Clinical trial NCT02364999
Conditions: Non-Small Cell Lung Cancer
Sponsor: Pfizer
Start date: 2015-04-01; Completion date: 2017-12-01
Enrollment: 719 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

Detailed description:

Arms: arm 1: Bevacizumab-Pfizer plus paclitaxel and carboplatin arm 2: Bevacizumab-EU plus paclitaxel and carboplatin
Interventions: intervention 1: Bevacizumab-Pfizer intervention 2: Bevacizumab-EU intervention 3: Paclitaxel intervention 4: Carboplatin
Intervention descriptions: intervention 1: Bevacizumab-Pfizer: 15 mg/kg IV on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles, followed by the assigned blinded bevacizumab monotherapy. intervention 2: bevacizumab-EU: 15 mg/kg IV on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles followed by the assigned blinded bevacizumab monotherapy. intervention 3: Paclitaxel 200 mg/m2 via IV infusions on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles. intervention 4: carboplatin AUC =6.0 via IV infusions on Day 1 of a 21-day cyclefor each of at least 4 and no more than six (6) 21-day cycles.

Protocol documents:
Prot_001.pdf: 
PF-06439535
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF PF-06439535 PLUS 
PACLITAXEL-CARBOPLATIN AND BEVACIZUMAB PLUS 
PACLITAXEL-CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF 
PATIENTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG 
CANCER
Compound:
PF-06439535
Compound Name:
Not Applicable
United States (US) Investigational New 
Drug (IND) Number:
117,038
European Clinical Trials Database 
(EudraCT) Number:
2014-003878-16
Protocol Number:
B7391003
Phase:
3


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Document History
Document
Version Date
Summary of Changes
Amendment 3
10 June 2016

For European Union (EU) change primary 
analysis from risk ratio (RR) to risk 
difference (RD) per Committee for Medicinal 
Products for Human Use (CHMP) request

Schedule of activities (SoA) Table 1 and 
Table 2 merged to clarify treatment periods 
and required procedures, remove 
redundancies and streamline text by referring 
to specific protocol sections rather than 
repeating instructions

Bevacizumab background and adverse event 
profile updated to reflect recent updates to 
Investigator Brochure based on updated 
prescribing information

Inclusion criterion 2: clarify criterion for 
intended study population

Inclusion criterion 6: window around 
baseline scan removed; specified in SoA

Inclusion criterion 8: addition of plasma 
creatinine and UPC ratio

Inclusion criterion 13: postmenopausal 
language revised per protocol template

Exclusion criterion 3: added language that 
was previously in body of protocol, to require 
review of mutation testing results prior to 
randomization, if testing is performed

Exclusion criterion 5: clarified language to 
exclude prior systemic therapy except prior 
neoadjuvant or adjuvant therapy if 
accompanied by surgery

Exclusion criterion 6: reduced window for 
prior radiotherapy from 4 weeks to 2 weeks 


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
Exclusion criterion 7: clarify allowed 
anticoagulation/NSAID therapy

Exclusion criterion 10: radiotherapy removed 
since previously addressed in exclusion 
criterion 6

Exclusion criterion 12: language revised to 
exclude active infections and remove window 
for prior anti-infective agents

Exclusion criterion 15: language added to 
define and allow treated and stable brain 
metastases 

Exclusion criterion 19: contraception 
language removed as previously stated in 
inclusion criterion 13.

Exclusion criterion 21: clarification to 
exclude active hepatitis B and C infection 
instead of past infection

Exclusion criterion 25: added prior 
immunotherapy and bevacizumab

Remove language regarding investigator’s
judgment in the following criterion:
exclusion criteria 2 (tumor involving major 
blood vessels): “in the opinion of the 
investigator”; 13 (comorbidities) “as per the 
investigator’s discretion”; 21 (hepatitis 
infection) “based on investigator clinical 
judgment” 

Addition of time window for protocol 
required testing (Screening); clarification of 
timeframe for vital sign (within 30 minutes)
and randomization (no more than 1 day prior 
to Day 1) 

Clarification of head CT/MRI requirement at 
time of confirmation scan

Inclusion of ECG in SOA as separate 
footnote that was previously inadvertently 


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omitted

Removal of redundancy around birth control 
requirements for female partners of study 
subjects to reflect updated protocol template 
language

Clarifications to bevacizumab dose 
adjustment guidelines/ Table 3

Drug administration and dosing section 
added to clarify dose calculations and dosing 
algorithms for all three study drugs, including 
threshold for protocol deviations

Carboplatin: clarify formulas used to 
calculate the dose

Concomitant medications: language added to 
allow use of bisphosphonates and 
Rank-Ligand inhibitors (previously stated in 
eligibility section)

Update of footnotes, references, template 
updates and typographical or clerical errors

Removal of redundancies to improve 
readability, address discrepancies among 
redundant sections, and to provide more 
clarity.

Clarification of enrollment, secondary
endpoints, last subject last visit, end of 
treatment, and end of trial 

Inclusion of wording for early unblinding for 
PK per sponsor requirement

Appendix 3 – Tumor staging added for 
reference
Amendment 2
06 July 2015
Changes incorporate feedback from investigators, 
regulatory agencies, and protocol template updates:

Clarification of Study Design language.


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
Update to global sample size, statistical 
considerations, and addition of Japan specific 
statistical analysis.

Removal of HBsAb test from SOA and 
protocol body.

Changed 5% to 10% throughout protocol 
regarding bevacizumab dose reductions due 
to change in weight.

Change of Partial Thromboplastin Time to 
Activated Partial Thromboplastin Time in 
SOA and protocol body.

Clarification of disease sites for tumor 
assessments in SOA and protocol body.

Clarification of mutation testing language.

Addition of reference to eligibility form to 
SOA Randomization section and protocol 
body.

SOA footnote #18 addition of dose delay 
language.

Clarification of survival follow-up language 
in SOA and protocol body.

Clarification of disease sites for CT and MRI 
throughout protocol.

Addition of clarification ‘based on 
investigator clinical judgment’ to exclusion 
criteria 21.

Addition of platinum-resistant recurrent 
epithelial ovarian, fallopian tube or primary 
peritoneal cancer, in combination with 
paclitaxel and carboplatin, pegylated 
liposomal doxorubicin or topotecan, to 
bevacizumab US indications per update to 
USPI in November 2014. 


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
Simplification of injection site information.

Addition of maximum allowed doses for 
carboplatin.

Clarification of inclusion criteria #6.

Clarification of exclusion criteria #2.

Clarification of exclusion criteria #15.

Addition of exclusion criteria regarding local 
radiation for painful bone metastases within 
the past 4 weeks.

Addition of inclusion criteria to require that 
patients be eligible to receive study treatment 
of bevacizumab, paclitaxel, and carboplatin 
for the treatment of advanced or metastatic 
non-squamous NSCLC.

Clarification of dosing, dose reduction, 
missed doses, and administration language.

Addition of instructions for bevacizumab 
preparation and administration for patients 
>110 kg.

Per standard of care, removal of 60-minute 
wait time following completion of paclitaxel, 
and clarification of carboplatin 
administration time.

Addition of toxicity information.

Addition of required discontinuation of 
bevacizumab due to severe or life threatening 
infusion reaction that is considered to be 
secondary to bevacizumab and not paclitaxel 
and/or carboplatin.

Table 3 clarification of congestive heart 
failure and infusion related reaction 
guidelines.

Clarification of Section 5.8 immunizations.


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
Addition of information on measurable 
lesions.

Removal of bone scan language.

Addition of blood sample collection time 
points for ADA/NAb and corresponding drug 
concentrations, as well as the plan to analyze 
the samples, according to the Scientific 
Advice from the EMA.

Clarification of population PK data analysis.

Update of document references.

Update of newly required sponsor template 
language and typographical or clerical errors.
Amendment 
1 (distributed 
to EU 
Voluntary 
Harmonizatio
n Process 
participating 
countries 
only)
05 May 2015

Addition of inclusion criteria to require that 
patients be eligible to receive study treatment 
of bevacizumab, paclitaxel, and carboplatin 
for the treatment of advanced or metastatic 
non-squamous NSCLC.

Clarification of mutation testing language.

Clarification of survival follow-up language.

Clarification of bevacizumab dose 
reductions.

Table 3 clarification of congestive heart 
failure and infusion related reaction 
guidelines.
Original 
protocol
04 November 2014
Not Applicable
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 


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Abbreviations
Abbreviation
Term
ADA
anti-drug antibodies
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine transaminase
AST
aspartate transaminase
ATE
arterial thromboembolic events
AUC72
area under the curve (0 to 72 hours)
AUCT
area under the curve (0 to last quantifiable time point)
AUCinf
area under the curve (0 to time infinity)
CBC
complete blood count
CHF
congestive heart failure
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CL
clearance 
Cmax
maximum serum concentration
CMC
chemistry, manufacturing, and controls
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
clinical study agreement
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
DAI
dosage and administration instructions
DEHP
di-(2-ethylhexyl)phthalate
DICOM
Digital Imaging and Communications in Medicine
DNA
deoxyribonucleic acid
DOR
duration of response
DVD
digital video disc
EC
ethics committee
eCRF
electronic case report form
ECOG
Eastern Cooperative Oncology Group
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EMA
European Medicines Authority
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)


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Abbreviation
Term
FIGO
International Federation of Gynecology and Obstetrics
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HCAb
hepatitis C antibody
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
institutional ethics committee
IgG1
immunoglobulin G1
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
institutional review committee
IRR
infusion related reaction
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IWRS
interactive web response system
KDR
kinase insert domain receptor
LFT
liver function test
LPLV
last patient last visit
LVEF
left ventricular ejection fraction
LSLV
last subject last visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance image (imaging)
MUGA
multi gated acquisition scan
N/A
not applicable
NAb
neutralizing antibodies
NCI
National Cancer Institute 
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ONJ
osteonecrosis of the jaw
ORR
objective response rate
OTC
over the counter
PCD
primary completion date
PD
Progressive disease
PFS
progression-free survival


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Abbreviation
Term
PK
pharmacokinetics
PMAP
population modeling analysis plan
PMAR
population modeling analysis report
PP
per-protocol
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PT
prothrombin time
RECIST
Response Evaluation Criteria In Solid Tumors
RD
risk difference
RR
risk ratio (relative risk)
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SOA
schedule of activities
SOC
standard of care
SPC
summary of product characteristics
SRSD
single reference safety document
TEAE
treatment emergent adverse event
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
UPC
urine protein to creatinine ratio 
US
United States
USP
United States Pharmacopeia
USPI
United States package insert
Vc
central volume
Vd
volume of distribution
VEGF
vascular endothelial growth factor
Vp
peripheral volume
WHO
World Health Organization
X ULN
times the upper limit of normal


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PROTOCOL SUMMARY
Introduction
PF-06439535 (bevacizumab-Pfizer) is being developed as a potential biosimilar to 
bevacizumab.  AVASTIN(bevacizumab) is the commercially available bevacizumab 
product in the United States, European Union (bevacizumab-EU), Japan, and other regions.
Bevacizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody 
(mAb) that is composed of 2 heavy chains and 2 light chains, which are linked by disulfide 
bonds.  It has an approximate molecular weight of 149kD and is produced in mammalian 
Chinese hamster ovary cells. 
Bevacizumab is a mAb that binds to and inhibits the biological activity of human vascular 
endothelial growth factor (VEGF) in in vitro and in vivo assay systems.  Bevacizumab-Pfizer 
has the same primary amino acid sequence as AVASTINand will be developed to be highly 
similar (biosimilar) to AVASTINas sourced from the European Union (bevacizumab-EU) 
and from the United States (bevacizumab-US).
STUDY OBJECTIVES AND ENDPOINTS
Primary Objective

The primary objective of this study is to compare the confirmed objective response 
rate (ORR) by Week 19 following treatment with bevacizumab-Pfizer in combination 
with paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in 
patients who have not received previous treatment for advanced non-squamous 
non-small cell lung cancer (NSCLC).
Secondary Objectives

To evaluate the safety of bevacizumab-Pfizer plus paclitaxel and carboplatin and 
bevacizumab-EU plus paclitaxel and carboplatin;

To evaluate secondary measures of tumor control; 

To evaluate the population pharmacokinetics (PK) of bevacizumab-Pfizer and 
bevacizumab-EU; 

To evaluate the immunogenicity of bevacizumab-Pfizer and bevacizumab-EU.
Primary Endpoint

Objective Response Rate (ORR), evaluating the best response achieved by 
Week 19 and subsequently confirmed by 6 weeks thereafter, in accordance with 
Response Evaluations Criteria in Solid Tumors (RECIST) version 1.1.


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Secondary Endpoints

Safety characterized by type, incidence, severity, timing, seriousness, and relationship 
to study therapy of adverse events, including cardiotoxicity and infusion-related 
reactions, and laboratory abnormalities at 1 year from randomization

Duration of response (DOR), 1 year progression-free survival (PFS) rate and 1-year 
survival rate from randomization;

Peak and trough bevacizumab-Pfizer and bevacizumab-EU concentrations at selected 
cycles up to 1 year from randomization

Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing 
antibodies (NAb) up to 1 year from randomization
STUDY DESIGN
This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial 
evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin 
versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients 
with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous 
NSCLC.
Approximately 355 patients will be enrolled in each treatment arm for a total of
approximately 710 patients at over 300 centers.  Patients will be randomized (1:1) to receive 
either treatment of bevacizumab-Pfizer plus paclitaxel and carboplatin or bevacizumab-EU 
plus paclitaxel and carboplatin for at least 4 and no more than 6 cycles, followed by the 
assigned blinded bevacizumab monotherapy.  Randomization will be stratified by region 
(according to the location of the drug depot supplying the site), sex (male/female) and 
smoking history (never/ever).  Patients will participate in the study for approximately 
13 months.  This includes about 1 month of screening and at least 1 year for treatment and 
follow-up.  Actual length of participation for individual patients will depend upon the actual 
duration of treatment.  Minimum expected participation is approximately 1 year unless 
shorter due to death, withdrawal of consent, or early termination of the trial.  See Figure 1 for 
details.


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Figure 1.
Study Schema
* Assigned bevacizumab monotherapy: Following completion of at least 4 and no more than 
6 cycles of chemotherapy






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by local approved laboratories, and the results must be reviewed and confirmed as negative for mutations prior to randomization.
3.
Physical Examination: includes head, ears, eyes, nose, mouth, skin, neck, heart and lung examinations, lymph nodes, abdomen, musculoskeletal, neurological systems,
and weight.  Height will be recorded at Screening only.  Genitourinary examination is only required if directed by signs or symptoms.
4.
Brief Physical Examination: performed as directed by signs and symptoms on Day 1 (pre-dose) of each cycle after Screening.
5.
Vital Signs: Temperature should be taken using the same method throughout the study.  Blood pressure, heart rate, and respiratory rate should be taken with the patient in 
the supine or sitting position after the patient has been resting quietly for at least 5 minutes and prior to dosing on dosing days.  Weight should be taken at the beginning of 
each cycle and will be used for dose calculation in accordance with Section 5.4.1.  On days of an infusion, vital signs should be taken within 30 minutes before the first 
infusion and within 30 minutes of the end of the last infusion.
6.
Baseline Signs and Symptoms: observed after Screening and before Cycle 1, Day 1 pre-dose are recorded as part of Medical History or as Brief Physical Exam findings.
7.
Inclusion/Exclusion Criteria: Eligibility criteria are to be reviewed to confirm eligibility prior to randomization.  
8.
Hematology: Tests include hemoglobin, white blood cells, platelets, and absolute neutrophil count.  Results of tests must be reviewed prior to each cycle of therapy.  
9.
Chemistry: Tests include ALT, AST, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, BUN or urea, magnesium, and 
albumin, and results must be reviewed prior to each cycle of therapy  
10. Coagulation: Tests include International Normalized Ratio (INR) for prothrombin time (or prothrombin time if INR is not available) and activated partial thromboplastin 
time.  Tests may be performed more frequently if clinically indicated.  Results of tests must be reviewed prior to dosing on Cycle 1 Day 1.
11. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test with sensitivity of at least 25 mIU/mL will be performed by the local 
certified laboratory, and 2 negative tests are required before receiving the first dose of investigational product.  The second negative test should be done during the first 
5 days of the menstrual period, immediately preceding the first dose of any study treatment.  See protocol Section 7.4 for details.
12. Urinalysis: If the results of the dipstick urine protein indicate 2+ proteinuria, follow-up should be performed with a quantitative urine protein analysis according to local 
standard practices with data captured on the AE CRF if AE criteria are met.  The results of the dipstick must be reviewed prior to each cycle of therapy.  
13. Serological tests (optional): See Exclusion criterion #21 for specifications.  If testing is performed, samples must be tested by local approved laboratories, and the results 
must be reviewed and eligibility confirmed prior to randomization.
14. Immunogenicity:  Blood Sampling for ADA/NAb prior to blinded bevacizumab.  If adverse events are considered possibly related to ADA formation, an additional 
sample may be collected at the time of the immunogenicity-related adverse events.
15. PKs:  Blood Sampling for Drug Concentration prior to blinded bevacizumab.  Post-dose samples will also be collected at 1 hour (0.5 hour) after the end of blinded
bevacizumab for Cycles 1 and 5 (if patient received Cycle 5).  If ADA/NAb sampling is conducted at the time of immunogenicity-related adverse events, a serum sample 
for drug concentration will also be collected at that sametime point .
16. Tumor Assessments:  Assessments must include CT with contrast or MRI of head, chest, abdomen (including adrenals) and other disease sites such as pelvis if clinically 
indicated. Tumor assessments are NOT to be scheduled based on cycle length or number of cycles received. Assessment delay to conform to treatment delays is not 
permitted.  The same method of tumor assessments should be used throughout the trial.  A confirmatory scan is required approximately 6 weeks (+7 days) for a CR/PR.
17. Randomization: Unless clinically indicated, screening physical examination and laboratory assessments including blood chemistry, hematology, and urinalysis, are not 
required to be repeated for randomization if they are performed 7 days prior to Cycle 1, Day 1, and results meet eligibility criteria.  Eligibility criteria are to be reviewed 
and sponsor confirmation of eligibility must be received prior to randomization.  Randomization is required on day 1 of first dose (but no more than 1 day prior). 
18. Paclitaxel and carboplatin administration: per dosing algorithm in protocol for a total of at least 4 and no more than 6 cycles. Premedication are to be administered 
according to the local label or institutional guidelines. Dose delay (up to 2 weeks) and dose reduction will be permitted per local guidelines.  See protocol Section 5.4.4 for 
details. 


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19. Blinded Bevacizumab: 15 mg/kg by intravenous (IV) infusion on Day 1 of each of the 3-week (21-day) cycles, see See protocol Section 5.4.2 for details
20. ECG: 12-lead ECG will be obtained at Screening, as clinically indicated, and at the End-of-Treatment Visit.
21. MUGA or ECHO:  to assess LVEF (Left ventricular ejection fraction);  the original methodology used for each patient must be used throughout the trial.
22. Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of 2 of the selected methods of contraception.  See protocol Section 4.4.1 for details.
23. Adverse Events: Patients must be followed for adverse events from the first day of study treatment through the patient’s last visit and at least 28 days after the last dose of 
study treatment, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later as assessed by the 
investigator.  Serious adverse events should be monitored and reported from the time that the patient provides informed consent, as described in the protocol, through and 
including 28 calendar days after the last study treatment.  Serious adverse events considered related to study treatments are to be reported whenever they occur even after 
28 days after the last study treatment. 
24. Prior Medication/ Treatments: Medications and non-drug treatments delivered prior to initial dosing will be recorded from 28 days prior to the start of study treatment.
25. Concomitant Treatments: recorded from initial dosing and monitored continuously by the investigator until at least 28 days following the last dose of study treatment to 
coincide with the safety evaluation period.  Patients discontinuing the active treatment phase will enter the follow-up phase during which survival and new anti-cancer 
therapy information will be collected until the study is completed or is terminated early.  
26. End-of-Treatment/Withdrawals: When patients discontinue all study treatment, patients should be evaluated 28 (+7) days after last dose or prior to the start of new 
anti-cancer therapy if initiated within 28 days after the last dose.
27. Survival Follow-up: After discontinuation from treatment, survival status will be collected by telephone contact every 2 months (14 days) until death or 1 year from 
patient randomization,.
28. 1 year post-randomization: Patients who continue to receive study treatment after one year will have assessments performed according to local standard of care (SOC); 
reduced data collection, although tumor assessment and safety data collection are required.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................22
APPENDICES .........................................................................................................................22
1. INTRODUCTION ...............................................................................................................23
1.1. Indication.................................................................................................................23
1.2. Background and Rationale ......................................................................................24
1.2.1. Background.................................................................................................24
1.2.2. Bevacizumab...............................................................................................24
1.2.2.1. US Prescribing Information ......................................................24
1.2.2.2. European Union Prescribing Information .................................24
1.2.2.3. Bevacizumab Pharmacokinetics................................................25
1.2.2.4. Bevacizumab Adverse Events...................................................25
1.2.2.5. Bevacizumab Immunogenicity..................................................27
1.2.3. Bevacizumab-Pfizer....................................................................................27
1.2.4. Paclitaxel.....................................................................................................29
1.2.5. Carboplatin .................................................................................................30
1.2.6. Rationale.....................................................................................................32
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................34
2.1. Objectives................................................................................................................34
2.1.1. Primary .......................................................................................................34
2.1.2. Secondary ...................................................................................................34
2.2. Endpoints.................................................................................................................34
2.2.1. Primary Endpoint........................................................................................34
2.2.2. Secondary Endpoints ..................................................................................34
3. STUDY DESIGN.................................................................................................................35
3.1. Study Overview.......................................................................................................35
4. PATIENT SELECTION......................................................................................................35
4.1. Inclusion Criteria.....................................................................................................35
4.2. Exclusion Criteria....................................................................................................37
4.3. Randomization Criteria ...........................................................................................40
4.4. Lifestyle Guidelines ................................................................................................40
4.4.1. Contraception..............................................................................................40


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4.5. Sponsor’s Qualified Medical Personnel..................................................................41
5. STUDY TREATMENTS.....................................................................................................41
5.1. Allocation to Treatment ..........................................................................................41
5.2. Breaking the Blind ..................................................................................................42
5.3. Patient Compliance .................................................................................................42
5.4. Drug Supplies..........................................................................................................42
5.4.1. Administration and dosing..........................................................................42
5.4.2. Bevacizumab...............................................................................................43
5.4.2.1. Dosage Form(s) and Packaging.................................................43
5.4.2.2. Preparation and Dispensing.......................................................43
5.4.3. Paclitaxel and Carboplatin..........................................................................47
5.4.3.1. Paclitaxel and Carboplatin Provision ........................................47
5.4.3.2. Premedication for Administration.............................................47
5.4.3.3. Regimen and Starting Dose(s)...................................................48
5.4.4. Missed/ Delayed Dose(s) of Study Treatment............................................49
5.5. Drug Storage ...........................................................................................................50
5.6. Drug Accountability................................................................................................51
5.7. Concomitant Treatment(s).......................................................................................51
5.8. Additional Anticancer and Prohibited Treatments Including Radiotherapy...........52
6. STUDY PROCEDURES .....................................................................................................52
6.1. Screening.................................................................................................................52
6.1.1. Screen Failure .............................................................................................53
6.2. Study Period ............................................................................................................53
6.3. End-of-Treatment/Withdrawal................................................................................53
6.4. Long Term Follow-up .............................................................................................53
6.4.1. Withdrawal .................................................................................................53
6.4.2. Lost to Follow-Up.......................................................................................54
7. ASSESSMENTS..................................................................................................................55
7.1. Efficacy Assessments..............................................................................................55
7.2. Safety Assessments .................................................................................................56
7.2.1. Adverse Events...........................................................................................56
7.2.2. Laboratory Safety Assessments..................................................................56


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7.2.3. Other Safety Assessments...........................................................................57
7.3. Pharmacokinetic Evaluations ..................................................................................57
7.4. Pregnancy Testing...................................................................................................57
7.5. Biomarkers ..............................................................................................................57
7.6. Immunogenicity Assessments.................................................................................58
7.7. Testing Lung Tissue for Mutations .........................................................................58
8. ADVERSE EVENT REPORTING......................................................................................58
8.1. Adverse Events........................................................................................................58
8.2. Reporting Period .....................................................................................................59
8.3. Definition of an Adverse Event...............................................................................59
8.4. Medication Errors....................................................................................................60
8.5. Abnormal Test Findings..........................................................................................60
8.6. Serious Adverse Events...........................................................................................61
8.6.1. Protocol-Specified Serious Adverse Events...............................................62
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................62
8.7. Hospitalization ........................................................................................................63
8.8. Severity Assessment: NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03..................................................................................64
8.9. Causality Assessment..............................................................................................65
8.10. Exposure During Pregnancy..................................................................................65
8.11. Occupational Exposure .........................................................................................67
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient 
Withdrawal)...............................................................................................................67
8.13. Eliciting Adverse Event Information ....................................................................67
8.14. Reporting Requirements........................................................................................67
8.14.1. Serious Adverse Event Reporting Requirements .....................................67
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................68
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................68
9. DATA ANALYSIS/STATISTICAL ...................................................................................68
9.1. Sample Size Determination.....................................................................................68
9.2. Analysis Population.................................................................................................69
9.2.1. Intent-to-Treat Population ..........................................................................69
9.2.2. Per-Protocol Population..............................................................................69


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9.2.3. Pharmacokinetics Population......................................................................69
9.2.4. Safety Population........................................................................................70
9.3. Efficacy Analysis ....................................................................................................70
9.3.1. Analysis of Primary Endpoint ....................................................................70
9.3.2. Analysis of Secondary Endpoints...............................................................71
9.3.2.1. Duration of Response................................................................71
9.3.2.2. Progression-Free Survival.........................................................71
9.3.2.3. 1-Year Survival .........................................................................71
9.3.2.4. Pharmacokinetics, Biomarkers and Immunogenicity................72
9.4. Safety Analysis........................................................................................................72
9.4.1. Adverse Events...........................................................................................72
9.4.2. Laboratory Abnormalities...........................................................................72
9.4.3. Prior Concomitant Medications..................................................................73
9.4.4. Pharmacokinetics, Biomarkers and Immunogenicity.................................73
9.4.4.1. Pharmacokinetics ......................................................................73
9.4.4.2. Biomarker Analysis...................................................................73
9.4.4.3. Immunogenicity ........................................................................73
9.4.5. Other Endpoints..........................................................................................74
9.5. Interim Analysis ......................................................................................................74
9.6. Early Unblinding For PK ........................................................................................74
9.7. Data Monitoring Committee ...................................................................................74
9.8. Central Radiology Review ......................................................................................75
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................75
11. DATA HANDLING AND RECORD KEEPING .............................................................75
11.1. Case Report Forms/Electronic Data Record .........................................................75
11.2. Record Retention...................................................................................................76
12. ETHICS..............................................................................................................................76
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................76
12.2. Ethical Conduct of the Study ................................................................................76
12.3. Patient Information and Consent...........................................................................77
12.4. Patient Recruitment...............................................................................................77


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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................77
13. DEFINITION OF END OF TRIAL...................................................................................78
13.1. End of Trial in a Member State.............................................................................78
13.2. End of Trial in All Other Participating Countries.................................................78
14. SPONSOR DISCONTINUATION CRITERIA ................................................................78
15. PUBLICATION OF STUDY RESULTS..........................................................................78
15.1. Communication of Results by Pfizer ....................................................................78
15.2. Publications by Investigators ................................................................................79
16. REFERENCES ..................................................................................................................81
LIST OF TABLES
Table 1.
Schedule of Activities ..........................................................................................14
Table 2.
Dosing Algorithm.................................................................................................43
Table 3.
Bevacizumab Dose Adjustment Guidelines .........................................................45
Table 4.
Hematology and Chemistry Panels.......................................................................56
Table 5.
Objective Response Status at Each Evaluation ....................................................88
APPENDICES
Appendix 1. ECOG Performance Status..................................................................................83
Appendix 2. Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 
Guidelines.............................................................................................................84
Appendix 3. Tumor Staging.....................................................................................................89


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1. INTRODUCTION
PF-06439535 (bevacizumab-Pfizer) is being developed as a potential biosimilar to 
bevacizumab.  AVASTIN(bevacizumab) is the commercially available bevacizumab 
product in the United States (bevacizumab-US), European Union (bevacizumab-EU), Japan, 
and other regions.
Bevacizumab is a recombinant humanized IgG1 monoclonal antibody (mAb) that is 
composed of 2 heavy chains and 2 light chains, which are linked by disulfide bonds.  It has 
an approximate molecular weight of 149kD and is produced in mammalian Chinese hamster 
ovary cells. 
Bevacizumab is a mAb that binds to and inhibits the biological activity of human vascular 
endothelial growth factor (VEGF) in in vitro and in vivo assay systems.  Bevacizumab-Pfizer 
has the same primary amino acid sequence as AVASTINand will be developed to be highly 
similar (biosimilar) to AVASTINas sourced from the European Union (bevacizumab-EU) 
and from the United States (bevacizumab-US). 
1.1. Indication
Bevacizumab-Pfizer is being evaluated as first-line treatment of patients with advanced 
non-squamous non-small cell lung cancer (NSCLC) and for extrapolation to other 
AVASTIN(bevacizumab) indications.
In the United States bevacizumab is approved for metastatic colorectal cancer, with 
intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment; metastatic 
colorectal cancer, with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based 
chemotherapy for second-line treatment in patients who have progressed on a first-line 
AVASTIN-containing regimen; non-squamous non-small cell lung cancer, with carboplatin 
and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or 
metastatic disease; glioblastoma, as a single agent for adult patients with progressive disease 
following prior therapy; metastatic renal cell carcinoma with interferon alfa; cervical cancer 
in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, 
recurrent, or metastatic disease; and platinum-resistant recurrent epithelial ovarian, fallopian 
tube or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal 
doxorubicin or topotecan.1
In the European Union bevacizumab is indicated for treatment of adult patients with 
metastatic carcinoma of the colon or rectum in combination with fluoropyrimidine-based 
chemotherapy; first-line treatment in combination with paclitaxel of adult patients with 
metastatic breast cancer; first-line treatment in combination with capecitabine of adult 
patients with metastatic breast cancer in whom treatment with other chemotherapy options 
including taxanes or anthracyclines is not considered appropriate; first-line treatment in 
addition to platinum-based chemotherapy of adult patients with unresectable advanced, 
metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell 
histology; first line treatment in combination with interferon alfa-2a of adult patients with 
advanced and/or metastatic renal cell cancer; front-line treatment in combination with 


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carboplatin and paclitaxel of adult patients with advanced (International Federation of 
Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian 
tube, or primary peritoneal cancer; treatment of adult patients in combination with 
carboplatin and gemcitabine with first recurrence of platinum-sensitive epithelial ovarian, 
fallopian tube or primary peritoneal cancer who have not received prior therapy with 
bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.2
In Japan bevacizumab is indicated for unresectable advanced or recurrent colorectal cancer; 
unresectable advanced or recurrent non-squamous non-small cell lung cancer; inoperable or 
recurrent breast cancer; malignant glioma including glioblastoma; and ovarian cancer.3
1.2. Background and Rationale
1.2.1. Background
Biological therapeutics are large complex protein molecules that require a wide variety of 
analytical methods to ensure consistent quality. As a result of their complexity and 
manufacturing methods, biologic products have inherent variability and the development of 
an exact replicate is not possible.  Biosimilars are structurally highly similar versions of 
marketed biological medicines that are supported by appropriate analytical testing and 
clinical trials to demonstrate that they are sufficiently “similar” (both in structure and clinical 
function) to the marketed biological product.
Development as a biosimilar requires head-to-head comparison to an approved reference 
product.  The European Union (EU) has a legal basis for approval of biosimilars, which 
defines a reference product as a product authorized in the EU (bevacizumab-EU).  Similarly, 
the United States Biologics Price Competition and Innovation Act created an abbreviated 
approval pathway for biological products that are demonstrated to be biosimilar with a Food 
and Drug Administration (FDA)-licensed biological product (bevacizumab-US).
1.2.2. Bevacizumab
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors; Flt-1 and 
kinase insert domain receptor (KDR), on the surface of endothelial cells.  The interaction of 
VEGF with its receptors leads to endothelial cell proliferation and new blood vessel 
formation in in vitro models of angiogenesis.1,2 The blockade interaction of VEGF by 
bevacizumab inhibits angiogenesis and tumor growth.  Administration of bevacizumab to 
xenotransplant models of colon cancer in nude (athymic) mice caused reduction of 
microvascular growth and inhibition of metastatic disease progression. 
1.2.2.1. US Prescribing Information
See AVASTINUS prescribing information.1
1.2.2.2. European Union Prescribing Information
See AVASTINEU Summary of Product Characteristics.2


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1.2.2.3. Bevacizumab Pharmacokinetics
According to the EU Summary of Product Characteristics (quotations are italicized):
The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients 
with solid tumours. In all clinical trials, bevacizumab was administered as an IV infusion. 
The rate of infusion was based on tolerability, with an initial infusion duration of 90 minutes.
The pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.
Distribution
The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male patients 
respectively, which is in the range that has been described for IgGs and other monoclonal 
antibodies.  The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female 
and male patients respectively, when bevacizumab is co-administered with anti-neoplastic 
agents.  After correcting for body weight, male patients had a larger Vc (+20%) than female 
patients.
Metabolism
Assessment of bevacizumab metabolism in rabbits following a single IV dose of 
125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native 
IgG molecule which does not bind VEGF.  The metabolism and elimination of bevacizumab 
is similar to endogenous IgG ie, primarily via proteolytic catabolism throughout the body, 
including endothelial cells, and does not rely primarily on elimination through the kidneys 
and liver.  Binding of the IgG to the FcRn receptor results in protection from cellular 
metabolism and the long terminal half-life.
Elimination
The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male 
patients, respectively.  After correcting for body weight, male patients had a higher 
bevacizumab clearance (+17%) than females.  According to the two-compartmental model, 
the elimination half-life is 18 days for a typical female patient and 20 days for a typical male 
patient.
Low albumin and high tumour burden are generally indicative of disease severity.  
Bevacizumab clearance was approximately 30% faster in patients with low levels of serum 
albumin and 7% faster in subjects with higher tumour burden when compared with a typical 
patient with median values of albumin and tumour burden.
1.2.2.4. Bevacizumab Adverse Events
The following is a summary of safety information from studies of patients receiving 
bevacizumab that is included in the AVASTINEU and US product labels. Bevacizumab is 
given to cancer patients who often have multiple comorbidities and it is typically 
administered as multiple doses in combination with cytotoxic chemotherapeutic agents.  In 
addition, some adverse drug reactions occur after repeated doses in cancer patients.


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The overall safety profile of AVASTINis based on data from over 4,500 patients with 
various malignancies, predominantly treated with AVASTINin combination with 
chemotherapy in clinical trials.  The most frequently observed adverse reactions across 
clinical trials in patients receiving AVASTINwere hypertension, fatigue or asthenia, 
diarrhea and abdominal pain.  The most serious adverse reactions observed in clinical trials 
were gastrointestinal perforations, surgery and wound healing complications, hemorrhage, 
and arterial thromboembolism. 
Depending on the patient population, the incidence of gastrointestinal perforation in 
AVASTIN-treated patients, some fatal, ranges up to 3.2% depending on the patient 
population.  Intra-abdominal inflammation may be a risk factor.  The majority of cases 
occurred within 50 days of initiation of AVASTIN. 
AVASTINmay adversely affect the wound healing process.  Across several indications, 
Grade 3-5 wound healing complications were observed at a higher rate in patients receiving 
bevacizumab compared to the control arm. 
AVASTINcan result in 2 distinct patterns of bleeding: minor hemorrhage, most commonly 
Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events.  Severe or fatal 
hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, central nervous 
system (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred more frequently in 
patients receiving AVASTINcompared to patients receiving only chemotherapy.  In 
clinical trials across all indications, the overall incidence of Grade 3-5 bleeding reactions 
ranged from 0.4% to 6.9% in AVASTIN-treated patients, compared with up to 2.9% of 
patients in the chemotherapy control group.
Uncommon but serious and sometimes fatal arterial thromboembolic events (ATEs) 
including cerebrovascular accidents, transient ischemic attacks, myocardial infarction, 
angina, and a variety of other ATEs occurred at a higher incidence in patients receiving 
AVASTINcompared to those in the control arm.  In clinical trials, the overall incidence of 
ATEs ranged up to 3.8% in the AVASTIN-containing arms compared with up to 1.7% in 
the chemotherapy control arms. 
In addition to the serious adverse reaction described above, special warnings and precautions 
are provided for gastrointestinal and non-gastrointestinal fistula formation, hypertension, 
posterior reversible encephalopathy syndrome, proteinuria, venous thromboembolism, 
congestive heart failure, neutropenia and infections, hypersensitivity/infusion reactions, 
osteonecrosis of the jaw, eye disorders, embryo-fetal toxicity and ovarian failure/infertility.
AVASTINhas been associated with serious and sometimes fatal fistulae formation.  In 
clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in 
patients with metastatic colorectal cancer and ovarian cancer, but were also reported less 
commonly in patients with other types of cancers.  Non-gastrointestinal perforations 
(eg, bronchopleural, tracheoesophageal, urogenital and biliary fistulae) were uncommon 
(0.1% to <1%) across indications.


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An increased incidence of hypertension (all Grades) of up to 42% has been observed in 
AVASTIN-treated patients, compared with up to 14% in those treated with comparator.  
Across clinical studies, the incidence of Grade 3 or 4 hypertension ranged from 5% to 18%.
The incidence and severity of proteinuria is increased in patients receiving AVASTINas 
compared to controls.  In clinical trials, proteinuria has been reported with the range of 
0.7% to 38% in patients receiving AVASTIN.  Proteinuria ranged in severity from clinically 
asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as 
Grade 1 proteinuria.  Grade 4 proteinuria (nephrotic syndrome) occurred in up to 1.4% of 
patients receiving AVASTINin clinical trials, in some instances with fatal outcome. 
Infusion reactions reported in the clinical trials 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 clinical studies, infusion reactions with the first dose of AVASTINwere uncommon 
(<3%) and severe reactions occurred in 0.2% of patients.  In some trials anaphylactic and 
anaphylactoid-type reactions were reported more frequently in patients receiving AVASTIN
in combination with chemotherapy than chemotherapy alone – up to 5% in 
bevacizumab-treated patients.
Complete information for bevacizumab-Pfizer and bevacizumab-EU may be found in the 
Single Reference Safety Document (SRSD), which for this study is the Investigator 
Brochure.
1.2.2.5. Bevacizumab Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity.  Anti-drug 
antibodies (ADA) have been evaluated in studies with bevacizumab in cancer patient 
populations.  Using an electrochemiluminescent based assay, 14 of 2,233 evaluable patients 
(0.63%) treated in clinical trials tested positive for anti-bevacizumab antibodies.  Among 
these 14 patients, 3 tested positive for neutralizing antibodies against bevacizumab using an 
enzyme-linked immunosorbent assay.  The clinical significance of anti-product antibody
formation is unknown.1
1.2.3. Bevacizumab-Pfizer
Pfizer has a step-wise development program including head-to-head comparison to 
AVASTIN(bevacizumab) sourced from the United States (bevacizumab-US) and the 
European Union (bevacizumab-EU) with regard to chemistry, manufacturing, and controls 
(CMC)/quality, non-clinical and clinical features and performance.  Head-to-head 
physiochemical and analytical data sufficiently demonstrated that bevacizumab-Pfizer is 
similar to bevacizumab-US and bevacizumab-EU to enable clinical studies. 
Pfizer developed bevacizumab-Pfizer to have the same dosage form, route of administration, 
and dosing regimen as AVASTINsourced from both the US and EU.  The dosing regimens 
will be consistent with those for which AVASTINis approved.


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Responses to bevacizumab-Pfizer and bevacizumab-EU appeared similar when administered 
by intravenous (IV) injection to sexually- and skeletally-immature male cynomolgus 
monkeys (4/group) at a dose of 10 mg/kg/dose twice weekly for 1 month (9 total doses). 
Mean systemic exposures (as assessed by Cmax and AUC72) for bevacizumab-Pfizer and 
bevacizumab-EU appeared similar.  Anti-drug antibodies (ADA) were not detected in 
animals dosed with bevacizumab-Pfizer vehicle, bevacizumab-EU vehicle, 
bevacizumab-Pfizer, or bevacizumab-EU.  However, drug present in samples may have 
interfered with the detection of ADA.  There were no bevacizumab-Pfizer- or 
bevacizumab-EU-related findings in clinical signs, body weight, food consumption, 
ophthalmology examinations, respiration rate, electrocardiograms, hematology, coagulation, 
clinical chemistry, or urinalysis parameters.  All animals survived to their scheduled 
euthanasia and there were no bevacizumab-Pfizer- or bevacizumab-EU-related changes in 
organ weights or necropsy findings.  The only bevacizumab-Pfizer- and 
bevacizumab-EU-related effect was the observation of physeal dysplasia in the distal femur, 
which was considered adverse for these growing animals.  There was no biologically- or 
toxicologically-relevant difference in the incidence and severity of the physeal dysplasia 
between bevacizumab-Pfizer and bevacizumab-EU-dosed groups.  Physeal dysplasia related 
to the inhibition of blood vessel formation is consistent with the known pharmacologic 
effects of bevacizumab on growing bone.
Pfizer has performed a single-dose pharmacokinetic similarity trial in healthy volunteers 
(B7391001).  Healthy male subjects received 1 dose (5 mg/kg intravenously over 90 minutes) 
of bevacizumab-Pfizer (33 subjects), bevacizumab-US (33 subjects), or bevacizumab-EU 
(35 subjects). Of the 101 subjects dosed, 97 subjects had a sufficient number of PK samples 
to be included in the PK analysis population.  PK similarity testing for a given 
test-to-reference comparison was to be considered demonstrated if 90% confidence intervals 
for the test-to-reference ratios of AUCT, AUCinf and Cmax were within the 80-125% 
bioequivalence acceptance window. 
For the PK similarity comparisons of bevacizumab-Pfizer to each of the 2 reference products 
(bevacizumab-EU and bevacizumab-US), the 90% confidence intervals for the 
test-to-reference ratios of Cmax, AUCT, and AUCinf were all within the bioequivalence 
window of 80% to 125%.  For the comparison of bevacizumab-EU to bevacizumab-US, the 
90% confidence intervals of the ratios of Cmax, AUCT, and AUCinf were also within 
80% to 125%.
The observed safety profiles for all treatment arms did not show any clinically important 
imbalances in the secondary endpoints, including drug-related adverse events and serious 
adverse events, drug-related changes in laboratory parameters, and immunogenicity. 
Immunogenicity was assessed through Day 100 of the study.  One subject in the 
bevacizumab-EU treatment group tested positive for ADA at baseline.  A total of 5 (5.0%) 
subjects tested positive at one or more time points post-dose through Day 100.  Two (6.1%), 
1 (2.9%), and 2 (6.1%) of total subjects from bevacizumab-Pfizer, bevacizumab-EU and 
bevacizumab-US, respectively, had at least one post-dose sample that tested positive through 
Day 100.  Overall, the immunogenicity profiles of bevacizumab-Pfizer, bevacizumab-US, 
and bevacizumab-EU were shown to be similar in the study.


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In conclusion, similarity among bevacizumab-Pfizer, bevacizumab-US, and bevacizumab-EU 
in terms of the primary endpoints (Cmax, AUCT, and AUCinf) was demonstrated.  The safety 
profiles of the drugs and incidence of anti-drug antibodies (ADA) were also similar.  For 
more details, please refer to the Investigator Brochure.
1.2.4. Paclitaxel
Paclitaxel is a natural product with antitumor activity and is obtained via a semi-synthetic 
process from Taxus baccata.  Paclitaxel is an antimicrotubule agent that promotes the 
assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization.  This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and mitotic 
cellular functions.  In addition, paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.4
Paclitaxel is indicated for the treatment of metastatic breast cancer.  While the paclitaxel 
prescribing information does not include combination with bevacizumab, the bevacizumab 
prescribing information specifies bevacizumab is indicated for treatment of NSCLC in 
combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally 
advance, recurrent or metastatic disease.
Common adverse events associated with the use of paclitaxel include neutropenia, 
leucopenia, thrombocytopenia, anemia, infections, hypersensitivity reactions, peripheral 
neuropathy, arthralgia, myalgia, gastrointestinal symptoms include nausea, vomiting, 
diarrhea, and mucositis, and alopecia.
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of 
patients receiving paclitaxel in clinical trials.  Fatal reactions have occurred in patients 
despite premedication.  All patients should be pretreated with corticosteroids.
Caution should also be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers 
(eg, rifampin) of CYP2C8.
Paclitaxel should not come in contact with plasticized polyvinylchloride (PVC) equipment or 
devices.  Diluted paclitaxel must be stored in bottles (glass, polypropylene) or plastic bags 
(polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4.  Caution should be exercised when paclitaxel is concomitantly administered with 
known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers 
(eg, rifampin and carbamazepine) of CYP3A4.  Caution should also be exercised when 
paclitaxel is concomitantly administered with known substrates (eg, repaglinide and 
rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8.


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Patients with a history of severe hypersensitivity reactions to products containing 
CremophorEL (eg, cyclosporine) should not be treated with paclitaxel.  Minor symptoms 
such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require 
interruption of therapy.  However, severe reactions, such as hypotension requiring treatment, 
dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate 
discontinuation of paclitaxel and aggressive symptomatic therapy.  Patients who have 
developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.
Hypotension, bradycardia, and hypertension have been observed during administration of 
paclitaxel, but generally do not require treatment.  Occasionally paclitaxel infusions must be 
interrupted or discontinued because of initial or recurrent hypertension.
There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients 
with serum total bilirubin >2 times upper limit of normal (ULN).  Extreme caution should be 
exercised when administering paclitaxel to such patients, with dose reduction as 
recommended in the prescribing information.
Injection site reactions to paclitaxel, including reactions secondary to extravasation, were 
usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the 
injection site.  More severe events such as phlebitis, cellulitis, induration, skin exfoliation, 
necrosis, and fibrosis have been reported with paclitaxel.  These reactions have been 
observed more frequently with the 24-hour infusion than with the 3-hour infusion.  
Recurrence of skin reactions at a site of previous extravasation following administration of 
paclitaxel at a different site, ie, “recall,” has been reported.
In some cases the onset of the injection site reaction either occurred during a prolonged 
infusion or was delayed by a week to 10 days.  A specific treatment for extravasation 
reactions is unknown at this time.  Given the possibility of extravasation, it is advisable to 
closely monitor the infusion site for possible infiltration during drug administration.
1.2.5. Carboplatin
Carboplatin is a platinum coordination compound used as a cancer chemotherapeutic agent.  
It produces predominantly interstrand deoxyribonucleic acid (DNA) cross-links rather than 
DNA-protein cross links for a cell-cycle nonspecific effect.  With the exception of 
carboplatin, there are no significant quantities of protein-free ultrafilterable 
platinum-containing species present in plasma.  Platinum from carboplatin becomes bound 
irreversibly to plasma proteins and is slowly eliminated with a half-life of 5 days at 
minimum.5
Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in 
combination with other approved chemotherapeutic agents and for palliative treatment of 
ovarian carcinoma recurrent after prior chemotherapy.  While the carboplatin prescribing 
information does not include combination with bevacizumab, the bevacizumab prescribing 
information specifies bevacizumab is indicated for treatment of NSCLC in combination with 
carboplatin and paclitaxel for first-line treatment of unresectable, locally advance, recurrent 
or metastatic disease.


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Common adverse events associated with the use of carboplatin include bone marrow 
suppression, anemia, thrombocytopenia, neutropenia, leucopenia, infections, bleedings, 
gastrointestinal toxicity including vomiting and nausea, peripheral neuropathies, 
nephrotoxicity, hepatic toxicity, electrolyte abnormalities, allergic reactions, injection site 
reactions, pain, and asthenia.
Carboplatin should not be employed in patients with severe bone marrow depression or 
significant bleeding.  Carboplatin is contraindicated in patients with a history of severe 
allergic reactions to cisplatin or other platinum-containing compounds; patients with 
pre-existing severe renal impairment, unless in the judgment of the physician and patient, the 
possible benefits of treatment outweigh the risks; patients with severe myelosuppression; and 
patients with bleeding tumors.
As is the case with other platinum compounds, allergic reactions to carboplatin have been 
reported.  These may occur within minutes of administration and should be managed with 
appropriate supportive therapy.  There is increased risk of allergic reactions, including 
anaphylaxis, in patients previously exposed to platinum therapy.
Carboplatin has limited nephrotoxic potential, but concomitant treatment with 
aminoglycosides has resulted in increased renal and/or audiologic toxicity and caution must 
be exercised when a patient receives both drugs.
Carboplatin can cause fetal harm when administered to a pregnant woman.  Carboplatin has 
been shown to be embryotoxic and teratogenic in rats receiving the drug during 
organogenesis.
Needles or intravenous sets containing aluminum parts that may come in contact with 
carboplatin should not be used for preparation or administration.  Aluminum reacts with 
carboplatin causing precipitate formation and/loss of potency.
Carboplatin is contraindicated in patients with a history of severe allergic reactions to 
cisplatin or other platinum-containing compounds.  Carboplatin should not be employed in 
patients with severe bone marrow depression or significant bleeding.
Hypersensitivity to carboplatin has been reported in 2% of the patients.  These allergic 
reactions have been similar in nature and severity to those reported with other 
platinum-containing compounds, ie, rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension.  Anaphylactic reactions have been reported as part of 
postmarketing surveillance.  These reactions have been successfully managed with standard 
epinephrine, corticosteroid, and antihistamine therapy.
Injection site reactions, including redness, swelling, and pain, have been reported during 
postmarketing surveillance.  Necrosis associated with extravasation has also been reported.5


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1.2.6. Rationale
In order to develop a biosimilar, comparative clinical data is generally required to 
demonstrate there are no clinically meaningful differences between the proposed biosimilar 
product and the reference product in clinical pharmacology, efficacy, and safety.  A healthy 
volunteer study comparing the PK of bevacizumab-Pfizer to bevacizumab-EU and 
bevacizumab-US, and bevacizumab-EU to bevacizumab-US, has been completed.  This 
comparative clinical study is designed to show that there are no clinically meaningful 
differences in the safety and efficacy profile of bevacizumab-Pfizer as compared to 
bevacizumab-EU in a patient population for which bevacizumab is indicated.
In order to support global development of bevacizumab-Pfizer as a potential biosimilar, one 
comparator arm is included in this study. The comparator to be used in this clinical trial is 
bevacizumab sourced from the EU (bevacizumab-EU).
The totality of data, including the 3-way analytical similarity assessment and the 3-way PK 
similarity data from Study B7391001, have established a scientific bridge between 
bevacizumab-EU and bevacizumab-US, and therefore adequately justify the use of 
bevacizumab-EU as the sole comparator in the proposed comparative efficacy and safety 
trial.
Patients with previously untreated advanced NSCLC represent a population with well 
categorized safety and efficacy profile for treatment with bevacizumab and paclitaxel and 
carboplatin.  As such, this population is considered to be a sensitive population to 
demonstrate that there are no clinically meaningful differences between bevacizumab-Pfizer 
and bevacizumab-EU.
The dose and regimen for bevacizumab-Pfizer and bevacizumab-EU in this comparative trial 
was chosen to be consistent with product labeling of bevacizumab-EU.  The chemotherapy 
given with the investigational products and the regimens used are considered standard of 
care.12
Demonstration of similar safety and efficacy profiles of bevacizumab-Pfizer with the 
innovator product will, in part, provide evidence that bevacizumab-Pfizer is biosimilar.
In order to determine the sample size of a biosimilarity trial, a point estimate of the primary 
endpoint has to be made.  In this study, the primary endpoint is based on best response by a 
second tumor assessment after 6 weeks by Week 19, which corresponds to the end of six 
3-week cycles. If the investigator identifies a complete or a partial response based on 
RECIST 1.1 criteria, those responses should be confirmed after 6 weeks with the same 
imaging sequence (whenever possible).  For assessment of the long term safety profile and 
the number of patients with anti-drug antibodies (ADA) at 1 year, the study will continue up 
to last subject last visit (LSLV) (see Section 13).
In order to keep this study in historical context, 3 randomized studies of bevacizumab plus 
paclitaxel and carboplatin were reviewed and key features were incorporated.6,7,8 For 
example, the patient population is similar to that of the Phase 3 study conducted by the 


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Eastern Cooperative Oncology Group (ECOG).6 Patients in that trial had recurrent or 
advanced non–small-cell lung cancer (Stage IIIB or IV).  Eligible patients were required to 
have histologically or cytologically confirmed, newly diagnosed stage IIIB (malignant 
pleural effusion) or Stage IV cancer or recurrent non–small-cell lung cancer for which they 
had not received chemotherapy.  Other inclusion criteria were measurable or nonmeasurable 
disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), an ECOG 
performance status of 0 or 1, and adequate hematologic, hepatic, and renal function 
(including urinary excretion of 500 mg of protein per day).  Exclusion criteria included but 
were not limited to histologic evidence of predominantly squamous-cell cancer; central
nervous system (CNS) metastases (to reduce concern about possible CNS hemorrhage); 
pregnancy or lactation; a history of documented hemorrhagic diathesis or coagulopathy; 
therapeutic anticoagulation; regular use of aspirin (>325 mg per day), nonsteroidal 
anti-inflammatory agents, or other agents known to inhibit platelet function; radiation therapy 
within 21 days before enrollment or major surgery within 28 days before enrollment; 
clinically significant cardiovascular disease; and medically uncontrolled hypertension.6
Though the eligibility criteria for this protocol are similar to those of the ECOG Phase 3 trial, 
there are differences with potential study population implications.  First, the new staging 
system for lung cancer introduced in 201010 now includes Stage IIIB with malignant effusion 
into Stage IV.  RECIST11 which required measurements of lesions in 2 perpendicular 
directions has been replaced with RECIST 1.1,12 which requires only the longest diameter of 
cancer lesions and the shortest diameter of lymph nodes to be measured.  The second and 
perhaps biggest difference is the exclusion of patient with known tumors that have epidermal 
growth factor rector (EGFR) sensitizing mutations and anaplastic lymphoma kinase (ALK)
rearrangements.  These tumors have a high response rate to approved tyrosine kinase 
inhibitors (TKI) targeting these tissues such as gefitinib, erlotinib, and 
crizotinib.13,14,15 Patients with these mutations are not eligible for this protocol.  While 
obtaining tissue for these mutations is now a standard of care for patients with NSCLC, it 
was not at the time of the ECOG Phase 3 trial.  It is not known whether patients with these 
mutations respond differently to chemotherapy and bevacizumab than those without the 
mutations, so this protocol assumes that response rates will not be different.  However, 
patients with these mutations may live longer than those without, so PFS and survival may be 
different from the Phase 3 ECOG trial.
Treatment assignments in the Phase 3 ECOG trial were stratified according to measurable 
versus nonmeasurable disease, prior radiation, therapy versus no prior radiation therapy, prior 
weight loss of less than 5% versus 5% or more, and non–small-cell lung cancer, stage IIIB, 
with pleural effusion versus Stage IV or recurrent disease.  The primary end point was 
overall survival.  The 95% confidence intervals for death overlapped for each of these 
parameters in the Phase 3 ECOG trial.  How response rates behaved by these stratification 
parameters is not known.  Because response rate is the primary efficacy endpoint, only 
patients with measureable disease are eligible.  The vast majority of patients in the 
Phase 3 ECOG study had no prior radiation therapy.  Most patients did not have 5% weight 
loss, and this degree of weight loss did not seem to effect survival.  Most patients had 
Stage IV disease (using the old staging system).  It seems that the stratification in the 
Phase 3 ECOG trial provided limited benefit.  In consultation with respected leaders in the 


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area of NSCLC, it was felt that the current study should be stratified for randomization 
balance by other factors.  The factors chosen are region (according to drug depot supplying 
the site), sex (male/female), and smoking history (never/ever).  It is recognized that sex and 
smoking history may be less important in terms of response because patients with tissue 
where the majority of cells are squamous cells are excluded.
Based on the data gathered thus far, bevacizumab-Pfizer appears to be similar to the 
innovator product; although confirmation is required in this Phase 3 study.  The benefit/risk 
data available for bevacizumab-Pfizer, including the Phase 1 data, support the product’s 
progression to the Phase 3 program.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary

The primary objective of this study is to compare the confirmed objective response 
rate (ORR) by Week 19 following treatment with bevacizumab-Pfizer in combination 
with paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in 
patients who have not received previous treatment for advanced NSCLC. 
2.1.2. Secondary

To evaluate the safety of bevacizumab-Pfizer plus paclitaxel and carboplatin and 
bevacizumab-EU plus paclitaxel and carboplatin;

To evaluate secondary measures of tumor control; 

To evaluate the population pharmacokinetics (PK) of bevacizumab-Pfizer and 
bevacizumab-EU; 

To evaluate the immunogenicity of bevacizumab-Pfizer and bevacizumab-EU.
2.2. Endpoints
2.2.1. Primary Endpoint

Objective Response Rate (ORR), evaluating the best response achieved by 
Week 19 and subsequently confirmed by 6 weeks thereafter, in accordance with 
Response Evaluations Criteria in Solid Tumors (RECIST) version 1.1.
2.2.2. Secondary Endpoints

Safety characterized by type, incidence, severity, timing, seriousness, and relationship 
to study therapy of adverse events, including cardiotoxicity and infusion-related 
reactions, and laboratory abnormalities at 1 year from randomization;

Duration of response (DOR), 1 year progression-free survival (PFS) rate and 1-year 
survival rate from randomization;


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
Peak and trough bevacizumab-Pfizer and bevacizumab-EU concentrations at selected 
cycles up to 1 year from randomization;

Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing 
antibodies (NAb) up to 1 year from randomization.
3. STUDY DESIGN
3.1. Study Overview
This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial 
evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin 
versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients 
with advanced (unresectable, locally advanced, recurrent or metastatic), non-squamous 
NSCLC.
Approximately 355 patients will be enrolled in each treatment arm for a total of 
approximately 710 patients at over 300 centers; up to approximately 10% more patients may 
be enrolled due to operational/logistical considerations.  Patients will be randomized (1:1) to 
receive at least 4 and no more than 6 cycles of either bevacizumab-Pfizer plus paclitaxel and 
carboplatin or bevacizumab-EU plus paclitaxel and carboplatin, followed by the assigned 
blinded bevacizumab monotherapy.  Randomization will be stratified by region (according to 
the location of the drug depot supplying the site), sex (male/female) and smoking history 
(never/ever).  Patients will participate in the study on average for approximately 13 months.  
This includes about 1 month of screening and at least 1 year of treatment and follow-up.  
Actual length of participation for individual patients will depend upon the actual duration of 
treatment.  Minimum expected participation is approximately 1 year unless shorter due to 
death, progression on therapy, withdrawal of consent, or early termination of the trial.  The 
study is considered complete (End of Study) when the last patient has completed the last 
subject last visit (LSLV).  LSLV is defined as up to 1 year from randomization of the last 
patient (End of Treatment) plus 28 day follow-up.  See study schema (Figure 1) in Study 
Design section for details.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male and female patients age 18 years of age, or age of consent in the region.


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2. Newly diagnosed Stage IIIB or IV non-small cell lung cancer (according to Revised 
International System for Staging Lung Cancer criteria of 2010) or recurrent non-small 
cell lung cancer (NSCLC).
3. Histologically or cytologically confirmed diagnosis of predominately non-squamous 
NSCLC.
4. At least one measurable lesion as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1).
5. For patients with recurrent disease, at least 6 months must have elapsed since 
completing adjuvant or neoadjuvant treatment.
6. Screening scan (computed tomography [CT] or magnetic resonance imaging [MRI]) 
of the head, chest, abdomen (with adrenal glands), and other disease sites as clinically 
indicated, to assess disease burden.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
8. Screening laboratory values within the following limits (where deviation of up to 
10% is acceptable for any single value if in the investigator’s opinion the patient does 
not have an increased safety risk):
Bone Marrow Function
a.
Absolute neutrophil count (ANC) 1.5 x 109 cells/L (1500/mm3);
b. Platelet count 100 x 109 cells/L (100,000/mm3);
c.
Hemoglobin 9.0 g/dL (90 g/L);
Renal Function
d. Serum or plasma creatinine 1.5 x upper limit of normal (ULN);
e.
Urine dipstick proteinuria <2+ (ie, either 0, trace, or 1+). If urine dipstick is 
>1+ then a 24 hour urine for protein must have demonstrated urinary excretion of 
500 mg of protein per day or urine protein to creatinine ratio (UPC) ratio <1; 
Liver Function
f.
Total bilirubin 1.5 x ULN (<3 ULN if Gilbert’s disease);
g. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
3 x ULN (5 x ULN if liver metastases are present).


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9. Recovery (to Grade 1 or baseline) from all clinically significant adverse effects of 
prior therapies (excluding alopecia).
10. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
11. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
12. Be eligible to receive study treatment of bevacizumab, paclitaxel, and carboplatin 
based on local standard of care, for the treatment of advanced or metastatic 
non-squamous NSCLC.
13. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
throughout the study and for at least 6 months after receipt of the last dose of study 
treatment. 
Female patients who are not of childbearing potential (ie, meet at least 1 of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level confirming the post-menopausal state.
All other female patients, (including females with tubal ligations) will be considered to be of 
childbearing potential.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Small cell lung cancer (SCLC) or combination SCLC and NSCLC.  Squamous-cell 
tumors and mixed adenosquamous carcinomas of predominantly squamous nature.
2. Evidence of a tumor that compresses or invades major blood vessels or tumor 
cavitation that is likely to bleed.
3. Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or 
EML4-ALK translocation positive mutations.  If mutation testing is performed, the 
results must be reviewed and confirmed as negative for mutations prior to 
randomization.


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4. History of other cancer within 5 years prior to screening for this study, with the 
exception of adequately treated ductal carcinoma in situ of the breast, cervical 
carcinoma in situ, or basal or squamous cell skin cancer.
5. Prior systemic therapy for NSCLC; prior neoadjuvant or adjuvant therapy is allowed 
if surgical resection for primary disease was performed. 
6.
History of local radiation for painful bone metastases in the last 2 weeks.  (Patients 
with bone metastases are eligible, however those with symptomatic or painful bone 
metastases should not have received palliative local radiation for at least 2 weeks 
prior to randomization.)
7. History of hemoptysis (>2.5 mL per event) in the last 3 months or severe bleeding.  
Evidence of current thrombotic or bleeding disorders. Therapeutic anticoagulation 
and/or coagulation abnormalities (eg, INR >1.5 and aPTT greater than ULN unless on 
prophylactic anticoagulation).
8. Medically uncontrolled hypertension or systolic blood pressure >150 mmHg or 
diastolic blood pressure >100 mmHg.
9. Peripheral motor or sensory neuropathy with value of grade 2.
10. Major surgery or any investigational agents, within 4 weeks before the administration 
of the first dose of study treatment.  Planned major surgery during the treatment 
period. 
11. Any unhealed wound or bone fracture.
12. Active infection.  Patients must be off of anti-infective agents. 
13. Comorbities that would increase the risk of toxicity.
14. Concurrent administration of other anticancer therapies.  Bisphosphonate or 
Rank-Ligand inhibitor therapy for pre-existing bone metastases or osteoporosis is 
allowed.
15. Known central nervous system (CNS) metastases, as evidenced by appropriate scans, 
clinical symptoms, cerebral edema, and/or progressive growth (if a suspected CNS 
lesion is not confirmed by pathology).  Treated and stable (asymptomatic; off 
steroids) brain metastases are allowed.
16. Active uncontrolled cardiac disease, such as cardiomyopathy, congestive heart failure 
(CHF) New York Heart Association (NYHA) functional classification of 3, unstable 
angina, or myocardial infarction within 12 months before first dose of study 
treatment.  Clinically significant cardiovascular disease, peripheral vascular disease, 
transient ischemic attack, cerebrovascular accident. 


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17. History of severe hypersensitivity reaction to any of the products to be administered 
during the study, including mammalian cell derived drug products, taxanes, 
bevacizumab, murine proteins, or excipients in their formulations.
18. Clinical contraindication to treatment with steroids preventing use as part of 
paclitaxel premedication.
19. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant.
20. Immunocompromised patients, including known seropositivity for human 
immunodeficiency virus (HIV). 
21. Known or demonstrated hepatitis infection as listed below. Testing to demonstrate 
eligibility is required only in countries where regulations mandate testing.  In all other 
countries, testing should be considered if a patient is at risk for having undiagnosed 
infection (for example due to history of injection drug use or due to geographic 
location). 
a.
Hepatitis B infection as detected by positive testing for hepatitis B surface antigen 
(HBsAg), and detectable viral load.
b. Hepatitis C infection as detected by positive hepatitis C antibody (HCAb) and 
detectable viral load.
22. Participation in other clinical studies involving investigational drug(s) within 4 weeks 
before randomization and/or during study participation.  Patients participating in 
observational studies not involving investigational drug(s) and/or long-term follow up 
of studies involving investigational drug(s) in which treatment was completed 
4 weeks before randomization are not excluded.
23. Other severe acute or chronic medical or psychiatric condition including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study.
24. Patients who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the trial.
25. Prior treatment with immunotherapy or bevacizumab.


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4.3. Randomization Criteria
Eligibility criteria are to be reviewed and sponsor confirmation of eligibility must be received 
and confirmed prior to randomization.

Randomization of eligible patients is required as close as possible to Day 1 dosing
and no more than 1 day prior to administration of first dose of investigational product.

The investigators or their pre-specified designee will randomize eligible patients by 
web-based interactive response system (IWRS) as described in the Impala Quick 
Reference Guide.

At the time of randomization, information about patient demographics and 
stratification factors will be requested.

The central computerized system will provide the randomization number and 
treatment assignment.
4.4. Lifestyle Guidelines
4.4.1. Contraception
In this study, patients of childbearing potential will receive bevacizumab-EU as well as 
paclitaxel and carboplatin, which have been associated with teratogenic risk.  Patients should 
be advised to avoid becoming pregnant and not to father a child while receiving treatment in 
this study.  While the teratogenicity of bevacizumab-Pfizer has not been studied, it is 
expected to be the same as that of bevacizumab-EU.  Those who, in the opinion of the 
investigator, are sexually active and at risk for pregnancy must agree to use 2 methods of 
highly effective contraception throughout the study and continue to do so for at least 
6 months after the last dose of study treatment.  The investigator or his/her designee, in 
consultation with the patient, will confirm the patient has selected 2 appropriate methods of 
contraception for the individual patient and his female partner from the list of permitted 
contraception methods (see below) and will confirm the patient has been instructed in their 
consistent and correct use.  Patients need to affirm that they meet the criteria for correct use 
of 2 of the selected methods of contraception.  The investigator or his/her designee will 
discuss with the patient the need to use highly effective contraception consistently and 
correctly according to the Schedule of Activities (Table 1) and document such conversation 
in the patient’s chart.  In addition, the investigator or his/her designee will instruct the patient
to call immediately if one or both selected contraception methods are discontinued, or if 
pregnancy is known or suspected in the patient or the patient’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 


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treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD) or intrauterine system 
(IUS).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study coordinator’s manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains,
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center
in the event that the investigational site staff cannot be reached to provide advice on a 
medical question or problem originating from another healthcare professional not involved in 
the patient’s participation in the study.  The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study.  
The contact number is not intended for use by the patient directly, and if a patient calls that 
number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
After a patient has provided written informed consent and completed the necessary Screening 
assessments, the clinical site must complete an Eligibility Review Form and send it to the 
sponsor for approval of patient randomization.  Upon receipt of the sponsor’s approval, the 
site may randomize the patient by contacting the online Interactive Web Response System 
(IWRS) to register the patient by indicating minimal information sufficient to distinguish one 
patient from another, and will then receive a unique patient identification number that will be 
retained throughout the study. 


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Following site initiation, the system will automatically trigger initial drug shipment to the site
when the first patient is screened.  The system will also automatically trigger additional 
shipments to replace investigational product (IP) that is used at the site.
Randomization will be according to a randomization schedule generated by the Sponsor, and 
to which the Sponsor’s personnel directly involved in the study conduct are blinded.  The 
only exception will be in the event of an emerging safety issue which may require blind 
breaking (Section 5.2). 
5.2. Breaking the Blind
Treatment assignments for this study will be blinded to the patients, investigator/study staff 
and Sponsor’s study team conducting the trial.  The study pharmacists (or qualified designee) 
preparing treatment infusions will be unblinded, and pharmacy records will be monitored by 
a Sponsor appointed unblinded monitor.
At the initiation of the study, the study site will be instructed on using IWRS for breaking the 
blind.  Blinding should only be broken in an emergency situation for reasons of individual 
patient safety when knowledge of the investigation product (IP) assignment is required for 
medical management.  The Investigator should contact the Sponsor’s study representative, 
whenever possible, before breaking the blind.  At all other times, the treatment and 
randomization information will be kept confidential and will not be released to the 
investigational/study staff until the conclusion of the study. 
If the blind for a patient has been broken, the reason must be fully documented in source 
documents and entered on the electronic case report form (eCRF) and the patient must be 
discontinued from all study treatment.  Any adverse event (AE) or serious adverse event 
(SAE) associated with breaking the blind must be recorded in source documents and eCRF
and reported as an SAE, if appropriate.
5.3. Patient Compliance
All study medications for this protocol are intravenous drugs administered by trained and 
qualified personnel.  Records of each dose will be maintained and variations in doses will be 
managed as per Section 5.4.1.  Patients who miss dosing or scheduled visits, tests or 
procedures for reasons other than adverse events or unavoidable administrative reasons will 
be reminded of the importance of maintaining the dosing schedule.  Repeat non-compliance 
may result in withdrawal from the study in accordance with Section 6.4.1.
5.4. Drug Supplies
5.4.1. Administration and dosing
The dosing algorithm for paclitaxel, carboplatin, and blinded bevacizumab are shown below. 
On treatment days when both bevacizumab and paclitaxel-carboplatin are administered, the 
order of administration should be: 1) paclitaxel, 2) carboplatin, 3) bevacizumab. 


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Dose recalculations at the beginning of each cycle is recommended but not required if the 
weight is within 10% of baseline (Cycle 1 Day 1 dosing).  The dose should be recalculated if 
the patient’s weight changes more than 10% from baseline or if the dose has been modified 
and be used as the new baseline going forward for future dose calculations. 
Regional standards for derivation of dose calculations such as rounding conventions or 
BSA/dose capping for safety concerns are acceptable.  Excluding these expected variations, 
administered doses of carboplatin, paclitaxel, or bevacizumab within a range of +/-10% from 
the intended dose would not be considered a deviation.
Table 2.
Dosing Algorithm
Dose Level
Paclitaxel
Carboplatin
Bevacizumab-Pfizer or 
bevacizumab-EU
(blinded bevacizumab)
Starting dose
200 mg/m
2
AUC 6 (max=900mg)
15 mg/kg
Dose level -1
(first episode of AE*)
175 mg/m
2
AUC 5 (max=750mg)
7.5mg/kg after discussion 
with sponsor 
Dose level -2
(second episode of AE*)
150 mg/m
2
AUC 4 (max=600mg)
Discontinue 
Dose level -3
(third episode of AE*)
Discontinue Therapy
--
*for carboplatin/paclitaxel:  Grade 3 or 4 febrile neutropenia, nausea, vomiting, stomatitis
5.4.2. Bevacizumab
5.4.2.1. Dosage Form(s) and Packaging
Bevacizumab (bevacizumab-Pfizer or bevacizumab-EU) will be provided by the Sponsor as 
blinded supplies in which the external packaging for each vial will appear identical and will 
be identified with a unique container number.  Each container will be packaged with a 
tamper-resistant seal.  Only the unblinded pharmacist or appropriately qualified unblinded 
staff member preparing the study medication is allowed to break the tamper-resistant seal.  
The Sponsor must be notified of any study medication in which the tamper-resistant seal has 
been broken and this medication should not be used. 
Bevacizumab-Pfizer and bevacizumab-EU are clear, colorless to pale brown liquid in a glass 
vial with a rubber stopper. Each 20 mL glass vial contains 400 mg of bevacizumab in 16 ml 
of solution.
5.4.2.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.


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Bevacizumab-Pfizer will be prepared and dispensed in accordance with the European 
Medicines Authority (EMA) approved labeling for AVASTIN(bevacizumab-EU).  See the 
Dosage and Administration Instructions (DAI), for instructions in how to prepare the 
investigational product for administration.
Study drug should be prepared and dispensed by an appropriately qualified and experienced 
unblinded member of the study staff (eg, unblinded physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.  No 
information concerning patient treatment assignments will be communicated from the 
unblinded pharmacist to blinded investigators, site study staff, Sponsor study staff, or study 
patients.
Vials of investigational product (bevacizumab) should be stored refrigerated (2-8C; 
36-46F) in original packaging until ready for use.  Prior to dose preparation, the vial should 
be gently inverted or swirled to mix thoroughly.  To avoid foaming, pharmacists should not 
shake vials.  Bevacizumab should not be mixed or diluted with Dextrose solutions.
Parenteral investigational products should be inspected visually for particulate matter and 
discoloration (ie, change in color) prior to administration, whenever the solution and 
container permit.  If particulates or discoloration are observed, do not use the vial(s) and 
notify the Study Monitor. 
The study drug product should not be mixed or diluted with other drugs.  Any unused portion 
left in the vial or bag should be discarded in accordance with local requirements.
5.4.2.2.1. Bevacizumab Regimen
Blinded bevacizumab will be administered once at the start of every 21-day cycle. The initial 
dose is 15 mg/kg delivered over 90 minutes as an intravenous infusion.  If the first infusion is 
well tolerated, the second infusion may be administered over 60 minutes.  If the 60-minute 
infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.  If 
during the shortened infusions, infusion related reactions occur, the length of the infusion can 
be lengthened at the discretion of the clinician.  For the infusion of bevacizumab in patients 
over 110 kg, the dilution volume and infusion time should be increased per the Dosage and 
Administration Instructions (DAI) document and institutional standards.  The concentration 
of bevacizumab solution should be kept within the range of 1.4 mg/ml to 16.50 mg/ml.2
Infusions should not be administered as an intravenous push or bolus injection.  Infusions 
should not be administered or mixed with dextrose solutions.
Assigned blinded bevacizumab may continue to be administered after the chemotherapy has 
been discontinued until RECIST 1.1 defined disease progression, unacceptable toxicity, 
discretion of the investigator, regulatory request, death, withdrawal of consent occurs, or end 
of treatment in accordance with Section 13 whichever comes first.


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5.4.2.2.2. Bevacizumab Regimen Adjustments
The infusion of the investigational product should be interrupted if the patient develops 
dyspnea or hypotension that is deemed clinically significant by the investigator.  If a patient 
experiences an allergic reaction, hypersensitivity, adult respiratory distress syndrome, of 
Grade 3 or Grade 4 according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE, version 4.03), they will be discontinued from treatment 
with the investigational product.  Additionally, if a patient experiences a drug-related 
bronchospasm of any grade according to NCI-CTCAE, they too will be discontinued from 
treatment with the investigational product.  For patients who experience infusion-associated 
symptoms not previously specified, infusions should be slowed to 50% or interrupted. 
No dose reductions from 15mg/kg are planned for bevacizumab-Pfizer or bevacizumab-EU.  
However, in rare cases where dose reduction is deemed necessary, the investigator can 
decrease the dose of blinded bevacizumab to 7.5 mg/kg with the concurrence of the Sponsor.  
In the event of toxicity attributed to bevacizumab, treatment should be either temporarily (up 
to 2 weeks) or permanently discontinued as described in Table 3.  Following a temporary 
discontinuation, treatment may resume in accordance with local standard of care.
Table 3.
Bevacizumab Dose Adjustment Guidelines
ADVERSE EVENT
ACTION
Infusion Reaction

Mild or moderate: decrease rate of infusion

Dyspnea or clinically significant hypotension:
interrupt infusion, administer appropriate medical therapy,
which may include intravenous fluids, epinephrine, 
corticosteroids, diphenhydramine, bronchodilators, or oxygen; 
monitor until complete resolution

Severe or life-threatening: permanently discontinue therapy
Gastrointestinal Perforations

Therapy should be permanently discontinued in patients who 
develop gastrointestinal perforation
Fistulae

Permanently discontinue bevacizumab in patients with 
tracheoesophageal (TE) fistula or any Grade 4 fistula 
(NCI-CTCAE v.4.03).  Limited information is available on the 
continued use of bevacizumab in patients with other fistulae.  In 
cases of internal fistula not arising in the gastrointestinal tract, 
discontinuation of bevacizumab should be considered.


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ADVERSE EVENT
ACTION
Wound Healing Complications

Therapy should not be initiated for at least 28 days following 
major surgery or until the surgical wound is fully healed.  In 
patients who experienced wound healing complications during 
therapy, treatment should be withheld until the wound is fully 
healed.  Therapy should be withheld for elective surgery.

Necrotising fasciitis, including fatal cases, has rarely been 
reported in patients treated with bevacizumab.  This condition is 
usually secondary to wound healing complications, 
gastrointestinal perforation or fistula formation.  Bevacizumab 
therapy should be discontinued in patients who develop 
necrotising fasciitis, and appropriate treatment should be 
promptly initiated.
Hypertension

Bevacizumab should be permanently discontinued if medically 
significant hypertension cannot be adequately controlled with 
antihypertensive therapy, or if the patient develops hypertensive 
crisis or hypertensive encephalopathy.
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)

In patients developing PRES, treatment of specific symptoms 
including control of hypertension is recommended along with 
discontinuation of bevacizumab.  The safety of reinitiating 
bevacizumab therapy in patients previously experiencing PRES 
is not known.
Proteinuria/nephrotic 
syndrome

Bevacizumab should be permanently discontinued in patients 
who develop nephrotic syndrome .
Arterial thromboembolism

Therapy should be permanently discontinued in patients who 
develop arterial thromboembolic reactions.
Venous thromboembolism 

Bevacizumab should be discontinued in patients with 
life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism.  Patients with thromboembolic reactions 
Grade 3 need to be closely monitored.
Haemorrhage

Bevacizumab should be discontinued permanently in patients 
who experience Grade 3 or 4 bleeding during bevacizumab 
therapy.

Bevacizumab treatment should be discontinued in cases of 
intracranial bleeding.
Pulmonary 
haemorrhage/haemoptysis

Patients with recent pulmonary haemorrhage/ haemoptysis 
(>2.5 ml of red blood) should not be treated with bevacizumab.
Congestive heart failure (CHF)

When treating patients with cardiovascular disease that has 
developed or worsened after the initiation of the study 
treatments, the investigator should determine the benefits and 
risks of continuing bevacizumab and/or paclitaxel/carboplatin.


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ADVERSE EVENT
ACTION
Osteonecrosis of the jaw (ONJ)

Caution should be exercised when bevacizumab and intravenous
or oral bisphosphonates are administered simultaneously or 
sequentially.

In patients who have previously received or are receiving 
intravenous or oral bisphosphonates invasive dental procedures 
should be avoided, if possible.
5.4.3. Paclitaxel and Carboplatin
5.4.3.1. Paclitaxel and Carboplatin Provision
Paclitaxel and carboplatin to be administered during this study will be branded or generic 
product available in the local region.  Note that nanoparticle protein-bound paclitaxel 
(nab-paclitaxel, Abraxane) may NOT be substituted for the cremophor formulation of 
paclitaxel.  Paclitaxel and carboplatin will be procured by study sites and reimbursed by the 
Sponsor through the contractual agreement with the study institution unless local regulations
or other limitations require direct provision of background therapies by the Sponsor.  
Paclitaxel and carboplatin are to be stored, prepared and administered according to locally 
approved product labeling.
5.4.3.2. Premedication for Administration
Premedication to ameliorate the toxicities associated with the chemotherapy are to be 
administered according to the local label or institutional guidelines. 
5.4.3.2.1. Paclitaxel
All patients should be pre-medicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reaction.  Such premedication may consist of dexamethasone 20 mg 
orally administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or 
ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel. Premedication regimens that are 
standard for the institution or region may be used instead.  Premedication will be supplied by 
the site.
5.4.3.2.2. Carboplatin
Carboplatin is administered as the second drug of the chemotherapy doublet combination.
Carboplatin can induce emesis, which can be more severe in patients with prior emetogenic 
therapy. The incidence and intensity of emesis have been reduced by using premedication 
with antiemetics which should be given per local standard of care.  Because anti-emetics may 
be given prior to the paclitaxel, extra doses as premedication may not be necessary, although 
additional doses may be required if the patient develops emesis.  Premedication according to 
institutional guidelines should be used if paclitaxel has been discontinued.


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5.4.3.3. Regimen and Starting Dose(s)
5.4.3.3.1. Paclitaxel
Following pre-medication, paclitaxel is administered as the first drug when chemotherapy is 
administered. Paclitaxel at a dose of 200 mg/m2 will be administered by IV infusion over 
3 hours on Day 1 in 21-day cycles.  In the absence of progressive disease, patients will 
receive paclitaxel treatment for at least 4 but no more than 6 cycles.  Dose reduction for 
toxicity is allowed.
5.4.3.3.2. Carboplatin
Carboplatin is administered over a minimum of 15 minutes, and can be administered 
immediately after the paclitaxel infusion has completed.  Patients will be administered 
carboplatin for at least 4 and no more than 6 cycles.  Dose reduction for toxicity is allowed.
The initial dose of carboplatin is based on the use of mathematical formulae, which are based 
on a patient’s pre-existing renal function or renal function and desired platelet nadir.  Renal 
excretion is the major route of elimination for carboplatin.  The use of dosing formulae, as 
compared to empirical dose calculation based on body surface area, allows compensation for 
patient variations in pretreatment renal function that might otherwise result in either under
dosing (in patients with above average renal function) or over dosing (in patients with 
impaired renal function).
A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate 
(GFR in mL/min) and carboplatin target area under the concentration versus time curve 
(AUC in mg/mL.min), has been proposed by Calvert.5,18
Total Dose (mg) = (target AUC is 6.0) x (GFR (ml/min) + 25).
Glomerular filtration rate (GFR) is estimated for males as: 
GFR=     [(140 – age) x (weight in kg)]
                             (72 * creatinine in mg/dL)
For females, a correction factor of 0.85 is used.
Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.
Alternate formulas per local standard of care may be utilized to derive the dose of 
carboplatin.
5.4.3.3.3. Dose Adjustments for Paclitaxel and Carboplatin
All study drug treatment associated or possibly associated toxicities should be managed by 
standard medical practice. Patient toxicity should be clinically assessed before, during, and 
after each infusion.  If the investigational product causes unmanageable levels of toxicity at 
any time in the study, the investigational product should be discontinued.  Instruction for 
treatment delays and dosing modifications for paclitaxel and carboplatin are as follows:


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
Reduced doses may not be increased.

Dose modifications should be based on the AE that requires the largest change.

Severity of AEs will be graded based on CTCAE version 4.03.

Study therapy will be delayed until the AE is graded 1, except in the case of anemia, 
neuropathy, alopecia, proteinuria, and laboratory abnormalities that are deemed 
unrelated to treatment and clinically insignificant per investigator.

If study treatments must be withheld due to hematologic toxicity, complete blood 
count (CBC) and platelet counts should be obtained weekly until the counts reach the 
lower acceptance limits for treatment as outlined. The treatment schedule will then 
proceed in the usual sequence.
Once a dose of paclitaxel has been reduced for a patient, all subsequent cycles should be 
administered at that dose, unless further dose reduction is required.  Treatment with 
paclitaxel will be stopped in case of RECIST defined disease progression, unacceptable 
toxicity, death, or withdrawal of consent occurs.
Dose delay (up to 2 weeks) and dose reduction of paclitaxel and/or carboplatin will be 
permitted per local guidelines. The dose adjustments for paclitaxel and carboplatin presented 
in Table 2 in the Administration and Dosing (Section 5.4.1) are to be used as a guideline for 
investigators.  Additional measures may be taken as necessary per investigator’s medical 
judgment and per locally approved labels as well as local standard of care.  Two dose 
reductions are allowed per patient, and all reductions should be considered permanent with 
no re-escalation permitted.  All dose adjustments should be documented in the patient source 
notes.  Missed dose(s) of paclitaxel will not be made up.  If paclitaxel dosing is held at any 
point, study procedures should proceed on schedule without any delay; this includes tumor 
assessments.
Dose reduction of carboplatin for hematologic toxicity should be made based on institutional 
or regional standard of care guidelines.  All dose reductions should be considered permanent 
with no re-escalation permitted.  All dose adjustments should be documented in the patient 
source notes.  Missed dose(s) of carboplatin will not be made up.  If carboplatin dosing is 
held at any point, study procedures should proceed on schedule without any delay; this 
includes tumor assessments.
In cases where a delay in dosing is required for one or more of the drugs, the date of Day 1 of 
the next cycle should be delayed and all drugs required for that cycle be given on the new 
scheduled Day 1.  Note that tumor assessments are calendar based and are not modified to fit 
a change in dosing schedule.
5.4.4. Missed/ Delayed Dose(s) of Study Treatment
Missed dose(s) of study treatment will not be made up.  If one of the chemotherapeutic 
agents is delayed, the other agent and bevacizumab treatment should be delayed and Day 1 of 
the cycle should be shifted.  If the both chemotherapeutic agents cannot be administered 
within 2 weeks, they should be discontinued.  If only one of the chemotherapeutic agents is 
discontinued, the other can be continued. Similarly if blinded bevacizumab cannot be 
administered for 2 weeks from scheduled time due to intolerable adverse events,


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bevacizumab should be discontinued.  The interval between treatment cycles should be no 
less than 3 weeks and no more than 5 weeks in order to maintain 3 weeks per cycle with a 
maximum 2 week delay.) Tumor assessments should not be shifted as they are calendar 
based.  If bevacizumab-Pfizer or bevacizumab-EU is held or discontinued, paclitaxel and/or 
carboplatin should be continued for at least 4 and no more than 6 cycles.  For those patients 
who discontinue chemotherapy and investigational products, every effort should be made to
remain on study for follow-up, at least through Week 19 and if there is a response through 
Week 25.
5.5. Drug Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all study 
treatments, including any investigational products, comparative agents and/or marketed 
products are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.
Bevacizumab should be stored refrigerated at 2 to 8Celsius in its original container to 
protect it from light and in accordance with the label.  See the Dosage and Administration 
Instructions (DAI) and Investigational Product Manual for complete details on storage 
conditions of the investigational product. 
Paclitaxel and carboplatin should be stored per the locally approved product labeling.  Refer 
to product labeling for complete details on handling and preparation requirements.
Paclitaxel is to be stored in original packaging between 20 to 25Celsius (68 to 
77Fahrenheit). Retain in original packaging to protect from light.  Contact of the undiluted 
paclitaxel concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used 
to prepare solutions for infusion is not recommended.  In order to minimize patient exposure 
to the plasticizer, (di-(2-ethylhexyl)phthalate (DEHP)], which may be leached from PVC 
infusion bags or sets, diluted paclitaxel should be stored in bottles (glass, polypropylene) or 
plastic bags (polypropylene, polyolefin) and administered through polyethylene 
administration sets.
Carboplatin is to be stored in original packaging at 25Celsius with excursions between 15 to 
30Celsius (59 to 86Fahrenheit) permitted.  Needles or intravenous administration sets 
containing aluminum parts that may come in contact with carboplatin should not be used for 
preparation and administration of the drug.  Aluminum can react with carboplatin causing 
precipitate formation and loss of potency. 
All parenteral products should be inspected for particulate matter and discoloration prior to 
use.  If any particulate matter or discoloration is observed, the products should not be used 
and the study monitor should be notified.
Storage conditions stated in the single reference safety document (SRSD) (ie, investigator’s
brochure) will be superseded by the storage conditions stated in the labeling.


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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements,
including any actions taken, must be documented and reported to the sponsor.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approved the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.  
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
The Investigational Product Manual should be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range.
5.6. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Medications used to prevent possible adverse events or treat adverse events are allowed at the 
discretion of the investigator.  Use of concomitant treatments should follow the standard of 
care for the treating institution.
Pretreatment for bevacizumab hypersensitivity reactions should not be given unless 
hypersensitivity reactions have occurred with prior administration in an individual patient.  
The treatment regimen can produce clinically significant myelosuppression.  Transfusions 


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and growth factors are allowed and should be used according to institutional guidelines.  
Bisphosphonate or Rank-Ligand inhibitor therapy for pre-existing bone metastases or 
osteoporosis is allowed.
Carboplatin has limited nephrotoxic potential, but concomitant treatment with 
aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must 
be exercised when a patient receives both drugs.
Carboplatin can induce emesis, which can be more severe in patients previously receiving 
emetogenic therapy.  The incidence and intensity of emesis have been reduced by using 
premedication with antiemetics.
Patients receiving paclitaxel should be pretreated with corticosteroids, diphenhydramine, and 
H2 antagonists as per the regional prescribing information or institutional guidelines.
Medications and non-drug treatments will be recorded from initial dosing and monitored 
continuously by the investigator until at least 28 days following the last dose of study 
treatment to coincide with the safety evaluation period.  Patients discontinuing the active 
treatment phase will enter the follow-up phase during which survival and new anti-cancer 
therapy information will be collected until the study is completed or is terminated early. 
5.8. Additional Anticancer and Prohibited Treatments Including Radiotherapy
Additional anticancer treatments including radiotherapy are prohibited, even for palliative 
treatment of bone or brain metastatic lesions.  The need for such additional treatments
constitutes progressive disease and the patient should be discontinued from study
medications under this study.
Patients participating in this study should discuss with their doctors the risks and benefits of 
immunizations (particularly live vaccine based immunizations) during this study.
No other investigational drug or treatment for benign indications may be used during 
treatment on this protocol, and concurrent participation in another clinical trial is not 
allowed.
6. STUDY PROCEDURES 
The Schedule of Activities (Table 1) provides an overview of the protocol visits and 
procedures.  The investigator may schedule visits (unplanned visits) in addition to those 
listed on the schedule of activities, in order to conduct evaluations or assessments required to 
protect the well-being of the patient.
6.1. Screening
Voluntary, written, dated, and signed institutional review committee (IRC) or institutional 
ethics committee (IEC) approved informed consent must be obtained before any study 
specific procedures are performed. 
For details on screening procedures, see the Schedule of Activities (Table 1).


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6.1.1. Screen Failure
Patients who completed the informed consent process but do not meet all eligibility criteria 
and therefore are not randomized to any treatment arm will be considered as screen failures.  
If the conditions that led to screen failure are resolved, the patient may be rescreened and if 
eligible, enrolled.
6.2. Study Period
For details on procedures during the study period, see the Schedule of Activities (Table 1).
6.3. End-of-Treatment/Withdrawal
See Schedule of Activities for details.
6.4. Long Term Follow-up 
For details on follow-up procedures, see the Schedule of Activities (Table 1).
6.4.1. Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol-required schedule of study 
visits or procedures at a given study site. 
Patients who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to 
this is when a patient specifically withdraws consent for any further contact with him/her or 
persons previously authorized by patient to provide this information. Patients should notify 
the investigator of the decision to withdraw consent from future follow-up in writing, 
whenever possible. The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is from further treatment with study 
drug only or also from study procedures and/or post treatment study follow-up, and entered 
on the appropriate CRF page. In the event that vital status (whether the patient is alive or 
dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law.
Criteria that may be used to discontinue patient from receipt of study medication will 
include, but will not be limited to:

Objective disease progression according to RECIST 1.1 as determined by the 
investigator;

Global deterioration of health status requiring discontinuation;

Adverse events;

Significant protocol violation;


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
Lost to follow-up;

Refusal for further treatment;

Study terminated by Sponsor;

Death.
Reasons for discontinuation from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;

Lost to follow-up;

Refusal for further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  In any circumstance, every effort should be made to document patient outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request that the 
patient return for a final visit, if applicable, and follow up with the patient regarding any 
unresolved Adverse Events (AEs).
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.4.2. Lost to Follow-Up
All reasonable efforts must be made to locate patients to determine and report their ongoing
status. This includes follow-up with persons authorized by the patient as noted above. Lost 
to follow-up is defined by the inability to reach the patient after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by patient to one 
registered mail letter. All attempts should be documented in the patient’s medical records. If 
it is determined that the patient has died, the site will use permissible local methods to obtain 
the date and cause of death. If investigator’s use of third-party representative to assist in the 
follow-up portion of the study has been included in the patient’s informed consent, then the 
investigator may use a Sponsor retained third-party representative to assist site staff with 
obtaining patient’s contact information or other public vital status data necessary to complete 
the follow-up portion of the study. The site staff and representative will consult publicly 
available sources, such as public health registries and databases, in order to obtain updated 
contact information. If after all attempts, the patient remains lost to follow-up, then the last 
known alive date as determined by the investigator should be reported and documented in the 
patient’s medical records.


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
Disease assessments are to be performed as scheduled according to calendar days, regardless 
of treatment delays resulting from toxicity.  Care must be taken in scheduling disease 
assessments to prevent the introduction of bias based on treatment delays.
Failure to perform any of the required disease assessments will result in the inability to 
determine disease status for the impacted time point.  A series of incomplete disease 
assessments will result in inability to determine disease response status and censoring of PFS 
back to the time of the last full assessment that did not show progression.  Frequently 
off-schedule or incomplete disease assessments have the potential to weaken the conclusion 
of this clinical trial.
CT and MRI are the best currently available and most reproducible methods of measuring 
target lesions selected for response assessment.  MRI should only be used when considered 
more appropriate than CT or when there is a contraindication for CT with contrast.  
Assessment delay to conform to treatment delays is not permitted.  The same method of 
tumor assessments should be used throughout the trial.
The CT scans should be performed with contrast agents unless contraindicated for medical 
reasons.  If IV contrast is medically contraindicated, the imaging modality to be used to 
follow the disease (either CT without contrast or MRI) should be the modality which best 
evaluates the disease, and the choice should be determined by the investigator in conjunction 
with the local radiologist.  Depending on the adequacy for evaluation of disease, a 
combination of CT without contrast and MRI should most often be used.  CT without 
contrast is preferred for evaluation of lesions in lung parenchyma.  MRI is not adequate for 
evaluation of lung parenchyma but should also be performed to evaluate all other aspects of 
the chest.  MRI of the abdomen and pelvis should substitute for CT with contrast unless the 
method does not adequately depict the individual’s disease, in which case CT without 
contrast is preferred. 
Other methods of evaluation should be used as appropriate.  For patients having effusions or 
ascites, cases having cytological proof of malignancy should be considered non-target 
legions.  Effusions that have not been evaluated using cytology or were found to be 
non-malignant should not be considered to be lung cancer legions.


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For the purpose of study endpoint analyses, the determination of best disease response (PR or 
CR) and progression will be made in accordance with RECIST v1.1 at the opinion of the 
investigator.  Responses must be confirmed by a second set of scans including brain scan
obtained 6 weeks (7 days) later.
For the purposes of quality control, central review of tumor assessments may be performed at 
the discretion of the Sponsor.  Materials to be forwarded for independent review upon 
request by the Sponsor are all imaging studies performed on study, preferably in digital 
format sent through the vendor’s internet link or on compact disc or digital video disc (DVD)
disc.  All digital media must be in Digital Imaging and Communications in Medicine
(DICOM) format.  Films may be forwarded for review if necessary; all films must be original 
(second original film acceptable) rather than copies of films.  Further information on 
materials to be forwarded for independent review will be provided in the core imaging 
laboratory Study Manual.
7.2. Safety Assessments
7.2.1. Adverse Events
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.03), timing, seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded as adverse events during the 
trial if they worsen in severity or increase in frequency.
7.2.2. Laboratory Safety Assessments
Hematology and Blood Chemistry: Hematology and blood chemistry tests will include the 
parameters presented in Table 4.  Blood tests will be drawn at the time points described in 
Schedule of Activities table and analyzed at local laboratories.  Additional blood tests may be 
performed per standard of care, at the investigator’s discretion for the purpose of planning 
treatment administration, dose modification, following adverse events, or as clinically 
indicated.
Table 4.
Hematology and Chemistry Panels
Hematology Panel
Blood Chemistry Panel
Hemoglobin
ALT
White Blood Cells
AST
Platelets
Alkaline Phosphatase
Absolute Neutrophil Count
Total Bilirubin
Serum or Plasma Creatinine
Coagulation Panel
Sodium
International Normalized Ratio for prothrombin time
Potassium
Activated Partial Thromboplastin Time
Total Calcium
Magnesium
BUN or Urea
Albumin


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7.2.3. Other Safety Assessments
See Schedule of Activities for details. 
7.3. Pharmacokinetic Evaluations
The drug concentrations of bevacizumab-Pfizer and bevacizumab-EU will be determined 
using serum samples collected at the time points specified in the Schedule of Activities
(Table 1).  Every effort will be made to collect these PK samples within the time window 
provided, as specified in the Schedule of Activities (Table 1).  The actual time of each 
sample collection will be recorded on the source document and eCRF. 
Details on sample collection, processing and shipment will be provided in the central 
laboratory manual. 
The drug concentration sample analysis will be analyzed by the designated analytical 
laboratory using a validated analytical method in compliance with Pfizer standard operating 
procedures. All samples, unless otherwise specified below, will be analyzed.
For the pre-dose samples collected during the single-agent bevacizumab-Pfizer or 
bevacizumab-EU treatment period, analysis will be conducted for samples collected every 
other cycle, starting from the initiation of the single agent bevacizumab-Pfizer or 
bevacizumab-EU therapy (eg, Cycles 7, 9, 11, 13, and so on, for a patient who initiates the 
single agent therapy from Cycle 7).  The other pre-dose samples collected during the 
single-agent bevacizumab-Pfizer or bevacizumab-EU treatment period (eg, Cycles 8, 10, 12, 
and so on, for a patient who initiates the single agent therapy from Cycle 7) will not be 
analyzed unless corresponding immunogenicity samples are to be analyzed. 
7.4. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL will be performed by the local certified laboratory, and 
2 negative tests are required before receiving the first dose of investigational product.  The 
second negative test should be done during the first 5 days of the menstrual period, 
immediately preceding the first dose of any study treatment.  In the absence of regular 
menstrual bleeding, the patient should have used 2 different methods of contraception for at 
least 1 month before the second pregnancy test.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected), per the schedule of activities and at the end of treatment visit to 
confirm the patient has not become pregnant during the study.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from study medication and remain on the 
study for follow up. Pregnancy tests may also be repeated as per request of IRBs or IECs or 
if required by local regulations.  Patients who have missed a menstrual period or who show 
an indeterminate or positive result may not further progress in the study until pregnancy is 
ruled out.
7.5. Biomarkers
No biomarkers will be collected for the purposes of research in this trial.


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7.6. Immunogenicity Assessments
Blood samples for assessment of ADA and neutralizing antibodies will be collected at time 
points specified on the Schedule of Assessments.  Details on the sample collection, 
processing, and shipment are provided in the central laboratory manual. 
The sample analysis will be conducted by the designated analytical laboratory using a 
validated analytical method in compliance with Pfizer standard operating procedures.  All 
samples, unless otherwise specified, will be analyzed.
For the pre-dose samples collected during the single-agent bevacizumab-Pfizer or 
bevacizumab-EU treatment period, analysis will be conducted for samples collected every 
other cycle, starting from the initiation of the single agent bevacizumab-Pfizer or 
bevacizumab-EU therapy (eg, Cycles 7, 9, 11, 13, and so on, for a patient who initiates the 
single agent therapy from Cycle 7).  The other pre-dose samples collected during the 
single-agent bevacizumab-Pfizer or bevacizumab-EU treatment period (eg, Cycles 8, 10, 12, 
and so on, for a patient who initiates the single agent therapy from Cycle 7) will not be 
analyzed unless the immunogenicity results suggest that there is a need to analyze these 
samples. 
A sensitive and specific immunoassay for detecting anti-drug antibodies in human serum will 
be used to analyze the ADA samples.  The ADA assay uses biotinylated- and 
ruthenium-labeled bevacizumab-Pfizer as reagents and has been validated in compliance with 
Good Laboratory Practice.  Analysis of ADA samples will follow a tiered approach.  
Samples will first be screened for ADA; any samples that are positive in the screening assay 
will be further analyzed to confirm the positive result and determine the antibody titers.  
Samples determined to be positive for ADA may be further characterized for neutralizing 
antibodies .
7.7. Testing Lung Tissue for Mutations
See Schedule of Activity for details. 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.


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As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the patient has taken at least 1 dose of investigational product through the patient’s last
visit.
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;


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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria for 
Adverse Events CTCAE Grade 5 (see the section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
patient safety or require intervention to prevent one of the other AE outcomes, then the
important medical event should be reported as serious.
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.


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8.6.1. Protocol-Specified Serious Adverse Events
Unless the investigator believes that there is a causal relationship between the investigational 
product or study drug and an efficacy endpoint specified below, the events highlighted below 
should not be reported by the investigator as SAEs as described in the Serious Adverse Event 
Reporting Requirements section of this protocol. These events are anticipated to occur in a 
population with non-squamous non-small cell lung cancer.  However, these events should 
still be captured as adverse events in the case report form.
Efficacy endpoints that will not be reported in an expedited manner:
1. Progression of the malignancy under study (including signs and symptoms of 
progression) will not be reported as SAEs unless the outcome is fatal within the safety 
reporting period.
2. Disease progression-related events that are fatal will not be reported individually in 
an expedited manner because they are anticipated to occur in the study population.
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epidemiological data, literature, or other data, then 
this will be submitted and reported in accordance with Pfizer’s safety reporting requirements.  
Aggregate analysis of safety data will be performed on a regular basis per internal standard 
operating procedures.
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (x ULN) concurrent with a total bilirubin value 2 x ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 x ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:


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
For patients with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 x ULN, or 
8 x ULN (whichever is smaller).
Concurrent with

For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 x ULN or
if the value reaches 3 x ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);


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
Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment: NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or within 
6 months of having been exposed (eg, because of treatment or environmental 
exposure) to the investigational product; or the female becomes, or is found to be 
pregnant within 6 months after discontinuing and/or being exposed to the study 
treatments;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).


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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment or within 6 months of having been exposed to the study treatments, 
the investigator must submit this information to the Pfizer drug safety unit on an SAE report
form and EDP supplemental form, regardless of whether an SAE has occurred.  In addition, 
the investigator must submit information regarding environmental exposure to a Pfizer 
product in a pregnant woman (eg, a patient reports that she is pregnant and has been exposed 
to a cytotoxic product by inhalation or spillage) using the EDP supplemental form.  This 
must be done irrespective of whether an AE has occurred and within 24 hours of awareness 
of the exposure. The information submitted should include the anticipated date of delivery 
(see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 


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expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE 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, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL 
Detailed methodology for summary and statistical analyses of the data collected in the study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
Sponsor.  The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
Patients will be randomized to a 1:1 ratio into 2 treatment groups.  Randomization will be 
stratified by region, gender, and smoking status.  The primary endpoint is best response by 
Week 19.  Response determination will be made at the site by the Investigator.  In order to 
consider a patient to be a responder, the response will need to be confirmed by a set of tumor 
assessments 6 weeks (7 days) later.  The primary efficacy analysis for equivalence will be 
performed when all patients has completed Week 19 tumor assessment and had the 
opportunity to subsequently confirm response at Week 25.  Once all patients have been 
followed until death, withdrawal of consent, or 1 year from randomization, whichever is 
shortest, analysis of secondary endpoints such as overall survival, PFS, PK/immunogenicity, 
and 1-year safety results can be conducted.. 
9.1. Sample Size Determination
Based on the results of a meta-analysis combining Sandler (2006),6 Johnson (2004),7 and 
Niho (2012),8 the objective response rate (ORR) to bevacizumab + chemotherapy 
combination therapy was estimated to be approximately 40% based on fixed effect model, 
and the response rate to chemotherapy alone was estimated to be 21% based on the fixed 
model.  For sample size calculation the ORR is assumed to be 38%. The relative risk (RR) 
for ((bevacizumab + chemotherapy)/ chemotherapy alone) was estimated to be 2.17 with 


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95% confidence interval (1.74, 2.70).  The margin (0.73, 1.37) maintained 43% of two-sided 
95% CI lower bound of the effect size based on the historical ORR data based on the
meta-analysis treatment estimate of bevacizumab + chemotherapy over chemotherapy alone 
based on a log scale (or about 50% on the linear scale).
A sample size of 656 patients (328 per treatment arm) provides approximately 85% power 
for achieving equivalence for the RR under the specified margin with 5% type I error1 rate 
assuming an ORR of 38% in both treatment arms. Considering a possible ~7.5% attrition 
rate for patients reaching evaluation for ORR, a total sample size of approximately 
710 patients (355 per treatment arm) will be randomized to achieve the target sample size of 
656. This target sample size of 656 patients will provide approximately a power of 90% 
given above assumptions and assuming ORR=41%.
A sample size of 656 patients (328 per treatment arm) provides approximately 86% power 
for achieving equivalence for the risk difference (RD) under specified margin of (-13%,
13%) with 2.5% type I error rate assuming an ORR of 38% in both treatment arms. 
A sample size of 656 patients (328 per treatment arm) will also provide approximately 
74% power for achieving equivalence for the RR under specified margin of (0.729, 1.371) 
with 2.5% type I error rate assuming an ORR of 38% in both treatment arms.  This target 
sample size of 656 patients will provide approximately a power of 82% given above 
assumptions and assuming ORR=41%.
9.2. Analysis Population
9.2.1. Intent-to-Treat Population
The Intent-to-Treat (ITT) Population is defined as all patients who are randomized to study
treatment.  The ITT population will be used for patient accountability and all efficacy 
analyses.  Patients will be assigned to treatment groups “as randomized” for efficacy 
analyses, but “as treated” for all other analyses.  For these other analyses, if there are any 
cases where patients received both drugs, they will be assigned to the treatment initially 
given.
9.2.2. Per-Protocol Population
The Per-Protocol (PP) Population is defined as all patients who are randomized and received 
the study treatment (bevacizumab-Pfizer or bevacizumab-EU) as planned and have no major 
protocol deviations.  The PP population will be used for sensitivity analyses of the primary 
and secondary objectives. The list of patients with major protocol deviation will be 
determined based on blinded data review prior to database release.
9.2.3. Pharmacokinetics Population
Patients in the per-protocol populations who have at least one post-dose drug concentration 
measurement will be included in the PK analysis.
                                                


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9.2.4. Safety Population
The safety population is defined as all patients who are randomized and receive at least one
dose of study treatment. The safety population will be used for the safety analyses including
ADA and NAb analyses.
9.3. Efficacy Analysis
9.3.1. Analysis of Primary Endpoint
The primary efficacy endpoint of the study is ORR defined as the percent of patients within 
each treatment group who achieved Complete Response (CR) or Partial Response (PR) by 
the time of the Week 19 efficacy analysis in accordance with the RECIST 1.1.  Confirmation 
of response is required by tumor assessments done approximately 6 weeks after the response.  
Responses that are not confirmed will not be counted in the primary analysis but may be 
included in a sensitivity analysis.
Two one-sided hypothesis tests will be carried out in the study for ORR in order to show that 
bevacizumab-Pfizer is equivalent to bevacizumab-EU.
For both US and Japan, equivalence will be tested based on RR, with following hypothesis:
TEST 1: H0a: θ1 / θ2 > Rub vs. H1a: θ1 / θ2 Rub
TEST 2: H0b: θ1 / θ2 < Rlb vs. H1b: θ1 / θ2 Rlb
Where θ1 is the ORR for patients randomized to bevacizumab-Pfizer, θ2 is the ORR for 
patients randomized to bevacizumab-EU, Rub is the largest acceptable ratio for equivalence, 
and Rlb is the smallest acceptable ratio for equivalence.  Note: Rlb = 1 / Rub. For US, 
Rub=1.37 and Rlb=0.73 and for Japan, Rub=1.371 and Rlb=0.729.
For the US, equivalence will be considered established if the 90% confidence interval of the 
risk ratio falls into the margins (0.73, 1.37).
For Japan, equivalence will be considered established if the 95% confidence interval of the 
risk ratio falls into the margins (0.729, 1.371).
For the EU, equivalence will be tested based on RD, with following hypothesis:
TEST 1: H0a: θ1 - θ2 > Rub vs. H1a: θ1 - θ2 Rub
TEST 2: H0b: θ1 - θ2 < Rlb vs. H1b: θ1 - θ2 Rlb
Where Rub is the largest acceptable difference for equivalence, and Rlb is the smallest 
acceptable difference for equivalence.  Note: Rlb = -Rub=-0.13.
For the EU equivalence will be considered established if the 95% confidence interval of the 
risk difference falls into the margins (-0.13, 0.13).


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For all other regions the primary hypothesis will be analyzed based on the US scenario unless 
otherwise requested by local regulators and outlined in the SAP.
Descriptive statistics (frequency and percentage) for CR, PR, and ORR in each treatment 
group will be presented. Depending on the region the 90% or 95% confidence interval of 
these response rates will be constructed.
Miettinen and Nurminen (1985)9 method will be used as the primary analysis method for the 
binomial distributed efficacy endpoint ORR.  Detailed analysis will be described in the SAP.
9.3.2. Analysis of Secondary Endpoints
9.3.2.1. Duration of Response
Duration of response (DOR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of Progressive Disease (PD) 
or to death due to any cause in the absence of documented PD.  Censoring for the DOR
endpoint will be assigned on the date of the last tumor assessment if no assessment of tumor
progression is identified and the patient does not die while on study.
DOR will only be calculated for the subgroup of patients with an objective response.
The Kaplan-Meier method will be used to assess DOR.
9.3.2.2. Progression-Free Survival
Progression-free survival (PFS) is defined as the time from date of randomization to first 
progression of disease (PD) or death due to any cause in the absence of documented PD.  
Censoring for the PFS endpoint will be assigned on the date of the last tumor assessment if 
no assessment of tumor progression is identified and the patient does not die while on the 
study.  Patients lacking an evaluation of disease after randomization will have their PFS time 
censored on the date of randomization with duration of 1 day.  Patients who start a new 
anti-cancer therapy prior to documented PD will have the endpoint censored at the date of the 
last tumor assessment prior to the start of the new therapy. 
The Kaplan-Meier method will be used to assess the 1-year PFS, to estimate the 1-year PFS 
rate, and the confidence intervals of the 1-year PFS rate.  A two-sided log-rank test will be 
used to compare the 1-year PFS between the two treatments. 
9.3.2.3. 1-Year Survival
Time to death is defined as the time from date of randomization to death due to any cause 
while the patient is on the study.  Patients will be censored for this endpoint on the date of the 
last tumor assessment if they do not die at that time. 
The Kaplan-Meier method will be used to assess the 1-year survival, to estimate the 1-year 
survival rate, and the confidence intervals of the 1-year survival rate.  A two-sided log-rank 
test will be used to compare the 1-year survival between the two treatments.


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9.3.2.4. Pharmacokinetics, Biomarkers and Immunogenicity
PK/Immunogenicity analyses will be performed at 1 year.  See Section 9.4.4.
9.4. Safety Analysis
All patients treated with at least one dose of study treatment (bevacizumab, paclitaxel or 
carboplatin) will be included in all safety analyses.  Listings of all patient data at 1 year from 
randomization will be prepared.  Data summaries will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate.  Details of planned 
analyses will be described in the SAP.
9.4.1. Adverse Events
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system.  The severity of adverse events will be graded according to 
the NCI CTCAE version 4.0316 whenever possible.
Adverse events (treatment emergent adverse events; treatment-related adverse events; 
adverse events classified as NCI CTCAE Grade 3 or higher; and serious adverse events) will 
be summarized by body system and preferred term according to MedDRA terminology.  
Treatment emergent adverse event (TEAE) is defined as any adverse event that occurs after 
the beginning of the study treatment or any pre-existing adverse event that worsens after the 
beginning of the study treatment.
Additionally, the Pfizer standard 3-tier adverse events reporting approach will be utilized in 
this study, details of this approach will be described in the SAP.
Adverse events leading to death or discontinuation of trial treatment will be presented by 
treatment group.
Adverse events recorded on the CRF as infusion related reactions (IRRs) will be summarized 
both as individual events and as a group for the purpose of comparing the overall incidence 
of IRRs in the 2 treatment arms. 
Selected adverse events and syndromes will be summarized using grouped Medical 
Dictionary for Regulatory Activities (MedDRA) codes in addition to presentation of 
individual AE preferred terms.  Among these groupings will be the following categories of 
adverse events:

Signs and symptoms of anaphylaxis will be captured and summarized in accordance 
with guidance provided by the Second Symposium on the Definition of Anaphylaxis.17

Clinically significant decrease in LVEF.
9.4.2. Laboratory Abnormalities 
Hematology and chemistry laboratory data will be summarized by treatment and visit.  The 
laboratory results will be graded according to NCI CTCAE severity grade.  The frequencies 


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of the worst severity grade observed will be displayed by study treatment.  Shift tables of 
baseline against each post-baseline visit will be provided for selected laboratory tests to 
examine the distribution of laboratory toxicities.  For parameters for which an NCI CTCAE 
scale does not exist, the frequency of patients with values below, within, and above the 
normal ranges will be summarized by treatment and visit.
Change from baseline will be additionally summarized by treatment group and visit.  
Baseline is defined as the most recent measurement prior to the beginning of the study 
treatment.
9.4.3. Prior Concomitant Medications
Collected prior and concomitant medications will be coded by the World Health 
Organization (WHO) medical dictionary; patients who received these medications will be 
listed and summarized by treatment group separately.
9.4.4. Pharmacokinetics, Biomarkers and Immunogenicity
9.4.4.1. Pharmacokinetics
The drug concentration-time data will be summarized by descriptive statistics (mean, 
standard deviation, median, minimum, and maximum) according to treatment.
Population PK assessment will be conducted using a nonlinear mixed effect modeling 
approach.  All patients who are treated with bevacizumab-Pfizer or bevacizumab-EU, have 
no major protocol deviations that can influence the PK assessment, and provide at least one 
post-dose drug concentration measurement will be included in the population PK analysis.  A 
structural PK model based on prior information will be used.  The population PK analysis 
will estimate typical value and variability for parameters including clearance (CL) and 
volume of distribution (Vd).  Also, the influence of selected potential covariates on the PK 
parameters will be explored; the potential covariates to be explored will include drug 
product, selected demographics (eg, body weight, sex), and ADA status.
The detailed procedures for the population PK analysis, including the model implementation 
and evaluation, will be described in the Population Modeling Analysis Plan (PMAP).  The 
results of the analysis will be summarized in a Population Modeling and Analysis Report 
(PMAR).
9.4.4.2. Biomarker Analysis
There are no biomarker assessments required for this trial.
9.4.4.3. Immunogenicity
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies will be summarized for each treatment.  For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit.  In addition, efforts will be made, as appropriate, to examine possible correlations of 
the ADA response with clinical data on the PK, safety and/or efficacy of each product.


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Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.
9.4.5. Other Endpoints
Demographic and baseline characteristics such as patient age, sex, height, weight, ethnicity, 
prior therapy, medical history, ECOG performance status, and tumor mutations will be 
tabulated and summarized using descriptive statistics.  Relationships between baseline 
patient characteristics and study outcome variables will be explored with appropriate 
techniques. 
Study drug administration for each study drug will be described in terms of the total number 
of cycles administered, the medium (range) of cycles administered, dose intensity, and 
reasons for the deviations from planned therapy. 
9.5. Interim Analysis
There will be no interim analysis in this study.  The primary analysis for efficacy conducted 
after all patients have undergone Week 25 tumor assessments unless discontinued earlier is 
considered the final analysis.  Secondary analyses done after all patients have been followed
for at least 1 year, unless discontinued earlier, are also considered final analyses.  Data 
collected on patients after 1 year from randomization are considered supplemental to the final 
analyses.
9.6. Early Unblinding For PK
The main purpose of this early unblinding is to prepare for the population PK analysis.  The 
selected study data will become unblinded prior to dataset release to allow early evaluation of 
PK models.  This evaluation will enable timely and seamless analysis/reporting of population 
PK after the database release.  This early unblinding will occur when at least 50% of the 
patients complete the week 25 assessments. The data comprising of PK, ADA, NAb and 
patient level demographic and baseline data will be unblinded. 
Individuals serving on the early unblinding team will not be members of the study’s blinded 
operations team from the time that they have access to the unblinded data until the 
completion of unblinding.
9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (EDMC).
The EDMC will be responsible for ongoing monitoring of the efficacy and safety of patients 
in the study according to its charter.  The recommendations made by the EDMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data which are not endpoints, to regulatory authorities, as appropriate.


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9.8. Central Radiology Review
As this is a randomized trial, central radiology review will not be performed.  However, for 
purposes of quality control, the Sponsor may elect to have all or some tumor assessments 
reviewed by an independent imaging vendor.
The central radiology review will be done by a vendor contracted with the Sponsor.  
Instructions for forwarding images for review will be provided in study documentation.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be patient to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to International Conference on Harmonisation 
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data is compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. Use of 
initials should be avoided in compliance with Pfizer guidelines. The study site will maintain 
a confidential list of patients who participated in the study linking their numerical code to the 
patient’s actual identity.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data consistent with applicable privacy 
laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed. The investigator 
will retain the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. All advertisements must be approved by the study Sponsor prior to 
use.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.  The study is considered complete (End 
of Study) when the last patient has completed the last subject last visit (LSLV). LSLV is 
defined as up to 1 year from randomization of the last patient (End of Treatment) plus 28 day 
follow-up.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as the time at which the last patient
has completed the LSLV, at which time study objectives have been met and the study is 
considered completed.  LSLV is defined as up to 1 year from randomization of the last 
patient (End of Treatment) plus 28 day follow-up.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of bevacizumab-Pfizer at any 
time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within one week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, , and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov


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Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.  For this protocol the primary completion date is when all patients have been 
followed for 1 year after randomization not including patients who died or withdrew consent 
prior to 1 year.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials,gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by the principal investigator, whether or not the results are favorable to the Pfizer product.
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


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If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, patient to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues. 


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16. REFERENCES
1.
AVASTIN(bevacizumab) United States Prescribing Information (USPI), December, 
2015. http://www.gene.com/download/pdf/avastin_prescribing.pdf.
2.
AVASTIN(bevacizumab) Summary of Product Characteristics (SPC), December 21, 
2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000582/WC500029271.pdf
3.
AVASTINPress Release from Chugai Pharmaceutical Co., Ltd. dated November 22, 
2013 accessed 15 February 2014. 
http://www.chugai-pharm.co.jp/hc/ss/english/news/detail/20131122150000.html.
4.
TAXOL(paclitaxel) US Prescribing Information April 2011.  
http://packageinserts.bms.com/pi/pi_taxol.pdf.
5.
PARAPLATIN(carboplatin) US Prescribing Information July 2010.  
http://packageinserts.bms.com/pi/pi_paraplatin.pdf.
6.
Sandler A, Gray R, Perry MC, et al.  Paclitaxel–carboplatin alone or with bevacizumab 
for non–small-cell lung cancer.  New Engl J Med 2006;355:2542-50.
7.
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.
8.
Niho S, Kunitoh H, Nokihara H, et al. 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.
9.
Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4: 213-226. 
10.
Edge SB, Byrd DR, Compton CC, et al. Lung. In: AJCC cancer staging manual. 7th ed. 
New York, NY: Springer; 2010: p. 253-70.
11.
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response 
to treatment in solid tumors. J Natl Cancer Inst 2000; 92(3):205-16.
12.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2):228-47.
13.
Iressa(Gefitinib) Summary of Product Characteristics.  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Informatio
n/human/001016/WC500036358.pdf accessed 23 September 2014.


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14.
Tarceva(Erlotinib) Prescribing Information.  
http://www.gene.com/download/pdf/tarceva_prescribing.pdf accessed 23 September 
2014.
15.
Xalkori(Crizotinib) Prescribing Information.  
http://labeling.pfizer.com/showlabeling.aspx?id=676 accessed 23 September 2014.
16.
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). In: 
Version 4. NIH Publication No. 09-5410. Washington, DC; 2010: 194 pages.
17.
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the
definition and management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
J Allergy Clin Immunol 2006; 117(2):391-7.
18.
Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective 
evaluation of a simple formula based on renal function. J Clin Oncol 1989; 
7(11):1748-56. 


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Appendix 1. ECOG Performance Status
Grade
ECOG Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% 
of waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to 
bed or chair.
5
Dead


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Appendix 2. Response Evaluation Criteria In Solid Tumors (RECIST) Version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumors : 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228-247
CATEGORIZING LESIONS AT BASELINE
Measureable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter at least 10 mm or greater when assessed by CT or 
MRI, measured in the axial plane.  If the slice thickness is greater than 5 mm 
(including any inter-slice gap), the longest diameter must be at least twice the slice 
thickness.

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray, only if 
the tumor is clearly outlined by well-aerated lung.

Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed 
by CT or MRI.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other lesions.
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, superficial legions, and abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal Sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions though to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
legions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded of following either as measurable or non-measurable disease.
Tumor Assessments
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within the window of time specified in the Schedule of Assessments prior to 
treatment and all disease must be documented appropriately.  If the baseline assessment is 
inadequate, subsequent statuses generally should be indeterminate.
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial.  Once selected as a target lesion, a lesion 
remains target throughout the trial.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the bases of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to look for partial response at later assessments. 

If two target lesions coalesce the longest diameter measurement of the coalesced mass 
is used.  If a large target lesion splits, the sum of the parts is used. 

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
Non-Target Disease
All non-target disease is non-target.  All measureable lesions not identified as target lesions 
are also included as non-target disease.  Measurements are not require but rather assessments 
will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, 
INCREASED.  Multiple non-target lesions in organ may be recorded as a single item on the 
case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same techniques as baseline, including consistent 
administration of contract and timing of scanning.  If not, subsequent objective statuses may 
be indeterminate. 
Target Disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measureable lesions.  The short diameter is used in the 
sum for target nodules, while the longest diameter is used in the sum for all other 
target legions.  All target lesions must be assessed.

Stable: Does not qualify for CR, PR, or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy) with a minimum absolute increase of 5 mm.

Indeterminate.  Progression has not been assessed, 

one or more target lesions have not been assessed,

or assessment methods used were inconsistent with those used at baseline and 
impaired assessment,

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure),

or one of more target lesions were excised or irradiated and have not reappeared 
or increased.
Non-Target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis). 

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended that the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be
indicated on the end of treatment CRF as off treatment due to Global Determination of 
Health Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 5 demonstrates how the objective response status is determined from the assessment of 
target, non-target, and new lesions at each evaluation.


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Table 5.
Objective Response Status at Each Evaluation
Target Lesions
Non-Target Lesions
New Lesions
Objective Status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Response (partial or complete) must be confirmed by tumor assessments conducted 6 weeks 
(7 days) after the response was noted.


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Appendix 3. Tumor Staging

SAP_000.pdf: 
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PROTOCOL B7391003
A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF 
PF-06439535 PLUS PACLITAXEL-CARBOPLATIN AND 
BEVACIZUMAB PLUS PACLITAXEL-CARBOPLATIN FOR THE 
FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED
NON-SQUAMOUS NON-SMALL CELL LUNG CANCER
Statistical Analysis Plan 
(SAP)
Version:
4.0
Author:
 (PEH, Stat Department)
 (Development China, Stat Department) /
(Early Oncology Development and Clinical Research-Statistics)
Date: 28 March 2017
PPD
PPD
PPD


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................5
2.2.1. Primary Objectives .......................................................................................5
2.2.2. Secondary Objectives ...................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES, DECISION RULES AND SAMPLE SIZE................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
4.3. Sample Size...............................................................................................................8
5. ANALYSIS POPULATIONS ...............................................................................................9
5.1. Intent-to-Treat Population.........................................................................................9
5.2. Per-Protocol Population ............................................................................................9
5.3. Safety Population ......................................................................................................9
5.4. Pharmacokinetics Population ....................................................................................9
5.5. Treatment Misallocations..........................................................................................9
5.6. Protocol Deviations.................................................................................................10
6. ENDPOINTS AND COVARIATES ...................................................................................10
6.1. Endpoints.................................................................................................................10
6.1.1. Primary Endpoint........................................................................................10
6.1.2. Secondary Endpoints ..................................................................................10
6.2. Covariates................................................................................................................10
6.3. Subgroup Analyses..................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................11
7.1. Objective Response Data ........................................................................................11
7.2. Time to Event Data .................................................................................................11
7.3. Pharmacokinetic Concentrations.............................................................................11
7.4. Missing Dates..........................................................................................................12


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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................12
8.1. Statistical Methods ..................................................................................................12
8.1.1. Analysis of Response Data .........................................................................12
8.1.2. Analysis of Time to Event Data..................................................................12
8.2. Statistical Analyses .................................................................................................13
8.2.1. Standard Analyses ......................................................................................13
8.2.1.1. Subject Disposition ...................................................................13
8.2.1.2. Demographics and Baseline Characteristics .............................13
8.2.1.3. Study Treatment Exposure........................................................13
8.2.1.4. Prior and Concomitant Medications..........................................13
8.2.2. Analyses of the Primary Efficacy Endpoint ...............................................13
8.2.3. Analyses of the Secondary Efficacy Endpoint ...........................................15
8.2.4. Analyses of Pharmacokinetic Endpoints ....................................................17
8.2.5. Immunogenicity Assessment......................................................................17
8.2.6. Safety Analyses ..........................................................................................17
9. REFERENCE.......................................................................................................................20
10. APPENDICES ...................................................................................................................21
LIST OF TABLES
Table 1.  Derivation of the Best Overall Response..................................................................14
Table 2. Assessment Windows ................................................................................................21
Table 3. Summary of Key efficacy analysis ............................................................................22
APPENDICES
Appendix 1. Assessment Windows to Derive the Time Point Response ................................21
Appendix 2. Summary of Key Efficacy Analyses...................................................................22
Appendix 3. Sample Code for the Miettinen and Nurminen Method Without Strata .............23
Appendix 3.1. For Risk Ratio ..................................................................................................23
Appendix 3.2. For Risk Difference..........................................................................................23
Appendix 4. Sample Code for the Miettinen and Nurminen Method With Strata ..................24
Appendix 4.1. For Risk Ratio ..................................................................................................24
Appendix 4.2. For Risk Difference..........................................................................................28


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Appendix 5. Sample Code for DOR, PFS and Survival ..........................................................33


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This amendment is based on protocol amendment 3. Following are changes compared to the 
previous version of SAP.
Section 3 – Update the number of study reports, data versions, and planned analyses.
Section 6.3 – Updated the subgroup analyses for primary efficacy endpoint on.
Section 7.1 – Updated the method to handle data for objective response data.
Section 8.1 – clarify how to derive the best overall response for primary efficacy endpoint.
Section 8.2.3 – For secondary endpoint on DOR, PFS and OS, the one-sided p-value from 
log-rank test is replaced with 2-sided p-value from log-rank test stratified by region, gender 
and smoking history; clarified the covariates included in the Cox proportional hazard model; 
and updated the censoring algorithms.
Appendix 1 – Added the assessment windows for derivation of time point response. 
2. INTRODUCTION
This document presents the Statistical Analysis Plan (SAP) for study B7391003 (Pfizer 
compound PF-06439535). This SAP is based on the final approved protocol 
amendment 3 for study B7391003 dated Jun. 10th, 2016. 
Note: in this document any text taken directly from the protocol is italicized. 
2.1. Study Design
This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial 
evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin 
versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients 
with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous 
NSCLC.
Approximately 355 patients will be enrolled in each treatment arm for a total of 
approximately 710 patients at over 300 centers.  Patients will be randomized (1:1) to receive 
either treatment of bevacizumab-Pfizer plus paclitaxel and carboplatin or bevacizumab-EU 
plus paclitaxel and carboplatin.  Randomization will be stratified by region (according to the 
location of the drug depot supplying the site), sex (male/female) and smoking history 
(never/ever).
2.2. Study Objectives
2.2.1. Primary Objectives
The primary objective of this study is to compare the confirmed objective response rate 
(ORR) by Week 19 following treatment with bevacizumab-Pfizer in combination with 
paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in patients 
who have not received previous treatment for advanced NSCLC.


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2.2.2. Secondary Objectives

To evaluate the safety of bevacizumab-Pfizer plus paclitaxel and carboplatin and 
bevacizumab-EU plus paclitaxel and carboplatin;

To evaluate the secondary measures of tumor control; 

To evaluate the population pharmacokinetics (PK) of bevacizumab-Pfizer and 
bevacizumab-EU;       

To evaluate the immunogenicity of bevacizumab-Pfizer and bevacizumab-EU.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned for this study. 
Primary completion date CSR: The data cut-off date for the primary efficacy analysis for 
equivalence will be when the last available patient has completed Week 19 tumor assessment 
and had the opportunity to subsequently confirm the response at the Week 25 tumor 
assessment, or early discontinued (withdrawal, lost to follow up, death, etc).  All analyses 
described in Section 8 will be carried out for this data snapshot. 
Week 55 CSR: The data cut-off for the Week 55 CSR will be when the last available patient 
has completed 1-year (Week 55) assessment or early discontinued.  There are no plans to 
repeat the primary endpoint analysis of objective response rate (ORR) in the Week 55 CSR; 
the analysis of other efficacy endpoints (descriptive statistics for the secondary efficacy 
endpoints), the safety analyses, and other analyses (PK analysis and immunogenicity 
assessment) as described in Section 8 will be updated with this data snapshot. 
If there are any patients who did not complete their last follow-up by the time of the data 
snapshot for Week 55 CSR (eg, a patient may come in for another follow-up visit after he/she 
completed the week 55 visit), then listings for these remaining data will be presented in a 
separate report.
These planned analyses are summarized as follows:
Data Version
Planned Analyses
First data snapshot (Week 19 with 
confirmation data at Week 25)

All possible analyses specified in Section 
8 of this document. 
Week 55 data snapshot (Week 55)

Repeat efficacy analyses for the secondary 
efficacy endpoints (Section 8.2.3).

Repeat the PK analysis (Section 8.2.4).

Repeat the immunogenicity analysis 
(Section 8.2.5).

Repeat safety analyses (Section 8.2.6).


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The study is considered complete (End of Study) when the last patient has completed the last
subject last visit (LSLV).  LSLV is defined as up to 1 year from randomization of the last
patient (End of Treatment) plus 28 day follow-up.
This study will use an external data monitoring committee (EDMC).  The EDMC will be 
responsible for ongoing monitoring of the efficacy and safety of patients in the study 
according to its charter. Detailed information about those entities is described in the DMC 
charter. 
Limited team members will be unblinded at the time of the primary efficacy analysis. A
separate document will be created to capture the details of the unblinding plan. Site 
personnel and patients will remind blinded until the completion of the study.
4. HYPOTHESES, DECISION RULES AND SAMPLE SIZE
4.1. Statistical Hypotheses
Two one-sided hypothesis tests will be carried out in the study for ORR in order to show that 
bevacizumab-Pfizer is equivalent to bevacizumab-EU.
For both US and Japan, equivalence will be tested based on relative risk (RR), with 
following hypothesis:
TEST 1: H0a: θ1 / θ2 > Rub vs. H1a: θ1 / θ2 Rub
TEST 2: H0b: θ1 / θ2 < Rlb vs. H1b: θ1 / θ2 Rlb
Where θ1 is the ORR for patients randomized to bevacizumab-Pfizer, θ2 is the ORR for 
patients randomized to bevacizumab-EU, Rub is the largest acceptable ratio for equivalence, 
and Rlb is the smallest acceptable ratio for equivalence.  Note: Rlb = 1 / Rub.  For US, 
Rub=1.37 and Rlb=0.73 and for Japan, Rub=1.371 and Rlb=0.729.For the EU, equivalence 
will be tested based on risk difference (RD), with following hypothesis:
TEST 1: H0a: θ1 - θ2 > Rub vs. H1a: θ1 - θ2 Rub
TEST 2: H0b: θ1 - θ2 < Rlb vs. H1b: θ1 - θ2 Rlb
Where Rub is the largest acceptable difference for equivalence, and Rlb is the smallest 
acceptable difference for equivalence.  Note: Rlb = -Rub=-0.13. 
4.2. Statistical Decision Rules
For the US, equivalence will be considered established if the 90% confidence interval of the 
risk ratio falls into the margins (0.73, 1.37).
For Japan, equivalence will be considered established if the 95% confidence interval of the 
risk ratio falls into the margins (0.729, 1.371).


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.
For the EU equivalence will be considered established if the 95% confidence interval of the 
risk difference falls into the margins (-0.13, 0.13).
For all other regions the primary hypothesis will be analyzed based on a US scenario unless
otherwise requested by local regulators.
4.3. Sample Size
Based on the results of a meta-analysis combining Sandler (2006),1 Johnson (2004),2 and 
Niho (2012),3 the objective response rate (ORR) to bevacizumab + chemotherapy 
combination therapy was estimated to be approximately 41%, and the response rate to 
chemotherapy alone was estimated to be 21%.  The relative risk (RR) for ((bevacizumab + 
chemotherapy)/ chemotherapy alone) was estimated to be 2.17 with 95% CI (1.74, 2.70).  
The margin 
(0.73, 1.37) maintained 43% of two-sided 95% CI lower bound of the effect size based on the 
historical ORR data based on the meta-analysis treatment estimate of bevacizumab + 
chemotherapy over chemotherapy alone based on a log scale (or about 50% on the linear 
scale).
A sample size of 656 patients (328 per treatment arm) provides approximately 85% power 
for achieving equivalence in relative risk (RR) under the specified margin with 5% type I 
error1 rate assuming an ORR of 38% in both treatment arms.  Considering a possible 
~7.5% attrition rate for patients reaching evaluation for ORR, a total sample size of 
approximately 710 patients (355 per treatment arm) will be randomized to achieve the target 
sample size of 656.  This target sample size of 656 patients will provide approximately a 
power of 90% given above assumptions and assuming ORR=41%.
A sample size of 656 patients (328 per treatment arm) provides approximately 86% power 
for achieving equivalence in risk difference (RD) under specified margin of (-13%, 13%) 
with 2.5% type I error rate assuming an ORR of 38% in both treatment arms. This target 
sample size of 656 patients will provide approximately a power of 84% given above 
assumptions and assuming ORR=41%.
A sample size of 656 patients (328 per treatment arm) will also provide approximately 
74% power for achieving equivalence in relative risk (RR) under specified margin of 
(0.729, 1.371) with 2.5% type I error rate assuming an ORR of 38% in both treatment arms. 
This target sample size of 656 patients will provide approximately a power of 82% given 
above assumptions and assuming ORR=41%.
Unless otherwise specified, analysis for all other geographical regions will follow 
US-specific analysis using risk ratio approach.
                                                
1 For two-sided tests of superiority the alpha level is divided between the lower bound and the upper bound of the test statistic, ie, for an 
alpha level of 5%, 2.5% is allocated to the upper bound and 2.5% is allocated to the lower bound, under a single null hypothesis of no 
difference. However, in equivalence tests, there are two null hypotheses, that is, the true response rate of the biosimilar is either clinically 
greater than the reference product or is clinically less than the reference product; the two null hypotheses cannot be true at the same time. 
Thus, the alpha level for the TOST method is determined by the one sided error rate of each individual test.


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5. ANALYSIS POPULATIONS
5.1. Intent-to-Treat Population
The Intent-to-Treat (ITT) Population is defined as all patients who are randomized to study
treatment.  The ITT population will be used for patient accountability and all efficacy 
analyses.  Patients will be assigned to treatment groups “as randomized” for efficacy 
analyses, but “as treated” for all other analyses.  For these other analyses, if there are any 
cases where patients received both drugs, they will be assigned to the treatment initially 
given.
5.2. Per-Protocol Population
The Per-Protocol (PP) Population is defined as all patients who are randomized and 
received the study treatment (bevacizumab-Pfizer or bevacizumab-EU) as planned and have 
no major protocol deviations.  The PP population will be used for sensitivity analyses of the 
primary and secondary objectives. The list of patients who will be excluded from this 
population and reason for exclusion will be determined prior to unblinding for the primary 
efficacy analysis. 
5.3. Safety Population
The safety population is defined as all patients who are randomized and receive at least one
dose of study treatment.  The safety population will be used for the safety analyses including
ADA and NAb analyses.
5.4. Pharmacokinetics Population
Patients in the PP population who have at least one post-dose drug concentration 
measurement will be included in the PK analysis.
5.5. Treatment Misallocations
If a patient was:

Randomized but not treated: the patient will be accounted for in the patient
disposition table and listing. The patient will be reported under the randomized 
treatment group for efficacy analysis.  The patient will not be included in safety 
analyses.

Treated but not randomized: the patient will be reported under the treatment they
actually received for the safety analyses. The patient will not be included in efficacy 
analyses.

Randomized but received incorrect treatment: if patient received the incorrect 
treatment they will be reported under the treatment they actually received for safety 
analyses; and they will be reported under the randomized treatment group for efficacy 
analysis.  The patient will be excluded from the PP population if this is deemed as a 
major protocol deviation.  Patient profiles on safety (demographics, adverse events, 
laboratory data, anti-drug antibody, concomitant medications) may be generated for 
further assessments. 


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5.6. Protocol Deviations
Protocol deviations will be determined on an ongoing basis per blinded data review.  Any 
patient with a major protocol deviation as determined by the study team will be excluded 
from the PP population. 
6. ENDPOINTS AND COVARIATES
6.1. Endpoints
6.1.1. Primary Endpoint

Objective Response Rate (ORR), evaluating the best response achieved by 
Week 19 and subsequently confirmed by 6 weeks thereafter, in accordance with 
Response Evaluations Criteria in Solid Tumors (RECIST)4 version 1.1.
6.1.2. Secondary Endpoints

Safety characterized by type, incidence, severity, timing, seriousness, and relationship 
to study therapy of adverse events, including cardiotoxicity and infusion-related 
reactions (IRR), and laboratory abnormalities;

Duration of response (DOR), 1 year progression-free survival (PFS) rate and 1-year
survival rate from randomization;

Peak and trough bevacizumab-Pfizer and bevacizumab-EU concentrations at selected
cycles up to 1 year from randomization;

Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing
antibodies (NAb) up to 1 year from randomization.
6.2. Covariates 
In the statistical analysis models for primary efficacy on ORR and secondary endpoints on 
DOR, PFS and OS, as described in Section 8.2.2 and 8.2.3, the following covariates from the 
CRF will be used to explore their impact on the outcome variable based on ITT population:

Region (according to the location of the drug depot supplying the site). Regions 
might be combined into aggregated levels to facilitate related analyses.; 

Gender (male/female);

Smoking history (never or ever (includes ex-smoker and smoker).
6.3. Subgroup Analyses
In addition, the following factors at screening will be used in the subgroup analyses for 
primary efficacy endpoint on ORR based on ITT population and a forest plot will be 
presented.

Smoking history (never or ever (includes ex-smoker and smoker))


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
Gender (male/female)

Region (according to the location of the drug depot supplying the site). Regions 
might be combined into aggregated levels to facilitate related analyses.

Age (≥65, <65)

Race (White, Black, Asian, Other)

Disease Stage (IIIB, IV, recurrent)

Prior radiation therapy (Yes, No)

Any prior systemic therapy, including adjuvant/neoadjuvant (Yes, No)

ECOG PS (0, 1)
7. HANDLING OF MISSING VALUES
7.1. Objective Response Data 
Objective response (CR or PR) will be derived based on investigator reported tumor 
assessments.  At each time point, missing response data will be considered as non-evaluable; 
the time point responsewill be used to derive the best objective response in accordance with 
RECIST 1.1.  In the best objective response rate calculation, if a patient has missing tumor 
outcome across all visits or if he/she had non-evaluable best overall response following 
RECIST 1.1, the patient will be considered as non-responder, and will be included in the 
denominator but will not be included in the numerator.
7.2. Time to Event Data
For the time-to-event endpoints (DOR, PFS, or survival), the missing data handling method 
will be censoring.  Censoring mechanisms for these endpoints are described in Section 8.2.3. 
7.3. Pharmacokinetic Concentrations
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  In the listings BLQ values will be reported as “<LLQ”, where 
LLQ will be replaced with the value for the lower limit of quantification. 
Deviations, missing concentrations and anomalous values
Patients who experience events that may affect their PK profile (eg, incomplete dosing due to 
injection reactions) may be excluded from the PK analysis. 
In drug concentration summary tables, statistics will be calculated having set concentrations 
to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);


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2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the PK analyst.
For patients with a quantifiable concentration value for the pre-dose PK sample collected 
before treatment initiation, the concentration-time data without any adjustment will be 
included in PK data summary if the pre-dose concentration value is 5% of Cmax from the 
same patient.  If the concentration value in the pre-dose sample in a patient is >5% of Cmax
from the same patient, the patient will be excluded from the PK data summary.
7.4. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of resolution cannot be prior to date 
of onset; if replacing resolution date with the 1st of the month results in a negative duration, 
the resolution date will be set to the onset date).  Pfizer standards are similarly used if both 
month and day are missing (January 1 unless negative time duration).  For overall survival 
and PFS, if conventions result in a negative duration, duration will be reset to 1 day. 
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
While every effort has been made to pre-specify all analyses in this statistical analysis plan, 
should any additional exploratory analyses be found to be necessary, the analyses and the 
reasons for them will be detailed in the clinical study report.
8.1. Statistical Methods 
For primary efficacy endpoint of objective response rate, secondary endpoints on DOR, PFS 
and overall survival (OS), outcome will be derived based on investigator tumor assessments. 
8.1.1. Analysis of Response Data 
Miettinen and Nurminen (1985)4 method without strata will be used as the primary analysis 
method for the binomial distributed efficacy endpoint ORR.  Estimated risk ratio, risk 
difference and the asymptotic 95% and 90% CI in ORR between bevacizumab-Pfizer and 
bevacizumab-EU will be computed and used in the hypothesis testing.
8.1.2. Analysis of Time to Event Data 
The time to event endpoints (DOR, PFS, and survival) will be assessed by the Kaplan-Meier 
method.  Time to event curves between the two treatment groups will be compared with a 
log-rank test along with the corresponding hazard ratio.  PFS rate and survival rate will be 
estimated along with the corresponding 95% CI. 


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8.2. Statistical Analyses 
8.2.1. Standard Analyses
8.2.1.1. Subject Disposition
A subject disposition table will be provided.  Subject disposition will be summarized by 
treatment group and will include the number and percentage of patients, randomized, treated, 
and analyzed for safety and efficacy.  The percentage of patients who are ongoing and 
discontinued in the treatment and follow up periods will be presented.
The percentages will use the number of randomized patients in each treatment group as the 
denominator.  The disposition summary will be based on the ITT population. 
8.2.1.2. Demographics and Baseline Characteristics
Demographic and baseline characteristics such as patient age, sex, height, weight, ethnicity, 
prior therapy, medical history, ECOG performance status and screening LVEF results will 
be tabulated and summarized using descriptive statistics.  These endpoints will be 
summarized descriptively by treatment group for the ITT population.
8.2.1.3. Study Treatment Exposure
Following endpoints will be summarized by treatment groups for both chemotherapy and 
bevacizumab-Pfizer/bevacizumab-EU:

Duration of treatment: number of cycles.
8.2.1.4. Prior and Concomitant Medications
Collected prior and concomitant medications will be summarized by treatment group for the 
safety population.
8.2.2. Analyses of the Primary Efficacy Endpoint
The primary efficacy endpoint is the best objective response rate achieved by Week 19 and 
subsequently confirmed, based on the investigator reported assessment.
To assess the best overall response, the response from each patient at different time point 
(time point response) will need to be derived, based on the clustered investigator reported 
tumor assessments following the assessment window as presented in Appendix 1, unless it is 
certain that the tumor assessments were from different visits.  The best overall response per 
patient will then be derived from the time point response in accordance with RECIST 1.1.  
The confirmation assessment for CR or PR must be at least 4 weeks later; the minimum 
criterion for SD duration is 5 weeks from the date of randomization.  The following table 
presents some typical scenarios for deriving the best overall response.


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Table 1.  Derivation of the Best Overall Response
Assessment 1
Assessment 2
Assessment 3
Assessment 4
Overall Response
CR
CR
PD
CR *
CR
NE
CR
PD
CR *
PR
CR
CR
PD
CR *
PR
CR
PD 
PR *
PR
PR
PD
PR *
PR
NE
PR
PD
PR *
PR
PR
CR
PD
PR *
CR
PR
Not allowed **.  
SD/PD/PR.  Review 
of the CR is 
recommended.
CR
PD 
SD ***
PR
PD
SD ***
SD or NE
CR
PD
SD ***
SD or NE
PR
PD
SD ***
SD
PD 
SD ***
PD
PD
NE
PD
PD
NE
NE
PD
Assume no response

The best overall response is CR/PR, if the assessments with PR/CR is ≥ 4 weeks apart (NE is allowed 
between the assessments of PR/CR); otherwise, it is SD if the minimum criteria for SD duration is met, else 
it is PD.
** 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.  
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. 
*** Unconfirmed responses are considered as stable disease, if the minimum criterion for SD duration is met.
The primary analysis for this endpoint will be based on the Miettinen and Nurminen 
(1985)4 method without strata.  Estimated risk ratio and risk difference and the asymptotic 
95% and 90% CI in ORR between bevacizumab-Pfizer and bevacizumab-EU will be
computed.  This analysis will be carried out by the BINOMIAL procedure in SAS 
(Appendix 3).  The risk ratio, risk difference and its associated 95% and 90% CI will be used 
in the hypothesis test as described in Section 4.  This analysis will be based on the ITT 
population.  Same analysis based on PP population will also be performed as a sensitivity 
analysis.
The Miettinen and Nurminen method will also be carried out with additional stratification 
variables described in Section 6.2, to assess whether these factors will affect the risk ratio / 
risk difference of ORR between the 2 treatment groups. This analysis will be performed 
based on both ITT population. Reference SAS code is available in the appendix.
In addition, descriptive statistics will also be presented for the best overall response by Week 
19 (confirmed at Week 25) by treatment group.


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8.2.3. Analyses of the Secondary Efficacy Endpoint
For DOR, PFS and survival (time to death), a Cox proportional hazard models may be 
performed; the model will include treatment and the covariates specified in Section 6.2.  The 
hazard ratios and the 95% CIs of the hazard ratios based on the model will be presented.
DOR
Duration of response (DOR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of Progressive Disease (PD) 
or to death due to any cause in the absence of documented PD.  Censoring for the DOR 
endpoint will be assigned on the date of the last tumor assessment if no assessment of tumor 
progression is identified and the patient does not die while on study. If no adequate disease 
assessment at baseline, the endpoint will be censored on the date of randomization with 
duration of 1 day. When a patient has missing tumor assessment(s) but remains as a CR or 
PR responder at the time of data analysis, the endpoint will be censored at the time of the last 
available tumor assessment where CR or PR is declared.  DOR will only be calculated for the 
subgroup of patients with a confirmed objective response achieved by week 19 from ITT 
population; same analysis will be repeated for PP population as a sensitivity analysis.
The Kaplan-Meier method will be used to estimate the DOR rate at 1-year. The 2-sided 95% 
CIs of the rate using the Greenwood’s formula will be reported.  Kaplan-Meier curves will 
also be plotted for each of the two treatment group at 1-year together with a 2-sided log-rank 
test stratified by region, gender and smoking history (as specified in Section 6.2) to compare
the DOR curve between the two treatment groups at 1-year.  The Kaplan-Meier method will 
also be used to obtain the estimates of median DOR associated with each treatment group.  
The 2-sided 95% CIs for the 25th, 50th and 75th percentiles of the DOR time using the 
Brookmeyer and Crowley method will be reported when estimable. 
At the time of the first data cut off (Week 19 and confirmed at Week 25), all above 
mentioned analyses will be performed for secondary endpoints.  The DOR endpoint will be 
censored based on the following algorithms:

If a Patients last known, 1) to be alive, 2) not to have started new (non-protocol) 
anti-cancer treatment, and 3) to be progression-free, and who have a baseline and at 
least one on-study disease assessment, are censored at the date of the last objective 
disease assessment that verified lack of progressive disease (even if there is 
unacceptably long interval between the assessments).

If no assessment of tumor progression is identified by the investigator assessment and 
the patient does not die, the endpoint will be censored on the date of the last available 
tumor assessment. 

If radiotherapy or surgery is used to manage any target lesion or the patient starts a 
new anti-cancer therapy prior to the documented PD, the endpoint will be censored on 
the date of the last available tumor assessment prior to the start of the new anti-cancer 
therapy. 


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Patients with documentation of progressive disease or death after an unacceptably long 
interval (> 14 weeks) since the last tumor assessment will be censored at the time of last 
objective assessment verifying lack of disease progression prior to the event.PFS and PFS 
Rates
PFS is defined as the time from date of randomization to first progression of disease (PD) or 
death due to any cause, whichever occurred first.  The analysis of this endpoint will be based 
on ITT population and same analysis based on PP population will also be performed as a 
sensitivity analysis.  The tumor assessment will be based on investigator assessment in 
accordance with RECIST 1.1.  The PFS endpoint will be censored based on the following 
algorithms:

If a Patients last known, 1) to be alive, 2) not to have started new (non-protocol) 
anti-cancer treatment, and 3) to be progression-free, and who have a baseline and at 
least one on-study disease assessment, are censored at the date of the last objective 
disease assessment that verified lack of disease progression (even if there is 
unacceptably long interval between the assessments).

If no assessment of tumor progression is identified by the investigator assessment and 
the patient does not die, the endpoint will be censored on the date of the last available 
tumor assessment. 

If no evaluation of disease is performed after randomization, the endpoint will be 
censored on the date of randomization with duration of 1 day.  (If patient died prior to 
the first scheduled disease assessment, death will be considered as an event). 

If radiotherapy or surgery is used to manage any target lesion or the patient starts a 
new anti-cancer therapy prior to the documented PD, the endpoint will be censored on 
the date of the last available tumor assessment prior to the start of the new therapy. 

Patients with documentation of progression or death after an unacceptably long 
interval (> 14 weeks) since the last tumor assessment will be censored at the time of 
last objective assessment verifying lack of disease progression prior to the event. 

If no adequate disease assessment at baseline, the endpoint will be censored on the 
date of randomization with duration of 1 day. 
Similar analyses, as described for DOR, will be carried out for PFS. 
Survival and Survival Rates
Survival (time to death) is defined as the time from date of randomization to death due to any 
causes.  Patients will be censored for this endpoint on the date known alive. Date of last 
known alive could be determined from onset date of AE, concomitant medication or any 
other documented assessments.  The Kaplan-Meier method will be used to estimate 1-year 
survival rates, the 2-sided 95% CIs of 1-year survival rate will also be reported.  
Kaplan-Meier curves will also be plotted for each of the two treatment group at 1-year 


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.
together with a 2-sided log-rank test stratified by region, gender and smoking history (as 
specified in Section 6.2) to compare the survival distribution between the 2 treatment groups
at the three timepoints.  The analysis will be carried out based on ITT population and same 
analysis will be repeated based on PP population as a sensitivity analysis.
8.2.4. Analyses of Pharmacokinetic Endpoints
The drug concentration-time data will be summarized by descriptive statistics (mean, 
standard deviation, median, minimum, and maximum) according to treatment.  A listing of 
all concentrations sorted by treatment, subject ID and nominal time postdose will be 
generated.  The concentration listing will also include the actual sampling times.  Deviations 
from the nominal time will be given in a separate listing.
Population PK assessment will be conducted using a nonlinear mixed effect modeling 
approach.  All patients who are treated with bevacizumab-Pfizer or bevacizumab-EU, have 
no major protocol deviations that can influence the PK assessment and provide at least one 
post-dose drug concentration measurement will be included in the population PK analysis.  A 
structural PK model based on prior information will be used.  The population PK analysis 
will estimate typical value and variability for parameters including clearance (CL) and 
volume of distribution (Vd).  Also, the influence of selected potential covariates on the PK 
parameters will be explored; the potential covariates to be explored will include drug 
product, selected demographics (eg, body weight, sex), and ADA status.
Details of the population PK data analysis will be reported in a Population Modeling 
Analysis Report that is separate from the Clinical Study Report.
8.2.5. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies will be summarized for each treatment.  For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit.  In addition, efforts will be made, as appropriate, to examine possible correlations of 
the ADA response with clinical data on the PK, safety and/or efficacy of each product.
Because the observed incidence of ADA is highly dependent on multiple factors including the 
assays used for ADA detection, timing of sample collection and immune status of the patients, 
the incidence of ADA observed in the planned study may differ from the incidence reported in 
historical clinical trials.
This analysis will be carried out with the safety population.
8.2.6. Safety Analyses
Patients who start treatment are assessed for toxicities up to at least 28 days after final dose 
of treatment or start of new anti-cancer therapy (whichever comes first). Toxicities observed 
beyond 28 days and recorded in the database per sponsor's agreement will be included in the 
summaries.


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.
The safety analyses will be carried out in the safety population.  The following safety 
endpoints will be summarized descriptively: 

Treatment emergent Adverse Events (TEAE), bevacizumab- related AE, Serious 
Adverse Events (SAE), and treatment related SAE;

Adverse events leading to delays, dose reduction and permanent discontinuation;

Echocardiogram (ECHO) or MUGA.
Treatment emergent adverse events (TEAE) is defined as any adverse event that occurs after 
the beginning of the study treatment (on or after Study Day 1) or any pre-existing adverse 
event that worsens after the beginning of the study treatment and at least 28 days after final 
dose of study treatment or start of new anticancer therapy (whichever comes first).  Whether 
an adverse event is related to the study treatment will be determined by the investigator. 
The Pfizer standard 3-tier adverse events reporting approach will be employed: 

Tier-1 events will be identified by the medical team on an ongoing basis and the final 
list of events will be determined before database lock.  Frequency and percentage of 
patients with each treatment group, risk difference (RD), 95% CI on RD Tier-2 events 
will be those events that occur in >= 10% patients in at least one treatment group.  
The frequency and percentage of patients, RD and 95% CI of RD will be provided for 
each event. 

Tier-3 events will be all other events that are neither Tier-1 nor Tier-2.  Only 
frequency and percentage of patients will be provided.
The 3-tier AE summary tables will be generated for all TEAEs and then for those that are 
related to the study treatment. 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA)6 to determine System Organ Class and Preferred Term. Common Terminology 
Criteria for Adverse Events (CTCAE)7, version 4.03, will be used to grade severity. Adverse 
events will be summarized by System Organ Class and Preferred Term and severity for each 
treatment group. CTCAE Grade 3 or higher adverse events will be additionally summarized 
separately by treatment group.
Selected adverse events and syndromes will be summarized using grouped MedDRA codes in 
addition to presentation of individual AE preferred terms.  Among these groupings will be 
the following categories of adverse events:

Signs and symptoms of anaphylaxis will be captured and summarized in accordance 
with guidance provided by the Second Symposium on the Definition of Anaphylaxis.

Clinically significant decrease in LVEF.


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ECHO or MUGA will be summarized by treatment and visit. Change from baseline and 
percent change from baseline will be summarized by treatment and visit for selected 
continuous variables.  Baseline is Day 1 and if Day 1 value is missing, the closest 
measurement prior to Day 1 will be used.
Shift tables of baseline against each post-baseline visit may be provided for selected 
laboratory tests to examine the distribution of laboratory toxicities.
Physical examination at screening phase will be collected in the CRF and will be listed in a 
data listing. Vital signs will be presented in listing format only.
Patient listings will be produced for all safety endpoints. 


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.
9. REFERENCE
1.
Sandler A, Gray R, Perry MC, et al.  Paclitaxel–carboplatin alone or with bevacizumab 
for non–small-cell lung cancer.  New Engl J Med 2006;355:2542-50.
2.
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.
3.
Niho S, Kunitoh H, Nokihara H, et al. 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.
4.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2):228-47.
5.
Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4: 213-226.
6.
http://www.meddra.org/
7.
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). In: 
Version 4. NIH Publication No. 09-5410. Washington, DC; 2010: 194 pages.


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10. APPENDICES
Appendix 1. Assessment Windows to Derive the Time Point Response
To derive the time point response for each patient, the assessment windows in Table 2 will be 
used to cluster the assessments.
Table 2. Assessment Windows
Assessments
Scheduled 
Assessment 
Day
Start Day of 
Assessment 
Window
End day of 
Assessment 
Window
1
42
22
63
2
84
64
105
3
126
106
147
4
168
148
200


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.
Appendix 2. Summary of Key Efficacy Analyses 
The key efficacy analyses are summarized in.
Table 3. Summary of Key efficacy analysis
Endpoint
Analysis 
Set
Statistical Method 
Covariates
Missing Data
Analyses type
ORR
ITT
Miettinen and Nurminen
without strata
Treatment
Non-responder 
imputation 
Primary analysis
ORR
PP
Miettinen and Nurminen
without strata
Treatment
Non-responder 
imputation 
Sensitivity 
analysis
ORR
ITT
Miettinen and Nurminen
with strata
Treatment and 
other covariates
Non-responder 
imputation 
Secondary 
analysis
ORR
PP
Miettinen and Nurminen
with strata
Treatment and 
other covariates
Non-responder 
imputation 
Secondary 
analysis
DOR
ITT
Kaplan-Meier 
Treatment
Censoring
Secondary 
analysis
DOR
PP
Kaplan-Meier 
Treatment
Censoring
Secondary 
analysis
PFS 
ITT
Kaplan-Meier
Treatment
Censoring
Secondary 
analysis
PFS 
PP
Kaplan-Meier
Treatment
Censoring
Secondary 
analysis
Survival
ITT
Kaplan-Meier
Treatment
Censoring
Secondary 
analysis
Survival
PP
Kaplan-Meier
Treatment
Censoring
Secondary 
analysis


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.
Appendix 3. Sample Code for the Miettinen and Nurminen Method Without Strata
Appendix 3.1. For Risk Ratio
First, manipulate study data to form the following structure.  The variable Count in the 
sample would be corresponding to the ORR count in the primary efficacy analysis. 
Data test;
Input   group $     resp $      count;
Cards;
  pfe          yes        210
  pfe          no         180
  eu           yes        202
  eu           no         188
;
run;
Then, apply the following codes to obtain the asymptotic 90% CI:
proc binomial data=test alpha=0.9;
eqv/as ratio margin=1.37;
po group;
ou resp;
weight count;
run;
quit;
Appendix 3.2. For Risk Difference
First, manipulate study data to form the same structure as in Appendix 3.1.  
Then, apply the following codes to obtain the asymptotic 95% CI:
proc binomial data=test alpha=0.95;
eqv/as diff margin=0.13;
po group;
ou resp;
weight count;
run;
quit;


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Appendix 4. Sample Code for the Miettinen and Nurminen Method With Strata
Appendix 4.1. For Risk Ratio
%macro MNRRFunc(RR=); 
/* calculate ML estimate of R1 and R0*/
r0s=0;
r1s=0;
/* initial value of weights sum */
wsum=0;
%do j=1 %to &size;
wsum=wsum+w&j;
%end;
/* paper equation (12) */
%do j= 1 %to &size;
AA=(&&nt&j+&&nc&j)*&RR;
BB=-(&&nt&j*&RR+&&yt&j+&&nc&j+&&yc&j*&RR);
CC= &&yc&j+&&yt&j;
r0&j=(-BB-sqrt(BB*BB-4*AA*CC))/(2*AA);
r1&j=r0&j*&RR; 
/* rounding the boundary values */
if r0&j>1 then r0&j=1;if r0&j<0 then r0&j=0;
if r1&j>1 then r1&j=1;if r1&j<0 then r1&j=0;
r0s=r0s+r0&j*w&j/wsum;
r1s=r1s+r1&j*w&j/wsum;
%end;
/* end of calculate ML estimate of R1 and R0*/
/* update the weights W, paper equation (18) */
%do j=1 %to &size;
w&j=1/((1-r1s)/(1-r0s)/&&nt&j+&RR/&&nc&j);
%end;
wsum=0;
%do j=1 %to &size;
wsum=wsum+w&j;
%end;


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/* calculate the variance V, paper equation (11) */
vsum=0;
%do j=1 %to &size;
v&j=(r1&j*(1-r1&j)/&&nt&j+(&RR**2)*r0&j*(1-
r0&j)/&&nc&j)*((&&nt&j+&&nc&j)/(&&nt&j+&&nc&j-1));
if v&j=0 then do;      
r0&j=0.001;
      
r1&j=0.001;
v&j=(r1&j*(1-r1&j)/&&nt&j+(&RR**2)*r0&j*(1-
r0&j)/&&nc&j)*((&&nt&j+&&nc&j)/(&&nt&j+&&nc&j-1));
end;
vsum=vsum+w&j**2*v&j/wsum**2;
%end;
/* calculate the score and the limits, paper equation (17)  */
t=0;
%do j=1 %to &size;
t=t+((&&yt&j/&&nt&j*w&j)-(&&yc&j/&&nc&j*w&j*&RR))/wsum/sqrt(vsum);
%end;
ZA1=t+probit(1-&alpha/2); /* upper limit */
ZA2=t-probit(1-&alpha/2); /* lower limit */
%mend;
/** Use bisection method and iterative procedure to find the limits for RR **/
%macro RRrootfinding(parainput=,size=,alpha=);
/* read in parameters from input dataset to global variables */
proc sql noprint;
   select nt, nc, yt, yc
     into :nt1 - :nt&size, :nc1 - :nc&size, :yt1 - :yt&size, :yc1 - :yc&size
           from &parainput;
/* main part of the macro */
data MNRR; 
/* set machine epsilon for bisection method*/
eps=0.000001;
/* read parameters from global variables*/
%do j=1 %to &size;
nt&j=&&nt&j;
nc&j=&&nc&j;


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yt&j=&&yt&j;
yc&j=&&yc&j;
/* following parameters are used to define the searching range */
/* 0.5 and 1 is added to avoid cases when cells has value 0 */
c1s&j=&&yt&j+0.5;
n1s&j=&&nt&j+1;
c0s&j=&&yc&j+0.5;
n0s&j=&&nc&j+1;
%end;
/* set initial values for weights */
%do j=1 %to &size;
w&j= 1/(1/&&nt&j+1/&&nc&j);
%end;
/**max RR and Min RR for searching*/;
b1=0;b0=0.01;
%do j=1 %to &size;
b1=max(b1,(c1s&j/n1s&j)/(c0s&j/n0s&j),(c0s&j/n0s&j)/(c1s&j/n1s&j));  
b0=min(b0,(c1s&j/n1s&j)/(c0s&j/n0s&j),(c0s&j/n0s&j)/(c1s&j/n1s&j));
%end;
b1=b1*100;
b0=b0/100;
/*Upper Limits, using bisection method */;
Uroot1=b0; RR=Uroot1; %MNRRFunc(RR=RR);y1=ZA1;  
Uroot3=b1; RR=Uroot3; %MNRRFunc(RR=RR);y3=ZA1;
y2=(b1+b0)/2;
i=0;
if y1*y3>0 then do;
put  "f does not have opposite sign at endpoints";
Uroot2=.;
end;
else do while (i<1000 and abs(y2)>eps);
i=i+1;
        Uroot2=(Uroot1+Uroot3)/2;
        RR=Uroot2; %MNRRFunc(RR=RR); y2=ZA1;
                RR=Uroot1; %MNRRFunc(RR=RR); y1=ZA1;


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               RR=Uroot3; %MNRRFunc(RR=RR); y3=ZA1;
           
               if y1*y2<0 then do;
        Uroot3=Uroot2;
        y3=y2;
       end;
       else do;
            Uroot1=Uroot2;
        y1=y2;
       end;
       end;
/*Lower Limits, using bisection method */;
%do j=1 %to &size;
w&j= 1/(1/&&nt&j+1/&&nc&j);
%end;
Lroot1=b0; RR=Lroot1; %MNRRFunc(RR=RR); y11=ZA2; 
Lroot3=b1; RR=Lroot3; %MNRRFunc(RR=RR); y33=ZA2;
y22=(b0+b1)/2;
i=0;
if y11*y33>0 then do;
                put  "f does not have opposite sign at endpoints" ;
    Lroot2=.;
end;
else do while (i<1000 and abs(y22)>eps);
i=i+1;
        Lroot2=(Lroot1+Lroot3)/2;
                RR=Lroot2; %MNRRFunc(RR=RR); y22=ZA2;
                RR=Lroot1; %MNRRFunc(RR=RR); y11=ZA2;
                RR=Lroot3; %MNRRFunc(RR=RR); y33=ZA2;
               if y11*y22<0 then do; 
                     Lroot3=Lroot2;
         y33=y22;
       end;
       else do;
            Lroot1=Lroot2;
        y11=y22;
       end;


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        end;
keep nt1 nt2 nc1 nc2 yc1 yc2 yt1 yt2 Lroot2 Uroot2;
run;
%mend;
/* provide feed in data to the macro*/
/* each line represent values in each stratum */
/* with total n in each arm (nt and nc) and responder in each arm (yt and yc) */
/* following example only contains one strata with 4 levels */
data data;
input nt nc yt yc;
cards;
100 110 60 70
120 110 80 70
120 115 70 70
130 120 75 75
;
run;
/* calculated CI based on RR with MN method with strata*/
/* parameter Size is the total levels of strata.If two strata is considered, each with 2 and 3 
levels, */
/* there will be 6 lines in the input dataset, and size=6  */
%RRrootfinding(parainput=data,size=4,alpha=0.05);
Appendix 4.2. For Risk Difference
%macro MNRDfunc(RD=);
/* force the restricted difference not equal to zero*/
if &RD=0 then RD=0.001; else RD=&RD;
/* calculate ML estimate of R1 and R0*/
r0s=0;
r1s=0;
/* initial value of weights sum */
wsum=0;
%do j=1 %to &size;
wsum=wsum+w&j;
%end;
/* paper equation (27),(28) */
%do j= 1 %to &size;
L0=&&yc&j*RD*(1-RD);
L1=(RD*&&nc&j-&&nc&j-&&nt&j-2*&&yc&j)*RD+(&&yt&j+&&yc&j);


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L2=(&&nt&j+2*&&nc&j)*RD-&&nc&j-&&nt&j-(&&yt&j+&&yc&j);
L3=&&nt&j+&&nc&j;
*************************;
q=(L2**3)/(27*(L3**3))-(L1*L2)/(6*L3*L3)+L0/(2*L3);
p=q/abs(q)*sqrt((L2*L2)/(9*L3*L3)-L1/(3*L3));
a=(1/3)*(arcos(-1)+arcos( q/(p**3)));
**************************;
r0&j=2*p*cos(a)-L2/(3*L3);
r1&j=r0&j+RD;
/* rounding the boundary values */
if r0&j>1 then r0&j=1;if r0&j<0 then r0&j=0;
if r1&j>1 then r1&j=1;if r1&j<0 then r1&j=0;
r0s=r0s+r0&j*w&j/wsum;
r1s=r1s+r1&j*w&j/wsum;
%end;
/* end of calculate ML estimate of R1 and R0*/
/* update the weights W, paper equation (16) */
%do j=1 %to &size;
w&j=1/(r1s*(1-r1s)/r0s/(1-r0s)/&&nt&j+1/&&nc&j);
%end;
wsum=0;
%do j=1 %to &size;
wsum=wsum+w&j;
%end;
/* calculate the variance V, paper equation (8) */
vsum=0;
%do j=1 %to &size;
v&j=(r1&j*(1-r1&j)/&&nt&j+r0&j*(1-
r0&j)/&&nc&j)*((&&nt&j+&&nc&j)/(&&nt&j+&&nc&j-1));
if v&j=0 then do;      
r0&j=0.001;
      
r1&j=0.001;
v&j=(r1&j*(1-r1&j)/&&nt&j+r0&j*(1-
r0&j)/&&nc&j)*((&&nt&j+&&nc&j)/(&&nt&j+&&nc&j-1));
end;
vsum=vsum+w&j**2*v&j/wsum**2;
%end;
/* calculate the score and the limits, paper equation (15) */


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t=0;
%do j=1 %to &size;
t=t+w&j*(&&yt&j/&&nt&j-&&yc&j/&&nc&j)/wsum/sqrt(vsum);
%end;
t=t-RD/sqrt(vsum);
Zmnd1=t-probit(1-&alpha/2);
Zmnd2=t+probit(1-&alpha/2);
%mend;
/** Use bisection method and iterative procedure to find the limits for RD **/
%macro RDrootfinding(parainput=,size=,alpha=);
/* read in parameters from input dataset to global variables */
proc sql noprint;
   select nt, nc, yt, yc
      into :nt1 - :nt&size, :nc1 - :nc&size, :yt1 - :yt&size, :yc1 - :yc&size
           from &parainput;
/* main part of the macro */
data MNRD;
/* set machine epsilon for bisection method*/
eps=0.000001;
/* read parameters from global variables*/
%do j=1 %to &size;
nt&j=&&nt&j;
nc&j=&&nc&j;
yt&j=&&yt&j;
yc&j=&&yc&j;
%end;
/* set initial values for weights */
%do j=1 %to &size;
w&j= 1/(1/&&nt&j+1/&&nc&j);
%end;
/**max RR and Min RR for searching*/;
b1=-0.999;
b0=0.999;


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/*Lower Limits, using bisection method */;
Lroot1=b0;RD=Lroot1;%MNRDfunc(RD=RD); y1=Zmnd1; 
Lroot3=b1;RD=Lroot3;%MNRDfunc(RD=RD); y3=Zmnd1; 
i=0;y2=2*eps;    
if y1*y3>0 then do;
     
put  "f does not have oposite sign at endpoints" ;
     
Lroot2=.;
end;
else do while (i<1000 and abs(y2)>eps);
        i=i+1;
        Lroot2=(Lroot1+Lroot3)/2;
        RD=Lroot2; %MNRDfunc(RD=RD); y2=Zmnd1;
        RD=Lroot1; %MNRDfunc(RD=RD); y1=Zmnd1;
        RD=Lroot3; %MNRDfunc(RD=RD); y3=Zmnd1;
if y1*y2<0 then do;
      
Lroot3=Lroot2;
y3=y2;
    end;
    else do;
Lroot1=Lroot2;
y1=y2;
    end;
end;
/*Upper Limits, using bisection method */;
    Uroot1=b0; RD=Uroot1; %MNRDfunc(RD=RD); y11=Zmnd2;
    Uroot3=b1; RD=Uroot3; %MNRDfunc(RD=RD); y33=Zmnd2;
     y22=2*eps;   
i=0;
if y11*y33>0 then do;
put  "f does not have oposite sign at endpoints" ;
Uroot2=.;
end;
else do while (i<1000 and abs(y22)>eps);
    
i=i+1;
     
Uroot2=(Uroot1+Uroot3)/2;


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RD=Uroot2; %MNRDfunc(RD=RD); y22=Zmnd2;
     
RD=Uroot1; %MNRDfunc(RD=RD); y11=Zmnd2;
     
RD=Uroot3; %MNRDfunc(RD=RD); y33=Zmnd2;
       
if y11*y22<0 then do;
             Uroot3=Uroot2;
y33=y22;
end;
        else do;
Uroot1=Uroot2;
y11=y22;
end;
end;
keep nt1 nt2 nc1 nc2 yc1 yc2 yt1 yt2 Lroot2 Uroot2;
run;
%mend;
/* provide feed in data to the macro*/
/* each line represent values in each stratum */
/* with total n in each arm (nt and nc) and responder in each arm (yt and yc) */
/* following example only contains one strata with 4 levels */
data data;
input nt nc yt yc;
cards;
100 110 60 70
120 110 80 70
120 115 70 70
130 120 75 75
;
run;
/* calculated CI based on RD with MN method with strata*/
/* parameter Size is the total levels of strata.If two strata is considered, each with 2 and 3 
levels, */
/* there will be 6 lines in the input dataset, and size=6  */
%RDrootfinding(parainput=data,size=4,alpha=0.05);


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Appendix 5. Sample Code for DOR, PFS and Survival
Analysis dataset event derivations
CNSR = 0 for patients who have an Event, and a value of 1 for patients who were censored.
AVAL is in weeks. AVAL is derived as: [ADT (date of event) – RANDDT +1] / 7 for patients with events 
where RANDDT is randomization date.
SAS code analogous to the following will be used:
proc lifetest data = adtte outsurv=survpl alpha=0.05 alphaqt=0.05;
     where aval ne . and cnsr ne . and trtpn ne .;
     strata trtpn;
     time aval * cnsr(1);
run;
quit;
The Kaplan-Meier Estimate of PFS at 25 weeks and 55 weeks will be derived using the TIMELIST= option in 
PROC LIFETEST
proc phreg data = adtte;
    where aval ne . and cnsr ne . and trtpn ne . and strata1 ne . and strata2 ne .;
    model aval * cnsr(1) = trtpn / alpha = 0.05 rl ties= efron;
    strata strata1 strata2;
run ;
quit;
proc lifetest data=adtte ;
     where aval ne . and cnsr ne . and trtpn ne . and strata1 ne . and strata2 ne .;
     time aval * cnsr(1);
     strata strata1 strata2/ group=trtpn; 
run;
quit;