial thromboplastin time is within the therapeutic range. 
5.2.5.1.8 Hematological Toxicities 
5.2.5.1.8.1 Thrombocytopenia 
For platelet count <50 × 103 /µL, at the day of the administration, bevacizumab will be held. 
If platelet count of <50 × 103 /µL persists for 3 weeks, the patient will discontinue 
bevacizumab. 
5.2.5.1.8.2 Neutropenia 
When combined with chemotherapy, bevacizumab increased the risk of neutropenia 
compared with chemotherapy alone. Additional information is provided in Section 5.2.5.2 
and Section 5.2.5.3. 
5.2.5.1.9 Gastrointestinal Perforation/Fistula 
Gastrointestinal perforations/fistulas were rare but occurred at an increased rate in 
bevacizumab-containing therapies. Gastrointestinal perforation should be included in the 
differential diagnosis of patients on bevacizumab therapy presenting with abdominal 
pain, fever of unclear source, or rectal/abdominal abscess. 

 
Protocol MYL-1402O-3001 
Page 74 of 154 
19 February 2019 
Confidential 
Bowel perforation: For new development of bowel perforation, fistula, or GI leak (any 
grade), the patient will discontinue bevacizumab but may continue on chemotherapy. 
5.2.5.1.10 Wound Healing Complications 
The incidence of wound healing and surgical complications, including serious and fatal 
complications, is increased in patients receiving Avastin (bevacizumab). Avastin 
(bevacizumab) has to be discontinued in patients who develop wound healing complications 
that require medical intervention. Avastin (bevacizumab) has to be witheld at least 28 days 
prior to elective surgery. Avastin (bevacizumab) should not be administered for at least 28 
days after surgery, and until the wound is fully healed. (Roche 2017) 
Bevacizumab delays wound healing in rabbits, and it may also compromise or delay wound 
healing in patients. The appropriate interval between surgery and initiation of bevacizumab 
required to avoid the risk of impaired wound healing has not been determined.  
5.2.5.1.11 Fertility and Pregnancy 
Pregnant women have to be advised of the potential risk to a fetus. Advise females of 
reproductive potential to use effective contraception during treatment with and for 6 months 
after the last dose of Avastin. 
Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, 
advise women not to breastfeed during treatment with Avastin and for 6 months following the 
final dose. (Roche 2017) 
5.2.5.1.12 Posterior Reversible Encephalopathy Syndrome (PRES) 
Posterior reversible encephalopathy syndrome (PRES; also known as reversible posterior 
leukoencepalopathy syndrome) is a clinical syndrome related to vasogenic edema of the 
white matter and has rarely been reported in association with bevacizumab therapy (<1%). 
Clinical presentations may include altered mental status, seizure, and cortical blindness. MRI 
scans are required for diagnosis: typical finding are vasogenic edema in the white matter of 
the posterior parietal and occipital lobes, and less frequently in the anterior distributions and 
the gray matter. In PRES associated with bevacizumab mild or significant BP elevations were 
seen in some but not all cases. PRES should be in the differential diagnosis in patients 
presented with unexplained mental status change, visual disturbance, seizure or other CNS 
finding. MRI is the key to diagnosis. This syndrome is potentially reversible, but timely 

 
Protocol MYL-1402O-3001 
Page 75 of 154 
19 February 2019 
Confidential 
correction of the underlying causes, including control of BP and interruption of the offending 
drug, is important in order to prevent irreversible tissue damage. 
Treatment Guidelines for Posterior Reversible Encephalopathy Syndrome (PRES):  
If a patient experiences PRES, bevacizumab should be permanently discontinued. Resuming 
bevacizumab should not be considered even if there is evidence that PRES is completely 
resolved. 
5.2.5.1.13 Congestive Heart Failure 
In previously untreated patients with a hematological malignancy, the incidence of CHF and 
decline in left ventricular ejection fraction (LVEF) were increased in patients receiving 
Avastin with anthracycline-based chemotherapy compared to patients receiving placebo with 
the same chemotherapy regimen. The proportion of patients with a decline in LVEF from 
baseline of ≥ 20% or a decline from baseline of 10% to < 50%, was 10% in patients receiving 
Avastin with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time 
to onset of left ventricular dysfunction or CHF was 1 to 6 months after the first dose in at 
least 85% of the patients and was resolved in 62% of the patients who developed CHF in the 
Avastin arm compared to 82% in the placebo arm. Discontinue Avastin in patients who 
develop CHF. (Roche 2017) 
5.2.5.2 Adjustments for Carboplatin 
Carboplatin dose adjustments should be in accordance with its package insert 
(Paraplatin 2010).  
NOTE: Adjustments to Carboplatin AUC 6 at baseline is not an option. All patients 
MUST be able to tolerate Carboplatin AUC 6 as their baseline dose. If there are concerns 
regarding tolerability at baseline then, this MUST be discussed with the Medical Monitor to 
confirm appropriate patient selection. 
In subsequent cycles, Carboplatin may be adjusted from AUC 6 to AUC 5 (a one level 
reduction) based on toxicities shown in Table 5-2. If the dose would need to be adjusted to 
AUC 4, then the patient must be discontinued. Dose adjustments outside of toxicities is not 
permissible.  

 
Protocol MYL-1402O-3001 
Page 76 of 154 
19 February 2019 
Confidential 
Table 5-2 
Carboplatin Dose Adjustments 
Toxicity Grade 
Peripheral Neuropathy 
Gastrointestinal 
Other 
0 
None 
None 
None 
1 
None 
None 
None 
2 
Decrease 1 level 
None 
None 
3 
Hold 
None 
Decrease 1 level 
4 
Hold 
Decrease 1 level 
Hold  
 
If Carboplatin is held for an AE, Carboplatin is not to be restarted. Likewise, if Carboplatin is 
dose reduced to an AE, Carboplatin should not be re-escalated. Multiple AEs occurring 
across multiple organ / body systems must be resolved or returned to a grade 1 prior to 
reintroduction (re treatment).  
The Calvert formula incorporates glomerular filtration rate (GFR) to calculate the patient’s 
carboplatin dose. Although the CrCl is always slightly higher than the GFR, the 2 estimates 
of renal function are used interchangeably in the Calvert formula. The GFR used in the 
Calvert formula for carboplatin dosing should not exceed 125 mL/min. Maximum 
carboplatin dose is based on target AUC. 
Calvert Formula 
Total Carboplatin Dose (mg) = (target AUC) x (GFR + 25) 
Table 5-3 
Maximum AUC-based Carboplatin Dose 
AUC 
Maximum Carboplatin Dose 
6 
900 mg 
5 
750 mg 
4 
600 mg 
Reference: http://ctep.cancer.gov/content/docs/Carboplatin_Information_Letter.pdf 
 
Patients who experience CTCAE ≥ grade 2 renal toxicity (serum creatinine >1.5 ULN) 
require recalculation of the carboplatin dose for subsequent cycles. 

 
Protocol MYL-1402O-3001 
Page 77 of 154 
19 February 2019 
Confidential 
The dose of Carboplatin is recalculated by IXRS at each cycle based on the patient’s actual 
/current weight and serum creatinine value to ensure all parameters are considered and the 
appropriate dose is calculated/administered.  
For patients who require carboplatin dose modification, if the creatinine at the time of dose 
modification is lower than the baseline creatinine that was used, the prior (higher) creatinine 
value should be used for the dose calculation. If the creatinine at the time of dose 
modification is higher than the baseline creatinine value, the current (higher) value should be 
used for the dose calculation. This is to ensure that patients receive the intended dose. Dose 
adjustment in case of renal toxicity should be as per protocol and managed by the site in 
consultation with the medical monitor, if there is any doubt. 
5.2.5.3 Adjustments for Paclitaxel 
For further details, not specified in the following sections of the protocol, referring to the use 
of paclitaxel, please refer to its package label (Taxol 2011). 
5.2.5.3.1 Dose Modifications for Hematologic Toxicity 
No cycle of treatment is to begin until ANC ≥1.5 × 103/µL and platelets ≥100 × 103/µL. 
Initiation of a new cycle will be delayed for a maximum of 3 weeks until these values are 
achieved. Patients who fail to recover adequate counts within a 3 week delay will be removed 
from chemotherapy treatment (both carboplatin and paclitaxel). 
Dose modifications for hematologic toxicity are based on nadir counts. 
5.2.5.3.1.1 Neutropenia 
Uncomplicated (absence of sepsis or fever) neutropenia of any grade does not require dose 
modification unless the neutropenia occurs with an ANC <0.5 × 103/µL lasting more than 7 
days. A 1-dose level reduction in the paclitaxel dose (reduction to175 mg/m2 or 160 mg/m2 in 
countries where is 175 mg/m2 the starting dose recommended in the label) is required for 
neutropenic fever (defined as grade 3 or 4 nadir neutropenic toxicity with temperature of 
38.0°C twice within 2 hours, or single temperature of 38.5°C). Patients who are hospitalized 
for fever with either grade 3 or 4 neutropenia may be treated with growth factors during the 
episode at the discretion of the treating physician. At least 2 days should elapse between the 
discontinuation of growth factors and the initiation of another cycle of chemotherapy in order 
to allow bone marrow progenitors to cease cell cycling. If febrile neutropenia occurs despite 
a 1 dose level reduction, then with subsequent cycles the patient will receive growth factors 

 
Protocol MYL-1402O-3001 
Page 78 of 154 
19 February 2019 
Confidential 
starting 24 hours to 48 hours after the completion of the subsequent cycle of chemotherapy 
and continuing until the ANC is ≥1.5 × 103/µL. At least 2 days should elapse between the last 
dose of growth factors and the initiation of another treatment cycle. If febrile neutropenia 
occurs despite the use of growth factors then with subsequent cycles the patient will receive a 
second dose reduction of paclitaxel (160 mg/m2). 
The dose of 160 mg/m2 is the lowest allowable dose for the protocol. Should a lower dose be 
required; the case MUST be discussed with the medical monitor and approved by the sponsor 
followed by appropriate documentation of the discussion by the PI.  
Note: Patients who receive growth factors for febrile neutropenia but who do not undergo a 
1-dose level reduction, are supposed to have a dose reduction and be evaluated if growth 
factors are required with the next cycle. 
5.2.5.3.1.2 Anemia 
Anemia is not an indication for dose reduction in any patient; however, a record of 
transfusions required should be detailed. Erythropoietin may be utilized, following 
international guidelines, and at the discretion of the treating physician in the event that 
patient’s hemoglobin drops below 9 g/dL while on therapy, and should be documented. 
5.2.5.3.2 Adjustment of Paclitaxel for Other Non-Hematological Toxicities 
Paclitaxel may be adjusted for other toxicities and all dose reductions are based on one-level 
reduction from a starting dose of 200 mg/m2 with a one dose level reduction to 175 mg/m2 
(Table 5-3). For countries where the recommended start level is 175 mg/m2, a one dose level 
reduction would be 160 mg/m2. 
If Paclitaxel is held for an AE, Paclitaxel is not to be restarted. Likewise, if Paclitaxel is dose 
reduced due to an AE, Paclitaxel should not be re-escalated. Multiple AEs occurring across 
multiple organ/body systems must be resolved or returned to a grade 1 prior to re-
introduction (re treatment). 
Please see additional guidance within this section for dosing adjustments for specific 
toxicities. 

 
Protocol MYL-1402O-3001 
Page 79 of 154 
19 February 2019 
Confidential 
Table 5-3 
Paclitaxel Dose Adjustments for Other Non-Hematological Toxicities 
aAll Other Adverse Events MUST be resolved or returned to grade 1 prior to re treatment.  
5.2.5.3.2.1 Management of Hypersensitivity Reactions 
Hypersensitivity reactions to paclitaxel or its vehicle (Cremophor) occur almost universally 
during the first few minutes of infusion. Continued treatment may be considered if the 
reaction was not life-threatening; however, patients must be cautioned of potential 
recurrences of the reaction. If the PI decides in the patients’ best interest continuation with 
treatment is recommended and the patient agrees; then treatment should continue on the same 
day of the occurrence. A suggested procedure would be to repeat the patient’s premedication 
with dexamethasone 20 mg i.v., cimetidine 300 mg (or ranitidine 50 mg) i.v., and 
diphenhydramine 50 mg i.v. 30 minutes before the paclitaxel reinfusion is to begin. Slowly 
infuse the paclitaxel by administering the drug first with 1 mL of the original i.v. solution 
diluted in 100 ml over 1 hour, then 5 mL in 100 mL over 1 hour, then 10 mL in 100 mL over 
1 hour, and finally the original solution at the original infusion rate. No additional dose 
adjustments should be made for other hypersensitivity reactions. 
Discontinuation of therapy due to hypersensitivity reaction requires notification of the 
medical monitor within 48 hrs. 
5.2.5.3.2.2 Adjustments to Paclitaxel for Peripheral Neuropathy 
Grade 3 or 4 peripheral neuropathy requires interruption of paclitaxel therapy until adverse 
effects resolve to grade 1 or less (Table 5-3). Grade 2 peripheral neuropathy will require a 
one-dose level reduction in paclitaxel. The medical monitor should be notified if grade 3 
or 4 neuropathy does not resolve to a grade 1 neuropathy or less 2 weeks after a cycle is 
due to be given (5 weeks after a previous dose). At this time consideration will be given 
with the medical monitor to removing the patient from chemotherapy. 
Toxicity 
Grade 
Peripheral 
Neuropathy 
Gastrointestinal 
Hepatic 
Othera 
0 
None 
None 
None 
None 
1 
None 
None 
None 
None 
2 
Decrease 1 level 
None 
Decrease 1 level 
Decrease 1 level 
3 
Hold 
Decrease 1 level 
Hold 
Decrease 1 level 
4 
Hold 
Hold 
Hold 
Hold 

 
Protocol MYL-1402O-3001 
Page 80 of 154 
19 February 2019 
Confidential 
5.2.5.3.2.3 Adjustments to Paclitaxel for Hepatic Toxicity 
Paclitaxel has significant hepatic metabolism. No dose modification is necessary for grade 1 
toxicity but a grade 2 toxicity requires a dose reduction of one level after resolution of the 
toxicity to grade 1 or less (Table 5-3). If resolution from grade 2 to grade 1 or lower does 
not occur within 2 weeks after a dose of paclitaxel is due (5 weeks after the last dose), 
the medical monitor should be notified. 
Grade 3 and 4 hepatic toxicity requires notification of the medical monitor. 
5.3 
Management of Overdose and Medication Errors 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol. A rounding of 5% or a deviation in between 5% to 
10% without associated AEs should not be reported, in between 5% to 10% with associated 
AEs or any beyond 10% must be promptly reported to the medical monitor (see study contact 
list for medical monitor telephone and fax details). Overdoses without signs or symptoms do 
not need to be recorded as AEs; in case of any AEs associated with the overdose, these 
should be reported on relevant AE/SAE sections in the eCRF. Any overdose above 10% 
should be reported as a deviation whether or not an AE occurs. Treatment of overdose should 
consist of general supportive measures. 
Signs or symptoms associated with medication errors must be recorded as AEs and should be 
reported on the relevant AE/SAE sections in the eCRF. 
5.4 
Prior and Concomitant Therapy 
Concomitant medications will be any drug taken at any time from Day 0 of Cycle 1, through 
the end of the treatment periods (i.e., Period 1, Period 2, and Extended Treatment Period), 
other than the interventional therapy (including bevacizumab, carboplatin, paclitaxel) and 
premedication (as described in Section 5.2). 
Prior medications will be any drug taken up to 6 months prior to Day 0 of Cycle 1. 
Use of all concomitant medications and prior medications will be recorded in the patient’s 
eCRF, along with the respective indication. The minimum requirement is that drug name and 
the dates of administration are to be recorded. This will include all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications. Any changes in concomitant 
medications will also be recorded in the patient’s eCRF. 

 
Protocol MYL-1402O-3001 
Page 81 of 154 
19 February 2019 
Confidential 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the PI (or designee). However, it is the responsibility 
of the PI to ensure that details regarding the medication are recorded in full in the eCRF. 
5.4.1 
Permitted Medications and Procedures 
The following prior and concomitant medications and procedures are permitted: 
• Prior treatment for brain metastases including whole brain radiotherapy, radiosurgery 
(Gamma Knife®, linear particle accelerator, or equivalent), or a combination, as 
deemed appropriate by the treating physician. However, it must be completed 
>14 days prior to Day 0 of Cycle 1. 
• Prior radiation therapy, completed >14 days prior to Day 0 of Cycle 1, is permitted 
provided <25% of bone marrow is involved, no mediastinal irradiation is involved 
and patient must have recovered from acute toxicities associated with radiation 
therapy. 
• Premedication according to the local standard of care prior to the administration of 
paclitaxel. 
• Placement of a vascular access device, or a closed pleurodesis, thoracentesis, or 
mediastinoscopy. 
5.4.2 
Prohibited Medications and Procedures 
The following prior and concomitant medications and procedures are prohibited: 
• A major surgical procedure, open biopsy, open pleurodesis, or significant traumatic 
injury within 28 days prior to Day 0 of Cycle 1 
• A core biopsy or other minor surgical procedure within 7 days prior to Day 0 of 
Cycle 1 
• Treatment with any other investigational drug, within the last 30 days or at least 5 half 
lives (if available), whichever is longer prior to Day 0 of Cycle 1. 
• Concomitant vaccination that contains an attenuated virus 
• Any drug that has not received regulatory approval for any indication at the time of 
study entry, from 30 days prior to Day 0 of Cycle 1 (Exclusion Criterion 15). 

 
Protocol MYL-1402O-3001 
Page 82 of 154 
19 February 2019 
Confidential 
• The use of any other systemic treatment for lung cancer. The use of treatments for 
bone metastases should be avoided related to the risk of jaw osteonecrosis, also if 
started during the study the patient will be considered to have progression of the 
disease, as in the event of any manipulation of target or non-target lesions with 
surgery or radiotherapy. 
In addition, caution should be exercised during concurrent administration of paclitaxel and 
active substances which are metabolized in the liver as such active substances may inhibit the 
metabolism of paclitaxel. The metabolism of paclitaxel is catalyzed, in part, by CYP450 
isoenzymes, CYP2C8, and 3A4. Clinical studies have demonstrated that CYP2C8-mediated 
metabolism of paclitaxel (to 6α-hydroxypaclitaxel) is the major metabolic pathway in 
humans. 
• Based on current knowledge, clinically relevant interactions between paclitaxel and other 
CYP2C8 substrates are not anticipated. 
• Concurrent administration of ketoconazole (a known potent inhibitor of CYP3A4) does 
not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be 
administered together without dosage adjustment. 
• Further data on the potential of interactions between paclitaxel and other CYP3A4 
substrates/inhibitors are limited. Therefore, caution should be exercised when 
administering paclitaxel concomitantly with medicines known to inhibit (e.g., 
erythromycin, fluoxetine, gemfibrozil) or induce (e.g., rifampicin, carbamazepine, 
phenytoin, phenobarbital, efavirenz, nevirapine) either CYP2C8 or 3A4. 
5.5 
Treatment Compliance 
The unblinded pharmacist (or authorized designee) is responsible for maintaining accurate 
records of the receipt and administration of all study treatment supplies during the course of 
the study and recorded in both the eCRF and the appropriate study drug accountability log by 
the patient. The unblinded study monitor will periodically monitor compliance by inspecting 
the source documents, study treatment accountability, inventory, and storage. 
Handling and accountability of MYL-1402O and Avastin will be performed only by the 
unblinded pharmacist, or designee, and the authorized unblinded study monitor. 
Chain of custody of the study drug will be followed in accordance with the individual site’s 
standard procedures, which will be documented by the site. 

 
Protocol MYL-1402O-3001 
Page 83 of 154 
19 February 2019 
Confidential 
Patients who miss 2 consecutive treatment cycle visits will be considered noncompliant and 
will be withdrawn from the study. 
For patients that withdraw from treatment or withdraw from the study please refer to 
Section 4.3. For patients who do not respond to treatment, please refer to Section 6.5 
(Period 1) or Section 6.6 (Period 2). 

 
Protocol MYL-1402O-3001 
Page 84 of 154 
19 February 2019 
Confidential 
6 Study Procedures and Assessments 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Events (Table 1-1). Throughout the study, every reasonable effort should be made to follow 
the timing of assessments and procedures in the Schedule of Events for each patient. 
Deviations from the schedule should be avoided; however, a ± 3-day visit window for cycle 
visits is allowed. Study treatment cycles should be scheduled with respect to the previous 
cycle. 
6.1 
Informed Consent 
Before performing any study procedures, all potential patients will sign an ICF. All potential 
patients will be informed of the full nature and purpose of the study, including possible risks 
and side effects, and given ample time and opportunity to read and understand this 
information. Patients will have the opportunity to have any questions answered before 
signing the ICF. The PI must address all questions raised by the patient. The PI or delegated 
designee will also sign the ICF. 
6.2 
Screening 
Screening will start from the time of signing the ICF and will last no more than 4 weeks 
(≤28 days) prior to the first dose of bevacizumab (Day 0 of Cycle 1 [Period 1]). Screening 
procedures also include baseline (Section 6.4) and randomization (Section 6.3) procedures. 
The following procedures will occur: 
• Signing of ICF 
• Evaluation for inclusion (Section 4.1) and exclusion (Section 4.2) criteria 
• Demographics 
• Collection of medical history 
• Physical examination 
• BSA calculation 
• Prior and concomitant medications 
• ECOG performance status 
• AEs with CTCAE (version 4.03) grading 

 
Protocol MYL-1402O-3001 
Page 85 of 154 
19 February 2019 
Confidential 
• Tumor assessment (RECIST 1.1; Section 12.1 [Appendix A]) (CT scan of thorax and 
abdomen). The CT scan will be transferred to the central imaging vendor for review 
and confirmation of readability and measurability of lesions 
• Brain imaging and/or bone scan (confirmatory X-rays/CT if Bone scan is positive), if 
required 
• Safety blood collection for laboratory assessments (Section 12.6 [Appendix F], Table 
12-4) 
o Hematology (approximately 5 mL of blood) 
o Chemistry (approximately 5 mL of blood) 
• Calculated CrCL 
• Urine dipstick 
• Prothrombin time or INR, if indicated (approximately 5 mL of blood) 
• Pregnancy serum test, if indicated 
The site will collect all the laboratory tests (including normal ranges) and complete all the 
screening pages of the CRF before consulting the medical monitor. The medical monitor will 
review all the inclusion and exclusion criteria, and then notify the site and any other parties, 
if the patient can be randomized. 
The RECIST tumor assessment should be within 28 days before the first dose. The sites need 
to consider that the time in between the randomization until the first dose be included in that 
28 days period. A patient will have tumor(s) assessed using radiographic exams (at least 
computed tomography [CT] or magnetic resonance imaging [MRI] of the thorax and 
abdomen). If any image study was done as the standard of care and accomplishes the 
specifications of the study and in the time frame that is allowed in the protocol, then it could 
be used for the study. 
During Screening, an additional check of each patient’s eligibility for the study will be 
conducted by the Independent image Vendor, to check measurability of the lesions and then 
by Medical Monitor to ensure that the patient is not failing any inclusion/exclusion criteria 
(example: patient having a Stage IV lung cancer with histologic or cytologic diagnosis of 
advanced non-squamous non-small cell lung carcinoma with unknown or negative sensitizing 
EGFR mutation, and negative or unknown EML4-ALK rearrangement, and all the safety 
conditions). 

 
Protocol MYL-1402O-3001 
Page 86 of 154 
19 February 2019 
Confidential 
Serologic testing for hepatitis (Hepatitis A, Hepatitis B, or Hepatitis C virus) is only required 
before confirming eligibility if alanine transaminase or aspartate transaminase ≥ ULN (in the 
absence of liver metastases) at screening. In case screening visit lab values are within ULN 
and baseline visit lab values are ≥ ULN, only clinically significant values (in the absence of 
liver metastases) will need to be investigated further prior to dosing, but a sporadic rise of 
either of these do not need serology testing for viral hepatitis at baseline. 
Screen Failure: Applies to patients that have provided signed informed consent (via ICF) 
and either through screening or occurrence of any event prior to randomization the patient is 
deemed ineligible for study participation. 
6.3 
Randomization 
Patients who meet all of the inclusion and none of exclusion criteria and who are approved 
by the medical monitor will be considered eligible for entry into the study and will be 
randomly assigned in a 1:1 ratio to one of the two treatment groups (MYL-1402O or Avastin) 
within 3 days prior to Day 0 of Cycle 1. The randomization procedures are described in 
Section 3.3.1. Patients will be stratified by the following criteria: gender (male or female), 
smoking status (smoker or <100 cigarettes in entire lifetime), and number of metastasis sites 
(one site or multiple sites). 
The following procedures will occur: 
• Re-evaluation for inclusion (Section 4.1) and exclusion (Section 4.2) criteria. 
• Randomization 
A patient who failed the screening process, could be re-consented with a new number 
assigned and complete a re-screening process within 56 days of the date of the first signed 
consent form; all the assessment should be performed in the appropriate time in accordance 
with protocol specifications. 
6.4 
Baseline 
Baseline assessments must be performed within 24 hours of Day 0 of Cycle 1 to confirm that 
the patient has remained eligible for treatment. The following procedures will occur: 
• Physical examination 
• Concomitant medications 
• Bioanalytical blood collection (Section 12.6 [Appendix F], Table 12-4) 

 
Protocol MYL-1402O-3001 
Page 87 of 154 
19 February 2019 
Confidential 
o Hematology and Chemistry: If safety blood lab assessments are more than 
7 days prior to baseline, then a new set of safety blood samples will be 
collected for safety assessments (Table 6-5). 
o Immunogenicity (6 samples of approximately 5 mL of blood immediately 
prior to the first dose of bevacizumab. If possible, within 1 hour before the 
first dose. 
o PK (approximately 5mL of blood) prior to the first dose of bevacizumab. PK 
samples when concomitant with Immunogenicity should be taken at the same 
time. 
• A pregnancy urine test will be done in female patients with childbearing potential. 
Baseline Failure: Any patient that meets initial eligibility requirements, is randomized to 
treatment, however does not receive first dose of bevacizumab and is deemed ineligible for 
continuation in Study MYL-1402O-3001. 
6.5 
Treatment Period 1 
Period 1 is defined as the period of study whereby tumor assessments are performed every 
6 weeks following Day 0 of Cycle 1 (the first dose of bevacizumab, either MYL-1402O or 
Avastin, in combination with CP) and continue every 6 weeks (window of ±3 days) through 
Week 18), regardless of delays of the cycles of treatment. Total duration of Period 1 will be 
18 weeks. Period 1 will include 3 assessments at the pre-specified time points (Week 6, 
Week 12, and Week 18) regardless of delays in treatment cycles. Tumor assessments must be 
done consistently throughout the study, using at least a CT scan of thorax and abdomen and 
using the same technique - CT or MRI, slice interval, contrast agent. 
If in the staging assessment, bone metastasis are discovered and are localized outside of the 
thorax and abdominal region, each metastasis should be included in the tumor response 
assessments and followed by X-ray, CT scan, or MRI as appropriate. In the event of central 
nervous system (CNS) involvement at baseline, imaging (CT/MRI) should include the CNS 
localization at each disease assessment time point. Should a patient demonstrate signs and/or 
symptoms of metastasis at any time and in the opinion of the PI imaging is warranted, such 
imaging may be performed (even if outside the imaging schedule per this study). 
Patients will start Period 1 receiving bevacizumab (MYL-1402O or Avastin) combination 
therapy (plus CP) on Day 0 of Cycle 1. Each cycle will start with the administration of 
bevacizumab (as either MYL-1402O or Avastin) followed by carboplatin and then paclitaxel. 

 
Protocol MYL-1402O-3001 
Page 88 of 154 
19 February 2019 
Confidential 
Each cycle will consist of 3 weeks (21 days ± 3 days) and patients may receive up to 6 cycles 
of bevacizumab combination therapy. Additional dosing information for bevacizumab (either 
MYL-1402O or Avastin) and CP is provided in Section 5.2. In addition, all patients will 
receive standard premedication per the paclitaxel label (Taxol 2011) or local institutional 
protocols. 
For each cycle of interventional therapy, safety and tolerability will be assessed from the start 
of bevacizumab infusion until prior to the next treatment cycle. 
In cases where treatment is delayed, discontinued, switched to bevacizumab monotherapy 
(due to intolerance of CP), or switched to CP (due to intolerance of bevacizumab), tumor 
assessments will still be performed at the selected time points (every 6 weeks after first dose 
of bevacizumab; Week 6, Week 12, and Week 18). At Week 18 assessments, the following 
may occur: 
If treatment is delayed during Period 1 and the principal investigator (PI) (or designee) 
considers continuing treatment with bevacizumab combination therapy (MYL-1402O plus 
CP or Avastin plus CP), then the assessment of tumor response will still occur at Week 18 and 
the patient may continue to receive combination therapy for up to 6 cycles, even if treatment 
continues after Week 18 tumor assessment (i.e., into Period 2). 
• If bevacizumab treatment is discontinued during Period 1 (i.e., intolerance to 
bevacizumab) the assessment of tumor response will still occur at Week 18. When the 
patient discontinues bevacizumab, then the patient will undergo the safety follow-up 
visit at 28 days (±7 days) after the last dose of bevacizumab. If the patient continues 
to receive treatment with CP, then treatment may continue for up to 6 cycles. Even if 
treatment continues after Week 18 tumor assessment, the patient will not enter 
Period 2. Once the 6 cycles are complete, the patient will not receive any additional 
interventional therapy per protocol. The EOT visit will occur after the last dose of 
interventional therapy (in this situation, CP). 
• If CP treatment is discontinued during Period 1 (i.e., intolerance to CP), then the 
assessment of tumor response will still occur at Week 18. At the time of CP 
discontinuation, if the patient has stable disease or better response (i.e., partial 
response [PR] or complete response [CR]), then the patient may receive bevacizumab 
monotherapy until PD or treatment discontinuation and even if treatment continues 
after Week 18 tumor assessment (i.e., into Period 2). If the patient discontinues 
bevacizumab at any time, then a safety follow-up visit (Section 6.8) will occur at 

 
Protocol MYL-1402O-3001 
Page 89 of 154 
19 February 2019 
Confidential 
28 days (±7 days) of last dose of bevacizumab. The EOT visit should also occur at the 
safety follow-up visit. 
Dose adjustment details are provided in Section 5.2.5. 
In cases where there is suspected PD, an additional scan may be conducted to confirm 
progression. If PD is confirmed prior to Week 18, no additional tumor assessments are 
required at Week 18. If a patient discontinues study therapy due to PD, then the PI (or 
designee) will update the patient’s contact information and will discuss with the patient the 
importance of continuing study participation for collecting safety and survival data (Table 
12-4). A safety follow-up visit (Section 6.8) will occur at 28 days (± 7 days) of last dose of 
bevacizumab and the EOT visit should also occur at the safety follow-up visit. 
In cases where there is withdrawal of consent, no further data collection will occur (Table 12-
4), effective on the date of patient providing signed withdrawal of consent (Section 4.3). 
The following procedures will occur: 
• Physical examination (Cycle 1 through Cycle 6) 
• Interval history (Cycle 1 through Cycle 6) 
• BSA calculation (Cycles 2 through Cycle 6, only if a change in the weight is more 
than 10%) 
• Concomitant medications (Cycle 1 through Cycle 6) 
• ECOG performance status (Cycles 2 through 6) 
• Adverse events with CTCAE grading (Cycle 1 through Cycle 6) 
• Tumor assessments are to be conducted every 6 weeks (± 3 days) during the first 
18 weeks. (Week 6 [Cycle 2], Week 12 [Cycle 4], and Week 18 [Cycle 6]). Although 
the tumor assessments are independent of the cycles, if there is a delay in the 
administration of the cycles due to toxicity, then the tumor assessment should keep 
the same schedule of every 6 weeks ± 3 days (Week 6, Week 12, and Week 18). 
• Brain imaging and/or bone X Rays, if required (Cycle 2, Cycle 4, and Cycle 6) with 
the tumor assessments 
• Bioanalytical blood collections for laboratory assessments (Section 12.6 
[Appendix F], Table 12-4). 

 
Protocol MYL-1402O-3001 
Page 90 of 154 
19 February 2019 
Confidential 
o Hematology (Cycles 2 through 6) (approximately 5mL of blood at each 
Cycle): At each cycle, collect blood samples prior bevacizumab 
administration. 
o Chemistry (Cycles 2 through 6) (At each cycle, approximately 5mL of blood): 
At each cycle, collect blood samples prior bevacizumab administration. 
o Immunogenicity (Cycles 2, 4, and 6) (At each cycle, 4 samples of 
approximately 5 mL of blood): At each cycle, collect blood samples prior 
bevacizumab administration. 
o PK (predose [if possible within 1 hour prior to bevacizumab dosing] and 
postdose [within 15 minutes after infusion]) to be collected at the following 
time points: (approximately 5mL of blood at each time point) 
 In Cycle 1: postdose 
 In Cycle 2: predose and postdose 
 In Cycle 3: predose 
 In Cycle 4: predose and postdose 
 In Cycle 5: predose 
 In Cycle 6: predose and postdose 
 All patients will have 2 additional PK samples collected in any cycle 
(1 to 6): 1 sample will be collected between Days 3 and 8 (inclusive) 
in any cycle, and 1 sample should be collected between Days 10 and 
18 (inclusive) in any cycle. 
 When a PK sample is concomitant with an immunogenicity sample it 
should be taken at the same time 
• Urine dipstick (Cycle 2 through Cycle 6) 
• Pregnancy urine test: A pregnancy urine test will be performed for female patients 
with childbearing ability prior to any interventional treatment (Cycle 2 through 
Cycle 6). 
For the complete list of assessments to be performed on Day 0 of each cycle, refer to the 
Schedule of Events. (Table 1-1) 

 
Protocol MYL-1402O-3001 
Page 91 of 154 
19 February 2019 
Confidential 
Period 1 Completer: Applies to a patient that completes Period 1 through Week 18 
assessments. 
Early Terminator: Applies to a patient that enters Period 1 and is terminated from the study 
prior to completing Week 18 assessments due to an adverse event (AE), death, PD, 
withdrawal of consent, or discontinuation from interventional therapy (bevacizumab 
[MYL-1402O or Avastin] and/or chemotherapy [carboplatin and paclitaxel]). 
6.6 
Treatment Period 2 
Period 2 is defined by the tumor assessments starting after the end of Period 1 (Week 18 
tumor assessments) and occurring every 12 weeks, regardless of delays of the cycles of 
treatment, at pre-specified time points (i.e., Week 30 and Week 42) until PD, discontinuation. 
Total duration of Period 2 will be 24 weeks. 
A patient is eligible to enter Period 2, provided the patient is a Period 1 Completer, has a 
demonstrated disease response of stable disease or better response (i.e., CR or PR), and had 
been receiving during Period 1 either bevacizumab combination therapy or bevacizumab 
monotherapy. 
A patient will be assessed for tumor response using the same type of radiographic exam(s) 
used in Screening Period and Period 1 (e.g., CT or MRI, contrast agent, slice intervals) for 
ongoing evaluation of tumors (e.g., target, non-target). 
• If the patient has not completed 6 cycles of bevacizumab combination therapy 
(bevacizumab plus CP) at Week 18 because of delays, then the patient may continue 
to receive combination therapy for up to 6 cycles. If the patient continues to have 
stable disease or better response (PR or CR), then the patient may subsequently 
receive bevacizumab monotherapy every 21 days until PD, death, withdrawal of 
consent, or discontinuation from interventional therapy. 
• If the patient has completed 6 cycles of bevacizumab combination therapy, then at the 
end of Cycle 6, the patient should be evaluated for tolerability to receive bevacizumab 
monotherapy in Period 2. 
o If it is determined after discussion with the medical monitor that the patient 
would be able to tolerate bevacizumab monotherapy then, after 6 cycles of 
bevacizumab combination therapy the patient will be considered a Period 1 
Completer, provided the patient completes Week 18 tumor assessments. If the 
patient continues to have stable disease or better response (PR or CR), then 

 
Protocol MYL-1402O-3001 
Page 92 of 154 
19 February 2019 
Confidential 
the patient may subsequently receive bevacizumab monotherapy (as per same 
randomization as Period 1) every 21 days until PD, death, withdrawal of 
consent, or discontinuation from interventional therapy. 
o If it is determined after discussion with the medical monitor that the patient 
would not be able to tolerate bevacizumab monotherapy then, after 6 cycles of 
bevacizumab combination therapy the patient will be considered a Period 1 
Completer, provided the patient completes Week 18 tumor assessments. The 
patient will not receive any additional interventional therapy. The patient will 
participate in a safety follow-up visit (Section 6.8) at 28 days (±7 days) of last 
dose of bevacizumab; the EOT visit should also occur at the safety follow-up 
visit. 
The first cycle of Period 2 will be designated as Cycle 701. If bevacizumab monotherapy is 
started earlier because of earlier discontinuation of chemotherapy, the tumor assessment will 
be continued as scheduled. The first assessments for Period 2 will be 12 weeks (± 3 days) 
after the assessment at Week 18. 
Patients experiencing PD will be discontinued from interventional therapy. A safety 
follow-up visit (Section 6.8) will occur at 28 days (± 7 days) of last dose of bevacizumab; the 
EOT visit should also occur at the safety follow-up visit. 
Week 42 efficacy assessments will be used to evaluate secondary endpoints. During Period 2, 
safety assessments will be collected for each cycle of therapy. 
The following procedures will occur: 
• Physical examination 
• Interval history 
• BSA calculation (only if a change in the weight is more than 10%) 
• Concomitant medications 
• ECOG performance status 
• AEs with CTCAE grading 
• Tumor assessments are to be conducted every 12 weeks (± 3 days; Week 30 
[Cycle 704] and Week 42 [Cycle 708]). 
• Brain imaging and/or bone scan, if required with tumor assessments 

 
Protocol MYL-1402O-3001 
Page 93 of 154 
19 February 2019 
Confidential 
• Bioanalytical blood collections for laboratory assessments (Section 12.6 [Appendix 
F], Table 12-4). 
o Hematology (approximately 5mL of blood): At each time cycle, collect blood 
samples prior bevacizumab administration. 
o Chemistry (approximately 5mL of blood): At each cycle, collect blood 
samples prior bevacizumab administration. 
o Immunogenicity (4 samples of approximately 5 mL of blood at each time 
point) 
 Cycle 704: predose 
 Cycle 708: predose. 
o PK (approximately 5mL of blood) 
 Cycle 704: predose. 
 Cycle 708: predose. 
• Urine dipstick 
• Pregnancy urine test: A pregnancy urine test will be performed for female patients 
with childbearing ability prior to any interventional treatment. 
For the complete list of assessments to be performed on Day 0 of each cycle for Period 2, 
refer to the Schedule of Events (Table 1-1). 
6.7 
Extended Treatment Period 
The Extended Treatment Period provides continued bevacizumab monotherapy to any patient 
that at Week 42 has maintained stable disease or better response (CR or PR) and is receiving 
benefit to continue treatment. During the Extended Treatment Period, a patient will receive 
bevacizumab monotherapy (either MYL-1402O or Avastin) until PD, death, unacceptable 
AE, withdrawal of consent, discontinuation from IMP for any reason, or 42 weeks post last 
patient randomized (trial closure). Centralized tumor assessment will not be performed 
during the extended treatment period. All dosing of IP should continue to follow the 
guidelines put forth in the protocol. Assessment of disease status should occur per the 
institutions standards. Safety evaluations should occur per the label recommendations for 
Avastin at minimum and per the institutions standards. Only AE/SAEs deemed by the 
investigator to be related to IP are to be reported during the Extended Treatment Period. 

 
Protocol MYL-1402O-3001 
Page 94 of 154 
19 February 2019 
Confidential 
6.8 
Safety Follow-Up Visit/End of Treatment Visit 
Patients withdrawing or terminating from the study or discontinuing bevacizumab treatment 
or after the dosing at week 42 are to complete a safety follow-up visit at 28 days (± 7 days) 
following last dose on bevacizumab therapy. Patients that have discontinued all 
interventional therapy will have an EOT visit as well, which may or may not occur with the 
safety follow-up visit. 
Potential reasons for termination from interventional therapy include: PD, withdrawal of 
consent, discontinuation from interventional therapy, or discontinuation due to SAE or AE. 
The following procedures will occur: 
• Physical examination 
• Interval history 
• Concomitant medications 
• ECOG performance status 
• AEs with CTCAE grading 
• Tumor assessments are at safety follow-up visit (F/U visit) if needed.  
Tumor assessments are performed only if needed to confirm a response for instance if 
a patient has discontinued after a first partial or complete response because toxicity or 
withdrawal of consent to treatment but not to tumor assessments and follow-up 
• Brain imaging and/ bone scan/or bone X-rays, if required (F/U visit) 
• Blood collections for laboratory assessments (Section 12.6 [Appendix F], Table 12-4). 
o Hematology (F/U visit) (approximately 5mL of blood) 
o Chemistry (F/U visit) (approximately 5mL of blood) 
o Immunogenicity (F/U visit) (4 samples of approximately 5 mL of blood) 
o PK (F/U visit) (approximately 5mL of blood) 
• Urine dipstick (F/U visit) 
• Pregnancy urine test (F/U visit): A pregnancy urine test will be performed for female 
patients with childbearing potential). 

 
Protocol MYL-1402O-3001 
Page 95 of 154 
19 February 2019 
Confidential 
For the complete list of assessments to be performed at the Safety Follow-Up visit, refer to 
the Schedule of Events (Table 1-1). 
6.9 
Study Closure 
Study closure will occur when one of the following is reached: 
1. All patients have discontinued from the study 
2. 42 weeks from the date the last patient was randomized to treatment. 
3. Administrative closure of study 
NOTE: Patients on study treatment at time of study closure will be advised by the PI and/or 
their associated primary health care provider on alternate therapies as per standard for the 
country. 
All treatment provided under the auspices of this protocol will cease at study closure. 
6.10 Unscheduled Visits 
Assessment during unscheduled visits should be guided by the reason for the visit. 
Unscheduled visits with all needed assessments are to be performed when there is suspicion 
of PD. An unscheduled MRI/CT can be performed at any scheduled/unscheduled visit when 
PD is suspected. If an event of death due to PD, a narrative description should be provided in 
the eCRF that includes clinical course and PD complications leading to death. 
6.11 Assessment of Efficacy 
6.11.1 
Tumor Response (RECIST) 
Tumor response will be assessed using RECIST 1.1 criteria (Section 12.1, Appendix A). 
Response (CR, PR, stable, and PD) will be evaluated using the international criteria proposed 
by the RECIST version 1.1 committee. (Eisenhauer et al 2009). 
Tumor assessments are to be conducted every 6 weeks (± 3 days) up to 18 weeks, 
independent of delays in treatment administration (Period 1 [Section 6.5]) and every 
12 weeks (± 3 days) independent of delays in treatment administration after 18 weeks.  
Imaging procedures are to be performed locally throughout the study. Please note, imaging is 
sent for central review through week 42. Confirmation of measurable disease is required 
prior to randomization. Although scans will be submitted for central review, local 
assessments will be used to determine disease response while on treatment 

 
Protocol MYL-1402O-3001 
Page 96 of 154 
19 February 2019 
Confidential 
One to 5 target lesions (with a maximum of 2 lesions per organ) should be identified at 
baseline and recorded in the eCRF. For the purpose of this protocol, measurable lesions such 
as bone (except bone lesion with measurable soft tissue), CNS, and skin lesions (except skin 
lesion with measurable tumoral lesion by CT scan), as well as irradiated, biopsied, or 
surgically-manipulated lesions are excluded. These measurable lesions are considered as 
non-target lesions. If radiation or manipulation is performed throughout the study, a target 
lesion is categorized as non-measurable. 
After radiation or manipulation of a target lesion, the assessment of the patient will be 
considered a PD, unless the extraordinary case that reasonable comments justify why such 
lesion shall still be considered measurable. The patient or the lesion may be censored, 
depending on the intervention performed. Any such on-study interventions shall be discussed 
beforehand with the medical monitor. 
At least a CT scan or MRI of thorax and abdomen will be performed in every assessment. 
The imaging method and settings used at baseline to document and assess a specific lesion 
shall be used throughout the study to consistently follow lesions according to RECIST 1.1. 
Details of imaging studies are provided in the Radiology Manual. 
Tumor assessments and eligibility of patients at screening will be determined by central 
medical imaging. To assess tumor response, a central radiology review of all images will be 
performed for data analysis. All routine protocol-planned imaging and any additional 
imaging performed due to clinical suspicion of PD (such as positron emission tomography, 
bone scan, correlative imaging of hot-spots) should also be provided to the central review. 
After each assessment PIs (or designees) will enter their evaluations in the eCRFs and will 
submit the images to the central image vendor no later than 5 days after the assessment. The 
PIs will make clinical decisions based in their evaluations. The central image vendor will not 
interact with the sites for treatment decisions. If PD is detected during the any period, the PI 
should inform the medical monitor. 
In the case of bone metastases evaluated by a bone scan during the staging and confirmed 
with either X-Ray or CT/MRI, images of these lesions are needed at every tumor assessment 
timepoint. The bone lesions that are not captured by the CT scan or MRI of the thorax and 
abdomen must be followed by X-rays or scans. 
 

 
Protocol MYL-1402O-3001 
Page 97 of 154 
19 February 2019 
Confidential 
6.11.1.1 Progressive Disease 
Progressive disease is defined according to RECIST as a >20% increase in the sum of 
diameters of target lesions; taking as reference the smallest sum on study (this includes the 
baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or 
more new lesions is also considered PD. A substantial worsening of non-target lesions can be 
a trigger for PD. 
In accordance with the Council for International Organizations of Medical Sciences VI 
recommendations, progression of the underlying disease and its consequences will not be 
collected as an AE even if they lead to hospitalization or meet any other seriousness criteria 
including death. Rather, progression of the underlying disease and its consequences should be 
reported in the eCRF within no more than 48 hours. The report will include: 
• Description of PD (e.g., increase in the sum of diameters of target lesions, appearance of 
new lesions, substantial worsening of non-target lesions, or clinically determined PD). 
• Date on which PD was declared in accordance with FDA Guidance for Industry - Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
• For PD based on a new lesion, the date of the first observation that the new lesion was 
detected. 
• If multiple assessments based on the sum of target lesion measurements are done at 
different times, the date of the last observation or radiological assessment of target lesions 
that shows a predefined increase in the sum of the target lesion measurements according 
to RECIST. 
• For PD based on substantial worsening of non-target lesions, the date of the first 
observation of substantial worsening. 
• For clinically-determined PD, the date of objectively assessed worsening. 
6.11.2 
Survival 
Progression-Free Survival (PFS): Progression-free survival is defined as the time from 
randomization to the first documentation of PD or to death due to any cause, whichever 
comes first. Analysis of PFS is described in Section 7.7.2. 

 
Protocol MYL-1402O-3001 
Page 98 of 154 
19 February 2019 
Confidential 
Overall Survival: Overall survival is defined as the time from randomization to date of 
death due to any cause. Analysis of OS is described in Section 7.7.2. If a patient dies because 
of disease progression during treatment, then a verbatim explanation of the circumstances of 
the death is expected, including evaluating the cause and if a treatment toxicity may be 
involved. 
6.12 Safety and Tolerability Assessments 
Safety and tolerability will be assessed based on the nature, frequency and severity of the 
reported AEs, the results of laboratory assessments, the immunogenicity results, and physical 
examination. Details of AEs and concomitant medications and procedures will be recorded 
on a continuous basis throughout the study. 
6.12.1 
Definitions of Adverse Events 
Adverse Event 
As per International Conference on Harmonisation (ICH) E2A, an AE is any untoward 
medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding or physical finding, symptom, or disease), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product 
Treatment-Emergent Adverse Event 
A treatment-emergent AE is an AE that started or deteriorated after the first administration of 
blinded MYL-1402O or Avastin through 100 days following the last dose of blinded 
MYL-1402O or Avastin. 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. 
All AEs judged by either the reporting PI (or designee) or the sponsor as having a reasonable 
causal relationship (i.e., “possible”, “probable”, or “definite”) to a study drug will be 
designated as adverse drug reactions. 

 
Protocol MYL-1402O-3001 
Page 99 of 154 
19 February 2019 
Confidential 
If the relationship to MYL-1402O or Avastin is not given by the PI (or designee), then the AE 
must be treated as if the relationship were “possible.” 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
o NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more 
severe. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly 
o NOTE: A congenital anomaly in an infant born to a mother who was exposed to 
the study drug during pregnancy is considered an SAE. However, a newly 
diagnosed pregnancy in a patient that has received the study drug is not 
considered an AE unless it is suspected that the study drug interacted with a 
contraceptive method and led to the pregnancy. The patient with newly diagnosed 
pregnancy will discontinue receiving study drug and will be followed-up every 
3 months until delivery or termination to gather information about the outcome of 
the pregnancy. 
• Is an important medical event 
o NOTE: Important Medical Event: Medical and scientific judgment should be 
exercised in deciding whether it is appropriate to consider other situations serious, 
such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 

 
Protocol MYL-1402O-3001 
Page 100 of 154 
19 February 2019 
Confidential 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an 
overnight stay. An elective hospital admission to treat a condition present before 
exposure to the study drug, or a hospital admission for a diagnostic evaluation of 
an AE, does not qualify the condition or event as an SAE. Further, an overnight 
stay in the hospital that is only due to transportation, organization, or 
accommodation problems and without medical background does not need to be 
considered an SAE. 
Events NOT to be reported as SAEs are hospitalizations for the following: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Treatment, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen 
• Admission to a hospital or other institution for general care due to social or economic 
reasons (e.g., no access to local ambulatory medical care) 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission 
Hospitalization also does not include the following: 
• Rehabilitation facilities 
• Hospice facilities 
• Respite care (e.g., caregiver relief) 
• Skilled nursing facilities 
• Nursing homes 
6.12.2 
Collection, Evaluation and Documentation of Adverse Events 
As referenced in Section 5 of the protocol, MYL-14O20 (test product) and Avastin (reference 
product) will be considered as the IMP. As such, and in relation to causality assessments, PIs 
should consider causality as it relates specifically to bevacizumab (either MYL-1402O or 
Avastin). The active collection period for AEs will be from the time the patient signs the ICF 

 
Protocol MYL-1402O-3001 
Page 101 of 154 
19 February 2019 
Confidential 
through the Safety Follow up Visit. SAEs only need to be reported after the Safety Follow up 
Visit if considered reasonably related to the IMP. Pre-existing diseases or conditions 
(reported at time of screening in medical history) will not be considered AEs unless there is 
an increase in the frequency or severity, or a change in the quality of the disease or condition. 
All SAEs should be immediately reported (within 24 hours) as per the study protocol contact 
list. 
Progression of NSCLC and its consequences will not be collected as an AE even if they lead 
to hospitalization or meet any other seriousness criteria including death. Rather, progression 
of NSCLC and its consequences should be entered in the relevant eCRF page within 
48 hours. A narrative description should be provided in the eCRF that includes clinical course 
and PD complications leading to death. 
6.12.2.1 Collection 
The PI (or designee) is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE, as described previously. At each visit, the patient will 
be allowed time to spontaneously report any issues since the last visit or evaluation. The PI 
(or designee) will then monitor and/or ask about or evaluate AEs using non-leading 
questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
Any AE recorded in the proper section of the study diary (paper or electronic) will also be 
transferred onto the eCRF. 
6.12.2.2 Evaluation 
6.12.2.2.1 Severity Assessment of Adverse Events 
The clinical severity of an AE will be graded whenever possible using the NCI-CTCAE 
criteria Version 4.03. A copy of these criteria will be provided to each study site. If an AE is 
not listed in the NCI-CTCAE, its clinical severity will be classified as follows (Table 6-1): 

 
Protocol MYL-1402O-3001 
Page 102 of 154 
19 February 2019 
Confidential 
Table 6-1 
Clinical Severity of Events 
The PI (or designee) will assess each AE as MILD, MODERATE, SEVERE, 
LIFE-THREATENING, or FATAL to describe the maximum intensity of the AE. 
Grade 1: MILD 
Does not interfere with patient's usual function 
Grade 2: MODERATE 
Interferes to some extent with patient's usual 
function 
Grade 3: SEVERE 
Interferes significantly with patient's usual function 
Grade 4: LIFE-THREATENING 
Risk of death at time of event 
Grade 5: DEATH 
Death related to AE 
Abbreviations: AE = adverse event; PI = principal investigator 
 
It is important to distinguish between severe AEs and serious AEs. Severity is a classification 
of intensity based on the NCI-CTC AE grading or on the above Table 6-1, whereas an SAE is 
an AE that meets any of the regulatory specified criteria required for designation as 
seriousness is described in Section 6.12.1. 
6.12.2.2.2 Action Taken with Investigational Medicinal Product and Chemotherapy 
The undertaken actions for an AE following treatment with IP (MYL-1402O or Avastin) are 
described in Table 6-2 for IP. The undertaken actions for an AE following chemotherapy are 
described in Table 6-3 for CP. Dose modification is also described in Section 5.2.5. 

 
Protocol MYL-1402O-3001 
Page 103 of 154 
19 February 2019 
Confidential 
Table 6-2 
Action Taken for an Adverse Event Associated with Investigational 
Medicinal Product (MYL-1402O or Avastin) 
Treatment interrupted 
The treatment was temporarily interrupted, with intent to restart. 
Treatment withdrawn 
The treatment was permanently discontinued 
Unknown 
Not known, not observed, not recorded, or refused 
No action taken 
The AE did not result in any modification of dose or frequency 
of dosing 
Not applicable 
The AE occurred prior to first dose or following last study dose 
Abbreviation: AE = adverse event; 
Table 6-3 
Action Taken for an Adverse Event Associated with Chemotherapy 
Dose reduced 
The dose regimen was reduced by changing its frequency, 
strength, or amount 
Treatment interrupted The treatment was temporarily interrupted, with intent to restart. 
Treatment withdrawn 
The treatment was permanently discontinued 
Unknown 
Not known, not observed, not recorded, or refused 
No action taken 
The AE did not result in any modification of dose or frequency 
of dosing 
Not applicable 
The AE occurred prior to first dose or following last dose 
Abbreviation: AE = adverse event; 
 
6.12.2.2.3 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is 
possibly related to the patient’s death, the outcome of death should be indicated for the AE 

 
Protocol MYL-1402O-3001 
Page 104 of 154 
19 February 2019 
Confidential 
which is the most plausible cause of death in the opinion of the PI (or designee). All other 
ongoing AE/SAEs will be recorded as not recovered/not resolved at the time of death. 
Note: Although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs. 
6.12.2.2.4 Causality Assessment – Relationship to Study Medication 
A causality assessment is the determination of whether there exists a reasonable possibility 
that the study product caused or contributed to an AE. The PI (or designee) must make an 
assessment of the relationship of each AE (serious and non-serious) to the study drug(s) and 
record this relationship in the eCRF. 
In addition, if the PI (or designee) determines an AE or SAE is associated with study 
procedures, the PI (or designee) must record this causal relationship in the source documents 
and eCRF as unrelated to study medication, while noting study related procedures as an 
alternative etiology, as appropriate. Adverse events related to study procedures must still be 
recorded in the eCRF in accordance with the reporting requirements, and as applicable, 
reported as an SAE in expedited manner. 
Factors that need to be considered when making a causality assessment include: 
• Temporal relationship with drug administration (e.g., time of onset) 
• Clinical and pathological characteristics of the event(s) 
• Pharmacological plausibility 
• Exclusion of confounding factors (medical and medication history) 
• Drug Interactions 
• De-challenge/re-challenge 
• Dose relationship 
A suspected relationship (definite, probable, possible) between the events and the study 
drug(s) means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. 
The PI (or designee) is responsible for assessing relationship of AEs to study drug in 
accordance with the following definitions (Table 6-4): 

 
Protocol MYL-1402O-3001 
Page 105 of 154 
19 February 2019 
Confidential 
Table 6-4 
Causality Assessment Categories 
DEFINITELY 
Causal 
relationship is 
certain 
For example: The temporal relationship between 
drug exposure and the AE onset/course is 
reasonable, there is a clinically compatible 
response to de-challenge, other causes have been 
eliminated; the event must be definitive 
pharmacologically or phenomenologically, using a 
satisfactory re-challenge procedure if necessary. 
PROBABLY 
High degree 
of certainty 
for causal 
relationship 
For example: The temporal relationship between 
drug exposure and AE onset/course is reasonable, 
there is a clinically compatible response to 
de-challenge (re-challenge is not required), 
unlikely to be attributed to disease or other drugs. 
POSSIBLY 
Causal 
relationship is 
uncertain 
For example: The temporal relationship between 
drug exposure and the AE onset/course is 
reasonable or unknown, de-challenge information 
is either unknown or equivocal, could also be 
explained by disease or other drugs. 
UNLIKELY 
Causal 
relationship is 
improbable 
Another explanation is more likely such as 
disease, environment, or other medication. Does 
not represent a known reaction to study drug. 
UNRELATED/NOT 
RELATED 
No possible 
relationship 
The temporal relationship between drug exposure 
and the AE onset/course is unreasonable or 
incompatible, or a causal relationship to study 
drug is impossible. 
 
If the relationship to the study drug(s) is considered to be unlikely or not related, an 
alternative suspected etiology should be provided if available (e.g., CP, other concomitant 
medications, intercurrent illness/events). 
6.12.2.2.5 Documentation 
All AEs occurring within the study period must be documented in the eCRF with the 
following information; where appropriate: 
• AE name or term in standard medical terminology 
• Start date and time – for SAEs, start date is defined as the date the AE became serious 

 
Protocol MYL-1402O-3001 
Page 106 of 154 
19 February 2019 
Confidential 
• When the AE stopped (stop date and time, or date and time of last observation if 
ongoing, recovering or not recovered) 
• Severity of the AE 
• Serious criteria (hospitalization, death) 
• Actions taken with study drug 
• Treatment (pharmacologic and non-pharmacologic) for the event 
• Outcome 
• The PI’s opinion regarding the AE relationship to blinded MYL-1402O or Avastin 
• Alternative etiology for the SAE if not considered related to blinded MYL-1402O or 
Avastin 
6.12.2.3 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established 
standards of care and per the PI’s (or designee’s) medical judgment. 
6.12.2.4 Emergency Unblinding 
Treatment assignment for an individual patient should be unblinded only in case of a 
medical/surgical emergency by the PI (or designee), when knowledge of the treatment 
assignment is urgently needed for the clinical management or welfare of the patient. 
If an SAE occurred, an SAE Report Form must be completed and forwarded to the Mylan 
PSRM. The PI must document the breaking of the code, and the reasons for doing so on the 
eCRF, in the site file, and in the medical notes. 
See Section 3.7 for unblinding procedures. 
6.12.2.5 Adverse Events of Special Interest 
Any non-serious AE that is not related to disease progression and results in permanent 
discontinuation of bevacizumab (MYL-1402O or Avastin) is considered an AE of special 
interest. These are to be reported on the SAE Reporting Form by checking the AE of Special 
Interest box within 24 hours of decision to terminate the patient’s participation in the study. 
Special attention will be paid to hypertension, proteinuria, bleeding, fistulas, GI perforations, 
wound healings, jaw osteonecrosis, leukoencephalopathies, venous and arterial 

 
Protocol MYL-1402O-3001 
Page 107 of 154 
19 February 2019 
Confidential 
thromboembolic events, and cardiac failure to fully characterize and compare the safety 
profile of the proposed biosimilar (MYL-1402O) and Avastin. 
6.12.2.6 Notification to Sponsor or Designee 
The SAE Reporting Form is to be completed, signed by the PI, and emailed (preferred) or 
faxed with supporting documentation (e.g., eCRFs, hospital records, laboratory reports) to 
Mylan PSRM for all SAEs and AEs that lead to discontinuation of blinded 
MYL-1402O/Avastin. Patient identity details (such as but not limited to name or 
clinic/hospital number) must not be visible on SAE forms or any supporting documentation 
provided by the PI. These should be “blacked out”, signed and dated before submission to 
Mylan or its designee. The patient identification number must be provided on every 
document. 
Note that Email is the preferred method of submission of Immediate Safety Reports 
including SAEs, AEs Leading to Discontinuation, and Pregnancy Exposures 
All Immediate Safety Reports must be notified within 24 hours to Mylan 
Product Safety & Risk Management: 
 
At that time of first notification, the investigator/designee should at least provide the 
following information: 
• Protocol number 
• Reporter (study site and PI (or designee) full name) 
• Study drug 
• Patient’s study number/identifier 
• SAE term 
• The seriousness criteria that were met 
• PI’s (or designee’s) opinion of the relationship to blinded MYL-1402O/Avastin and 
chemotherapy 
PV MAIL HUB FOR IMMEDIATE SAFETY REPORTS 
pvclinical@mylan.com 
If an acknowledgement is not received within 24 hours, forward via 
Fax: +1 304 285 6409 

 
Protocol MYL-1402O-3001 
Page 108 of 154 
19 February 2019 
Confidential 
And if available: 
• Severity 
• Patient’s age 
• Date of first dose of interventional therapy 
• Date of last dose of interventional therapy, if applicable 
• Start and stop of the event (date and time) 
• A brief description of the event, outcome to date, and any actions taken 
• Concomitant medication at onset of the event 
• Relevant past medical history 
• Relevant laboratory test findings 
• Whether and when the PI (or designee) was unblinded to the patient’s treatment 
assignment 
If the initial notification of an SAE is by telephone, within 24 hours of the initial telephone 
notification the investigator must email the written SAE Report Form that describes the SAE 
to the Mylan PSRM email listed above. 
6.12.2.7 Follow-Up of Adverse Events 
Any AE will be followed-up to a satisfactory resolution, until it becomes stable, or until it 
can be explained by another known cause (i.e., concurrent condition or medication) and 
clinical judgment indicates that further evaluation is not warranted. All findings relevant to 
the final outcome of an AE must be reported in the patient’s medical record and recorded on 
the appropriate eCRF page. 
The investigator may be requested by Mylan GmbH/designee to obtain specific additional 
follow up information in an expedited fashion. This information collected for SAEs is more 
detailed than that captured on the AE eCRF. In general, this will include a description of the 
SAE in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality. Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided. In the case of a fatal 
SAE, autopsy findings/death certificate (if available) may be requested by Mylan GmbH or 
its designated representative. 

 
Protocol MYL-1402O-3001 
Page 109 of 154 
19 February 2019 
Confidential 
Any missing or additional relevant information concerning the SAE should be provided on a 
follow-up SAE Report Form. Ensure that any additional information requested by sponsor or 
designee about the event, as outlined above (e.g., hospital reports, autopsy report) is provided 
to sponsor/designee as soon as it is available. 
6.12.2.8 Notification and Submission to Regulatory Authorities and Ethics Committees 
The PI (and any designee) is required to comply with applicable regulations (including local 
law and guidance) regarding notification to his/her regulatory authority, IRB, independent 
ethics committees (IECs), institutional ethics committees, and institutions. 
Suspected unexpected serious adverse reactions, SAEs or other cases as required by the 
concerned competent authorities and IECs will be reported by the sponsor/representative to 
all concerned parties within applicable timelines. The sponsor/representative will also submit 
periodic safety reports (e.g., Development Safety Update Reports) as required by local and 
international regulations. 
6.12.3 
Pregnancy 
All patients of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation and during the 6 months following last study drug. Patient should be 
instructed to contact the PI (or designee) or other study staff immediately if pregnancy occurs 
or is suspected. 
Pregnancy testing will be conducted as detailed in the Schedule of Events (Table). A woman 
who is found to be pregnant at the screening visit will be excluded from the study and will be 
considered to be a screening failure. 
A woman who becomes pregnant following administration of any study drug will be 
immediately discontinued from further study drug. The Pregnancy Report Form must be 
completed and reported to Mylan PSRM (pvclinical@mylan.com or fax: +1 304 285 6409) 
within 24 hours from the time of initial awareness. 
A male patient that has a partner that becomes pregnant during the study l will not be 
discontinued from study drug. Exposed partner pregnancies (conception during study or 
within 6 months of last dose) are also reportable to Mylan provided that consent and any 
required releases are obtained from the patient’s partner. Study personnel should contact their 
clinical research associate to obtain a partner pregnancy informed consent form upon 

 
Protocol MYL-1402O-3001 
Page 110 of 154 
19 February 2019 
Confidential 
learning of a partner pregnancy. Consent of the pregnant partner must be obtained before any 
details of the pregnancy can be shared with the sponsor. If the pregnant partner provides 
consent to have the pregnancy followed, the site should collect the information specified on 
the Pregnancy Report Form and forward the completed form to Mylan PSRM. 
Non-exposed pregnancies (before randomization and >6 months following last study drug 
administration) are not reportable. 
The PI (or designee) is responsible for following up the pregnancy at 3 monthly intervals 
until delivery or termination. While pregnancy itself is not considered an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or a SAE. Any SAE in the mother, fetus, or newborn is to be reported on 
the SAE. A spontaneous abortion or congenital anomaly is always considered to be an SAE. 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered to be an elective procedure and not an AE; nevertheless, Mylan requests that the 
outcome (e.g., elective termination) be reported within 24 hours and sent as a follow up on 
the Delivery and Infant Follow-up Form. 
6.12.4 
Physical Examination 
A complete physical examination will be performed at the screening visit before exposure to 
any study treatment, and then at selected time points during the study (Schedule of Events 
Table). Vital signs and patient weight will be routinely recorded as part of the physical 
examination, whereas patient height will be recorded only at baseline. 
6.12.5 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG performance scale (Oken et al 1982) is a 6-point categorical scale, ranging from 
0 (asymptomatic) to 5 (death). The ECOG performance scale is evaluated at selected visits 
during the study and a change from baseline calculated. The ECOG performance scale score 
changes from baseline can then be categorized on a 3-point categorical scale: deteriorated, 
unchanged, and improved. Improvement or deterioration of performance status requires a 
decrease or an increase from baseline, respectively, of at least 1 point on the 
ECOG performance scale. 

 
Protocol MYL-1402O-3001 
Page 111 of 154 
19 February 2019 
Confidential 
6.13 Safety Monitoring 
Safety will be evaluated periodically internally by Mylan and Medical Monitors and Mylan 
Safety personnel, and externally with the Steering Committee and in an ad hoc frequency 
with a designated data and safety monitoring board (DSMB)  
Safety blinded evaluations will be done against historical data from 5 historical published 
randomized trials that evaluated this combination in lung cancer and safety information from 
regulatory documents of bevacizumab publicly available. The Sponsor or the Steering 
Committee will call an independent DSMB evaluation of unblinded data if there is any 
concern about the risk to the population of the study during the periodic safety evaluations, 
the decisions will be documented. 
6.14 Laboratory Analyses 
Samples for the laboratory tests listed in Table 6-5 will be collected and analyzed locally at 
the time points specified in the Schedule of Events (Table 1-1). It should be ensured that 
variability is minimized by using the same laboratory facility throughout the study. The 
required laboratory tests are to be analyzed and reviewed by the treating investigator before 
each new cycle of treatment. Additionally, the review will be documented in source by either 
signing and dating the laboratory report or noting the review in the patient’s note. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgment of the PI (or designee) are to be recorded as AEs or SAEs. 

 
Protocol MYL-1402O-3001 
Page 112 of 154 
19 February 2019 
Confidential 
Table 6-5 
Laboratory Tests 
Chemistry Panel 
Hematology Panel 
Urinalysis Panel 
BRt (Total Bilirubin) 
Alk Phos (Alkaline Phosphatase) 
ALT (Alanine Aminotransferase) 
AST (Aspartate 
Aminotransferase) 
CCr (Creatinine Clearance) 
Creatinine 
NA (Sodium) 
K (Potassium) 
Total Protein 
Albumin 
PT/INR (International 
Normalized Ratio), and aPTT (at 
screening, if on anticoagulants) 
WBC (White Blood 
Cell count) 
ANC (Absolute 
Neutrophil Count) 
Hb (Hemoglobin) 
Platelet count 
Urine dipstick (and 24-hour 
urine protein, if indicated) 
Pregnancy test (only if child 
bearing potential) [Serum 
hCG only at screening) 
Total protein (conditional, 
only if urine dipstick 2+ or 
more) 
 
6.15 Sample Collections 
The following procedures are performed centrally throughout the study: PK and 
immunogenicity blood sampling. Safety laboratory assessments will be performed locally. 
Details of blood sample collections are provided in the Schedule of Events and summary of 
total blood collected in Table 12-4. All blood samples for bioanalysis that are collected at 
each time point must be processed immediately according to the following general 
procedure: 
1. Draw blood into a properly labeled 5 mL gold top serum separator tube (SST) and fill 
completely. 
NOTE: It is important to make every reasonable effort to collect a full 5 mL volume 
of blood at each sample draw. For the immediately post-dose samples use a different 
venipuncture location or catheter than the infusion or take it after flushing the line. 
2. Thoroughly mix the blood with the clotting activation agent by inverting the tube 
5 times. 

 
Protocol MYL-1402O-3001 
Page 113 of 154 
19 February 2019 
Confidential 
3. Place tubes in an upright position and allow the blood to clot at room temperature at 
least 30 minutes. 
4. Centrifuge SST tubes within 60 minutes of collection for 10 minutes at 
1100 to 1300 × g. 
5. After centrifugation, transfer the serum from the SST collection tube evenly into the 2 
labeled cryo-vials (Primary and Back-up) and immediately cap the tubes tightly. 
NOTE: Ensure that the label information on the cryo-vials matches the label 
information on the blood collection tube. It is important to transfer as much serum as 
possible from the serum separator tube into the cryo-vials. 
6. Place the serum storage tubes upright in a freezer at or below –20°C (–70°C preferred 
where available) within 90 minutes of collection. In the circumstance where the 
sample will be stored for more than 60 days prior to shipment, ensure immediate 
transfer to a –70°C freezer. 
NOTE: Ensure the samples have been frozen 24 hours prior to shipment. 
Primary and back up samples from the same subject visit must not be shipped 
together, ship the back-up aliquot once the central laboratory confirms receipt 
of the primary aliquot. 
Premium courier with temperature monitoring is required for the shipment of 
these samples, please refer to your courier information. 
6.15.1 
Immunogenicity Blood Sampling 
Blood samples will be collected for immunogenicity analysis from all patients and will be 
analyzed at a central laboratory. Up to 4 blood samples will be collected at each time point, 
1 sample will be used to determine the presence of antidrug (bevacizumab) antibody (ADA) 
and 1 sample will be used to determine the presence of neutralizing antibodies against 
bevacizumab, if applicable. The other 2 samples collected will be stored in reserve for 
potential supplemental immunogenicity testing and/or characterization. 
For the assessment of immunogenicity, blood samples will be collected at the following time 
points as presented in Table (a summary total blood collected in Table 12-4 and will 
correspond to collection of PK samples Section 6.15.2), as follows: 

 
Protocol MYL-1402O-3001 
Page 114 of 154 
19 February 2019 
Confidential 
• For immunogenicity analysis, an unscheduled blood sample will be collected with a 
drug concentration sample if a hypersensitivity reaction occurs, as quickly/soon as 
possible after the event occurs. 
• Baseline (pre-dose): Six samples of 5 mL each will be collected if possible within 1 
hour before administration of drug in Cycle 1 for use in analytical method 
optimization and validation. 
• In Period 1 at Cycles 2, 4, and 6: Four blood samples of 5 mL each for 
immunogenicity testing will be collected before dosing. 
• Period 2: At Cycle 704 and Cycle 708, four blood samples of 5 mL each for 
immunogenicity testing will be collected before dosing and at the same time when the 
corresponding PK samples are collected. 
• Safety Follow-Up visit: Four blood samples of 5 mL each for immunogenicity testing 
will be collected at the safety follow-up visit (28 days [±7 days] after last dose of 
interventional therapy), which is the same time when the corresponding PK samples 
are collected. 
The blood samples will be collected via an indwelling i.v. catheter or by direct venipuncture, 
and the exact times of blood sampling will be recorded in the appropriate eCRF and 
individual source documents. Sample handling instructions are specified in the laboratory 
manual. 
Immunogenicity will be analyzed for ADA using fully validated analytical methods. 
Bioanalytical methodology and procedures will be documented in a sample analysis protocol. 
Details of immunogenicity assessment methodology and procedures will be documented in a 
sample analysis protocol. 
6.15.2 
Pharmacokinetic Blood Sampling 
Blood samples will be collected for PK analysis from all patients and will be analyzed at a 
central laboratory. To facilitate an accurate PopPK evaluation, it is imperative that the actual 
date/time of the start and end of dosing is accurately recorded for all patients, in addition to 
the actual date/time of all PK blood sample collections. Details of blood sample collections 
are provided in the Schedule of Events (Table 1-1) and summary of total blood collected in 
Table 12-4. 

 
Protocol MYL-1402O-3001 
Page 115 of 154 
19 February 2019 
Confidential 
For the assessment of bevacizumab concentrations in serum, a blood sample (1 × 5 mL) will 
be collected at the following time points: 
• For PK analysis, an unscheduled drug concentration blood sample will be collected 
with one immunogenicity sample if a hypersensitivity reaction occurs, as 
quickly/soon as possible after the event occurs. 
• Baseline (pre-dose): If possible within 1 hour before administration of drug in 
Cycle 1, a PK sample will be collected from all patients in both treatment arms. 
• PK (predose [if possible within 1 hour prior to bevacizumab dosing] and postdose 
[within 15 minutes after bevacizumab infusion, the postdose samples need to be taken 
from a different catheter or vein puncture location than the infusion catheter or after 
flushing the line]) to be collected at the following time points: (approximately 5mL of 
blood at each time point). 
o In Cycle 1: postdose 
o In Cycle 2: predose and postdose 
o In Cycle 3: predose 
o In Cycle 4: predose and postdose 
o In Cycle 5: predose 
o In Cycle 6: predose and postdose 
o All patients will have 2 additional PK samples collected in any cycle (1 to 6): 
1 sample will be collected between Days 3 and 8 (inclusive) in any cycle, and 
1 sample should be collected between Days 10 and 18 (inclusive) in any cycle. 
• Period 2: A sample will be collected prior to dosing (approximately 5mL of blood at each 
time point) in Cycle 704 and 708, which is the same time that the corresponding 
immunogenicity samples are collected. 
o During Period 2, a PK sample will be collected at predose of Cycle 704 and 
Cycle 708.  
• An unscheduled drug concentration blood sample (approximately 5mL of blood) will be 
collected with one immunogenicity sample if a hypersensitivity reaction occurs, as 
quickly/soon as possible after the event occurs. 

 
Protocol MYL-1402O-3001 
Page 116 of 154 
19 February 2019 
Confidential 
• Safety Follow-Up Visit: Sample collected at the safety follow-up visit (28 days [±7 days] 
after last dose of interventional therapy) (approximately 5mL of blood), which is the 
same time that the corresponding immunogenicity samples are collected. 
In total, up to 18 PK samples (18 samples × 5 mL each = 90 mL of blood) will be collected 
during the study. 
The blood samples will be collected via an indwelling i.v. catheter or by direct venipuncture 
into serum separator tubes, and the exact times of blood sampling will be recorded in the 
eCRF and individual source documents. The PK dose samples need to be taken from a 
different catheter or vein puncture location than the infusion catheter or after flushing the 
line. Sample handling instructions can be found in the laboratory manual. 
Pharmacokinetic samples will be analyzed for bevacizumab concentrations by using fully 
validated analytical methods. Bioanalytical methodology and procedures will be documented 
in a sample analysis protocol. 
6.15.3 
Safety Blood Sampling 
The following procedures are performed locally throughout the study: hematology, 
chemistry, coagulation, urinalysis, and pregnancy testing. Details of blood sample collections 
are provided in the Schedule of Events (Table 1-1) and summary of total blood collected in 
Table 12-4. 
The total amount of blood collected per patient is not expected to exceed 355 mL over the 
study (Table 12-4). 
All samples for the scheduled safety laboratory tests must be taken before study treatment 
administration. Blood samples will be taken using standard venipuncture techniques. 
All samples should be stored and shipped as described in the Laboratory Manual. 

 
Protocol MYL-1402O-3001 
Page 117 of 154 
19 February 2019 
Confidential 
7 Statistical and Analytical Plan 
7.1 
Efficacy Endpoints 
7.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the ORR based on best tumor responses as assessed by an 
independent review at any time point during the first 18 weeks,  according to RECIST 1.1. 
The ORR is defined as the proportion of patients with CR or PR as the best overall timepoint 
response during the first 18 weeks.  
An ORR based on the best tumor responses confirmed at  a second time point will be 
evaluated as a sensitivity analysis. This ORR is defined as the proportion of patients with CR 
or PR as the best overall response during the first 18 weeks and whose tumor responses has 
been confirmed at least 4 weeks after the first assessment or 6 weeks at subsequent 
assessments.  
Patients with response that cannot be evaluated per RECIST 1.1 will be scored as non-
responders. In addition, ORRs as assessed by investigators will also be presented and 
analyzed using the same methods for the ORRs assessed by the independent review. 
7.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will consist of the following. 
• DCR (CR, PR, or stable disease) during the first 18 weeks 
• PFS, defined as the time from randomization to the first documentation of PD or to 
death due to any cause, whichever comes first 
• OS, defined as the time from randomization to date of death due to any cause 
• DR, is defined as the time from start of the first documentation of objective tumor 
response (CR or PR) to the first documentation of tumor progression (i.e., PD) or to 
death due to any cause, whichever comes first. 
7.2 
Pharmacokinetic Endpoints 
The pharmacokinetics endpoints will be as follows: 
• PopPK measures of exposure of MYL-1402O and the reference product Avastin (e.g., 
AUC, Cmax, Cmin, CL, Vc, and the terminal elimination half-life). 

 
Protocol MYL-1402O-3001 
Page 118 of 154 
19 February 2019 
Confidential 
7.3 
Safety Endpoints 
The safety endpoints will be as follows: 
• Incidence, nature, and severity of AEs including adverse drug reactions graded 
according to CTCAE. 
• Detection of antibodies to bevacizumab. 
7.4 
Sample Size Calculations 
To meet the different regulatory requirements, the primary endpoint will be analyzed using 
two approaches (ratio of ORR and difference of ORR between treatments). These different 
approaches lead to different sample size requirements. The sample size calculations for this 
study are presented in Section 7.4.3 
7.4.1 
FDA Regulatory Requirements  
The primary efficacy analysis is based on the ratio of the MYL-1402O ORR to the Avastin 
ORR at Week 18.  
Following FDA’s advice, four randomized clinical studies were included in a meta-analysis 
to estimate the treatment effect of bevacizumab in combination with chemotherapy inpatients 
with NSCLC and to derive a similarity margin for the ratio of the ORRs. These four studies 
were Johnson et al, 2004; Sandler et al, 2006; Reck et al, 2010; and Niho et al, 2012. The 
control arm in three studies used was paclitaxel plus carboplatin as background 
chemotherapy regimen while in the study by Reck et al, 2010 gemcitabine was used as 
chemotherapy.  
Table 7-1 
Meta-Analysis 
 
Control CT 
Bevacizumab plus CT 
 
 
Study 
(CR+PR)/
N 
ORR % 
(CR+PR)/
N 
ORR % 
Risk ratio 
Weight 
(fixed) 
Johnson et 
al 
6/32 
18.8 
11/34 
32.4 
0.580 
3.5% 
Nishio et 
al 
20/59 
33.9 
68/121 
56.2 
0.603 
14.7% 
Reck et al 
71/327 
21.7 
114/329 
34.7 
0.627 
37.4% 

 
Protocol MYL-1402O-3001 
Page 119 of 154 
19 February 2019 
Confidential 
Sandler 
59/392 
15.1 
133/381 
34.9 
0.431 
44.4% 
Meta-
analysis 
156/810 
19.3 
326/865 
 
37.7 
0.535 
70% CI 
0.49-0.58 
 
The p-value for testing the heterogeneity among the four selected studies was 0.230, 
indicating that the heterogeneity among the four studies in the meta-analysis was not 
significant. Hence, a fixed effects approach was used for the meta-analysis. The meta-
analysis yields a risk ratio of 0.53 and an ORR for Bevacizumab plus Chemotherapy of 38%. 
This selection of studies and meta-analysis has been also discussed by He K at al., 2016. 
Based on the meta-analysis, a symmetric equivalence margin for the risk ratio of (0.73, 1.36) 
was derived by maintaining 50% of the treatment effect. 
The limits for the equivalence margin have been derived using the following approach: The 
reverse of the upper bound of 70% CI, 1/0.58 = 1.72, indicates 72% more effect with 
bevacizumab. The biosimilar should retain a substantial portion of that benefit. The clinical 
margin representing the acceptable level of inferiority was therefore set at 50% of this 72% 
increase, i.e., 1.362 [= (1.72-1)/2+1]. The lower margin is the reciprocal of the upper margin, 
i.e., 1/1.362 =0.730  
A sample size of 588 patients (294 per treatment group) will provide 80% power for testing 
equivalence of MYL-1402O and Avastin at 1-sided 5 % level of significance, for the primary 
endpoint ORR at Week 18. This sample size assumes that the ORR at Week 18 will be 38.0% 
for both MYL-1402O and Avastin. Statistical equivalence will be declared if the 2-sided 90% 
confidence interval (CI) of the ratio of the 2 treatment groups falls wholly within an 
asymmetrical equivalence region defined as (0.73, 1.36). 
7.4.2 
EU/EMA Regulatory Requirements 
The efficacy analysis for EMA requirement is based on the difference of the MYL-1402O 
ORR and the Avastin ORR at Week 18.  
The meta-analysis of the four studies results in a risk difference of -17.1% with a 70% a CI of 
(-19.3%, -14.3%). The proposed equivalence margin of (-12.5%, 12.5%) maintains 65% of 
lower limit of the CI for the risk difference.  
A sample size of 628 patients (314 per treatment group) will provide 80% power for testing 
equivalence of MYL-1402O and Avastin at 1-sided 2.5 % level of significance, for the 

 
Protocol MYL-1402O-3001 
Page 120 of 154 
19 February 2019 
Confidential 
primary endpoint ORR at Week 18. This sample size assumes that the ORR at Week 18 will 
be 38.0% for both MYL-1402O and Avastin. Statistical equivalence will be declared if the 
2-sided 95% CI of the difference of the 2 treatment groups falls wholly within an 
equivalence.  
7.4.3 
Study Sample Size Determination 
The EMA requirement needs a larger sample size, therefore the planned sample size for this 
study will be based on the size for the EMA requirement which is 628 patients (314 per 
treatment group). The proposed sample size is also in the same range (620-671 patients) of 
other studies (ClinTrials Identifiers: NCT02272413 and NCT02754882) conducted by other 
sponsors that have evaluated a biosimilar bevacizumab using NSCLC indication.  
Given that a single post baseline assessment is needed for ITT, an attrition rate of 2% is 
assumed for the study, which leads to the number of 640 patients (320 per treatment group) to 
be randomized 
As described in Section 7.7.7 a blinded interim analysis with aim of a sample size re-
estimation will be performed after at least 30% of the patients have completed week 18. This 
blinded sample size re-estimation (BSSR) may have an effect on the actual type I error. (see 
Friede T, 2004; Kieser M, 2000). The magnitude of the Type I error increase was investigated 
by performing simulations for the situation with and without BSSR. Results from the 
simulations suggest that the impact of a BSSR on the actual type I error is small. Therefore, a 
Type I error adjustment has not been considered for the sample size estimation. 
It is estimated that approximately 864 screened patients will yield approximately 640 patients 
for 1:1 randomization for having at least 628 evaluable patients, taking in to account the 
attrition rate of 2%. 
7.5 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Intent-to-Treat (ITT) Set: The ITT set will consist of all randomized patients. All analyses 
using the ITT set will group patients according to randomized treatment. The ITT set will be 
used for the efficacy and other analyses. 
Safety Set (SS): The SS will consist of all randomized patients who complete at least one 
dose or partial dose of MYL-1402O or Avastin. All analyses using the SS will group patients 
according to treatment actually received. The SS will be used for the safety analyses and the 
immunogenicity analyses. 

 
Protocol MYL-1402O-3001 
Page 121 of 154 
19 February 2019 
Confidential 
Per Protocol (PP) set: The PP set will consist of all randomized patients who complete at 
least one dose of MYL-1402O or Avastin and do not have protocol deviations having 
significant impact on the (study) endpoints during the study. Major protocol deviations will 
be defined in the SAP. Further exclusions from the PP set due to major protocol deviations 
will be decided in a Blinded Data Review Meeting prior to study unblinding. All analyses 
using the PP set will group patients according to randomized treatment. The PP set will be 
used for the sensitivity analyses of the efficacy endpoints. 
Population PK (PopPK) Set: The PopPK set will consist of all randomized patients who 
complete at least 1 dose of allocated study medication and who provide at least 1 evaluable 
post-dose drug concentration for PopPK analysis. All analyses using the PopPK set will 
group patients according to treatment actually received. 
7.6 
Description of Subgroups to be Analyzed 
The analysis of primary and key secondary endpoints will be done for the following 
subgroups, if applicable: 
• Age (<65 years of age median or ≥65 years of age median) 
• Gender (Male or Female) 
• Race (Caucasian or non-Caucasian; Asian or non-Asian) 
• Smoking status (smoker or <100 cigarettes in entire lifetime) 
• Number of metastasis sites (1 or multiple) 
• Prior weight loss (≥5% from the historical weight during the last 3 months or <5%). 
• Prior radiation therapy (0 or ≥1) 
• Prior adjuvant chemotherapy (0 or 1) 
• ECOG performance scale at screening (0 or 1) 
• EGFR mutation status (unknown or negative) 
• EML4-ALK alterations (unknown or negative) 
Additional subgroups will be detailed in the SAP. 
7.7 
Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.2 or later (SAS Institute, 
Inc., Cary, North Carolina). Continuous variables will be summarized using mean, standard 

 
Protocol MYL-1402O-3001 
Page 122 of 154 
19 February 2019 
Confidential 
deviation, median, minimum and maximum values. Categorical variables will be summarized 
using frequency counts and percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions will be described in the 
SAP. 
The statistical test for the primary efficacy endpoint will be performed using a 5% 
significance level (1-sided), leading to a 90% (2-sided) CI for FDA requirement, while using 
a 2.5% significance level (1-sided), leading to a 95% (2-sided) CI for EMA requirement. 
For the secondary efficacy endpoints, no formal hypothesis testing will be performed. The 
time to event secondary endpoints will be analyzed using log-rank tests. 
No adjustments for multiplicity will be made. 
7.7.1 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is analyzed differently to meet the requirements of the FDA 
(Section 7.7.1.1) and the EMA (Section 7.7.1.2). It is expected that both approaches, will lead 
to congruent conclusions, although the results will be discussed separately for the two 
requirements to a certain extent. Therefore, no adjustment of the type I error is done for the 
primary analysis. 
7.7.1.1 Efficacy Endpoint Analysis to Meet the FDA Requirements 
The overall response rates by independent review up to Week 18 for both MYL-1402O and 
Avastin will be calculated and the ratio of the ORRs will be used to determine if 
MYL-1402O is equivalent to Avastin. A 2-sided 90% CI for the ratio of the ORRs at Week 18 
will be calculated based on the method of logarithmic transformation with no adjustment for 
covariates (Blackwelder 1993). This primary endpoint analysis will be conducted using in the 
ITT set. 
The statistical hypotheses associated with the primary analysis of ORR at Week 18 are as 
follows: 
• H0: (ORRMYL-1402O / ORRAvastin ≤0.73) or (ORRMYL-1402O / ORRAvastin ≥1.36) 
• H1: 0.73 < (ORRMYL-1402O / ORRAvastin <1.36, 
where ORRMYL-1402O and ORRAvastin are the ORRs for MYL-1402O and Avastin, 
respectively. 

 
Protocol MYL-1402O-3001 
Page 123 of 154 
19 February 2019 
Confidential 
The use of a 90% CI to evaluate equivalence is the same as performing two 1-sided tests at 
an alpha level of 0.05 for each test. 
7.7.1.2 Efficacy Endpoint Analysis to Meet the EMA Requirements 
The difference in the ORRs at Week 18 will be evaluated using an unstratified 
Cochran-Mantel-Haenszel (CMH) test. An asymptotic 2-sided 95% CI for the difference in 
ORRs at Week 18 will be calculated. 
The statistical hypotheses associated with the primary analysis of ORR at Week 18 for EMA 
are as follows: 
• H0: (ORRMYL-1402O - ORRAvastin ≤ -12.5%) or (ORRMYL-1402O - ORRAvastin ≥ 12.5%) 
• H1: -12.5% < (ORRMYL-1402O - ORRAvastin) < 12.5%, 
Where ORRMYL-1402O and ORRAvastin are the ORR for MYL-1402O and Avastin, 
respectively. 
In addition, ORRs by PI will also be presented and analyzed using the same methods for the 
ORRs by independent reviewer. 
7.7.2 
Analyses of Secondary Efficacy Endpoints 
Disease control rate will be calculated for each treatment group. The ratio of the DCRs and 
its 90% CI will be estimated using the method of logarithmic transformation with no 
adjustment for covariates. The difference in the DCRs between treatment groups will be 
estimated using an unstratified CMH test and an asymptotic 2-sided 95% CI for the 
difference in DCRs will be also calculated. 
Progression-free survival and OS will be evaluated. Kaplan-Meier plots by treatment will be 
presented. For descriptive purposes, the estimate of the median PFS and OS (in months) will 
be presented along with the p-value from the log-rank test. Survival rates at Weeks 18, 30 and 
42, will be presented along with estimates of the relative risk and associated 95% CI at each 
time point (Brookmeyer 1982). In addition, a Cox regression model will be used to estimate 
the HR and the corresponding 95% CI for the treatment effect. The main Cox PH model will 
have treatment and no covariates. Sensitivity analyses may be performed if necessary with 
covariates added to the main model. In addition, results of analysis of DCR and PFS by PI 
(or designee) will also be presented 

 
Protocol MYL-1402O-3001 
Page 124 of 154 
19 February 2019 
Confidential 
The secondary efficacy endpoints of duration of response and time to response will be 
evaluated using the same statistical analysis methods that were used for the secondary 
endpoints PFS and OS. It is not intended that the study is powered for this secondary 
endpoint to demonstrate bioequivalence, but comparability of the results will be evaluated. 
To comply with differing expectations from FDA and EMA, for all secondary endpoints that 
evaluates ratio, a 90% CI will be used, while a 95% CI will be used when difference is 
evaluated. 
7.7.3 
Population Pharmacokinetic Analyses 
Serum concentrations of bevacizumab will be listed and summarized. 
Population PK methods will be used to compare exposure parameters between treatment 
arms. Population PK analysis will be conducted using NONMEM version 7 or later (ICON 
Solutions, Roche 2017; Beal 2009). 
In accordance with the FDA Guidance for Industry, Population Pharmacokinetics, 
(FDA 1999), in order to enable a timely PopPK analysis, the PopPK analysis dataset will be 
constructed using a real-time data assembly approach. CRF data (e.g., patient demographics, 
lab values, dose administration times, and PK sample collection times) will be assembled in 
analysis dataset format and merged with reported concentration values as they become 
available prior to database lock, but without the treatment assignment. 
Graphical exploration of the concentration compared with time data will be conducted to 
provide visual inspection of the PK profile of MYL-1402O compared with that of Avastin 
and to guide the modelling process. 
Model building will start from published population analyses using a two-compartment 
model. Prior model structure, covariates, and model parameters will be used as Bayesian 
priors to support the analysis to the extent appropriate for the dataset and final model 
structure. 
Consistent with the literature, a 2-compartment linear model will initially be described with 
CL, inter-compartmental clearance, Vc, and volume of the peripheral compartment (Vp). 
Other model adjustments (e.g., target-mediated disposition) may be made if required to 
provide appropriate description of the data. 
Also consistent with the literature, inter-individual variability in CL and Vc will initially be 
assigned with log-normal distribution. Model appropriateness will be evaluated. An attempt 

 
Protocol MYL-1402O-3001 
Page 125 of 154 
19 February 2019 
Confidential 
to add inter-individual variability to additional structural parameters will be explored, but 
may not be feasible based on the sparseness of the data. Residual variability will initially be 
modelled with a constant coefficient of variation model. The inclusion of an additional term 
for additive residual variability will be evaluated. 
Potentially influential covariates will be evaluated using a forward selection followed by 
backward elimination process. The evaluated covariates will be limited to those reported as 
significant in the prior literature, or any other covariate (e.g., other demographic or 
laboratory values, ADA titer levels, or ADA status) for which there is graphical evidence for 
a potentially strong effect. 
First-order conditional estimation method will be used initially for parameter estimation. 
Individual patient empirical Bayesian parameter estimates will be produced for each model 
parameter with inter-individual variability included in the model. Pharmacokinetic 
parameters reflecting exposure to drug (e.g. AUC, Cmax, Cmin, CL, Vc, and the terminal 
elimination half-life) will be reported for each patient. Only descriptive and exploratory 
statistics of each treatment arm will be provided. 
Final population fixed- and random-effect parameter estimates will be presented in tabular 
form with estimates of uncertainty (i.e., standard errors of the estimates), according to the 
most appropriate assumptions retained during model building. 
Full details of the PopPK analysis, including methods for handling data (missing values, 
outliers), will be documented in a PopPK analysis plan, in accordance with FDA guidance. 
7.7.4 
Safety Analyses 
Treatment-emergent AEs and SAEs will be descriptively summarized by system organ class, 
preferred term, and treatment group. Overall, descriptive summaries will be produced along 
with severity and relationship to the IMP. TEAEs will be coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA). 
The ECOG performance status will be summarized for each visit. Shifts from baseline to the 
best and worst post-baseline score may be tabulated. 
Descriptive summaries of observed values and change from baseline will be presented for 
clinical laboratory evaluations (hematology and biochemistry) by treatment group. 
Assessments of laboratory variables according to clinical relevance will be summarized by 
visit and treatment group for each clinical laboratory parameter in frequency tables. 

 
Protocol MYL-1402O-3001 
Page 126 of 154 
19 February 2019 
Confidential 
Additionally, for each laboratory parameter, shifts in value from baseline to all post-baseline 
visits will be presented by treatment arm in shift tables. 
The assessment of categorical urinalysis variables will be summarized by visit for each urine 
parameter by treatment arm (frequency tables). Additionally, for each of the urine parameter, 
shifts in assessments from baseline to all post-baseline visits will be presented for each 
treatment arm (shift tables). 
For vital signs and physical exam data, descriptive summaries of observed values and 
changes from baseline will be presented by visit and treatment group. 
7.7.5 
Immunogenicity Analysis 
The number and percent of patients who are tested positive for ADA until week 42 will be 
provided for each treatment group. In addition, the number of samples that are positive for 
ADA until week 42 for each treatment group will also be provided. 
7.7.6 
Other Analyses 
Summary statistical analyses will be provided for demographics and baseline characteristics, 
medical history, prior and concomitant medications, and risk factor variables at baseline. 
7.7.7 
Interim Analyses 
A blinded sample size re-estimation (BSSR) interim analysis will be conducted when at least 
30% of the required patients have either discontinued early or completed Week 18 on study. 
This interim analysis will be used to estimate the ORR at Week 18 for total sample in the ITT 
analysis. The estimated ORR will be used to perform a BSSR for the primary endpoints 
based on, the risk ratio and difference. Three outcomes for the estimated overall ORR are 
possible  
(1) The ORR in the interim analysis ≤ 36 % 
Then sample size will be re-estimated for the risk ratio and increased up to a 
maximum of 670 patient to maintain the power for testing for FDA requirement 
(2) The ORR in the interim analysis is > 36 % and < 40 % 
Then sample size will be unchanged  
(3) The ORR in the interim analysis ≥ 40 % 

 
Protocol MYL-1402O-3001 
Page 127 of 154 
19 February 2019 
Confidential 
Then sample size will be re-estimated for the risk difference and increased up to a 
maximum of 670 patient to maintain the power for testing for EMA requirement 
Simulations for estimating the actual type I error rate have been performed for the primary 
endpoints of risk ratio and the risk difference for a study conduct with and without sample 
size increase. The impact on actual type I error is small also in the case of a BSSR compared 
to the conduct without a BSSR. The method to adjust the sample size will be detailed in the 
SAP together with results for the simulation of the actual type I error rate. 
7.8 
Data Quality Assurance 
The progress of the study will be monitored by onsite, written, e-mail, and telephone 
communications between personnel at the study center and Mylan GmbH. The PI (or 
designee) will allow Mylan GmbH, monitors, or designee(s) to inspect all: eCRFs; patient 
records (source documents); signed ICF; records of study medication receipt, storage, and 
disposition, and regulatory files related to the study. 
At the time of database lock, the clinical database will be audited in order to ensure accuracy 
of the key variables as well as to provide an estimated error rate for the final, locked 
database. The audit will involve a comparison of CRF values with values from data listings 
generated from the clinical database. Values identified as critical safety and efficacy variables 
will be confirmed for 100% of the patients. In addition, a random sample of patients will be 
selected for which all data values, excluding comment fields, will be checked. The number of 
patients to be randomly reviewed will be determined in order to provide sufficient accuracy 
for the estimated error rate of the clinical database. 
This study will be subject to audit by the sponsor or designee at intervals to ensure that the 
clinical study is conducted and data are generated, documented (recorded), and reported in 
compliance with the study protocol; ICH, Good Clinical Practice (GCP) E6 consolidated 
guidelines; and other applicable regulations. The extent, nature, and frequency of audits will 
be based on such considerations as the study objectives and/or endpoints, the purpose of the 
study, study design complexity and enrolment rate. The sponsor or designee may conduct 
audits on any selected study sites, requiring access to patient notes, study documentation, and 
facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for ethics committees or regulatory 
affairs according to GCP guidelines. The PI (or designee) agrees to cooperate with the auditor 

 
Protocol MYL-1402O-3001 
Page 128 of 154 
19 February 2019 
Confidential 
during the visit and will be available to supply the auditor with eCRF print-outs or other files 
necessary to conduct that audit. Any findings will be strictly confidential. 
If a Regulatory Authority informs the PI (or designee) that it intends to conduct an 
inspection, the PI (or designee) shall notify the sponsor immediately. 
7.8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the PI (or designee) 
agrees to maintain adequate case histories for the patients treated as part of the research under 
this protocol. The PI (or designee) agrees to maintain accurate eCRFs and source 
documentation as part of the case histories. These source documents may include laboratory 
reports, ECG strips. 
PPD will supply the eCRFs. Study center personnel will enter patient data into an electronic 
system for capturing, managing and reporting clinical research data. The analysis data sets 
will be a combination of these data and data from other sources (e.g., laboratory data). 
Clinical data management will be performed in accordance with applicable Mylan GmbH 
standards and data cleaning procedures to ensure the integrity of the data, e.g, removing 
errors and inconsistencies in the data. Adverse events and concomitant medication terms will 
be coded using the MedDRA and WHO Drug Dictionary, respectively. 
After the final database lock, each study site will receive a CD-ROM containing all of their 
center-specific eCRF data as entered into the electronic system for data capture for the study, 
including full discrepancy and audit history. Additionally, a CD-ROM copy of all of the study 
site’s data from the study will be created and sent to Mylan GmbH for storage. PPD will 
maintain a duplicate CD-ROM copy for their records. In all cases, patient initials will not be 
collected or transmitted to the Mylan GmbH. 

 
Protocol MYL-1402O-3001 
Page 129 of 154 
19 February 2019 
Confidential 
8 Ethics 
8.1 
Independent Ethics Committee or Institutional Review Board 
Government regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC before participation of human patients in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study l patients, 
and any other written information regarding this study to be provided to the patient or the 
patient’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6 (R2): 
GCP will be maintained by the site and will be available for review by the sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The PI (or designee) is responsible for providing written summaries of the progress and 
status of the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. 
The PI (or designee) must promptly supply the sponsor or its designee, the IRB/IEC, and, 
where applicable, the institution, with written reports on any changes significantly affecting 
the conduct of the study or increasing the risk to patients. 
8.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
8.3 
Patient Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50, ICH E6 (R2) guidelines, and local regulations as appropriate, shall be 
obtained from each patient before entering the study or performing any unusual or non-
routine procedure that involves risk to the patient. An informed consent template may be 
provided by the sponsor to investigative sites. If any institution-specific modifications to 
study-related procedures are proposed or made by the site, the consent should be reviewed by 
the sponsor or its designee or both before IRB/IEC submission. Once reviewed, the consent 
will be submitted by the PI to his or her IRB/IEC for review and approval before the start of 
the study. If the ICF is revised during the course of the study, all active participating patients 
must sign the revised form. 

 
Protocol MYL-1402O-3001 
Page 130 of 154 
19 February 2019 
Confidential 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the PI 
(or designee) is assured that the patient/legal guardian understands the implications of 
participating in the study, the patient/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The PI (or designee) shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient or legal guardian. 

 
Protocol MYL-1402O-3001 
Page 131 of 154 
19 February 2019 
Confidential 
9 Principal Investigator’s Obligations 
The following administrative items are meant to guide the PI in the conduct of the study but 
may be subject to change based on industry and government standard operating procedures, 
working practice documents, or guidelines. Changes will be reported to the IRB/IEC but will 
not result in protocol amendments. 
9.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the patient (or the patient’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, regulatory authorities or the IRB/IEC. 
The PI (or designee) and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 
Financial Disclosure and Obligations 
The PI (or designees) are required to provide financial disclosure information to allow the 
sponsor to submit the complete and accurate certification or disclosure statements required 
under 21 CFR 54. In addition, the PI (or designee) must provide to the sponsor a commitment 
to promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the patient’s disease. 
9.3 
Investigator Documentation 
Prior to beginning the study, the PI (or designee) will be asked to comply with ICH E6 
(R2) 8.2 and Title 21 of the CFR by providing the following essential documents, including 
but not limited to: 
• IRB/IEC approval 

 
Protocol MYL-1402O-3001 
Page 132 of 154 
19 February 2019 
Confidential 
• Original PI-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
• Curriculum vitae for the PI and each subinvestigator listed on Form FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the PIs must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the patient or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the 
site, in accordance with 42 CFR 493 
9.4 
Study Conduct 
The PI agrees that the study will be conducted according to the principles of ICH E6 (R1). 
The PI (or designee) will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of patients begins. 
9.5 
Adherence to Protocol 
The PI agrees to conduct the study as outlined in this protocol in accordance with ICH E6 
(R1) and all applicable guidelines and regulations. 
9.6 
Adverse Events and Study Report Requirements 
By participating in this study the PI agrees to submit reports of SAEs according to the time 
line and method outlined in the protocol. In addition, the PI agrees to submit annual reports 
to the study site IRB/IEC as appropriate. 
9.7 
Investigator’s Final Report 
Upon completion of the study, the PI, where applicable will provide the IRB/IEC with a 
summary of the study’s outcome and the sponsor and regulatory authority(ies) with any 
reports required. 

 
Protocol MYL-1402O-3001 
Page 133 of 154 
19 February 2019 
Confidential 
9.8 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the PI/institution 
as to when these documents no longer need to be retained. 
9.8.1 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the PIs to determine how the manuscript is 
written and edited, the number and order of authors, the publication to which it will be 
submitted, and other related issues. The sponsor has final approval authority over all such 
issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 

 
Protocol MYL-1402O-3001 
Page 134 of 154 
19 February 2019 
Confidential 
10 Study Management 
The administrative structure will include an external Steering Committee and a DSMB. 
10.1 Monitoring 
10.1.1 
External Steering Committee 
An External Steering Committee will be established to review safety and medical issues to 
collaborate on medical expert decisions. The details will be described in the charter and will 
include responsibilities, membership, and meeting frequency and structure. 
10.1.2 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board details will be described in the charter and will 
include responsibilities, membership, and meeting frequency and structure. 
10.1.3 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the PI and study site at periodic intervals, in 
addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the PI and personnel. 
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between them for critical data. All entries, corrections, and alterations are to be 
made by the responsible PI or his or her designee. The monitor cannot enter data in the eCRF. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
10.1.4 
Inspection of Records 
The PIs and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In 
the event of an audit, the PI agrees to allow the sponsor, representatives of the sponsor, or a 
regulatory agency (e.g, FDA or other regulatory agency) access to all study records. 

 
Protocol MYL-1402O-3001 
Page 135 of 154 
19 February 2019 
Confidential 
The PI should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the PI’s IRB/IEC for 
approval before patients can be enrolled into an amended protocol. 
10.2.2 
Protocol Deviations 
The PI or designee must document and explain in the patient’s source documentation any 
deviation from the approved protocol. The PI may implement a deviation from, or a change 
of, the protocol to eliminate an immediate hazard to study patients without prior IRB/IEC 
approval. As soon as possible after such an occurrence, the implemented deviation or change, 
the reasons for it, and any proposed protocol amendments should be submitted to the 
IRB/IEC for review and approval, to the sponsor for agreement, and to the regulatory 
authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the PI. A 
significant deviation occurs when there is nonadherence to the protocol by the patient or PI 
that results in a significant, additional risk to the patient. Significant deviations can include 
nonadherence to inclusion or exclusion criteria, enrollment of the patient without prior 
sponsor approval, or nonadherence to FDA regulations or ICH GCP guidelines, and will lead 
to the patient being withdrawn from the study (Section 3.5, Section 4.3). 
Protocol deviations will be observed throughout the course of monitoring visits. Principal 
investigators will be notified by the monitor of deviations and they need to be documented. 
The IRB/IEC should be notified by the site of all protocol deviations in a timely manner. 
10.3 Study Termination 
Although Mylan GmbH has every intention of completing the study, Mylan GmbH reserves 
the right to discontinue the trial at any time for clinical or administrative reasons. 

 
Protocol MYL-1402O-3001 
Page 136 of 154 
19 February 2019 
Confidential 
The end of the study is defined as the time when all patients have completed at least 
15 months after the randomization of the last patient, 250 death events are recorded, all 
patients have discontinued the study, or administrative end of the study, whichever occurs 
first. 
10.4 Interim and Final Clinical Study Report 
An interim clinical study report will be written at the time of the 18 week assessment and an 
addendum as the final clinical study report will be written at the EOS with all final data 
included. 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, a PI signatory will be identified for 
the approval of the clinical study report. The PI will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the clinical study report, the sponsor will provide the PI with the full 
summary of the study results. The PI is encouraged to share the summary results with the 
study patients, as appropriate. The study results will be posted on publicly available clinical 
trial registers. 

 
Protocol MYL-1402O-3001 
Page 137 of 154 
19 February 2019 
Confidential 
11 Reference List 
AHA 1994: The Criteria Committee of the New York Heart Association. (1994). 
Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. (9th ed.). 
Boston: Little, Brown & Co. pp. 253–256. 
Avastin (bevacizumab) [package insert]. Genentech, Inc. South San Francisco, CA; 2017.  
Beal S, Sheiner LB, Boeckmann A, Bauer, RJ, NONMEM User's Guides. (1989-2009), Icon 
Development Solutions, Ellicott City, MD, USA, 2009. 
Blackwelder W.C. (1993). "Sample size and Power for prospective analysis of relative risk", 
Statistics in Medicine, 12: 691-698. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38: 29-41. 
ClinicalTrials.gov [Internet]. US National Library of Medicine. Identifier NCT02272413. 
Boehringer Ingelheim. Phase III Trial BI 695502 Plus Chemotherapy vs. Avastin® Plus 
Chemotherapy in Patients with Lung Cancer [cited April 04, 2018]; Available from: 
https://clinicaltrials.gov/ct2/show/NCT02272413 
ClinicalTrials.gov [Internet]. US National Library of Medicine. Identifier NCT02754882. 
Samsung Bioepis Co., Ltd. A Study Comparing SB8 and Avastin® in Patients with 
Advanced Non-squamous Non-small Cell Lung Cancer [cited April 04, 2018]; Available 
from: https://clinicaltrials.gov/ct2/show/NCT02754882 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron.1976; 16(1):31-41. Department of Health and Human Services (DHHS), Food and 
Drug Administration, Center for Drug Evaluation and Research and Center for Biologics 
Evaluation and Research (US). Guidance for Industry, Population Pharmacokinetics. 
February, 1999. 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research and Center for Biologics Evaluation and Research (US). 
Guidance for industry: Population pharmacokinetics. February 1999. [35 screens]. Available 
from: 
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UC
M133184.pdf 

 
Protocol MYL-1402O-3001 
Page 138 of 154 
19 February 2019 
Confidential 
Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The Eighth Edition Lung Cancer Stage 
Classification. Chest. 2017 Jan;151(1):193-203. 
Eillis, RE. The distribution of active bone marrow in the adult. Phys Med Biol 1961; 
5(3):255-8. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Euro J Cancer. 2009;45(2):228-47. 
Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, Garrett-Mayer E, Herbst 
RS, Lilenbaum RC, Sima C, Venook AP, Gonen M, Schilsky RL, Meropol NJ, Schnipper LE. 
American Society of Clinical Oncology perspective: Raising the bar for clinical trials by 
defining clinically meaningful outcomes. J Clin Oncol. 2014 Apr 20;32(12):1277-80.  
Friede T, Kieser M. Sample size recalculation for binary data in internal pilot study designs. 
Pharmaceutical Statistics 2004; 3:269-279. 
Globocan 2012. Estimated cancer incidence, mortality, prevalence, and disability-adjusted 
life years (DALYs) worldwide in 2012. International Agency for Research on Cancer. WHO. 
Available from: http://globocan.iarc.fr/. American Cancer Society Inc. Cancer Facts & 
Figures 2012. Available from: 
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc 044738.pdf 
He K, Chen H, Gwise T. Statistical Considerations in Evaluating a Biosimilar Product in an 
Oncology Clinical Study. Clin Cancer Res. 2016; 22: 5167-5170 
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in 
previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 
2004; 22(11):2184-91. 
Kieser M, Friede T. Recalculating the sample size in internal pilot study designs with control 
of the type I error rate. Statistics in Medicine 2000; 19:901-911. 
Lu JF, Bruno R, Eppler S, et al. Clinical pharmacokinetics of bevacizumab in patients with 
solid tumors. Cancer Chemother Pharmacol. 2008; 62:779–786. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987; 
317(17):1098. 
Mylan Biologics Switzerland. MYL 1402O. Investigator’s brochure, Edition 3.0. Zurich; 
2017. 

 
Protocol MYL-1402O-3001 
Page 139 of 154 
19 February 2019 
Confidential 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN 
Guidelines). Non-small cell lung cancer. Version 2.2018 
Niho S, Kunitoh H, Nokihara H, et al; JO19907 Study Group. Randomized phase II study of 
first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with 
advanced non-squamous non-small-cell lung cancer. Lung Cancer. 2012; 76(3):362-7. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 
Paraplatin (carboplatin) [package insert], Bristol-Myers Squibb Company, Princeton, (NJ); 
2010. 21 p. 
Reck M, von Pawel J, Zatloukal P, et al; BO17704 Study Group. Overall survival with 
cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous 
non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 
2010; 21(9):1804-9. 
Roche 2017: Avastin (bevacizumab) [package insert]. Roche Registration Ltd. Welwyn 
Garden City, United Kingdom; 2017 [last updated 27 July 2017]. Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000582/hu
man_med_000663.jsp&mid=WC0b01ac058001d124 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for 
non-small-cell lung cancer. N Engl J Med. 2006; 355(24):2542-50. 
Soria JC, Mauguen A, Reck M, et al; meta-analysis of bevacizumab in advanced NSCLC 
collaborative group. Systematic review and meta-analysis of randomised, phase II/III trials 
adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with 
advanced non-small-cell lung cancer. Ann Oncol. 2013; 24(1):20-30. 
Taxol (paclitaxel) [package insert] Bristol-Myers Squibb Company, Princeton, NJ; 2011, 
53 p. 
Zhou C, Wu YL, Chen G, et al. BEYOND: A randomized, double-blind, placebo-controlled, 
multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo 
in Chinese patients with advanced or recurrent nonsquamous non–small-cell lung cancer. 
J Clin Oncol. 2015; 33(19):2197-2204. 
 

 
Protocol MYL-1402O-3001 
Page 140 of 154 
19 February 2019 
Confidential 
12 Appendices 
12.1 Appendix A: Tumor Assessment According to RECIST Criteria Version 1.1 
(Eisenhauer 2009) 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter in the plane of measurement to be recorded) as ≥10 mm with CT 
or MRI scan (using a slice thickness no greater than 5 mm), ≥10 mm caliper measurement by 
clinical examination, or ≥20 mm by chest x-ray. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in 
short axis when assessed by CT or MRI scan (scan slice thickness recommended to be no 
greater than 5 mm). 
Ultrasound: Ultrasound should not be used to assess tumor lesions. The same holds true for 
endoscopy or laparoscopy. 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm), are 
considered non-measurable disease. Bone lesions (without measurable soft tissue by CT scan 
or MRI), CNS and leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis pulmonis, abdominal masses, skin (without tumoral lesion measurable by 
CTscan) and cystic lesions are all non-measurable. 
Clinical lesions: Clinical lesions will only be considered as lesions when they are superficial 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules and palpable lymph 
nodes). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. Skin and palpable lesions are to be assessed 
as non-measurable non-target disease (without tumoral lesion measurable by CT scan). 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ (bilateral organs are 
considered as one organ: left kidney + right kidney = kidney) and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 

 
Protocol MYL-1402O-3001 
Page 141 of 154 
19 February 2019 
Confidential 
imaging techniques or clinically). A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter. The baseline sum longest 
diameter will be used as reference by which to characterize the objective tumor response. 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as nonmeasurable 
lesions. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. Bone lesions need to be followed by CT scan or X-
Rays 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node 
must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study with at least a 5 mm absolute increase 
in the sum of all lesions. The appearance of one or more new lesions* denotes disease 
progression. 
Stable Disease (SD): Neither sufficient nor shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target 
lesions and/or maintenance of tumor marker level above the normal limits. 

 
Protocol MYL-1402O-3001 
Page 142 of 154 
19 February 2019 
Confidential 
Progressive Disease (PD): Substantial, unequivocal progression of existing non-target 
lesions. 
Evaluation of Overall Response at week 18 
In this study the overall response at week 18 is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the treatment started). The participant's overall 
response at 18 weeks assignment will depend on the achievement of both measurement and 
confirmation criteria (for additional sensitivity analysis of ORR) based on assessment every 
6 weeks (Table 12-2). The overall response for all combination of tumor responses (target 
and non-target lesions) with and without appearance of new lesion is given in Table 12-1. 
Table 12-1 
Overall Responses for Target and Non-Target Lesions With and Without 
the Appearance of New Lesions 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
non-PD or not all 
evaluated 
no 
PR 
SD 
non-PD or not all 
evaluated 
no 
SD 
Not all evaluated 
Non-PD 
no 
NE 
PD 
Any 
yes or no 
PD 
Any 
PD 
yes or no 
PD 
Any 
Any 
yes 
PD 
Abbreviations CR=complete response; PR=partial response; NE=nonevaluable; SD=stable disease; 
PD=progressive disease. 
 

 
Protocol MYL-1402O-3001 
Page 143 of 154 
19 February 2019 
Confidential 
Table 12-2 
Best Overall Response at 18 weeks with Confirmed Assessment at 
subsequent Time Point  
Overall Response 
any Time Point 
during the first 18 
weeks of treatment 
Overall Response 
Subsequent Time Point 
 Overall Response at 18 weeksb,c 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for 
SD duration met; otherwise, PD 
CR 
PD 
SD provided minimum criteria for 
SD duration met; otherwise, PD 
CR 
NE 
SD provided minimum criteria for 
SD duration met; otherwise, NE 
PR 
CR 
PR or CR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration met; otherwise, PD 
PR 
NE 
SD provided minimum criteria for 
SD duration met; otherwise, NE 
NE 
NE 
NE 
Abbreviations CR=complete response; PR=partial response; NE=nonevaluable; SD=stable disease; 
PD=progressive disease; BOR=best overall response. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met, i.e., 6 weeks. However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
b Best Overall Response, with confirmed assessment, is done as part of the sensitivity analysis 
c In cases, when a response is observed first time at week 18 a confirmation of imaging scan may be scheduled 
after week 18 

 
Protocol MYL-1402O-3001 
Page 144 of 154 
19 February 2019 
Confidential 
12.2 1Appendix B  
Eastern Cooperative Oncology Group Performance Status 
Grade 
ECOG Performance Status  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair 
5 
Dead 
Source: Oken et al 1982; available at http://ecog-acrin.org/resources/ecog-performance-status 
 
 

 
Protocol MYL-1402O-3001 
Page 145 of 154 
19 February 2019 
Confidential 
12.3 Appendix C 
 
Bone Marrow 
Table 12-3 
Distribution of Bone Marrow (by Weighing Cadaveric Bones) 
Site 
% Total Red Marrow 
Pelvis (made up of) 
40.0 
 Pelvic bones 
22.3 
 Sacrum 
13.6 
 Femoral head/neck 
3.8 
Thoracic spine 
14.1 
Lumbar spine 
10.9 
Head 
13.1 
Upper limb girdle (made up of) 
8.3 
 Scapulae 
4.8 
 Humeri 
1.9 
 Clavicles 
1.5 
Ribs 
7.9 
Cervical spine 
3.4 
Sternum 
2.3 
Source: Eillis, RE. The distribution of active bone marrow in the adult. Phys Med Biol 1961; 5(3):255-88. 
 
 

 
Protocol MYL-1402O-3001 
Page 146 of 154 
19 February 2019 
Confidential 
12.4 Appendix D 
 
Creatinine Clearance Calculations using Cockcroft and 
Gault Formula 
For the calculation of the carboplatin dose: 
Calvert Formula 
Total Carboplatin Dose (mg) = (target AUC) × (GFR + 25) 
Calvert Formula Worksheet 
You Need: 
• Patient age: _______ 
• Patient weight in Kg: ________ 
• Male or Female: _______ 
• Serum Creatinine: _________ 
• AUC (6 or 5): _______ 
 
{140 – (patient age)} × (patient weight in kg) (× 0.85 in 
women) 
 = GFR  
Cockcroft & 
Gault Method 
72 × (serum creatinine) 
 
(Can use Creatinine Clearance for GFR) 
(GFR + 25) × AUC = dose in mg 
 

 
Protocol MYL-1402O-3001 
Page 147 of 154 
19 February 2019 
Confidential 
12.5 Appendix E 
 
Calculation of Paclitaxel Dose using Montseller Formula 
and based on Body Surface Area 
For the calculation of the paclitaxel dose, the Mosteller formula (Mosteller 1987) equation is 
to be used to calculate the patient’s body surface area (BSA) where BSA is in m2, W is weight 
in kg, and H is height in cm (the dose does not need to be modified, if the change in weight is 
<10% from the prior calculation): 
 
or if height is in m: 
 
 

 
Protocol MYL-1402O-3001 
Page 148 of 154 
19 February 2019  
 
Confidential 
12.6 Appendix F: Bioanalytical Blood Sampling Collection Summary for 
Immunogenicity, Pharmacokinetics, and Safety Samples 
Blood samples will be collected for analyses of immunogenicity, PK, and Safety and a 
summary of the total blood draw at each time point is summarized in Table 12-4. 
 

 
Protocol MYL-1402O-3001 
Page 149 of 154 
19 February 2019 
 
Confidential 
Table 12-4 
Summary of Blood Sampling by Time Point 
Period 
Time Point 
Immunogenicity 
Samplesa 
Pharmacokinetics 
Samplesa 
Safety Samples 
Total 
Amount 
Number 
of Tubes 
Screening 
Screeningb 
 
 
2 × 5 mLb; 1 × 5 mLc 
15 mL 
3 
Baseline, if possible within 1 
hour prior of Day 0 of Cycle 1 
dose 
6 × 5 mL predosea 
1 × 5 mL predosea, 
2 × 5 mL within 24 hrs. 
predosee 
45 mL 
9 
Period 1 
Cycle 1 
 
1 × 5 mL postdosed  
 
5 mL 
1 
Cycle 2 
4 × 5 mL predosea 
1 × 5 mL predosea, 
1 × 5 mL postdosed 
2 × 5 mL within 72 hrs. 
predosee 
40 mL 
8 
Cycle 3 
 
1 × 5 mL predosed 
2 × 5 mL within 72 hrs. 
predosee 
15 mL 
3 
Cycle 4 
4 × 5 mL predosea 
1 × 5 mL predosea, 
1 × 5 mL postdosed 
2 × 5 mL within 72 hrs 
predosee 
40 mL 
8 
Cycle 5 
 
1 × 5 mL predosed 
2 × 5 mL within 72 hrs 
predosee 
15 mL 
3 
Cycle 6 
4 × 5 mL predosea 
1 × 5 mL predosea, 
1 × 5 mL postdosed 
2 × 5 mL within 72 hrs. 
predosee 
40 mL 
8 
Any cycle: Day 3 through Day 
8 
 
1 × 5 mL f 
 
5 mL 
1 
Any cycle: Day 10 and Day 18 
 
1 × 5 mL f 
 
5 mL 
1 
Period 2 
Cycle 704  
4 × 5 mL predosea 
1 × 5 mL predosea 
2 × 5 mL within 72 hrs. 
predosee 
35 mL 
7 
Cycle 708  
4 × 5 mL predosea 
1 × 5 mL predosea 
2 × 5 mL within 72 hrs. 
predosee 
35 mL 
7 
Unplanned 
Hypersensitivity Reactiong 
4 × 5 mL predosea 
1 × 5 mL predosea 
 
25 mL 
5 
Safety 
Follow-Up 
visith 
Safety Follow-Up visit/End of 
Treatment Visit 
4 × 5 mL  
1 × 5 mL 
2 × 5 mL 
35 mL 
7 

 
Protocol MYL-1402O-3001 
Page 150 of 154 
19 February 2019 
 
Confidential 
a 
Immunogenicity and pharmacokinetic predose samples should be collected at the same timepoint. If possible, predose samples should be collected 
within 1 hour prior to dosing. 
b 
Two samples will be collected at Screening as part of evaluation of hematology and chemistry inclusion/exclusion criteria. 
c 
Female patients that are of child bearing potential will have a serum pregnancy test conducted during screening. 
d 
Postdose blood draws should occur < 15 minutes after dosing. 
e 
Predose for safety samples for Cycle 1 should be within 24 hours prior to dosing. However, if the safety screening lab was done during the last 7 days 
prior the first dose it would not be necessary to repeat it. Predose for safety samples for Cycle 2 onwards should be within 72 hours prior to dosing. 
f 
Two additional samples collected for pharmacokinetics: One sample will be collected between Day 3 and Day 8 (inclusive) in any cycle, and 1 sample 
should be collected between Day 10 and Day 18 (inclusive) in any cycle. 
g 
In the event of a hypersensitivity reaction, immunogenicity sample and PK sample should be drawn as quickly as possible after the reaction occurs. 
h 
Safety follow-up visit samples to be collected ≤28 days ±7 days after bevacizumab discontinuation. 
 
 
 
 
 
 
 
 

 
Protocol MYL-1402O-3001 
Page 151 of 154 
19 February 2019  
 
Confidential 
12.7 Appendix G: Initial Disease Diagnosis 
Disease Stage at Initial Disease Diagnosis 
TNM staging as per AJCC 8th Edition Classification along with Diagrams (Detterbeck et al 
2017).  
Table 12-5 
Definitions for T, N, and M Descriptors 
T (Primary Tumor) 
Label 
T0 
No Primary Tumor 
 
Tis 
Carcinoma in situ (Squamous or Adenocarcinoma) 
Tis 
T1 
Tumor≤3 cm, 
 
T1a 
(mi) 
Minimally Invasive adenocarcinoma 
T1a (mi) 
T1a 
Superficial Spreading tumor in central Airwaysa 
T1ass 
T1a 
Tumor≤1 cm 
T1a≤1 
T1b 
Tumor>1 but ≤2 cm 
T1b>1-2 
T1c 
Tumor>2 but ≤3 cm 
T1c>2-3 
T2 
Tumor >3 but ≤5 cm or tumor involving: 
Visceral Pleurab 
main bronchus (not carina), atelectasis to hilumb 
 
T2Visc Pl 
T2Centr 
T2a 
Tumor >3 but ≤4 cm 
T2a>3-4 
T2b 
Tumor >4 but ≤5 cm 
T2b>4-5 
T3 
Tumor >5 but ≤7 cm 
Or Invading chest wall, pericardium, phrenic nerve,  
Or separate tumor nodule(s) in the same lobe 
T3 >5-7 
T3 Inv 
T3 Satell 
T4 
Tumor >7 
Or tumor Invading; mediastinum, diaphragm, heart, great 
vessels, recurrent laryngeal nerve, carina, trachea, esophagus 
spine; 
Or tumor Nodule(s) in the different Ipsilateral lobe 
T4>7 
T4 Inv 
 
T4 Nod Ipsi 
N (Regional Lymph Nodes) 
 
N0 
No regional node metastasis  
 
N1 
Metastasis in ipsilateral pulmonary or hilar nodes  
 
N2 
Metastasis in ipsilateral mediastinal/subcarinal nodes 
 

 
Protocol MYL-1402O-3001 
Page 152 of 154 
19 February 2019  
 
Confidential 
N3 
Metastasis in contralateral mediastinal/hilar, or 
supraclavicular nodes 
 
M (Distant Metastasis) 
 
M0 
No distant Metastasis 
 
M1a 
Malignant pleural/ pericardial effusioncor pleural/ pericardial 
nodules 
Or separate tumor Nodule(s) in a Contralateral lobe 
M1a  
 
M1a Contra 
Nod 
M1b 
Single extrathoracic metastasis 
M1bSingle 
M1c 
Multiple extrathoracic metastasis (1 or >1organ) 
M1cMulti 
 
 
 
TX, NX, T or N status not able to be assessed 
 
a Superficial spread of tumor(s), of any size AND confined to the tracheal and/or bronchial wall  
b T2a classification if >3 ≤4cm, T2b classification if >4 ≤5cm. 
c Pleural effusion(s) must have positive (malignant) cytology to be considered M1a. 
Table 12-6 
Lung Cancer Stage Grouping (Eighth Edition) 
STAGE 
T 
N 
M 
Occult 
TX 
NO 
MO 
O 
Tis 
NO 
MO 
IA1 
T1a (mi)/T1a  
NO 
MO 
IA2 
T1b 
NO 
MO 
IA3 
T1c 
NO 
MO 
IB 
T2a 
NO 
MO 
IIA 
T2b 
NO 
MO 
IIB 
T1a - T2b 
N1 
MO 
 
T3 
NO 
MO 
IIIA 
T1a - T2b 
N2 
MO 
 
T3 
N1 
MO 
 
T4 
NO/ N1 
MO 
IIIB 
T1a - T2b 
N3 
MO 
 
T3/ T4 
N2 
MO 
IIIC 
T3/ T4 
N3 
MO 
IVA 
Any T 
Any N 
M1a/M1b  
IVB 
Any T 
Any N 
M1c 

 
Protocol MYL-1402O-3001 
Page 153 of 154 
19 February 2019  
 
Confidential 
 
 
M1A - Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial 
nodules or malignant pleural or pericardial effusion 
M1B - Single extra thoracic metastasis in a single organ 
(M1A and M1B will be stratified as one metastatic site in IXRS) 
M1C - Multiple extra thoracic metastases in one or several organs 
(M1C will be stratified as multiple metastatic sites in IXRS) 

 
Protocol MYL-1402O-3001 
Page 154 of 154 
19 February 2019  
 
Confidential 
 
Important Points: 
• If multiple ribs are involved then staging will be considered as M1C. If ribs are part 
of an encroaching lesion, then staging will be considered M1B. 
• Even if there are multiple lesions in the contralateral (opposite) lung, staging will be 
classified as M1A. 
• For pleural and/or pericardial effusions without any other metastatic lesion(s): In 
order to be considered metastatic disease; effusions must have a confirmatory 
pathology report (cytology) confirming malignancy. Confirmed malignant effusions 
w/o any other metastatic lesion will be classified as M1A.