Clinical trial NCT04325698
Conditions: Advanced Non-squamous NSCLC
Sponsor: Pfizer
Start date: 2020-06-11; Completion date: 2021-05-10
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The current study will compare the efficacy, safety, pharmacokinetics and immunogenicity of PF-06439535 (CN) in combination with paclitaxel and carboplatin versus bevacizumab sourced from the European Union (bevacizumab-EU) with paclitaxel and carboplatin in Chinese participants with advanced non-squamous NSCLC in the first-line treatment setting.

Detailed description:

Arms: arm 1: PF-06439535 (CN) + paclitaxel + carboplatin arm 2: Bevacizumab-EU + paclitaxel + carboplatin
Interventions: intervention 1: PF-06439535 (CN) intervention 2: Bevacizumab-EU intervention 3: Paclitaxel intervention 4: Carboplatin
Intervention descriptions: intervention 1: 15 mg/kg, IV on day 1 of each 21 day cycle for up to 2 years, or until progression or unacceptable toxicity develops. intervention 2: 15 mg/kg, IV on day 1 of each 21 day cycle until disease progression, unacceptable toxicity or 25 weeks. At Week 25, the participants with clinical benefit will received PF-06439535 (CN) monotherapy for up to 2 years from randomization in this study intervention 3: 175 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: AUC 5 (max=750mg) 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.

Protocol documents:
Prot_000.pdf: 
PF-06439535 (CN)
Protocol B7391007
Final Protocol, 27 Jun 2019
PFIZER CONFIDENTIAL
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A RANDOMIZED, DOUBLE-BLIND BRIDGING SAFETY AND EFFICACY STUDY
OF PF-06439535 (CN) PLUS PACLITAXEL-CARBOPLATIN VERSUS
BEVACIZUMAB PLUS PACLITAXEL-CARBOPLATIN FOR THE FIRST-LINE 
TREATMENT OF CHINESE PARTICIPANTS WITH ADVANCED 
NON-SQUAMOUS NON-SMALL CELL LUNG CANCER
Investigational Product Number:
PF-06439535 (CN)
Investigational Product Name:
Bevacizumab Injection
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
B7391007
Phase:
3
Short Title: A BRIDGING STUDY OF PF-06439535 (CN) PLUS 
PACLITAXEL-CARBOPLATIN VERSUS BEVACIZUMAB PLUS 
PACLITAXEL-CARBOPLATIN IN CHINESE PARTICIPANTS WITH 
ADVANCED NON-SQUAMOUS NSCLC
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
27 Jun 2019
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................20
2.1. Study Rationale .......................................................................................................20
2.2. Background .............................................................................................................21
2.2.1. Clinical Overview.......................................................................................21
2.2.1.1. Bevacizumab .............................................................................21
2.2.1.4. Paclitaxel as Background Therapy for Study B7391007 ..........30
2.2.1.5. Carboplatin as Background Therapy for Study B7391007 .......32
2.3. Benefit/Risk Assessment.........................................................................................33
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................34
4. STUDY DESIGN.................................................................................................................35
4.1. Overall Design.........................................................................................................35
4.2. Scientific Rationale for Study Design.....................................................................35
4.3. Justification for Dose ..............................................................................................37
4.4. End of Study Definition ..........................................................................................37
5. STUDY POPULATION......................................................................................................37
5.1. Inclusion Criteria.....................................................................................................37
5.2. Exclusion Criteria....................................................................................................38
5.3. Lifestyle Considerations..........................................................................................42
5.3.1. Contraception..............................................................................................42
5.4. Screen Failures ........................................................................................................42
6. INVESTIGATIONAL PRODUCT......................................................................................42
6.1. Investigational Product(s) Administered.................................................................43
6.1.1. Administration............................................................................................43
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6.1.1.1. Bevacizumab .............................................................................44
6.1.1.2. Paclitaxel and Carboplatin.........................................................45
6.2. Preparation/Handling/Storage/Accountability ........................................................46
6.2.1. Preparation and Dispensing........................................................................48
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................48
6.3.1. Allocation to Investigational Product .........................................................48
6.3.2. Breaking the Blind......................................................................................48
6.4. Investigational product Compliance........................................................................49
6.5. Concomitant Therapy..............................................................................................49
6.5.1. Additional Anticancer and Prohibited Treatments Including 
Radiotherapy....................................................................................................50
6.5.2. Rescue Medicine.........................................................................................50
6.6. Dose Modification...................................................................................................50
6.6.1. Bevacizumab Regimen Adjustments..........................................................50
6.6.2. Paclitaxel and Carboplatin Regimen Adjustments .....................................52
6.7. Intervention After the End of the Study..................................................................53
7. DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................................54
7.1. Discontinuation of Investigational Product.............................................................54
7.1.1. Temporary Discontinuation........................................................................54
7.2. Participant Discontinuation/Withdrawal From the Study.......................................54
7.3. Lost to Follow-up....................................................................................................55
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................56
8.1. Efficacy Assessments..............................................................................................57
8.1.1. Imaging Assessments..................................................................................57
8.2. Safety Assessments .................................................................................................58
8.2.1. Physical Examinations................................................................................58
8.2.2. Vital Signs ..................................................................................................58
8.2.3. Electrocardiograms.....................................................................................59
8.2.4. Clinical Safety Laboratory Assessments ....................................................59
8.2.5. MUGA or ECHO........................................................................................60
8.2.6. Pregnancy Testing ......................................................................................60
8.3. Adverse Events and Serious Adverse Events..........................................................60


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......61
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................61
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................61
8.3.2. Method of Detecting AEs and SAEs ..........................................................62
8.3.3. Follow-up of AEs and SAEs.......................................................................62
8.3.4. Regulatory Reporting Requirements for SAEs...........................................62
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................63
8.3.5.1. Exposure During Pregnancy......................................................63
8.3.5.2. Exposure During Breastfeeding ................................................63
8.3.5.3. Occupational Exposure .............................................................63
8.3.6. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................63
8.3.7. Medication Errors .......................................................................................64
8.4. Treatment of Overdose............................................................................................65
8.5. Pharmacokinetics ....................................................................................................65
8.5.1. Analysis of Anti-drug (bevacizumab) Antibodies......................................66
8.6. Pharmacodynamics..................................................................................................66
8.7. Genetics...................................................................................................................66
8.7.1. Specified Genetics ......................................................................................66
8.8. Biomarkers ..............................................................................................................66
8.8.1. Specified Gene Expression (ribonucleic acid [RNA]) Research................67
8.8.2. Specified Protein Research.........................................................................67
8.8.3. Specified Metabolomic Research ...............................................................67
8.8.4. Testing Lung Tissue for Mutations.............................................................67
8.9. Health Economics ...................................................................................................67
9. STATISTICAL CONSIDERATIONS ................................................................................67
9.1. Estimands and Statistical Hypotheses.....................................................................68
9.1.1. Estimands....................................................................................................68
9.3. Populations for Analysis .........................................................................................69
9.4. Statistical Analyses .................................................................................................69
9.4.1. Efficacy Analyses .......................................................................................69
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9.4.1.1. Analysis of the Primary Endpoint .............................................69
9.4.2. Safety Analyses ..........................................................................................70
9.4.2.1. Adverse Events..........................................................................70
9.4.2.2. Laboratory Test Abnormalities .................................................70
9.4.2.3. Prior Concomitant Medications ................................................71
9.4.3. Other Analyses............................................................................................71
9.4.3.1. Pharmacokinetics ......................................................................71
9.4.3.2. Biomarker Analysis...................................................................71
9.4.3.3. Immunogenicity ........................................................................71
9.5. Interim Analyses .....................................................................................................72
9.5.1. Data Monitoring Committee.......................................................................72
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................73
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............73
10.1.1. Regulatory and Ethical Considerations ....................................................73
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................73
10.1.2. Informed Consent Process ........................................................................74
10.1.3. Data Protection .........................................................................................75
10.1.4. Dissemination of Clinical Study Data ......................................................75
10.1.5. Data Quality Assurance ............................................................................76
10.1.6. Source Documents....................................................................................77
10.1.7. Study and Site Closure..............................................................................78
10.1.8. Publication Policy.....................................................................................78
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................79
10.2. Appendix 2: Clinical Laboratory Tests .................................................................80
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................81
10.3.1. Definition of AE .......................................................................................81
10.3.2. Definition of SAE.....................................................................................82
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................84
10.3.4. Reporting of SAEs....................................................................................86


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................88
10.4.1. Male Participant Reproductive Inclusion Criteria....................................88
10.4.2. Female Participant Reproductive Inclusion Criteria.................................88
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................89
10.4.4. Contraception Methods.............................................................................90
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........93
10.6. Appendix 6: Response Evaluation Criteria In Solid Tumors (RECIST) 
Version 1.1 Guidelines ..............................................................................................95
10.7. Appendix 7: American Joint Committee on Cancer (AJCC) Definitions of 
Tumor, Node, Metastases (TNM) and Prognostic Stage Groups............................100
10.8. Appendix 8: ECOG Performance Status.............................................................102
10.9. Appendix 9: ECG Findings of Potential Clinical Concern .................................103
10.10. Appendix 10: Abbreviations .............................................................................105
11. REFERENCES ................................................................................................................109
LIST OF TABLES
Table 2.
Summary of BOR and ORR (Week 19) (Unstratified) – ITT 
Population.................................................................................................25
Table 3.
Treatment-Emergent Adverse Events (All Causalities) - Safety 
Population.................................................................................................27
Table 4.
Dosing Algorithm .....................................................................................44
Table 5.
Bevacizumab Dose Adjustment Guidelines .............................................51
Table 6.
Protocol-Required Safety Laboratory Assessments .................................80
Table 7.
Objective Response Status at Each Evaluation ........................................99
LIST OF FIGURES
Figure 1.
B7391007 Study Schema..........................................................................12
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Objectives
Estimands
Endpoints
the immunogenicity.
characteristics of 
PF-06439535 
(CN) relative to 
bevacizumab-EU without 
regard to discontinuation
of treatment or use of 
concomitant therapy.
Overall Design
This is a double-blind, randomized, parallel-group, bridging clinical trial evaluating the 
efficacy and safety of PF-06439535 (CN) plus paclitaxel and carboplatin versus
bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for participants with 
advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.
Approximately 108 participants will be enrolled in each treatment arm for a total of 
approximately 216 participants at over 30 centers.  Participants will be randomized (1:1) to 
receive either PF-06439535 (CN) 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 until investigator-assessed disease progression defined by 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, unacceptable toxicity, death, 
withdrawal of consent occurs, lost to follow-up, or 25 weeks, whichever comes first.  At 
Week 25, all of the participants who continue to demonstrate clinical benefit in the opinion of 
the investigator, will receive PF-06439535 (CN) monotherapy for up to 2 years from 
randomization in this study, or until no further benefit from treatment (eg, investigator 
assessed disease progression, unacceptable toxicity, death, withdrawal of consent, lost to 
follow-up), whichever occurs first.  Randomization will be stratified by sex (male/female) 
and smoking history (yes/no).  Efficacy, safety, PK and immunogenicity assessments and 
procedures will be undertaken as described in the Schedule of Activities, Study Flowchart 1
and 2.  
Actual length of participation for individual participants will depend upon the actual duration 
of treatment.  Participants will be expected to participate in the study for approximately 
26 months.  This includes up to 1 month of screening, 24 months for treatment and 28 days 
of safety follow-up.  A participant has completed the study if he/she has completed all phases 
of the study including the last visit.  The end of the study is defined as the date of the last 
visit of the last participant in the study.  
Number of Participants
A total sample size of approximately 216 participants (108 per treatment arm) will be 
randomized to achieve the target sample size of 200.  


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Intervention Groups and Duration
There are two treatment arms:
Arm A PF-06439535 (CN) + paclitaxel + carboplatin.
Arm B Bevacizumab-EU + paclitaxel + carboplatin.
Assigned PF-06439535 (CN) or bevacizumab-EU monotherapy following completion of at 
least 4 and no more than 6 cycles of combination with chemotherapy will proceed until 
investigator-assessed disease progression defined by RECIST 1.1, unacceptable toxicity, 
death, withdrawal of consent occurs, or lost to follow-up or 25 weeks, whichever comes first.
At Week 25, all of the participants who continue to demonstrate clinical benefit in the 
opinion of the investigator, will receive PF-06439535 (CN) monotherapy for up to 2 years 
from randomization in this study, or until no further benefit from treatment (eg, investigator 
assessed disease progression, unacceptable toxicity, death, withdrawal of consent, lost to 
follow-up), whichever occurs first.  This will require participants initially randomized to 
Arm B to switch from bevacizumab-EU to PF-06439535 (CN) monotherapy starting at 
Week 25 (Cycle 9).  
Data Monitoring Committee: 
This study will use an external data monitoring committee (E-DMC).
Statistical Methods:
This study is descriptive in nature, and hence no statistical hypothesis testing will be done.  
For efficacy, descriptive statistics for complete response (CR), partial response (PR) and
objective response rate (ORR) by treatment group will be presented.  The frequency, 
percentage and 90% confidence interval of these response rates will be constructed.  The 
estimated risk difference and risk ratio in ORR between PF-06439535 (CN) and 
bevacizumab-EU will be computed, and the corresponding 90% confidence intervals will be 
calculated using Miettinen and Nurminen (1985) method.  Safety, pharmacokinetics (PK), 
and immunogenicity will be summarized by treatment group.
After all participants have completed the Week 25 visit (ie, the last participant randomized 
has completed the Week 25 visit) or have otherwise died, withdrawn consent, or are lost to 
follow-up, primary study completion will be achieved.  A database snapshot (containing data 
up to and including the Week 25 visit for every participant) will be performed after the 
primary completion date (PCD) and a study report will be developed to support the new drug 
application.  Data collected after the Week 25 visit will be summarized in a supplemental 
clinical study report which will describe safety results during the monotherapy extension 
period and will be considered as supplemental to the clinical study report for the PCD.


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In general, efficacy, safety, PK and immunogenicity as of the Week 25 visit will be analyzed 
by treatment group in the study report for the PCD.  In the supplemental clinical study report, 
safety will be summarized across all patients, and PK and immunogenicity (which are to be 
collected at end of treatment/withdrawal visit) will be listed.  
1.2. Schema
Figure 1.
B7391007 Study Schema
B7391007 Study Schema
* Following completion of at least 4 and no more than 6 cycles of chemotherapy, assigned PF-06439535 
(CN) or bevacizumab-EU monotherapy for up to but not including Week 25.
# PF-06439535 (CN) will be provided for all of the participants who continue to demonstrate clinical benefit in 
the opinion of the investigator up to 2 years from randomization.




























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Table 2.
Summary of BOR and ORR (Week 19) (Unstratified) – ITT Population
Number (%) of 
Participants
PF-06439535
(N=358)
Bevacizumab-EU
(N=361)
Total
(N=719)
Objective progression
15 (4.2)
14 (3.9)
29 (4.0)
Indeterminatea
27 (7.5)
20 (5.5)
47 (6.55)
Objective response rate 
(CR+PR)
162 (45.3)
161 (44.6)
323 (44.9)
95% Exact CIb
[40.01, 50.57]
[39.40, 49.89]
[41.25, 48.64]
Treatment comparison (versus bevacizumab-EU)
Un-stratified risk difference in ORR 
(%)c
0.6531
95% CI of difference (%)c
[-6.6080, 7.9082]
Treatment comparison (versus bevacizumab-EU)
Un-stratified risk ratiod
1.0146
95% CI of risk ratiod
[0.8628, 1.1933]
90% CI of risk ratiod
[0.8856, 1.1625]
ORR data from the primary completion date, PCD (08 May 2017).
ORR was defined as the percentage of participants within each treatment group who achieved CR or PR by 
Week 19 of the study, which was subsequently confirmed by Week 25, in accordance with RECIST, Version 
1.1.
Abbreviations: BOR=best overall response; CI=confidence interval; CR=complete response; EU=European 
Union; ITT=intent-to-treat; N=total number of participants; ORR=objective response rate; PR=partial 
response; RECIST=Response Evaluation Criteria in Solid Tumors.  
a.
Indeterminate: Early deaths, unevaluable tumor assessment, and early study discontinuations.  
b.
Exact method based on F-distribution was used.
c.
Calculated based on 2-sided Miettinen and Nurminen method without strata for risk difference for 
confirmed response.  EU equivalence margins (95% CI in -13% to 13%).
d.
Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed 
response.  US equivalence margins (90% CI in 0.73 to 1.37) and Japan equivalence margins (95% CI in 
0.729 to 1.371).
There were no clinically meaningful differences between PF–06439535 and
bevacizumab-EU shown in the analyses for all the secondary efficacy endpoints.
The results support an overall conclusion of no clinically meaningful difference in efficacy 
between PF–06439535 and AVASTIN (bevacizumab–EU).  


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2.2.1.3.3. Similarity in Safety – Study B7391003
A single, comparative clinical efficacy and safety trial (B7391003) was conducted to 
compare the safety profiles of PF-06439535 and bevacizumab-EU in the sensitive population 
of participants with non-squamous NSCLC.  The results of this study are summarized below.
A summary of all causality TEAEs, SAEs, discontinuations of any treatment, temporary 
discontinuations, dose reductions and infusion rate reductions are provided in Table 3.  
Overall, these events were comparable between the PF-06439535 group and the 
bevacizumab-EU group.
Table 3.
Treatment-Emergent Adverse Events (All Causalities) - Safety Population
Number (%) of Participants
PF-06439535
(N=356)
Bevacizumab-E
U
(N=358)
Total
(N=714)
Number of adverse events 
2442
2470
4912
Participants with adverse events 
344 (96.6)
347 (96.9)
691 (96.8)
Participants with serious adverse 
events 
81 (22.8)
80 (22.3)
161 (22.5)
Participants with Grade 3 or 4 adverse 
events 
159 (44.7)
159 (44.4)
318 (44.5)
Participants with Grade 5 adverse 
events 
21 (5.9)
24 (6.7)
45 (6.3)
Participants discontinued any 
treatment due to adverse events 
85 (23.9)
86 (24.0)
171 (23.9)
Participants discontinued 
bevacizumab only due to adverse 
events
37 (10.4)
29 (8.1)
66 (9.2)
Participants discontinued 
bevacizumab and chemotherapy due 
to adverse events
30 (8.4)
28 (7.8)
58 (8.1)
Participants discontinued paclitaxel 
due to adverse events 
53 (14.9)
60 (16.8)
113 (15.8)
Participants discontinued carboplatin 
due to adverse events 
49 (13.8)
54 (15.1)
103 (14.4)


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Table 3.
Treatment-Emergent Adverse Events (All Causalities) - Safety Population
Number (%) of Participants
PF-06439535
(N=356)
Bevacizumab-E
U
(N=358)
Total
(N=714)
Participants temporarily discontinued 
bevacizumab only due to adverse 
events
42 (11.8)
39 (10.9)
81 (11.3)
Participants temporarily discontinued 
bevacizumab and chemotherapy due 
to adverse events
52 (14.6)
52 (14.5)
104 (14.6)
Participants temporarily discontinued 
paclitaxel due to adverse events
56 (15.7)
59 (16.5)
115 (16.1)
Participants temporarily discontinued 
carboplatin due to adverse events
53 (14.9)
51 (14.2)
104 (14.6)
Participants with dose reduction of 
bevacizumab only due to adverse 
events
0
0
0
Participants with dose reduction of 
bevacizumab and chemotherapy due 
to adverse events
0
0
0
Participants with dose reduction of 
paclitaxel due to adverse events
27 (7.6)
38 (10.6)
65 (9.1)
Participants with dose reduction of 
carboplatin due to adverse events
22 (6.2)
38 (10.6)
60 (8.4)
Participants with infusion rate reduced 
for bevacizumab only due to adverse 
events
0
0
0
Participants with infusion rate reduced 
for bevacizumab and chemotherapy 
due to adverse events
0
0
0
Participants with infusion rate reduced 
for paclitaxel due to adverse events 
2 (0.6)
0
2 (0.3)
Participants with infusion rate reduced 
for carboplatin due to adverse events
1 (0.3)
0
1 (0.1)


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Table 3.
Treatment-Emergent Adverse Events (All Causalities) - Safety Population
Number (%) of Participants
PF-06439535
(N=356)
Bevacizumab-E
U
(N=358)
Total
(N=714)
Included data up to 28 days after the last dose of study drug or to start of subsequent anti-cancer therapy 
(whichever occurred first).
Except for the “number of adverse events”, participants were counted only once per treatment in each row.
Serious adverse events - according to the investigator’s assessment.
Severity counts were based on the maximum severity or grade of events.
MedDRA version 20.1 coding dictionary applied.
Abbreviations: EU=European Union; MedDRA=Medical Dictionary for Regulatory Activities; N=number 
of participants evaluable for adverse events.
The majority of the participants in this study had at least 1 treatment emergent adverse event 
(TEAE (all causality), with 344 (96.6%) participants in the PF-06439535 group, and 
347 (96.9%) participants in the bevacizumab-EU group reporting a total of 2442 and 
2470 TEAEs (Table 3).  
A total of 161 (22.5%) participants had at least 1 serious adverse event (SAE) (all causality) 
with 81 (22.8%) participants in the PF-06439535 group, and 80 (22.3%) participants in the 
bevacizumab-EU group.  The most frequently reported SAEs (>1% of participants in either 
treatment group) were pneumonia, with 8 (2.2%) participants in the PF-06439535 group, and 
6 (1.7%) participants in the bevacizumab-EU group; febrile neutropenia (5 [1.4%] 
participants in the PF-06439535 group and 7 [2.0%] participants in the bevacizumab-EU 
group); and pulmonary embolism (7 [2.0%] participants in the PF-06439535 group, and 
2 [0.6%] participants in the bevacizumab-EU group).
TEAEs of special interest were selected based on the established safety profile of 
bevacizumab and reported as Tier-1 AEs.  The identified TEAEs of special interest included 
ATE events, bleeding/hemorrhage (including pulmonary hemorrhage), cardiac disorders, 
congestive heart failure, hypertension (Grade 3 or higher), proteinuria/nephrotic syndrome, 
venous thromboembolic events (VTE), gastrointestinal (GI) perforations, and wound healing 
complications.  Overall, all causality TEAEs of special interest were comparable and no
clinically meaningful differences were noted between the 2 treatment groups.
Nineteen (19 [5.3%]) participants in the PF-06439535 group, and 22 (6.1%) participants in 
the bevacizumab-EU group reported infusion related reactions (IRRs) as per the 
investigator’s assessment.  A total of 21 (2.9%) participants (12 [3.4%] participants in the 
PF-06439535 group, and 9 [2.5%] participants in the bevacizumab-EU group reported 
bevacizumab-related IRRs in this study.  IRRs reported by the investigators were comparable 
between the two treatment groups.  In addition, the incidence of potential hypersensitivity 
TEAEs was comparable among the 2 treatment groups in the retrospective analysis of 
TEAEs retrieved by using standardized Medical Dictionary for Regulatory Activities 
[MedDRA] queries (SMQs) of hypersensitivity and anaphylactic reactions.




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Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of 
participants 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.
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.


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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.
2.2.1.5. Carboplatin as Background Therapy for Study B7391007
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.12
Carboplatin is indicated for the initial treatment of advanced ovarian carcinoma in 
combination with other approved chemotherapeutic agents and for 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 advanced, recurrent or 
metastatic disease.
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.


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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.12
2.3. Benefit/Risk Assessment
PF-06439535 (CN) is being developed as a potential biosimilar to bevacizumab, marketed 
under the brand name AVASTIN.  Bevacizumab (AVASTIN) is commercially available in 
the United States (bevacizumab-US), European Union (bevacizumab-EU), China 
(bevacizumab-CN), Japan, and other regions.  In China, bevacizumab is licensed for the 
treatment of metastatic colorectal cancer (mCRC) and first-line non-squamous NSCLC.  
Lung cancer is the most common cancer among men and the leading cause of cancer related 
morbidity and mortality worldwide.  NSCLC accounts for 85% of total lung cancer cases.13  
Bevacizumab has shown anti-tumor activity in previously untreated NSCLC patients, which
also 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 PF-06439535 (CN) and bevacizumab-EU.
For the potential risk, the overall safety profile of AVASTIN is based on data from over 
5700 patients with various malignancies, predominantly treated with AVASTIN in 
combination with chemotherapy in clinical trials.  The most frequently observed adverse 
reactions across clinical trials in participants receiving AVASTIN were hypertension, fatigue 
or asthenia, diarrhea and abdominal pain.  Analyses of the clinical safety data suggest that the 
occurrence of hypertension and proteinuria with AVASTIN therapy are likely to be 
dose-dependent.1,2


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More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PF-06439535 (CN) and bevacizumab may be found in the 
investigator’s brochure, which is the single reference safety document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To explore similarity in efficacy of 
PF-06439535 (CN) and bevacizumab-
EU, each in combination with 
paclitaxel and carboplatin, based on a 
descriptive estimation of objective 
response rate (ORR).

The primary estimand is the 
treatment effect of PF-
06439535 (CN) relative to 
bevacizumab-EU by Week 
19 and subsequently 
confirmed by Week 25 
without regard to 
discontinuation of treatment 
or use of concomitant 
therapy.  If a participant 
takes anti-cancer 
medication, all responses 
after that timepoint are 
excluded from the analysis.

ORR, evaluating best overall 
responses achieved by Week 19 and 
subsequently confirmed by Week 25, 
in accordance with Response 
Evaluations Criteria in Solid Tumors 
(RECIST) version 1.1.
Secondary: 
Secondary:
Secondary: 

To evaluate the safety of 
PF-06439535 (CN) plus paclitaxel 
and carboplatin, versus bevacizumab-
EU plus paclitaxel and carboplatin;

To evaluate the pharmacokinetics 
(PK) of PF-06439535 (CN) and 
bevacizumab-EU; 

To evaluate the immunogenicity of 
PF-06439535 (CN) and bevacizumab-
EU.

The estimand for safety 
evaluation is to compare the 
safety characteristics for PF-
06439535 (CN) relative to 
bevacizumab-EU without 
regard to discontinuation of 
treatment or use of 
concomitant therapy;

The estimand for 
PK evaluation is to compare 
the PK characteristics of 
PF-06439535 (CN) relative 
to bevacizumab-EU under 
the scenario of no major 
protocol deviations that may 
influence the PK 
assessment;

The estimand for 
immunogenicity evaluation 
is to compare the 
immunogenicity 
characteristics of 
PF-06439535 (CN) relative 
to bevacizumab-EU without 
regard to discontinuation of 
treatment or use of 
concomitant therapy.

Safety characterized by type, 
incidence, severity, timing, 
seriousness, and relationship to 
investigational product of adverse 
events, including cardiotoxicity and 
infusion related reactions, and 
laboratory abnormalities;

Trough and apparent peak 
PF-06439535 (CN) and 
bevacizumab-EU concentrations;

Incidence of anti-drug 
(bevacizumab) antibodies (ADA), 
including neutralizing antibodies 
(NAb).








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1. Male and female participants age 18 years of age.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Newly diagnosed Stage IIIB, IIIC or IV non-small cell lung cancer (NSCLC) 
(according to American Joint Committee on Cancer (AJCC) Staging Manual, 8th
Edition, last updated 05 June 2018, see Appendix 7) or recurrent NSCLC.
4. Histologically or cytologically confirmed diagnosis of non-squamous NSCLC.  
5. At least one measurable lesion as defined by RECIST v1.1.
6. For participants with recurrent disease, at least 6 months must have elapsed since 
completing adjuvant or neoadjuvant treatment.
7. 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.
8. ECOG Performance Status of 0 or 1.
9. Recovery (to Grade 1 or baseline) from all clinically significant adverse effects of 
prior therapies (excluding alopecia).
10. Be eligible to receive investigational product of bevacizumab, paclitaxel, and 
carboplatin based on local standard of care, for the treatment of advanced or 
metastatic non-squamous NSCLC.
Informed Consent:
11. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.  
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Disease Characteristics:
1. Small cell lung cancer (SCLC) or combination SCLC and NSCLC.  Squamous-cell 
tumors and mixed adenosquamous carcinomas.


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2. Evidence of a tumor that compresses or invades major blood vessels or tumor 
cavitation that, in the opinion of the investigator, is likely to bleed.
3. Known EGFR activating mutations (for example, exon 19 deletion or exon 21 L858R 
substitution mutations) or ALK rearrangements.  If EGFR or ALK testing is 
performed, the results must be reviewed and confirmed as negative for EGFR and 
ALK prior to randomization.
4. Prior systemic therapy for advanced NSCLC; prior neoadjuvant or adjuvant therapy is 
allowed if surgical resection for primary disease was performed.  
5.
History of local radiation for painful bone metastases in the last 2 weeks.  
(Participants 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 and should not expect to require palliative local 
radiation during the study.)
6. Active uncontrolled or symptomatic central nervous system (CNS) metastases, as 
evidenced by clinical symptoms, cerebral edema, and/or progressive growth (if a 
suspected CNS lesion is not confirmed by pathology).  Treated and stable 
(asymptomatic; off steroids at least 4 weeks) brain metastases are allowed.
7. Prior treatment with immunotherapy or bevacizumab for lung cancer.
Medical Conditions:
8. 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.
9. 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, international normalized ratio (INR) >1.5 and 
aPTT greater than ULN unless on prophylactic anticoagulation).
10. Medically uncontrolled hypertension or systolic blood pressure >150 mmHg or 
diastolic blood pressure >100 mmHg.
11. Peripheral motor or sensory neuropathy with value of grade 2.
12. Major surgery or any investigational agents, within 4 weeks prior to the start of the 
first dose of investigational product.  Planned major surgery during the treatment 
period.  
13. Any unhealed wound or bone fracture.
14. Active infection.  Participants must not be taking anti-infective agents.


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15. 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 investigational 
product.  Clinically significant cardiovascular disease, peripheral vascular disease, 
transient ischemic attack, cerebrovascular accident.
16. 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.
17. Clinical contraindication to treatment with steroids preventing use as part of 
paclitaxel premedication.
18. Immunocompromised participants, including known seropositivity for human 
immunodeficiency virus (HIV).  
19. Known or demonstrated hepatitis infection as listed below.  
a.
Hepatitis B infection as detected by positive testing for hepatitis B surface antigen 
(HBsAg), and detectable viral load; or negative for HBsAg, positive for hepatitis 
B core antibody (anti-HBc), and detectable viral load.
b. Hepatitis C infection as detected by positive hepatitis C antibody (anti-HCV) and 
detectable viral load.
20. Comorbidities that (in the opinion of the investigator) would increase the risk of 
toxicity.
21. Other 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 participant inappropriate for entry into 
this study.
Prior/Concomitant Therapy:
22. Concurrent administration of other anticancer therapies.  Bisphosphonate or 
Rank-Ligand inhibitor therapy already given before randomization for pre-existing 
bone metastases or osteoporosis is allowed.


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Prior/Concurrent Clinical Study Experience:
23. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
the start of the first dose of investigational product and/or during study participation.  
Participants 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 prior to the start of the first dose of 
investigational product are not excluded.
Diagnostic Assessments:
24. Inadequate organ function, evidenced from the screening laboratory values (where 
deviation of up to 10% is acceptable for any single value if in the investigator’s 
opinion the participant 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
a.
Serum or plasma creatinine >1.5 x upper limit of normal (ULN);
b. Urine dipstick proteinuria 2+.  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 can be included.
Liver Function
a.
Total bilirubin >1.5 x ULN (3 ULN if Gilbert’s disease);
b. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
>3 x ULN (>5 x ULN if liver metastases are present).
Other Exclusions:
25. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.  


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5.3. Lifestyle Considerations
5.3.1. Contraception
In this study, participants of childbearing potential will receive bevacizumab-EU as well as 
paclitaxel and carboplatin, which have been associated with teratogenic risk.  Participants 
should be advised to avoid becoming pregnant and not to father a child while receiving 
treatment in this study.  While the teratogenicity of PF-06439535 (CN) has not been studied, 
it is expected to be the same as that of bevacizumab-EU.  
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the schedule of activities (SoA), the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception).  In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to investigational product.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  
6. INVESTIGATIONAL PRODUCT
Investigational product is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.


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6.1. Investigational Product(s) Administered
Intervention Name
PF-06439535 (CN)
Bevacizumab-EU
ARM Name
Arm A
Arm B
Type
Intervention Type: Drug
Dose Formulation
solution for injection
Unit Dose Strength(s)
Each vial contains 100 mg of bevacizumab in 4 ml of 
solution at a concentration of 25 mg/mL
Dosage Level(s)
15 mg/kg
Route of 
Administration
Injection
Investigational 
Medicinal Product 
(IMP) and 
Noninvestigational 
Medicinal Product 
(NIMP)
IMP 
Sourcing
Provided centrally by the sponsor 
Packaging and Labeling
Investigational product will be provided in a glass vial with a 
rubber stopper.  Each glass will be labeled as required per 
country requirement.
Paclitaxel and carboplatin are background therapies and will be provided by the sponsor.  
Refer to the paclitaxel and carboplatin Package Insert for information on formulation, 
preparation, and administration.
6.1.1. Administration
The dosing algorithm for paclitaxel, carboplatin, and PF-06439535 (CN) or bevacizumab-EU
are shown below.  
Paclitaxel, carboplatin, and PF-06439535 (CN) or bevacizumab-EU are administered on 
21-day cycles.  On treatment days when both bevacizumab and paclitaxel-carboplatin are 
administered, the order of administration should be: 1) paclitaxel, 2) carboplatin, 3) 
PF-06439535 (CN) or bevacizumab-EU.  
Dose recalculation 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 participant’s weight changes more than 10% from baseline or if the dose has been 
reduced, and should be used as the new baseline going forward for future dose calculations.  
Regional standards for derivation of dose calculations such as rounding conventions or body 
surface area (BSA)/dose capping for safety concerns are acceptable.  Excluding these 
expected variations, administered doses of carboplatin, paclitaxel, or PF-06439535 (CN) or 
bevacizumab-EU within a range of ±10% from the intended dose would not be considered a 
deviation.
Missed dose(s) of investigational product will not be made up.


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Table 4.
Dosing Algorithm
Dose Level
Paclitaxel
Carboplatin
PF-06439535 (CN) or 
bevacizumab-EU
Starting dose
175 mg/m2
AUC 5 (max=750mg)
15 mg/kg
Dose level -1
(first episode of AE*)
150 mg/m2
AUC 4 (max=600mg)
7.5mg/kg after discussion 
with sponsor 
Dose level -2
(second episode of AE*)
135 mg/m2
Discontinue
Discontinue 
Dose level -3
(third episode of AE*)
Discontinue Therapy
--
*for carboplatin/paclitaxel: Grade 3 or 4 febrile neutropenia, nausea, vomiting, stomatitis.
6.1.1.1. Bevacizumab
6.1.1.1.1. Dosage Form(s) and Packaging
Bevacizumab (PF-06439535 [CN] or bevacizumab-EU) will be provided by the sponsor in 
which the external packaging for each vial will appear identical and will be identified with a 
unique container number.  After randomization, bevacizumab (PF-06439535 [CN] or 
bevacizumab-EU) will be provided as blinded supplies.  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.  
PF-06439535 (CN) and bevacizumab-EU are clear, colorless to pale brown liquid in a glass 
vial with a rubber stopper.  Each appropriately sized glass vial contains 100 mg of 
bevacizumab in 4 ml of solution.
For additional information please refer to the Investigational Product (IP) Manual.
6.1.1.1.2. Bevacizumab Regimen
PF-06439535 (CN) or bevacizumab-EU 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, subsequent infusions may be 
administered over 30 minutes up until Week 25 (Cycle 9).  The Week 25 (Cycle 9) infusion 
time should be increased to 90 minutes in the interest of patient safety considering the 
potential switch in treatments, and if tolerable the subsequent infusion at Week 28 (Cycle 10) 
may be administered over 60 minutes.  If this 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 duration of the infusion can be lengthened at 
the discretion of the investigator.  For the infusion of bevacizumab in participants over 
110 kg, the dilution volume and infusion time should be increased per Investigational 
Product Manual and institutional standards.  The concentration of diluted bevacizumab 
solution should be kept within the range of 1.4 mg/ml to 16.5 mg/ml.


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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 
25 weeks, whichever comes first.  
At Week 25, participants continuing to demonstrate clinical benefit in the opinion of the 
investigator will receive PF-06439535 (CN) monotherapy in a blinded manner for up to 
2 years following randomization in this study or until no further benefit from treatment 
(eg, investigator assessed disease progression, unacceptable toxicity, death, withdrawal of 
consent, lost to follow-up), whichever occurs first.
6.1.1.2. Paclitaxel and Carboplatin
6.1.1.2.1. Paclitaxel and Carboplatin Provision
Paclitaxel and carboplatin to be administered during this study will be centrally provided by 
the sponsor.  Paclitaxel and carboplatin are to be stored, prepared and administered according 
to the product labeling.
6.1.1.2.2. Premedication for Administration
Premedication to ameliorate the toxicities associated with the chemotherapy are to be 
administered according to the local label or institutional guidelines.  
6.1.1.2.2.1. Paclitaxel
All participants 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 intravenous (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.
6.1.1.2.2.2. Carboplatin
Carboplatin is administered as the second drug of the chemotherapy doublet combination.
Carboplatin can induce emesis, which can be more severe in participants 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 participant develops emesis.  
Premedication according to institutional guidelines should be used if paclitaxel has been 
discontinued.  


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6.1.1.2.3. Regimen and Starting Dose(s)
6.1.1.2.3.1. Paclitaxel
Following pre-medication, paclitaxel is administered as the first drug when chemotherapy is 
administered.  Paclitaxel at a dose of 175 mg/m2 will be administered by IV infusion over 
3 hours on Day 1 in 21-day cycles.  In the absence of progressive disease, participants will 
receive paclitaxel treatment for at least 4 but no more than 6 cycles.  Dose reduction for 
toxicity is allowed.
6.1.1.2.3.2. Carboplatin
Carboplatin is administered over a minimum of 15 minutes, and can be administered 
immediately after the paclitaxel infusion has completed.  Participants 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 participant’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 participant variations in pretreatment renal function that might otherwise 
result in either under dosing (in participants with above average renal function) or over 
dosing (in participants with impaired renal function).
A simple formula for calculating dosage, based upon a participant’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.3
Total Dose (mg) = (target AUC is 5.00) 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.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all investigational products received and any 
discrepancies are reported and resolved before use of the investigational product, as
applicable for temperature-monitored shipments.  


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2. Only participants enrolled in the study may receive investigational product and only 
authorized site staff may supply or administer investigational product.  All 
investigational products must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.  At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for investigational product accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All 
investigational products will be accounted for using an investigational product 
accountability form/record.  
4. Further guidance and information for the final disposition of unused investigational 
products are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.  
6. Investigational products should be stored in their original containers and in 
accordance with the labels.  
7. See the IP manual for storage conditions of the investigational product once diluted.
8. Any excursions from the investigational product label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the investigational product to the storage 
conditions described in the labeling, as soon as possible.  Once an excursion is 
identified, the investigational product must be quarantined and not used until Pfizer 
provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval 
will be considered a protocol deviation.  Specific details regarding the definition of an 
excursion and information the site should report for each excursion will be provided 
to the site in the IP manual.  
9. 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 investigator 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.


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Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.
6.2.1. Preparation and Dispensing
See the investigational product manual (IP manual) for instructions on how to prepare the 
investigational product for administration.  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance.
Investigational products will be prepared by qualified unblinded site personnel according to 
the IP manual.  The investigational product will be administered to blinded participants.
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.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Participants will be assigned to receive investigational product according to randomization 
scheme.  Investigators will remain blinded to each participant’s assigned investigational 
product throughout the course of the study.  In order to maintain this blind, an otherwise 
uninvolved third party will be responsible for the preparation and dispensing of all 
investigational product and will endeavor to ensure that there are no differences in time taken 
to dispense or visual presentation following randomization.
This third party will instruct the participant to avoid discussing the taste, dosing frequency, or 
packaging of the investigational product with the investigator.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
investigational product records at the site(s) to verify that randomization/dispensing has been 
done accurately.
6.3.2. Breaking the Blind 
The interactive response technology (IRT) will be programmed with blind-breaking 
instructions.  In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is warranted.  Participant 
safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s treatment assignment unless this could 
delay further management of the participant.  If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind.  The date 
and reason that the blind was broken must be recorded in the source documentation and data 
collection tool (DCT).


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The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Investigational product Compliance
Participant compliance with investigational product will be assessed at each visit.  
Compliance will be assessed by the dosing schedule.  Deviation(s) from the prescribed 
dosage regimen should be recorded in the case report form (CRF).
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 6.1.1.  Participants 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 7.2.
6.5. Concomitant Therapy
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 
participant.  The treatment regimen can produce clinically significant myelosuppression.  
Transfusions and growth factors are allowed and should be used according to institutional 
guidelines.  Bisphosphonate or Rank-Ligand inhibitor therapy already given before 
randomization 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 participant receives both drugs.
Carboplatin can induce emesis, which can be more severe in participants previously 
receiving emetogenic therapy.  The incidence and intensity of emesis have been reduced by 
using premedication with antiemetics.
Participants receiving paclitaxel should be pretreated with corticosteroids, diphenhydramine, 
and H2 antagonists as per the regional prescribing information or institutional guidelines.
Prior medications and non-drug treatments delivered prior to initial dosing will be recorded 
from 28 days prior to the start of investigational product.  Concomitant Therapy, including
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 
investigational product or prior to the start of new anti-cancer therapy if initiated within 
28 days after the last dose, to coincide with the safety evaluation period.  


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6.5.1. Additional Anticancer and Prohibited Treatments Including Radiotherapy
Additional anticancer treatments including, but not limited to radiotherapy are prohibited, 
even for palliative treatment of bone or brain metastatic lesions.  The need for such additional 
treatments is suggestive of progressive disease and the participant should be discontinued 
from study medications under this study.
Participants 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.
6.5.2. Rescue Medicine 
There is no rescue therapy to reverse the adverse events (AEs) observed with the
investigational product; standard medical supportive care must be provided to manage the 
AEs.  
6.6. Dose Modification 
PF-06439535 (CN)/bevacizumab-EU, paclitaxel and carboplatin will be given as specified in 
Section 6.1.1.  The dosing schedule may also be adjusted due to toxicity.
6.6.1. Bevacizumab Regimen Adjustments
The infusion of the investigational product should be interrupted if the participant develops 
dyspnea or hypotension that is deemed clinically significant by the investigator.  If a 
participant 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 participant 
experiences a drug-related bronchospasm of any grade according to NCI-CTCAE, they will 
be discontinued from treatment with the investigational product.  For participants who 
experience infusion-associated symptoms not previously specified, infusions should be 
slowed to 50% or interrupted.  
No dose reductions from 15 mg/kg are planned for PF-06439535 (CN) or bevacizumab-EU.  
However, in rare cases where dose reduction is deemed necessary, the investigator can 
decrease the dose of PF-06439535 (CN) or bevacizumab-EU to 7.5 mg/kg with the 
concurrence of the sponsor (Table 5).  In the event of toxicity attributed to bevacizumab, 
treatment should be either temporarily (up to 2 weeks) or permanently discontinued as 
described in Table 5.  Following a temporary discontinuation, treatment may resume in 
accordance with local standard of care.


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Table 5.
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 participants who 
develop gastrointestinal perforation.
Fistulae

Permanently discontinue bevacizumab in participants 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 participants with other fistulae.  In cases of internal 
fistula not arising in the gastrointestinal tract, discontinuation of 
bevacizumab should be considered.
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 participants 
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 participants treated with bevacizumab.  This condition is usually 
secondary to wound healing complications, gastrointestinal 
perforation or fistula formation.  Bevacizumab therapy should be 
discontinued in participants 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 participant develops hypertensive 
crisis or hypertensive encephalopathy.
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)

In participants developing PRES, treatment of specific symptoms 
including control of hypertension is recommended along with 
discontinuation of bevacizumab.  The safety of reinitiating 
bevacizumab therapy in participants previously experiencing PRES 
is not known.
Proteinuria/nephrotic 
syndrome

Bevacizumab should be permanently discontinued in participants 
who develop nephrotic syndrome.


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Table 5.
Bevacizumab Dose Adjustment Guidelines
ADVERSE EVENT
ACTION
Arterial thromboembolism

Therapy should be permanently discontinued in participants who 
develop arterial thromboembolic reactions.
Venous thromboembolism 

Bevacizumab should be discontinued in participants with 
life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism.  Participants with thromboembolic reactions 
Grade 3 need to be closely monitored.
Haemorrhage

Bevacizumab should be discontinued permanently in participants 
who experience Grade 3 or 4 bleeding during bevacizumab therapy.

Bevacizumab treatment should be discontinued in cases of 
intracranial bleeding.
Pulmonary 
haemorrhage/haemoptysis

Participants with recent pulmonary haemorrhage/haemoptysis 
(>2.5 ml of red blood) should not be treated with bevacizumab.
Congestive heart failure (CHF)

When treating participants with cardiovascular disease that has 
developed or worsened after the initiation of the investigational 
products, the investigator should determine the benefits and risks of 
continuing bevacizumab and/or paclitaxel/carboplatin.
Osteonecrosis of the jaw (ONJ)

Caution should be exercised when bevacizumab and intravenous or 
oral bisphosphonates are administered simultaneously or 
sequentially.

In participants who have previously received or are receiving 
intravenous or oral bisphosphonates invasive dental procedures 
should be avoided, if possible.
6.6.2. Paclitaxel and Carboplatin Regimen Adjustments
All paclitaxel and/or carboplatin associated or possibly associated toxicities should be 
managed by standard medical practice.  Participant toxicity should be clinically assessed 
before, during, and after each infusion.  If paclitaxel and/or carboplatin cause unmanageable 
levels of toxicity at any time in the study, the treatment should be discontinued.  Instruction 
for treatment delays and dosing modifications for paclitaxel and carboplatin are as follows:

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 Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  


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
Paclitaxel and/or carboplatin 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 paclitaxel and/or carboplatin 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 participant, 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 4 in the Administration (Section 6.1.1) 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.  All reductions 
should be considered permanent with no re-escalation permitted.  All dose adjustments 
should be documented in the participant 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 
participant 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.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants after the end of the study.


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7. DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Investigational Product
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.1. Temporary Discontinuation
PF-06439535 (CN)/bevacizumab-EU, paclitaxel and carboplatin may be temporary 
discontinuation due to toxicity as specified in Section 6.6.
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 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 continue.  Similarly, if PF-06439535 
(CN) or bevacizumab-EU cannot be administered for 2 weeks from scheduled time due to
intolerable adverse events, 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 PF-06439535 (CN) 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 participants 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.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  
The early discontinuation visit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the 
investigational product and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.


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If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants who request to discontinue receipt of investigational product 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 participant specifically withdraws consent for any further 
contact with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the participant 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.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
investigational product.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it infeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
In the screening period, demographics and medical/cancer history should be documented, 
include information on prior anti-tumor regimens (including chemotherapy and radiation 
therapy and duration of treatment), driver genetic alteration test results, if known, and 
progression or relapse date.  Testing for driver genetic alterations is not required, however 
participant records are to be reviewed for known EGFR activating mutations (for example, 
exon 19 deletion or exon 21 L858R substitution mutations) or ALK rearrangements.  If 
EGFR or ALK testing is performed, samples must be tested by local certificated laboratories, 


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and the results must be reviewed and confirmed as negative for EGFR and ALK prior to 
randomization.
Unless otherwise specified, Section 8.1, 8.1.1, 8.2.1, 8.2.2, 8.2.3, 8.2.4 and 8.2.5 below are 
primarily intended to provide instructions for completing protocol required tests and 
procedures relevant to the Treatment Period.  Since the Extension Period is intended solely to 
provide access to study treatment for participants who continue to receive clinical benefit 
beyond the Treatment Period there are minimal protocol required tests and procedures as 
described in the Schedule of Activities Study Flowcharts.  It is the responsibility of the 
investigator to perform tests and procedures necessary and according to local standard of care 
to ensure the safety and well-being of the participant from the time the participant enters the 
Extension Period.
8.1. 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 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.
8.1.1. Imaging Assessments
Baseline 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.  
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.  
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 


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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 participants having effusions 
or ascites, cases having cytological proof of malignancy should be considered non-target 
lesions.  Effusions that have not been evaluated using cytology or were found to be 
non-malignant should not be considered to be lung cancer legions.  
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 in the opinion of the 
investigator.  Responses must be confirmed by a second set of scans including head scan 
obtained 6 weeks (7 days) later.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the head, ears, 
eyes, nose, mouth, skin, neck, heart and lung examinations, lymph nodes, abdomen, 
musculoskeletal, neurological systems, and weight.  Height and weight will also be measured 
and recorded.  Weight should be measured at the beginning of each cycle and will be used for 
dose calculation in accordance with Section 6.1.1.  But height will be recorded at Screening 
only.  Genitourinary examination is only required if directed by signs or symptoms.
A brief physical examination will be performed as directed by signs and symptoms on Day 1 
(pre-dose) of each cycle after Screening.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
8.2.2. Vital Signs
Oral temperature, blood pressure, pulse rate, and respiratory rate will be assessed.
Temperature should be taken using the same method throughout the study.  Blood pressure, 
pulse rate, and respiratory rate should be taken with the participant in the supine or sitting 
position after the participant has been resting quietly for at least 5 minutes and prior to dosing 
on dosing days.  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.


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8.2.3. Electrocardiograms
12-Lead electrocardiograms (ECGs) should be collected at times specified in the SoA section 
of this protocol using an ECG machine that automatically calculates the heart rate and 
PR interval, QT interval, QTc, and QRS complex.  All scheduled ECGs should be performed 
after the participant has rested quietly for at least 10 minutes.  
If a postdose QTc remains ≥30 msec from the baseline and is >450 msec; or b) an absolute 
QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, at the 
discretion of the investigator), or QTc gets progressively longer, the participant should 
undergo continuous ECG monitoring.  A cardiologist should be consulted if the QTc does not 
return to less than the criterion listed above after 8 hours of monitoring (or sooner, at the 
discretion of the investigator).  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTc value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 9.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of investigational product 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.


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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.5. MUGA or ECHO
Multiple-gated acquisition (MUGA) or Echocardiogram (ECHO) will be used to assess left 
ventricular ejection fraction (LVEF) of each participant.  See the SoA for the timing and 
frequency.  The original methodology used for each participant must be used throughout the 
trial.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in Woman of Childbearing Potential 
(WOCBP) at the times listed in the SoA.  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and a second negative pregnancy 
test result will be required at the baseline visit prior the participant’s receiving the 
investigational product.  Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the treatment visit.  Pregnancy tests may also be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required.  In such cases, the participant must be excluded if the 
serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
investigational product (see Section 7).  
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days after the last administration of the investigational product.  
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of investigational product but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF), not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the investigational product or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3.  The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety 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 must be reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period.  


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8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.  
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
investigational product under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a investigational product under clinical investigation.  
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.


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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants will be collected after the start of 
investigational product and until 6 months after discontinuing the investigational product.  
If a pregnancy is reported, the investigator should inform the sponsor within [24 hours] of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
The following disease-related events (DREs) are common in participants with non-squamous 
NSCLC and can be serious/life threatening:

Non-fatal progression of the malignancy under study (including signs and symptoms 
of progression).


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Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE.  These events will be recorded on the 
corresponding efficacy assessment pages in the participant’s CRF within the appropriate time 
frame.  
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a DRE):

The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant.
OR

The investigator considers that there is a reasonable possibility that the event was 
related to investigational product.
8.3.7. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant 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 study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.  
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of bevacizumab (PF-06439535 (CN) or bevacizumab-EU greater 
than 15 mg/kg or the assigned dose according to the dose adjustment (Section 6.6 Dose 
Modification) within a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory test abnormalities 
until PF-06439535 (CN) or bevacizumab-EU can no longer be detected systemically 
(at least 86 days).
3. Obtain a blood sample for pharmacokinetic (PK) analysis within 2 days from the date 
of the last dose of investigational product if requested by the medical monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
The drug concentrations of PF-06439535 (CN) and bevacizumab-EU will be determined 
using serum samples collected at the time points specified in the SoA.  Every effort will be 
made to collect these PK samples within the time window provided, as specified in the 
Schedule of Activities.  The actual time of each sample collection will be recorded on the 
source document and electronic CRF (eCRF).  
Details on sample collection, processing and shipment will be provided in the central 
laboratory manual.  




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8.8.1. Specified Gene Expression (ribonucleic acid [RNA]) Research
Specified gene expression (RNA) research is not included in this study.
8.8.2. Specified Protein Research
Specified protein research is not included in this study.
8.8.3. Specified Metabolomic Research
Specified metabolomic research is not included in this study.
8.8.4. Testing Lung Tissue for Mutations
Testing for driver genetic alterations is not required, however participant records are to be 
reviewed for known EGFR activating mutations (for example, exon 19 deletion or exon 21 
L858R substitution mutations) or ALK rearrangements.  If EGFR or ALK testing is
performed, samples must be tested by local certificated laboratories, and the results must be
reviewed and confirmed as negative for EGFR and ALK prior to randomization.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
After all participants have completed the Week 25 visit (ie, the last participant randomized 
has completed the Week 25 visit) or have otherwise died, withdrawn consent or been lost to 
follow-up, the study will be considered to have reached primary completion.  A database 
snapshot (containing data up to and including the Week 25 visit for every participant) will be 
performed after the primary completion date (PCD) and a study report will be developed to 
support the new drug application.  Data collected after Week 25 will be summarized in a 
supplemental clinical study report which will describe safety results during the monotherapy 
extension period and will be considered as supplemental to the clinical study report for the 
PCD.
In general, efficacy, safety, PK and immunogenicity as of the Week 25 visit will be analyzed 
by treatment group in the study report for the PCD.  In the supplemental clinical study report,
safety will be summarized across all participants, and PK and immunogenicity (which are to 
be collected at end of treatment/withdrawal visit) will be listed.  






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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.
Descriptive statistics for CR, PR and ORR by treatment group, risk difference of ORR and 
risk ratio of ORR (RR) between treatment groups will be presented.  The frequency, 
percentage and 90% confidence interval of these response rates will be constructed.  The 
estimated risk difference and risk ratio in ORR between PF-06439535 (CN) and 
bevacizumab-EU will be computed, and the corresponding 90% confidence intervals will be 
calculated based on Miettinen and Nurminen (1985) method.  
9.4.2. Safety Analyses
Safety population will be used for all safety analyses.  Listings of all individual data 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.
9.4.2.1. 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 4.03.25
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 investigational product or any pre-existing adverse event that worsens 
after the beginning of the investigational product.
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 summarizing 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.  
9.4.2.2. Laboratory Test 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 
of the worst severity grade observed will be displayed by investigational product.  Shift 
tables of baseline against each post baseline visit will be provided for selected laboratory 


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tests to examine the distribution of laboratory toxicities.  For parameters for which an 
NCI-CTCAE scale does not exist, the frequency of participants 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 
investigational product.
9.4.2.3. Prior Concomitant Medications
Collected prior and concomitant medications will be coded by the World Health 
Organization (WHO) medical dictionary; participants who received these medications will be 
listed and summarized by treatment group separately.
9.4.3. Other Analyses 
Demographic and baseline characteristics such as participant age, sex, height, weight, 
ethnicity, prior therapy, medical history, ECOG performance status, and tumor mutations 
will be tabulated and summarized using descriptive statistics.  Administration for each 
investigational product 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.
9.4.3.1. Pharmacokinetics
The drug concentration-time data will be summarized by descriptive statistics (mean, 
standard deviation, median, minimum, and maximum) according to treatment.
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, if conducted, will be summarized in a Population Modeling and 
Analysis Report (PMAR) separate from the clinical study report (CSR).
9.4.3.2. Biomarker Analysis
There are no biomarker assessments required for this trial.
9.4.3.3. Immunogenicity
For the immunogenicity data, the percentage of participants with positive ADA and 
neutralizing antibodies will be summarized for each treatment.  For participants 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 
participants, the incidence of ADA observed in the planned study may differ from the 
incidence reported in historical clinical trials.
9.5. Interim Analyses
There will be no interim analysis in this study.  
9.5.1. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC).  
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter.  The recommendations made by the E-DMC 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 that are not endpoints, to regulatory authorities, as appropriate.  


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. 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 
regulatory 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.  


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data.  
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICD.


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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study 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 addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
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
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in participants) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant 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.


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EudraCT
Pfizer posts European Union (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 PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.  
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have 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.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  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.


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Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in Study Data Monitoring Plan.


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10.1.7. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further investigational product development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first.  
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.


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Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements.  
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.9. 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 investigator site file (ISF).  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
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 investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator 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 participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Coagulation
Urinalysis
Other
Hemoglobin
WBC count
Platelet count
Absolute Neutrophil 
count
AST, ALT 
Alkaline phosphatase
Total bilirubin
Serum/Plasma
Creatinine,
Sodium
Potassium
Total Calcium
BUN/urea
Magnesium
Albumin
INR/prothrombin 
time (or 
prothrombin time if 
INR is not 
available)
APTT
pH
Protein
Glucose
Ketones
Bilirubin
Blood
Leukocyte esterase
Quantitative urine protein 
analysis when dipstick urine 
protein ≥2+.
Pregnancy 
test (β-hCG)
Serological tests
HBsAg
Anti-HBc
Anti-HCV
Anti-HIV
HBV DNA when 1) 
HBsAg-positive, or 
2) HBsAg-negative, 
anti-HBc positive;
HCV RNA when anti-
HCV positive
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; -hCG = beta-human 
chorionic gonadotropin; BUN = blood urea nitrogen; 
HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis B core antibody;
anti-HCV = hepatitis C antibody; anti-HIV = human immunodeficiency virus antibody; 
WBC = white blood cell; APTT = Activated Partial Thromboplastin Time; I
NR = International Normalized Ratio.
Investigators must document their review of each laboratory safety report.






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whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, 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.

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 
active collection 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 active collection period, then the event leading to death 
must be recorded as an AE on the CRF, and as an SAE with Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 5 (see the Assessment of Intensity
section).










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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 90 days after the last dose of investigational product, 
which corresponds to the time needed to eliminate investigational product(s) plus an 
additional 90 days (a spermatogenesis cycle): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.  
OR

Must agree to use contraception/barrier as detailed below.  

Agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

Use of an additional highly effective contraceptive method with a failure rate of 
<1% per year as described below in Section 10.4.4 for a female partner of 
childbearing potential.  
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
below during the intervention period and for at least 6 months after the last dose 
of investigational product, which corresponds to the time needed to eliminate any 
investigational product(s).  

A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period.  The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of 
investigational product.


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The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.  
10.4.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of investigational product, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.  
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause.  

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.


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10.4.4. Contraception Methods
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Iinjectable.
3. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the investigational product.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

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).

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 participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an 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 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety 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 Safety 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 
preprocedure 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.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety 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 sponsor.  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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory 
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator 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 and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.6. Appendix 6: 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.


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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.

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 Activities 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.


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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 required 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’).
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 Progressive Disease (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.


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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.

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of stable disease (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
Participants 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 7 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 7.
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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10.7. Appendix 7: American Joint Committee on Cancer (AJCC) Definitions of Tumor, 
Node, Metastases (TNM) and Prognostic Stage Groups
Excerpts from the AJCC Staging Manual, 8th Edition, last updated 05 June 2018, to ensure 
consistency and appropriate documentation of staging.
Definitions of AJCC TNM
Definition of primary tumor (T)
Definition of Regional Lymph Node (N)


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Definition of Distant Metastasis (M)
AJCC Prognostic Stage Groups


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10.8. Appendix 8: 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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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
ADA
anti-drug antibodies
AE
adverse event
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
Anti- HBc
hepatitis B core antibody
Anti-HCV
hepatitis C antibody
AST
aspartate aminotransferase
ATE
arterial thromboembolism
AUC
area under the concentration versus time curve 
AUCT
area under the curve (0 to last quantifiable time point)
AUCinf,
area under the curve (0 to time infinity)
AV
atrioventricular
BSA
body surface area
CBC
complete blood count
CDE
Center for Drug Evaluation
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cmax
maximum serum concentration
CN
China
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
DCT
data collection tool 
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRE
disease-related events
EC
ethics committee
ECG
electrocardiogram


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Abbreviation
Term
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
E-DMC
external data monitoring committee
EDP
exposure during pregnancy
EGFR
epidermal growth factor rector
EMA
European Medicines Authority
EML4-ALK
echinoderm microtubule-associated protein like 4- anaplastic 
lymphoma kinase
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
IgG1
immunoglobulin G1
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRR
infusion related reaction
IRT
interactive response technology
ISF
investigator site file
ITT
Intent to Treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
KDR
kinase insert domain receptor
LVEF
left ventricular ejection fraction
LFT
liver function test
mCRC
metastatic colorectal cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
Multiple-gated acquisition


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Abbreviation
Term
N/A
not applicable
NAb
neutralizing antibodies
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for 
Adverse Events
NMPA
National Medical Products Administration 
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate 
OS
overall survival
PCD
primary completion date
PD
progressive disease 
PFS
progression-free survival
PK
pharmacokinetic
PMAP
Population Modeling Analysis Plan
PMAR
Population Modeling and Analysis Report
PR
partial response
PT
prothrombin time
PVC
polyvinylchloride
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RR
risk ratio (relative risk)
QTc
Q-T Corrected
QTcF
QT interval corrected by the Fridericia formula 
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SD
stable disease
SMQs
standardised Medical Dictionary for Regulatory Activities 
queries 
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment emergent adverse event
TKI
tyrosine kinase inhibitors
TNM
Tumor, Node, Metastases
ULN
upper limit of normal
UPC
urine protein to creatinine ratio
US
United States
VTE
venous thromboembolic events
VEGF
vascular endothelial growth factor
WHO
World Health Organization


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Abbreviation
Term
WOCBP
Woman of Childbearing Potential




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13.
Siegel R, Ma J, Zou Z, et al.  Cancer statistics.  CA Cancer J Clin, 2014, 64(1):9-29.
14.
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.
15.
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.
16.
EdgeSB, Byrd DR, Compton CC, et al.  Lung.  In: AJCC cancer staging manual.  7th 
ed.  New York, NY: Springer; 2010: p.  253-70.
17.
TherasseP, 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.
18.
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.
19.
Iressa(Gefitinib) Summary of Product Characteristics.  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Informatio 
n/human/001016/WC500036358.pdfaccessed 23 September 2014.
20.
Tarceva(Erlotinib) Prescribing Information.  
http://www.gene.com/download/pdf/tarceva_prescribing.pdfaccessed 23 September 
2014.
21.
Xalkori(Crizotinib) Prescribing Information.  
http://labeling.pfizer.com/showlabeling.aspx?id=676accessed 23 September 2014.
22.
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.
23.
C.  Zhou, Y.  Wu, G.  Chen, et al.  BEYOND: A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus 
Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent 
Nonsquamous Non–Small-Cell Lung Cancer.  J Clin Oncol 2015; 33:2197-2204.
24.
C.  Zhou, G.  Jiang, Y.  Wu, et al.  Safety and efficacy of first-line bevacizumab 
combination therapy in Chinese population with advanced non-squamous NSCLC: data
of subgroup analyses from MO19390 (SAiL) study.  Clin Transl Oncol (2014) 16:463–
468.


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25.
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.

SAP_001.pdf: 
Protocol B7391007 (PF-06439535 (CN)) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol B7391007
A RANDOMIZED, DOUBLE-BLIND BRIDGING SAFETY AND EFFICACY STUDY 
OF PF-06439535 (CN) PLUS PACLITAXEL-CARBOPLATIN VERSUS
BEVACIZUMAB-PLUS PACLITAXEL-CARBOPLATIN FOR THE FIRST-LINE 
TREATMENT OF CHINESE PARTICIPANTS WITH ADVANCED 
NON-SQUAMOUS NON-SMALL CELL LUNG CANCER
Statistical Analysis Plan 
(SAP)
Version:
1  
Date:
05 Jul 2019  


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Estimand .........................................................................................6
2.1.2. Secondary Estimands....................................................................................6
2.1.2.1. Estimand for Safety Evaluation...................................................6
2.1.2.2. Estimand for PK Evaluation........................................................7
2.1.2.3. Estimand for Immunogenicity Evaluation ..................................7
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint ......................................................................................................8
3.2. Secondary Endpoints.................................................................................................8
3.3. Other Endpoint(s)......................................................................................................9
3.4. Baseline Variables.....................................................................................................9
3.4.1. Covariates .....................................................................................................9
3.4.3. Other Baseline Variables..............................................................................9
3.5. Safety Endpoints .......................................................................................................9
3.5.1. Adverse Events ...........................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................11
4.1. Treatment Misallocations........................................................................................11
4.2. Protocol Deviations.................................................................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................13
5.2.1. Analyses for Binary Endpoints...................................................................13
5.2.2. Analyses for Continuous Endpoints ...........................................................13
5.2.3. Analyses for Categorical Endpoints ...........................................................14
5.3. Methods to Manage Missing Data ..........................................................................14
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5.3.1. Objective Response Data............................................................................14
5.3.2. Pharmacokinetic Concentrations ................................................................14
5.3.3. Missing Dates .............................................................................................15
6. ANALYSES AND SUMMARIES ......................................................................................15
6.1. Primary Endpoint ....................................................................................................15
6.1.1. Objective Response Rate (ORR) Achieved by Week 19............................15
6.1.1.1. Main Analysis ...........................................................................15
6.2. Secondary Endpoint(s) ............................................................................................17
6.2.1. Safety Endpoints.........................................................................................17
6.2.2. Pharmacokinetic Endpoints ........................................................................17
6.2.3. Immunogenicity Endpoints.........................................................................18
6.3. Other Endpoint(s)....................................................................................................18
6.4. Subset Analyses.......................................................................................................18
6.5. Baseline and Other Summaries and Analyses.........................................................18
6.5.1. Baseline Summaries....................................................................................18
6.5.2. Study Conduct and Participant Disposition................................................19
6.5.3. Study Treatment Exposure .........................................................................19
6.5.4. Prior and Concomitant Medications...........................................................19
6.6. Safety Summaries and Analyses .............................................................................19
6.6.1. Adverse Events...........................................................................................19
6.6.1.1. Anaphylaxis...............................................................................20
6.6.2. Laboratory Data..........................................................................................20
6.6.3. Vital Signs ..................................................................................................20
6.6.4. LVEF assessed by MUGA or ECHO .........................................................21
6.6.5. Physical Examination .................................................................................21
7. INTERIM ANALYSES.......................................................................................................21
8. REFERENCES ....................................................................................................................22
9. APPENDICES .....................................................................................................................23
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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Derivation of the Best Overall Response..................................................16
Table 3.
Assessment Windows...............................................................................23
APPENDICES
Appendix 1. Assessment Windows to Derive the Time Point Response ................................23
Appendix 2. Summary of Efficacy Analyses...........................................................................24
Appendix 3. Sample Code for the Miettinen and Nurminen Method Without Strata .............25
Appendix 3.1. For Risk Ratio ..................................................................................................25
Appendix 3.2. For Risk Difference..........................................................................................25
Appendix 4.1. For Risk Ratio ..................................................................................................26
Appendix 4.2. For Risk Difference..........................................................................................30
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol 
Amendment
Rationale
Specific Changes
1
05 July 2019
Original 
27 Jun 2019
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B7391007. Two clinical study report (CSR) 
will be produced for this study. The primary CSR will be conducted on the primary 
completion date (PCD) using data as of Week 25, and the supplemental CSR will be 
conducted at the end of study using limited data from Week 25. This document mainly focus 
on the PCD analyses, and briefly describe the limited safety analyses for supplemental CSR. 
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition or its analysis will also be reflected in a 
protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Primary Objective:

To explore similarity in efficacy of PF-06439535 (CN) and bevacizumab-EU, each in 
combination with paclitaxel and carboplatin, based on a descriptive estimation of 
objective response rate (ORR).
Secondary Objectives:

To evaluate the safety of PF-06439535 (CN) plus paclitaxel and carboplatin and 
bevacizumab-EU plus paclitaxel and carboplatin;

To evaluate the pharmacokinetics (PK) of PF-06439535 (CN) and bevacizumab-EU; 

To evaluate the immunogenicity of PF-06439535 (CN) and bevacizumab-EU.
Primary Endpoint:

ORR, evaluating best overall responses achieved by Week 19 and subsequently 
confirmed by Week 25, 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 investigational product of adverse events, including cardiotoxicity and infusion 
related reactions, and laboratory abnormalities;

Trough and apparent peak PF-06439535 (CN) and bevacizumab-EU concentrations at 
selected cycles;

Incidence of anti-drug (bevacizumab) antibodies (ADA), including neutralizing 
antibodies (NAb).
2.1.1. Primary Estimand
Primary estimand (Hypothetical and Treatment Policy) estimate the population average 
treatment effect of ORR for PF-06439535 (CN) relative to bevacizumab-EU by Week 19 for 
all randomized participants with advanced non-squamous NSCLC, reflecting the impact of 
new anti-cancer medications, but regardless of any other interventions. The estimand is 
defined according to the primary objective and is in alignment with the primary endpoint.  It 
includes the following 4 attributes: 

Population: Patients who are diagnosed as advanced non-squamous NSCLC, as 
defined by the inclusion and exclusion criteria, and who are randomized;

Variable: the best objective response achieved by Week 19 and subsequently 
confirmed by Week 25, in accordance with Response Evaluations Criteria in Solid 
Tumors (RECIST) version 1.1;

Interventions: All responses data after start of new anti-cancer medications are 
excluded from the analysis. Other intercurrent events such as administration of 
concomitant therapy or adherence to randomized treatment assignment are not 
considered for analysis;

Population-level summary: Difference and ratio of the objective response rate (ORR) 
between PF-06439535 (CN) and bevacizumab-EU.
2.1.2. Secondary Estimands
2.1.2.1. Estimand for Safety Evaluation
Secondary Estimand for Safety (Treatment Policy) estimate the population average treatment 
effect for the safety endpoints for PF-06439535 (CN) relative to bevacizumab-EU up to 
Week 25 for all randomized participants with advanced non-squamous NSCLC, regardless of 
any intervention. The estimand is defined according to the secondary safety objective and is 
in alignment with the safety endpoints.  It includes the following 4 attributes: 

Population: Patients who are diagnosed as advanced non-squamous NSCLC, as 
defined by the inclusion and exclusion criteria, and who are randomized;


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
Variable: Safety characteristics by type, incidence, severity, timing, seriousness, and 
relationship to investigational product of adverse events, including cardiotoxicity and 
infusion related reactions, and laboratory abnormalities;

Interventions: Administration of concomitant therapy or adherence to randomized 
treatment assignment is not considered for analysis. All data collected (after 
concomitant therapy or after discontinuation of treatment) are included;

Population-level summary: Summary of the AEs frequency and percentage for 
PF-06439535 (CN) and bevacizumab-EU treatment respectively and in total; 
Difference of the selected AEs (Pfizer Tier-1 and Tier-2 events) percentage between 
PF-06439535 (CN) and bevacizumab-EU. 
2.1.2.2. Estimand for PK Evaluation
Secondary Estimand for PK (Hypothetical) estimate the population average treatment effect 
for the PK endpoints for PF-06439535 (CN) relative to bevacizumab-EU for all randomized 
participants with advanced non-squamous NSCLC, reflecting the impact of protocol 
deviations, if any, which may affect the PK assessment. The estimand is defined according 
to the secondary PK objective and is in alignment with the PK endpoint. It includes the 
following 4 attributes: 

Population: Patients who are diagnosed as advanced non-squamous NSCLC, as 
defined by the inclusion and exclusion criteria, and who are randomized;

Variable: Trough and apparent peak PF-06439535 (CN) and bevacizumab-EU 
concentrations;

Interventions: All data after an intervention (use of concomitant therapy prohibited by 
the protocol, use of a subsequent line of therapy, dosing error, discontinuation of 
treatment, discontinuation of study, etc), maybe excluded; The intervenations will be 
defined prior to unblinding the database;

Population-level summary: Descriptive summary of PK concentrations for 
PF-06439535 (CN) and bevacizumab-EU treatment respectively.
2.1.2.3. Estimand for Immunogenicity Evaluation
Secondary Estimand for Immunogenicity (Treatment Policy) estimate the population average 
treatment effect for the immunogenicity endpoints for PF-06439535 (CN) relative to 
bevacizumab-EU for all randomized participants with advanced non-squamous NSCLC, 
regardless of any intervention. The estimand is defined according to the secondary 
immunogenicity objective and is in alignment with the immunogenicity endpoint.  It includes 
the following 4 attributes: 

Population: Patients who are diagnosed as advanced non-squamous NSCLC, as 
defined by the inclusion and exclusion criteria, and who are randomized;


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
Variable: Incidence of anti-drug (bevacizumab) antibodies (ADA), including 
neutralizing antibodies (NAb);

Interventions: Administration of concomitant therapy or adherence to randomized 
treatment assignment is not considered for analysis. All data collected (after 
concomitant therapy or after discontinuation of treatment) are included;

Population-level summary: Summary of the positive ADA and NAb percentage for 
PF-06439535 (CN) and bevacizumab-EU treatment respectively.
2.2. Study Design
This is a double-blind, randomized, parallel-group clinical bridging trial evaluating the 
efficacy and safety of PF-06439535 (CN) plus paclitaxel and carboplatin versus 
bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for participants with 
advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.
Approximately 108 participants will be enrolled in each treatment arm for a total of 
approximately 216 participants at over 30 centers in China, with the aim to achieve a target 
sample size of 200. Participants will be randomized (1:1) to receive either PF-06439535 (CN) 
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 until investigator assessed disease progression defined by RECIST 1.1, 
unacceptable toxicity, death, withdrawal of consent, lost to follow-up, or Week 25,
whichever comes first. At Week 25, all of the participants who continue to demonstrate 
clinical benefit in the opinion of the investigator, will receive PF-06439535 (CN)
monotherapy for up to 2 years from randomization in this study, or until no further benefit 
from treatment (eg, investigator assessed disease progression, unacceptable toxicity, death, 
withdrawal of consent, lost to follow-up), whichever occurs first.  Randomization will be 
stratified by sex (male/female) and smoking history (yes/no). 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint

ORR, evaluating best overall responses achieved by Week 19 and subsequently 
confirmed by Week 25, in accordance with Response Evaluations Criteria in Solid 
Tumors (RECIST) version 1.1
3.2. Secondary Endpoints

Safety characterized by type, incidence, severity, timing, seriousness, and relationship 
to investigational product of adverse events, including cardiotoxicity and infusion 
related reactions, and laboratory abnormalities;

Trough (collected at Cycle 1, Cycle 5) and apparent peak (collected at Cycle 1, 
Cycle 5 and End of Treatments) PF-06439535 (CN) and bevacizumab-EU 
concentrations;




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On-treatment period is defined as the time from the first dose of investigational product
through a minimum of 28 calendar days after the last administration of investigational 
product or start of new anticancer therapy, whichever occurs first.
The safety analyses will be carried out in the safety population. The following safety 
endpoints will be summarized descriptively:
•
Treatment emergent adverse events (TEAE), treatment related adverse events, 
bevacizumab-related adverse events, CTCAE Grade 3 or higher adverse events and 
serious adverse events;
•
Adverse events leading to delays, dose reduction and permanent discontinuation;
•
Left ventricular ejection fraction (LVEF) as assessed by Multiple-gated acquisition 
(MUGA) or echocardiogram (ECHO).
3.5.1. Adverse Events
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) to determine System Organ Class and Preferred Term. National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be 
used to grade severity.
Treatment emergent adverse event (TEAE) is defined as any adverse event that occurs after 
the beginning of the investigational product during the on-treatment period.
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers. Different analyses will be performed for different tiers (see Section 6.6.1).
Tier 1 events: These are prespecified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan.
Tier 2 events: These are events that are not tier 1 but are “common.” A Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term (PT) is defined as a Tier 2 event if there 
are at least 10% occurrence in any treatment group.
CCI


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
For purposes of analysis, the following populations are defined:
Defined Population for 
Analysis
Description
Intent-to-Treat Population The Intent to Treat (ITT) Population is defined as all 
participants who are randomized to investigational product.  
The ITT population will be used for participant accountability 
and all efficacy analyses.  
Per Protocol Population
The Per Protocol (PP) Population is defined as all participants 
who are randomized and received the investigational product 
(PF-06439535 (CN) or bevacizumab) as planned and have no 
major protocol deviations.  The PP population will be used for 
sensitivity analyses of the primary efficacy endpoint.  The list 
of participants in PP population will be determined based on 
blinded data review prior to database release.
Safety Population
The safety population is defined as all participants who are 
randomized and receive at least one dose of investigational 
product.  The safety population will be used for the safety 
analyses including ADA and NAb analyses.
Pharmacokinetics 
Population
Participants in the per protocol population who have at least one 
post dose drug concentration measurement, and have no major 
protocol deviations which could influence the pharmacokinetic 
assessment will be included in the PK analysis.
4.1. 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 first/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 a major protocol deviation. Patient profiles on safety (demographics, adverse 






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5.2.3. Analyses for Categorical Endpoints
The number and percentage of patients in each category will be provided for categorical
variables. For Tier-1 and Tier-2 adverse events, besides the number and percentage 
summary for each category, the risk difference (RD) and 95% CI on RD calculated using the 
exact method by Chan and Zhang (1999)7 will be provided for each event.
5.3. Methods to Manage Missing Data
5.3.1. 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 response will 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.
5.3.2. 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);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalously 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 peak 
concentration (Cycle 1) from the same patient. If the concentration value in the pre-dose 
sample in a patient is >5% of peak concentration (Cycle 1) from the same patient, the patient 
will be excluded from the PK data summary.


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5.3.3. 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). 
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.
6. ANALYSES AND SUMMARIES
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.
6.1. Primary Endpoint
6.1.1. Objective Response Rate (ORR) Achieved by Week 19
6.1.1.1. Main Analysis

Estimand strategy: Compound estimand using hypothetical strategy for new 
anti-cancer medications and treatment policy strategy for the other intercurrent events 
(Section 2.1.1).

Analysis set: Intent to Treat Population (Section 4).  

Analysis methodology: Miettinen and Nurminen (1985)6 method without strata will 
be used as the primary analysis method for the efficacy endpoint ORR 
(Section 5.2.1).  

Intercurrent events and missing data: All response data after start of new anti-cancer 
medications will be excluded and the other intercurrent events will not be considerd 
(Section 2.1.1); missing response data will be considered as non-evaluable 
(Section 5.3.1).

The best overall response per patient will 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. Table 2 presents some typical scenarios for deriving the best overall 
response.

Estimated risk ratio and risk difference and the asymptotic 90% CI in ORR between 
PF-06439535 (CN) and bevacizumab-EU will be computed.  The Miettinen and 
Nurminen analysis method without strata will be carried out by the BINOMIAL 
procedure. A sample of the SAS codes with PROC BINOMIAL is provided in the 












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6.6.4. LVEF assessed by MUGA or ECHO
Multiple-gated acquisition (MUGA) or Echocardiogram (ECHO) will be used to assess left 
ventricular ejection fraction (LVEF) of each participant. LVEF will be summarized by 
treatment and visit.  Absolute decline in LVEF and shift summary from baseline will be 
summarized by treatment and visit.  Baseline is defined as the most recent measurement prior 
to the beginning of the investigational product.
6.6.5. Physical Examination
Physical examination at screening phase will be collected in the CRF and will be listed in a 
data listing.
7. INTERIM ANALYSES
There will be no interim analyses in this study.  


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8. REFERENCES
1.
Sandler A, Gray R, Perry MC, et al (2006) Paclitaxel-carboplatin alone or with 
bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24):2542-2550. 
doi:10.1056/NEJMoa061884.
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.
C. Zhou, Y. Wu, G. Chen, et al. BEYOND: A Randomized, Double-Blind, Placebo-
Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus 
Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent 
Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol 2015; 33:2197-2204.
5.
C. Zhou, G. Jiang, Y. Wu, et al. Safety and efficacy of first-line bevacizumab 
combination therapy in Chinese population with advanced non-squamous NSCLC: data
of subgroup analyses from MO19390 (SAiL) study. Clin Transl Oncol (2014) 
16:463-468.
6.
Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine
1985; 4: 213-226. 
7.
Chan, I.S. and Z. Zhang. Test-based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 1999. 55(4): p. 1202-9.


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9. 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 3 will be 
used to cluster the assessments.
Table 3.
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 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=1.33;
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 90% CI:
proc binomial data=test alpha=0.9;
eqv/as diff margin=0.13;
po group;
ou resp;
weight count;
run;
quit;


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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;
CCI


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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;


Protocol B7391007 (PF-06439535 (CN)) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 34
    
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);