Clinical trial NCT05546476
Conditions: Non-small Cell Lung Cancer Pancreatic Cancer Colorectal Cancer Loss of Appetite Fatigue Cachexia
Keywords: cancer anorexia cachexia weight loss loss of appetite fatigue
Sponsor: Pfizer
Start date: 2022-11-21; Completion date: 2025-04-23
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Study to evaluate the efficacy, safety and tolerability of ponsegromab compared to placebo in patients with cancer, cachexia, and elevated GDF 15.

Detailed description:
A 12 week double blind study to evaluate the efficacy, safety and tolerability of ponsegromab compared to placebo in patients with cancer, cachexia, and elevated GDF 15.

During the initial 12-week treatment period (Part A), a total of 3 doses of ponsegromab or placebo will be administered 4 weeks apart subcutaneously. Each dose contains two injections. Part B is an optional open-label treatment period consisting of ponsegromab administered every 4 weeks subcutaneously for up to one year. Part B does not include placebo.

Assessments include:

* Body weight measurements
* Measure the impact of ponsegromab compared to placebo on physical activity.
* Measure the impact of ponsegromab compared to placebo on appetite, fatigue, nausea, vomiting and physical function questionnaires.
* Blood samples to evaluate safety and additional endpoints including the amount of study drug in the blood and the effects of the study drug on levels of GDF15
* Up to 3 additional blood samples (two samples during Part A and one sample during Part B, if relevant) in a subset of participants as part of a substudy for more comprehensive assessment of the amount of study drug in the blood and of the effects of the study drug on levels of GDF-15.

Arms: arm 1: ponsegromab low dose subcutaneous injection every 4 weeks arm 2: Match placebo subcutaneous injection every 4 weeks arm 3: ponsegromab medium dose subcutaneous injection every 4 weeks arm 4: ponsegromab high dose subcutaneous injection every 4 weeks
Interventions: intervention 1: ponsegromab intervention 2: Placebo for ponsegromab
Intervention descriptions: intervention 1: Double-Blind ponsegromab Treatment followed by Open Label ponsegromab Treatment intervention 2: Double-Blind placebo Treatment followed by Open Label ponsegromab Treatment

Protocol documents:
Prot_000.pdf: 
Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 1
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY, SAFETY AND TOLERABILITY OF 
PONSEGROMAB IN PATIENTS WITH CANCER, CACHEXIA, AND ELEVATED 
CONCENTRATIONS OF GDF-15, FOLLOWED BY AN OPTIONAL OPEN-LABEL 
TREATMENT PERIOD (PROACC -1)
Study Intervention Number:
PF-06946860
Study Intervention Name:
ponsegromab
US IND Number:
139674
EudraCT/CTIS Number:
2022-003016-87
ClinicalTrials.gov ID:
NCT05546476
Pediatric Investigational Plan Number:
NA
Protocol Number:
C3651003
Phase:
2
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Phase 2 Study of the Efficacy and Safety of Ponsegromab in Patients with 
Cancer, Cachexia and Elevated GDF-15. (PROACC -1)
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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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 2
Document History
Document 
Version Date
Amendment 2
24 May 2023
Amendment 1
27 October 2022
Original protocol
17 June 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 
Protocol Amendment Summary of Changes Table
Amendment 2 (24 May 2023)
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate PK substudy, changes to eligibility criteria, and other clarifications. 
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Incorporated PK substudy 
design
Additional PK/PD 
samples included for a 
subset of participants 
in response to 
regulatory request.
1.1. Synopsis, 1.2 Schema, 1.3 
Schedule of Activities, 3. 
Objectives, Endpoints and 
Estimands, 4.1 Overall Design, 
4.2 Scientific Rationale for 
Study Design, 8.1 
Administrative Procedures, 
8.1.3 Additional Visits for PK 
substudy, 8.1.4 Home Health 
Visits, 9.5 Sample Size 
Determination
Removed eGFR requirement
Ponsegromab is not 
excreted by the 
kidney. Insufficient 
rationale to support 
eGFR requirement.
1.1. Synopsis; 5.2. Exclusion 
Criteria (# 11)
Added exclusionary 
medications used for increasing 
To minimize potential 
for confounding of 
primary endpoint.
6.9.1 Prohibited During the 
Study
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 3
Description of Change
Brief Rationale
Section # and Name
appetite/body weight and 
weight loss.
Clarified permitted medications
Clarification 
6.9.2 Permitted During the 
Study
Removed Appendix 9 detailing 
France requirements
Decision made to not 
proceed with France 
Appendix 9. Country Specific
Requirements, 10.9.1 France
Added Appendix 12: list of 
platinum-based chemotherapy
Additional guidance 
since stratification at 
randomization is based 
upon participant being 
on platinum-based 
chemotherapy or not.
Appendix 12: List of Platinum-
based Chemotherapy
Non-substantial Modification(s)
Added ClinicalTrials.gov ID 
number
Information available 
Title page and Section 1.1 
synopsis
Separated SoA for Part A and 
Part B; removed visit numbers
Clarification 
1.3. Schedule of Activities  
Clarified text regarding SOC 
therapy timing 
Clarification
1.1. Synopsis; 5.1. Inclusion 
Criteria (#2)
Clarified expectations of 
evaluation and timing of 
participation.
Clarification
1.1. Synopsis; 5.1 Inclusion 
Criteria (#5)
Clarified that participants 
previously dosed with IP are 
excluded
Clarification
1.1. Synopsis; 5.2. Exclusion 
Criteria (#9)
Consolidated exclusion criteria 
related to prior concomitant 
medications since information
is covered in section 6.9 prior 
and concomitant therapy
Clarification
1.1. Synopsis; 5.2. Exclusion 
Criteria (# 7) 
Updated to include “result may 
be confirmed by a single repeat 
test, if necessary” and “if there 
is liver involvement by the 
tumor”
Clarification
1.1. Synopsis; 5.2. Exclusion 
Criteria (#10)
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 4
Description of Change
Brief Rationale
Section # and Name
Added exclusion criteria #12 to 
clarify participants cannot 
adhere to a calorie-restricted 
diet with the intention weight 
loss
Clarification
1.1. Synopsis; 5.2. Exclusion 
Criteria (#12)
Added examples for injection 
site combinations
Clarification
6.1.1 Administration
Editorial clarifications 
To provide 
clarification, correct 
typos, and improve 
readability
1.1. Synopsis; 5.2. Exclusion 
Criteria (#s 1 & 4), 2.3.1 Risk 
Assessment, 2.3.3 Overall 
Benefit/Risk Conclusion, 4.1 
Overall Design, 4.2 Scientific 
Rationale, 4.3 Justification for 
Dose, 4.4 End of study 
definition, 5.4 Screen Failures, 
6.1.1 Administration, 6.5 Study 
Intervention Compliance, 6.9 
Prior and Concomitant 
Therapy, 7.1 Discontinuation 
of Study Intervention, 7.3 Lost 
to Follow-up, 8.1.1 Screening 
Visit, 8.1.2 Week 5 Visit, 8.1.4
Home Health Visits, 8.2.2 
Patient Reported Outcomes, 
8.3.3.1 Blood Pressure and 
Pulse Rate, 8.3.4 
Electrocardiograms, 8.3.7.1
Imaging Safety Assessment, 
8.4.5.1 Exposure During 
Pregnancy, 8.5 
Pharmacokinetics, 8.7.1 GDF-
15, 9.3.2 Primary Endpoint 
analysis, 9.3.5 Other Analyses, 
9.4.1 PK/PD Unblinding Plan, 
10.4.2 Female Participant 
Reproductive Inclusion Criteria
Updated visit windows for 
Part A and for Part B added 
contraception checks for 
follow up Part A and follow 
Protocol 
Administrative 
Change Letter dated 
13 Feb 2023
1.3 Schedule of Activities, 
8.1.5 Transportation, 3. 
Objectives, Endpoints and 
Estimands, 8.4.1. Time Period 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 5
Description of Change
Brief Rationale
Section # and Name
up Part B; added 
transportation allowance to 
footnote ‘a’.
Added section for
transportation.
Updated evaluation of safety 
and tolerability in Part B to 
also include vital signs and 
ECG abnormalities
Updated the time period for 
actively eliciting and 
collecting AEs and SAEs.
Updated the serum cystatin 
C (SCys) test to be 
performed at Screening to 
capture the baseline value
and Frequency for Collecting 
AE and SAE Information, 10.2 
Appendix 2 Clinical 
Laboratory
Added updated clinical 
information
To include 
information from the 
latest IB update
2.2.1 Clinical Overview, 
2.2.1.1 Phase 1b Body Weight 
Data, 2.2.1.3 Summary of 
Pharmacokinetics, 2.2.1.4 
Summary of GDF-15 response, 
2.2.1.5 Immunogenicity, 2.3.2 
Benefit Assessment
Protocol template updates
Protocol template 
version 14 April 2023
Title page and Appendices
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 6
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
1. PROTOCOL SUMMARY...................................................................................................13
1.1. Synopsis ..................................................................................................................13
1.2. Schema ....................................................................................................................23
1.3. Schedule of Activities .............................................................................................24
2. INTRODUCTION ...............................................................................................................30
2.1. Study Rationale .......................................................................................................30
2.2. Background .............................................................................................................30
2.2.1. Clinical Overview.......................................................................................31
2.2.1.1. Phase 1b Body Weight Data Summary.....................................32
2.2.1.2. Summary of Safety Data ...........................................................32
2.2.1.3. Summary of Pharmacokinetics..................................................33
2.2.1.4. Summary of GDF-15 Response ................................................34
2.2.1.5. Immunogenicity ........................................................................34
2.3. Benefit/Risk Assessment.........................................................................................34
2.3.1. Risk Assessment.........................................................................................35
2.3.2. Benefit Assessment.....................................................................................37
2.3.3. Overall Benefit/Risk Conclusion................................................................37
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................37
4. STUDY DESIGN.................................................................................................................42
4.1. Overall Design.........................................................................................................42
4.2. Scientific Rationale for Study Design.....................................................................44
4.2.1. Patient Input Into Design............................................................................45
4.2.2. Diversity of Study Population ....................................................................46
4.2.3. Choice of Contraception/Barrier Requirements .........................................47
4.2.4. Collection of Retained Research Samples..................................................47
4.3. Justification for Dose ..............................................................................................47
4.4. End of Study Definition ..........................................................................................48
5. STUDY POPULATION......................................................................................................49
5.1. Inclusion Criteria.....................................................................................................49
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Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
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5.2. Exclusion Criteria....................................................................................................50
5.3. Lifestyle Considerations..........................................................................................52
5.3.1. Contraception..............................................................................................52
5.4. Screen Failures ........................................................................................................52
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................53
6.1. Study Intervention(s) Administered........................................................................53
6.1.1. Administration............................................................................................53
6.2. Preparation, Handling, Storage, and Accountability...............................................54
6.2.1. Preparation and Dispensing........................................................................55
6.3. Assignment to Study Intervention...........................................................................55
6.4. Blinding...................................................................................................................56
6.4.1. Blinding of Participants..............................................................................56
6.4.2. Blinding of Site Personnel..........................................................................56
6.4.3. Blinding of the Sponsor..............................................................................56
6.4.4. Breaking the Blind......................................................................................56
6.5. Study Intervention Compliance...............................................................................57
6.6. Dose Modification...................................................................................................57
6.7. Continued Access to Study Intervention After the End of the Study......................57
6.8. Treatment of Overdose............................................................................................57
6.9. Prior and Concomitant Therapy..............................................................................58
6.9.1. Prohibited During the Study.......................................................................58
6.9.2. Permitted During the Study ........................................................................59
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................59
7.1. Discontinuation of Study Intervention ....................................................................59
7.1.1. COVID-19 ..................................................................................................60
7.2. Participant Discontinuation/Withdrawal From the Study.......................................61
7.2.1. Withdrawal of Consent...............................................................................61
7.3. Lost to Follow-Up ...................................................................................................62
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................62
8.1. Administrative Procedures ......................................................................................62
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Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
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8.1.1. Screening Visit............................................................................................63
8.1.2. Week 5 Visit ...............................................................................................63
8.1.3. Additional Visits for PK Substudy .............................................................64
8.1.4. Home Health Visits.....................................................................................64
8.1.5. Transportation.............................................................................................64
8.2. Efficacy Assessments..............................................................................................64
8.2.1. Body Weight...............................................................................................64
8.2.2. Patient Reported Outcomes ........................................................................65
8.2.2.1. Functional Assessment of Anorexia-Cachexia Therapy 
(FAACT) ...........................................................................................66
8.2.2.2. Patient’s Global Impression of Severity (PGI-S) of 
Appetite, Fatigue, and Physical Function..........................................66
8.2.2.3. Patient’s Global Impression of Change (PGI-C) of 
Appetite, Fatigue, and Physical Function..........................................66
8.2.2.4. PROMIS – Fatigue (version 7a)................................................67
8.2.2.5. PROMIS – Physical Function (version 8c)...............................67
8.2.2.6. Cancer-Related Cachexia Symptom Diary 2.0 .........................67
8.2.2.7. Qualitative Exit Interviews........................................................67
8.2.2.8. Patient’s Global Impression of Severity (PGI-S) of 
Physical Activity and Walking..........................................................68
8.2.2.9. Patient’s Global Impression of Change (PGI-C) of 
Physical Activity and Walking..........................................................68
8.2.3. Physical Activity.........................................................................................68
8.2.3.1. Comfort and Wearability Questionnaire for Digital 
Measures............................................................................................68
8.3. Safety Assessments .................................................................................................69
8.3.1. Physical Examinations................................................................................69
8.3.2. Eastern Cooperative Oncology Group (ECOG) Performance Status.........70
8.3.3. Vital Signs ..................................................................................................70
8.3.3.1. Blood Pressure and Pulse Rate..................................................70
8.3.4. Electrocardiograms.....................................................................................70
8.3.5. Clinical Safety Laboratory Assessments ....................................................70
8.3.6. Pregnancy Testing ......................................................................................71
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 9
8.3.7. Imaging Assessment-CT Scan....................................................................71
8.3.7.1. Imaging Safety Assessment ......................................................71
8.3.7.2. Imaging Efficacy Assessment ...................................................72
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................72
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......73
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................73
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................74
8.4.2. Method of Detecting AEs and SAEs ..........................................................74
8.4.3. Follow-Up of AEs and SAEs......................................................................74
8.4.4. Regulatory Reporting Requirements for SAEs...........................................74
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................75
8.4.5.1. Exposure During Pregnancy......................................................75
8.4.5.2. Exposure During Breastfeeding ................................................77
8.4.5.3. Occupational Exposure .............................................................77
8.4.6. Cardiovascular and Death Events...............................................................77
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................77
8.4.8. Adverse Events of Special Interest.............................................................78
8.4.8.1. Lack of Efficacy........................................................................78
8.4.9. Medical Device Deficiencies......................................................................78
8.4.10. Medication Errors.....................................................................................78
8.5. Pharmacokinetics ....................................................................................................79
8.6. Genetics...................................................................................................................80
8.6.1. Specified Genetics ......................................................................................80
8.6.2. Retained Research Samples for Genetics ...................................................80
8.7. Biomarkers ..............................................................................................................80
8.7.1. GDF-15.......................................................................................................80
8.7.2. Circulating Biomarkers...............................................................................81
8.7.3. Specified Gene Expression (RNA) Research .............................................81
8.7.4. Specified Protein Research.........................................................................81
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 10
8.7.5. Specified Metabolomic Research ...............................................................82
8.7.6. Retained Research Samples for Biomarkers...............................................82
8.8. Immunogenicity Assessments.................................................................................82
8.9. Health Economics ...................................................................................................83
9. STATISTICAL CONSIDERATIONS ................................................................................83
9.1. Statistical Hypotheses .............................................................................................83
9.1.1. Estimands....................................................................................................83
9.1.1.1. Primary Estimand......................................................................83
9.1.1.2. Secondary Estimands ................................................................85
9.2. Analysis Sets ...........................................................................................................86
9.3. Statistical Analyses .................................................................................................87
9.3.1. General Considerations...............................................................................88
9.3.1.1. Analyses for Continuous Endpoints..........................................88
9.3.2. Primary Endpoint Analysis.........................................................................89
9.3.3. Secondary Endpoints Analysis ...................................................................90
9.3.4. Tertiary/Exploratory Endpoints Analysis...................................................90
9.3.5. Other Analyses............................................................................................91
9.4. Interim Analyses .....................................................................................................91
9.4.1. PK/PD Unblinding Plan..............................................................................92
9.5. Sample Size Determination.....................................................................................92
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................94
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............94
10.1.1. Regulatory and Ethical Considerations ....................................................94
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................94
10.1.2. Financial Disclosure .................................................................................95
10.1.3. Informed Consent Process ........................................................................95
10.1.4. Data Protection .........................................................................................96
10.1.5. Committees Structure ...............................................................................97
10.1.5.1. Data Monitoring Committee ...................................................97
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 11
10.1.5.2. Executive Steering Committee................................................97
10.1.5.3. Operations Steering Committee ..............................................97
10.1.6. Dissemination of Clinical Study Data ......................................................97
10.1.7. Data Quality Assurance ............................................................................99
10.1.8. Source Documents..................................................................................100
10.1.9. Study and Site Start and Closure ............................................................100
10.1.10. Publication Policy.................................................................................101
10.1.11. Sponsor’s Medically Qualified Individual............................................102
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................103
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................104
10.3.1. Definition of AE .....................................................................................104
10.3.2. Definition of an SAE ..............................................................................105
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................107
10.3.4. Reporting of SAEs..................................................................................111
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................112
10.4.1. Male Participant Reproductive Inclusion Criteria..................................112
10.4.2. Female Participant Reproductive Inclusion Criteria...............................112
10.4.3. Woman of Childbearing Potential ..........................................................112
10.4.4. Contraception Methods...........................................................................113
10.5. Appendix 5: Genetics..........................................................................................115
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .....116
10.7. Appendix 7: Kidney Safety Monitoring Guidelines ...........................................118
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................118
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............118
10.7.2.1. Adults (18 Years and Above)-2021 CKD-EPI Equations.....118
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................118
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................119
10.9. Appendix 9: Comfort and Wearability Questionnaire ........................................121
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 12
10.10. Appendix 10: ECOG Performance Status.........................................................123
10.11. Appendix 11: RECIST 1.1 Tumor Assessment Criteria RECIST 
(Response Evaluation Criteria In Solid Tumors) version 1.1 Guidelines ...............124
10.12. Appendix 12: List of Platinum-Based Chemotherapies....................................129
10.13. Appendix 13: Abbreviations .............................................................................130
10.14. Appendix 14: Protocol Amendment History.....................................................136
11. REFERENCES ................................................................................................................144
LIST OF TABLES
Table 1.
Schedule of Activities for Part A Double-Blind.......................................24
Table 2.
Schedule of Activities for Participants Enrolled in Optional Part B 
OLT...........................................................................................................28
Table 3.
Summary of Predicted Steady State Total ponsegromab Exposures 
and Associated Safety Margins and Exposure Multiples Following 
Q4W SC Doses.........................................................................................48
Table 4.
Summary of Predicted Steady State Unbound ponsegromab 
Exposures and Associated Exposure Multiples Following Q4W SC 
Doses.........................................................................................................48
Table 5.
Objective Response Status at each Evaluation.......................................128
Table 6.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only ...............................................................................128
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 13
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, 
Safety, and Tolerability of Ponsegromab in Patients With Cancer, Cachexia, and Elevated 
Concentrations of GDF-15, Followed by an Optional Open-Label Treatment Period. 
Brief Title:
A Phase 2 Study of the Efficacy and Safety of Ponsegromab in Patients with Cancer, 
Cachexia and Elevated GDF-15. (PROACC -1)
Regulatory Agency Identification Number(s):
US IND Number:
139674
[EudraCT/CTIS] Number:
2022-003016-87
ClinicalTrials.gov ID: 
NCT05546476
Pediatric Investigational Plan Number:
NA
Protocol Number:
C3651003
Phase:
2
Rationale:
Patients with advanced cancer and elevated concentrations of GDF-15 frequently develop 
cachexia which impacts their quality of life and survival. Inhibiting the activity of GDF-15 in 
such patients may help reverse cachexia and improve their quality of life. This study will 
evaluate the efficacy, safety, and tolerability of ponsegromab, an inhibitor of GDF-15,
compared to placebo, in patients with cancer, cachexia, and elevated concentrations of 
GDF-15. 
This study is also known as PROACC -1, Patient Reported Outcomes and Activity in 
CanCer.
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Objectives, Endpoints, and Estimands:
Part A
Objectives
Endpoints
Estimands
Primary
Primary
Primary

To evaluate the effect of 
ponsegromab compared 
with placebo on body 
weight in participants 
with cancer, cachexia, and 
elevated concentrations of 
GDF-15.
Change from baseline body 
weight at Week 12.
Estimand 1 (similar to 
“hypothetical”) is the difference 
between ponsegromab and 
placebo in mean change from 
baseline in body weight at 
Week 12, in participants with 
cancer, cachexia and elevated 
concentrations of GDF-15, 
under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures, 
prohibited medications or 
participants’ non-compliance 
with dosing.

Secondary

Secondary

Secondary
To evaluate the effect of 
ponsegromab compared to 
placebo on physical activity and 
gait as measured by wearable 
digital sensors in participants 
with cancer, cachexia, and 
elevated concentrations of 
GDF-15.

Change from baseline in each 
of the physical activity and 
gait endpoints measured with 
remote digital sensors at 
Week 12: 

Moderate to vigorous 
physical activity time;

Sedentary activity time;

Non sedentary activity 
time;

Total vector magnitude;

Mean activity level during 
M6min;

Mean gait speed;

95th percentile gait speed.
Estimand 2 (similar to 
“hypothetical”) is the difference 
between ponsegromab and 
placebo in mean change from 
baseline in each of the physical 
activity and gait endpoints at 
Week 12, in participants with 
cancer, cachexia and elevated
concentrations of GDF-15, 
under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures, 
prohibited medications or 
participants’ non-compliance 
with dosing.
To evaluate the effect of 
ponsegromab compared to 
placebo on the appetite-related 
symptoms as measured by 
FAACT in participants with 
cancer, cachexia, and elevated 
concentrations of GDF-15.
Change from baseline in 
FAACT sub-scale scores at 
Week 12:

FAACT-ACS;

FAACT-5IASS.
Estimand 3 (similar to 
“hypothetical”) is the difference 
between ponsegromab and 
placebo in mean change from 
baseline in each FAACT 
sub-scale score at Week 12, in 
participants with cancer, 
cachexia and elevated 
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Objectives
Endpoints
Estimands
concentrations of GDF-15, 
under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures, 
prohibited medications or 
participants’ non-compliance 
with dosing.
To evaluate the effect of 
ponsegromab compared to 
placebo on anorexia/appetite 
nausea, vomiting, and fatigue 
measured by the CRCSD, 
Pfizer-developed instrument, in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.
Change from baseline score for 
the questions from the CRCSD 
at Week 12 related to:

Anorexia/appetite;

Nausea and vomiting;

Fatigue.
Estimand 4 (similar to 
“hypothetical”) is the difference 
between ponsegromab and 
placebo in mean change from 
baseline in each of the 
anorexia/appetite, nausea, 
vomiting, and fatigue questions 
from the CRCSD at Week 12, in 
participants with cancer, 
cachexia and elevated 
concentrations of GDF-15, 
under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effect of 
prohibited procedures, 
prohibited medications or 
participants’ non-compliance 
with dosing.
To characterize the safety and 
tolerability of repeated SC
administrations of ponsegromab 
compared to placebo in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.
Incidence of adverse events,  
safety laboratory tests, vital 
signs and ECG abnormalities*
There are no defined estimands 
for the incidence of adverse 
events, safety laboratory tests, 
vital signs and ECG 
abnormalities, and these 
endpoints will be summarized 
using Pfizer data standards as 
applicable.
* Safety, tolerability and survival will also be characterized in Part B once all applicable participants have 
completed Part B of the study. These data will be reported as part of the supplemental CSR.
Overall Design:
This is a Phase 2, randomized, double-blind, placebo-controlled study of the efficacy, safety,
and tolerability of three different doses of ponsegromab compared to placebo, administered 
for 12 weeks, in patients with NSCLC, PANC, or CRC who have elevated concentrations of 
GDF-15 and cachexia. The double-blind period is followed by an optional open-label (Part 
B) extension period.
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The Screening visit will occur no more than 28 days and no less than 7 days, prior to 
Randomization. The 7-day minimum duration between Screening and Randomization visits 
will ensure that the GDF-15 results are available to inform the investigator’s assessment of 
eligibility and the 7-day collection of PRO and physical activity data. Following the 
Screening period to confirm eligibility, approximately 168 study participants, who meet the 
entry criteria, will be randomized to study intervention (one of 3 dose groups of 
ponsegromab or matching placebo) and will be stratified by treatment with or without 
platinum-based chemotherapy, which is known to induce GDF-15 and therefore may impact 
the response to ponsegromab treatment. The 12-week double-blind dosing period (Part A) 
will consist of a total of 3 doses administered Q4W SC.
A PK substudy will be conducted in approximately 36 of the approximately 168 participants 
(approximately 9 in each treatment group in Part A). Up to 3 additional PK and PD samples 
(two samples during Part A and one sample during Part B, if relevant), will be collected in 
these participants at timepoints during the study outlined in Sections 1.2 schema and 1.3 
SoA.
On completion of Part A, participants will have the opportunity to enter an optional OLT 
period (Part B) consisting of ponsegromab 400 mg Q4W SC for up to 1 year. The 
investigator and participant must decide at the Week 8 visit if they wish to continue to the 
optional OLT period. 
Participants opting to continue to the optional OLT period will receive their first dose of 
open-label ponsegromab 400 mg at the Week 12 visit, which is the last visit of the 
double-blind portion. Upon completion of the optional OLT period, there will be a follow-up 
visit (Week 72) which is to occur 56 to 63 days post last dose of study intervention.
Participants who do not proceed with the optional OLT period are to complete the Week 12 
visit and a follow-up visit at Week 16. 
Additional follow-up may be conducted for safety evaluation, at the discretion of the 
investigator.
The optional OLT period will continue as currently planned, unless the following factors 
develop in which case the optional OLT period may be modified:

Upon completion of the double-blind portion, the final analysis shows a lack of 
efficacy for the primary endpoint and/or inadequate safety and tolerability;

An alternative method of study intervention delivery become available;

A lower dose of ponsegromab is shown to be efficacious; 

The sponsor decides to terminate the study/clinical development program. 
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
Participants may withdraw from the optional OLT period at any time, for reasons 
such as the following:

The study participant withdraws consent or dies;
The study participant experiences an AE attributable to intervention;
A change in study participant’s medical condition that, in the investigator’s 
judgment, makes it inappropriate to continue study participation.
An independent oversight committee in the form of an IRC will monitor the safety, 
efficacy, and tolerability of the study participants and the study conduct. There will 
also be an Executive Steering Committee and an Operations Steering Committee. 
Number of Participants:
Approximately 168 participants will be enrolled in the study, of which up to approximately 
36 participants will be enrolled in the PK substudy.
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and randomization to study intervention. A participant will be considered enrolled if 
the informed consent is not withdrawn prior to participating in any study activity after 
Screening. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Study Population:
Inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study:
1. Participants aged ≥18 years (or the minimum age of consent if > 18 in accordance 
with local regulations) at screening who have signed informed consent. 
a.
A female participant is eligible to participate if she is not pregnant or 
breastfeeding.
b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
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2. Documented histologic or cytologic active diagnosis of NSCLC, PANC, or CRC and
are currently receiving, or have completed, standard of care treatment for this cancer
(which may include systemic therapy).
3. Cachexia defined by Fearon criteria of weight loss as (See Section 8.1.1 for details if 
the participant’s body weight is unavailable from medical record):

BMI <20 kg/m2 with involuntary weight loss of >2% within 6 months prior to 
screening; 
or

Involuntary weight loss of >5% within 6 months prior to screening irrespective of 
BMI.
4. Serum GDF-15 concentrations of ≥1.5 ng/mL (as measured using the Investigational 
Use Only Roche Elecsys GDF-15 assay)10 at Screening.
5. Participants who are assessed by the investigator to have:

an ECOG PS ≤3, and;

a life expectancy of at least 4 months to be able to complete Part A.
6. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Current active reversible causes of decreased food intake, as determined by the 
Investigator. These causes may include, but are not limited to:

NCI CTCAE Grade 3 or 4 oral mucositis;

NCI CTCAE Grade 3 or 4 GI disorders [nausea, vomiting, diarrhea, and 
constipation];

mechanical obstructions interfering with the participant’s ability to eat.
2. Receiving tube feedings or parenteral nutrition (either total or partial) at the time of 
Screening or Randomization.
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3. Cachexia caused by other reasons, as determined by the investigator, including, but 
not limited to: 

Severe COPD requiring use of home O2;

NYHA class III-IV heart failure;

AIDS.
4. Undergoing major surgery (central venous access placement and tumor biopsies are 
not considered major surgery) within 4 weeks prior to randomization. Patient must 
have recovered from acute effects of surgery prior to screening. Patient should not 
have plans to undergo major surgical procedures during the study.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
6. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (IgG protein) or molecules made of components of monoclonal 
antibody. 
7. Current use of any prohibited concomitant medication(s) within 4 weeks prior to first 
dose of study intervention. Refer to Section 6.9.
8. Concurrent administration of investigational products (including drug, biologic 
agents, or vaccines) are not permitted within 30 days (or as determined by the local 
requirement) or 5 half-lives (whichever is longer) of the first dose of study 
intervention through the duration of the study (including both Part A and B). Refer to 
Section 6.9.
9. Enrollment and previously dosed in a prior study with ponsegromab.
10. History of severe liver disease or cirrhosis, unrelated to metastatic cancer. Potential 
study participants with the following liver function test abnormalities will be 
excluded; result may be confirmed by a single repeat test, if necessary: 

Total bilirubin ≥1.5 × ULN (except for Gilbert’s syndrome) 

AST >3 × ULN (AST > 5X ULN if there is liver involvement by the tumor) 

ALT >3 × ULN (ALT >5X ULN if there is liver involvement by the tumor) 
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
Alkaline phosphatase >3 x ULN (Alkaline phosphatase >5X ULN if there is liver 
involvement by the tumor and/or in case of bone metastases, or if considered 
related to prior surgery e.g. pancreaticoduodenectomy).
11. Renal disease requiring dialysis.
12. Current adherence to a calorie-restricted diet with the intention of weight loss.
13. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members. 
Study Arms and Duration:
Following a 28-day screening period to confirm eligibility, study participants who meet the 
entry criteria will be randomized to study intervention (one of 3 dose groups of ponsegromab 
or placebo). The 12-week double-blind dosing period (Part A) will consist of a total of 3 SC 
doses, administered Q4W. On completion of Part A, participants will have the opportunity to 
enter an optional open-label treatment period (Part B) consisting of ponsegromab 
400 mg Q4W SC for up to 1 year. 
Study Intervention(s)
Intervention Name
ponsegromab
ponsegromab
ponsegromab
placebo
Arm Name
(group of 
participants 
receiving a specific 
treatment or no 
treatment)
ponsegromab 
Double-Blind 
Treatment 100 mg
ponsegromab 
Double-Blind 
Treatment 200 mg
ponsegromab 
Double-Blind 
Treatment 400 mg
placebo 
Double-Blind 
Treatment
Dose Level
100 mg Q4W
200 mg Q4W
400 mg Q4W
placebo Q4W
Unit Dose Strength(s)
100 mg/ mL
100 mg/ mL
100 mg/ mL
placebo
Route of 
Administration
SC
SC
SC
SC
Use
experimental
experimental
experimental
placebo-
active-comparator
IMP or NIMP/AxMP
IMP
IMP
IMP
IMP
Statistical Methods:
The sample size in the ponsegromab and placebo arms is based on the primary efficacy 
endpoint, mean change from baseline in body weight at Week 12. Approximately 
168 randomized participants are proposed, to ensure completion of approximately 
120 participants, assuming a discontinuation rate of approximately 30%. 120 completing
participants, in a 1:1:1:1 ratio, plus 39 participants from an informative meta-analytic 
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predictive prior (based on historical results from internal and external studies, robustified by 
the inclusion of a weakly informative component to handle any possible prior-data conflict)
gives acceptable Operating Characteristics in that the probability of achieving statistical 
significance (at the 5% significance level, using a 1-sided t-test), for a true difference 
between ponsegromab and placebo of 2.7 kg, is approximately 80% (with a conservative 
standard deviation of 4.9 kg). 
The primary estimand will be the population level estimate of the difference between 
ponsegromab and placebo in the mean change from baseline in body weight at Week 12,
under the scenario of no discontinuation of study intervention and without the potential 
confounding effect of prohibited procedures, prohibited medications or participants’ 
non-compliance with dosing. Data collected after a participant has discontinued study 
intervention, has undergone a prohibited procedure, received prohibited medications, or has 
inadequate compliance will be censored and treated as missing data.
The primary endpoint analysis will be a Bayesian Emax model applied to results from an 
MMRM analysis. Change from baseline in body weight will be first analyzed using an 
MMRM model fitted to all post-treatment dosing timepoints up to Week 12 (ie, Weeks 4, 8,
and 12). The primary analysis will include all participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention. The MMRM model will 
include participant as a random term, and baseline, time (as a factor), baseline-by-time 
interaction, treatment and treatment -by -time interaction as fixed terms in the model.
Additional terms for type of therapy [ie, platinum or not] and type of cancer will be fitted in 
the model. An unstructured covariance matrix will be fitted to the repeated times within 
subject, and the Kenward Roger approximation will be used for estimating degrees of 
freedom. No adjustments will be made for multiplicity. A Bayesian Emax model will then be 
fitted to the Lsmeans and Ses from Week 12 only. The posterior medians and 90% credible 
intervals will be reported for each randomized dose (including placebo) and their differences 
relative to placebo. 
Secondary endpoints of physical activity and gait, FAACT sub-scales and questions from the 
CRCSD, will be analyzed using an MMRM model with similar estimands to the primary 
estimand. Safety and tolerability data will be summarized descriptively through appropriate 
data tabulation, descriptive statistics, categorical summaries, and graphical presentations, as 
appropriate, in accordance with Pfizer Data Standards.
Ethical Considerations:
Considering all available clinical and nonclinical data, the benefit-risk profile of 
ponsegromab is favorable and supports continued clinical development in patients with 
cancer and cachexia. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ponsegromab may be found in the IB, which is the SRSD for this 
study.
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Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with ponsegromab are justified by the anticipated benefits that may 
be afforded to participants with cancer and cachexia.
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1.2. Schema
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2. INTRODUCTION
Ponsegromab is an inhibitor of GDF-15 that is currently being investigated in participants 
with cancer, cachexia, and elevated concentrations of GDF-15. Ponsegromab is also being 
investigated in patients with heart failure and elevated concentrations of GDF-15. 
2.1. Study Rationale 
Patients with cancer suffer considerable morbidity related to both tumor progression and the 
side effects of therapies targeting the underlying malignancy. As cancers progress, patients 
frequently develop cachexia, a loss of weight due to the catabolism of muscle and fat 
tissue.1,2 The progressive worsening of cachexia impacts a cancer patient’s quality of life and 
contributes to poor survival.
The purpose of the study is to evaluate the efficacy, safety and tolerability of ponsegromab 
compared to placebo in the treatment of patients with cancer, cachexia, and elevated 
concentrations of GDF-15.
This study is also known as PROACC-1, Patient Reported Outcomes and Activity in CanCer.
2.2. Background 
At the present time, treatments for cancer related cachexia are limited. Pharmacologic 
interventions associated with improvements in appetite improvement or body weight gain 
include progesterone analogues and corticosteroids.1 The ASCO, in its 2020 Management of 
Cachexia Guidelines, stated that there is no recommended pharmacologic standard of care 
for patients with cancer associated cachexia.2
One of the biomarkers associated with cancer cachexia is the cytokine GDF-15.3 GDF-15, 
also known as MIC-1, is a member of the TGFb superfamily. In healthy individuals the 
major source of circulating GDF-15 is believed to be the liver, although it is also expressed 
by the kidneys, lung and adipose tissue.4 GDF-15 is secreted by tumor cells and is associated 
with cachexia in cancer patients.5,6,7
In addition, published clinical data and internal animal model data suggest that 
administration of platinum therapy can induce increases in serum GDF-15 concentrations. 
Clinical literature and internal animal model data8 also suggest that the nausea, emesis and 
anorexia observed with platinum therapy may be mediated, at least in part, by 
platinum-induced elevations in GDF-15. 
Therefore, it is hypothesized that cachexia in many types of cancer, including NSCLC, 
PANC, and CRC, is largely mediated via GDF-15 and that suppression of GDF-15 in these 
patients may lead to improvement in serious aspects of cachexia such as anorexia leading to 
unintended weight loss, fatigue and impaired mobility. Furthermore, given the observations 
of GDF-15 elevation with platinum therapy, patients receiving standard of care antitumor
treatment that includes systemic platinum- based therapy, may be a specific population that 
could potentially gather additional- benefit from GDF-15 inhibition.8
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Ponsegromab is an anti-GDF-15 mAb that is currently being investigated in study 
participants with cancer who have elevated concentrations of GDF-15 and cachexia. The 
objective of this clinical study is to determine if ponsegromab administered at three different 
doses every 4-weeks over 12-weeks can reduce the study participants’ cachexia related 
symptom burden and improve their quality of life compared to placebo during 12-weeks of 
treatment.
A summary of relevant, currently available data on ponsegromab is provided in this protocol. 
Additional detail, and further information for this compound, may be found in the IB, 
including its physical, chemical, pharmaceutical properties and formulation, non-clinical 
studies, and its known effects in humans. 
2.2.1. Clinical Overview
To date, the safety of ponsegromab has been assessed in 2 completed Phase 1 clinical studies 
in healthy adult volunteers (C3651001 and C3651002) and in 2 completed Phase 1b studies 
in patients with elevated serum GDF-15 levels and cancer cachexia (C3651009) or cancer 
anorexia (C3651010). A total of 80 participants were exposed to this at least one dose of 
ponsegromab across these studies. A summary of the completed studies is presented in the 
table below. 
Completed Clinical Studies with Ponsegromab
Study 
Identifier
Study Design 
and Type of 
Control
Dosing Regimen, 
Formulation, Dose
Number of 
Participants 
Randomized
Population
Treatment 
Duration 
C3651001
Phase 1, 
double-blind, 
randomized, 
sponsor-open, 
placebo 
controlled, 
single 
ascending 
dose study.
Ponsegromab or 
placebo. 
Subcutaneously 
administered 
solution
Dose: 
0.1, 0.3, 1, 3, 10, 
30, 100 and 300 mg
Total: 63
47 ponsegromaba, 
16 placebo
Eight sequential 
cohorts of 
healthy adult 
participants. 
Single dose 
C3651002
Phase 1, 
double-blind,
randomized, 
sponsor-open, 
placebo 
controlled, 
single dose 
study.
Ponsegromab or 
placebo. 
Subcutaneously 
administered 
solution
Dose: 100 mg
Total: 8
6 ponsegromab, 
2 placebo
One cohort of 
healthy adult 
Japanese 
participants. 
Single dose 
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Completed Clinical Studies with Ponsegromab
Study 
Identifier
Study Design 
and Type of 
Control
Dosing Regimen, 
Formulation, Dose
Number of 
Participants 
Randomized
Population
Treatment 
Duration 
C3651009
Phase 1b, 
open-label 
multiple dose 
study
Ponsegromab
Subcutaneously 
administered 
solution
Dose: 200 mg Q3W
Total: 11
10 ponsegromabb
Participants 
with cancer, 
cachexia, and 
serum GDF-15 
levels ≥ 1500 
pg/ml.
12 weeks
C3651010
Phase 1b, 
double-blind, 
randomized, 
placebo 
controlled 
followed by 
open-label 
extension
Ponsegromab or 
placebo
Subcutaneously 
administered 
solution
Dose: 200 mg Q3W
Total: 18
Double-blind 
period
12 ponsegromab
6 placebo
Open-label 
period:
14 ponsegromabc
Participants 
with cancer, 
anorexia, and 
serum GDF-15 
levels ≥ 1500 
pg/ml.
6 weeks 
followed by 
18 week 
open label 
extension.
a.
N=6 per dose except for the 300 mg dose group where N=5.
b.
1 participant randomized and not dosed.
c.
Of these 14, 5 received placebo and 9 received ponsegromab during the preceding double-blind period.
More detailed information for the completed studies may be found in the ponsegromab IB, 
which is the SRSD for this study. 
2.2.1.1. Phase 1b Body Weight Data Summary
While the primary objective of Phase 1b C3651009 study was to evaluate the safety, 
tolerability, PK/PD, and immunogenicity of ponsegromab 200 mg Q3W (through 12 weeks/5 
doses) in cancer patients with cachexia, change of body weight from baseline was also 
evaluated, as a signal of clinical efficacy. Mean increases from baseline in body weight were 
observed at all time points during the 12-week treatment period and 12-week follow-up
period.  The mean (SD) body weight increase from baseline was 4.46 (4.75) kg at Week 12, 
with a mean (SD) percent increase from baseline of 5.81 (5.87).
Body weight data are not presented for C3651010 study given that this study was terminated 
for non-safety reasons, with less than 50% of originally planned number of participants 
enrolled, precluding meaningful evaluation for changes in body weight.
2.2.1.2. Summary of Safety Data
In the single arm, open-label, Phase 1b C3651009 study of patients with cancer, cachexia, 
and elevated GDF-15 levels, there were 92 TEAEs reported for 10 participants dosed with 
ponsegromab 200 mg Q3W SC.  None of these TEAEs were attributed to study intervention
by the investigator or sponsor. Of these non-treatment related TEAEs, most were mild or 
moderate; 5 were serious, of which one was fatal due to neoplasm progression during the 
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follow-up period (131 days after randomization). No deaths occurred during the treatment 
period. 
In the Phase1B study C3651010 study in patients with cancer, anorexia and elevated GDF-15 
levels, there were 58 TEAEs (including 8 SAEs) across 18 participants. Only 1 TEAE 
(myalgia) was considered treatment-related by the investigator. The incidence and severity of 
TEAEs were similar between the two treatment arms. In the double-blind treatment phase 
there were 3 deaths: one in a participant receiving placebo due to a cardiac arrest and 2 in the 
ponsegromab 200 mg Q3W treatment arm, one due to respiratory failure and one due to acute 
myocardial infarction. During the open label extension there were 3 deaths attributed due to 
disease progression. None of these deaths were considered treatment related.
2.2.1.3. Summary of Pharmacokinetics
Following single dose administration of ponsegromab to healthy non-Japanese participants, 
SC absorption of unbound ponsegromab for the 3 to 300 mg dose groups occurred with 
median Tmax ranging from 2.25 to 7.00 days. In general, over the 10 to 300 mg dose range, 
increases in geometric mean unbound Cmax in serum were approximately dose-proportional 
and increases in unbound AUClast and AUCinf in serum appeared to be greater than dose-
proportional. The geometric mean CL/F appeared to decrease with increasing dose, and mean 
terminal t½ increased with increasing dose, ranging from 3.52 to 11.1 days across the 10 to 
300 mg dose groups.
Following single doses of SC ponsegromab in healthy participants, absorption of total 
ponsegromab occurred with median Tmax ranging from 6.00 to 14.0 days across the 1 to 300 
mg dose groups. In general, increases in geometric mean total Cmax, AUClast, and AUCinf  in 
serum appeared to be less than dose-proportional over the 10 to 100 mg dose range, while 
increases in exposure from 100 to 300 mg doses were largely dose proportional. The mean 
terminal t½ values increased from 20.1 days for the 10 mg group to 30.9 days for the 300 mg 
group. The long terminal t½of total ponsegromab in serum is driven primarily by the half-life 
of bound ponsegromab (ponsegromab-GDF-15 complex), as the unbound ponsegromab 
terminal t½ values observed over the same dose ranges were much shorter. Unbound 
ponsegromab (not total ponsegromab) is the active moiety that accounts for pharmacological 
activity of the drug.
At a single 100 mg SC dose, the geometric mean unbound ponsegromab Cmax, AUClast, and 
AUCinf in Japanese participants were approximately 50%, 70%, and 71% higher, 
respectively, than those observed in non-Japanese participants. Similarly, the geometric mean 
total Cmax, AUClast, AUCinf in Japanese participants were approximately 48%, 65%, and 66% 
higher, respectively.
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2.2.1.4. Summary of GDF-15 Response
In study C3651001, following single SC administration of 1 to 300 mg doses of 
ponsegromab to healthy non-Japanese adults, the median duration of serum unbound GDF-15 
suppression (defined as last time post-dose with unbound GDF-15 concentration reported as 
below LLOQ which was 42.4 pg/mL) increased with increasing dose of ponsegromab, 
ranging from 0.17 day for the 1 mg dose group to 75.61 days for the 300 mg dose group. 
There was generally no change from baseline in measures of unbound GDF-15 in 
participants treated with placebo, ponsegromab 0.1 and 0.3 mg groups. Following a single 
SC administration of ponsegromab 100 mg in healthy Japanese adult participants in study 
C3651002, serum unbound GDF-15 concentrations were suppressed to below the LLOQ 
starting on Day 1, with the median duration of suppression of 40.49 days, ranging from 9.00-
88.07 days in individual participants.
In study C3651009, following SC administration of ponsegromab at 200 mg Q3W through 
Week 12 (Day 85) in participants with cancer, cachexia and elevated serum GDF-15 
concentrations, median unbound GDF-15 concentrations were suppressed from the baseline 
concentration of 2269 pg/mL to below the LLOQ at all visits between Day 1 and Week 15 
(Day 106). 
2.2.1.5. Immunogenicity
Based on the available ADA/Nab data from the Phase 1 C3651001 and C3651002 studies 
conducted in healthy participants (n=53), none of the 53 participants had pre-existing ADA at 
baseline and the overall incidence of treatment-induced ADA was 9.43% (5/53 participants). 
Nab was observed in 1 participant across the 2 studies. Overall, there was no apparent effect 
of ADA observed on the PK, PD and safety profile of ponsegromab. 
In C3651009 and C3651010 studies, following SC administration of ponsegromab at 200 mg 
Q3W through 12 and 24 weeks, respectively, in participants with cancer, cachexia or 
anorexia, and elevated serum GDF-15 concentrations, the incidence of treatment-induced 
ADA was very low with overall incidence of treatment-induced ADA of 0 and 9.1% (1/11), 
respectively, and no incidence of Nab was observed in either study. 
2.3. Benefit/Risk Assessment
Based on the available clinical data described in the IB, no safety concerns have been 
identified in the four clinical trials completed to date. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ponsegromab may be found in the IB which is the SRSD for this study.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) ponsegromab
SC injection site reactions and hypersensitivity 
reactions. 
Although there were no injection site reactions or 
delayed hypersensitivity reactions observed in the 
completed clinical studies, as with all injectable 
mAbs, there is the potential for injection site 
reactions or delayed hypersensitivity reactions.
The following exclusion criteria is added: 
History of allergic or anaphylactic reaction to 
any therapeutic or diagnostic monoclonal 
antibody (IgG protein) or molecules made of 
components of monoclonal antibody. 
Additionally, injection site reactions will be 
monitored, and injection sites rotated. 
Use of a placebo arm. 
Use of a placebo arm represents a risk of lack of 
benefit for those not receiving active therapy. As 
there are no data on efficacy yet, this risk cannot be 
assessed. 
Participants will continue to receive standard 
of care throughout the study for their 
underlying cancer. The study has been 
designed with, a 3 active: 1 placebo 
randomization ratio, in order to increase 
participants’ chances of receiving active 
therapy.
Study Procedure
Challenges in collecting the requisite amount of 
blood required.
Participants may be anemic or have a concomitant 
condition that makes it difficult to collect requisite 
volume of bio-samples. 
Effort to streamline bio sample collection in 
the SoA and reduce volume collected where 
feasible.
Additional CT scans.
Participants may undergo up to two additional CT 
scans beyond standard of care, thereby increasing 
exposure to radiation.
Participants will not be required to undergo 
additional CT scans if they had a SOC CT 
scan within 3 weeks prior to the Screening 
visit, between Weeks 10-12 or within 7 days 
after the Week 12 visit.
Use of ECG patches.
Mild skin reactions/irritations attributed to use of 
ECG patches were observed in completed studies 
with ponsegromab.
Sites will be reminded to clean and dry the 
study participant’s skin before attaching the 
ECG electrodes; And after removing the 
electrodes, clean the study participant’s skin 
with soap and water.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other
The COVID-19 pandemic may pose risks to study 
participation.
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a study 
procedure at a study facility.
Sites will follow local guidelines to minimize 
risk of SARS-CoV-2 infection at a study 
facility. Non-dosing visits may be conducted 
by a qualified site staff member/phlebotomist
at the participant’s home, in order to reduce 
the risk of exposure at the site. 
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2.3.2. Benefit Assessment
Clinical data on any potential benefit of ponsegromab in patients with cancer, cachexia, and 
elevated serum GDF-15 concentrations, are limited to observations from the single arm, 
open-label, Phase 1b C3651009 study of ponsegromab 200 mg Q3W. Mean increases from 
baseline in body weight were observed at all time points during the 12-week treatment period 
and 12-week follow-up period. In addition, median serum unbound GDF-15 concentrations 
were suppressed in these participants from elevated baseline concentrations to below the 
lower level of quantification at all visits from Day 1 through week 15, with last dose of 
ponsegromab 200 mg Q3W at 12 weeks (see Section 2.2.1.4). Similar suppression of serum 
unbound GDF-15 concentrations was observed throughout treatment with ponsegromab in 
patients with cancer, anorexia, and elevated serum GDF-15 concentrations enrolled in the 
Phase 1b C3651010 study. No safety concerns were identified in the 80 participants who 
received at least one dose of ponsegromab across four clinical trials completed to date.
Based upon these clinical data and nonclinical data, it is hypothesized that dosing with 
ponsegromab may improve participants appetite and support maintenance of body weight in 
participants enrolled in this study. More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events of ponsegromab may be found in 
the IB, which is the SRSD for this study.
It is estimated that 50%-80%9 of patients with advanced malignant cancer suffer with 
cachexia which results in worse outcomes. Therefore, the development of ponsegromab for 
the treatment of cachexia may satisfy an area of high unmet need.
2.3.3. Overall Benefit/Risk Conclusion
This study is designed primarily to assess efficacy, safety, tolerability, pharmacokinetics and 
pharmacodynamics of ponsegromab in participants with cancer who have cachexia and 
elevated concentrations of GDF-15. 
Considering all available clinical and nonclinical data, the benefit-risk profile of 
ponsegromab is favorable and supports continued clinical development in patients with 
cancer, cachexia and elevated serum GDF-15 concentrations. 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Part A
Objectives
Endpoints
Estimands
Primary
Primary
Primary

To evaluate the effect of 
ponsegromab  compared with 
placebo on body weight in 
participants with cancer, 

Change from baseline 
body weight at Week 
12.

Estimand 1 (similar to 
“hypothetical”) is the 
difference between 
ponsegromab and 
placebo in mean change 
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Objectives
Endpoints
Estimands
cachexia, and elevated 
concentrations of GDF-15.
from baseline in body 
weight at Week 12, in 
participants with cancer, 
cachexia and elevated 
concentrations of GDF-
15, under the scenario 
of no discontinuation of 
study intervention and 
without the potential 
confounding effect of 
prohibited procedures, 
prohibited medications
or participants’ 
non-compliance with 
dosing.

Secondary

Secondary

Secondary

To evaluate the effect of 
ponsegromab compared to 
placebo on physical activity 
and gait as measured by 
wearable digital sensors in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
in physical activity 
and gait endpoints 
measured with remote 
digital sensors at 
Week 12.

Moderate to vigorous 
physical activity time;

Sedentary activity 
time;

Non sedentary activity 
time;

Total vector 
magnitude;

Mean activity level 
during M6min;

Mean gait speed;

95th percentile gait 
speed.

Estimand 2 (similar to 
“hypothetical”) is the 
difference between 
ponsegromab and 
placebo in mean change 
from baseline in each of 
the physical activity and 
gait endpoints at 
Week 12, in participants 
with cancer, cachexia 
and elevated
concentrations of 
GDF-15, under the 
scenario of no 
discontinuation of study 
intervention and without 
the potential 
confounding effect of 
prohibited procedures, 
prohibited medications
or participants’ 
non-compliance with 
dosing.

To evaluate the effect of 
ponsegromab compared to 
placebo on the appetite-related 
symptoms as measured by 
FAACT in participants with 
cancer, cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
in FAACT sub-scale 
scores at Week 12:

FAACT-ACS;

FAACT-5IASS.

Estimand 3 (similar to 
“hypothetical”) is the 
difference between 
ponsegromab and 
placebo in mean change 
from baseline in each 
FAACT sub-scale score 
at Week 12, in 
participants with cancer, 
cachexia and elevated 
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Objectives
Endpoints
Estimands
concentrations of GDF-
15, under the scenario 
of no discontinuation of 
study intervention and 
without the potential 
confounding effect of 
prohibited procedures, 
prohibited medications
or participants’ 
non-compliance with 
dosing.

To evaluate the effect of 
ponsegromab compared to 
placebo on anorexia/appetite 
nausea, vomiting, and fatigue 
measured by the CRCSD, 
Pfizer-developed instrument, in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
score for the questions 
from the CRCSD at 
Week 12 related to:

Anorexia/appetite;

Nausea and vomiting;

Fatigue.

Estimand 4 (similar to 
“hypothetical”) is the 
difference between 
ponsegromab and 
placebo in mean change 
from baseline in each of 
the anorexia/appetite, 
nausea, vomiting, and 
fatigue questions from 
the CRCSD at Week 12, 
in participants with 
cancer, cachexia and 
elevated concentrations 
of GDF-15, under the 
scenario of no 
discontinuation of study 
intervention and without 
the potential 
confounding effect of 
prohibited procedures, 
prohibited medications
or participants’ 
non-compliance with 
dosing.

To characterize the safety and 
tolerability of repeated SC 
administrations of 
ponsegromab compared to 
placebo in participants with
cancer, cachexia, and elevated 
concentrations of GDF-15.

Incidence of adverse 
events, safety 
laboratory tests, vital 
signs and ECG 
abnormalities.*

There are no defined 
estimands for the 
incidence of adverse 
events, safety laboratory 
tests, vital signs, and 
ECG abnormalities, and 
these endpoints will be 
summarized using 
Pfizer data standards as 
applicable.

Tertiary/Exploratory

Tertiary/Exploratory

Tertiary/Exploratory

To evaluate the effect of 
ponsegromab compared to 

Change from baseline 
in additional physical 

Not Applicable.
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Objectives
Endpoints
Estimands
placebo on physical activity 
and gait as measured by 
wearable digital sensors in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.
activity and gait 
endpoints measured 
with remote digital 
sensors at Week 12.

To evaluate the effect of 
ponsegromab compared to 
placebo on HRQoL as 
measured by FAACT in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
in additional FAACT 
total and sub-scale 
scores at Week 12.

Not Applicable.

To evaluate PK of 
ponsegromab following 
repeated SC administration to 
participants with cancer 
cachexia and elevated 
concentrations of GDF-15.

Serum unbound and 
total concentrations of 
ponsegromab on Day 
1, Week 4, 5, 8, 10, 
12, and 16, plus Week 
9 and 11 in PK 
substudy only

Not Applicable.

To evaluate the effect of 
repeated SC administration of 
ponsegromab on circulating 
GDF-15 concentrations in 
participants with cancer 
cachexia, and elevated 
concentrations of GDF-15.

Serum unbound and 
total concentrations of 
GDF-15 on Day 1, 
Week 4, 5, 8, 10, 12, 
and 16, plus Week 9 
and 11 in PK substudy 
only

Not Applicable.

To evaluate the 
immunogenicity profile of 
ponsegromab following 
repeated SC administration in 
participants with cancer 
cachexia, and elevated 
concentrations of GDF-15.

Incidence of ADA and 
NAb.

Not Applicable.

To evaluate the effect of 
ponsegromab compared to 
placebo on Patient-Reported 
Outcomes Version 
PROMIS-Fatigue 
questionnaire in participants 
with cancer, cachexia, and 
elevated concentrations of 
GDF-15.

Change from baseline 
score for 
PROMIS-Fatigue at 
Week 12.

Not Applicable.

To evaluate the effect of 
ponsegromab compared to 
placebo on PROMIS Physical 
Function-Short Form 8c in 

Change from baseline 
score for 
PROMIS-Physical 
Function at Week 12.

Not Applicable.
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Objectives
Endpoints
Estimands
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

To evaluate the effect of 
ponsegromab compared to 
placebo on PGI-S and PGI-C in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
PGI-S at week 12;

PGI-C at Week 12.

Not Applicable.

To evaluate the effect of 
ponsegromab compared to 
placebo on tumor burden and 
tumor status in participants 
with cancer, cachexia, and 
elevated concentrations of 
GDF-15.

Tumor status 
according to RECIST 
1.1 guidelines using 
CT scan at Week 12.

Not Applicable.

To evaluate the effect of 
ponsegromab compared to 
placebo on body composition 
as measured by CT scan in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
in LSMI derived from
CT scans at Week 12.

Percent change from 
baseline in skeletal 
muscle and adipose 
tissue measures 
derived from CT scans
at Week 12.

Not applicable

To evaluate the effect of 
ponsegromab compared to 
placebo on albumin and 
pre-albumin levels in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Change from baseline 
albumin and pre-
albumin levels at 
Week 12.

Not Applicable.

To evaluate the effect of 
ponsegromab compared to 
placebo on survival in 
participants with cancer, 
cachexia, and elevated 
concentrations of GDF-15.

Survival status at end 
of Part A.*

Not Applicable.
* Safety, tolerability and survival will also be characterized in Part B once all applicable participants have 
completed Part B of the study. These data will be reported as part of the supplemental CSR.
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Part B
In addition, the following objectives will be evaluated using data from Part B, as data permit:
Objectives
Endpoints
Estimands
Tertiary/Exploratory
Tertiary/Exploratory
Tertiary/Exploratory

To evaluate the effect of ponsegromab 
on body weight in participants with 
cancer, cachexia, and elevated 
concentrations of GDF-15.

Change from baseline body 
weight, in Part B of the 
study.

Not Applicable.

To characterize the safety and 
tolerability of repeated SC 
administrations of ponsegromab in 
participants with cancer cachexia, and 
elevated concentrations of GDF-15, 
during the open-label treatment 
period.

Incidence of adverse events, 
safety laboratory tests, vital 
signs and ECG 
abnormalities, in Part B of 
the study.

Not Applicable.

To evaluate the PK of ponsegromab 
following repeated SC administration
in participants with cancer cachexia,
and elevated concentrations of 
GDF-15, during the open-label 
treatment period.

Serum unbound and total 
concentrations of 
ponsegromab at Weeks 16, 
24, 36, 48, 64, and 72 plus 
flexible PK timepoint in PK 
substudy.

Not Applicable.

To evaluate the effect of repeated SC 
administration of ponsegromab on 
circulating GDF-15 concentrations in 
participants with cancer cachexia, and 
elevated concentrations of GDF-15, 
during the open-label treatment 
period.

Serum unbound and total 
concentrations of GDF-15 at 
Weeks 16, 24, 36, 48, 64, 
and 72, plus flexible PD
timepoint in PK substudy. 

Not Applicable.

To assess the immunogenicity of 
ponsegromab following repeated SC 
administration in participants with 
cancer cachexia, and elevated 
concentrations of GDF-15, during the 
open-label treatment period.

Incidence of ADA and Nab.

Not Applicable.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 2, randomized, double blind, placebo-controlled study of the efficacy, safety, 
and tolerability of three different doses of ponsegromab compared to matching placebo in 
patients with NSCLC, CRC, or PANC, receiving standard of care (which may include
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systemic therapy), who have elevated levels of GDF-15 and cachexia. The double-blind 
period is followed by an optional open-label extension period.
The Screening visit will occur no more than 28 days and no less than 7 days, prior to 
Randomization. The 7-day minimum duration between Screening and Randomization visits 
will ensure that the GDF-15 results are available to inform the investigator’s assessment of 
eligibility and the 7-day collection of PRO and physical activity data. Following the 
Screening period to confirm eligibility, approximately 168 study participants, who meet the 
entry criteria, will be randomized to study intervention (one of 3 dose groups of 
ponsegromab or matching placebo) and will be stratified by treatment with or without 
platinum-based chemotherapy (see Appendix 12), which is known to induce GDF-15 and 
therefore may impact the response to ponsegromab treatment. The 12-week double-blind 
dosing period (Part A) will consist of a total of 3 doses administered Q4W SC.
A PK substudy will be conducted in approximately 36 of the approximately 168 participants
(approximately 9 in each treatment group in Part A). Up to 3 additional PK and PD samples 
(two samples during Part A and one sample during Part B, if relevant), will be collected in 
these participants at timepoints during the study outlined in Sections 1.2 schema and 1.3 
SoA.
On completion of Part A, participants will have the opportunity to enter an optional OLT 
period (Part B) consisting of ponsegromab 400 mg Q4W SC for up to 1 year. The 
investigator and participant must decide at the Week 8 visit if they wish to continue to the 
optional OLT period. 
Participants opting to continue to the OLT period will receive their first dose of open-label 
ponsegromab 400 mg at the Week 12 visit, which is the last visit of the double-blind portion. 
Upon completion of the OLT period, there will be a follow-up visit (Week 72) which is to 
occur 56 to 63 days post last dose of study intervention.
Participants who do not proceed with the optional OLT period are to complete the Week 12 
visit and a follow-up visit at Week 16. 
Additional follow-up may be conducted for safety evaluation, at the discretion of the 
investigator.
The optional OLT period will continue as currently planned, unless the following factors 
develop in which case the open-label extension may be modified:

Upon completion of the double-blind portion, the final analysis shows a lack of 
efficacy for the primary endpoint and/or inadequate safety and tolerability;

An alternative method of study intervention delivery become available;

A lower dose of ponsegromab is shown to be efficacious; 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 44

The sponsor decides to terminate the study/clinical development program. 

Participants may withdraw from the optional OLT period at any time, for reasons 
such as the following:

The study participant withdraws consent or dies;

The study participant experiences an AE attributable to study intervention.

A change in study participant’s medical condition that, in the investigator’s 
judgment, makes it inappropriate to continue study participation.
An independent oversight committee in the form of an IRC will monitor the safety, efficacy, 
and tolerability of the study participants and the study conduct. There will also be an 
Executive Steering Committee and an Operation Steering Committee.
Study design aspects have been informed by feedback obtained during the conduct of the 
ponsegromab Phase 1b studies to enhance recruitment, reduce participant dropout and reduce 
the likelihood of missing data.
4.2. Scientific Rationale for Study Design
The purpose of this study is to evaluate the efficacy, safety, and tolerability of ponsegromab, 
an inhibitor of GDF-15, compared to placebo, in patients with cancer, cachexia, and elevated 
concentrations of GDF-15.
Elevated concentrations of circulating GDF-15 have been reported in literature5,6,7 in patients 
experiencing weight loss with a variety of tumor types and a greater magnitude of elevation 
was associated with worse survival. Biospecimens from healthy adults10 (n=739) and patients 
with cancer (from both external commercial biorepositories and an internal study) were 
analyzed for GDF-15 concentrations. The cancer sample set contained 399 NSCLC, 
116 pancreatic cancer, and 157 colorectal cancer patients. Analysis of both the cancer and 
healthy sample sets using the Roche Elecsys assay,10 confirmed literature reported elevations 
in GDF-15 concentrations in NSCLC, PANC, and CRC patients in comparison to healthy 
subjects (approximately 4-fold, 5-fold, and 4-fold, respectively). An ad-hoc analysis of 
samples from NSCLC patients from an internal Pfizer study demonstrated that higher 
GDF-15 concentrations were associated with a reduction in body weight. These data were 
also used to determine the GDF-15 inclusion criteria for this study to be the 95th percentile of 
GDF-15 concentrations reported in these healthy subjects (≥1.5 ng/mL). 
In addition, published clinical data and internal animal model data suggest that 
administration of platinum therapy can induce increases in serum GDF-15 concentrations. 
Clinical literature and internal animal8 model data also suggest that the nausea, emesis and 
anorexia observed with platinum therapy may be mediated, at least in part, by platinum
induced- elevations in GDF-15. 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 45
Therefore, it is hypothesized that cachexia in many types of cancer, including NSCLC, 
PANC and CRC, is largely mediated via GDF-15 and that suppression of GDF-15 in these 
patients may lead to improvement in serious aspects of cachexia such as anorexia leading to 
unintended weight loss, fatigue and impaired mobility. Furthermore, given the observations 
of GDF-15 elevation with platinum therapy, patients receiving standard of care anti-tumor 
treatment that includes systemic platinum-based therapy, may be a specific population that 
could potentially gather additional benefit from GDF-15 inhibition. Therefore, randomization 
will be stratified by presence/absence of background platinum therapy due to this association 
of platinum and GDF-15 levels.
The primary endpoint is the change in body weight from baseline. The study will also assess 
secondary and exploratory endpoints including physical activity, safety, fatigue, appetite, 
immunogenicity, PK and PD.
Patient safety will be monitored primarily via clinical laboratory tests, vital signs, ECG and 
adverse event monitoring. To supplement the standard clinical safety laboratory tests 
assessed at this stage of development, albumin and pre-albumin will be included as measures 
of nutritional status. Additionally, CT scans will be performed for evaluation of tumor 
burden by the investigator and measurement of the skeletal muscle area and adipose tissue 
area at the 3rd lumbar vertebral level by a central imaging laboratory.
Assessment of the impact of ponsegromab on other aspects of cachexia, such as anorexia, 
nausea, vomiting and fatigue, will be studied. These will be measured through the use of 
ePRO instruments administered to patients at home and during clinic visits. 
Another characteristic of cachexia is a decline in performance status with impairment in the 
patients’ ability to carry out desired activities. Assessment of the potential impact of 
ponsegromab on activity measures (eg, gait speed, activity time) via wearable digital sensors 
will be included in this study to better understand the effects of PF-06946860 on patients’
physical function. 
Sparse unbound and total ponsegromab and GDF-15 concentrations will be measured in this 
study to (1) characterize ponsegromab  PK in this population; (2) assess the range of baseline 
GDF-15 values and variability in this population; (3) characterize the dose/exposure-GDF-15 
response after ponsegromab treatment in this population, and (4) evaluate GDF-15 
suppression effect on body weight response. Participants enrolled in the PK substudy will 
have additional PK and PD assessments to enhance PK/PD characterization. As ponsegromab 
is a monoclonal antibody, immunogenicity samples will be collected for the determination of 
ADA and NAb.
4.2.1. Patient Input Into Design
Previously patients and caregivers were interviewed in order to better understand what 
symptoms are most burdensome to patients and what might impact their decision to 
participate in a clinical study. All patients had cancer (prostate, non-small cell lung, 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 46
colorectal or pancreatic cancer) and had experienced significant unintentional weight loss 
and other symptoms of cachexia. 
Patients and caregivers also provided input on the study design which triggered incorporation 
of options to potentially enhance patient participation and retention, and highlighted the 
following additional considerations which are anticipated to be of value to patients: 

Decision to maintain a dosing frequency that aligns with SOC treatment visits.

Option for home/tele-visits with physician or in-person physician appointments 
where feasible.

Confirmed the importance to patients of including the option to receive open-label 
treatment following double-blind period.

Patients emphasized the significance of having their overall experiences with the 
study treatment heard by the Sponsor. This led to the incorporation of phone 
interviews in order to facilitate a more holistic assessment. 

Highlighted the value of appropriate training, including to home HCPs, on 
important aspects of the disease and the potential social and psychological impact. 
4.2.2. Diversity of Study Population
Reasonable attempts will be made to enroll participants that are representative of the patient 
population that will be treated with ponsegromab in clinical practice. The team will follow 
best practices for diverse study population enrollment and retention. The following strategies 
may be explored in support of diverse recruitment efforts:

Inclusion of diversity questions into the Feasibility Survey and Pre-Trial 
Assessment to identify sites with access to diverse patient populations.

Discussion with investigator sites ahead of selection to assess preparedness, 
mitigation strategies for reaching diversity goals, and active inclusion.

Encouragement of investigator sites to complete the Investigator Site Recruitment 
Plan.

Provide investigator sites with site kit materials designed for use with diverse 
patient populations.

Implement as needed targeted digital outreach to diverse patient groups.

Have proactive discussions with investigator sites throughout the enrollment 
period to assess and reevaluate site specific strategies as needed to best position 
each site for the most diverse representation enrollment outcomes.
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 47

Monitor diverse enrollment to identify potential opportunities to include diverse 
populations.
4.2.3. Choice of Contraception/Barrier Requirements 
Studies to evaluate the developmental toxicity of ponsegromab have not been conducted. 
However, based upon the calculated safety margins, no contraception methods are required 
for male participants, and the use of a highly effective method of contraception is required 
for female participants (see Appendix 4).
4.2.4. Collection of Retained Research Samples
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
In the part A of this study, ponsegromab will be administered with 100, 200, or 
400 mg Q4W SC for a total of 3 doses. The proposed doses were determined based on all 
relevant information obtained from nonclinical safety studies and clinical data (including 
safety, tolerability, PK and PD) available. These clinical data included data from 2 completed 
studies in healthy participants (C3651001 and C3651002, see IB), clinical data (including 
safety, tolerability, PK, and PD) from the phase 1b study in cancer cachexia patients
(C3651009), and the expected duration of GDF-15 suppression, defined as the time it 
suppress GDF-15 to below the median observed in healthy subjects (0.71 ng/mL).
The median baseline GDF-15 in NSCLC, PANC, and CRC patients are expected to be 
approximately 3.02, 3.32, and 3.50 ng/mL, respectively, and the 95th percentile are expected 
to be 8.69, 9.35, and 13.4 ng/mL, respectively. It is assumed that the composition of the 
cancer types will be similar to that observed in study C3651009, which is 4:4:3 for NSCLC, 
CRC, and PANC, respectively. Based on preliminary population PK/PD simulations, the 
proposed 100 mg Q4W SC dose is expected to suppress the unbound GDF-15 concentration 
in ~64%, and ~28% of the assumed cancer cachexia patients for 2, and 4 weeks, respectively. 
The proposed 200 mg Q4W SC dose is expected to suppress the unbound GDF-15 
concentration in ~92%, and ~72% of the cancer cachexia patients for 2, and 4 weeks, 
respectively. The proposed high dose of 400 mg Q4W SC dose is expected to suppress the 
unbound GDF-15 concentration in >90% of the cancer cachexia patients for 4 weeks.
Based on these preliminary PK/PD simulations, the predicted steady state total ponsegromab 
Cmax, AUCtau, and Cavg, following 100, 200, and 400 mg Q4W SC doses, along with the 
corresponding safety margins calculated using exposure data from the 6-month toxicology 
study in monkeys (See IB), and exposure multiples calculated using total exposure data 
following a single 300 mg SC dose to healthy participants in study C3651001 are 
summarized in Table 3. The corresponding steady state unbound ponsegromab exposures and 
exposure multiples calculated using unbound exposure data from study C3651001, are 
summarized in Table 4.
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 48
Table 3.
Summary of Predicted Steady State Total ponsegromab Exposures and 
Associated Safety Margins and Exposure Multiples Following Q4W SC
Doses
Dose
(mg, Q4W SC)
Cmax
(µg/mL)
AUCtau
(µg•day/mL)
Cavg
(µg/mL)
Safety Margina
Exposure Multipleb
Cmax
Cavg
Cmax
AUCtau
100
16.4
413
14.8
57
53
0.85
0.54
200
29.5
739
26.4
32
30
1.5
0.96
400
52.8
1302
46.5
18
17
2.7
1.7
a.
Based on the predicted steady state total Cmax and Cavg following Q4W SC doses of ponsegromab at 100, 200, and 
400 mg relative to the NOAEL total Cmax (934 µg /mL) and Cavg (786 µg /mL) observed in the 6-month toxicology 
study in monkey (IB).
b.
Based on the predicted steady state total Cmax and AUCtau following Q4W SC doses of ponsegromab at 100, 200, 
and 400 mg relative to the total Cmax (19.2 µg /mL), and AUCinf (766 µg•day /mL) observed following the 300 mg 
single SC dose from C3651001.
Table 4.
Summary of Predicted Steady State Unbound ponsegromab Exposures 
and Associated Exposure Multiples Following Q4W SC Doses 
Dose 
(mg, Q4W SC)
Cmax
(µg/mL)
AUCtau
(µg•day/mL)
Cavg
(µg/mL)
Exposure Multiplea
Cmax
AUCtau
100
3.14
51.9
1.85
0.15
0.08
200
11.5
238
8.50
0.55
0.38
400 
32.1
726
25.9
1.5
1.1
a.
Based on the predicted steady state unbound Cmax and AUCtau following Q4W SC doses of ponsegromab at 100, 
200, and 400 mg relative to the unbound Cmax (20.9 µg /mL)and AUCinf (632 µg•day /mL) observed following the 
300 mg single dose from study C3651001.
Given the safety margins, the observed safety data in healthy participants from studies 
C3651001 and C3651002, with up to ponsegromab 300 mg SC single doses, and the
observed safety data in participants with cancer, cachexia or anorexia, and elevated serum 
GDF-15 concentrations from studies C3651009 and C3651010, with repeated doses of
ponsegromab 200 mg SC Q3W, the proposed 100, 200, and 400 mg Q4W SC doses are 
expected to have an acceptable safety and tolerability profile. 
Upon completion of Part A, participants will have the opportunity to enter an optional 
open-label treatment period (Part B) and receive the high dose of 400 mg Q4W SC as a 
no-regret approach until a lower efficacious dose is identified either at the interim analysis or 
the end of Part A.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study 
globally.
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 49
A participant is considered to have completed the study if they have either completed Part A 
(including follow-up), or has completed Part A and has entered, and completed, the OLT
extension Part B, as described in the SoA.
The PCD is the date of the last visit for Part A (Week 12,) for the last participant.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants aged ≥18 years (or the minimum age of consent if >18 in accordance 
with local regulations) at Screening who have signed informed consent. 
a.
A female participant is eligible to participate if she is not pregnant or 
breastfeeding.
b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Disease Characteristics:
2. Documented histologic or cytologic active diagnosis of NSCLC, PANC, or CRC and 
are currently receiving, or have completed, SOC treatment for this cancer (which may 
include systemic therapy).
3. Cachexia defined by Fearon criteria of weight loss as (See Section 8.1.1 for details if 
the participant’s body weight is unavailable from medical record):

BMI <20 kg/m2 with involuntary weight loss of >2% within 6 months prior to 
Screening; 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 50
or

involuntary weight loss of >5% within 6 months prior to screening irrespective of 
BMI.
4. Serum GDF-15 concentrations of ≥1.5 ng/mL (as measured using the Investigational 
Use Only Roche Elecsys GDF 15 assay)10 at Screening.
5. Participants who are assessed by the investigator to have:

an ECOG PS ≤3, and,

a life expectancy of at least 4 months to be able to complete Part A.
Other Inclusion Criteria:
6. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Current active reversible causes of decreased food intake, as determined by the 
Investigator. These causes may include, but are not limited to:

NCI CTCAE Grade 3 or 4 oral mucositis;

NCI CTCAE Grade 3 or 4 GI disorders (nausea, vomiting, diarrhea, and 
constipation);

Mechanical obstructions interfering with the participant’s ability to eat. 
2. Receiving tube feedings or parenteral nutrition (either total or partial) at the time of 
Screening or Randomization.
3. Cachexia caused by other reasons, as determined by the investigator, including, but 
not limited to: 

Severe COPD requiring use of home O2;

NYHA class III-IV heart failure;

AIDS.
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 51
4. Undergoing major surgery (central venous access placement and tumor biopsies are 
not considered major surgery) within 4 weeks prior to randomization. Patient must 
have recovered from acute effects of surgery prior to Screening. Patient should not 
have plans to undergo major surgical procedures during the study.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
6. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (IgG protein) or molecules made of components of monoclonal 
antibody. 
Prior/Concurrent Therapy:
7. Current use of any prohibited concomitant medication(s) within 4 weeks prior to first 
dose of study intervention. Refer to Section 6.9.
Prior/Concurrent Clinical Study Experience:
8. Concurrent administration of investigational products (including drug, biologic 
agents, or vaccines) are not permitted within 30 days (or as determined by the local 
requirement) or 5 half-lives (whichever is longer) of the first dose of study 
intervention. Refer to Section 6.9 .
9. Enrollment and previously dosed in a prior study with ponsegromab.
Diagnostic Assessments:
10. History of severe liver disease or cirrhosis, unrelated to metastatic cancer. Potential 
study participants with the following liver function test abnormalities will also be 
excluded; result may be confirmed by a single repeat test, if necessary: 

Total bilirubin ≥1.5 × ULN (except for Gilbert’s syndrome) 

AST >3 × ULN (AST > 5X ULN if there is liver involvement by the tumor) 

ALT >3 × ULN (ALT >5X ULN if there is liver involvement by the tumor) 

Alkaline phosphatase >3 x ULN (Alkaline phosphatase >5X ULN if there is liver 
involvement by the tumor and/or in case of bone metastases, or if considered 
related to prior surgery e.g. pancreaticoduodenectomy).
11. Renal disease requiring dialysis. 
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
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TMF Doc ID: 164.01
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Other Exclusion Criteria:
12. Current adherence to a calorie-restricted diet with the intention weight loss.
13. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
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 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,
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, 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 enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, and any SAE.
Individuals who qualify for this study but are not randomized for administrative reasons, may 
be rescreened. Individuals who do not meet the criteria for participation in this study (screen 
failure) may be rescreened once with sponsor notification if, in the judgement of the 
investigator, the reason for initial ineligibility is considered to be resolved, or there has been 
a change in eligibility status. 
For individuals who are rescreened for any reason, all screening procedures must be 
repeated, unless discussed with, and agreed by, the Sponsor in advance, and the participant 
assigned a new SSID.
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Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
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6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational interventions, marketed products, 
placebo and medical devices, and other interventions (eg, surgical and behavioral) intended 
to be administered to the study participants during the study conduct. 
For the purposes of this protocol, study intervention refers to ponsegromab (PF-06946860, 
IMP) and placebo (IMP).
6.1. Study Intervention(s) Administered
Intervention Name
ponsegromab (PF-06946860)
placebo
Arm Name
(group of participants receiving 
a specific treatment or no 
treatment)
ponsegromab Double-Blind Treatment
placebo Double-Blind 
Treatment 
Type
biologic
placebo
Unit Dose Strength(s)
100 mg/mL
placebo
Dosage Level(s)
100 mg, 200 mg, and 400 mg Q4W
Matching placebo Q4W
Route of Administration
SC
SC
Use
experimental
experimental
IMP or NIMP/AxMP
IMP 
IMP 
Sourcing
provided centrally by the sponsor 
provided centrally by the 
sponsor
Packaging and Labeling
Study intervention will be provided in 
6-mL glass vial with a 1 mL withdraw 
volume.  Each vial will be labeled as 
required per country requirement.
Study intervention will be 
provided in 6-mL glass vial 
with a 1 mL withdraw volume. 
Each vial will be labeled as 
required per country 
requirement.
Current/Former Name(s) or 
Alias(es)
ponsegromab 
placebo 
6.1.1. Administration
Each dose of investigational product must be administered by appropriately qualified health 
care personnel in a clinic setting. During the double blind portion (Part A) of the study, 
investigational product will be administered at a dose of 100 mg, 200 mg, 400 mg, or 
matching placebo Q4W SC for a total of 3 doses. On completion of Part A, participants will 
have the opportunity to enter an optional OLT period (Part B) consisting of ponsegromab 
400 mg Q4W SC for up to 1 year. For participants who are receiving standard of care (which 
may include systemic therapy), premedication is permitted consistent with institutional 
guidelines, and, may include an antihistamine, anti-inflammatory agent, or pain reliever.  In 
such cases, ponsegromab is to be administered first, followed by any required 
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Ponsegromab (PF-06946860)
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premedications. If the standard of care systemic antineoplastic treatment is to be 
administered on the same day of dosing with study intervention (ponsegromab or matching 
placebo in Part A or ponsegromab in Part B), where feasible, the study intervention will be 
administered prior to the standard of care treatment. 
Study intervention will be administered in a divided dose requiring 2 separate SC injections 
given in rapid succession every 4 weeks. The permitted injection sites are the abdomen, 
upper arm (right or left) and the thigh (right or left). The following combination of injection 
sites are provided as examples:

Two injections in abdomen (each injection should be administered into a different 
quadrant and separated by at least 3 cm)

One injection into each upper arm

One injection into each thigh

One injection in the arm (right or left) and one injection in the leg (right or left) or

One injection in arm or leg (left or right) and one in the abdomen. 
The injections can be rotated with each administration for participant comfort. If participants 
are receiving other, non-study intervention injectable agents, those interventions should be 
administered in a quadrant different from where the study intervention was administered. 
Additionally, areas with scarring, redness, tattoos, or other visible marks should be avoided.
Refer to the IP manual for additional details regarding the preparation, injection site 
administration, handling, storage and accountability.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions 
(eg, temperature) have been maintained during transit for all study interventions
received and any discrepancies are reported and resolved before use of the study 
intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions 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 temperatures since previously documented upon 
return to business.
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4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the IP Manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP Manual. All destruction must be adequately 
documented. 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.
9. Upon identification of a product complaint, notify the sponsor within 1 business day 
of discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention for 
administration. Study intervention 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. A second staff member will verify the dispensing. 
6.3. Assignment to Study Intervention
All participants will be centrally assigned to randomized study intervention using a central 
randomization list. Allocation of participants to treatment groups will proceed through the 
use of an IRT system. The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s ID and 
password, the protocol number, and the participant number. The site personnel will then be 
provided with a randomization number corresponding to the assigned treatment group, and 
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DU or container number(s) when study intervention is being supplied via the IRT system. 
The IRT system will provide a confirmation report containing the participant number, 
randomization number, and DU or container number assigned. The confirmation report must 
be stored in the site’s files. 
Study intervention will be dispensed at the study visits summarized in the SoA. 
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.4. Blinding
This is a double-blind study with blinding of ponsegromab versus placebo for each dose 
level.
6.4.1. Blinding of Participants
Participants will be blinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be blinded to participants’ assigned study intervention. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
6.4.3. Blinding of the Sponsor
Sponsor staff will be blinded to participants’ assigned study intervention, except for sponsor 
staff involved in the assignment or distribution of study intervention.
6.4.4. Breaking the Blind 
The 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 study medical monitor 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 CRF.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
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6.5. Study Intervention Compliance
The study intervention will be administered to participants directly by an appropriately 
qualified individual. The date and time of each dose administered will be recorded in the 
source documents and recorded in the CRF. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by designated healthcare 
personnel if the study intervention is administered at the participant’s home or a member of 
the study site staff other than the person administering the study intervention if the study 
intervention is administered at the clinic. 
Deviation(s) from the protocol-specified dosage regimen should be recorded in the CRF. In 
exceptional circumstances and with agreement from the Sponsor, the study intervention may 
be administered outside of the window for a given dosing visit; in such circumstances, the 
rationale should be recorded in the CRF. 
A record of the number of the study intervention (ponsegromab or placebo vials) 
administered to each participant must be maintained and reconciled with study intervention
and compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or missed doses, will also be recorded in the CRF.
6.6. Dose Modification 
There is no dose modification of study intervention anticipated for a given participant in this 
study.
6.7. Continued Access to Study Intervention After the End of the Study
The study design includes an optional open-label treatment period for up to 1 year (Part B) as 
described in Section 4.1. An expanded access program may be available after the open label 
treatment period.
6.8. Treatment of Overdose
Given the allowed visit window, an overdose will be defined as more than 2 doses of 
ponsegromab 400 mg administered in a period of 4 weeks, eg, any dose of ponsegromab 
greater than 900 mg within a 4-week period will be considered an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate for at least 5 half-lives or 28 calendar days after the overdose 
of ponsegromab (whichever is longer). The duration of monitoring required will be 
provided by the sponsor.
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3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 5-7 days from the date of the last dose 
of study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant. 
6.9. Prior and Concomitant Therapy
Details on all concomitant treatment (including antitumor treatments and steroid usage) will 
be determined from participant and/or medical records, at each visit from Screening until the 
end of study visit and will be recorded on the CRF. Investigators should specify reasons for 
modifications to or discontinuations of prescribed antitumor treatments. At the Screening 
visit and each clinic visit, details of previous and current treatment with a platinum-based
therapy will be determined from participant and/or medical records. The information will be 
recorded on the CRF at each visit. Specifically at the Screening visit, current treatment with 
or without platinum-based chemotherapy will be utilized for stratification of study 
participants who meet the entry criteria at the Randomization visit. (see Appendix 12)
6.9.1. Prohibited During the Study

Initiation of new treatment with systemic glucocorticoids within the 4 weeks prior 
to the first dose of study intervention through Week 16; Stable (ie, no significant 
change to dosage or frequency of administration in prior 4 weeks) steroid therapy 
eg, dexamethasone as part of pre-medication or daily oral prednisone is 
permissible. Initiation of steroid therapy following randomization (eg,  for 
management of immune-related AEs that occur as a consequence of 
immunotherapy) may be permitted following discussion with Sponsor

Concurrent administration of anamorelin hydrochloride is not permitted within 
30 days prior to first dose of study intervention through Week 16.

Concurrent administration of megestrol acetate, olanzapine, cannabinoids, or 
mirtazapine, if prescribed for purpose of increasing appetite/body weight, are not 
permitted within 30 days prior to first dose of study intervention through Week 
16. Use of these medications on a short-term, as required basis, for management 
of symptoms (eg, chemotherapy-induced nausea and vomiting) is permitted.

Concurrent administration of a GLP-1 receptor agonist-based therapy (eg,
semaglutide, liraglutide, tirzepatide), if prescribed specifically to promote weight 
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loss, is not permitted within 30 days prior to first dose of study intervention 
through Week 16. Use of such therapies for indication of diabetes mellitus is 
permitted.

Investigational products (including drug, biologic agents, or vaccines) are not 
permitted within 30 days (or as determined by the local requirement) or 
5 half-lives (whichever is longer) of the first dose of study intervention through 
the duration of the study (including both Part A and B).
6.9.2. Permitted During the Study

Hormonal contraceptives that meet the requirements of this study are allowed to 
be used in participants who are WOCBP (see Appendix 4).

All standard of care (which may include systemic therapy) including required 
premedications (see Section 6.1.1).

Background biologics are permitted as indicated by the label (not contra-indicated 
for combination with an investigational mAb).
Participants in this study will be allowed to be on concomitant medications that have been 
prescribed according to their label and monitored as per local standard of care. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention may include the following:

Progression of underlying disease such that the investigator no longer considers 
participation appropriate, or of potential benefit to the participant.

Hospitalization that in the opinion of the investigator would render continued 
participation unfeasible.

If a participant experiences Grade 3 AEs judged by the Investigator as related to 
randomized study intervention, the study intervention will be temporarily 
discontinued until the treatment-related AEs return to Grade 2 (or less). If the 
treatment-related AEs return to Grade 2 (or less) or resolve within 4 weeks, 
continuation of dosing with study intervention may be considered. If these AEs do 
not return to Grade 2 (or less) within 4 weeks, and after discussion with the 
sponsor, the participant will be permanently discontinued from the study 
intervention. 
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
If a participant experiences Grade 4 AEs judged by the Investigator as related to 
randomized study intervention, the participant will be permanently discontinued 
from the study intervention.

Severe allergic reaction to study intervention.

Intent to become pregnant or pregnancy confirmed by b-hCG testing.

Drug-induced liver injury as described in Section 10.6, Appendix 6.
Note that discontinuation of study intervention does not represent withdrawal from the study.
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for follow up. All cases of planned or potential discontinuation of study 
intervention should be discussed with Sponsor before classifying a subject as ‘Discontinued 
from Study Intervention’ and completing an Early Termination visit. See the SoA for data to 
be collected at the time of discontinuation of study intervention and follow-up for any further 
evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.Follow-Up:
Participants will undergo review of concomitant treatments, vital signs, and assessment for 
resolution of any treatment-related AEs through approximately 56 days following 
discontinuation of study intervention. Participants continuing to experience AEs at this point 
following discontinuation of treatment will continue to be followed at least every 4 weeks 
until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected. If the unresolved AE is considered by the investigator as possibly 
related to or associated with ADA formation, the participant will be asked to return for drug 
concentration and ADA blood sampling at up to 3-month intervals, until the last follow-up of 
the AE.
7.1.1. COVID-19
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment should continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case temporary or permanent discontinuation may be required. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Participant refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.
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 enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention 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 them 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 study intervention 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.
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7.3. Lost to Follow-Up 
To prevent participants being lost to follow-up, their contact details, including next of kin 
contacts should be collected initially, if permitted, and updated regularly by the site staff or 
representative. The Investigator should educate the participant on the importance of contact 
with the Investigator throughout the study. Repeated attempts will be made to locate and 
obtain pertinent medical information for participants who are potentially lost to follow up.
If a participant fails to return to the clinic for/attend a required study visitthe site must 
attempt to contact the participant and reschedule the missed visit as soon as possible, counsel 
the participant on the importance of maintaining the assigned visit schedule, and ascertain 
whether the participant wishes to and/or should continue in the study.
Where permissible by local regulations, the ICD will include language to grant the option to 
employ patient locator agencies to assist in obtaining updated contact information or 
ascertainment of vital status of lost participants using publicly available source.
A participant will be classified as lost to follow up only if they have failed to return for the 
required study visits and their visit status remains unknown despite multiple attempts to 
contact them via telephone, fax, email, certified letter or through patient locator agencies (if 
allowed by local regulations). These contact attempts should be documented in the 
participant’s medical record. The participant will then be considered lost to follow-up and 
discontinuation of study will be documented in source data and CRF as the date of last 
contact.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative 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.
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.
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 make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
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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 they have 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.
Safety/laboratory/analyte results that have been collected for the purposes of this study and 
could unblind the study will not be reported to investigative sites or other blinded personnel 
until the study has been unblinded.
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.
The total blood sampling volume for each part of the study is estimated as follows for 
individual participants:

Part A, where participants are not enrolled in the PK substudy = 145 mL

Part A, where participants are enrolled in the PK substudy = 165 mL

Optional Part B, where participants are not enrolled in the PK substudy = 125 mL

Optional Part B. where participants are enrolled in the PK substudy = 135 mL
The actual collection times of blood sampling may change. Additional blood samples may be 
taken for safety assessments at times specified by Pfizer, provided the total volume taken 
during the study does not exceed 550 mL during any period of 56 consecutive days. In 
addition, if a participant has an unplanned site visit for any reason (chemotherapy, radiology, 
other doctor appointments, etc.), collect an unplanned PK and GDF-15 sample during this 
visit, if feasible, provided the total volume taken during the study does not exceed 550 mL 
during any period of 56 consecutive days.
8.1.1. Screening Visit
The Screening visit will occur no more than 28 days and no less than 7 days, prior to 
Randomization. The 7-day minimum duration between Screening and Randomization visits 
will ensure that the GDF-15 results and the 7-day collection of PRO and physical activity 
data are available to inform the investigator’s assessment of eligibility.
At the Screening visit only, the evaluation of the Fearon Criteria eligibility criteria is to be 
assessed using the participant’s body weight from their medical record.  If the participant’s 
body weight is unavailable from medical record, the participant’s weight is to be captured 
utilizing question 1 of the PG-SGA questionnaire.11
8.1.2. Week 5 Visit
The Week 5 visit is considered an optional visit to collect PK and GDF-15 samples as well as 
measurement of weight and SAE/AE monitoring based upon participant availability. It will 
not be considered a protocol deviation if the participant is unable to make this visit.
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8.1.3. Additional Visits for PK Substudy
Participants enrolled in the PK substudy will have an additional visit, as per SoA, at Week 9 
and Week 11 in Part A, and one flexible visit in Part B that can occur 1, 2 or 3 weeks 
following any dose after or including the Week 20 dose. The purpose of these additional PK 
visits is to obtain blood samples for PK and PD assessment.  These visits may be performed 
at the participant’s home rather than at the study site if feasible and permitted by country, 
study site, and participant.
8.1.4. Home Health Visits
A home health care service/phlebotomist may be utilized to facilitate the Week 5, Week 9 
(PK substudy only), Week 10, and Week 11 (PK substudy only) visits. Home health visits 
include a healthcare provider conducting an in-person study visit at the participant’s location, 
rather than an in-person study visit at the site. The following may be performed during a 
home health visit (see the SoA):

PK and PD sample collection.
Note: Body weight does not need to be obtained if the visit is conducted offsite.
8.1.5. Transportation
Transportation to and from the study site may be provided for study participants for Part A 
visits, as permitted by the country, study site and participant.
8.2. Efficacy Assessments
8.2.1. Body Weight
Body weight will be measured in duplicate as indicated in the SoA. The second weight 
measurement should be obtained at least 1-2 minutes apart from the first measurement. 
Weight will be recorded using a calibrated scale (with the same scale used if possible for the 
duration of the study) reporting weight in kg, and accuracy to the nearest 0.1 kg; ie, the 
device must be able to distinguish a difference between 68.4 kg versus 68.3 kg. The scale 
must be placed on a stable, flat surface. Body weight does not need to be obtained if the visit 
is conducted offsite.
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Weight measurements should be taken under the following conditions, where feasible:

After void of urine;

After removal of shoes, socks, bulky layers of clothing and jackets so that only 
light clothing remains; 

While remaining still during the measurement.
8.2.2. Patient Reported Outcomes
Patient Reported Outcome 
(PRO) Measure 
Frequency
Completion 
location
Number of 
Questions
Completion 
Time
FAACT
Baseline, Week 4, Week 8, 
Week 12 or ED Part A
At clinic
39
~15 minutes
PGI-S of appetite, fatigue, and 
physical function
Baseline, Week 4, Week 8, 
Week 12 or ED Part A
At clinic
3
PGI-C of appetite, fatigue, and 
physical function
Week 4, Week 8, Week 12 or ED
Part A
At clinic
3
PROMIS-Fatigue 7a (“Past 7 days” 
recall version)
Baseline, Week 4, Week 8, 
Week 12 or ED Part A
At clinic
7
PROMIS-Physical Function 8c 
(no recall version)
Baseline, Week 4, Week 8, 
Week 12 or ED Part A
At clinic
8
Cancer-Related Cachexia Symptom 
Diary 2.0
(appetite, fatigue, nausea, and 
vomiting)
Daily including the Screening 
period (minimum of 
7 consecutive days) to Week 12
or ED Part A
At home
4
~2 minutes
Qualitative Exit Interview 
Week 12 or ED Part A
Via phone
N/A
Up to 60
minutes
PGI-S of physical activity and 
walking
At the end of the 7-day 
consecutive monitoring 
period/wearing the digital 
sensors for Screening (at home), 
Week 8 (approximately Day 63 
at home), Week 10 
(approximately Day 77 at home), 
at Week 12 (approximately Day 
85 at the clinic) or ED Part A
At home/in 
clinic
2
~2 minutes
PGI-C of physical activity and 
walking
At the end of the 7-day 
consecutive monitoring period
for Week 8 (approximately Day 
63 at home), Week 10 
(approximately Day 77 at home) 
and at Week 12 (approximately 
Day 85 at the clinic), or ED 
Part A
At home/in 
clinic
2
~2 minutes
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All PRO assessments, with the exception of the Exit Qualitative Interview, are implemented 
using a sponsor-provided ePRO device and completed by study participants at home 
(handheld device), or at the clinic (tablet), as per the SoA. 
Every effort should be made to have the study participant complete all PRO assessments as 
per the SoA. Site-based PRO assessments should be completed by the participant at the 
beginning of the visit before any medical procedures or interactions with the medical staff (as 
much as practically possible) take place.
Additional details are provided in the ePRO/eCOA User Manual
8.2.2.1. Functional Assessment of Anorexia-Cachexia Therapy (FAACT)
The FAACT combines the FACT-G core instrument and ACS. 
FACT-G is a summated score of 27 items pertaining to physical well-being (7 items), 
emotional well-being (6 items), functional well-being (7 items), and social well being 
(7 items) in the past 7 days. Each of the items uses a 5-point (0 to 4) scale. ACS is a 12 item 
summated scale containing items specific to patients’ perceptions of appetite and weight, also 
using the 5 point scale. Adding the 12 ACS items to the FACT-G produces the 39 item 
FAACT. Higher scores are associated with a higher health-related quality of life. For 
additional details regarding scoring refer to FACIT User’s Manual.
8.2.2.2. Patient’s Global Impression of Severity (PGI-S) of Appetite, Fatigue, and 
Physical Function
The PGI-S consists of 3 questions that ask the study participants to evaluate the severity of 
their appetite loss, fatigue, and physical function over the past 7 days, on a 5-point verbal 
response scale that ranges from “None” to “Very severe”.
The PGI-S is recommended by FDA for use as an anchor measure to generate an appropriate 
threshold that represents meaningful within individual change in the target patient 
population.
8.2.2.3. Patient’s Global Impression of Change (PGI-C) of Appetite, Fatigue, and 
Physical Function
The PGI-C consists of 3 questions that ask the study participants to rate the overall change in 
their level of appetite, fatigue, and physical function since they started taking the study 
intervention on a 5-point verbal rating scale that ranges from “Much better” to “Much 
worse”. 
The PGI-C is recommended by FDA for use as an anchor measure to generate an appropriate 
threshold that represents meaningful within-individual change in the target patient 
population.
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8.2.2.4. PROMIS – Fatigue (version 7a)
The PROMIS Fatigue 7a is a self-reported measure that assesses a range of symptoms in the 
past 7 days from mild subjective feelings of tiredness to an overwhelming, debilitating, and 
sustained sense of exhaustion that likely decreases one’s ability to execute daily activities 
and function normally in family or social roles.
The short form 7A consists of 7 items that study participants will rate from 1: “Never” to 5: 
“Always”. A global raw score ranging from 7 to 35 is calculated and can be translated into a 
T score (Mean = 50, standard deviation (SD) = 10) using the applicable score conversion 
table provided in the PROMIS User’s Manual.
8.2.2.5. PROMIS – Physical Function (version 8c)
The PROMIS Physical Function short form 8C is a self-reported 8 item measure that assesses 
capability rather than actual performance of physical activities. It includes the functioning of 
one’s upper extremities (dexterity) and lower extremities (walking and mobility), as well as 
instrumental activities of daily living. A single Physical Function capability score is obtained 
from a short form. A global raw score ranging from 8 to 40 is calculated and can be 
translated into a T score (Mean = 50, SD = 10) using the applicable score conversion table 
provided in the PROMIS User’s Manual.
8.2.2.6. Cancer-Related Cachexia Symptom Diary 2.0
The CRCSD is a daily, self-reported questionnaire that measures severity of symptoms 
related to cancer cachexia: appetite, nausea, vomiting, and fatigue. It was developed based on 
qualitative research with patients as well as review of literature and other existing relevant 
measures. The measure consists of 4 questions that ask study participants to rate the severity 
of their symptoms over the past 24 hours on an 11 point NRS.
8.2.2.7. Qualitative Exit Interviews
Qualitative exit interviews with a selected group of English-speaking participants (up to 40) 
at selected sites will be conducted by telephone at the end of Part A, as indicated in the SoA. 
The interviews will be conducted by trained moderators, that are not part of study site staff, 
will be audio recorded and transcribed, and are anticipated to be approximately 60 minutes in 
duration. 
The transcripts and interviewer field notes will be used to examine changes in symptoms and 
impacts experienced over the period of study duration, to describe treatment experience, and 
the importance of any improvement reported by the study participants. Following the 
analysis of the qualitative data, a summary report that describes the study objectives, 
methods, participants, and results of the qualitative interviews will be reported separately 
from the CSR.
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8.2.2.8. Patient’s Global Impression of Severity (PGI-S) of Physical Activity and 
Walking
The PGI-S of physical activity and walking consists of 2 questions that ask the study 
participants to evaluate the severity of limitations of physical activity and walking over the 
past 7 days, on a 5-point verbal response scale that ranges from “None” to “Very severe”. 
The PGI-S is to be administered at the end of the 7-day monitoring period for Screening
(+1) (at home), Week 8 (approximately Day 63 +1 at home), Week 10 (approximately 
Day 77 +1 at home), and at the Week 12 visit (approximately Day 85 at the clinic).
8.2.2.9. Patient’s Global Impression of Change (PGI-C) of Physical Activity and 
Walking 
The PGI-C of physical activity and walking consists of 2 questions that ask the study 
participants to rate the overall change in their level of physical activity and walking since 
they started taking the study intervention on a 5-point verbal rating scale that ranges from 
“Much better” to “Much worse”. The PGI-C is to be administered at the end of the 7-day 
monitoring period for Week 8 (approximately Day 63 +1 at home), Week 10 
(approximately Day 77 +1 at home) and at the Week 12 visit (approximately Day 85 at the 
clinic).
8.2.3. Physical Activity
Monitoring of physical activity and gait via accelerometry (wearable digital sensors) will be 
conducted in participants during the following 3 periods: Screening (with a target of at least 
1 consecutive week of monitoring prior to first dose of IP), Week 8 (from Week 8 to Week 9)
and from Week 10 to Week 12. The digital sensors will be worn continuously for one week 
during Screening and Week 8; and will be worn continuously for two weeks between
Week 10 and Week 12.
Placement of the sensors: one sensor will be placed on the lumbar region and one sensor will 
be placed on the non-dominant wrist. Participants will be asked to wear the sensor on the 
wrist continuously (approximately 24/day; can remove for short periods of time as needed). 
the sensor worn on the lumbar only needs to be worn while awake during the monitoring
periods.
The participant is able to remove the activity monitors for charging or other activities without 
it being considered a protocol deviation. Please refer to the activity monitoring manual for 
detailed instructions.
8.2.3.1. Comfort and Wearability Questionnaire for Digital Measures
To measure comfort and wearability of the wearable digital sensors, the participant will be 
asked to complete a Comfort and Wearability Questionnaire at Week 12 or at Early 
discontinuation visit. Data will be captured on the CRF. See Appendix 9.
The Digital Sensors technical training guide will be provided separately.
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8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
Although not observed so far with ponsegromab, injection site reactions and delayed 
hypersensitivity reactions are theoretically possible in response to injected monoclonal 
antibodies. Participants should be monitored after receiving injections for clinical signs of 
systemic immune reactions, and any such reactions assessed and reported as part of standard 
safety/AE monitoring, including adverse events that are manifestations of injection site 
reactions. Additional assessments may be conducted at investigator discretion and/or until 
any symptoms resolve. If deemed appropriate by the investigator, a consultation with a 
dermatologist may be performed. Documentation of a reaction may include items such as 
investigator notes, photographs, dermatologist report and/or clinic notes. As part of the safety 
analysis, any cases of potential anaphylaxis will be assessed by the sponsor against the 
Sampson criteria.12
8.3.1. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.
A full physical examination will include, at a minimum, head, ears, eyes, nose, mouth, skin, 
heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. Height and weight will also be measured and recorded. Height will be 
measured at Screening only, in cm and accuracy to the nearest 0.1 cm. Body weight will be 
measured in duplicate at each visit, in kg, and accuracy to the nearest 0.1 kg. Please refer to 
Section 8.2.1 for additional details regarding collection of body weight.
An abbreviated physical examination will be focused on general appearance, the respiratory 
and cardiovascular systems, and subject-reported symptoms.
Physical examinations (full and abbreviated) will be conducted as detailed in the SoA, 
however full exams may be performed for findings during previous exam, new/open AEs, or 
at investigator discretion. 
All physical exams (full and abbreviated) will include an assessment for ascites and/or 
edema. In addition, ascites and/or edema will be captured as an AE on the AE CRF.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
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definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Eastern Cooperative Oncology Group (ECOG) Performance Status
The assessment of ECOG performance status may be conducted by a physician, trained 
physician's assistant, or nurse practitioner as acceptable according to local regulation. See 
Appendix 10.
8.3.3. Vital Signs
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.3.1. Blood Pressure and Pulse Rate
BP and PR measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
Single BP and PR measurements should be preceded by at least 5 minutes of rest with the 
participant in a supine position, in a quiet setting without distractions (eg, television, cell 
phones) and the results recorded in the CRF.
Vital signs will be taken before collection for laboratory tests, if feasible, but it would not be 
considered a protocol deviation if collected after laboratory tests.  .
8.3.4. Electrocardiograms
A single standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should 
be collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. At all visits, a single standard 12-lead ECG will be collected.
If the site does not have an ECG machine that performs automated calculations, the 
investigator is permitted to calculate the standard intervals.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.5. Clinical Safety Laboratory Assessments
All laboratory samples are to be sent to the central lab.
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA.
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
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The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that 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 significant and abnormal during 
participation in the study or within up to the time of the final planned follow-up visit after the 
last dose of study intervention should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or study 
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.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.6. Pregnancy Testing 
A serum pregnancy test is only required at Screening and will be sent to the central lab. 
Following Screening, pregnancy tests may be urine or serum tests, and must have a 
sensitivity of at least 25 mIU/mL. Pregnancy tests will be performed in 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 to the participant’s receiving the study intervention.
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 
study. Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. For urine samples collected after the screening visit, the urine sample should be 
tested at the site facility and results are to be confirmed negative and recorded in the 
database. Pregnancy test results must be reviewed and confirmed as negative in order to 
continue dosing with study intervention.
8.3.7. Imaging Assessment-CT Scan
8.3.7.1. Imaging Safety Assessment
CT scans will be acquired during the study to monitor the tumor burden. All CT scans will 
need to include chest, abdomen, and pelvis to be acceptable for this study.
If SOC CT scan with chest, abdomen, and pelvis was performed within 3 weeks prior to the 
Screening the visit, then a CT scan at Screening is not needed. If a SOC CT scan is being 
performed at the Week 12 visit, between Weeks 10-12 or within 7 days after the Week 12 
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visit as part of SOC, then an additional CT scan is not needed. Similarly, if SOC CT scan is  
performed 2 weeks prior or 7 days after the ED visit, then an additional CT scan is not 
needed.
Monitoring of the tumor burden will be performed by the site following standard 
RECIST 1.1 criteria (outlined in Appendix 11). The RECIST 1.1 categorization is to be 
entered in the CRF after each scan.
All follow up testing and final diagnosis will be left to the discretion of the medical 
professionals at the site or those with an existing physician participant relationship. The PI 
will be responsible for reporting any AEs identified from incidental findings as described in 
the AE reporting section. 
8.3.7.2. Imaging Efficacy Assessment
CT scans are to include the chest, abdomen and pelvis. All CT scans will be collected for the 
RECIST assessment by the study site. The CT scans will then need to be submitted to a 
central imaging vendor for the measurement of body composition. The central imaging 
assessments will be performed solely for the analysis of the skeletal muscle area and adipose 
tissue areas at the 3rd lumbar vertebral level. Additional exploratory body composition 
measurements may be performed, but may not be reported in the CSR. The analyses from the 
central review of the CT scans for body composition will not be shared with the site or study 
participant. The central imaging laboratory will not be performing a clinical assessment of 
the images and no incidental findings will be shared with the principal investigator, site staff 
or participant. All medical reviews of CT scan images will be the sole responsibility of the 
site staff.
Instructions for central image upload will be provided in a separate manual. In addition to 
submitting all CT scans to a central repository, sites will still be required to save all 
participants’ radiologic images for source verification and for potential questions. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
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 the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
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During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. 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 undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of the time of the final planned follow-up 
visit, except as indicated below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness 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 its being available.
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8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.4.2. 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.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or 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 provided in Appendix 3.
8.4.4. 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 toward the safety of participants and the safety of a 
study intervention 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 study intervention under clinical investigation. The 
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sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having 
been exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by eg, skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by eg, skin contact then inseminates his female partner prior to or 
around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, 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. Details of the 
pregnancy will be collected after the start of study intervention and until at least 
5 terminal half-lives after the last dose (ie, at least 8 weeks).

If EDP occurs in the setting of environmental exposure, the investigator must 
report information to Pfizer Safety using the CT SAE Report Form and EDP 
Supplemental Form. Since the exposure information does not pertain to the 
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.
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).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be 
reported as an SAE;

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 study intervention. 
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 
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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.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or 
having been exposed to study intervention (ie, environmental exposure). An 
example of environmental EDB is a female family member or healthcare provider 
who reports that she is breastfeeding after having been exposed to the study 
intervention by inhalation, or skin contact.
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so 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.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure 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 about the occupational exposure
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 must be maintained in the 
investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
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8.4.8. Adverse Events of Special Interest
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.4.1 through An AESI is to be recorded as an AE or SAE on the CRF. In addition, 
an AESI that is also an SAE must be reported using the CT SAE Report Form.
8.4.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE. 
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

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.
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 the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL serum, will be 
collected for measurement of serum unbound and total concentrations of ponsegromab as 
specified in the SoA. The PK sample collection at the Week 5 visit is considered an optional
sample and it will not be considered a protocol deviation if the participant is unable to make 
this visit. In addition, if a participant has an unplanned site visit for any reason, 
(chemotherapy, radiology, other doctor appointments, etc), a PK sample may be collected, if 
feasible, provided the total volume taken during the study does not exceed 550 mL during 
any period of 56 consecutive days.
The actual times may change, but the number of samples will remain the same. Collection of 
samples within the protocol-allowed visit window, as defined in SoA or noted above will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF.
Samples will be used to evaluate the PK of ponsegromab. Samples collected for analyses of 
ponsegromab serum concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for metabolite identification and/or 
evaluation of the bioanalytical method, or for other internal exploratory purposes.
Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of serum concentrations of ponsegromab (unbound and 
total) will be analyzed using a validated analytical method(s) in compliance with applicable 
SOPs. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
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If the sample is unable to be collected during F/U part A and F/U part B, it will not be 
considered a protocol deviation.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 2-mL blood sample optimized for DNA isolation Prep D1.5 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s) and 
cancer cachexia. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.7. Biomarkers
Collection of samples for biomarker research is also part of this study, see Section 8.7.6. 
8.7.1. GDF-15
Blood samples of approximately 6 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of serum concentrations of total and unbound GDF-15 at time 
points specified in the SoA. The GDF-15 sample collection at the Week 5 visit is considered 
an optional sample. It will not be considered a protocol deviation if the participant is unable 
to make this visit. In addition, if a participant has an unplanned site visit for any reason, 
(chemotherapy, radiology, other doctor appointments, etc.), a GDF-15 sample may be 
collected, if feasible, provided the total volume taken during the study does not exceed 
550 mL during any period of 56 consecutive days.
At the Screening visit, two GDF-15 samples will be collected (6-mL for each). One GDF-15 
(Roche) sample will be analyzed using the IUO Roche Elecsys GDF-15 assay, for 
determination of enrollment eligibility. In addition, this sample may be used to help support 
development of a potential companion diagnostic test for ponsegromab. This screening assay 
will be validated in a CLIA accredited central laboratory. The second Screening GDF-15 
(Pfizer) sample, as well as the GDF-15 samples collected at the other time points specified in 
the SoA, will be analyzed for unbound and total GDF-15 using validated Pfizer assays in 
compliance with applicable SOPs.
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
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The actual times may change, but the number of samples will remain the same. Collection of 
samples within the protocol-allowed visit window, as defined in the SoA or above will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF.
Sample will be used to evaluate the PD of ponsegromab. Samples collected for PD analyses 
may also be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study, and/or evaluation of bioanalytical methods, or for other internal exploratory 
purposes.
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
GDF-15 concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
If the sample is unable to be collected during F/U part A and F/U part B, it will not be 
considered a protocol deviation.
8.7.2. Circulating Biomarkers
Albumin and pre-albumin will be assessed as a biomarker for nutritional status. A serum
sample of approximately 6 mL will be collected for measurement of albumin and pre-
albumin as specified in the SoA.
Laboratory/analyte results for albumin and pre-albumin collected from baseline through EOT 
of Part A, that could unblind the study will not be reported to investigator sites or other 
blinded personnel until the study has been unblinded.
8.7.3. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.7.4. Specified Protein Research 
Specified protein research is not included in this study.
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8.7.5. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.7.6. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study according to the SoA:

A 2-mL whole blood (Prep B 1.5 optimized for plasma).

A 2-mL whole blood (Prep B 2.5 optimized for serum).
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA.
Retained Research Samples may be used for research related to the study intervention(s) and 
cancer cachexia. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.8. Immunogenicity Assessments
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL serum, will be 
collected for determination of ADA and NAb as specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for determination of ADA and NAb may also be used for additional 
characterization of the immune response and/or evaluation of the bioanalytical method, or for 
other internal exploratory purposes. These data will be used for internal exploratory 
purposes.
Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent. Participant confidentiality will be maintained.
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs. Samples determined to be positive for ADA may be further characterized for NAb, if 
feasible.
The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from the 
immunogenicity sample handling procedure (eg, sample collection and processing steps, 
interim storage, or shipping conditions), including any actions taken, must be documented 
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and reported to the sponsor. On a case-by-case basis, the sponsor may make a determination 
as to whether sample integrity has been compromised.
Immunogenicity information that would unblind the study will not be reported to investigator 
sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
If the sample is unable to be collected during F/U Part A and F/U Part B, it will not be 
considered a protocol deviation.
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 the 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.
9.1. Statistical Hypotheses
The null hypothesis of no difference between ponsegromab and placebo will be tested for 
each primary and selected secondary and tertiary endpoints. The alternative hypothesis is that 
ponsegromab is superior to placebo.
9.1.1. Estimands
9.1.1.1. Primary Estimand
Estimand related to the body weight primary objective:
Estimand 1 (similar to “hypothetical”) is intended to provide a population level estimate of 
the treatment effect on the change from baseline in body weight for ponsegromab compared 
with placebo in all evaluable participants under the scenario of no discontinuation of study
intervention and without the potential confounding effect of prohibited procedures, 
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prohibited medications or participants’ non-compliance with dosing (ie, using the Censored 
analysis set, as defined in Section 9.2).

Population: Participants with cancer, cachexia, and elevated concentrations of 
GDF-15.

Endpoint: Change from baseline in body weight at Week 12.

Intercurrent Events:
a.
Discontinuation of study intervention: Data collected after a participant has 
discontinued study intervention will be censored and treated as missing data.
b. Prohibited procedures: Data collected after a participant has undergone prohibited 
procedures, that would modulate the primary endpoint will be censored and 
treated as missing data. Any procedures will be reviewed prior to database lock to 
determine which would be classed as “prohibited” for this estimand.
c.
Prohibited medications: Data collected after a participant has received prohibited 
medications, that would modulate the primary endpoint, will be censored and 
treated as missing data. The list of concomitant medications will be reviewed 
prior to database lock to determine which would be classed as “prohibited” for 
this estimand.
d. Inadequate compliance: Data collected after a participant has missed a dose will 
be censored and treated as missing data. 
Missing data due to censoring, study withdrawal or other reasons, are assumed to 
be missing at random in the analysis.

Population-level summary: Difference in mean change from baseline body weight at 
Week 12 between ponsegromab and placebo.
Alternative estimands (eg, one similar to “treatment policy”, using a complete analysis set 
where all observations post-discontinuation, prohibited procedure, prohibited medications or 
inadequate compliance, will be included) for the primary objective may be used in order to 
examine the robustness of the results and will be detailed in the SAP.
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9.1.1.2. Secondary Estimands
Estimand related to the physical activity and gait secondary objective:
Estimand 2 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline in each of the physical activity and gait endpoints at 
Week 12:

Moderate to vigorous physical activity time;

Sedentary activity time;

Non sedentary activity time;

Total vector magnitude; 

Mean activity level during M6min;

Mean gait speed;

95th percentile gait speed.

Population-level summary: Difference in mean change from baseline for the physical 
activity and gait endpoints at Week 12 between ponsegromab and placebo.
Estimand related to the appetite-related symptoms as measured by FAACT secondary 
objective:
Estimand 3 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline in each FAACT sub-scale score at Week 12:

FAACT-ACS;

FAACT-5IASS.

Population-level summary: Difference in mean change from baseline for the FAACT 
sub-scale scores at Week 12 between ponsegromab and placebo.
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Estimand related to the anorexia/appetite, nausea, vomiting and fatigue measured by the 
CRCSD secondary objective:
Estimand 4 will be similar to Estimand 1, except for the following:

Endpoint: Change from baseline score for each of the questions from the CRCSD at 
Week 12:

Anorexia/appetite;

Nausea and vomiting;

Fatigue. 

Population-level summary: Difference in mean change from baseline in each of the 
questions from the CRCSD at Week 12 between ponsegromab and placebo.
Estimands related to the safety and tolerability secondary objective:
There are no defined estimands for the incidence of adverse events, safety laboratory tests, 
vital signs and ECG abnormalities, and these endpoints will be summarized using Pfizer data 
standards as applicable.
Estimands related to tertiary/exploratory objectives:
Tertiary/exploratory endpoints may be analyzed using similar estimands or analyzed in a 
descriptive manner without reference to an estimand. Other supporting estimands may be 
used for some of the primary and secondary endpoints as a means to examine the robustness
of results, compare to available literature and/or be used for future study planning as needed.
Details of these estimands and analyses will be presented in the SAP.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
"Enrolled" means a participant's, or their legally authorized
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after Screening.
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
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Participant Analysis Set
Description
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Evaluable
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the randomized intervention.
Safety analysis set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the study intervention they 
actually received.
Defined Analysis Set
Description
Censored
All evaluable participants. For participants who discontinue 
study intervention, or receive a prohibited procedure or 
prohibited medication, all observations post-discontinuation, 
or post-procedure, will be censored and treated as missing 
data. For participants who miss a dose, all observations 
post-missed dose will be censored and treated as missing 
data. 
PK
All participants randomly assigned to study intervention and 
who take at least 1 dose of ponsegromab and in whom at least 
1 PK concentration value is reported.
PD
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 PD (GDF-15) concentration value is reported.
Immunogenicity 
All participants randomly assigned to study intervention and 
who take at least 1 dose of ponsegromab and in whom at least 
1 ADA result is reported. 
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
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9.3.1. General Considerations
Part A and Part B of the study will be presented separately. For objectives relating to Part A 
of the study, each treatment arm will be reported separately through the 12-week 
double-blind treatment period only (including follow-up for any participants not continuing 
onto Part B of the study).
9.3.1.1. Analyses for Continuous Endpoints
MMRM Model
The MMRM model will include participant as a random term, and baseline, time (as a 
factor), baseline-by-time interaction, treatment and treatment-by-time interaction as fixed 
terms in the model. An unstructured covariance matrix will be fitted to the repeated times 
within subject (other covariance matrices will be considered if necessary), and the Kenward 
Roger approximation will be used for estimating degrees of freedom. Additional terms may 
be fitted in the model (eg, type of therapy [ie, platinum or not], type of cancer), as 
appropriate.
Bayesian Emax Model
The Bayesian four-parameter Emax model will use dose as a continuous variable. The model 
structure will take the form: 
 = 	 +
∗

E0 is the placebo response, dose is the randomized dose (placebo dose = 0), Emax is the 
maximum effect, ED50 is the dose producing 50% of the maximum effect and Hill is the 
slope parameter. The model will utilize a Bayesian methodology approach.
The default prior distributions for the Hill parameter and the ED50 are based on a meta-
analysis of clinical dose response data13,14,15 and are listed below. These default distributions 
will be updated if the meta-data, and their analysis, are updated before the completion of the 
current study.
Parameter
Prior
log(ED50)
log(P50) + t(Mean=0, SD=1.73, df=5)
log(Hill)
t(Mean = 0, SD =0.85, df=5)
The correlation between these two parameters is currently -0.45 based on the analysis of the 
meta-data, which also would be updated if the historical analysis is updated.
The predicted ED50 for the compound (P50), and prior distributions for the placebo response 
(E0), the difference in response (difTarget) between the highest dose (400 mg) and placebo, 
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and the residual standard deviation (sigma) will be specified for the analysis endpoint. Note 
that Emax is derived from other parameters and is thus not explicitly supplied. 
9.3.2. Primary Endpoint Analysis
The primary endpoint analysis will be a Bayesian Emax model applied to results from an 
MMRM analysis. 
Change from baseline in body weight at Week 12 will first be analyzed using Estimand 1 and 
an MMRM model (as per Section 9.3.1.1). The MMRM model will be fitted to the change 
from baseline at all post-treatment dosing timepoints up to Week 12 (ie, Weeks 4, 8, and 12)
using the Censored analysis set. Additional terms for type of therapy [ie, platinum or not] and 
type of cancer will be fitted in the model. Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and p-values) will be provided. 
A Bayesian Emax model will then be fitted to the Week 12 LSmeans and SEs from the 
MMRM analysis. The predicted ED50 for the compound (P50) is currently ~150 mg Q4W 
dose, based on latest data for the compound (this may be updated as new data become 
available). Prior distributions for the placebo response (E0), the difference in response 
(difTarget) between the highest dose (400 mg) and placebo, and the residual standard 
deviation (sigma) are: 
E0: An informative meta-analytic predictive16,17 prior, based on historical results from 
internal and external studies, robustified by the inclusion of a weakly informative 
component to handle any possible prior-data conflict, will be used for the placebo 
change from baseline at Week 12. This will be approximated by a t-distribution with a 
mean of -0.58 kg, an SD of 1.84 kg and 3 degrees of freedom. If additional relevant 
data become available during the study, a sensitivity analysis may be performed by 
incorporating the new data, using the same approach as above. Further details on the 
prior derivation will be given in the statistical analysis plan (SAP).
difTarget: A vague t-distribution will be used for the 400 mg placebo-corrected 
change from baseline at Week 12 with a mean of 0, a SD equal to 10 times the 
predicted standard deviation (ie, 49 kg) and 5 degrees of freedom.
sigma: A uniform prior will be used, with a range we are confident will include the 
population value. A lower bound of 0.49 kg and an upper bound of 49 kg will be 
used.
The posterior medians and 90% credible intervals (5th and 95th percentiles of the relevant 
posterior distribution) will be reported for each randomized dose (including placebo) and 
their differences relative to placebo. If the Emax model cannot be fitted to the data, or the data 
do not support a dose-response, the model may be simplified, or the analysis may not be 
performed and the primary results for the study will be based on the MMRM results at 
Week 12. More details on how this will be assessed will be described in the SAP. No 
adjustments will be made for multiplicity.
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9.3.3. Secondary Endpoints Analysis
Endpoint
Statistical Analysis Methods
Change from baseline in each of the physical activity 
and gait endpoints at Week 12:

Moderate to vigorous physical activity time;

Sedentary activity time;

Non sedentary activity time;

Total vector magnitude;

Mean activity level during M6min;

Mean gait speed;

95th percentile gait speed.
Change from baseline in physical activity and gait 
endpoints will be analyzed separately using 
Estimand 2 and an MMRM model (as per
Section 9.3.1.1). The MMRM model will be fitted to 
the change from baseline at all post-treatment 
timepoints up to Week 12 using the Censored 
analysis set.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and p 
values) will be provided. No adjustments will be 
made for multiplicity.
Change from baseline in each of the FAACT 
sub-scale scores at Week 12:

FAACT-ACS;

FAACT-5IASS.
Change from baseline in FAACT sub-scale scores 
will be analyzed separately using Estimand 3 and an 
MMRM model (as per Section 9.3.1.1). The MMRM 
model will be fitted to the change from baseline at all 
post-treatment timepoints up to Week 12 using the 
Censored analysis set.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and 
p values) will be provided. No adjustments will be 
made for multiplicity.
Change from baseline for each of the questions from 
the CRCSD at Week 12: 

Anorexia/appetite;

Nausea and vomiting;

Fatigue.
Change from baseline in questions from the CRCSD
will be analyzed separately using Estimand 4 and an 
MMRM model (as per Section 9.3.1.1). The MMRM 
model will be fitted to the change from baseline 
weekly averages at all post-treatment timepoints up 
to Week 12 using the Censored analysis set.
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs and 
p values) will be provided. No adjustments will be 
made for multiplicity.
Incidence of adverse events, safety laboratory tests, 
vital signs and ECG abnormalities.
All safety analyses will be performed on the safety 
population. The safety data will be summarized in 
accordance with Pfizer Data Standards. All safety 
data will be summarized descriptively through 
appropriate data tabulation, descriptive statistics, 
categorical summaries, and graphical presentations, 
as appropriate.
Part B safety data will be reported once all 
applicable participants have completed Part B of the 
study. More details will be provided in the SAP.
9.3.4. Tertiary/Exploratory Endpoints Analysis
The analysis of exploratory endpoints will be detailed in the SAP.
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9.3.5. Other Analyses 
Selected data collected at Screening may be reported. These data may include demographic 
data, concomitant medications, GDF-15 concentrations, height, weight, BMI, and ECOG PS. 
In addition, a subset of medical history data will be reported; this may include type and stage 
of cancer, where feasible. Other data collected at Screening that are used for 
inclusion/exclusion criteria, such as laboratory data, will be considered source data, and will 
not be required to be reported, unless otherwise noted.
As permitted by data, and determined by the sponsor, the PK/PD relationship between serum 
ponsegromab concentration and the effect on primary, secondary and/or tertiary endpoints 
may be explored using a population PK/PD approach. The population PK/PD analysis, if 
conducted, will be reported in a separate report.
Up to 40 exit interviews will be conducted by telephone at Week 12 or early discontinuation. 
Interviews will be conducted by trained moderators and are anticipated to be approximately 
60 minutes in duration. Using the transcripts and interviewer field notes, dominant trends 
will be identified in each interview and compared across all the interviews to describe the 
participant experience with a focus on the themes or patterns in the way the treatment 
experience is described, and the importance of any improvements reported. Following the 
analysis, a comprehensive summary report that fully describes the study objectives, methods, 
participants and results of the qualitative interviews will be prepared and reported separately 
from the CSR.
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR. 
CT scans will be collected, retained, analyzed for tumor burden, skeletal muscle, adipose 
tissue, and may be used for additional research related to the study intervention(s) and cancer 
cachexia. The results of such additional research analyses may not be included in the CSR.
9.4. Interim Analyses
Interim analyses may be performed to assess efficacy and/or safety after at least 
approximately 25% of the planned participants, ie, approximately 30 participants, complete 
their study participation through Week 12 of the study. Interim analysis results may be used 
for decisions regarding stopping for futility, stopping for early success, conducting a sample 
size re-estimation, or adapting the study after the interim analysis. Participants may be 
discontinued from the study intervention/study as a result of the interim analysis, as 
described in Section 7. 
Before any interim analysis is performed, the details of the objectives, decision criteria,
dissemination plan, and method of maintaining the study blind (if applicable) as per Pfizer’s 
SOPs will be documented and approved in an IRC charter. In addition, the analysis details 
will be documented and approved in the SAP.
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Following completion of Part A (PCD), the data will be analyzed and reported in the main 
CSR. The results for Part B will be reported separately at the end of Part B.
9.4.1. PK/PD Unblinding Plan 
If needed, a PK/PD unblinding plan will be developed to safeguard the study blind for 
members of the study team. These procedures will be in accordance with applicable Pfizer 
SOPs for releasing randomization codes and breaking the study blind. Under this plan, a 
limited number of individuals, not on the study team, will be unblinded, with the purpose of 
composing PK/PD and/or immunogenicity analysis sets and conducting PK/PD analysis that 
will not be made available to the study team until after database lock.  
9.5. Sample Size Determination
A sufficient number of participants will be screened to achieve a total of approximately 
168 participants, with 42 participants randomly assigned to ponsegromab 100, 200 or 400 mg 
and placebo in approximately a 1:1:1:1 ratio. This is expected to ensure completion through 
Week 12 of the study of approximately 120 completing participants (30 in each of 
ponsegromab 100, 200 or 400 mg and placebo), assuming a discontinuation rate of 
approximately 30% (if this rate is higher, or there is a high rate of non-compliance, more 
participants may be randomized to ensure the required number of completing participants). 
The sample size in the ponsegromab and placebo arms is based on the primary efficacy 
endpoint, mean change from baseline in body weight at Week 12. An informative 
meta-analytic predictive prior, based on historical results from internal and external studies, 
robustified by the inclusion of a weakly informative component to handle any possible 
prior-data conflict, will be used for the placebo response and is expected to equate to an
effective sample size of 39 placebo participants. Further details on the prior derivation will be 
given in the statistical analysis plan SAP.
120 completing participants, in a 1:1:1:1 ratio, plus 39 participants from the placebo prior, 
gives acceptable Operating Characteristics in that:

The probability of achieving statistical significance (at the 5% significance level, 
using a 1-sided t-test), for a true difference between ponsegromab and placebo of 
2.7 kg, is approximately 80%.

An observed difference between ponsegromab and placebo of 1.8 kg is expected 
to achieve statistical significance (at the 5% significance level, using a 1-sided t-
test).
A conservative estimate of the standard deviation, for the change from baseline in body 
weight at 12 weeks of 4.9 has been used. 
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The sample size determination has been performed using pairwise comparisons. This is 
considered to be a conservative approach since the primary analysis will utilize a Bayesian 
Emax dose-response model, which would be anticipated to best describe the dose-response in 
the presence of an effective compound.15
Evaluable participants are defined as in Section 9.2. Participants who withdraw from the 
study will not be replaced.
Of the approximately 168 planned randomized participants, up to approximately 36 are 
planned to be randomized (to ponsegromab 100, 200 or 400 mg and placebo in 
approximately a 1:1:1:1 ratio) into the additional PK substudy. This sample size has been 
chosen empirically to provide sufficient data to adequately characterize ponsegromab PK and 
GDF-15 effect and PK/PD relationship in cancer patients with cachexia and elevated 
concentrations of GDF-15.
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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 CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, 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.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, 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 study 
intervention, 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 the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative
and answer all questions regarding the study. The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (if allowed by local regulations) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, privacy and data protection requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each participant or their 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 or their legally authorized representative must be informed that their 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 or their legally authorized 
representative.
The participant or their legally authorized representative must be informed that their 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 their legally authorized 
representative is fully informed about their right to access and correct their personal data and 
to withdraw consent for the processing of their personal data.
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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or their legally authorized representative must be reconsented to the most current 
version of the IRB/EC-approved ICD(s) during their participation in the study as required per 
local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
Participants who are rescreened are required to sign a new ICD.
10.1.4. 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 will 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 participants 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 their actual identity and medical record ID. 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.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
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10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use an IRC. The IRC is independent of the study team and includes only 
internal members. The IRC charter describes the role of the IRC in more detail.
The IRC will be responsible for ongoing monitoring of the efficacy and safety of participants 
in the study according to the charter. The IRC will conduct an initial review of the unblinded 
safety data once the first 20 randomized participants have safety data through at least 
6 weeks after randomization. Thereafter, the IRC will review safety data approximately every 
3 months to ascertain whether there is a ponsegromab-related safety concern by evaluating 
treatment emergent AEs, including those related to study intervention, using the NCI CTCAE 
grading system, and by reviewing the AEs in both the active treatment arms and placebo. The 
IRC will also review data collected on the administration of anti-cancer therapy, to ascertain 
if there is an imbalance in the rates of discontinuation of anti-cancer therapies across the
treatment arms. The IRC will issue periodic recommendations to the study team, based on its 
periodic review of the unblinded study data. Such recommendations may include 
modification to or discontinuation of a study treatment arm or termination of the study. The 
recommendations made by the IRC will be forwarded to the appropriate authorized Pfizer 
personnel for review and final decision. Pfizer will communicate such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data that are not 
endpoints, to regulatory authorities and investigators, as appropriate. 
10.1.5.2. Executive Steering Committee
The Executive Steering Committee will be responsible for reviewing the protocol and may 
make suggestions on protocol design and amendments. This committee will with work 
jointly with the Operations Steering Committee to provide guidance regarding identified 
issues with study conduct. They will also lead authorship and provide oversight of study 
publications in collaboration with the sponsor. The charter describes the role of the Executive 
Steering Committee in more detail.
10.1.5.3. Operations Steering Committee
The Operations Steering Committee comprised of medical representatives from each country
or region, Pfizer clinical colleagues and Pfizer operations colleagues, will oversee 
recruitment, retention, and quality issues within the country or region. This committee will 
work jointly with the Executive Steering Committee to ensure that identified issues are 
effectively addressed at each participating site. The charter describes the role of the 
Operations Steering Committee in more detail.
10.1.6. 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 EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
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laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its 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 results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
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.
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10.1.7. 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.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and
regulatory agency inspections and provide direct access to source records and 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.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (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, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
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.
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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.
10.1.8. 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 eCRF that are 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 a source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the data management 
plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring 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 guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. 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.
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The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/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 the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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.
10.1.10. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer 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-intervention or  
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Pfizer-related information necessary for the appropriate scientific presentation or 
understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system. 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they 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 issues.
Hematology
Chemistry
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Urea and creatinine, 
SCys (at Screening only)
Sodium
Potassium
AST, ALT
Total bilirubin
Alkaline phosphatase
Total protein
Glucose (non-fasting)
At Screening only:

FSHa
Per SoA or as needed:

Pregnancy test (b-hCG or urine 
test)b
For potential DILI:
AST/ALT 
T bili, direct and indirect bili 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol or 
protein adduct levels 
Hepatitis serology (even if screening 
negative) 
For potential DICI/DIKI: 
Creatinine (Scr) 
CystatinC (Scys) 
eGFR (Scr only and combined Scr+Scys) 
Spot (dipstick) UACR
a.
For confirmation of postmenopausal status only.
b.
Serum b-hCG will be collected at Screening for female participants of childbearing potential. Local 
urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/EC. 
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. 
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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant 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), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic  
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant
medical events that 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 
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100 fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 

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 definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure 
rate of <1% per year) during the intervention period and for at least 8 weeks after 
the last dose of study intervention, which corresponds to the time needed to 
eliminate any reproductive safety risk of the study intervention(s). If a highly 
effective, user-dependent method is chosen, she agrees to concurrently use an
effective barrier method of contraception. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of study 
intervention.
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
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 study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;
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
Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a 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.
2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
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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 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*;

Intravaginal + barrier*;

Transdermal + barrier*.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*;

Injectable + barrier*.
Sexual Abstinence
8. 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 study intervention. 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.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Therefore, where local regulations and 
IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to or study interventions of this class to understand treatments 
for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a study 
report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the code and 
the participant’s personally identifying information (eg, name, address) will be held 
securely at the study site. 
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10.6. Appendix 6: 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 DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili 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 T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
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Rises in AST/ALT and T bili 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. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/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/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or 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, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the 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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10.7. Appendix 7: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to eGFR [Scr-based eGFR] or [eCrCl]). Baseline and 
postbaseline Scys makes it feasible to distinguish AKI from other causes of Scr increase. If 
Scr increase is confirmed after baseline, then reflex measurement of Scys is indicated to 
estimate the combined Scr-Scys eGFR calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)-2021 CKD-EPI Equations
2021 
CKD-EPI 
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age
Female
if >0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age
Male
if ≤0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age
Male
if >0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age
2021 
CKD-EPI 
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if >0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if >0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if >0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if >0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49.18
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to CTCAE
criteria.
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10.9. Appendix 9: Comfort and Wearability Questionnaire
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10.11. Appendix 11: RECIST 1.1 Tumor Assessment Criteria RECIST (Response 
Evaluation Criteria In Solid Tumors) version 1.1 Guidelines
Adapted from Eisenhauer E.A., et al.19
*Since MRIs are not included in this study, the RECIST criteria only applies to CT scans.
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI* (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease 
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, clinical lesions that cannot be accurately measured 
with calipers, 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 thought 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 
lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING 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 28 days prior to treatment and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
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 basis 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 assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used. If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded. If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target. All measurable 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 
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INCREASED, INCREASED. Multiple non-target lesions in one organ may be recorded as a 
single item on the CRF (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION.
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case must 
be discussed with the radiologist to determine if substitution is possible. If not, subsequent 
objective statuses are indeterminate.
Target disease

Complete response: 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: Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions. The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions. 
All target lesions must be assessed.

Stable: Does not qualify for CR, PR, or progression. All target lesions must be 
assessed. Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.

Objective progression: 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 documented, and: 
1. One or more target measurable lesions have not been assessed; or 
2. Assessment methods used were inconsistent with those used at baseline; or
3. One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure); or
4. One or 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 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 the residual lesion be investigated with 
biopsy or fine needle aspirate. If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status. Every effort should be made to document objective progression even after 
discontinuation of treatment.
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Table 5.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
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
If the protocol allows enrollment of patients with only non-target disease, the following 
Table 6 will be used:
Table 6.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
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10.12. Appendix 12: List of Platinum-Based Chemotherapies
Platinum-based chemotherapies include the following:
Cisplatin
Oxaliplatin
Carboplatin
Nedaplatin
Lobaplatin
Heptaplatin
Miriplatin
Satraplatin
Picoplatin
Phenanthriplatin
The list above is non-exhaustive and please review list of chemotherapies carefully with your 
pharmacist and/or Pfizer study team to determine if any should be considered as platinum-
based. Please note agents are listed above using generic terms and trade names are not 
included.
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10.13. Appendix 13: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
A1 to A3
albuminuria (KDIGO albuminuria severity standardization)
Abs
absolute
ACS
anorexia and cachexia subscale
ADA
anti-drug antibodies
ADE
adverse device effect
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
AIDS
Acquired Immunodeficiency Syndrome
AKI
acute kidney injury
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUCinf
area under the serum concentration time profile from time zero
extrapolated to infinite time
AUClast
area under the serum concentration time profile from time zero to
the time of the last quantifiable concentration
AUCtau
area under the serum concentration-time curve over the dosing
interval tau
AV
atrioventricular
AxMP
auxiliary medicinal product
BA
bioavailability
BE
bioequivalence
b-hCG
b-human chorionic gonadotropin
BioMeT
biometric monitoring technology
BMI
Body Mass Index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
Cavg
average concentration
CFR
Code of Federal Regulations
CL/F
apparent clearance for oral dosing
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology 
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Abbreviation
Term
CLIA
clinical laboratory improvement amendments
Cmax
maximum observed concentration
CMC
Chemistry, Manufacturing and Controls
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRC
colorectal cancer
CRCSD
Cancer related cachexia symptom diary
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CT
computed tomography/clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trial Information System
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction 
DHT
digital health technology
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
DRE
disease-related event
DU
dispensable unit
EC
ethics committee
eCOA
electronic clinical outcome assessment
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
ED
Early discontinuation
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
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Abbreviation
Term
Emax
maximal effect
EOT
end of treatment
ePRO
electronic Patient Reported Outcome
eSAE
electronic serious adverse event
ESR
erythrocyte sedimentation rate
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FAACT
Functional Assessment of Anorexia-Cachexia Therapy
FAACT-5IASS
Functional Assessment of Anorexia/Cachexia Therapy 5-item 
Anorexia Symptom Scale
FAACT-ACS
Functional Assessment of Anorexia-Cachexia Therapy- anorexia 
and cachexia subscale
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-G
Functional Assessment of Cancer Therapy - General
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
F/U
follow-up
G1 to G5
Grade (KDIGO eGFR category standardization)
GCP
Good Clinical Practice
GDF-15
growth differentiation factor 15
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP-1
Glucagon-like peptide-1
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCP
health care professional
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HRU
healthcare resource utilization
hs-CRP
high-sensitivity C-reactive protein
Ht
height
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
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Abbreviation
Term
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
Investigational product
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IRB
Institutional Review Board
IRC
internal review committee
IRT
Interactive Response Technology
ISO
International Organization for Standardization
IUO
Investigational Use Only
IWR
Interactive Web-based Response
K
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function)
KDIGO
Kidney Disease: Improving Global Outcomes
LBBB
left bundle branch block
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function test
LLOQ
lower limit of quantification
LPD
local product document
LSmeans
Least-Squares Means
LSMI
Lumbar Skeletal Muscle Index
M6min
Maximum daily 6 minutes of activity
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device regulation
MQI
medically qualified individual
MRI
magnetic resonance imaging
NA
not applicable
NAb
neutralizing antibodies
NCI
National Cancer Institute
NDCMC
newly diagnosed chronic medical condition
NIMP
noninvestigational medicinal product
NOAEL
no observed adverse effect level
NRS
numerical rating scale
NSCLC
non-small cell lung cancer
NT-pro-BNP
N-terminal-pro hormone B-type natriuretic peptide
NYHA
New York Heart Association
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Abbreviation
Term
OLT
Open-label treatment
PBMC
peripheral blood mononuclear cell
PANC
pancreatic cancer
PCD
Primary completion date
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PFS
prefilled syringe
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PG-SGA
Patient Generated-Subjective Global Assessment 
PI
principal investigator
PK
pharmacokinetic(s)
PR
pulse rate
PRO
Patient Reported Outcomes
PROACC-1
Patient Reported Outcomes and Activity in CanCer
PROMIS
Patient-Reported Outcomes Measurement Information System
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PTH
parathormone
PVC
premature ventricular contraction
Q3W
administered every 3 weeks
Q4W
administered every 4 weeks
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
QTL
quality tolerance limit
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous(ly)
Scr
serum creatinine
Scys
serum cystatin C
SD
Standard deviation
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
Single Reference Safety Document
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Abbreviation
Term
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal elimination half-life
T3
total triiodothyronine
T4
total thyroxine
TB
tuberculosis 
T bili
total bilirubin
TEAE
treatment emergent adverse event
THC
tetrahydrocannabinol
Tmax
time for Cmax
TOC
table of contents
TSH
thyroid-stimulating hormone
UACR
urine albumin/creatinine ratio
UADE
unanticipated adverse device effect
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
USPI
United States Prescribing Information
UTI
urinary tract infection
VZV
varicella zoster virus
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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10.14. Appendix 14: Protocol Amendment History
Amendment 1 (27 October 2022)
Overall Rationale for the Amendment: The overall rationale for this amendment is to 
incorporate and clarify various protocol elements related to stopping criteria of the study 
invention, assessment of weight change, CT scan regions and patient reported outcomes. The 
details are described below.
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
1.1. Synopsis; 3. 
Objectives, 
Endpoints, and 
Estimands
moved CRCSD from 
tertiary to secondary.
To support 
validation of 
CRCSD
Substantial
1.3. Schedule of 
Activities  
Added vital signs, physical 
exams, chemistry and 
hematology assessments 
every 3 months in Part B; 
also expanded Part B visits 
such that all visits are 
visualized in the table rather 
than one column for visits 
16-60; added ECOG PS to 
Part B (visit 20 and ED).
Additional 
timepoints for 
procedures added 
for evaluation of 
safety
Substantial
1.3. Schedule of 
Activities; 8.3.1. 
Physical 
Examination

Updated physical 
exam plan: 

updated SoA 
footnote ‘e’ to 
include evaluation of 
ascites and edema 
and reporting as an 
AE;

Added a separate 
line for abbreviated 
physical exam to 
clarify which visits 
should be full 
physical exam 
added for 
evaluation of 
weight change and 
clarified which type 
of type of physical 
exam would be 
required for 
specific visits 
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
versus abbreviated 
physical exam; 

Updated Week 8 
physical exam from 
full physical exam to 
abbreviated physical 
exam;

Added abbreviated 
physical exam at 
Week 4, 24, 36, 48, 
and 60;

Added text to 
include evaluation of 
ascites and edema 
and reporting as an 
AE.
1.3. Schedule of 
Activities; 3. 
Objectives, 
Endpoints and 
Estimands; 4.2 
Scientific 
Rationale for 
Study Design; 
8.3.7. Imaging 
Assessment-CT 
scan; 9.3.5 Other 
Analyses

Clarified specific 
required body 
regions for CT scans 
in SoA footnote ‘o’; 

Clarified specific 
body regions for CT 
scans and added text 
to clarify that all CT 
scans will be 
collected centrally to 
allow for a central 
review of body 
composition 
measures; 

Added an 
exploratory/tertiary 
objective for 
evaluation of LSMI 
and skeletal muscle 
Added for LSMI 
and skeletal muscle 
and adipose tissue 
measures 
evaluation and 
analysis
substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
and adipose tissue 
measures derived 
from CT scans. 
1.3. Schedule of 
Activities; 8.2.2. 
Patient Reported 
Outcomes
Added an additional 
question related to physical 
activity to PGI-S and 
PGI-C.
Added for 
anchoring of 
physical function 
assessments
Substantial
7.1. 
Discontinuation 
of Study 
Intervention
added stopping criteria for 
participants experiencing 
Grade 3 or 4 AEs.
stopping rules 
added to assess 
toxicity associated 
with PF-06946860 
leading to 
discontinuation or 
delay in 
administration of 
anti-cancer therapy
Substantial
1.1. Synopsis; 
5.1. Inclusion 
Criteria 
(criterion #5)
updated to reflect inclusion 
of ECOG PS≤3 and removal 
of sponsor discussion of 
ECOG PS of 4.
updated to allow 
meaningful 
interpretation of 
results
Substantial
1.1. Synopsis; 
5.2. Exclusion 
Criteria 
(criterion # 11) 
Added specific criteria for 
exclusion due to liver 
enzyme lab abnormalities.
Added specific 
values to quantify 
threshold
Substantial
6.9. Prior and 
Concomitant 
Therapy 
Added text to clarify that 
reasons for discontinuing 
and modifying SOC 
therapies will be recorded 
on a CRF.
Added for 
evaluation of SOC 
therapies
Substantial
1.1 Synopsis and 
2.1 Study 
Rationale
Added study name and 
description.
Modification to 
incorporate study 
name
nonsubstantial
1.1. Synopsis and 
3. Objectives, 
Updated objectives for 
FAACT.
Modification
nonsubstantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Endpoints and 
Estimands
1.1 Synopsis and 
5.1 Inclusion 
Criteria
Updated Inclusion Criterion 
#3 to clarify the Fearon 
criteria of weight loss.
Clarification
nonsubstantial
Title page and 
Section 1.1 
synopsis
Updated Eudra CT number.
Changed 
submission from 
CTR to National 
route
nonsubstantial
1.1 Synopsis and 
3. Objectives, 
Endpoints and 
Estimands and 
9.1.1.1. Primary 
Estimand 
Updated Estimands to 
include prohibited 
medications.
Clarification
nonsubstantial
1.1. Synopsis; 3. 
Objectives, 
Endpoints, and 
Estimands
Updated physical function 
endpoints.
Clarification
nonsubstantial
1.3 Schedule of 
Activities
Expanded the visit windows 
for part B from ±1 to ±3.
Updated to allow 
for additional 
flexibility
nonsubstantial
1.3 Schedule of 
Activities and 
8.3.6 Pregnancy 
Testing
Updated footnote f. to 
clarify that following the 
Screening visit, a urine 
pregnancy test may be 
performed; removed 
duplicative text.
Clarification
nonsubstantial
1.3 Schedule of 
Activities
Clarified that retained 
samples will not be 
collected for China.
Clarification
nonsubstantial
1.3. Schedule of 
Activities; 8.2.2. 
Modified SoA footnotes ‘k’ 
and ‘l’ to clarify physical 
Clarification
nonsubstantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Patient Reported 
Outcomes
activity collection period 
description;
Clarified in table and text 
for physical activity 
collection period.
2.2.1.3 Summary 
of 
Pharmacokinetics
The following sentence was 
corrected to describe 
information regarding 
ponsegromab rather than 
GDF-15: “The mean 
terminal t½ increased with 
increasing dose, ranging 
from 3.52~11.1 days and 
20.1~30.9 days for the 
unbound and total 
ponsegromab, respectively, 
across the 10 to 300 mg 
dose groups.”
Update
nonsubstantial
2.2.1.5 
Immunogenicity
Added immunogenicity data 
based upon completion of 
the C3651009 CSR.
Update
nonsubstantial
2.3.1 Risk 
Assessment
Corrected text in the 
sentence related to injection 
site reactions in Phase 1 
studies in healthy 
participants and added use 
of ECG patches.
Clarification
nonsubstantial
3 Objectives, 
Endpoints, and 
Estimands
Modified objectives table to 
include prohibited 
medications to estimands; 
modified physical activity 
endpoints.
Clarification
nonsubstantial
4.4 End of Study 
Definition
Updated the end of study 
definition and defined 
primary completion date.
Clarification
nonsubstantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
6.9.2 Permitted 
During the Study
Removed duplicative text 
regarding the collection of 
all concomitant therapies 
since already stated in 6.9 
Prior and Concomitant 
Therapy.
Clarification
nonsubstantial
8.1. 
Administrative 
Procedures; 8.5. 
Pharmacokinetics
;8.7.1. GDF-15
Added text to collect PK 
and GDF-15 samples at any 
unplanned site visit when 
feasible.
Clarification
nonsubstantial
8.2.2 Patient 
Reported 
Outcomes
Clarified text for physical 
activity collection period 
language in table.
Clarification
nonsubstantial
8.2.3 Physical 
Activity 
Clarified description of 
physical activity collection 
period.
Clarification
nonsubstantial
8.3.6 Pregnancy 
Testing
Clarified test is only 
required at Screening and 
will be sent to central lab.
Clarification
nonsubstantial
8.5 
Pharmacokinetic; 
8.7.1 GDF-15
To align with Section 8, 
clarified blood volume does 
not exceed 550 mL during 
any period of 
56 consecutive days.
Clarification
nonsubstantial
8.7.1 GDF-15 
Added rationale for sample 
collection for potential 
companion diagnostic test 
for ponsegromab.
Clarification
nonsubstantial
9.1.1.1 Primary 
Estimands

Added text to clarify 
the management of 
data collected after a 
participant has 
received prohibited 
medications that 
Clarification
nonsubstantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
would modulate the 
primary endpoint;

Updated text to 
provide clarity on 
prohibited 
procedures and 
inadequate 
compliance.
9.1.1.2 Secondary 
Estimands and 
9.3.3 Secondary 
Endpoints 
Analysis 
Modified text to correspond 
to the updates made to the 
FAACT, physical activity 
and CRCSD objectives and 
endpoints.
Clarification
nonsubstantial
9.2 Analysis Sets
Added “prohibited 
medications” to censored 
analysis set.
Clarification
Nonsubstantial
9.4 Interim 
Analysis
Added text to describe end 
of study data reporting.
Update
Nonsubstantial
10.1.5.1. Data 
Monitoring 
Committee 
Included additional details 
related to the IRC data 
review.
added to 
incorporate details 
of IRC review and 
timelines
Nonsubstantial
10.2. Appendix 2. 
Clinical 
Laboratory Tests

Clarified that 
glucose sample is 
collected 
non-fasting; 

Moved potential 
DILI lab tests under 
other; 

Added potential 
DICI/DIKI lab test 
under other.
Update
Nonsubstantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
10.3.3. 
Recording/Report
ing and 
Follow-up of AEs 
and/or SAEs 
During the Active 
Collection Period
Added severity grading 
table and descriptions to 
align with CTCAE v5.
To align with safety 
reporting of 
adverse events
Nonsubstantial
10.13. Appendix 
13. RECIST 1.1 
Tumor 
Assessment 
Criteria RECIST 
(Response 
Evaluation 
Criteria In Solid 
Tumors) version 
1.1 Guidelines
Added note to specify that 
the RECIST criteria only 
applies to CT scans in this 
study.
Clarification
nonsubstantial
1.3. Schedule of 
Activities
The PROMIS (fatigue 7A & 
physical function 8c) 
assessment corrected to be 
linked with footnote ‘j’ 
rather than ‘.
Protocol 
Administrative 
Change Letter 
dated 28 July 2022
Nonsubstantial
4.3. Justification 
for Dose 
The titles and corresponding 
footnotes for Table 1 and 2 
corrected to reflect that the 
predicted total and unbound 
Cmax , AUCtau, and Cavg are 
steady-state exposures.
Protocol 
Administrative 
Change Letter 
dated 28 July 2022 
Nonsubstantial
6.1.1. 
Administration 
Specific instructions added 
to describe injection sites of 
administration of 
ponsegromab and placebo. 
Protocol 
Administrative
Change Letter 
dated 28 July 2022 
Nonsubstantial
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11. REFERENCES
1
Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO Clinical 
Practice Guidelines. ESMO Open. 2021;6(3):100092.
2
Roeland EJ, Bohlke K, Baracos VE, et al. Management of Cancer Cachexia: ASCO 
Guideline. J Clin Oncol. 2020;38(21):2438-2453.
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Ahmed DS, Isnard S, Lin J, et al. GDF15/GFRAL Pathway as a Metabolic Signature for 
Cachexia in Patients with Cancer. J Cancer. 2021;12(4):1125-1132.
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Tsai VW, Husaini Y, Manandhar R, et al. Anorexia/cachexia of chronic diseases: a role 
for the TGF-b family cytokine MIC-1/GDF15. J Cachexia Sarcopenia Muscle. 
2012;3(4):239-43.
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Lu ZH, Yang L, Yu JW, et al. Weight loss correlates with macrophage inhibitory 
cytokine-1 expression and might influence outcome in patients with advanced 
esophageal squamous cell carcinoma. Asian Pac J Cancer Prev. 2014;15(15):6047-52.
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Lerner L, Hayes TG, Tao N, et al. Plasma growth differentiation factor 15 is associated 
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Lerner L, Tao J, Liu Q, et al. MAP3K11/GDF15 axis is a critical driver of cancer 
cachexia. J Cachexia Sarcopenia Muscle. 2016;7(4):467-482.
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Altena, R, Fehrmann RSN, Boer, H., et al. Growth differentiation factor 15 (GDF-15) 
plasma levels increase during bleomycin-and cisplatin-based treatment of testicular 
cancer patients and relate to endothelial damage. PLoS One. 2015;10(1): e0115372.
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Von Haeling S, Anker MS, Anker SD. Prevalence and clinical impact of cachexia in 
chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J Cachexia 
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090177e19da07ca7\Approved\Approved On: 02-Jun-2023 06:15 (GMT)


Ponsegromab (PF-06946860)
Protocol C3651003
Final Protocol Amendment 2 24 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
TMF Doc ID: 164.01
Page 145
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090177e19da07ca7\Approved\Approved On: 02-Jun-2023 06:15 (GMT)

SAP_001.pdf: 
Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 of 6 0
Pr ot o c ol C 3 6 5 1 0 0 3
A P H A S E 2, R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D S T U D Y T O 
I N V E S TI G AT E T H E E F FI C A C Y, S A F E T Y A N D T O L E R A BI LI T Y O F P O N S E G R O M A B I N 
P A TI E N T S WI T H C A N C E R, C A C H E XI A,  AN D E L E V A T E D C O N C E N T R A TI O N S O F G D F -
1 5, F O L L O W E D B Y A N O P TI O N A L O P E N -L A B E L T R E A T M E N T P E RI O D ( P R O AC C -1)
St ati sti c al A n al y si s Pl a n 
( S AP)
V er si o n : 
3
D at e:
0 5 A pr 2 0 2 4
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 of 6 0
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ..................................................................................................................5
LI S T O F FI G U R E S ................................................................................................................5
A P P E N DI C E S .......................................................................................................................5
1. V E R SI O N HI S T O R Y .........................................................................................................7
2. I N T R O D U C TI O N ...............................................................................................................8
2. 1. M o difi c ati o n s t o t h e A n al y si s Pl a n D e s cri b e d i n t h e Pr ot o c ol ................................. 9
2. 2. St u d y O bj e cti v e s, E n d p oi nt s, a n d E sti m a n d s ........................................................9
2. 2. 1. Pri m ar y E sti m a n d( s) ...............................................................................1 2
2. 2. 2. S e c o n d ar y E sti m a n d( s) ...........................................................................1 4
2. 3. St u d y D e si g n .......................................................................................................1 5
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D C O N V E N T I O N S ........1 6
3. 1. Pri m ar y E n d p oi nt( s) ............................................................................................1 6
3. 1. 1. C h a n g e fr o m b a s eli n e b o d y w ei g ht at W e e k 1 2 ......................................1 6
3. 2. S e c o n d ar y E n d p oi nt( s) ........................................................................................1 6
3. 2. 1. C h a n g e fr o m b a s eli n e i n p h y si c al a cti vit y a n d g ait e n d p oi nt s 
m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k 1 2 .......................................1 6
3. 2. 2. C h a n g e fr o m b a s eli n e i n F A A C T s u b -s c al e s c or e s at W e e k -1 2 ..............1 8
3. 2. 3. C h a n g e fr o m b a s eli n e s c or e f or t h e q u e sti o n s fr o m t h e C a n c er 
R el at e d C a c h e xi a S y m pt o m Di ar y ( C R C S D) at W e e k 1 2 r el at e d t o:
............1 8
3. 2. 4. I n ci d e n c e of a d v er s e e v e nt s, s af et y l a b or at or y t e st s, vit al si g n s a n d 
E C G a b n or m aliti e s .......................................................................................1 8
3. 2. 4. 1. A d v er s e E v e nt s ......................................................................1 8
3. 2. 4. 2. L a b or at or y D at a .....................................................................1 9
3. 2. 4. 3. Vit al Si g n s ..............................................................................1 9
3. 2. 4. 4. El e ctr o c ar di o gr a m s ( E C G s) ....................................................1 9
3. 3. Ot h er S af et y E n d p oi nt( s) .....................................................................................1 9
3. 4. Ot h er E n d p oi nt s/ E x pl or at or y E n d p oi nt s ..............................................................2 0
3. 4. 1. C h a n g e fr o m b a s eli n e i n a d diti o n al p h y si c al a cti vit y a n d g ait 
e n d p oi nt s m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k  1 2.......................2 0
3. 4. 2. C h a n g e fr o m b a s eli n e i n a d diti o n al F A A C T t ot al a n d s u b -s c al e 
s c or e s at W e e k 1 2 .......................................................................................2 0
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 of 6 0
3. 4. 3. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of p o n s e gr o m a b o n D a y 1, 
W e e k s 4, 5, 8, 1 0, 1 2, a n d 1 6 (f oll o w -u p), pl u s W e e k 9 a n d 1 1 i n P K 
s u b st u d y o nl y ...............................................................................................2 0
3. 4. 4. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of G D F -1 5 o n D a y 1, 
W e e k s 4, 5, 8, 1 0, 1 2, a n d 1 6 (f oll o w -u p), pl u s W e e k 9 a n d 1 1 i n P K 
s u b st u d y o nl y ...............................................................................................2 1
3. 4. 5. I n ci d e n c e of A D A a n d N A b .....................................................................2 1
3. 4. 6. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -F ati g u e at W e e k 1 2 ................2 1
3. 4. 7. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -P h y si c al F u n c ti o n at 
W e e k 1 2 .......................................................................................................2 1
3. 4. 8. P ati e nt’ s Gl o b al I m pr e s si o n of C h a n g e ( P GI -C) at W e e k 1 2; C h a n g e 
fr o m b a s eli n e i n P ati e nt’ s Gl o b al I m pr e s si o n of S e v erit y ( P GI-S) at 
W e e k 1 2 .......................................................................................................2 2
3. 4. 8. 1. P GI - C.....................................................................................2 2
3. 4. 8. 2. P GI - S .....................................................................................2 2
3. 4. 9. T u m or s t at u s a c c or di n g t o R E CI S T 1. 1 g ui d eli n e s u si n g C T s c a n at 
W e e k 1 2 .......................................................................................................2 2
3. 4. 1 0. C h a n g e fr o m b a s eli n e i n L S MI d eri v e d fr o m C T s c a n s a t We e k 1 2; 
P er c e nt c h a n g e fr o m b a s eli n e i n s k el et al m u s cl e a n d a di p o s e ti s s u e 
m e a s ur e s d eri v e d fr o m C T s c a n s at W e e k 1 2 ..............................................2 2
3. 4. 1 1 . C h a n g e fr o m b a s eli n e al b u mi n a n d pr e-al b u mi n l e v el s at W e e k  1 2 ......2 3
3. 4. 1 2. S ur vi v al st at u s at e n d of P art A .............................................................2 3
3. 4. 1 3. R e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y 
w e i g ht at We e k 1 2 ........................................................................................2 3
3. 5. B a s eli n e V ari a bl e s ..............................................................................................2 3
4. A N A L Y SI S S E T S ( P O P U L A TI O N S F O R A N A L Y SI S) .....................................................2 5
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S .......................................................2 6
5. 1. H y p ot h e s e s a n d D e ci si o n R ul e s ..........................................................................2 6
5. 2. G e n er al M et h o d s .................................................................................................2 6
5. 2. 1. S u m m ari e s f or C o nti n u o u s E n d p oi nt s .....................................................2 7
5. 2. 2. S u m m ari e s f or C at e g ori c al E n d p oi nt s .....................................................2 7
5. 2. 3. Mi x e d M o d el s R e p e at e d M e a s ur e s ( M M R M) A n al y si s ............................2 7
5. 2. 4. B a y e si a n E m a x M o d el ............................................................................2 8
5. 2. 5. A n al y si s of C o v ari a n c e ( A N C O V A) .........................................................2 8
5. 2. 6. C u m ul ati v e I n ci d e n c e Pl ot s .....................................................................2 9
5. 2. 7. C o x Pr o p orti o n al H a z ar d s M o d el ............................................................2 9
5. 2. 8. L o gi sti c R e gr e s si o n .................................................................................2 9
5. 3. M et h o d s t o M a n a g e Mi s si n g D at a .......................................................................2 9
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 of 6 0
5. 3. 1. M ulti pl e I m p ut ati o n ..................................................................................3 0
6. A N A L Y S E S A N D S U M M A RI E S ......................................................................................3 0
6. 1. Pri m ar y E n d p oi nt( s) ............................................................................................3 0
6. 1. 1. C h a n g e fr o m b a s eli n e b o d y w ei g ht at W e e k 1 2 ......................................3 0
6. 1. 1. 1. M ai n A n al y si s .........................................................................3 0
6. 1. 1. 2. S e n siti vit y/ S u p pl e m e nt ar y A n al y s e s .......................................3 1
6. 2. S e c o n d ar y E n d p oi nt( s) ........................................................................................3 2
6. 2. 1. C h a n g e fr o m b a s eli n e i n p h y si c al a cti vit y a n d g ait e n d p oi nt s 
m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k 1 2 .......................................3 2
6. 2. 2. C h a n g e fr o m b a s eli n e i n F A A C T s u b -s c al e s c or e s at W e e k 1 2 ..............3 2
6. 2. 3. C h a n g e fr o m b a s eli n e s c or e f or e a c h of t h e q u e sti o n s fr o m t h e 
C R C S D at W e e k 1 2 .....................................................................................3 2
6. 2. 4. I n ci d e n c e of a d v er s e e v e nt s, s af et y l a b or at or y t e st s, vit al si g n s a n d 
E C G a b n or m aliti e s .......................................................................................3 2
6. 2. 4. 1. A d v er s e E v e nt s ......................................................................3 2
6. 2. 4. 2. L a b or at or y D at a .....................................................................3 4
6. 2. 4. 3. Vit al Si g n s ..............................................................................3 4
6. 2. 4. 4. E C G s .....................................................................................3 4
6. 3. Ot h er S af et y S u m m ari e s a n d A n al y s e s E n d p oi nt( s) ............................................3 5
6. 4. Ot h er E n d p oi nt s/ E x pl or at or y E n d p oi nt s ...............................................................3 5
6. 4. 1. C h a n g e fr o m b a s eli n e i n a d diti o n al p h y si c al a cti vit y a n d g ait 
e n d p oi nt s m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k  1 2.......................3 5
6. 4. 2. C h a n g e fr o m b a s eli n e i n a d diti o n al F A A C T t ot al a n d s u b -s c al e 
s c or e s at W e e k 1 2 .......................................................................................3 5
6. 4. 3. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of p o n s e gr o m a b o n D a y 1, 
W e e k s 4, 5, 8, 1 0, 1 2 a n d 1 6 (f oll o w -u p), pl u s W e e k 9 a n d 1 1 i n P K 
s u b st u d y o nl y ...............................................................................................3 5
6. 4. 4. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of G D F -1 5 o n D a y 1, 
W e e k s 4, 5, 8, 1 0, 1 2 a n d 1 6 (f oll o w -u p), pl u s W e e k 9 a n d 1 1 i n P K 
s u b st u d y o nl y ...............................................................................................3 6
6. 4. 5. I n ci d e n c e of A D A a n d N A b .....................................................................3 6
6. 4. 6. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -F ati g u e at W e e k 1 2 ................3 7
6. 4. 7. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -P h y si c al F u n c ti o n at 
W e e k 1 2 .......................................................................................................3 7
6. 4. 8. P GI -C at W e e k  1 2; C h a n g e fr o m b a s eli n e i n P GI-S at W e e k 1 2 .............3 7
6. 4. 9. T u m or st at u s a c c or di n g t o R E CI S T 1. 1 g ui d eli n e s u si n g C T s c a n at 
W e e k 1 2 .......................................................................................................3 7
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 of 6 0
6. 4. 1 0. C h a n g e fr o m b a s eli n e i n L S MI d eri v e d fr o m C T s c a n s at W e e k 1 2; 
P er c e nt c h a n g e fr o m b a s eli n e i n s k el et al m u s cl e a n d a di p o s e ti s s u e 
m e a s ur e s d eri v e d fr o m C T s c a n s at W e e k 1 2 ..............................................3 7
6. 4. 1 1. C h a n g e fr o m b a s eli n e al b u mi n a n d pr e -al b u mi n l e v el s at W e e k  1 2 ......3 8
6. 4. 1 2. S ur vi v al st at u s at e n d of P art A .............................................................3 8
6. 4. 1 3. R e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y 
w e i g ht at We e k 1 2 ........................................................................................3 8
6. 5. S u b s et A n al y s e s .................................................................................................3 8
6. 6. B a s eli n e a n d Ot h er S u m m ari e s a n d A n al y s e s ....................................................3 9
6. 6. 1. B a s eli n e S u m m ari e s ...............................................................................3 9
6. 6. 2. St u d y C o n d u ct a n d P arti ci p a nt Di s p o siti o n ..............................................3 9
6. 6. 3. C o n c o mit a nt M e di c ati o n s a n d N o n dr u g Tr e at m e nt s/ Pr o c e d ur e s .............4 0
6. 6. 4. Tr e at m e nt C o m pli a n c e ............................................................................4 0
6. 6. 5. R et ai n e d R e s e ar c h S a m pl e s ...................................................................4 0
6. 6. 6. P o p ul ati o n P K .........................................................................................4 0
7. I N T E RI M A N A L Y S E S ......................................................................................................4 0
7. 1. I ntr o d u cti o n .........................................................................................................4 0
7. 2. I nt eri m A n al y s e s a n d S u m m ari e s ........................................................................4 1
7. 2. 1. Effi c a c y E n d p oi nt s ..................................................................................4 1
7. 2. 2. S af et y E n d p oi nt s .....................................................................................4 1
7. 2. 3. Ot h er S u m m ari e s ....................................................................................4 1
8. R E F E R E N C E S ................................................................................................................4 2
LI S T O F T A B L E S
T a bl e 1.
S u m m ar y of C h a n g e s ..............................................................................7
LI S T O F FI G U R E S
Fi g ur e 1. St u d y D e si g n ........................................................................................................1 5
A P P E N DI C E S
A p p e n di x 1. F A A C T S c ori n g G ui d eli n e s ..............................................................................4 3
A p p e n di x 2. S a m p s o n Crit eri a .............................................................................................4 6
A p p e n di x 3. P R O MI S S c or e C o n v er si o n T a bl e s ..................................................................4 8
A p p e n di x 4. E x a m pl e S A S C o d e .........................................................................................4 9
A p p e n di x 5. B a y e si a n E m a x M o d el M et h o d ol o g y D et ail s ....................................................5 3
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 6 of 6 0
A p p e n di x 6. C at e g ori c al Cl a s s e s f or E C G a n d Vit al Si g n s of P ot e nti al Cli ni c al C o n c er n .....5 6
A p p e n di x 7. I m m u n o g e ni cit y T er m s a n d D efi niti o n s ............................................................5 7
A p p e n di x 8. Li st of A b br e vi ati o n s ........................................................................................5 8
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 7 of 6 0
1. V E R SI O N HI S T O R Y
T a bl e 1.
S u m m ar y  of C h a n g e s
V er si o n/
D at e
A s s o ci at e d 
Pr ot o c ol 
A m e n d m e nt
R ati o n al e
S p e cifi c C h a n g e s
3
0 5 A pr 2 0 2 4
A m e n d m e nt 2
2 4 M a y 2 0 2 3
A d diti o n al 
cl arifi c ati o n s, 
d efi niti o n s, a n d 
o ut p ut s r e q uir e d 
f oll o wi n g B D R

H e a d er: R e pl a c e d c o m p o u n d n u m b er wit h c o m p o u n d 
n a m e

2. 2. 1: f or E sti m a n d 1 b - cl arifi e d i nt er c urr e nt e v e nt

2. 3: A d d e d a d diti o n al d et ail s a b o ut st u d y d e si g n

3/ 3. 4. 1 0: Cl arifi c ati o n of b a s eli n e d efi niti o n

3: Cl arifi c ati o n of effi c a c y d at a i n cl u si o n f or P art A

3. 2. 1: C orr e cti o n of d efi niti o n of n o n -s e d e nt ar y 
p h y si c al a cti vit y ti m e

3. 2. 1: F urt h er cl arifi c ati o n of di git al w e e kl y a v er a g e 
c al c u l ati o n a n d c o m pli a n c e d efi niti o n

3. 2. 3: Cl arifi c ati o n of C R C S D w e e kl y a v er a g e 
c al c ul ati o n

3. 2. 4. 1/ 6. 2. 4. 1: D et ail s of Ti er 1 e v e nt s u p d at e d .  
R ef er e n c e t o S a m p s o n crit eri a a d d e d

3. 4. 1: U p d at e d “ C a d e n c e” t o “ A v er a g e C a d e n c e”

3. 4. 1 3: R e s p o n d er d efi niti o n a d d e d f or b o d y w ei g ht

3. 5: D efi niti o n s a d d e d f or b a s eli n e B MI -a dj u st e d 
w ei g ht l o s s c at e g or y, s ar c o p e ni a a n d i nfl a m m ati o n 
v ari a bl e s

5. 2: A d diti o n of ‘ P o n s e gr o m a b C o m bi n e d’ tr e at m e nt 
gr o u p

5. 2. 1: Q u artil e s a d d e d t o s u m m ari e s

5. 2. 4: Cl arifi c ati o n t h at B a y e si a n E m a x m o d el 
p ar a m et er s n ot i n cl u d e d i n C S R

5. 2. 8/ A p p e n di x 4: L o gi sti c r e gr e s si o n d et ail s a d d e d f or 
r e s p o n d er a n al y si s

5. 3. 1: M ulti pl e i m p ut ati o n d et ail s a d d e d f or r e s p o n d er 
a n al y si s

6. 1. 1. 2: A d diti o n al s u p pl e m e nt ar y a n al y s e s a d d e d f or 
b o d y w ei g ht

6. 2. 1/ 6. 4. 1 0: R e m o v e d b o x pl ot s f or all e n d p oi nt s

6. 2. 1: A d diti o n al s u m m ar y of a m o u nt of a v ail a bl e 
di git al d at a

5. 2/ 6. 4. 3/ 6. 4. 4/ 6. 6. 1: Cl arifi c ati o n t h at s e p ar at e P K 
s u b st u d y o ut p ut s m a y b e r e p ort e d i n s u p pl e m e nt al 
C S R

6. 4. 1 3: R e s p o n d er a n al y si s a d d e d f or b o d y w ei g ht

6. 6. 1: A d diti o n al e n d p oi nt s f or s u m m ar y at b a s eli n e 

6. 6. 5: Cl arifi c ati o n t h at C R P m a y b e i n cl u d e d i n C S R

8: A d diti o n al r ef er e n c e s

A p p e n di x 8: A b br e vi ati o n s u p d at e d
2
1 1 D e c 2 0 2 3
A m e n d m e nt 2
2 4 M a y 2 0 2 3
A d diti o n al P K/ P D 
s a m pl e s i n cl u d e d 
f or a s u b s et of 
p arti ci p a nt s ( P K 
s u b st u d y) i n 
r e s p o n s e t o 
r e g ul at or y 
r e q u e st
I nt eri m a n al y si s 
d et ail s a d d e d
A p pli e d n e w S A P t e m pl at e
G e n er al u p d at e s a n d cl arifi c ati o n
St u d y titl e u p d at e d
2. 2. 1/ 4: Cl arifi e d ‘i n a d e q u at e c o m pli a n c e’ d efi niti o n
2. 2. 2/ 3. 2. 3/ 6. 2. 3: c h a n g e d w or di n g of C R C S D 
e n d p oi nt s
3. 2. 1: D efi niti o n of “ c o m pli a nt d a y” a n d w e e kl y 
a v er a g e c al c ul ati o n s u p d at e d
3. 2. 4: I m m u n o g e ni c A E s a d d e d
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 8 of 6 0
3. 4. 3/ 3. 4. 4: Pr ot o c ol w or di n g u p d at e d
3. 4. 1 0: E x cl u si o n of r a di o - att e n u ati o n m e a s ur e m e nt s; 
a d d e d f or m ul a f or L S MI
3. 5: A d d e d d efi niti o n f or pr e vi o u s b o d y w ei g ht l o s s
4: A d d e d a d diti o n al w or di n g f or ‘ a ct u al’ d o s e
5. 1: A d diti o n al e n d p oi nt s li st e d f or t e sti n g
5. 2. 5: A N C O V A d et ail s a d d e d
6. 1. 1. 1: Cl arifi c ati o n of ti m e p oi nt s i n cl u d e d i n M M R M 
a n al y si s
6. 1. 1. 2: Cl arifi c ati o n t h at o nl y B a y e si a n a n al y si s i s 
b ei n g r e p e at e d f or s e n siti vit y a n al y si s
6. 2. 4: I n cl u si o n of p o n s e gr o m a b c o m bi n e d a n d 
o v er all tr e at m e nt gr o u p s; a d diti o n of I S R a n d 
i m m u n o g e ni c A E s u m m ari e s
6. 4. 5: C u m ul ati v e p er c e nt a g e of A D A/ N A b p o siti v e 
p arti ci p a nt s a d d e d; cl arifi c ati o n c h a n g e s m a d e
6. 4. 6/ 6. 4. 7/ 6. 4. 1 0: A d diti o n al pl ot s a n d a n al y si s 
i n cl u d e d
6. 5: A d diti o n al s u b s et a n al y si s a n d s c att er pl ot f or 
G D F -1 5 l e v el s
6. 6. 1: A d diti o n al b a s eli n e c a n c er d et ail s i n cl u d e d
7. 2: I nt eri m a n al y si s d et ail s a d d e d
8: R ef er e n c e s e cti o n a d d e d
A p p e n di x 4: I n cl u d e d A N C O V A c o d e
A p p e n di x 5: D et ail s of B a y e si a n E m a x m et h o d ol o g y 
u p d at e d
U p d at e s f or P K s u b st u d y
2. 2/ 3. 4. 3/ 3. 4. 4/ 6. 4. 3/ 6. 4. 4: P K/ P D e n d p oi nt s u p d at e d 
t o i n cl u de e xtr a ti m e p oi nt s
2. 3: P K s u b st u d y d e s cri pti o n a d d e d; Fi g ur e 1 
u p d at e d
3. 4. 3: Tr o u g h ti m e p oi nt s u p d at e d t o i n cl u d e P K 
s u b st u d y
5. 2 G e n er al n ot e o n r e p orti n g P K s u b st u d y a s p art of 
m ai n st u d y
6. 4. 3: P K e n d p oi nt s u p d at e d a n d a n al y si s f or P K 
s u b st u d y a d d e d
6 . 4. 4: P D e n d p oi nt s u p d at e d a n d G D F-1 5 a n al y si s 
f or P K s u b st u d y a d d e d
6. 6: B a s eli n e s u m m ari e s a d d e d f or P K s u b st u d y 
1
0 9 N o v 2 0 2 2
Ori gi n al 
1 7 J u n e 2 0 2 2
A m e n d m e nt 1
2 7 O ct 2 0 2 2
N/ A
N/ A
2. I N T R O D U C TI O N
T hi s st ati sti c al a n al y si s pl a n ( S A P) pr o vi d e s t h e d et ail e d m et h o d ol o g y f or s u m m ar y a n d 
st ati sti c al a n al y s e s of t h e d at a c oll e ct e d i n P art A of  St u d y C 3 6 5 1 0 0 3 (i n cl u di n g f oll o w-u p 
f or P art A if a p arti ci p a nt d o e s n ot c o nti n u e t o P art B of t h e st u d y). T hi s do c u m e nt m a y 
m o dif y t h e pl a n s o utli n e d i n t h e pr ot o c ol; h o w e v er, a n y m aj or m o difi c ati o n s of t h e pri m ar y 
e n d p oi nt d efi niti o n or it s a n al y si s will al s o b e r efl e ct e d i n a pr ot o c ol a m e n d m e nt. T h e 
m et h o d ol o g y f or s u m m ar y a n d st ati sti c al a n al y s e s of t h e d at a c oll e ct e d i n P art B of t h e 
st u d y will b e d et ail e d i n a s u p pl e m e nt al S A P.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 9 of 6 0
2. 1. M o difi c ati o n s
t o t h e A n al y si s Pl a n D e s cri b e d i n t h e Pr ot o c ol
N ot a p pli c a bl e.
2. 2. St u d y  O bj e cti v e s, E n d p oi nt s, a n d E sti m a n d s
T y p e
O bj e cti v e s
E n d p oi nt s
E sti m a n d s
Pri m ar y :
Pri m ar y: 
Pri m ar y:
Pri m ar y: 
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
wit h pl a c e b o o n b o d y 
w ei g ht i n p arti ci p a nt s 
wit h c a n c er, c a c h e xi a, 
a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m b a s eli n e 
b o d y w ei g ht at W e e k 
1 2.

E sti m a n d 1 ( si mil ar t o 
“ h y p ot h eti c al”) i s t h e 
diff er e n c e b et w e e n 
p o n s e gr o m a b a n d pl a c e b o 
i n m e a n c h a n g e fr o m 
b a s eli n e i n b o d y w ei g ht at 
W e e k
1 2, i n p arti ci p a nt s 
wit h c a n c er, c a c h e xi a a n d 
el e v at e d c o n c e ntr ati o n s of 
G D F -1 5, u n d er t h e 
s c e n ari o of n o 
di s c o nti n u ati o n of st u d y 
i nt er v enti o n a n d wit h o ut 
t h e p ot e nti al c o nf o u n di n g 
eff e ct of pr o hi bit e d 
pr o c e d ur e s, pr o hi bit e d 
m e di c ati o n s or 
p arti ci p a nt s’ 
n o n -c o m pli a n c e wit h 
d o si n g.
S e c o n d ar y :
S e c o n d ar y:
S e c o n d ar y:
S e c o n d ar y:
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n p h y si c al 
a cti vit y a n d g ait a s 
m e a s ur e d b y w e ar a bl e 
di git al s e n s or s i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of 
G D F -1 5.

C h a n g e fr o m b a s eli n e 
i n p h y si c al a cti vit y a n d 
g ait e n d p oi nt s 
m e a s ur e d wit h r e m ot e 
di git al s e n s or s a t 
W e e k 1 2: 

M o d er at e t o 
vi g or o u s p h y si c al 
a cti vit y ti m e;

S e d e nt ar y a cti vit y 
ti m e;

N o n -s e d e nt ar y 
p h y si c al a cti vit y 
ti m e

T ot al v e ct or 
m a g nit u d e

M e a n a cti vit y l e v el 
d uri n g M 6 mi n 
( m a xi m u m d ail y 6 
mi n ut e s of a cti vit y) ;

M e a n g ait s p e e d;

9 5 t h p er c e ntil e g ait 
s p e e d.

E sti m a n d 2 ( si mil ar t o 
“ h y p ot h eti c al”) i s t h e 
diff er e n c e b et w e e n 
p o n s e gr o m a b a n d pl a c e b o 
i n m e a n c h a n g e fr o m 
b a s eli n e i n e a c h of t h e 
p h y si c al a cti vit y a n d g ait 
e n d p oi nt s at W e e k 1 2, i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a a n d el e v at e d 
c o n c e ntr ati o n s of G D F -1 5, 
u n d er t h e s c e n ari o of n o 
di s c o nti n u ati o n of st u d y 
i nt er v e nti o n a n d wit h o ut 
t h e p ot e nti al c o nf o u n di n g 
eff e ct of pr o hi bit e d 
pr o c e d ur e s, pr o hi bit e d 
m e di c ati o n s or 
p arti ci p a nt s’ 
n o n -c o m pli a n c e wit h 
d o si n g.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n t h e 
a p p etit e -r el at e d 
s y m pt o m s a s m e a s ur e d 
b y F A A C T i n 
p arti ci p a nt s wit h c a n c er, 

C h a n g e fr o m b a s eli n e 
i n F A A C T s u b-s c al e 
s c or e s at W e e k 1 2:

F A A C T- A C S;

F A A C T- 5I A S S.

E sti m a n d 3 ( si mil ar t o 
“ h y p ot h eti c al”) i s t h e 
diff er e n c e b et w e e n 
p o n s e gr o m a b a n d pl a c e b o 
i n m e a n c h a n g e fr o m 
b a s eli n e i n e a c h F A A C T 
s u b s c al e s c or e at W e e k 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 0 of 6 0
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.
1 2 , i n p arti ci p a nt s wit h 
c a n c er, c a c h e xi a a n d 
el e v at e d c o n c e ntr ati o n s of 
G D F -1 5, u n d er t h e 
s c e n ari o of n o 
di s c o nti n u ati o n of st u d y 
i nt er v e nti o n a n d wit h o ut 
t h e p ot e nti al c o nf o u n di n g 
eff e ct of pr o hi bit e d 
pr o c e d ur e s, pr o hi bit e d 
m e di c ati o n s or 
p arti ci p a nt s’ 
n o n -c o m pli a n c e wit h 
d o si n g.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n 
a n or e xi a/ a p p etit e, 
n a u s e a, v o miti n g a n d 
f ati g u e m e a s ur e d b y t h e 
C R C S D, Pfi z er -
d e v el o p e d i n str u m e nt, i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m 
b a s eli n e s c or e f or 
t h e q u e sti o n s fr o m 
t h e C R C S D at 
W e e k
1 2 r el at e d t o:

A n or e xi a/ a p p etit e;

N a u s e a a n d 
v o miti n g;

F ati g u e.

E sti m a n d 4 ( si mil ar t o 
“ h y p ot h eti c al”) i s t h e 
diff er e n c e b et w e e n 
p o n s e gr o m a b a n d pl a c e b o 
i n m e a n c h a n g e fr o m 
b a s eli n e i n e a c h of t h e 
a n or e xi a/ a p p etit e, n a u s e a, 
v o miti n g a n d f ati g u e 
q u e sti o n s fr o m t h e 
C R C S D at W e e k 1 2, i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a a n d el e v at e d 
c o n c e ntr ati o n s of G D F -1 5, 
u n d er t h e s c e n ari o of n o 
di s c o nti n u ati o n of st u d y 
i nt er v e nti o n a n d wit h o ut 
t h e p ot e nti al c o nf o u n di n g 
eff e ct of pr o hi bit e d 
pr o c e d ur e s, pr o hi bit e d 
m e di c ati o n s or 
p arti ci p a nt s’ 
n o n -c o m pli a n c e wit h 
d o si n g.
S af et y

T o c h ar a ct eri z e t h e 
s af et y a n d t ol er a bilit y of 
r e p e at e d S C 
a d mi ni str ati o n s of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

I n ci d e n c e of a d v er s e 
e v e nt s, s af et y 
l a b or at or y t e st s, vit al 
si g n s a n d E C G 
a b n or m aliti e s. *

T h er e ar e n o d efi n e d 
e sti m a n d s f or t h e 
i n ci d e n c e of a d v er s e 
e v e nt s, s af et y l a b or at or y 
t e st s, vit al si g n s, a n d E C G 
a b n or m aliti e s, a n d t h e s e 
e n d p oi nt s will b e 
s u m m ari z e d u si n g Pfi z er 
d at a st a n d ar d s a s 
a p pli c a bl e.
T erti ar y /
E x pl or at or y :
T erti ar y/ E x pl or at or y:
T erti ar y/ E x p l or at or y:
T erti ar y/ E x pl or at or y:
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n p h y si c al 
a cti vit y a n d g ait a s 
m e a s ur e d b y w e ar a bl e 
di git al s e n s or s i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of 
G D F -1 5.

C h a n g e fr o m b a s eli n e 
i n a d diti o n al p h y si c al 
a cti vit y a n d g ait 
e n d p oi nt s m e a s ur e d 
wit h r e m ot e di git al 
s e n s or s at W e e k 1 2.

N ot A p pli c a bl e.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 1 of 6 0
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n H R Q o L a s 
m e a s ur e d b y F A A C T i n 
p arti ci p a nt s wit h c a n c er , 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m b a s eli n e 
i n a d diti o n al F A A C T 
t ot al a n d s u b-s c al e 
s c or e s at W e e k 1 2.

N ot A p pli c a bl e.
P h ar m a c o ki n eti c s

T o e v al u at e P K of 
p o n s e gr o m a b f oll o wi n g 
r e p e at e d S C 
a d mi ni str ati o n t o 
p arti ci p a nt s wit h c a n c er 
c a c h e xi a a n d el e v at e d 
c o n c e ntr ati o n s of 
G D F -1 5.

S er u m u n b o u n d a n d 
t ot al c o n c e ntr ati o n s of 
p o n s e gr o m a b o n D a y 
1, W e e k 4, 5, 8, 1 0 1 2, 
a n d 1 6, pl u s W e e k 9 
a n d 1 1 i n P K s u b st u d y 
o nl y.

N ot A p pli c a bl e.
Bi o m ar k er s

T o e v al u at e t h e eff e ct of 
r e p e at e d S C
a d mi ni str ati o n of 
p o n s e gr o m a b o n 
cir c ul ati n g G D F -1 5 
c o n c e ntr ati o n s i n 
p arti ci p a nt s wit h c a n c er 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

S er u m u n b o u n d a n d 
t ot al c o n c e ntr ati o n s of 
G D F -1 5 o n D a y 1, 
W e e k 4, 5, 8, 1 0, 1 2, 
a n d 1 6, pl u s W e e k 9 
a n d 1 1 i n P K s u b st u d y 
o nl y.

N ot A p pli c a bl e.
I m m u n o g e ni cit y

T o e v al u at e t h e 
i m m u n o g e ni cit y pr ofil e 
of p o n s e gr o m a b 
f oll o wi n g r e p e at e d S C 
a d mi ni str ati o n i n 
p arti ci p a nt s wit h c a n c er 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

I n ci d e n c e of A D A a n d 
N A b.

N ot A p pli c a bl e.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n P ati e nt-
R e p ort e d O ut c o m e s 
V er si o n 
P R O MI S -F ati g u e 
q u e sti o n n air e i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m b a s eli n e 
s c or e f or 
P R O MI S -F ati g u e at 
W e e k 1 2.

N ot A p pli c a bl e.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n P R O MI S 
P h y si c al F u n cti o n -S h ort 
F or m 8 c i n p arti ci p a nt s 
wit h c a n c er, c a c h e xi a, 
a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m b a s eli n e 
s c or e f or 
P R O MI S -P h y si c al 
F u n cti o n at W e e k 1 2.

N ot A p pli c a bl e.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n P GI- S a n d 

C h a n g e fr o m b a s eli n e 
P GI -S at w e e k 1 2;

P GI -C at W e e k 1 2.

N ot A p pli c a bl e.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 2 of 6 0
P GI -C (a p p etit e, f ati g u e, 
p h y si c al f u n cti o n, 
p h y si c al a cti vit y a n d 
w al ki n g) i n p arti ci p a nt s 
wit h c a n c er, c a c h e xi a, 
a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n t u m or 
b ur d e n a n d t u m or st at u s 
i n p arti ci p a nt s wit h 
c a n c er, c a c h e xi a, a n d 
el e v at e d c o n c e ntr ati o n s 
of G D F -1 5.

T u m or st at u s 
a c c or di n g t o R E CI S T 
1. 1 g ui d eli n e s u si n g 
C T s c a n at W e e k 1 2.

N ot A p pli c a bl e.
Effi c a c y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n b o d y 
c o m p o siti o n a s 
m e a s ur e d b y C T s c a n i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

C h a n g e fr o m b a s eli n e 
i n L S MI d eri v e d fr o m 
C T s c a n s at W e e k 1 2;

P er c e nt c h a n g e fr o m 
b a s eli n e i n s k el et al 
m u s cl e a n d a di p o s e 
ti s s u e m e a s ur e s 
d eri v e d fr o m C T s c a n s 
at W e e k 1 2.

N ot A p pli c a bl e
Bi o m ar k er s

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n al b u mi n 
a n d pr e -al b u mi n l e v el s 
i n p arti ci p a nt s wit h 
c a n c er, c a c h e xi a, a n d 
el e v at e d c o n c e ntr ati o n s 
of G D F -1 5.

C h a n g e fr o m b a s eli n e 
al b u mi n a n d pr e -
al b u mi n l e v el s at 
W e e k 1 2.

N ot A p pli c a bl e.
S af et y

T o e v al u at e t h e eff e ct of 
p o n s e gr o m a b c o m p ar e d 
t o pl a c e b o o n s ur vi v al i n 
p arti ci p a nt s wit h c a n c er, 
c a c h e xi a, a n d el e v at e d 
c o n c e ntr ati o n s of G D F -
1 5.

S ur vi v al st at u s at e n d 
of P art A. *

N ot A p pli c a bl e.
* S af et y, t ol er a bilit y a n d s ur vi v al will al s o b e c h ar a ct eri z e d i n P art B o n c e all a p pli c a bl e p arti ci p a nt s h a v e 
c o m pl et e d P art B of t h e st u d y. T h e s e d at a will b e r e p ort e d i n a s e p ar at e C S R.
2. 2. 1. Pri m ar y  E sti m a n d( s)
E sti m a n d s r el at e d t o t h e b o d y w ei g ht pri m ar y o bj e cti v e:
E sti m a n d 1 ( si mil ar t o “ h y p ot h eti c al”) i s i nt e n d e d t o pr o vi d e a p o p ul ati o n l e v el e sti m at e of 
t h e tr e at m e nt eff e ct o n t h e c h a n g e fr o m b a s eli n e i n b o d y w ei g ht f or p o n s e gr o m a b c o m p ar e d 
wit h pl a c e b o i n all e v al u a bl e p arti ci p a nt s u n d er t h e s c e n ari o o f n o di s c o nti n u ati o n of st u d y 
i nt er v e nti o n a n d wit h o ut t h e p ot e nti al c o nf o u n di n g eff e ct of pr o hi bit e d pr o c e d ur e s , pr o hi bit e d 
m e di c ati o n s
or p arti ci p a nt s’  n o n-c o m pli a n c e wit h d o si n g (i e, u si n g t h e C e n s or e d a n al y si s 
s et, a s d efi n e d i n S e cti o n 4 ).

P o p ul ati o n: P arti ci p a nt s wit h c a n c er, c a c h e xi a, a n d el e v at e d c o n c e ntr ati o n s of 
G D F- 1 5.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 3 of 6 0

E n d p oi nt: C h a n g e fr o m b a s eli n e i n b o d y w ei g ht at W e e k 1 2.

I nt er c urr e nt E v e nt s:
a.
Di s c o nti n u ati o n of st u d y i nt er v e nti o n: D at a c oll e ct e d aft er a p arti ci p a nt h a s 
di s c o nti n u e d st u d y i nt er v e nti o n will b e c e n s or e d a n d tr e at e d a s mi s si n g d at a.
b.
Pr o hi bit e d pr o c e d ur e s: D at a c oll e ct e d aft er a p arti ci p a nt h a s u n d er g o n e 
pr o hi bit e d pr o c e d ur e s, t h at w o ul d m o d ul at e t h e pri m ar y e n d p oi nt, will b e 
c e n s or e d a n d tr e at e d a s mi s si n g d at a. A n y pr o c e d ur e s will b e r e vi e w e d pri or t o 
d at a b a s e l o c k t o d et er mi n e w hi c h w o ul d b e cl a s s e d a s “ pr o hi bit e d”  f or t hi s 
e sti m a n d.
c.
Pr o hi bit e d m e di c ati o n s - D at a c oll e ct e d aft er a p arti ci p a nt h a s r e c ei v e d pr o hi bit e d 
m e di c ati o n s, t h at w o ul d m o d ul at e t h e pri m ar y e n d p oi nt, will b e c e n s or e d a n d 
tr e at e d a s mi s si n g d at a. T h e li st of c o n c o mit a nt m e di c ati o n s will b e r e vi e w e d 
pri or t o d at a b a s e l o c k t o d et er mi n e w hi c h w o ul d b e cl a s s e d a s “ pr o hi bit e d” f or 
t hi s e sti m a n d.
d.
I n a d e q u at e c o m pli a n c e: D at a c oll e ct e d aft er a p arti ci p a nt h a s mi s s e d a d o s e, or 
h a s r e c ei v e d a n i n c o m pl et e d o s e, will b e c e n s or e d a n d tr e at e d a s mi s si n g d at a.  
Mi s si n g d at a d u e t o c e n s ori n g, st u d y wit h dr a w al or ot h er r e a s o n s, ar e a s s u m e d 
t o b e mi s si n g at r a n d o m i n t h e a n al y si s.

P o p ul ati o n -l e v el s u m m ar y: Diff er e n c e i n m e a n c h a n g e fr o m b a s eli n e b o d y w ei g ht at 
W e e k 1 2 b et w e e n p o n s e gr o m a b a n d pl a c e b o.
E sti m a n d 1 b ( si mil ar t o “tr e at m e nt p oli c y”) i s i nt e n d e d t o pr o vi d e a p o p ul ati o n l e v el e sti m at e 
of  t h e tr e at m e nt eff e ct o n t h e c h a n g e fr o m b a s eli n e i n b o d y w ei g ht f or p o n s e gr o m a b 
c o m p ar e d wit h pl a c e b o i n all e v al u a bl e p arti ci p a nt s r e g ar dl e s s of di s c o nti n u ati o n of st u d y 
i nt er v e nti o n, d o si n g c o m pli a n c e, pr o hi bit e d pr o c e d ur e s or pr o hi bit e d m e di c ati o n s (i e, u si n g 
t h e C o m pl et e a n al y si s s et a s d efi n e d i n S e cti o n 4 ).

P o p ul ati o n: P arti ci p a nt s wit h c a n c er, c a c h e xi a, a n d el e v at e d c o n c e ntr ati o n s of 
G D F- 1 5.

E n d p oi nt: C h a n g e fr o m b a s eli n e i n b o d y w ei g ht at W e e k 1 2.

I nt er c urr e nt E v e nt s: T h er e ar e n o c h a n g e s m a d e b a s e d o n i nt er c urr e nt e v e nt s.  F or 
p arti ci p a nt s w h o di s c o nti n u e st u d y i nt er v e nti o n, r e c ei v e a pr o hi bit e d pr o c e d ur e, 
pr o hi bit e d m e di c ati o n a n d/ or mi s s a d o s e, or r e c ei v e a n i n c o m pl et e d o s e, all 
o b s er v ati o n s p o st -di s c o nti n u ati o n, p o st -pr o c e d ur e, p o st -m e di c ati o n or p o st -
mi s s e d/i n c o m pl et e d o s e will b e i n cl u d e d i n t h e a n al y si s s et.

P o p ul ati o n -l e v el s u m m ar y: Diff er e n c e i n m e a n c h a n g e fr o m b a s eli n e b o d y w ei g ht at 
W e e k 1 2 b et w e e n p o n s e gr o m a b a n d pl a c e b o.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 4 of 6 0
2. 2. 2. S e c o n d ar y  E sti m a n d( s)
E sti m a n d r el at e d t o t h e p h y si c al a cti vit y a n d g ait s e c o n d ar y o bj e cti v e:
E sti m a n d 2 will b e si mil ar t o E sti m a n d 1, e x c e pt f or t h e f oll o wi n g:

E n d p oi nt: C h a n g e fr o m b a s eli n e i n e a c h of t h e p h y si c al a cti vit y a n d g ait e n d p oi nt s at 
W e e k 1 2:
-
M o d er at e t o vi g or o u s p h y si c al a cti vit y ti m e;
-
S e d e nt ar y a cti vit y ti m e;
-
N o n s e d e nt ar y a cti vit y ti m e;
-
T ot al v e ct or m a g nit u d e;
-
M e a n a cti vit y l e v el d uri n g M 6 mi n
( m a xi m u m d ail y 6 mi n s of a cti vit y);
-
M e a n g ait s p e e d;
-
9 5 t h p er c e ntil e g ait s p e e d.

P o p ul ati o n -l e v el s u m m ar y: Diff er e n c e i n m e a n c h a n g e fr o m b a s eli n e f or t h e p h y si c al 
a cti vit y a n d g ait e n d p oi nt s at W e e k 1 2 b et w e e n p o n s e gr o m a b a n d pl a c e b o.
E sti m a n d r el at e d t o t h e a p p etit e -r el at e d s y m pt o m s a s m e a s ur e d b y F A A C T s e c o n d ar y 
o bj e cti v e:
E sti m a n d 3 will b e si mil ar t o E sti m a n d 1, e x c e pt f or t h e f oll o wi n g:

E n d p oi nt: C h a n g e fr o m b a s eli n e i n e a c h F A A C T s u b s c al e s c or e at W e e k 1 2:
-
F A A C T -A C S
-
F A A C T -5I A S S 

P o p ul ati o n -l e v el s u m m ar y: Diff er e n c e i n m e a n c h a n g e fr o m b a s eli n e f or t h e F A A C T 
s u b s c al e s c or e s at W e e k 1 2 b et w e e n p o n s e gr o m a b a n d pl a c e b o.
E sti m a n d r el at e d t o t h e a n or e xi a/ a p p etit e, n a u s e a, v o miti n g a n d f ati g u e m e a s ur e d b y
t h e C R C S D s e c o n d a r y o bj e cti v e:
E sti m a n d 4 will b e si mil ar t o E sti m a n d 1, e x c e pt f or t h e f oll o wi n g:

E n d p oi nt: C h a n g e fr o m b a s eli n e s c or e f or e a c h of t h e q u e sti o n s fr o m t h e C R C S D at 
W e e k 1 2:
-
A n or e xi a/ a p p etit e;
-
N a u s e a ;
-
V o miti n g;
-
F ati g u e. 

P o p ul ati o n -l e v el s u m m ar y: Diff er e n c e i n m e a n c h a n g e fr o m b a s eli n e i n e a c h of t h e 
q u e sti o n s fr o m t h e C R C S D at W e e k 1 2 b et w e e n p o n s e gr o m a b a n d pl a c e b o.
E sti m a n d s r el at e d t o t h e s af et y a n d t ol er a bilit y s e c o n d ar y o bj e cti v e:
T h er e ar e n o d efi n e d e sti m a n d s f or t h e i n ci d e n c e of a d v er s e e v e nt s, s af et y l a b or at or y t e st s, 
vit al si g n s a n d E C G a b n or m aliti e s, a n d t h e s e e n d p oi nt s will b e s u m m ari z e d u si n g Pfi z er 
d at a st a n d ar d s a s a p pli c a bl e.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 5 of 6 0
2. 3. St u d y  D e si g n
T hi s i s a P h a s e 2, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d st u d y of t h e effi c a c y, s af et y, 
a n d t o l er a bilit y of t hr e e diff er e nt d o s e s of p o n s e gr o m a b c o m p ar e d t o m at c hi n g pl a c e b o i n 
p ati e nt s wit h N S C L C, C R C, or P A N C, r e c ei vi n g st a n d ar d of c ar e ( w hi c h m a y i n cl u d e 
s y st e mi c t h er a p y), w h o h a v e el e v at e d l e v el s of G D F -1 5 a n d c a c h e xi a. T h e d o u bl e -bli n d 
p eri o d i s f oll o w e d b y a n o pti o n al o p e n-l a b el e xt e n si o n p eri o d.
F oll o wi n g t h e S cr e e ni n g p eri o d t o c o nfir m eli gi bilit y, a p pr o xi m at el y 1 6 8 st u d y p arti ci p a nt s, 
w h o m e et t h e e ntr y crit eri a, will b e r a n d o mi z e d t o st u d y i nt er v e nti o n ( o n e of 3 d o s e gr o u p s 
of p o n s e gr o m a b or m at c hi n g pl a c e b o) a n d will b e str atifi e d b y tr e at m e nt wit h or wit h o ut 
pl ati n u m -b a s e d c h e m ot h er a p y, w hi c h i s k n o w n t o i n d u c e G D F -1 5 a n d t h er ef or e m a y i m p a ct 
t h e r e s p o n s e t o p o n s e gr o m a b tr e at m e nt. T h e 1 2-w e e k d o u bl e -bli n d d o si n g p eri o d ( P art A) 
will c o n si st of a t ot al of 3 d o s e s a d mi ni st er e d Q 4 W S C.
A P K s u b st u d y will b e c o n d u ct e d i n a p pr o xi m at el y 3 6 of t h e a p pr o xi m at el y 1 6 8 p arti ci p a nt s 
( a p pr o xi m at el y 9 i n e a c h tr e at m e nt gr o u p i n P art A). U p t o 3 a d diti o n al P K a n d P D s a m pl e s 
(t w o s a m pl e s d uri n g P art A a n d o n e s a m pl e d uri n g P art B, if r el e v a nt), will b e c oll e ct e d i n 
t h e s e p arti ci p a nt s. 
O n c o m pl eti o n of P art A, p arti ci p a nt s will h a v e t h e o p p ort u nit y t o e nt er a n o pti o n al O L T 
p eri o d ( P art B) c o n si sti n g of p o n s e gr o m a b 4 0 0 m g Q 4 W S C f or u p t o 1 y e ar. T h e 
i n v e sti g at or a n d p arti ci p a nt m u st d e ci d e at t h e W e e k 8 vi sit if t h e y wi s h t o c o nti n u e t o t h e 
o pti o n al O L T p eri o d. P arti ci p a nt s w h o d o n ot pr o c e e d wit h t h e o pti o n al O L T p eri o d ar e t o 
c o m pl et e t h e W e e k 1 2 vi sit a n d a f oll o w -u p vi sit at W e e k 1 6.
Fi g ur e 1 l a y s o ut t h e str u ct ur e of t h e st u d y, i n cl u di n g f oll o w-u p, f or all p arti ci p a nt s d e p e n di n g 
o n w h et h er t h e y e nt er t h e o pti o n al O L T p eri o d. 
Fi g ur e 1. St u d y D e si g n
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 6 of 6 0
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D C O N V E N TI O N S
F or all s af et y e n d p oi nt s, u nl e s s ot h er wi s e st at e d, b a s eli n e i s d efi n e d a s t h e l a st -pr e -d o s e 
m e a s ur e m e nt. F or all effi c a c y e n d p oi nt s, u nl e s s ot h er wi s e st at e d, b a s eli n e
i s d efi n e d a s t h e 
l a st m e a s ur e m e nt pri or t o, or o n, st u d y d a y 1.
F or t h o s e p arti ci p a nt s c o nti n ui n g i nt o P art B of t h e st u d y, s af et y d at a c oll e ct e d pri or t o 
d o si n g at W e e k 1 2 will b e i n cl u d e d i n t h e s u m m ar y a n d st ati sti c al a n al y s e s of P art A of t h e 
st u d y. H o w e v er, effi c a c y d at a c oll e ct e d u p t o a n d i n cl u di n g W e e k  1 2 will b e i n cl u d e d, 
r e g ar dl e s s of w h et h er it i s pr e- or p o st -d o s e at W e e k 1 2.
3. 1. Pri m ar y  E n d p oi nt( s)
3. 1. 1. C h a n g e fr o m b a s eli n e b o d y  wei g ht at W e e k 1 2
B o d y w ei g ht will b e m e a s ur e d i n d u pli c at e. W ei g ht will b e r e c or d e d u si n g a c ali br at e d s c al e 
( wit h t h e s a m e s c al e u s e d if p o s si bl e f or t h e d ur ati o n of t h e st u d y) r e p orti n g w ei g ht i n k g, 
a n d a c c ur a c y t o t h e n e ar e st 0. 1 k g.  T h e a v er a g e of t h e d u pli c at e b o d y w ei g ht s c oll e ct e d at 
e a c h a s s e s s m e nt ti m e will b e c al c ul at e d. If o n e of t h e t w o d u pli c at e s i s mi s si n g, t h e n o n -
mi s si n g v al u e will b e u s e d f or t h e a v er a g e, a n d mi s si n g v al u e s will n ot b e i m p ut e d.
B a s eli n e i s d efi n e d a s t h e a v er a g e of t h e d u pli c at e m e a s ur e m e nt s at t h e l a st pr e -d o s e 
m e a s ur e m e nt ti m e. C h a n g e fr o m b a s eli n e a n d p er c e nt c h a n g e fr o m b a s eli n e i n b o d y w ei g ht 
will b e c al c ul at e d f or all p o st -b a s eli n e a v er a g e s.
3. 2. S e c o n d ar y  E n d p oi nt( s)
3. 2. 1. C h a n g e fr o m b a s eli n e i n p h y si c al a cti vit y  a n d g ait e n d p oi nt s m e a s ur e d wit h 
r e m ot e di git al s e n s or s at W e e k 1 2
M o d er at e t o vi g or o u s p h y si c al a cti vit y ti m e ( M V P A; mi n s/ d a y)

S e d e nt ar y a cti vit y ti m e ( mi n s/ d a y)

N o n -s e d e nt ar y p h y si c al a cti vit y ti m e ( mi n s/ d a y)

T ot al v e ct or m a g nit u d e ( v e ct or m a g nit u d e of t h e a cti vit y c o u nt s X, Y, Z; a u/ d a y)

M e a n a cti vit y l e v el d uri n g m a xi m u m d ail y 6 mi n ut e s of a cti vit y ( M 6 mi n s; a u/ d a y)

M e a n g ait s p e e d ( m/ s)

9 5 t h p er c e ntil e g ait s p e e d ( m/ s)
N ot e: a u = ar bitr ar y u nit s
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 7 of 6 0
M o nit ori n g of p h y si c al a cti vit y a n d g ait vi a a c c el er o m etr y ( w e ar a bl e di git al s e n s or s) will b e 
c o n d u ct e d i n p arti ci p a nt s. P arti ci p a nt s wi ll b e a s k e d t o w e ar t h e s e n s or o n t h e wri st 
c o nti n u o u sl y, a n d t h e s e n s or o n t h e l u m b ar r e gi o n o nl y d uri n g t h e d a y d uri n g t h e m o nit ori n g 
p eri o d s . T h e di git al s e n s or s will b e w or n c o nti n u o u sl y f or o n e w e e k d uri n g S cr e e ni n g a n d 
W e e k 8; a n d will b e w or n c o nti n u o u sl y f or t w o w e e k s b et w e e n W e e k 1 0 a n d W e e k 1 2.
R a w d at a fr o m b ot h d e vi c e s will b e c oll e ct e d d ail y. W e e k l y a v er a g e s ( o n D a y 1 a n d at 
W e e k s 8, 1 0 a n d 1 2) will b e c al c ul at e d a s t h e m e a n t a k e n o v er 8 d a y s f or e a c h vi sit:  

D a y 1 ( s cr e e ni n g): 
o
If t h e P GI-S/ C d at e f all s wit hi n t h e s cr e e ni n g d e vi c e e x p o s ur e p eri o d: St arti n g o n t h e 
P GI -S/ C d at e, or fir st n o n -z er o w e ar d a y pri or t o t h e P GI -S/ C d at e, a n d e n di n g -7 
d a y s pri or, or o n t h e d e vi c e e x p o s ur e st art d at e, w hi c h e v er i s s o o n er.
o
If t h e P GI-S/ C d at e d o e s n ot f all wit hi n t h e s cr e e ni n g d e vi c e e x p o s ur e p eri o d: 

St arti n g o n t h e fir st n o n -z er o w e ar d a y pri or t o t h e P GI-S/ C d at e, wit hi n t h e 
s cr e e ni n g d e vi c e e x p o s ur e p eri o d, a n d e n di n g -7 d a y s pri or, or o n t h e d e vi c e 
e x p o s ur e st art d at e, w hi c h e v er i s s o o n er. 

If n o d ay s ar e a v ail a bl e: St arti n g o n t h e fir st n o n -z er o w e ar d a y aft er t h e P GI-S/ C 
d at e, wit hi n t h e s cr e e ni n g d e vi c e e x p o s ur e p eri o d, a n d e n di n g + 7 d a y s l at er, or 
o n t h e d e vi c e e x p o s ur e e n d d at e or D a y -1, w hi c h e v er i s s o o n er.
o
If t h e P GI-S/ C d at e i s n ot r e p ort e d: St arti n g o n t h e fir st n o n -z er o w e ar d a y cl o s e st t o 
t h e d e vi c e e x p o s ur e e n d d at e, or o n D a y -1, w hi c h e v er i s s o o n er, a n d e n di n g -7 d a y s 
pri or, or o n t h e d e vi c e e x p o s ur e st art d at e, w hi c h e v er i s s o o n er.

W e e k 8: St arti n g o n t h e W e e k 8 vi sit d a y a n d e n di n g + 7 d a y s l at er or o n t h e d a y b ef or e 
t h e n e xt vi sit d a y, w hi c h e v er i s s o o n er ( e. g. if t h e We e k 8 vi sit d at e i s D a y 5 7, t h e W e e k  
8 a v er a g e will b e t a k e n o v er D a y s 5 7 t o 6 4; h o w e v er, if t h e W e e k 1 0 vi sit o c c ur s o n D a y 
6 4, t h e W e e k  8 a v er a g e will b e t a k e n o v er D ay s 5 7 t o 6 3 o nl y)

W e e k 1 0: St arti n g o n t h e W e e k 1 0 vi sit d a y a n d e n di n g + 7 d a y s l at er or o n t h e d a y 
b ef or e t h e st art d a y f or t h e W e e k 1 2 a v er a g e ( e. g. if t h e W e e k 1 0 vi sit d a y i s D a y 7 1, t h e 
W e e k 1 0 a v er a g e will b e t a k e n o v er D a y s 7 1 t o 7 8; h o w e v er, if t h e W e e k 1 2 st art d at e i s 
D a y 7 7, t h e W e e k 1 0 a v er a g e will b e t a k e n o v er D a y s 7 1 t o 7 6 o nl y)

W e e k 1 2: St arti n g o n t h e W e e k 1 2 vi sit d a y -8 d a y s, a n d e n di n g o n t h e d a y b ef or e t h e 
W e e k 1 2 vi sit d a y ( e. g. if t h e W e e k 1 2 vi sit o c c ur s o n D a y 8 5, t h e W e e k 1 2 a v er a g e will 
b e t a k e n o v er D a y s 7 7 t o 8 4).
If f e w er t h a n 3 d a y s of d at a ar e r e c or d e d o n t h e l u m b ar d e vi c e, t h e a v er a g e s h o ul d b e 
tr e at e d a s mi s si n g.  If f e w er t h a n 3 c o m pli a nt d a y s of d at a ar e r e c or d e d o n t h e wri st d e vi c e, 
t h e a v er a g e s h o ul d b e tr e at e d a s mi s si ng ( a d a y i s d efi n e d a s c o m pli a nt if at l e a st 7 h o ur s of 
a w a k e w e ar or 1 8 h o ur s of t ot al w e ar ti m e ar e pr e s e nt) .
B a s eli n e i s d efi n e d a s t h e m e a n t a k e n o v er t h e 8 d a y s of w e ar d uri n g s cr e e ni n g, i. e. D a y 1 
w e e kl y a v er a g e ( a s d e s cri b e d a b o v e).  C h a n g e fr o m b a s eli n e will b e c al c ul at e d f or all p o st -
b a s eli n e w e e kl y a v er a g e s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 8 of 6 0
3. 2. 2. C h a n g e fr o m b a s eli n e i n F A A C T s u b -s c al e s c or e s at W e e k -1 2

F A A C T -A C S

F A A C T -5I A S S
T h e F A A C T c o m bi n e s t h e F A C T -G c or e i n str u m e nt a n d A C S. F A C T -G i s a s u m m at e d s c or e 
of 2 7 it e m s p ert ai ni n g t o p h y si c al w ell -b ei n g ( 7 it e m s), e m oti o n al w ell-b ei n g ( 6 it e m s), 
f u n cti o n al w ell-b ei n g ( 7 it e m s), a n d s o ci al w ell b ei n g ( 7 it e m s) i n t h e p a st 7 d a y s. E a c h of 
t h e it e m s u s e s a 5-p oi nt ( 0 t o 4) s c al e. A C S i s a 1 2 it e m s u m m at e d s c al e c o nt ai ni n g it e m s 
s p e cifi c t o p ati e nt s’  p er c e pti o n s of a p p etit e a n d w ei g ht, al s o u si n g t h e 5 p oi nt s c al e. A d di n g 
t h e 1 2 A C S it e m s t o t h e F A C T-G pr o d u c e s t h e 3 9 it e m F A A C T. Hi g h er s c or e s ar e 
a s s o ci at e d wit h a hi g h er h e alt h -r el at e d q u alit y of lif e. 
S e e A p p e n di x 1 f or F A A C T s c ori n g g ui d eli n e s s h o wi n g t h e c al c ul ati o n of F A A C T s u b s c al e s 
a n d t ot al s c or e s (i n cl u di n g F A A C T -A C S a n d -5I A S S). 
C h a n g e fr o m b a s eli n e will b e c al c ul at e d at all p o st -b a s eli n e ti m e p oi nt s.
3. 2. 3. C h a n g e fr o m b a s eli n e s c or e f or t h e q u e sti o n s fr o m t h e C a n c er R el at e d 
C a c h e xi a S y m pt o m Di ar y  ( C R C S D) at W e e k 1 2 r el at e d t o:

A n or e xi a/ a p p etit e

N a u s e a;

V o miti n g;

F ati g u e
T h e C R C S D i s a d ail y ( e v e ni n g), s elf-r e p orte d q u e sti o n n air e t h at m e a s ur e s s e v erit y of 
s y m pt o m s r el at e d t o c a n c er c a c h e xi a: a p p etit e, n a u s e a, v o miti n g, a n d f ati g u e. T h e m e a s ur e 
c o n si st s of 4 q u e sti o n s t h at a s k st u d y p arti ci p a nt s t o r at e t h e s e v erit y of t h eir s y m pt o m s o v er 
t h e p a st 2 4 h o ur s o n a n 1 1 p oi nt N R S , a p art fr o m V o miti n g w hi c h i s m e a s ur e d o n a 
n u m eri c al v al u e fr o m 0 t o 3 0. 
W e e k l y a v er a g e s ( o n D a y 1 a n d at We e k s 4, 8 a n d 1 2) will e a c h b e c al c ul at e d a s t h e m e a n 
t a k e n o v er t h e 7 d a y s i m m e di at el y pri or ( e. g. if t h e We e k 4 vi sit o c c ur s o n D a y 2 9, t h e We e k 
4 a v er a g e will b e t a k e n o v er D a y s 2 2 t o 2 8;  if t h e W e e k 8 vi sit o c c ur s o n D a y 5 7, t h e W e e k 
8 a v er a g e will b e t a k e n o v er D a y s 5 0 t o 5 6; a n d if t h e W e e k  1 2 vi sit o c c ur s o n D a y 8 5, t h e 
W e e k 1 2 a v er a g e will b e t a k e n o v er D a y s 7 8 t o 8 4) . If f e w er t h an 4 d a y s of s c or e s ar e 
r e c or d e d, t h e m e a n s h o ul d b e tr e at e d a s mi s si n g.
B a s eli n e i s d efi n e d a s t h e m e a n t a k e n o v er t h e 7 d a y s pri or t o D a y 1 ( e. g. D a y s -7 t o -1).  
C h a n g e fr o m b a s eli n e will b e c al c ul at e d f or all p o st -b a s eli n e w e e kl y a v er a g e s.
3. 2. 4. I n ci d e n c e of a d v er s e e v e nt s, s af et y l a b or at or y t e st s, vit al si g n s a n d E C G 
a b n or m aliti e s
3. 2. 4. 1. A d v er s e E v e nt s
A n a d v er s e e v e nt ( A E) i s c o n si d er e d a Tr e at m e nt E m er g e nt A d v er s e E v e nt ( T E A E), r el ati v e 
t o a gi v e n tr e at m e nt, if t h e e v e nt st art s d uri n g t h e eff e cti v e d ur ati o n of tre at m e nt, i. e. st arti n g 
o n, or aft er, t h e d at e a n d ti m e of t h e fir st d o s e, b ut b ef or e t h e e n d of P art A (i. e. W e e k  1 2 f or 
p arti ci p a nt s c o nti n ui n g t o P art B; or f oll o w -u p c o nt a ct [ 2 8 -3 5 d a y s aft er l a st d o s e], f or t h o s e 
p arti ci p a nt s n ot c o nti n ui n g t o P art B o f t h e st u d y). 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 1 9 of 6 0
A Tr e at m e nt -E m er g e nt S eri o u s A d v er s e E v e nt ( T E S A E) i s a T E A E w hi c h al s o m e et s t h e 
d ef i niti o n of a S eri o u s A d v er s e E v e nt ( S A E)
A 3 -ti er a p pr o a c h will b e u s e d t o s u m m ari z e T E A E s. U n d er t hi s a p pr o a c h, T E A E s ar e 
cl a s sifi e d i nt o 1 of 3 ti er s: -
Ti er 1 e v e nt s: T h e s e ar e pr e s p e cifi e d e v e nt s of cli ni c al i m p ort a n c e a n d ar e 
m ai nt ai n e d i n a li st i n t h e pr o d u ct’ s S af et y R e vi e w Pl a n ( or si mil ar, e. g. S af et y 
S ur v eill a n c e R e vi e w Pl a n). A p p e n di x 2
Ti er 2 e v e nt s: T h e s e ar e e v e nt s t h at ar e n ot ti er 1 b ut ar e “ c o m m o n.” A M e di c al 
Di cti o n ar y f or R e g ul at or y A cti viti e s ( M e d D R A) pr ef err e d t er m ( P T) i s d efi n e d a s a 
Ti er 2 e v e nt if t h er e ar e at l e a st 5 % of p arti ci p a nt s r e p orti n g t h e e v e nt i n a n y 
tr e at m e nt gr o u p.
Ti er 3 e v e nt s: T h e s e ar e e v e nt s t h at ar e n eit h er Ti er 1 n or Ti er 2 e v e nt s.
P ot e nti al i m m u n o g e ni c A E s will b e m e di c all y e v al u at e d a n d c at e g ori z e d a s p er g ui d a n c e s 
a s: 1) H y p er s e n siti vit y, 2) A n a p h yl a xi s, 3) A n gi o e d e m a, 4) D el a y e d I -A E r e s p o n s e a n d / or 
5) C yt o ki n e R el e a s e s y n dr o m e. S e e A p p e n di x 2 f or S a m p s o n Crit eri a.
3. 2. 4. 2. L a b or at or y  Dat a
S af et y l a b or at or y t e st s ( h e m at ol o g y, c h e mi str y, a n d ot h er cli ni c al l a b or at or y t e st s) will b e 
p erf or m e d a s d e s cri b e d i n t h e pr ot o c ol.
T o d et er mi n e if t h er e ar e a n y cli ni c all y si g nifi c a nt l a b or at or y a b n or m aliti e s, t h e s af et y 
l a b or at or y t e st s will b e a s s e s s e d a g ai n st t h e crit eri a s pe cifi e d i n t h e s p o n s or r e p orti n g 
st a n d ar d s. T h e a s s e s s m e nt will t a k e i nt o a c c o u nt w h et h er e a c h p arti ci p a nt’ s b a s eli n e t e st 
r e s ult i s wit hi n or o ut si d e t h e l a b or at or y r ef er e n c e r a n g e f or t h e p arti c ul ar l a b or at or y 
p ar a m et er.
3. 2. 4. 3. Vit al Si g n s
A si n gl e m e a s ur e m e nt of p ul s e r at e a n d s u pi n e s y st oli c a n d di a st oli c bl o o d pr e s s ur e ( B P) 
will b e t a k e n at t h e ti m e s s p e cifi e d i n t h e pr ot o c ol .
C h a n g e fr o m b a s eli n e will b e c al c ul at e d f or all p o st -b a s eli n e ti m e p oi nt s.
3. 2. 4. 4.
El e ctr o c ar di o gr a m s ( E C G s)
A si n gl e st a n d ar d 1 2 -l e a d E C G wil l b e c oll e ct e d at ti m e s s p e cifi e d i n t h e pr ot o c ol .
C h a n g e fr o m b a s eli n e f or E C G s ( h e art r at e, Q T, Q T c F, P R a n d Q R S i nt er v al) will b e 
c al c ul at e d f or all p o st -b a s eli n e ti m e p oi nt s.
3. 3. Ot h er S af et y  E n d p oi nt( s)
S e e S e cti o n 3. 2. 4 .
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 0 of 6 0
3. 4. Ot h er E n d p oi nt s / E x pl or at or y  E n d p oi nt s
3. 4. 1. C h a n g e fr o m b a s eli n e i n a d diti o n al p h y si c al a cti vit y  a n d g ait e n d p oi nt s 
m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k 1 2
S e e S e cti o n 3. 2. 1 .
T h e a d diti o n al p h y si c al a cti vit y a n d g ait e n d p oi nt s ar e:
Fr o m t h e wri st d e vi c e:

Li g ht, M o d er at e, Vi g or o u s A cti vit y Ti m e ( mi n s/ d a y)

N u m b er of St e p s p er D a y ( st e p s/ d a y)

Sl e e p Ti m e ( mi n s/ d a y)

C al ori e s ( c al)

M a x 1 5/ 6 0 mi n s of a cti vit y l e v el ( M 1 5 mi n s, M 6 0 mi n s; a u/ d a y)

A v er a g e a cti vit y c o u nt s f or t h e m o st a cti v e 1 0 h o ur s of t h e d a y ( M 1 0 hr; a u/ d a y)

A v er a g e a cti vit y c o u nt s f or t h e l e a st a cti v e 5 h o ur s of t h e d a y ( L 5 hr; a u/ d a y)
Fr o m t h e l u m b ar d e vi c e:

Stri d e D ur ati o n ( s)

D o u bl e S u p p ort D ur ati o n ( s)

Si n gl e Li m b S u p p ort D ur ati o n ( s)

St a n c e D ur ati o n ( s)

S wi n g D ur ati o n ( s)

Stri d e L e n gt h s ( m)

N u m b er of St e p s ( A v er a g e C a d e n c e) ( st e p s/ mi n)

T ot al N u m b er of St e p s p er D a y ( st e p s/ d a y)
3. 4. 2. C h a n g e fr o m b a s eli n e i n a d diti o n al F A A C T t ot al a n d s u b -s c al e s c or e s at W e e k 
1 2
S e e S e cti o n 3. 2. 2 .
T h e a d diti o n al F A A C T t ot al a n d s u b -s c al e s c or e s ar e:

P h y si c al W ell -b ei n g ( P W B) 

S o ci al/ F a mil y W ell -b ei n g ( S W B )

E m oti o n al W ell -b ei n g ( E W B)

F u n cti o n al W ell -b ei n g ( F W B)

F A C T -G T ot al s c or e 

F A A C T T ot al s c or e
3. 4. 3. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of p o n s e gr o m a b o n D a y  1, W e e k s 4, 5, 
8, 1 0, 1 2, a n d 1 6 (f oll o w- u p) , pl u s W e e k 9 a n d 1 1 i n P K s u b st u d y o nl y
Bl o o d s a m pl e s will b e c oll e ct e d f or m e a s ur e m e nt of s er u m u n b o u n d a n d t ot al 
c o n c e ntr ati o n s of p o n s e gr o m a b a s s p e cifi e d i n t h e pr ot o c ol . T h e P K s a m pl e c oll e cti o n at t h e 
W e e k 5 vi sit i s c o n si d er e d a n o pti o n al s a m pl e a n d it will n ot b e c o n si d er e d a pr ot o c ol 
d e vi ati o n if t h e p arti ci p a nt i s u n a bl e t o m a k e t hi s vi sit.  I n a d diti o n, if a p arti ci p a nt h a s a n 
u n pl a n n e d sit e vi sit f or a n y r e a s o n, ( c h e m ot h er a p y, r a di ol o g y, ot h er d o ct or a p p oi nt m e nt s, 
et c.), a P K s a m pl e m a y b e c oll e ct e d, if f e a si bl e.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 1 of 6 0
Tr o u g h c o n c e ntr ati o n s ( C tr o u g h) ar e d efi n e d a s t h e s a m pl e s m e a s ur e d pr e-d o s e at W e e k s 4, 
8, a n d 1 2.
3. 4. 4. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of G D F -1 5 o n D a y  1, W e e k s 4, 5, 8, 1 0, 
1 2, a n d 1 6 (f oll o w- u p) , pl u s W e e k 9 a n d 1 1 i n P K s u b st u d y o nl y
Bl o o d s a m pl e s will b e c oll e ct e d f or m e a s ur e m e nt of s er u m c o n c e ntr ati o n s of t ot al a n d 
u n b o u n d G D F- 1 5 at ti m e p oi nt s s p e cifi e d i n t h e pr ot o c ol. T h e G D F -1 5 s a m pl e c oll e cti o n at 
t h e W e e k 5 vi sit i s c o n si d er e d a n o pti o n al s a m pl e.  It will n ot b e c o n si d er e d a pr ot o c ol 
d e vi ati o n if t h e p arti ci p a nt i s u n a bl e t o m a k e t hi s vi sit. I n a d diti o n, if a p arti ci p a nt h a s a n 
u n pl a n n e d sit e vi sit f or a n y r e a s o n, ( c h e m ot h er a p y, r a di ol o g y, ot h er d o ct or a p p oi nt m e nt s, 
et c.), a G D F -1 5 s a m pl e m a y b e c oll e ct e d, if f e a si bl e.
C h a n g e fr o m b a s eli n e a n d f ol d c h a n g e fr o m b a s eli n e (i. e. p o st -d o s e / b a s eli n e), f or t ot al a n d 
u n b o u n d G D F -1 5, will b e c al c ul at e d f or all p o st -b a s eli n e ti m e p oi nt s.  
A d diti o n all y, t h e u n b o u n d G D F -1 5 will b e c o m p ar e d t o t h e m e di a n h e alt h y v ol u nt e er l e v el, at 
all ti m e p oi nt s, t o cr e at e a n e n d p oi nt wit h t w o l e v el s (‘ Y e s’ a n d ‘ N o’) i n di c ati n g w h et h er t h e 
c o n c e ntr ati o n i s b el o w t h e e sti m at e d h e alt h y v ol u nt e er m e di a n l e v el ( < 0. 3 n g/ m L) or n ot ( ≥ 
0. 3 n g/ m L) .
3. 4. 5. I n ci d e n c e of AD A  a n d N Ab
Bl o o d s a m pl e s will b e c oll e ct e d f or d et er mi n ati o n of A D A a n d N A b a s s p e cifi e d i n t h e 
pr ot o c ol. S e e A p p e n di x 7 f or i m m u n o g e ni cit y t er m s a n d d efi niti o n s.
3. 4. 6. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -F ati g u e at W e e k 1 2
T h e P R O MI S F ati g u e 7 a i s a s elf -r e p ort e d m e a s ur e t h at a s s e s s e s a r a n g e of s y m pt o m s i n 
t h e p ast 7 d a y s fr o m mil d s u bj e cti v e f e eli n g s of tir e d n e s s t o a n o v er w h el mi n g, d e bilit ati n g, 
a n d s u st ai n e d s e n s e of e x h a u sti o n t h at li k el y d e cr e a s e s o n e’ s a bilit y t o e x e c ut e d ail y 
a cti viti e s a n d f u n cti o n n or m all y i n f a mil y or s o ci al r ol e s.
T h e s h ort f or m 7 A c o n s i st s of 7 it e m s t h at st u d y p arti ci p a nt s will r at e fr o m 1 t o 5 . A gl o b al 
r a w s c or e r a n gi n g fr o m 7 t o 3 5 i s c al c ul at e d a n d c a n b e tr a n sl at e d i nt o a T s c or e ( M e a n = 
5 0, st a n d ar d d e vi ati o n ( S D) = 1 0) u si n g t h e F ati g u e 7 a S h ort F or m s c or e c o n v er si o n t a bl e, 
pr o v i d e d i n A p p e n di x 3 .
C h a n g e fr o m b a s eli n e f or P R O MI S -F ati g u e T -s c or e will b e c al c ul at e d f or all p o st b a s eli n e 
ti m e p oi nt s.
3. 4. 7. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S-P h y si c al F u n cti o n at W e e k 1 2
T h e P R O MI S P h y si c al F u n cti o n s h ort f or m 8 C i s a s elf -r e p ort e d 8 it e m m e a s ur e t h at 
a s s e s s e s c a p a bilit y r at h er t h a n a ct u al p erf or m a n c e of p h y si c al a cti viti e s. It i n cl u d e s t h e 
f u n cti o ni n g of o n e’ s u p p er e xtr e miti e s ( d e xt erit y) a n d l o w er e xtr e miti e s ( w al ki n g a n d 
m o bilit y), a s w ell a s i n str u m e nt al a cti viti e s of d ail y li vi n g.
A si n gl e P h y si c al F u n cti o n c a p a bilit y s c or e i s o bt ai n e d fr o m a s h ort f or m. A gl o b al r a w s c or e 
r a n gi n g fr o m 8 t o 4 0 i s c al c ul at e d a n d c a n b e tr a n sl at e d i nt o a T s c or e ( M e a n = 5 0, S D = 1 0) 
u si n g t h e P h y si c al F u n cti o n S h ort F or m 8 c s c or e c o n v er si o n t a bl e, pr o vi d e d i n A p p e n di x 3 .
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 2 of 6 0
C h a n g e fr o m b a s eli n e f or P R O MI S -P h y si c al F u n cti o n T -s c or e will b e c al c ul at e d f or all p o st 
b a s eli n e ti m e p oi nt s.
3. 4. 8. P ati e nt’ s Gl o b al I m pr e s si o n of C h a n g e ( P GI -C) at W e e k 1 2; C h a n g e fr o m 
b a s eli n e i n P ati e nt’ s Gl o b al I m pr e s si o n of S e v erit y  ( P GI-S) at W e e k 1 2 
3. 4. 8. 1. P GI - C
T h e P GI -C c o n si st s of 5 q u e sti o n s t h at a s k t h e st u d y p arti ci p a nt s t o r at e t h e o v er all c h a n g e 
i n t h eir l e v el of a p p etite, f ati g u e, p h y si c al f u n cti o n, p h y si c al a cti vit y a n d w al ki n g si n c e t h e y 
st art e d t a ki n g t h e st u d y i nt er v e nti o n o n a 5 -p oi nt v er b al r ati n g s c al e t h at r a n g e s fr o m “ M u c h 
b ett er” t o “ M u c h w or s e”. 
T h e P GI - C i s r e c o m m e n d e d b y F D A f or u s e a s a n a n c h or m e a s ur e t o g e n er at e a n 
a p pr o pri at e t hr e s h ol d t h at r e pr e s e nt s m e a ni n gf ul wit hi n -i n di vi d u al c h a n g e i n t h e t ar g et 
p ati e nt p o p ul ati o n.
3. 4. 8. 2. P GI - S
T h e P GI -S c o n si st s of 5 q u e sti o n s t h at a s k t h e st u d y p arti ci p a nt s t o e v al u at e t h e s e v erit y of 
t h eir a p p etit e l o s s, f ati g u e, p h y si cal f u n cti o n, li mit ati o n s of p h y si c al a cti vit y a n d w al ki n g o v er 
t h e p a st 7 d a y s, o n a 5-p oi nt v er b al r e s p o n s e s c al e t h at r a n g e s fr o m “ N o n e” t o “ V er y 
s e v er e”. 
T h e P GI -S i s r e c o m m e n d e d b y F D A f or u s e a s a n a n c h or m e a s ur e t o g e n er at e a n 
a p pr o pri at e t hr e s h ol d t h at r e pr e s e nt s m e a ni n gf ul wit hi n i n di vi d u al c h a n g e i n t h e t ar g et 
p ati e nt p o p ul ati o n.
T h e c h a n g e fr o m b a s eli n e i n P GI -S will b e c al c ul at e d f or all p o st -b a s eli n e ti m e p oi nt s.
3. 4. 9. T u m or st at u s a c c or di n g t o R E CI S T 1. 1 g ui d eli n e s u si n g C T s c a n at W e e k 1 2
C T s c a n s w ill b e a c q uir e d d uri n g t h e st u d y t o m o nit or t h e t u m or b ur d e n. M o nit ori n g of t h e 
t u m or b ur d e n will b e p erf or m e d b y t h e sit e f oll o wi n g st a n d ar d R E CI S T 1. 1 crit eri a ( o utli n e d 
i n A p p e n di x 1 1 of t h e pr ot o c ol).
3. 4. 1 0. C h a n g e fr o m b a s eli n e i n L S MI d eri v e d fr o m C T s c a n s at W e e k 1 2; P er c e nt 
c h a n g e fr o m b a s eli n e i n s k el et al m u s cl e a n d a di p o s e ti s s u e m e a s ur e s d eri v e d fr o m 
C T s c a n s at W e e k 1 2
C T s c a n s will al s o b e s u b mitt e d t o a c e ntr al i m a gi n g v e n d or f or t h e m e a s ur e m e nt of b o d y 
c o m p o siti o n ( s k el et al m u s cl e ar e a a n d a di p o s e t i s s u e ar e a s at t h e 3r d l u m b ar v ert e br al 
l e v el). 
T h e e n d p oi nt s ar e: 

L S MI ( c m 2 / m2 ): L S MI = s k el et al m u s cl e ar e a ( c m2) / h ei g ht ( m)2

S k el et al m u s cl e ar e a ( c m 2 )

S u b c ut a n e o u s a di p o s e ar e a ( c m 2 )

Vi s c er al a di p o s e ar e a ( c m 2 )

I ntr a m u s c ul ar a di p o s e ar e a ( c m2 )

S k el et al m u s cl e r a di o -att e n u ati o n ( H o u n sfi el d U nit s, H U)

S u b c ut a n e o u s a di p o s e r a di o -att e n u ati o n ( H o u n sfi el d U nit s, H U)

Vi s c er al a di p o s e r a di o -att e n u ati o n ( H o u n sfi el d U nit s, H U)
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 3 of 6 0

I ntr a m u s c ul ar a di p o s e r a di o-att e n u ati o n ( H o u n sfi el d U nit s, H U)
B a s eli n e i s d efi n e d a s t h e l a st m e a s ur e m e nt pri or t o, or o n, st u d y d a y 8. C h a n g e fr o m 
b a s eli n e f or L S MI will b e c al c ul at e d f or all p o st b a s eli n e ti m e p oi nt s.
P er c e nt c h a n g e fr o m b a s eli n e f or t h e r e m ai ni n g s k el et al m u s cl e a n d a di p o s e ti s s u e 
m e a s ur e s will b e
c al c ul at e d f or all p o st b a s eli n e ti m e p oi nt s.
P er c e nt c h a n g e fr o m b a s eli n e i n r a di o -att e n u ati o n m e a s ur e m e nt s at p o st b a s eli n e 
ti m e p oi nt s will b e e x cl u d e d f or a p arti ci p a nt if t h e I V c o ntr a st u s e d at t h at ti m e p oi nt i s 
diff er e nt t o t h at u s e d at b a s eli n e.
A d d iti o n al e x pl or at or y b o d y c o m p o siti o n m e a s ur e m e nt s m a y b e p erf or m e d b ut m a y n ot b e 
r e p ort e d i n t h e C S R.
3. 4. 1 1. C h a n g e fr o m b a s eli n e al b u mi n a n d pr e -al b u mi n l e v el s at W e e k 1 2
Al b u mi n a n d pr e -al b u mi n will b e a s s e s s e d a s a bi o m ar k er f or n utriti o n al st at u s. A s er u m 
s a m pl e of a p pr o xi m at el y 6 m L will b e c oll e ct e d f or m e a s ur e m e nt of al b u mi n a n d pr e -al b u mi n 
a s s p e cifi e d i n t h e Pr ot o c ol .
T h e f ol d c h a n g e fr o m b a s eli n e i n al b u mi n a n d pr e -al b u mi n will b e c al c ul at e d f or all p o st -
b a s eli n e ti m e p oi nt s.
3. 4. 1 2. S ur vi v al st at u s at e n d of P a rt A
T h e s ur vi v al st at u s at t h e e n d of P art A will b e r e c or d e d f or e a c h p arti ci p a nt. E n d of P art A i s 
c o n si d er e d W e e k  1 2 f or all p arti ci p a nt s (r e g ar dl e s s of w h et h er t h e y e nt er t h e o pti o n al P art B 
or n ot). 
T h e ti m e ( d a y s) t o d e at h d uri n g P art A ( u p t o W e e k 1 2) will al s o b e c al c ul at e d f or e a c h 
p arti ci p a nt.
3. 4. 1 3. R e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y  wei g ht at 
W e e k 1 2 
A d diti o n all y, r e s p o n s e, a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y w ei g ht at 
W e e k 1 2, will b e d efi n e d a s h a vi n g t w o l e v el s: ‘ R e s p o n s e’ a n d ‘ N o n -r e s p o n s e’.  T h e f or m er 
will b e b a s e d o n p arti ci p a nt s h a vi n g a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y w ei g ht at W e e k 
1 2.  Ot h er wi s e, p arti ci p a nt s will b e cl a s s e d a s h a vi n g a ‘ N o n -r e s p o n s e’.  P arti ci p a nt s wit h a n 
i nt er c urr e nt e v e nt of pr e m at ur e di s c o nti n u ati o n of st u d y i nt er v e nti o n, pr o hi bit e d 
pr o c e d ur e/ m e di c ati o n or i n a d e q u at e c o m pli a n c e pri or t o W e e k  1 2 will h a v e t h eir W e e k 1 2 
v al u e c e n s or e d (if n ot mi s si n g). Mi s si n g or c e n s or e d v al u e s at W e e k  1 2 will b e i m p ut e d a s 
d e s cri b e d i n S e cti o n 5. 3. 1 .  P arti ci p ant s w h o di e d uri n g t h e st u d y will b e cl a s s e d a s h a vi n g a 
‘ N o n-r e s p o n s e’ aft er i m p ut ati o n.  T hi s e n d p oi nt will b e c al c ul at e d si mil arl y f or We e k  4 a n d 
W e e k 8.
3. 5. B a s eli n e V ari a bl e s
P er c e nt w ei g ht l o s s i n t h e 6 m o nt h s pri or t o s cr e e ni n g vi sit ( S V) will b e c al c ulat e d a s: 
   ℎ     6    ℎ         [  ] −
     ℎ [  ]
   ℎ     6    ℎ         [  ]
×
1 0 0
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 4 of 6 0
If w ei g ht fr o m 6 m o nt h s pri or t o S V i s mi s si n g, w ei g ht fr o m t h e cl o s e st ti m e p oi nt aft er 6 
m o nt h s s h o ul d b e u s e d, e. g. if a p arti ci p a nt h a s a w ei g ht a v ail a bl e fr o m 8 m o nt h s, 6 m o nt h s, 
a n d 4 m o nt h s pri or t o S V, t h e w ei g ht fr o m 6 m o nt h s pri or t o S V s h o ul d b e u s e d. If a 
p arti ci p a nt h a s a w ei g ht a v ail a bl e f or 9 m o nt h s, 4 m o nt h s, a n d 2 m o nt h s pri or t o S V, t h e 
w e i g ht fr o m 4 m o nt h s pri or t o S V s h o ul d b e u s e d. 
B M I-a dj u st e d w ei g ht l o s s c at e g or y ( 0/ 1/ 2/ 3/ 4) will b e d et er mi n e d b a s e d o n t h e p er c e nt 
w e i g ht l o s s i n t h e 6 m o nt h s pri or t o s cr e e ni n g vi sit a n d t h e B MI at s cr e e ni n g u si n g t h e 
f oll o wi n g gr a di n g s y st e m d ev el o p e d b y M arti n ( 2 0 1 5) 1 : 
S ar c o p e ni a st at u s at b a s eli n e will b e d et er mi n e d.  P arti ci p a nt s wit h b a s eli n e l u m b ar s k el et al 
m u s cl e i n d e x ( L S MI) ≤ 3 8. 5 c m 2 / m2 i n w o m e n, a n d ≤ 5 2. 4 c m 2 / m2 i n m e n, will b e d efi n e d a s 
h a vi n g s ar c o p e ni a.
T h e f oll o wi n g b a s eli n e i nfl a m m ati o n v ari a bl e s will b e d et er mi n e d f or p a rti ci p a nt s, if p o s si bl e 
( n ot e t h at t h e r e c or d e d u nit s m a y diff er fr o m t h e u nit s r e q uir e d i n c al c ul ati o n s):

C- r e a cti v e pr ot ei n ( C R P) ( m g/ d L): fr o m R et ai n e d R e s e ar c h S a m pl e s o n D a y 1

C R P -al b u mi n r ati o: C R P o n D a y 1 ( m g/ d L) / al b u mi n ( m g/ d L) o n D a y 1
[ N ot e: C R P c o n c e ntr ati o n s b el o w t h e li mit of q u a ntifi c ati o n ( B L Q) will b e s et t o t h e 
l o w er li mit of q u a ntifi c ati o n ( L L Q) pri or t o c al c ul ati o n of t h e r ati o]

M o difi e d Gl a s g o w Pr o g n o sti c S c or e o n D a y 1:  
0: if C R P ≤ 1 m g/ d L
1: if C R P > 1 m g/ d L
2: if C R P > 1 m g/ d L a n d al b u mi n < 3. 5 g/ d L

N e utr o p hil -l y m p h o c yt e r ati o ( N L R): n e utr o p hil c o u nt at s cr e e ni n g / l y m p h o c yt e c o u nt 
at s cr e e ni n g

Pl at el et -l y m p h o c yt e r ati o ( P L R): pl at el et c o u nt at s cr e e ni n g / l y m p h o c yt e c o u nt at 
s cr e e ni n g
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 5 of 6 0
4. A N A L Y SI S S E T S ( P O P U L A TI O N S F O R A N A L Y SI S )
D at a f or all p arti ci p a nt s will b e a s s e s s e d t o d et er mi n e if p arti ci p a nt s m e et t h e crit eri a f or 
i n cl u si o n i n e a c h a n al y si s p o p ul ati o n pri or t o u n bli n di n g a n d r el e a si n g t h e d at a b a s e a n d 
cl a s sifi c ati o n s will b e d o c u m e nt e d p er st a n d ar d o p er ati n g pr o c e d ur e s.
P arti c i p a nt A n al y si s 
S et
D e s cri pti o n
E nr oll e d 
“ E nr oll e d” m e a n s a p arti ci p a nt’s, or t h eir l e g all y a ut h ori z e d 
r e pr e s e nt ati v e’s, a gr e e m e nt t o p arti ci p at e i n a cli ni c al 
st u d y f oll o wi n g c o m pl eti o n of t h e i nf or m e d c o n s e nt 
pr o c e s s a n d r a n d o mi z ati o n t o st u d y i nt er v e nti o n. A 
p arti ci p a nt will b e c o n si d er e d e nr oll e d if t h e i nf or m e d 
c o n s e nt i s n ot wit h dr a w n pri or t o p arti ci p ati n g i n a n y st u d y 
a cti vit y aft er S cr e e ni n g. P ot e nti al p arti ci p a nt s w h o ar e 
s cr e e n e d f or t h e p ur p o s e of d et er mi ni n g eli gi bilit y f or t h e 
st u d y, b ut d o n ot p arti ci p at e i n t h e st u d y, ar e n ot 
c o n si d er e d e nr oll e d, u nl e s s ot h er wi s e s p e cifi e d b y t h e 
pr ot o c ol. 
E v al u a bl e 
All p arti ci p a nt s r a n d o ml y a s si g n e d t o st u d y i nt er v e nti o n 
a n d w h o t a k e at l e a st 1 d o s e of st u d y i nt er v e nti o n. 
P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e r a n d o mi z e d 
i nt er v e nti o n.
S af et y a n al y si s s et
All p arti ci p a nt s r a n d o ml y a s si g n e d t o st u d y i nt er v e nti o n 
a n d w h o t a k e at l e a st 1 d o s e of st u d y i nt er v e nti o n. 
P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e st u d y 
i nt er v e nti o n t h e y a ct u all y r e c ei v e d. T hi s will b e t h e st u d y 
i nt er v e nti o n r e c ei v e d b y t h e p arti ci p a nt f or t h e m aj orit y of 
t h e ti m e p oi nt s d uri n g t h e r el e v a nt p art of t h e st u d y. If a 
p arti ci p a nt r e c ei v e s a n e q u al n u m b er of diff er e nt d o s e s, 
t h e n t h e l o w e st of t h o s e d o s e s will b e u s e d. If a p arti ci p a nt 
r e c ei v e s a n e q u al n u m b er of pl a c e b o a n d a gi v e n d o s e of 
p o n s e gr o m a b, t h e p o n s e gr o m a b d o s e will b e u s e d.
D efi n e d A n al y si s S et
D e s cri pti o n
C e n s or e d
All e v al u a bl e p arti ci p a nt s. F or p arti ci p a nt s w h o 
di s c o nti n u e st u d y i nt er v e nti o n, or r e c ei v e a pr o hi bit e d 
pr o c e d ur e or pr o hi bit e d m e di c ati o n , all o b s er v ati o n s 
p o st -di s c o nti n u ati o n , or p o st-pr o c e d ur e, will b e c e n s or e d 
a n d tr e at e d a s mi s si n g d at a. F or p arti ci p a nt s w h o mi s s a 
d o s e , or r e c ei v e a n i n c o m pl et e d o s e, all o b s er v ati o n s 
p o st -mi s s e d/ i n c o m pl et e d o s e will b e c e n s or e d a n d tr e at e d 
a s mi s si n g d at a. 
C o m pl et e
All e v al u a bl e p arti ci p a nt s.  F or p arti ci p a nt s w h o 
di s c o nti n u e st u d y i nt er v e nti o n, r e c ei v e a pr o hi bit e d 
pr o c e d ur e or pr o hi bit e d m e di c ati o n, a n d/ or mi s s a d o s e, 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 6 of 6 0
D efi n e d A n al y si s S et
D e s cri pti o n
or r e c ei v e a n i n c o m pl et e d o s e, all o b s er v ati o n s p o st -
di s c o nti n u ati o n, p o st -pr o c e d ur e or p o st -
mi s s e d/i n c o m pl et e d o s e will b e i n cl u d e d i n t h e a n al y si s 
s et.
P K
All p arti ci p a nt s r a n d o ml y a s si g n e d t o st u d y i nt er v e nti o n 
a n d w h o t a k e at l e a st 1 d o s e of p o n s e gr o m a b a n d i n 
w h o m at l e a st 1 P K c o n c e ntr ati o n v al u e i s r e p ort e d.
P D
All p arti ci p a nt s r a n d o ml y a s si g n e d t o st u d y i nt er v e nti o n 
a n d w h o t a k e at l e a st 1 d o s e of st u d y i nt er v e nti o n a n d i n 
w h o m at l e a st 1 P D ( G D F -1 5) c o n c e ntr ati o n v al u e i s 
r e p ort e d.
I m m u n o g e ni cit y 
All p arti ci p a nt s r a n d o ml y a s si g n e d t o st u d y i nt er v e nti o n 
a n d w h o t a k e at l e a st 1 d o s e of p o n s e gr o m a b a n d i n 
w h o m at l e a st 1 A D A r e s ult i s r e p ort e d. 
F or p arti ci p a nt s w h o di s c o nti n u e st u d y i nt er v e nti o n, t h e d at e of di s c o nti n u ati o n of st u d y 
i nt er v e nti o n i s d efi n e d a s t h e d at e of l a st d o s e of I P + 2 9 d a y s.  
Li sti n g s of n o n -dr u g tr e at m e nt( s)/ pr o c e d ur e( s) a n d c o n c o mit a nt m e di c ati o n( s) will b e 
pr o vi d e d ( s e e S e cti o n 6. 6. 3 ).  T h e s e will b e bli n d e d t a bl e s a n d will b e r e vi e w e d pri or t o 
d at a b a s e l o c k t o d et er mi n e w hi c h pr o c e d ur e s a n d m e di c ati o n s w o ul d b e cl a s s e d a s 
“ pr o hi bit e d”.
P arti ci p a nt s w h o ar e r a n d o mi z e d t o t h e wr o n g str at u m, i n err or, will h a v e t h e i n c orr e ct 
str at u m a s si g n m e nt r e m ai n i n I M P A L A b ut t h e cli ni c al d at a b a s e will i n cl u d e t h e c orr e ct 
str at u m. T h e l att er will s u b s e q u e ntl y b e u s e d f or all r el e v a nt a n al y s e s, a s a p pr o pri at e.
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S
5. 1. H y p ot h e s e s a n d D e ci si o n R ul e s
T h e n ull h y p ot h e si s of n o diff er e n c e b et w e e n p o n s e gr o m a b a n d pl a c e b o will b e t e st e d f or 
e a c h pri m ar y, a n d s el e ct e d s e c o n d ar y ( p h y si c al a cti vit y, F A A C T a n d C R C S D) a n d t erti ar y 
( P R O MI S-f atig u e, P R O MI S -p h y si c al f u n cti o n, L S MI a n d s ur vi v al st at u s) e n d p oi nt s. T h e 
alt er n ati v e h y p ot h e si s i s t h at p o n s e gr o m a b i s s u p eri or t o pl a c e b o.  T h e T y p e I err or r at e ( α -
l e v el) u s e d f or t h e st ati sti c al i nf er e n c e will b e 5 % ( 1-si d e d).  E a c h d o s e of p o n s e gr o m a b will 
b e c o m p ar e d s e p ar at el y wit h pl a c e b o.  N o a dj u st m e nt f or m ulti pl e c o m p ari s o n s will b e 
m a d e.
F or all ot h er e n d p oi nt s, t h e r e s ult s of a n y st ati sti c al a n al y s e s ar e f or e x pl or at or y p ur p o s e s 
o nl y a n d t h er e i s n o f or m al h y p ot h e si s t e sti n g.
5. 2. G e n er al M et h o d s
U nl e s s ot h er wi s e st at e d, t h e m ai n c o h ort a n d P K s u b st u d y will b e r e p ort e d t o g et h er.  N ot e 
t h at t h e s e p ar at e pr e s e nt ati o n s f or t h e p arti ci p a nt s i n t h e P K s u b st u d y m a y b e r e p ort e d i n a 
s u p pl e m e nt al C S R r at h er t h a n t h e m ai n C S R.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 7 of 6 0
T h e a n al y s e s r el at e d t o t h e pri m ar y, s e c o n d ar y a n d e x pl or at or y e n d p oi nt s will b e b a s e d o n 
t h e a p pr o pri at e p o p ul ati o n f or a n al y si s ( s e e S e cti o n 4 ).
U nl e s s ot h er wi s e st at e d, all s u m m ari e s a n d pl ot s will b e pr e s e nt e d b y tr e at m e nt gr o u p.  T h e 
f oll o wi n g tr e at m e nt gr o u p l a b el s ( or si mil ar) will b e u s e d:
-
Pl a c e b o
-
P o n s e gr o m a b 1 0 0 m g 
-
P o n s e gr o m a b 2 0 0 m g 
-
P o n s e gr o m a b 4 0 0 m g 
A ‘ P o n s e gr o m a b C o m bi n e d’ gr o u p will al s o b e pr e s e nt e d f or s af et y s u m m ari e s.
5. 2. 1. S u m m ari e s f or C o nti n u o u s E n d p oi nt s
U nl e s s ot h er wi s e st at e d, c o nti n u o u s v ari a bl e s will b e pr e s e nt e d u si n g s u m m ar y st ati sti c s: 
n u m b er of o b s er v ati o n s, arit h m eti c m e a n, st a n d ar d d e vi ati o n ( S D), m e di a n a n d Q 1, Q 3 
a n d/ or r a n g e ( mi ni m u m a n d m a xi m u m) v al u e s.  F or e n d p oi nt s t o b e a n al y z e d o n t h e n at ur al 
l o g s c al e (l o ge ), t h e g e o m etri c m e a n a n d g e o m etri c c o effi ci e nt of v ari ati o n ( C V) will 
a d diti o n all y b e c al c ul at e d.
5. 2. 2. S u m m ari e s f or C at e g ori c al E n d p oi nt s
C at e g ori c al v ari a bl e s will b e pr e s e nt e d u si n g s u m m ar y st ati sti c s: n u m b er of o b s er v ati o n s 
a n d p er c e nt a g e s.
5. 2. 3. Mi x e d M o d el s R e p e at e d M e a s ur e s ( M M R M) A n al y si s
T h e M M R M m o d el will i n cl u d e p arti ci p a nt a s a r a n d o m t er m, a n d b a s eli n e, ti m e ( a s a f a ct or), 
b a s eli n e -b y -ti m e i nt er a cti o n, tr e at m e nt a n d tr e at m e nt-b y -ti m e i nt er a cti o n a s fi x e d t er m s i n 
t h e m o d el. A n u n str u ct ur e d c o v ari a n c e m atri x will b e fitt e d t o t h e r e p e at e d ti m e s wit hi n 
s u bj e ct ( ot h er c o v ari a n c e m atri c e s will b e c o n si d er e d if n e c e s s ar y), a n d t h e K e n w ar d R o g er 
a p pr o xi m ati o n will b e u s e d f or e sti m ati n g d e gr e e s of fr e e d o m. A d diti o n al t er m s m a y b e fitt e d 
i n t h e m o d el ( e g, t y p e of t h er a p y [i e, pl ati n u m or n ot], t y p e of c a n c er), a s a p pr o pri at e.
L e a st -s q u ar e s ( L S) m e a n s ( a n d 9 0 % CI s) a n d L S m e a n diff er e n c e s v er s u s pl a c e b o ( a n d 
9 0 % CI s, a n d p -v al u e s f or pri m ar y a n d s el e ct e d s e c o n d ar y/t erti ar y e n d p oi nt s), at e a c h 
ti m e p oi nt, will b e pr o vi d e d. N o a dj u st m e nt s will b e m a d e f or m ulti pli cit y. I n a d diti o n, pr ofil e 
pl ot s of t h e L S m e a n s a n d diff er e n c e s ( a n d 9 0 % CI s f or b ot h) will b e pr o d u c e d o v er ti m e, 
wit h a s e p ar at e li n e f or e a c h tr e at m e nt gr o u p.
St a n d ar d S A S o ut p ut will b e pr o vi d e d t o s u p p ort t h e st ati sti c al s u m m ar y t a bl e f or t h e 
a n al y si s m o d el b ut will n ot b e i n cl u d e d i n t h e C S R.
E x a m pl e S A S c o d e i s pr o vi d e d i n A p p e n di x 4 .
St ati sti c al M o d el Di a g n o sti c s
T h e pr e s e n c e of o utli er s will b e i n v e sti g at e d f or t hi s m o d el. A n o utli er will b e d efi n e d a s a n y 
r e s p o n s e d at a v al u e wit h a st u d e nti z e d ( c o n diti o n al) r e si d u al gr e at er t h a n 3, or l e s s t h a n 3. 
A li sti n g will b e pr e s e nt e d of a n y p arti ci p a nt s m e eti n g t h e s e crit eri a a n d will b e i n cl u d e d wit h 
st a n d ar d S A S o ut p ut. T h e a s s u m pti o n s of n or m alit y will b e v erifi e d gr a p hi c all y u si n g 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 8 of 6 0
r e si d u al pl ot s. F or e a c h fitt e d m o d el, a s et of c o n diti o n al st u d e nti z e d r e si d u al pl ot s will b e 
pr o d u c e d, i n cl u di n g r e si d u al pl ot, hi st o gr a m of n or m alit y, q u artil e -q u artil e ( Q Q) pl ot a n d 
s u m m ar y of fit st ati sti c s. T h e r e si d u al pl ot s will n ot b e i n cl u d e d i n t h e C S R.
If t h er e ar e o utli er s or m aj or d e vi ati o n s fr o m n or m alit y, t h e n t h e eff e ct of t h e s e o n t h e 
c o n cl u si o n s m a y b e i n v e sti g at e d t hr o u g h a lt er n ati v e tr a n sf or m ati o n s a n d/ or a n al y s e s 
e x cl u di n g o utli er s. J u stifi c ati o n f or a n y alt er n ati v e t o t h e pl a n n e d a n al y si s will b e gi v e n i n t h e 
r e p ort of t h e st u d y.
5. 2. 4. B a y e si a n E m a x M o d el
T h e B a y e si a n f o ur -p ar a m et er E m a x m o d el will u s e d o s e a s a c o nti n u o u s v ari a bl e. T h e 
m o d el str u ct ur e will t a k e t h e f or m: 
   =   +
    ∗              E 0 i s t h e pl a c e b o r e s p o n s e, d o s e i s t h e r a n d o mi z e d d o s e ( pl a c e b o d o s e = 0), Em a x i s t h e 
m a xi m u m eff e ct, E D
5 0 i s t h e d o s e pr o d u ci n g 5 0 % of th e m a xi m u m eff e ct a n d Hill i s t h e sl o p e 
p ar a m et er. T h e m o d el will utili z e a B a y e si a n m et h o d ol o g y a p pr o a c h a s d e s cri b e d i n 
A p p e n di x 5 .
E sti m at e s of t h e m o d el p ar a m et er s of E 0 , E m a x, E D 5 0 a n d Hill a n d t h eir 9 5 % cr e di bl e i nt er v al s 
will b e pr o d u c e d t o s u p p ort t h e st ati sti c al s u m m ar y t a bl e f or t h e a n al y si s m o d el b ut will n ot 
b e i n cl u d e d i n t h e C S R.
T h e p o st eri or m e di a n s a n d 9 0 % cr e di bl e i nt er v al s ( 5 t h a n d 9 5 t h p er c e ntil e s of t h e r el e v a nt 
p o st eri or di stri b uti o n) will b e r e p ort e d f or e a c h r a n d o mi z e d d o s e (i n cl u di n g pl a c e b o) a n d 
t h eir diff er e n c e s r el ati v e t o pl a c e b o. Pl ot s of t h e p o st eri or m e di a n s a n d diff er e n c e s 
(i n cl u di n g cr e di bl e i nt er v al s f or b ot h) will b e pr o d u c e d v er s u s d o s e. N o a dj u st m e nt s will b e 
m a d e f or m ulti pli cit y.
If t h e Em a x m o d el c a n n ot b e fitt e d t o t h e d at a, or t h e d at a d o n ot s u p p ort a d o s e -r e s p o n s e, 
t h e m o d el m a y b e si m plifi e d, or t h e a n al y si s m a y n ot b e p erf or m e d.
5. 2. 5. A n al y si s of C o v ari a n c e ( AN C O V A )
T h e A N C O V A m o d el will i n cl u d e b a s eli n e a n d tr e at m e nt a s fi x e d t er m s i n t h e m o d el.  
A d diti o n al t er m s m a y b e fitt e d i n t h e m o d el ( e g, t y p e of t h er a p y [i e, pl ati n u m or n ot], t y p e of 
c a n c er), a s a p pr o pri at e.  L S m e a n s ( a n d 9 0 % CI s) a n d L S m e a n diff er e n c e s v er s u s pl a c e b o 
( a n d 9 0 % CI s) will b e pr o vi d e d. N o a dj u st m e nt s will b e m a d e f or m ulti pli cit y. I n a d diti o n, 
pl ot s of t h e L S m e a n s a n d diff er e n c e s ( a n d 9 0 % CI s f or b ot h) will b e pr o d u c e d.
St a n d ar d S A S o ut p ut will b e pr o vi d e d t o s u p p ort t h e st ati st i c al s u m m ar y t a bl e f or t h e 
a n al y si s m o d el b ut will n ot b e i n cl u d e d i n t h e C S R.
E x a m pl e S A S c o d e i s pr o vi d e d i n A p p e n di x 4 .
St ati sti c al m o d el di a g n o sti c s will b e a s s e s s e d i n a si mil ar w a y t o t h at d e s cri b e d i n S e cti o n 
5. 2. 3 .
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 2 9 of 6 0
5. 2. 6. C u m ul ati v e I n ci d e n c e Pl ot s
C u m ul ati v e i n ci d e n c e pl ot s will b e pr o d u c e d b a s e d o n t h e ti m e t o t h e e v e nt of i nt er e st 
( st arti n g fr o m t h e ti m e of st art of d o si n g o n D a y 1) f or e a c h tr e at m e nt gr o u p s e p ar at el y, all 
tr e at m e nt s o n t h e s a m e pl ot. T hi s will b e b a s e d o n pl otti n g t h e c u m ul ati v e i n ci d e n c e f u n cti o n 
( wit h n o c o m p eti n g ri s k s), w hi c h will b e pr e s e nt e d a s a p er c e nt a g e o n t h e y-a xi s. 
P arti ci p a nt s w h o di s c o nti n u e fr o m t h e st u d y or fr o m st u d y i nt er v e nti o n will b e c e n s or e d at 
t h e a s s o ci at e d di s c o nti n u ati o n d at e.  T h e n u m b er of p arti ci p a nt s at ri s k at e a c h ti m ep oi nt 
m a y b e i n cl u d e d.
E x a m pl e S A S c o d e i s pr o vi d e d i n A p p e n di x 4 .
5. 2. 7. C o x Pr o p orti o n al H a z ar d s M o d el
T h e C o x pr o p orti o n al h a z ar d s m o d el will i n cl u d e t r e at m e nt a s a fi x e d t er m i n t h e m o d el.  
A d diti o n al t er m s will b e fitt e d i n t h e m o d el ( e g, t y p e of t h er a p y [i e, pl ati n u m or n ot], t y p e of 
c a n c er), a s a p pr o pri at e.  H a z ar d r ati o s v er s u s pl a c e b o ( a n d 9 0 % CI s a n d p -v al u e) will b e 
pr o vi d e d.  N o a dj u st m e nt s will b e m a d e f or m ulti pli cit y. If t h e m o d el i s d e e m e d i n a p pr o pri at e 
( e. g. t h e a s s u m pti o n of pr o p orti o n al h a z ar d s i s n ot m et), t h e a n al y si s m a y n ot b e p erf or m e d. 
St a n d ar d S A S o ut p ut will b e pr o vi d e d t o s u p p ort t h e st ati sti c al s u m m ar y t a bl e f or t h e 
a n al y si s m o d el.
E x a m pl e S A S c o d e i s pr o vi d e d i n A p p e n di x 4 .
5. 2. 8. L o gi sti c R e gr e s si o n
T h e l o gi sti c r e gr e s si o n m o d el will i n cl u d e b a s eli n e a n d tr e at m e nt a s fi x e d t er m s i n t h e 
m o d el.  A d diti o n al t er m s m a y b e fitt e d i n t h e m o d el ( e g, t y p e of t h er a p y [i. e. pl ati n u m or n ot] 
a n d t y p e of c a n c er), a s a p pr o pri at e. Mi s si n g v al u e s ( e. g. d u e t o c e n s ori n g) will b e i m p ut e d 
f or mi s si n g d at a u si n g a m ulti pl e i m p ut ati o n m et h o d a s d e s cri b e d i n S e cti o n 5. 3. 1 . O d d s 
( a n d 9 0 % CI s) a n d o d d s r ati o s v er s u s pl a c e b o ( a n d 9 0 % CI s a n d p-v al u e s) will b e pr o vi d e d.  
N o a dj u st m e nt s will b e m a d e f or m ulti pli cit y. 
St a n d ar d S A S o ut p ut will b e pr o vi d e d t o s u p p ort t h e st ati sti c al s u m m ar y t a bl e f or t h e 
a n al y si s m o d el a n d m ulti pl e i m p ut ati o n a p pr o a c h b ut will n ot b e i n cl u d e d i n t h e C S R. 
E x a m pl e S A S c o d e i s pr o vi d e d i n A p p e n di x 4 .
5. 3. M et h o d s t o M a n a g e Mi s si n g D at a
F or t h e a n al y si s of s af et y e n d p oi nt s, t h e s p o n s or d at a st a n d ar d r ul e s f or i m p ut ati o n will b e 
a p pli e d.
I n all P D d at a pr e s e nt ati o n s ( e x c e pt li sti n g s), c o n c e ntr ati o n s b el o w t h e li mit of q u a ntifi c ati o n 
( B L Q) will b e s et t o t h e l o w er li mit of q u a ntifi c ati o n ( L L Q).  
I n all P K d at a pr e s e nt ati o n s ( e x c e pt li sti n g s), c o n c e ntr ati o n s b el o w t h e li mit of q u a ntifi c ati o n 
( B L Q) will b e s et t o z er o. 
I n li sti n g s, B L Q v al u e s (f or P K or P D) will b e r e p ort e d a s “ < L L Q”, w h er e L L Q will b e r e pl a c e d 
wit h t h e v al u e f or t h e L L Q.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 0 of 6 0
F or P K a n d P D s u m m ar y t a bl e s a n d pl ot s of m e di a n pr ofil e s, st ati sti c s will b e c al c ul at e d 
h a vi n g s et c o n c e ntr ati o n s t o mi s si n g if o n e of t h e f oll o wi n g c a s e s i s tr u e:
1.
A c o n c e ntr ati o n h a s b e e n c oll e ct e d a s N D (i. e. n ot d o n e) or N S (i. e. n o s a m pl e),
2.
A d e vi ati o n i n s a m pli n g ti m e i s of s uffi ci e nt c o n c er n or a c o n c e ntr ati o n h a s b e e n 
fl a g g e d a n o m al o u s b y t h e p h ar m a c o ki n eti ci st/ st ati sti ci a n.
5. 3. 1. M ulti pl e I m p ut ati o n
F or s u m m ari zi n g t h e pr o p orti o n of r e s p o n s e s ( e. g. r e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e 
fr o m b a s eli n e i n b o d y w ei g ht at W e e k 1 2), all p er c e nt c h a n g e fr o m b a s eli n e d at a fr o m t h e 
c e n s or e d a n al y si s s et will b e i n cl u d e d ( all ti m e p oi nt s u p t o a n d i n cl u di n g W e e k 1 2, i. e. 
W e e k s 4, 8 a n d 1 2). A m ulti pl e i m p ut ati o n m et h o d will b e i m pl e m e nt e d, u si n g a m ulti v ari at e 
i m p ut ati o n m et h o d b y c h ai n e d e q u ati o n s, w hi c h i s still v ali d wit h a n ar bitr ar y mi s si n g d at a 
p att er n. T h e m o d el will i n cl u d e b a s eli n e a n d tr e at m e nt.  A d diti o n al t er m s f or t y p e of t h er a p y 
[i. e. pl ati n u m or n ot] a n d t y p e of c a n c er will al s o b e i n cl u d e d, a s a p pr o pri at e. T w e nt y s et s of 
i m p ut ati o n s of e a c h mi s si n g v al u e will b e c o n str u ct e d fr o m t h e m ulti pl e i m p ut ati o n m et h o d 
a n d t h e pr o p orti o n of r e s p o n s e s b y tr e at m e nt will b e d et er mi n e d wit h a s s o ci at e d st a n d ar d 
err or s utili zi n g a n or m al a p pr o xi m ati o n a n d will b e c o m bi n e d u si n g st a n d ar d m ulti pl e 
i m p ut ati o n t e c h ni q u e s pr o p o s e d b y R u bi n2 t o yi el d o v er all e sti m at e s a n d CI s. If t h er e i s 
m or e mi s si n g d at a i n t h e st u d y t h a n a nti ci p at e d, t h e n u m b er of i m p ut ati o n s et s m a y b e 
i n cr e a s e d a s r e q uir e d. N ot e t h at d at a f or p arti ci p a nt s w h o di e d uri n g t h e st u d y will b e 
i n cl u d e d i n t h e i m p ut ati o n b ut will t h e n b e cl a s s e d a s h a vi n g a ‘ N o n-r e s p o n s e’ aft er 
i m p ut ati o n.
F or l o gi sti c r e gr e s si o n, all p er c e nt c h a n g e fr o m b a s eli n e d at a fr o m t h e c e n s or e d a n al y si s s et 
will b e i n cl u d e d ( all ti m e p oi nt s u p t o a n d i n cl u di n g W e e k 1 2, i. e. W e e k s 4, 8 a n d 1 2). T h e 
s a m e i m p ut e d d at a s et s a s pr o d u c e d f or t h e pr o p orti o n of r e s p o n s e s a b o v e will b e utili z e d, 
w h er e a L o gi sti c R e gr e s si o n m o d el ( a s d e s cri b e d i n S e cti o n 5. 2. 8 ) will b e a p pli e d t o e a c h of 
t h e 2 0 i m p ut e d d at a s et s s e p ar at el y. P ar a m et er e sti m at e s, of t h e l o g o d d s f or e a c h tr e at m e nt 
a n d l o g o d d s r ati o s f or e a c h d o s e r el ati v e t o pl a c e b o, will b e c o m bi n e d u si n g st a n d ar d 
m ulti pl e i m p ut ati o n t e c h ni q u e s pr o p o s e d b y R u bi n
2 t o yi el d o v er all e sti m at e s of t h e l o g o d d s 
a n d l o g o d d s r ati o s a n d t h eir a s s o ci at e d st a n d ar d err or s a n d will b e u s e d t o cr e at e 9 0 % CI s 
o n t h e l o g -o d d s s c al e. T h e l o g o d d s ( a n d CI s) a n d l o g o d d s r ati o s ( a n d CI s) will b e b a c k
tr a n sf or m e d i nt o o d d s a n d o d d s r ati o s ( a n d CI s) f or fi n al r e p orti n g.
6. A N A L Y S E S A N D S U M M A RI E S
U nl e s s ot h er wi s e s p e cifi e d, all a n al y s e s will b e c arri e d o ut u si n g t h e C e n s or e d A n al y si s S et 
a s d efi n e d i n S e cti o n 4 .
6. 1. Pri m ar y  E n d p oi nt ( s)
6. 1. 1. C h a n g e fr o m b a s eli n e b o d y  wei g ht at W e e k 1 2
6. 1. 1. 1. M ai n
A n al y si s
A b s ol ut e v al u e s, c h a n g e s fr o m b a s eli n e a n d p er c e nt c h a n g e s fr o m b a s eli n e i n b o d y w ei g ht 
will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 
5. 2. 1 .  T a bl e s will i n cl u d e b a s eli n e a n d all p o st-b a s eli n e ti m e p oi nt s. B o x a n d w h i s k er pl ot s
( or si mil ar) of a b s ol ut e v al u e s, c h a n g e s fr o m b a s eli n e a n d p er c e nt c h a n g e s fr o m b a s eli n e 
o v er ti m e will al s o b e pr o d u c e d, wit h all tr e at m e nt s o n t h e s a m e pl ot.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 1 of 6 0
C h a n g e fr o m b a s eli n e i n b o d y w ei g ht will b e a n al y z e d u si n g a n M M R M m o d el a s d e s cri b e d 
i n S e cti o n 5. 2. 3 . All p o st -tr e at m e nt d o si n g ti m e p oi nt s u p t o W e e k 1 2 (i e. W e e k s 4, 8 a n d 1 2)
will b e i n cl u d e d i n t h e m o d el.  A d diti o n al t er m s f or t y p e of t h er a p y [i. e. pl ati n u m or n ot] a n d 
t y p e of c a n c er will b e fitt e d i n t h e m o d el.  A d diti o n al pl ot s of L S m e a n s a n d diff er e n c e s 
(i n cl u di n g 9 0 % CI s f or b ot h), f or We e k 1 2 o nl y, will b e pr o d u c e d o v er tr e at m e nt. 
A B a y e si a n E m a x m o d e l, a s d e s cri b e d i n S e cti o n 5. 2. 4 , will t h e n b e fitt e d t o t h e W e e k 1 2 
L S m e a n s a n d S E s fr o m t h e M M R M a n al y si s. T hi s will b e u s e d t o e sti m at e t h e tr e at m e nt 
eff e ct r el at e d t o t h e pri m ar y E sti m a n d 1 ( a s d e s cri b e d i n S e cti o n 2. 2. 1 ). If t h e Em a x m o d el 
a n al y si s i s n ot p erf or m e d, t h e pri m ar y r e s ult s f or t h e st u d y will b e b a s e d o n t h e M M R M 
r e s ult s at W e e k 1 2.
6. 1. 1. 2. S e n siti vit y/ S u p pl e m e nt ar y  An al y s e s
A s e n siti vit y a n al y si s will b e p erf or m e d f or t h e B a y e si a n E m a x m o d el o n t h e pri m ar y 
e n d p oi nt. T h e s a m e B a y e si a n E m a x m o d el a n al y si s a s i n S e cti o n 6. 1. 1. 1 will b e p erf or m e d 
a n d r e p ort e d, a p pli e d t o t h e C e n s or e d A n al y si s S et ( a s d e s cri b e d i n S e cti o n 4 ), b ut u si n g a 
v a g u e pri or f or t h e pl a c e b o c h a n g e fr o m b a s eli n e at W e e k 1 2 ( E 0 ).  T hi s will b e a 
t-di stri b uti o n wit h a m e a n of 0 a n d a st a n d ar d d e vi ati o n e q u al t o 1 0 ti m e s t h e pr e di ct e d 
st a n d a r d d e vi ati o n, i. e. t( M e a n = 0, S D = 4 9, df = 5).
A n e x pl or at or y a n al y si s f or t h e pri m ar y e n d p oi nt, will b e p erf or m e d t o e sti m at e t h e tr e at m e nt 
eff e ct r el at e d t o E sti m a n d 1 b ( a s d e s cri b e d i n S e cti o n 2. 2. 1 ). T h e s a m e s u m m ari e s a n d 
a n al y si s a s i n S e cti o n 6. 1. 1. 1 ( e x c e pt t h e a d diti o n al w e e k 1 2 o nl y pl ot s of L S m e a n s a n d 
diff er e n c e s) will b e p erf or m e d a n d r e p ort e d, b ut a p pli e d t o t h e C o m pl et e A n al y si s S et ( a s 
d e s cri b e d i n S e cti o n 4 ).
A s u p pl e m e nt ar y a n al y si s will b e p erf or m e d f or t h e p er c e nt c h a n g e fr o m b a s eli n e i n b o d y 
w e i g ht, u si n g a n M M R M m o d el a s d e s cri b e d i n S e cti o n 5. 2. 3 .  All p o st-tr e at m e nt d o si n g 
ti m e p oi nt s u p t o W e e k 1 2 (i e. W e e k s 4, 8 a n d 1 2) will b e i n cl u d e d i n t h e m o d el.  A d diti o n al 
t er m s f or t y p e of t h er a p y [i. e. pl ati n u m or n ot] a n d t y p e of c a n c er will b e fitt e d i n t h e m o d el. 
A n a d diti o n al s u p pl e m e nt ar y a n al y si s will b e p erf or m e d f or t h e p er c e nt c h a n g e fr o m 
b a s eli n e i n b o d y w ei g ht at W e e k  1 2 o nl y, b y s u m m ari zi n g d e s cri pti v el y b y tr e at m e nt gr o u p 
( a s d e s cri b e d i n S e cti o n 5. 2. 2 ) b a s e d o n t h e f oll o wi n g c at e g ori e s:
3- C at e g ori e s
≥ 1 % l o s s: 
% C F B ≤ - 1
St a bl e: 
-1 > % C F B < 1
≥ 1 % g ai n: 
% C F B ≥1
5- C at e g ori e s
≥ 3. 5 % l o s s: % C F B ≤ -3. 5
≥ 1 % l o s s: 
-3. 5 > % C F B ≤ - 1
St a bl e: 
-1 > % C F B < 1
≥ 1 % g ai n: 
1 ≤ % C F B < 3. 5
≥ 3. 5 % g ai n: % C F B ≥3. 5
B ar c h art s of t h e s e p er c e nt a g e s of p arti ci p a nt s i n e a c h c at e g or y at W e e k 1 2 will al s o b e 
pr o d u c e d, wit h all tr e at m e nt s o n t h e s a m e pl ot ( o n e pl ot f or t h e 3 -c at e g or y d efi niti o n a n d 
o n e f or t h e 5-c at e g or y d efi niti o n).
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 2 of 6 0
6. 2. S e c o n d ar y  E n d p oi nt( s)
6. 2. 1. C h a n g e fr o m b a s eli n e i n p h y si c al a cti vit y  a n d g ait e n d p oi nt s m e a s ur e d wit h 
r e m ot e di git al s e n s or s at W e e k 1 2
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n t h e p h y si c al a cti vit y a n d g ait e n d p oi nt s (li st e d 
i n S e cti o n 3. 2. 1 ) will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s 
d e s cri b e d i n S e cti o n 5. 2. 1 .  T a bl e s will i n cl u d e b a s eli n e a n d all p o st-b a s eli n e ti m e p oi nt s. 
C h a n g e fr o m b a s eli n e i n t h e p h y si c al a cti vit y a n d g ait e n d p oi nt s will b e a n al y z e d u si n g a n 
M M R M m o d el a s d e s cri b e d i n
S e cti o n 5. 2. 3 . All ti m e p oi nt s u p t o W e e k  1 2 will b e i n cl u d e d i n 
t h e m o d el. A d diti o n al t er m s f or t y p e of t h er a p y [i. e. pl ati n u m or n ot] a n d t y p e of c a n c er will 
b e fitt e d i n t h e m o d el.  T hi s will b e u s e d t o e sti m at e t h e tr e at m e nt eff e ct r el at e d t o E sti m a n d 
2 ( a s d e s cri b e d i n S e cti o n 0 ). 
A d diti o n all y, t h e a m o u nt of a v ail a bl e p h y si c al a cti vit y a n d g ait d at a will b e s u m m ari z e d 
d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 2 .  If it i s 
d e e m e d t h at t h e a m o u nt of a v ail a bl e d at a i s i n s uffi ci e nt or t o o i m b al a n c e d a cr o s s t h e 
tr e at m e nt gr o u p s, t h e r e s ult s of t h e M M R M a n al y si s m a y n ot b e i n cl u d e d i n t h e C S R.
6. 2. 2. C h a n g e fr o m b a s eli n e i n F A A C T s u b -s c al e s c or e s at W e e k 1 2
F A A C T -A C S a n d F A A C T -5I A S S will b e s u m m ari z e d a n d a n al y z e d i n a si mil ar w a y t o t h e 
s e c o n d ar y e n d p oi nt d e s cri b e d i n S e cti o n 6. 2. 1 , T h e s e a n al y s e s will e sti m at e t h e tr e at m e nt 
eff e ct r el at e d t o E sti m a n d 3 ( a s d e s cri b e d i n S e cti o n 0 ).
6. 2. 3. C h a n g e fr o m b a s eli n e s c or e f or e a c h of t h e q u e sti o n s fr o m t h e C R C S D at W e e k 
1 2

A n or e xi a/ a p p etit e;

N a u s e a;

V o miti n g;

F ati g u e
W e e k l y a v er a g e d at a f or e a c h of t h e C R C S D e n d p oi nt s will b e s u m mari z e d a n d a n al y z e d i n 
a si mil ar w a y t o t h e s e c o n d ar y e n d p oi nt d e s cri b e d i n S e cti o n 6. 2. 1 . T h e s e a n al y s e s will 
e sti m at e t h e tr e at m e nt eff e ct r el at e d t o E sti m a n d 4 ( a s d e s cri b e d i n S e cti o n 0 ).
6. 2. 4. I n ci d e n c e of a d v er s e e v e nt s, s af et y l a b or at or y t e st s, vit al si g n s a n d E C G 
a b n or m aliti e s
A n al y si s o f a d v er s e e v e nt s, l a b or at or y a b n or m aliti e s, vit al si g n s a n d E C G a b n or m aliti e s will 
u s e t h e S af et y A n al y si s S et d ef i n e d i n S e cti o n 4 .
6. 2. 4. 1. A d v er s e E v e nt s
A d v er s e e v e nt s ( Ti er 1, 2 a n d 3 A E s a s d e s cri b e d i n S e cti o n 3. 2. 4. 1 ) will b e s u m m ari z e d b y 
tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d o v er all, i n a c c or d a n c e wit h s p o n s or 
r e p orti n g st a n d ar d s. T h e a d v er s e e v e nt s will b e s ort e d i n d e s c e n di n g fr e q u e n c y wit hi n a 
s y st e m or g a n cl a s s.  If a p pli c a bl e, s u bj e ct di s c o nti n u ati o n s d u e t o a d v er s e e v e nt s will b e 
d et ail e d a n d s u m m ari z e d.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 3 of 6 0
I n ci d e n c e a n d s e v erit y of T E A E a n d T E S A E t a bl e s will a d diti o n all y b e pr o d u c e d (‘ All 
c a u s alit y’ a n d ‘ Tr e at m e nt r el at e d’, s e p ar at el y) t o s u m m ari s e t h e t ot al n u m b er of a d v er s e 
e v e nt s b y pr ef err e d t er m, w hi c h will b e r e p ort e d b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b 
c o m bi n e d) a n d o v er all. 
T E A E s cl a s s e d a s Ti er 2 e v e nt s will e a c h b e t a b ul at e d b y tr e at m e nt gr o u p (i n cl u di n g 
p o n s e gr o m a b c o m bi n e d). T h e n u m b er a n d p er c e nt a g e of p arti ci p a nt s will b e pr e s e nt e d, 
al o n g wit h t h e ri s k diff er e n c e ( a n d 9 5 % c o nfi d e n c e i nt er v al) b et w e e n e a c h d o s e of 
p o n s e gr o m a b a n d pl a c e b o. N o a dj u st m e nt f or m ulti pli cit y will b e u s e d.
Ti er 2 T E A E s will al s o b e pr e s e nt e d gr a p hi c all y i n t w o -p a n el pl ot s; t h e l eft p a n el will pr e s e nt 
t h e pr o p orti o n s of T E A E s o b s er v e d i n a d o s e gr o u p of (i n cl u di n g p o n s e gr o m a b c o m bi n ed) 
a n d s e p ar at el y pl a c e b o, w hil e t h e ri g ht p a n el will di s pl a y t h e 9 5 % c o nfi d e n c e i nt er v al f or t h e 
ri s k diff er e n c e s f or e a c h T E A E. A v erti c al li n e c orr e s p o n di n g t o t h e v al u e of 0 will b e a d d e d 
t o t h e ri g ht-h a n d pl ot. E a c h p a n el will b e p a g e d b y d o s e of p o n s e gr o m a b. 
Ti er 2 T E A E o ut p ut s will b e or d er e d i n d e s c e n di n g p oi nt e sti m at e of ri s k diff er e n c e wit hi n 
S y st e m Or g a n Cl a s s. If t w o or m or e e v e nt s h a v e t h e s a m e fr e q u e n c y, t h e y will b e s ort e d 
al p h a b eti c all y b y pr ef err e d t er m.  F o ot n ot e s will b e i n cl u d e d o n t h e t a bl e s t o pr o vi d e pr o p er 
i nt er pr et ati o n of c o nfi d e n c e i nt er v al s a n d t o d e s cri b e h o w t h e c o m p ari s o n w a s c o n d u ct e d, 
e. g. “ C o nfi d e n c e i nt er v al s ar e n ot a dj u st e d f or m ulti pli cit y a n d s h o ul d b e u s e d f or s cr e e ni n g 
p ur p o s e s o nl y. 9 5 % C o nfi d e n c e i nt er v al s ar e pr o vi d e d t o h el p g a u g e t h e pr e ci si o n of t h e 
e sti m at e s f or Ri s k Diff er e n c e. Ri s k Diff er e n c e i s c o m p ut e d a s p o n s e gr o m a b v er s u s 
pl a c e b o.”
It s h o ul d b e r e c o g ni z e d t h at m o st st u di e s ar e n ot d e si g n e d t o r eli a bl y d e m o n str at e a c a u s al 
r el ati o n s hi p b et w e e n t h e u s e of a p h ar m a c e uti c al pr o d u ct a n d a n a d v er s e e v e nt or a gr o u p 
of  a d v er s e e v e nt s. E x c e pt f or s el e ct e v e nt s i n u ni q u e sit u ati o n s, st u di e s d o n ot e m pl o y 
f or m al a dj u di c ati o n pr o c e d ur e s f or t h e p ur p o s e of e v e nt cl a s sifi c ati o n. A s s u c h, s af et y 
a n al y si s i s g e n er all y c o n si d er e d a s a n e x pl or at or y a n al y si s a n d it s p ur p o s e i s t o g e n er at e 
h y p ot h e s e s f or f urt h er i n v e sti g ati o n. T h e 3 -ti er a p pr o a c h f a cilit at e s t hi s e x pl or at or y a n al y si s.
T E A E s cl a s s e d a s Ti er 1 e v e nt s will b e t a b ul at e d b y tr e at m e nt gr o u p (i n cl u di n g 
p o n s e gr o m a b c o m bi n e d ).  N ot e t h at Ti er 1 e v e nt s ar e n ot pl a n n e d t o b e pr e s e nt e d 
gr a p hi c all y d u e t o t h e s m all n u m b er of e x p e ct e d e v e nt s.
I nj e cti o n sit e r e a cti o n s (I S R) will al s o b e s u m m ari z e d b y tr e at m e nt gr o u p (i n cl u di n g 
p o n s e gr o m a b c o m bi n e d) a n d o v er all, i n a c c or d a n c e wit h s p o n s or r e p orti n g st a n d ar d s. T h e 
I S R s will b e s ort e d i n d e s c e n di n g fr e q u e n c y wit hi n a s y st e m or g a n cl a s s. I n ci d e n c e a n d 
s e v erit y of I S R t a bl e s will a d diti o n all y b e pr o d u c e d (‘ All c a u s alit y’ a n d ‘ Tr e at m e nt r el at e d’, 
s e p ar at el y) t o s u m m ari z e t h e t ot al n u m b er of I S R b y pr ef err e d t er m, w hi c h will b e r e p ort e d 
b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d o v er all.
P ot e nti al i m m u n o g e ni c A E s will b e s u m m ari z e d b y m e di c al e v al u ati o n c at e g or y a n d 
tr e at m e nt gr o u p s (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d o v er all. T h e n u m b er a n d 
p er c e nt a g e of p arti ci p a nt s, j u d g e d t o h a v e m et t h e i m m u n e r e a cti o n crit eri a (i nj e cti o n sit e 
r e a cti o n s, p ot e nti al c a s e s of a n gi o e d e m a, a n a p h yl a xi s, h y p er s e n siti vit y, d el a y e d 
h y p er s e n siti vit y r e a cti o n s a n d e v e nt s p ot e nti all y m e eti n g t h e S a m p s o n crit eri a), will b e 
t a b ul at e d b y tr e at m e nt gr o u p ( a n d wit h p o n s e gr o m a b tr e at m e nt gr o u p s c o m bi n e d o nl y) a n d 
o v er all, a n d b y s e v erit y.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 4 of 6 0
6. 2. 4. 2. L a b or at or y  D at a
L a b or at or y d at a will b e li st e d a n d s u m m ari z e d b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b 
c o m bi n e d) a n d o v e r all, i n a c c or d a n c e wit h t h e s p o n s or r e p orti n g st a n d ar d s.
6. 2. 4. 3. Vit al Si g n s
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n s u pi n e s y st oli c a n d di a st oli c B P, a n d p ul s e 
r at e will b e s u m m ari z e d b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d o v er all, 
a n d ti m e p oi nt, a c c or di n g t o s p o n s or r e p orti n g st a n d ar d s. T a bl e s will b e p a g e d b y p ar a m et er.  
I n a d diti o n, c h a n g e s fr o m b a s eli n e will b e a n al y z e d u si n g a n M M R M m o d el, a s d e s cri b e d i n 
S e cti o n 5. 2. 3 . T h e M M R M m o d el will b e fitt e d t o t h e c h a n g e fr o m b a s eli n e at all p o st-
tr e at m e nt ti m e p oi nt s u p t o We e k 1 2 u si n g t h e s af et y a n al y si s s et ( a s d efi n e d i n S e cti o n 4 ). 
A d diti o n al t er m s will b e fitt e d i n t h e m o d el ( e g, t y p e of t h er a p y [i e, pl ati n u m or n ot], t y p e of 
c a n c er), a s a p pr o pri at e.
M a xi m u m d e cr e a s e fr o m b a s eli n e f or s u pi n e s y st oli c a n d di a st oli c bl o o d pr e s s ur e s a n d 
m a xi m u m i n cr e a s e fr o m b a s eli n e f or s u pi n e p ul s e r at e will b e s u m m ari z e d b y tr e at m e nt 
gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d o v er all, a c c or di n g t o s p o n s or r e p orti n g 
st a n d ar d s.
M a xi m u m a b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e f or s u pi n e vit al si g n s will al s o b e 
s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d 
o v er all, u si n g c at e g ori e s a s d efi n e d i n A p p e n di x 6 . N u m b er s a n d p er c e nt a g e s of p arti ci p a nt s 
m e eti n g t h e c at e g ori c al crit eri a will b e pr o vi d e d. All pl a n n e d a n d u n pl a n n e d p o st d o s e ti m e 
p oi nt s will b e c o u nt e d i n t h e s e c at e g ori c al s u m m ari e s. All v al u e s m e eti n g t h e crit eri a of 
p ot e nti al cli ni c al c o n c er n will b e li st e d.
6. 2. 4. 4. E C G s
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e f or t h e E C G p ar a m et er s (i e, H R, P R i nt er v al, 
Q T i nt er v al, Q T c F a n d Q R S c o m pl e x) will b e s u m m ari z e d b y tr e at m e nt gr o u p (i n cl u di n g 
p o n s e gr o m a b c o m bi n e d) a n d o v er all, a n d ti m e p oi nt a c c or di n g t o s p o n s or r e p orti n g 
st a n d ar d s. T a bl e s will b e p a g e d b y p ar a m et er. 
I n a d diti o n, c h a n g e s fr o m b a s eli n e will b e a n al y z e d u si n g a n M M R M m o d el, a s d e s cri b e d i n 
S e cti o n 5. 2. 3 . T h e M M R M m o d el will b e fitt e d t o t h e c h a n g e fr o m b a s eli n e at all p o st-
tr e at m e nt ti m e p oi nt s u p t o We e k 1 2 u si n g t h e s af et y a n al y si s s et ( a s d efi n e d i n S e cti o n 4 ). 
A d diti o n al t er m s will b e fitt e d i n t h e m o d el ( e g, t y p e of t h er a p y [i e, pl ati n u m or n ot], t y p e of 
c a n c er), a s a p pr o pri at e.
M a xi m u m i n cr e a s e fr o m b a s eli n e f or Q T c F will b e s u m m ari z e d b y tr e at m e nt gr o u p (i n cl u di n g 
p o n s e gr o m a b c o m bi n e d) a n d o v er all, a c c or di n g t o s p o n s or r e p orti n g st a n d ar d s. 
M a xi m u m a b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e f or Q T c F, P R a n d Q R S will al s o b e 
s u m m a ri z e d d e s cri pti v el y b y tr e at m e nt gr o u p (i n cl u di n g p o n s e gr o m a b c o m bi n e d) a n d 
o v er all, u si n g c at e g ori e s a s d efi n e d i n A p p e n di x 6 . N u m b er s a n d p er c e nt a g e s of p arti ci p a nt s 
m e eti n g t h e c at e g ori c al crit eri a will b e pr o vi d e d. All pl a n n e d a n d u n pl a n n e d p o st d o s e 
ti m e p oi nt s will b e c o u nt e d i n t h e s e c at e g ori c al s u m m ari e s. All v al u e s m e eti n g t h e crit eri a of 
p ot e nti al cli ni c al c o n c er n will b e li st e d. 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 5 of 6 0
Li sti n g s of p arti ci p a nt s wit h a n y si n gl e p o st d o s e v al u e > 5 0 0 m s e c will al s o b e pr o d u c e d f or 
Q T c F.
6. 3. Ot h er S af et y  S u m m ari e s a n d A n al y s e s E n d p oi nt( s)
S e e S e cti o n 6. 2. 4 .
6. 4. Ot h er E n d p oi nt s/ E x pl or at or y  E n d p oi nt s
6. 4. 1. C h a n g e fr o m b a s eli n e i n a d diti o n al p h y si c al a cti vit y  a n d g ait e n d p oi nt s 
m e a s ur e d wit h r e m ot e di git al s e n s or s at W e e k 1 2
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n t h e a d diti o n al p h y si c al a cti vit y a n d g ait 
e n d p oi nt s (li st e d i n S e cti o n 3. 4. 1 ) will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d 
ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 .
6. 4. 2. C h a n g e fr o m b a s eli n e i n a d diti o n al F A A C T t ot al a n d s u b -s c al e s c or e s at W e e k 
1 2
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n t h e a d diti o n al F A A C T t ot al a n d s u b -s c al e 
s c or e s (li st e d i n S e cti o n 3. 4. 2 ) will b e s u m m ari z e d d e s cr i pti v el y b y tr e at m e nt gr o u p a n d 
ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 .
6. 4. 3. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of p o n s e gr o m a b o n D a y  1, W e e k s 4, 5, 
8, 1 0, 1 2 a n d 1 6 (f oll o w- u p) , pl u s W e e k 9 a n d 1 1 i n P K s u b st u d y o nl y
P K a n al y s e s will b e p erf or m e d u si n g t h e P K a n al y si s s et, a s d efi n e d i n S e cti o n 4 .
A li sti n g of s er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s, s ort e d b y tr e at m e nt gr o u p, p arti ci p a nt 
a n d ti m e p oi nt, will b e pr o d u c e d. T h e li sti n g will al s o i n cl u d e t h e a ct u al ti m e s a n d will i n cl u d e 
a ll p arti ci p a nt s a n d all ti m e p oi nt s. 
A d diti o n all y, t h e f oll o wi n g pr e s e nt ati o n s f or s er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of 
p o n s e gr o m a b will b e pr o d u c e d, s e p ar at el y f or 1) all p arti ci p a nt s ( e x cl u di n g We e k 9 a n d 1 1 
ti m e p oi nt s) a n d 2) f or o nl y p arti ci p a nt s i n t h e P K s u b st u d y (i n cl u di n g all ti m e p oi nt s): 

A s u m m ar y of c o n c e ntr ati o n s b y tr e at m e nt gr o u p a n d ti m e p oi nt, w h er e t h e s et of 
st ati sti c s will i n cl u d e n, arit h m eti c m e a n, S D, c o effi ci e nt of v ari ati o n ( C V %), 
mi ni m u m, Q 1, m e di a n, Q 3, m a xi m u m, g e o m etri c m e a n, g e o m etri c C V %, a n d t h e 
n u m b er of c o n c e ntr ati o n s a b o v e t h e L L Q

M e di a n c o n c e ntr ati o n -ti m e pl ot ( o n a s e mi-l o g s c al e, all tr e at m e nt s o n t h e s a m e 
pl ot), Q 1 a n d Q 3 m a y b e i n cl u d e d

M e a n ( ± S D) c o n c e ntr ati o n -ti m e pl ot ( o n a s e mi-l o g s c al e, all tr e at m e nt s o n t h e sa m e 
pl ot)

M e di a n tr o u g h c o n c e ntr ati o n -ti m e pl ot ( o n a li n e ar s c al e, all tr e at m e nt s o n t h e s a m e 
pl ot), Q 1 a n d Q 3 m a y b e i n cl u d e d

M e a n
( ± S D) tr o u g h c o n c e ntr ati o n-ti m e pl ot ( o n a li n e ar s c al e, all tr e at m e nt s o n t h e 
s a m e pl ot) .
N ot e t h at t h e s e p ar at e pr e s e nt at i o n s f or t h e p arti ci p a nt s i n t h e P K s u b st u d y m a y b e r e p ort e d 
i n a s u p pl e m e nt al C S R r at h er t h a n t h e m ai n C S R.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 6 of 6 0
6. 4. 4. S er u m u n b o u n d a n d t ot al c o n c e ntr ati o n s of G D F -1 5 o n D a y  1, W e e k s 4, 5, 8, 1 0, 
1 2 a n d 1 6 (f oll o w -u p ), pl u s W e e k 9 a n d 1 1 i n P K s u b st u d y o nl y
P D a n al y s e s will b e p erf or m e d u si n g t h e P D a n al y si s s et, a s d efi n e d i n S e cti o n 4 .
A li sti n g of u n b o u n d a n d t ot al G D F -1 5 s er u m c o n c e ntr ati o n l e v el s, s ort e d b y tr e at m e nt 
gr o u p, p arti ci p a nt a n d ti m e p oi nt, will b e pr o d u c e d. T h e li sti n g will al s o i n cl u d e t h e f ol d 
c h a n g e fr o m b a s eli n e a n d will i n cl u d e all p arti ci p a nt s a n d all ti m e p oi nt s .  F or u n b o u n d G D F-
1 5, t h e li sti n g will al s o i n cl u d e a c ol u m n t o i n di c at e w h et h er t h e a b s ol ut e G D F -1 5 
c o n c e ntr ati o n i s b el o w t h e h e alt h y v ol u nt e er m e di a n l e v el or n ot.
A d diti o n all y, t h e f oll o wi n g pr e s e nt ati o n s f or u n b o u n d a n d t ot al G D F -1 5 s er u m c o n c e ntr ati o n 
l e v el s will b e pr o d u c e d, s e p ar at el y f or 1) all p arti ci p a nt s ( e x cl u din g W e e k 9 a n d 1 1 
ti m e p oi nt s) a n d 2) f or o nl y p arti ci p a nt s i n t h e P K s u b st u d y (i n cl u di n g all ti m e p oi nt s):

A s u m m ar y of c o n c e ntr ati o n s ( a b s ol ut e v al u e s a n d f ol d c h a n g e s fr o m b a s eli n e) b y 
tr e at m e nt gr o u p a n d ti m e p oi nt, w h er e t h e s et of st ati sti c s will i n cl u d e ( a s d at a p er mit) 
n, arit h m eti c m e a n, S D, C V %, mi ni m u m, Q 1, m e di a n, Q 3, m a xi m u m, g e o m etri c 
m e a n, g e o m etri c C V % a n d t h e n u m b er of c o n c e ntr ati o n s a b o v e t h e L L Q

A s u m m ar y of w h et h er t h e a b s ol ut e u n b o u n d G D F -1 5 c o n c e ntr ati o n s ar e b el o w t h e 
h e alt h y v ol u nt e er m e di a n l e v el or n ot, b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s 
d e s cri b e d i n S e cti o n 5. 2. 2

M e di a n c o n c e ntr ati o n -ti m e pl ot s (f or a b s ol ut e v al u e s o nl y) ( o n a li n e ar s c al e, all 
tr e at m e nt s o n t h e s a m e pl ot), Q 1 a n d Q 3 m a y b e i n cl u d e d

M e a n ( ± S D, if a p pr o pri at e) c o n c e ntr ati o n -ti m e pl ot s (f or a b s ol ut e v al u e s o nl y) ( o n a 
li n e ar s c al e, all tr e at m e nt s o n t h e s a m e pl ot).
I n all pr e s e nt ati o n s, t h e f ol d c h a n g e s will b e pr e s e nt e d a s p er c e nt c h a n g e fr o m b a s eli n e 
([f ol d c h a n g e fr o m b a s eli n e -1]* 1 0 0).
N ot e t h at t h e s e p ar at e pr e s e nt ati o n s f or t h e p arti ci p a nt s i n t h e P K s u b st u d y m a y b e r e p ort e d 
i n a s u p pl e m e nt al C S R r at h er t h a n t h e m ai n C S R.
6. 4. 5. I n ci d e n c e of AD A  a n d N Ab
I m m u n o g e nicit y a n al y s e s will b e p erf or m e d o n t h e i m m u n o g e ni cit y a n al y si s s et d efi n e d i n 
S e cti o n 4 . 
If a p pli c a bl e a n d d at a p er mit, i m m u n o g e ni cit y a n al y s e s will i n cl u d e:                                                                

A li sti n g of A D A a n d N A b r e s ult s f or all p arti ci p a nt s  

A s u m m ar y ( b ot h t a bl e a n d fi g ur e, if a p pr o pri at e) of t h e o v er all i n ci d e n c e of A D A a n d 
N A b

T h e p er c e nt a g e of p arti ci p a nt s w h o ar e A D A a n d N A b p o siti v e at e a c h ti m e p oi nt a n d 
t h e c u m ul ati v e p er c e nt a g e of A D A -p o siti v e or N A b -p o siti v e p arti ci p a nt s u p t o e a c h 
ti m e p oi nt.
If a p pr o pri at e ( e. g. t h e n u m b er of A D A-p o siti v e p arti ci p a nt s i s ≥3 p er tr e at m e nt gr o u p), t h e
a d diti o n al a n al y s e s b el o w m a y b e p erf or m e d:

A s p a g h etti pl ot of i n di vi d u al p arti ci p a nt A D A a n d N A b tit er o v er ti m e 

A s u m m ar y of A D A a n d N A b tit er b y ti m e
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 7 of 6 0

A n al y si s of u n b o u n d a n d t ot al p o n s e gr o m a b c o n c e ntr ati o n b y A D A a n d N A b st at u s. 
T hi s m a y i n cl u d e s u m m ar y t a bl e s a n d b o x a n d/ or s p a g h etti pl ot s of c o n c e ntr ati o n 
d at a b y A D A a n d N A b st at u s

A n al y si s of u n b o u n d a n d/ or t ot al p o n s e gr o m a b c o n c e ntr ati o n b y m a xi m u m A D A a n d 
N A b tit er t ertil e, w hi c h m a y i n cl u d e s u m m ar y t a bl e s a n d b o x pl ot s of c o n c e ntr ati o n 
d at a b y t it er t ertil e if a l ar g e n u m b er of A D A-p o siti v e p arti ci p a nt s i s r e p ort e d ( e. g 
n > 1 0)

A n al y si s of u n b o u n d a n d/ or t ot al G D F -1 5 c o n c e ntr ati o n ( a s d at a p er mit) b y A D A a n d 
N A b st at u s, w hi c h m a y i n cl u d e s u m m ar y t a bl e s a n d b o x a n d/ or s p a g h etti pl ot s of 
c o n c e ntr ati o n d at a b y A D A a n d N A b st at u s

A n al y si s of u n b o u n d a n d/ or t ot al G D F -1 5 c o n c e ntr ati o n ( a s d at a p er mit) b y m a xi m u m 
A D A a n d N A b tit er t ertil e, w hi c h m a y i n cl u d e s u m m ar y t a bl e s a n d b o x pl ot s of 
c o n c e ntr ati o n d at a b y tit er t ertil e if a l ar g e n u m b er of A D A -p o siti v e p arti ci p a nt s i s 
r e p ort e d ( e. g n > 1 0)

A n i n di vi d u al pl ot of u n b o u n d a n d t ot al p o n s e gr o m a b c o n c e ntr ati o n, u n b o u n d a n d/ or 
t ot al G D F-1 5 c o n c e ntr ati o n ( a s d at a p er mit), A D A a n d N A b tit er i n A D A -p o siti v e 
p arti ci p a nt s.
6. 4. 6. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -F ati g u e at W e e k 1 2
P R O MI S F ati g u e T -s c or e will b e s u m m ari z e d a n d a n al y z e d i n a si mil ar w a y t o t h e 
s e c o n d ar y e n d p oi nt d e s cri b e d i n S e cti o n 6. 2. 1 .
6. 4. 7. C h a n g e fr o m b a s eli n e s c or e f or P R O MI S -P h y si c al F u n cti o n at W e e k 1 2
P R O MI S P h y si c al F u n cti o n T -s c or e will b e s u m m ari z e d a n d a n al y z e d i n a si mil ar w a y t o t h e 
s e c o n d ar y e n d p oi nt d e s cri b e d i n S e cti o n 6. 2. 1 .
6. 4. 8. P GI -C at W e e k 1 2; C h a n g e fr o m b a s eli n e i n P GI -S at W e e k 1 2 
A b s ol ut e v al u e s i n P GI -C will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt
a s d e s cri b e d i n S e cti o n 5. 2. 2 .
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n P GI -S will b e s u m m ari z e d d e s cri pti v el y b y 
tr e at m e nt gr o u p a n d ti m e p oi nt a s d e s cri b e d i n S e cti o n 5. 2. 2 .
6. 4. 9. T u m or st at u s a c c or di n g t o R E CI S T 1. 1 g ui d eli n e s u si n g C T s c a n at W e e k 1 2
T h e o v er all t u m or r e s p o n s e will b e s u m m ari z e d b y tr e at m e nt, a s d e s cri b e d i n S e cti o n 5. 2. 2 , 
u si n g t h e c at e g ori e s d efi n e d i n A p p e n di x 1 1 of t h e pr ot o c ol.
6. 4. 1 0. C h a n g e fr o m b a s eli n e i n L S MI d eri v e d fr o m C T s c a n s at W e e k 1 2; P er c e nt 
c h a n g e fr o m b a s eli n e i n s k el et al m u s cl e a n d a di p o s e ti s s u e m e a s ur e s d eri v e d fr o m 
C T s c a n s at W e e k 1 2
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n L S MI will b e s u m m ari z e d d e s cri pti v el y b y 
tr e at m e nt gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 .  
C h a n g e fr o m b a s eli n e i n L S MI will b e a n al y z e d u si n g A N C O V A a s d e s cri b e d i n S e cti o n 
5. 2. 5 . A d diti o n al ter m s f or t y p e of t h er a p y [i. e. pl ati n u m or n ot] a n d t y p e of c a n c er will b e 
fitt e d i n t h e m o d el.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 8 of 6 0
A b s ol ut e v al u e s a n d p er c e nt c h a n g e s fr o m b a s eli n e i n s k el et al m u s cl e a n d a di p o s e ti s s u e 
m e a s ur e s (li st e d i n S e cti o n 3. 4. 1 0 ) will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d 
ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 .
6. 4. 1 1. C h a n g e fr o m b a s eli n e al b u mi n a n d pr e -al b u mi n l e v el s at W e e k 1 2
A b s ol ut e v al u e s a n d f ol d c h a n g e s fr o m b a s eli n e i n al b u mi n a n d pr e -al b u mi n will b e 
s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 .
6. 4. 1 2. S ur vi v al st at u s at e n d of P art A
S ur vi v al st at u s at t h e e n d of P art A ( W e e k 1 2) will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt 
gr o u p a n d o v er all , a s d e s cri b e d i n S e cti o n 5. 2. 2 . 
Ti m e t o d e at h will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p, a s d e s cri b e d i n S e cti o n 
5. 2. 1 . A c u m ul ati v e i n ci d e n c e pl ot, a s d e s cri b e d i n S e cti o n 5. 2. 6 will al s o b e pr o d u c e d. Ti m e 
t o d e at h will b e a n al y z e d u si n g a C o x-pr o p orti o n al h a z ar d s m o d el, a s d e s cri b e d i n S e cti o n 
5. 2. 7 .  All d e at h s will ad diti o n all y b e li st e d.
6. 4. 1 3. R e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y  wei g ht at 
W e e k 1 2
R e s p o n s e a s d efi n e d b y a ≥3. 5 % i n cr e a s e fr o m b a s eli n e i n b o d y w ei g ht will b e s u m m ari z e d 
d e s cri pti v el y b y tr e at m e nt gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 2 , wit h n o 
i m p ut ati o n f or mi s si n g d at a, i n cl u di n g all p o st-b a s eli n e ti m e p oi nt s u p t o W e e k 1 2 (i e. W e e k s 
4, 8 a n d 1 2).  B ar c h art s of t h e p er c e nt a g e s o v er ti m e will al s o b e pr o d u c e d, wit h all 
tr e at m e nt s o n t h e s a m e pl ot.
T h e p er c e nt a g e of r e s p o n s e s ( a n d 9 0 % CI s) at W e e k 1 2 will al s o b e r e p ort e d b y tr e at m e nt 
af t er m ulti pl e i m p ut ati o n f or mi s si n g v al u e s a s p er S e cti o n 5. 3. 1 .  T h e s e r e s p on s e s will al s o 
b e a n al y z e d s e p ar at el y u si n g a l o gi sti c r e gr e s si o n m o d el ( a s d e s cri b e d i n S e cti o n 5. 2. 8 ), 
w h er e mi s si n g v al u e s will b e i m p ut e d u si n g m ulti pl e i m p ut ati o n a s p er S e cti o n 5. 3. 1 . T h e 
l o gi sti c r e gr e s si o n m o d el will b e fitt e d t o t h e d at a at W e e k  1 2 o nl y.
6. 5. S u b s et A n al y s e s
A d diti o n al a n al y s e s will b e p erf or m e d o n t h e pri m ar y e n d p oi nt ( c h a n g e fr o m b a s eli n e b o d y 
w e i g ht) t o a s s e s s t h e eff e ct of t h e f oll o wi n g t w o s u b gr o u p f a ct or s:  

T y p e of c a n c er (i. e. N S C L C, P A N C or C R C)

T y p e of t h er a p y (i e, pl ati n u m or n ot) at r a n d o mi z ati o n [ +/ - 2 8 d a y s]

S cr e e ni n g R o c h e G D F -1 5 ( di c h ot o mi z e d u si n g < or ≥ o v er all st u d y m e di a n l e v el ( or 
a n alt er n ati v e c ut -p oi nt, if a p pr o pri at e))
T h e s e a n al y s e s will b e p erf or m e d o n t h e c e n s or e d a n al y si s s et, a s d efi n e d i n S e cti o n 4 .
F or e a c h s u b gr o u p f a ct or, a b s ol ut e v al u e s, c h a n g e s fr o m b a s eli n e a n d p er c e nt c h a n g e s 
fr o m b a s eli n e i n b o d y w ei g ht will b e s u m m ari z e d d e s cri pti v el y b y s u b gr o u p f a ct or, tr e at m e nt 
gr o u p a n d ti m e p oi nt, a s d e s cri b e d i n S e cti o n 5. 2. 1 . T a bl e s will i n cl u d e b a s eli n e a n d all p o st-
b a s eli n e ti m e p oi nt s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 3 9 of 6 0
F or e a c h s u b gr o u p f a ct or, c h a n g e fr o m b a s eli n e i n b o d y w ei g ht will b e a n al y z e d u si n g a n 
M M R M m o d el, a s d e s cri b e d i n S e cti o n 6. 1. 1. 1 .  A d diti o n al t er m s f or t h e s u b gr o u p f a ct or a n d 
it s i nt er a cti o n wit h tr e at m e nt gr o u p, ti m e a n d t h e tr e at m e nt-b y -ti m e i nt er a cti o n, will b e 
i n cl u d e d i n t h e m o d el.  Ot h er t er m s ( e g, t y p e of t h er a p y [i. e. pl ati n u m or n ot] a n d t y p e of 
c a n c er; d e s cri b e d i n S e cti o n 6. 1. 1. 1 ) will b e dr o p p e d fr o m t h e m o d el, a s a p pr o pri at e.  L S 
m e a n s ( a n d 9 0 % CI s) a n d m e a n diff er e n c e s v er s u s pl a c e b o ( a n d 9 0 % CI s) will b e pr o vi d e d. 
T h e p -v al u e s f or t h e s u b gr o u p i nt er a cti o n t er m s will b e i n cl u d e d i n t h e t a bl e s, e. g. a s a 
f o ot n ot e.  N o a dj u st m e nt s will b e m a d e f or m ulti pli cit y.
If t h e M M R M m o d el c a n n ot b e fitt e d t o t h e d at a, or t h e m o d el i s d e e m e d i n a p pr o pri at e, t h e 
m o d el m a y b e si m plifi e d, or t h e a n al y si s m a y n ot b e p erf or m e d.
A d diti o n all y, s cr e e ni n g R o c h e G D F -1 5 will b e pl ott e d v s W e e k 1 2 c h a n g e fr o m b a s eli n e 
b o d y w ei g ht u si n g a s c att er pl ot. T h e pl ot will i n cl u d e all p arti ci p a nt s a n d m a y b e 
c ol or e d/tr elli s e d b y diff er e nt c a n c er t y p e s a n d/ or t y p e of t h er a p y.
6. 6. B a s eli n e a n d Ot h er S u m m ari e s a n d A n al y s e s
6. 6. 1. B a s eli n e S u m m ari e s
D e m o gr a p hi c d at a, c o n c o mit a nt m e di c ati o n s, G D F -1 5 c o n c e ntr ati o n s ( at s cr e e ni n g, u si n g 
t h e R o c h e El e c s y s a s s a y), h ei g ht, w ei g ht, B MI, E C O G P S ( at s cr e e ni n g). L S MI, s ar c o p e ni a 
st at u s a n d B MI -a dj u st e d w ei g ht l o s s c at e g or y will b e s u m m ari z e d, a s d efi n e d i n S e cti o n 
5. 2. 1 or 5. 2. 2 , a s a p pr o pri at e. 
I n a d diti o n, a s u b s et of m e di c al hi st or y d at a will b e r e p ort e d; t hi s will i n cl u d e t y p e a n d st a g e 
of c a n c er , T N M st a g e, t h e e xt e nt of t h e c a n cer ( e. g m et a st ati c v s n o n -m et a st ati c; l o c ati o n of 
m et a st ati c di s e a s e), t h e ti m e fr o m c a n c er di a g n o si s t o r a n d o mi z ati o n, a n d t h e p er c e nt 
w e i g ht l o s s i n t h e 6 m o nt h s pri or t o s cr e e ni n g, w h er e f e a si bl e.  C a n c er t h er a p y d et ail s will 
al s o b e s u m m ari z e d, a s d efi n e d i n S e cti o n 5. 2. 1 or 5. 2. 2 , a s a p pr opri at e, i n cl u di n g li n e a n d 
t y p e of pri or c a n c er t h er a p y, t y p e a n d i nt e nt of c urr e nt c a n c er t h er a p y a n d w h et h er 
p arti ci p a nt s ar e c urr e ntl y r e c ei vi n g n o c a n c er tr e at m e nt, or c a n c er tr e at m e nt wit h or wit h o ut 
pl ati n u m -b a s e d c h e m ot h er a p y ( b ot h at r a n d o mi z ati o n [ +/- 2 8 d a y s] a n d d uri n g tr e at m e nt 
p h a s e) a n d w h et h er s ur g er y or r a di ati o n w a s p art of t hi s c a n c er tr e at m e nt . 
B a s eli n e i nfl a m m ati o n will al s o b e s u m m ari z e d, a s d efi n e d i n S e cti o n 5. 2. 1 or 5. 2. 2 , a s 
a p pr o pri at e, i n cl u di n g C R P, al b u mi n, C R P -al b u mi n r ati o, m o difi e d Gl a s g o w Pr o g n o sti c 
S c or e, N L R a n d P L R. 
T h e a b o v e b a s eli n e s u m m ari e s will al s o b e pr o d u c e d s e p ar at el y f or t h e P K s u b st u d y o nl y 
b ut m a y b e r e p ort e d i n a s u p pl e m e nt al C S R r at h er t h a n t h e m ai n C S R.
Ot h er d at a c oll e ct e d at S cr e e ni n g t h at ar e u s e d f or i n cl u si o n/ e x cl u si o n crit eri a, s u c h a s 
l a b or at or y d at a, will b e c o n si d er e d s o ur c e d at a, a n d will n ot b e r e q uir e d t o b e r e p ort e d, 
u nl e s s ot h er wi s e n ot e d.
6. 6. 2. St u d y  C o n d u ct a n d P arti ci p a nt Di s p o siti o n
P arti ci p a nt e v al u ati o n gr o u p s will s h o w p arti ci p a nt di s p o siti o n f or e a c h p h a s e of P art A of 
t h e st u d y ( s cr e e ni n g, tr e at m e nt a n d f oll o w-u p f or p arti ci p a nt s n ot c o nti n ui n g t o P art B of t h e 
st u d y) . T h e y will a d diti o n all y s h o w w hi c h p arti ci p a nt s w er e a n al y z e d f or effi c a c y, P K, P D, 
i m m u n o g e ni cit y a s w ell a s f or s af et y. Fr e q u e n c y c o u nt s a n d p er c e nt a g e s will b e s u p pli e d f or 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 0 of 6 0
p arti ci p a nt di s c o nti n u ati o n( s) b y tr e at m e nt gr o u p a n d o v er all.  D at a will b e r e p ort e d i n 
a c c or d a n c e wit h t h e s p o n s or r e p orti n g st a n d ar d s.
6. 6. 3. C o n c o mit a nt M e di c ati o n s a n d N o n dr u g Tr e at m e nt s/ Pr o c e d ur e s
All pri or a n d c o n c o mit a nt m e di c ati o n( s) a s w ell a s n o n -dr u g tr e at m e nt( s)/ pr o c e d ur e( s) will b e 
r e p ort e d a c c or di n g t o c urr e nt s p o n s or r e p ortin g st a n d ar d s .
A d diti o n all y, a n y a cti o n s t a k e n wit h p arti ci p a nt s’ a nti -c a n c er t h er a p y ( e. g. di s c o nti n u ati o n or 
d o s e -r e d u cti o n) d uri n g t h e st u d y will b e s u m m ari z e d d e s cri pti v el y b y tr e at m e nt gr o u p, a s 
d ef i n e d i n S e cti o n 5. 2. 2 .
6. 6. 4. Tr e at m e nt C o m pli a n c e
A s u m m ar y t a bl e of tr e at m e nt c o m pli a n c e will b e pr o d u c e d a c c or di n g t o c urr e nt s p o n s or 
r e p orti n g st a n d ar d s.
6. 6. 5. R et ai n e d R e s e ar c h S a m pl e s
P h ar m a c o g e n o mi c or bi o m a r k er d at a fr o m R et ai n e d R e s e ar c h S a m pl e s m a y b e c oll e ct e d 
d uri n g or aft er t h e tri al a n d r et ai n e d f or f ut ur e a n al y s e s; t h e r e s ult s of s u c h a n al y s e s ( ot h er 
t h a n C R P, a s d e s cri b e d i n S e cti o n 3. 5 ) ar e n ot pl a n n e d t o b e i n cl u d e d i n t h e C S R.
6. 6. 6. P o p ul ati o n P K
A s p er mitt e d b y d at a, a n d d et er mi n e d b y t h e s p o n s or, t h e P K/ P D r el ati o n s hi p b et w e e n 
s er u m p o n s e gr o m a b c o n c e ntr ati o n a n d t h e eff e ct o n pri m ar y, s e c o n d ar y a n d/ or t erti ar y 
e n d p oi nt s m a y b e e x pl or e d u si n g a p o p ul ati o n P K/ P D a p pr o a c h. T h e p o p ul ati o n P K/ P D 
a n al y si s, if c o n d u ct e d, will b e r e p ort e d i n a s e p ar at e r e p ort.
7. I N T E RI M A N A L Y S E S
7. 1. I ntr o d u cti o n
I nt eri m a n al y s e s m a y b e p erf or m e d t o a s s e s s effi c a c y a n d/ or s af ety aft er at l e a st 
a p pr o xi m at el y 2 5 % of t h e pl a n n e d p arti ci p a nt s, i e, a p pr o xi m at el y 3 0 p arti ci p a nt s, c o m pl et e 
t h eir st u d y p arti ci p ati o n t hr o u g h W e e k 1 2 of t h e st u d y. I nt eri m a n al y si s r e s ult s m a y b e u s e d 
f or d e ci si o n s r e g ar di n g st o p pi n g f or f utilit y, st o p pi n g f or e arl y s u c c e s s, c o n d u cti n g a s a m pl e 
si z e r e -e sti m ati o n, or a d a pti n g t h e st u d y aft er t h e i nt eri m a n al y si s. P arti ci p a nt s m a y b e 
di s c o nti n u e d fr o m t h e st u d y i nt er v e nti o n/ st u d y a s a r e s ult of t h e i nt eri m a n al y si s, a s 
d e s cri b e d i n t h e pr ot o c ol.
B ef or e a n y i nt eri m a n al y si s i s p erf or m e d, t h e d et ail s of t h e o bj e cti v e s, d e ci si o n crit eri a, 
di s s e mi n ati o n pl a n, a n d m et h o d of m ai nt ai ni n g t h e st u d y bli n d (if a p pli c a bl e) a s p er Pfi z er’ s 
S O P s will b e d o c u m e nt e d a n d a p pr o v e d i n a n I R C c h art er.
I n a d diti o n, o n g oi n g m o nitori n g of t h e s af et y of p arti ci p a nt s will b e p erf or m e d b y a n I R C.  
F urt h er d et ail s ar e pr o vi d e d i n S e cti o n 1 0. 1. 5. 1 of t h e pr ot o c ol a n d will b e f urt h er 
d o c u m e nt e d i n a n I R C c h art er .
F oll o wi n g c o m pl eti o n of P art A ( P C D), t h e d at a will b e a n al y z e d a n d r e p ort e d i n t h e C S R.  
T h e r e s ult s f or P art B will b e r e p ort e d s e p ar at el y at t h e e n d of P art B.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 1 of 6 0
7. 2. I nt eri m An al y s e s a n d S u m m ari e s
A n i nt eri m a n al y si s m a y b e c o n d u ct e d aft er a p pr o xi m at el y 5 0 % of r a n d o mi z e d p arti ci p a nt s 
r e a c h t h e W e e k  1 2 vi sit i n P art A or di s c onti n u e t h e st u d y pri or t o t h at vi sit. 
T h e p arti ci p a nt s t o b e i n cl u d e d i n t h e i nt eri m a n al y si s ar e:
I nt eri m P o p ul ati o n
D e s cri pti o n
I nt eri m S af et y P o p ul ati o n
All p arti ci p a nt s r a n d o mi z e d pri or t o t h e d at e of d at a s n a p s h ot. 
I nt eri m Effi c a c y P o p ul ati o n
P arti ci p a nt s w h o w er e r a n d o mi z e d u p t o 1 1 S E P 2 0 2 3 
All i nt eri m a n al y s e s will b e c arri e d o ut u si n g t h e r el e v a nt A n al y si s S et ( a s d efi n e d i n S e cti o n 
4 ) a p pli e d t o t h e I nt eri m P o p ul ati o n s d e s cri b e d a b o v e.
7. 2. 1. Effi c a c y  E n d p oi nt s
F or b o d y w ei g ht , t h e d e s cri pti v e s u m m ari e s a n d m ai n st ati sti c al a n al y s e s, d e s cri b e d i n 
S e cti o n 6. 1. 1. 1 , will b e p erf or m e d.  A d diti o n all y, B a y e si a n pr e di cti v e pr o b a biliti e s will b e 
c al c ul at e d, s e p ar at el y f or e a c h d o s e v er s u s pl a c e b o, f or e n d of st u d y s u c c e s s b a s e d o n 
b ot h t h e M M R M r e s ult s at W e e k  1 2 a n d t h e pri m ar y B a y e si a n Em a x m o d el r e s ult s.  T h e 
pr e di cti v e pr o b a biliti e s will b e c al c ul at e d u si n g t h e m et h o d d e s cri b e d b y Gri e v e ( 1 9 9 1) 3 , 
i n c or p or ati n g v a g u e pri or s.   A d diti o n all y, t h e s u b s et s u m m ar y t a bl e s b y t u m or t y p e, a s 
d e s cri b e d i n S e cti o n 6. 5 , will b e pr o d u c e d.
F or di git al e n d p oi nt s ( g ait s p e e d, 9 5t h p er c e ntil e g ait s p e e d, M V P A  a n d s e d e nt ar y 
a cti vit y  ti m e), P R O s ( F A A C T-A C S, F A A C T -5I A S S, C R C S D -a p p etit e, C R C S D -f ati g u e, 
P R O MI S -f ati g u e a n d P R O MI S-p h y si c al f u n cti o n) a n d L S MI , t h e d e s cri pti v e s u m m ari e s 
a n d st ati sti c al a n al y s e s, d e s cri b e d i n S e cti o n s 6. 2. 1 , 6. 2. 2 , 6. 2. 3 , 6. 4. 6 , 6. 4. 7 a n d 6. 4. 1 0 , 
will b e p erf or m e d.  A d diti o n all y, B a y e si a n p r e di cti v e pr o b a biliti e s will b e c al c ul at e d , 
s e p ar at el y f or e a c h d o s e v er s u s pl a c e b o, u si n g t h e m et h o d d e s cri b e d b y Gri e v e ( 1 9 9 1) 3 , 
i n c or p or ati n g v ag u e pri or s, f or e n d of st u d y st ati sti c al si g nifi c a n c e b a s e d o n t h e 
M M R M/ A N C O V A r e s ult s at W e e k 1 2.
A d diti o n all y, t h e o v er all t u m or r e s p o n s e a c c or di n g t o R E CI S T g ui d eli n e s will b e s u m m ari z e d 
a s d e s cri b e d i n S e cti o n 6. 4. 9 .
7. 2. 2. S af et y E n d p oi nt s
A d v er s e e v e nt s, l a b or at or y a b n or m aliti e s, vit al si g n s a n d E C G a b n or m aliti e s will b e 
s u m m ari z e d a n d a n al y z e d a s d e s cri b e d i n S e cti o n 6. 2. 4 .  A s u b s et of t h e s e o ut p ut s, 
pr e vi o u sl y a gr e e d wit h t h e C 3 6 5 1 0 0 3 I R C, will b e pr o d u c e d.
7. 2. 3. Ot h er S u m m ari e s
B a s eli n e s u m m ari e s will b e pr o d u c e d, a s d e s cri b e d i n S e cti o n 6. 6. 1 , f or b ot h t h e i nt eri m 
S af et y a n d Effi c a c y p o p ul ati o n s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 2 of 6 0
8. R E F E R E N C E S
1.
M arti n L ( 2 0 1 5): Di a g n o sti c crit eri a f or t h e cl a s sifi c ati o n of c a n c er - as s o ci at e d w ei g ht 
l o s s. J Cli n O n c ol. 2 0 1 5 J a n 1; 3 3( 1): 9 0-9. 
2.
R u bi n D B. M ulti pl e I m p ut ati o n f or N o nr e s p o n s e i n S ur v e y s. 1 9 8 7; W il e y, N e w Y or k. 
3.
Gri e v e A P ( 1 9 9 1): Pr e di cti v e pr o b a bilit y i n cli ni c al tri al s: Bi o m etri c s, 4 7( 1) 3 2 3 -9.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 3 of 6 0
A P P E N DI C E S
A p p e n di x 1. F A A C T S c ori n g G ui d eli n e s
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 4 of 6 0
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 5 of 6 0
* F or g ui d eli n e s o n h a n dli n g mi s si n g d at a a n d s c ori n g o pti o n s, pl e a s e r ef er t o t h e A d mi ni str ati o n a n d 
S c ori n g G ui d eli n e s i n t h e m a n u al or o n -li n e at w w w.f a cit. or g.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 6 of 6 0
A p p e n di x 2. S a m p s o n Crit eri a
Cli ni c al Crit eri a f or Di a g n o si n g A n a p h yl a xi s
Pr o gr a m m ati c all y I d e ntif yi n g P ot e nti al C a s e s of A n a p h yl a xi s
A p arti ci p a nt i s s ai d t o h a v e a n e pi s o d e f ulfilli n g t h e S a m p s o n Crit eri a if at l e a st o n e of t h e 
f oll o wi n g crit eri a i s m et:
Crit eri o n 1: T h e p arti ci p a nt e x p eri e n c e d a n o n s et of b ot h C o n diti o n 1 a n d C o n diti o n 2 
b el o w, o n t h e d a y of, or o n t h e d a y aft er, st u d y dr u g a d mi ni str ati o n.
a)
C o n diti o n 1: a s ki n or m u c o s al m e m br a n e a d v er s e e v e nt ( A E) ( u si n g 
M e d D R A P T s u n d er S ki n or M u c o s al M e m br a n e gr o u pi n g), 
b) C o n diti o n 2: a r e s pir at or y c o m pr o mi s e A E ( u si n g M e d D R A P T s u n d er t h e 
R e s pir at or y gr o u pi n g), or a n e n d -or g a n d y sf u n cti o n/r e d u c e d bl o o d pr e s s ur e 
A E ( u si n g M e d D R A P T s u n d er E n d -or g a n d y sf u n cti o n or R e d u c e d Bl o o d 
Pr e s s ur e gr o u pi n g), or r e d u c e d s y st oli c bl o o d pr e s s ur e ( c h ar a ct eri z e d b y a 
P T of h y p ot e n si o n, bl o o d pr e s s ur e d e cr e a s e d or bl o o d pr e s s ur e s y st oli c 
d e cr e a s e d).
Crit eri o n 2: T h e p arti ci p a nt e x p eri e n c e d a n o n s et of a n y 2 or m or e c o n diti o n s b el o w, o n t h e 
d a y of , or o n t h e d a y aft er , st u d y dr u g a d mi ni str ati o n.
a) C o n diti o n 1: a s ki n or m u c o u s m e m br a n e i n v ol v e m e nt A E ( u si n g M e d D R A 
P T s u n d er S ki n or M u c o s al M e m br a n e gr o u pi n g)
b) C o n diti o n 2: a r e s pir at or y c o m pr o mi s e A E ( u si n g M e d D R A P T s u n d er t h e 
R e s pir at or y gr o u pi n g); 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 7 of 6 0
c) C o n diti o n 3: a n e n d -or g a n d y sf u n cti o n/r e d u c e d bl o o d pr e s s ur e A E ( u si n g 
M e d D R A P T s u n d er ‘ E n d -Or g a n D y sf u n cti o n or R e d u c e d Bl o o d Pr e s s ur e 
gr o u pi n g), or r e d u c e d s y st oli c bl o o d pr e s s ur e ( c h ar a ct eri z e d b y a P T of 
h y p ot e n si o n, bl o o d pr e s s ur e d e cr e a s e d or bl o o d pr e s s ur e s y st oli c 
d e cr e a s e d);
d) C o n diti o n 4: a g a str oi nt e sti n al A E ( u si n g M e d D R A P T s u n d er t h e 
g a str oi nt e sti n al gr o u pi n g).
If t h e s a m e s p e cifi c A E b el o n g s t o m or e t h a n o n e C o n diti o n/ A E gr o u pi n g a b o v e 
(i. e., ‘ S ki n or M u c o s al M e m br a n e’ gr o u pi n g, ‘ R e s pir at or y C o m pr o mi s e’ 
gr o u pi n g, ‘ E n d -Or g a n D y sf u n cti o n/ R e d u c e d Bl o o d Pr e s s ur e’ gr o u pi n g, 
‘ G a str oi nt e sti n al’ gr o u pi n g), t h e e v e nt s h o ul d b e a s si g n e d t o n ot m or e t h a n o n e 
of  t h e a b o v e C o n diti o n s a n d i n s u c h a w a y a s t o m a xi mi z e t h e n u m b er of 
C o n diti o n s f ulfill e d t o s u p p ort Crit eri o n 2. F or e x a m pl e, if t h e A E of D y s p n e a 
( w hi c h b el o n g s t o t h e ‘ R e s pir at or y C o m pr o mi s e’ gr o u pi n g) a n d t h e A E of C h e st 
P ai n ( w hi c h m a y b el o n g eit h er t o t h e ‘ R e s pir at or y C o m pr o mi s e’ gr o u pi n g or t o 
t h e ‘ E n d-Or g a n D y sf u n cti o n/ R e d u c e d Bl o o d Pr e s s ur e’ gr o u pi n g) o c c urr e d, 
t he n t h e A E of C h e st P ai n will b e a s si g n e d t o t h e ‘ E n d -Or g a n D y sf u n cti o n/ 
R e d u c e d Bl o o d Pr e s s ur e’ gr o u pi n g, s o t h at Crit eri o n 2 i s f ulfill e d (if t h e A E of 
C h e st P ai n w er e a s si g n e d t o t h e ‘ R e s pir at or y C o m pr o mi s e’ gr o u pi n g, t h e n 
Crit eri o n 2 w o ul d n ot b e f ulfil l e d b e c a u s e t h e A E of D y s p n e a al s o b el o n g s t o 
t h e ‘ R e s pir at or y C o m pr o mi s e’ gr o u pi n g).
Crit eri o n 3: T h e p arti ci p a nt e x p eri e n c e d r e d u c e d s y st oli c bl o o d pr e s s ur e ( c h ar a ct eri z e d b y 
a P T of h y p ot e n si o n, bl o o d pr e s s ur e d e cr e a s e d or bl o o d pr e s s ur e s y st oli c 
d e cr e a s e d) o n t h e d a y of , or o n t h e d a y aft er , st u d y dr u g a d mi ni str ati o n , a n d at 
l e a st 1 q u alif yi n g e v e nt. A q u alif yi n g e v e nt i s d efi n e d a s a n y of t h e f oll o wi n g 
o c c urri n g d uri n g t h e c urr e nt st u d y or, if a p pli c a bl e, i n t h e p ar e nt st u d y fr o m 
w h i c h t h e p arti ci p a nt r oll e d o v er i nt o t h e c urr e nt st u d y, aft er t h e fir st 
a d mi ni str ati o n of t h e st u d y dr u g (i n t h e c urr e nt or t h e p ar e nt st u d y, a s 
a p pli c a bl e) a n d b ef or e t h e a d mi ni str ati o n of t h e s a m e st u d y dr u g a s s o ci at e d 
wit h t h e c urr e nt r e d u c e d s y st oli c bl o o d pr e s s ur e e v e nt :
a) A n e v e nt m e eti n g Crit eri o n 1 or Crit eri o n 2;
b) A n I nj e cti o n Sit e r e a cti o n (I S R), a s r e p ort e d b y t h e i n v e sti g at or;
c) A n A E u n d er t h e A n a p h yl a cti c R e a cti o n St a n d ar di s e d M e d D R A Q u er y 
( S M Q), or t h e A n gi o e d e m a S M Q, or t h e H y p er s e n siti vit y S M Q, c o n si d er e d 
t o b e r el at e d t o t h e st u d y dr u g, a s r e p ort e d b y t h e i n v e sti g at or.
F or e pi s o d e s wit h m ulti pl e A E s f ulfilli n g m or e t h a n o n e S a m p s o n Crit eri a at t h e s a m e vi sit, 
t h e f oll o wi n g hi er ar c h y i s u s e d: Crit eri o n 1, Crit eri o n 2, Crit eri o n 3. F or e x a m pl e, w h e n 
Crit eri o n 1 i s f ulf ill e d, Crit eri o n 2 a n d Crit eri o n 3 ar e n ot e v al u at e d.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 8 of 6 0
A p p e n di x 3. P R O MI S S c or e C o n v er si o n T a bl e s
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)
C O P Y RI G H T E D M A T E RI A L


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 4 9 of 6 0
A p p e n di x 4. E x a m pl e S A S C o d e
E x a m pl e S A S c o d e f or M M R M M o d el
p r o c  m i x e d  d a t a  =  d a t a s e t  m e t h o d = r e m l ;
c l a s s  s u b j e c t  t r e a t m e n t  t i m e  t h e r a p y  c a n c e r ;
m o d e l  c f b  =  t r e a t m e n t  b a s e  t i m e  b a s e * t i m e  t i m e * t r e a t m e n t  t h e r a p y  
c a n c e r  /  d d f m = k r  r e s i d u a l  o u t p = r e s i d _ o u t ;
r e p e a t e d  t i m e  / s u b j e c t = s u b j i d  t y p e  =  u n ;
l s m e a n s  t r e a t m e n t * t i m e / d i f f  c l  a l p h a = 0 . 1 ;
o d s  o u t p u t  l s m e a n s = l s m e a n s _ o u t ;
o d s  o u t p u t  d i f f s = d i f f s _ o u t ;
r u n ;
E x a m pl e S A S c o d e f or A N C O V A M o d el
p r o c  m i x e d  d a t a  =  d a t a s e t ;
c l a s s  t r e a t m e n t  t h e r a p y  c a n c e r ;
m o d e l  c f b  =  t r e a t m e n t  b a s e  t h e r a p y  c a n c e r  /  r e s i d u a l  o u t p = r e s i d _ o u t ;
l s m e a n s  t r e a t m e n t  /  d i f f  c l  a l p h a = 0 . 1 ;
o d s  o u t p u t  l s m e a n s = l s m e a n s _ o u t ;
o d s  o u t p u t  d i f f s = d i f f s _ o u t ;
r u n ;
E x a m pl e S A S c o d e f or C o x Pr o p orti o n al H a z ar d s M o d el:
p r o c  p h r e g  d a t a = d a t a s e t ;
c l a s s  t r e a t m e n t ( r e f = ’ P l a c e b o ’ )  /  p a r a m = r e f  o r d e r = i n t e r n a l ;
c l a s s  t h e r a p y  c a n c e r ;
m o d e l  t i m e * c e n s o r ( 1 ) =  t h e r a p y  c a n c e r  t r e a t m e n t  /  t i e s = B r e s l o w  
r i s k l i m i t s  a l p h a = 0 . 1 ;
h a z a r d r a t i o  ‘ C o m p a r i s o n s  v s  P l a c e b o ’  t r e a t m e n t  /  d i f f = r e f  a l p h a = 0 . 1 ;
r u n ;
E x a m pl e S A S c o d e f or C u m ul ati v e I n ci d e n c e Pl ot s:
p r o c  l i f e t e s t  d a t a  =  d a t a s e t  m e t h o d = k m  p l o t s = c i f  o u t c i f = c i f a t r i s k  
i n t e r v a l s = 0  t o  1 2  b y  4 ;  
s t r a t a  t r e a t m e n t ;
t i m e  d a y * c e n s o r ( 1 )  /  e v e n t c o d e = 0 ;
r u n ;  
N O T E: t h e c e n s or v ari a bl e h a s a v al u e = 1 w h e n t h e r el at e d ti m e i s c e n s or e d a n d h a s a 
v al u e = 0 w h e n t h e e v e nt of i nt er e st o c c ur s. T h er e s h o ul d b e n o ot h er v al u e s a v ail a bl e f or 
t hi s c e n s or e d v ari a bl e i n t hi s d at a s et (i n cl u di n g mi s si n g v al u e s). If r e q uir e d, mi s si n g 
o b s er v ati o n s s h o ul d b e r e m o v e d pri or t o a n al y si s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 0 of 6 0
E x a m pl e S A S c o d e f or Pr o p orti o n of R e s p o n s e s ( wit h m ulti pl e i m p ut ati o n): 
A s s u m e t h e S A S d at a s et i s i n a l o n g f or m at. T h e v ari a bl e ‘tr e at m e nt ’ s h o ul d b e c o d e d 
si mil ar t o ‘ Pl a c e b o’, ‘ P o n s e gr o m a b 1 0 0 m g’, ‘ P o n s e gr o m a b 2 0 0 m g’, ‘ P o n s e gr o m a b 4 0 0 m g’, 
s o t h at ‘ Pl a c e b o’ c o m e s fir st.
N O T E:  If a p arti ci p a nt di s c o nti n u e s d u e t o d e at h, t h e y s h o ul d b e i n cl u d e d i n t h e i m p ut ati o n, 
b ut o n c e t h eir v al u e h a s b e e n i m p ut e d t h e n t h e y s h o ul d b e cl a s sifi e d a s a n o n r e s p o n d er. 
p r o c  s o r t  d a t a = a n a l y s i s  o u t = a n a l y s i s _ l o n g ;  
   b y  s u b j i d  t i m e  t r e a t m e n t  t h e r a p y  c a n c e r  b a s e ;  
r u n ;  
*  C r e a t e  w i d e  d a t a s e t  f o r  m u l t i p l e  i m p u t a t i o n ;  
p r o c  t r a n s p o s e  d a t a =  a n a l y s i s _ l o n g  o u t = a n a l y s i s _ w i d e  p r e f i x = w k ;  
   b y  s u b j i d  t r e a t m e n t  t h e r a p y  c a n c e r  b a s e ;  
   i d  t i m e ;  
   v a r  p c f b ;  
r u n ;  
*  P e r f o r m  m u l t i p l e  i m p u t a t i o n ;  
p r o c  m i  d a t a = a n a l y s i s _ w i d e  s e e d = 1 6 9  n i m p u t e = 2 0  o u t = a n a l y s i s _ m i ;  
   c l a s s  t r e a t m e n t ;
   f c s  n b i t e r = 1 0  r e g ( / d e t a i l s ) ;  
   v a r  b a s e  t r e a t m e n t  t h e r a p y  c a n c e r  w k 4  w k 8  w k 1 2 ;  
r u n ;  
*  N e e d  t o  a d d  i n  h e r e  c o d e  t o  c l a s s i f y  a n y  p a r t i c i p a n t s  t h a t  d i s c o n t i n u e  
d u e  t o  d e a t h  a s  n o n  r e s p o n d e r s ;
*  D e t e r m i n e  r e s p o n d e r s  a n d  n o n - r e s p o n d e r s  a t  W e e k  1 2  f o r  a l l  i m p u t e d    
  d a t a s e t s ;  
d a t a  a n a l y s i s _ m i _ 1 2 ;  
   s e t  a n a l y s i s _ m i ;  
   i f  w k 1 2  > =  3 . 5  a n d  w k 1 2  n e  .  t h e n  r e s p  =  1 ;  
   i f  w k 1 2  <  3 . 5  a n d  w k 1 2  n e  .  t h e n  r e s p  =  0 ;  
r u n ;  
*  C r e a t e  d a t a s e t s  a n d  c o m b i n e  p r o p o r t i o n s ;  
p r o c  f r e q  d a t a = a n a l y s i s _ m i _ 1 2 ;  
  t a b l e s  _ i m p u t a t i o n _ *  t r e a t m e n t  * r e s p  /  o u t = p r o p _ m i  o u t p c t ;  
r u n ;  
d a t a  p r o p _ m i _ 0 ;  
   s e t  p r o p _ m i ;  
   i f  r e s p = 0 ;  
   k e e p  _ i m p u t a t i o n _  t r e a t m e n t  c o u n t ;  
   r e n a m e  c o u n t = c o u n t _ 0 ;  
r u n ;  
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 1 of 6 0
d a t a  p r o p _ m i _ 1 ;  
   s e t  p r o p _ m i ;  
   i f  r e s p = 1 ;  
   k e e p  _ i m p u t a t i o n _  t r e a t m e n t  c o u n t ;  
   r e n a m e  c o u n t = c o u n t _ 1 ;  
r u n ;  
d a t a  p r o p _ m i _ c o m b i n e d ;  
   m e r g e  p r o p _ m i _ 0  p r o p _ m i _ 1 ;  
   b y  _ i m p u t a t i o n _  t r e a t m e n t ;  
   t o t a l  =  c o u n t _ 0  +  c o u n t _ 1 ;  
   p  =  c o u n t _ 1  /  t o t a l ;  
   q  =  c o u n t _ 0  /  t o t a l ;  
   s e _ p  =  s q r t ( ( p * q ) / t o t a l ) ;  
r u n ;  
p r o c  s o r t  d a t a = p r o p _ m i _ c o m b i n e d ;   b y  t r e a t m e n t  _ i m p u t a t i o n _ ;   r u n ;
p r o c  m i a n a l y z e  d a t a = p r o p _ m i _ c o m b i n e d  a l p h a = 0 . 1 ;  
   b y  t r e a t m e n t ;  
   m o d e l e f f e c t s  p ;  
   s t d e r r  s e _ p ;  
   o d s  o u t p u t  p a r a m e t e r e s t i m a t e s = p r o p _ m i _ o u t ;  
r u n ;  
E x a m pl e S A S c o d e f or L o gi sti c R e gr e s si o n M o d el ( wit h m ulti pl e i m p ut ati o n):
T h e s a m e i m p ut e d d at a s et s a s pr o d u c e d a b o v e f or t h e ‘ Pr o p orti o n of R e s p o n s e s’ will b e 
utili z e d. N ot e: t h e i m p ut e d d at a s et s h o ul d b e or d er e d wit h ‘ R e s p’ = 1 fir st t o e n s ur e t h at t h e 
o d d s r ati o s ar e f or a r e s p o n s e = 1 a n d t h e r ef er e n c e gr o u p i s Pl a c e b o.
*  F i t  l o g i s t i c  r e g r e s s i o n s  t o  e a c h  i m p u t e d  d a t a s e t  a n d  c o m b i n e  r e s u l t s ;  
p r o c  s o r t  d a t a = a n a l y s i s _ m i _ 1 2 ;  b y  _ i m p u t a t i o n _  t r e a t m e n t  d e s c e n d i n g  r e s p ;  
r u n ;
p r o c  g e n m o d  d a t a = a n a l y s i s _ m i _ 1 2  o r d e r = i n t e r n a l   d e s c e n d i n g ;
   b y  _ i m p u t a t i o n _ ;
   c l a s s  r e s p  t r e a t m e n t ;
   m o d e l  r e s p  =  t r e a t m e n t  t h e r a p y  c a n c e r  b a s e
          /  d i s t = b i n  l i n k = l o g i t  a l p h a = 0 . 1 ;
   l s m e a n s  t r e a t m e n t  /  c l  d i f f  a l p h a = 0 . 1  e x p ;
   o d s  o u t p u t  l s m e a n s = o d d s _ m i  d i f f s = o d d s r a t _ m i ;
r u n ;
* O d d s  r a t i o s ;
d a t a  o d d s r a t _ m i ;
   s e t  o d d s r a t _ m i ( w h e r e = ( _ T R E A T T X T = " P l a c e b o " ) ) ;
   i f  T R E A T T X T  =  '  P o n s e g r o m a b  1 0 0 m g  '  t h e n  t r e a t m e n t  =  1 0 0 ;
   i f  T R E A T T X T  =  '  P o n s e g r o m a b  2 0 0 m g  '  t h e n  t r e a t m e n t  =  2 0 0 ;
   i f  T R E A T T X T  =  '  P o n s e g r o m a b  4 0 0 m g  '  t h e n  t r e a t m e n t  =  4 0 0 ;
   i f  t r e a t m e n t  =  .  t h e n  d e l e t e ;
   S E  =  S t d E r r ;
r u n ;
p r o c  s o r t  d a t a = o d d s r a t _ m i ;  b y  t r e a t m e n t  _ i m p u t a t i o n _ ;   r u n ;
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 2 of 6 0
p r o c  m i a n a l y z e  d a t a = o d d s r a t _ m i   a l p h a = 0 . 1 ;   
   b y  t r e a t m e n t ;
   m o d e l e f f e c t s  e s t i m a t e ;
   s t d e r r  S E ;
   o d s  o u t p u t  p a r a m e t e r e s t i m a t e s = O d d s R a t i o s _ m i _ o u t ;
r u n ;
d a t a  O d d s R a t i o s _ m i _ o u t ;
   s e t  O d d s R a t i o s _ m i _ o u t ;
   o d d s r a t i o  =  e x p ( e s t i m a t e ) ;
   L C L o d d s r a t i o  =  e x p ( L C L M e a n ) ;
   U C L o d d s r a t i o  =  e x p ( U C L M e a n ) ;
r u n ;
*  O d d s ;
d a t a  o d d s _ m i ;
s e t  o d d s _ m i ;
   i f  T R E A T T X T  =  ' P l a c e b o '  t h e n  t r e a t m e n t  =  0 ;
   i f  T R E A T T X T  =  ' P o n s e g r o m a b  1 0 0 m g  '  t h e n  t r e a t m e n t  =  1 0 0 ;
   i f  T R E A T T X T  =  ' P o n s e g r o m a b  2 0 0 m g  '  t h e n  t r e a t m e n t  =  2 0 0 ;
   i f  T R E A T T X T  =  ' P o n s e g r o m a b  4 0 0 m g  '  t h e n  t r e a t m e n t  =  4 0 0 ;
   i f  t r e a t m e n t  =  .  t h e n  d e l e t e ;
   S E  =  S t d E r r ;
r u n ;
p r o c  s o r t  d a t a = o d d s _ m i ;  b y  t r e a t m e n t  _ i m p u t a t i o n _ ;   r u n ;
p r o c  m i a n a l y z e  d a t a = o d d s _ m i   a l p h a = 0 . 1 ;  
   b y  t r e a t m e n t ;
   m o d e l e f f e c t s  e s t i m a t e ;
   s t d e r r  S E ;
   o d s  o u t p u t  p a r a m e t e r e s t i m a t e s = O d d s _ m i _ o u t ;
r u n ;
d a t a  O d d s _ m i _ o u t ;
   s e t  O d d s _ m i _ o u t ;
   o d d s  =  e x p ( e s t i m a t e ) ;
   L C L o d d s  =  e x p ( L C L M e a n ) ;
   U C L o d d s  =  e x p ( U C L M e a n ) ;
r u n ;
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 3 of 6 0
A p p e n di x 5. B a y e si a n E m a x M o d el M et h o d ol o g y  D et ail s
D at a Pr o vi d e d b y Pr o gr a m m er
A . c s v d at a s et of L S m e a n s fr o m t h e M M R M a n al y si s s h o ul d b e pr o d u c e d b y pr o gr a m mi n g 
f or u s e i n R b y t h e r e p orti n g st ati sti ci a n a n d Q C st ati sti ci a n.  T h e fil e s h o ul d b e i n t h e 
f oll o wi n g f or m at ( N ot e t h at c ol u m n h e a d er s s h o ul d b e l a b ell e d a s s p e cifi e d b el o w (i n cl u di n g 
c a pit ali z ati o n), a s R i s c a s e s e n siti v e): -
D o s e
M e a n
S E
0 
0
0. 3
2. 5 
0. 2 
0. 4
1 0
0. 4 
0. 5
4 0
0. 3 
0. 3
8 0
1. 6 
0. 4
1 2 0
1. 8 
0. 5
T h e r e si d u al st a n d ar d d e vi ati o n ( R e si d u al _ S D) o n W e e k 1 2 fr o m t h e u n str u ct ur e d 
c o v ari a n c e m atri x fr o m t h e M M R M will al s o b e pr o vi d e d b y pr o gr a m mi n g i n a s e p ar at e . c s v 
fil e.
Fitti n g t h e E m a x M o d el
T h e 4- p ar a m et er E m a x m o d el will b e fitt e d u si n g t h e l at e st v er si o n ( c urr e ntl y 2. 3. 5) of t h e 
cli n D R p a c k a g e. T hi s a n al y si s will b e c o n d u ct e d b y t h e r e p orti n g st ati sti ci a n. A diff er e nt 
st ati sti ci a n will c o n d u ct Q C of t h e a n al y si s. T h e o ut p ut s of t h e a n al y si s wil l b e pr o vi d e d a s 
. c s v fil e s t o t h e pr o gr a m mi n g t e a m f or cr e ati o n of pr o gr a m mi n g t a bl e s a n d fi g ur e s.
T h e d ef a ult b ur n -i n a n d n u m b er of s a m pl e s will b e utili z e d al o n g wit h t hi n ni n g of 2 0, w hi c h 
will i n cl u d e 3 c h ai n s t o a s s e s s c o n v er g e n c e.  
M o d el di a g n o sti c s will b e e x a mi n e d, i n cl u di n g tr a c e a n d a ut o -c orr el ati o n s pl ot s. If t h e s e 
r ai s e c o n c er n s o v er m o d el c o n v er g e n c e, a d diti o n al b ur n-i n s, s a m pl e s a n d t hi n ni n g will b e 
i n v e sti g at e d t o i m pr o v e c o n v er g e n c e.  C h a n g e s t o t h e pri or s b el o w m a y al s o b e c o n si d er e d 
( e. g. i n cr e a s e pr e ci si o n of hill) t o i m pr o v e c o n v er g e n c e, if d e e m e d n e c e s s ar y, a n d w o ul d b e 
d o c u m e nt e d i n fi n al t a bl e s a s a p pr o pri at e. T h e fi n al di a g n o sti c pl ot s will n ot b e i n cl u d e d i n 
t h e cli ni c al st u d y r e p ort.
Pri or s
Pri or di stri b uti o n s will b e s p e cifi e d f or t h e pl a c e b o r e s p o n s e ( E 0 ), t h e diff er e n c e i n r e s p o n s e 
( dif T ar g et) b et w e e n t h e hi g h e st d o s e ( d T ar g et = 4 0 0 m g) a n d pl a c e b o, a n d t h e r e si d u al 
st a n d ar d d e vi ati o n ( si g m a).  N ot e t h at E m a x i s d eri v e d fr o m ot h er p ar a m et er s a n d i s t h u s 
n ot e x pli citl y s u p pli e d.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 4 of 6 0
P ar a m et er
Pri or
E 0
t( Me a n = -0. 5 8, S D = 1. 8 4, df = 3)
dif T ar g et
t( Me a n = 0, S D = 4 9, df = 5)
si g m a
U nif or m(l b = 0. 4 9, u b = 4 9)
E 0 : A n i nf or m ati v e m et a -a n al yti c pr e di cti v e pri or , b a s e d o n hi st ori c al r e s ult s fr o m i nt er n al a n d 
e xt er n al st u di e s, r o b u stifi e d b y t h e i n cl u si o n of a w e a kl y i nf or m ati v e c o m p o n e nt t o h a n dl e a n y 
p o s si bl e pri or -d at a c o nfli ct, will b e u s e d f or t h e pl a c e b o c h a n g e fr o m b a s eli n e at W e e k 1 2 . 
T hi s will b e a p pr o xi m at e d b y a t -di stri b uti o n wit h a m e a n of -0. 5 8 k g, a n S D of 1. 8 4 k g a n d 3 
d e gr e e s of fr e e d o m. If a d diti o n al r el e v a nt d at a b e c o m e a v ail a bl e d uri n g t h e st u d y, a 
s e n siti vit y a n al y si s m a y b e p erf or m e d b y i n c or p or ati n g t h e n e w d at a, u si n g t h e s a m e 
a p pr o a c h a s a b o v e. 
dif T ar g et: A v a g u e t -di stri b uti o n will b e u s e d f or t h e 4 0 0 m g pl a c e b o c orr e ct e d c h a n g e fr o m 
b a s eli n e at W e e k 1 2 wit h a m e a n of 0, a S D e q u al t o 1 0 ti m e s t h e pr e di ct e d st a n d ar d 
d e vi ati o n (i e, 4 9 k g) a n d 5 d e gr e e s of fr e e d o m.
si g m a: A u nif or m pri or will b e u s e d, wit h a r a n g e w e ar e c o nfi d e nt will i n cl u d e t h e p o p ul ati o n 
v al u e. A l o w er b o u n d of 0. 4 9 k g a n d a n u p p er b o u n d of 4 9 k g will b e u s e d.
Cli n D R d ef a ult s etti n g s will b e u s e d t o s p e cif y pri or di stri b uti o n s f or t h e Hill p ar a m et er a n d 
t h e E D5 0 .  T h e d ef a ult di stri b uti o n s i n t h e c urre nt v er si o n of cli n D R ( v er si o n 2. 3. 5) ar e b a s e d 
o n a m et a- a n al y si s of cli ni c al d o s e r e s p o n s e d at a a n d ar e li st e d b el o w.  T h e s e d ef a ult 
di stri b uti o n s will b e u p d at e d if t h e m et a -d at a, a n d t h eir a n al y si s, ar e u p d at e d b ef or e t h e 
c o m pl eti o n of t h e c urr e nt st u d y.
P ar a m et er
Pri or
l o g( E D5 0 )
l o g( P5 0 ) + t( M e a n = 0, S D = 1. 7 3, df = 5)
l o g( Hill)
t( Me a n = 0, S D = 0. 8 5, df = 5)
T h e c orr el ati o n b et w e e n t h e s e t w o p ar a m et er s i s c urr e ntl y -0. 4 5 b a s e d o n t h e a n al y si s of 
t h e m et a-d at a, w hi c h al s o w o ul d b e u p d at e d if t h e hi st ori c al a n al y si s i s u p d at e d.
T h e pr e di ct e d E D 5 0 f or t h e c o m p o u n d ( P5 0 ) i s c urr e ntl y ~ 1 5 0 m g
Q 4 W d o s e, b a s e d o n l at e st 
d at a f or t h e c o m p o u n d (t hi s m a y b e u p d at e d a s n e w d at a b e c o m e a v ail a bl e).
R C o d e
T h e f oll o wi n g R c o d e i s i n cl u d e d a s a n e x a m pl e t h at will b e u s e d a s a b a si s f or t h e a n al y si s: 
li br ary( cli n D R) 
m mr m R e s < - r e a d. c s v(“ L S m e a n s. c s v", h e a d er = T, stri n g s A s F a ct or s = F) 
# D et er mi n e ' eff e cti v e' s u bj e ct n u m b er s b a s e d o n M M R M S D at W e e k  1 2: 
m mr m _ s d < - 0. 8 2 5 
# Pr o vi d e d b y pr o gr a m mi n g 
m mr m R e s $ n < - tr u n c(( m mr m _ s d/ m mr m R e s $ s e) ^ 2, 0) 
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 5 of 6 0
# S et -u p pri or s a n d M C M C o pti o n s: 
pri or _ m mr m < - e m a x Pri or. c o ntr ol( e p m u = -0. 5 8, e p s c a = 1. 8 4, 
             dif T ar g et m u = 0, dif T ar g et s c a = 4 9, 
             d T ar g et = 4 0 0, eff df = 5,
             p 5 0 = 1 5 0, 
            si g m al o w = 0. 4 9, si g m a u p = 4 9) 
m c m c _ m mr m < - m c m c. c o ntr ol( c h ai n s = 3, t hi n = 2 0, s e e d = 1 6 9) 
# R u n E m a x m o d el: # 
e m a x M M R M < - fit E m a x B( m mr m R e s $ m e a n, m mr m R e s $ d o s e, pri or _ m mr m, m o d Ty p e = 4,
c o u nt = m mr m R e s $ n, m s S at = m mr m _ s d ^ 2, m c m c = m c m c _ m mr m) 
# Di a g n o sti c s a n d o ut p ut: 
st a n _tr a c e( e m a x M M R M $ e st a nfit) 
# L o o k at tr a c e 
st a n _ d e n s( e m a x M M R M $ e st a nfit) 
# L o o k at d e n siti e s 
st a n _ a c( e m a x M M R M $ e st a nfit) 
# L o o k at a ut o c orr el ati o n 
s u m m ar y ( e m a x M M R M) 
# S u m m ar y  of m o d el p ar a m et er s 
pl ot( e m a x M M R M) 
# L o o k at fitt e d v s. o b s er v e d d at a t o c h e c k m o d el fit
e m a x M M R M o ut < - pr e di ct( e m a x M M R M, d o s e v e c = m mr m R e s $ d o s e, cl e v = 0. 9 0) 
# G et d o s e 
pr e di cti o n s 
# P o st eri or pr e di cti v e c h e c k f or n o n -m o n ot o n e d o s e r e s p o n s e
p o st C h e c k < -c h e c k M o n o E m a x( y = m mr m R e s $ m e a n, d o s e = m m r m R e s $ d o s e,
                p ar m = c o ef( e m a x M M R M), si g m a 2 =( si g m a( e m a x M M R M)) ^ 2, n v e c = m mr m R e s $ n)
D at a Pr o vi d e d b y St ati sti ci a n
M o d el p ar a m et er s, p o st eri or m e di a n s a n d cr e di bl e i nt er v al s, a n d p o st eri or diff er e n c e s a n d 
cr e di bl e i nt er v al s, a s s p e cifi e d i n S e cti o n 5. 2. 4 , will be o ut p ut a n d pr o vi d e d b a c k t o 
pr o gr a m mi n g i n . c s v fil e s aft er Q C i s c o m pl et e.
A d diti o n all y, at i nt eri m, p o st eri or m e a n diff er e n c e s ( v er s u s pl a c e b o) a n d st a n d ar d err or s f or 
e a c h r a n d o mi z e d d o s e will b e o ut p ut a n d pr o vi d e d b a c k t o pr o gr a m mi n g i n a . c s v fil e f or t h e 
c al c ul ati o n of pr e di cti v e pr o b a biliti e s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 6 of 6 0
A p p e n di x 6. C at e g ori c al Cl a s s e s f or E C G a n d Vit al Si g n s of P ot e nti al Cli ni c al C o n c er n
C ate g ories f or Q Tc F
A bs ol ute val ue of Q Tc F ( msec)
4 7 0 a n d 4 8 0
> 4 8 0 a n d 5 0 0
> 5 0 0
I ncrease fr o m baseli ne i n Q Tc F ( msec)
3 0 a n d 6 0
> 6 0
C ate g ories f or P R a n d Q R S
P R ( m s)
m a x. ≥3 0 0
P R ( m s) i n cr e a s e fr o m 
b a s eli n e
B a s eli n e > 2 0 0 a n d m a x. 
≥2 5 % i n cr e a s e
B a s eli n e ≤2 0 0 a n d m a x. 
≥5 0 % i n cr e a s e
Q R S ( m s)
m a x. ≥1 4 0
Q R S ( m s) i n cr e a s e fr o m 
b a s eli n e
≥5 0 % i n cr e a s e
C ate g ories f or Vit al Si g ns
S y st oli c B P ( m m H g)
mi n. < 9 0
S y st oli c B P ( m m H g) c h a n g e fr o m 
b a s eli n e
m a x. d e cr e a s e ≥3 0
m a x. i n cr e a s e ≥3 0
Di a st oli c B P ( m m H g)
mi n. < 5 0
Di a st oli c B P ( m m H g) c h a n g e fr o m 
b a s eli n e
m a x. d e cr e a s e ≥2 0
m a x. i n cr e a s e ≥2 0
S u pi n e p ul s e r at e ( b p m)
mi n. < 4 0
m a x. > 1 2 0
M e a s ur e m e nt s t h at f ulfill t h e s e crit eri a ar e t o b e li st e d.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 7 of 6 0
A p p e n di x 7. I m m u n o g e ni cit y T er m s a n d D efi niti o n s
T er m
D efi niti o n
Tr e at m e nt -i n d u c e d 
A D A 
B a s eli n e A D A tit er i s mi s si n g or n e g ati v e a n d s u bj e ct h a s ≥ 1 p o st -tr e at m e nt p o siti v e A D A tit er. 
Tr e at m e nt -b o o st e d 
A D A
B a s eli n e A D A tit er i s p o siti v e a n d s u bj e ct h a s a ≥ 4 -f ol d dil uti o n i n cr e a s e ( or ot h er t hr e s h ol d v al u e 
a s d efi n e d i n t h e S A P) i n A D A tit er fr o m b a s eli n e i n ≥ 1 p o st -tr e at m e nt s a m pl e. If A D A tit er i s l o g 1 0 
tr a n sf or m e d, a 4-f ol d dil uti o n i n cr e a s e i s e q ui v al e nt t o 0. 6 0 2 u nit i n cr e a s e i n tit er (l o g 1 0) fr o m 
b a s eli n e. If A D A tit er i s l o g 2 tr a n sf or m e d, a 4 -f ol d dil uti o n i n cr e a s e i s e q ui v al e nt t o 2 u nit i n cr e a s e i n 
tit er (l o g 2) fr o m b a s eli n e.
A D A -p o siti v e s u bj e ct
A s u bj e ct wit h ≥ 1 tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d A D A r e s p o n s e.    
A D A -n e g ati v e s u bj e ct
A n A D A e v al u a bl e s u bj e ct wit h o ut tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d A D A r e s p o n s e. S u bj e ct 
eit h er h a s ( 1) all A D A -n e g ati v e r e s ult s t hr o u g h o ut t h e st u d y or ( 2) i s A D A p o siti v e at b a s eli n e b ut 
di d n ot b e c o m e tr e at m e nt -b o o st e d p o st -d o s e. 
A D A i n ci d e n c e
T h e p er c e nt of A D A -p o siti v e s u bj e ct s i n a tr e at m e nt gr o u p/ c o h ort or st u d y . 
Tr e at m e nt -i n d u c e d 
N A b 
B a s eli n e N A b tit er i s mi s si n g or n e g ati v e or A D A -n e g ati v e a n d s u bj e ct h a s ≥ 1 p o st -tr e at m e nt 
p o siti v e N A b tit er .
Tr e at m e nt -b o o st e d 
N A b
B a s eli n e N A b tit er i s p o siti v e a n d s u bj e ct h a s a ≥ 4 -f ol d dil uti o n i n cr e a s e ( or ot h er t hr e s h ol d a s 
d efi n e d i n t h e S A P) i n N A b tit er fr o m b a s eli n e i n ≥ 1 p o st -tr e at m e nt s a m pl e. If N A b tit er i s l o g 1 0 
tr a n sf or m e d, a 4-f ol d dil uti o n i n cr e a s e i s e q ui v al e nt t o 0. 6 0 2 u nit i n cr e a s e i n tit er (l o g 1 0) fr o m 
b a s eli n e. If N A b tit er i s l o g 2 tr a n sf or m e d, a 4 -f ol d dil uti o n i n cr e a s e i s e q ui v al e nt t o 2 u nit i n cr e a s e i n 
tit er (l o g 2) fr o m b a s eli n e.
N A b- p o siti v e s u bj e ct
A n A D A -p o siti v e s u bj e ct wit h ≥ 1 tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d N A b r e s p o n s e. F or A D A -
p o siti v e (tr e at m e nt -b o o st e d) s u bj e ct s , su bj e ct i s N A b p o siti v e o nl y if t h e s u bj e ct h a s ≥1 tr e at m e nt -
i n d u c e d or tr e at m e nt-b o o st e d N A b r e s p o n s e at t h e vi sit w h e r e t h e s u bj e ct h a s a tr e at m e nt -b o o st e d 
A D A r e s p o n s e . For vi sit s w h er e t h e s u bj e ct di d n ot s h o w a b o o st e d A D A r e s p o n s e, t h e s u bj e ct i s 
cl a s sifi e d a s N A b -n e g ati v e f or t h e vi sit e v e n if t h e s u bj e ct h a s p o st -tr e at m e nt p o siti v e N A b tit er f or 
t h at vi sit.     
N A b -n e g ati v e s u bj e ct
N A b e v al u a bl e p arti ci p a nt w h o i s eit h er ( 1) a n A D A -n e g ati v e s u bj e ct or ( 2) a n A D A -p o siti v e s u bj e ct 
wit h o ut tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d N A b r e s p o n s e (i. e. s u bj e ct h a s all N A b-n e g ati v e 
r e s ult s t hr o u g h o ut t h e st u d y or s u bj e ct i s N A b p o siti v e at b a s eli n e b ut di d n ot b e c o m e tr e at m e nt-
b o o st e d p o st -d o s e) . 
N ot e: i n t h e e v e nt a s u bj e ct i s A D A -p o siti v e at b a s eli n e b ut di d n ot s h o w a b o o st e d r e s p o n s e p o st -
tr e at m e nt, s u bj e ct i s cl a s sifi e d a s A D A-n e g ati v e a n d N A b -n e g ati v e at t h e s u bj e ct l e v el e v e n if t h e 
s u bj e ct h a s p o st -tr e at m e nt p o siti v e N A b tit er. A s s u c h all A D A-n e g ati v e s u bj e ct s ar e N A b -n e g ati v e 
r e g ar dl e s s of N A b tit er d at a.”
N A b i n ci d e n c e
T h e p er c e nt of N A b -p o siti v e s u bj e ct s i n a tr e at m e nt gr o u p / c o h ort or st u d y . 
D ur ati o n of A D A  a n d N Ab r e s p o n s e ( s u bj e ct -l e v el d efi niti o n s): r e c o m m e n d e d f or st u di e s wit h ≥ 1 6 w e e k s of A D A  
m e a s ur e m e nt s 
Tr a n si e nt A D A  
A n A D A -p o siti v e s u bj e ct wit h ( 1) a tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d A D A s a m pl e d et e ct e d 
o nl y at 1 s a m pli n g ti m e ( e x cl u di n g t h e l a st ti m e p oi nt) p o st -tr e at m e nt, or ( 2) tr e at m e nt-i n d u c e d or 
tr e at m e nt-b o o st e d A D A s a m pl e s d et e ct e d at ≥ 2 ti m e p oi nt s w h er e t h e fir st a n d l a st p o siti v e 
s a m pl e s (irr e s p e cti v e of a n y n e g ati v e s a m pl e s i n b et w e e n) ar e s e p ar at e d b y < 1 6 w e e k s, a n d t h e 
s u bj e ct’ s l a st s a m pl e i s A D A n e g ati v e. 
P er si st e nt A D A 
A n A D A -p o siti v e s u bj e ct wit h fir st a n d l a st p o siti v e A D A s a m pl e s (tr e at m e nt -i n d u c e d or tr e at m e nt-
b o o st e d) d et e ct e d o v er a p eri o d of ≥ 1 6 w e e k s p o st -tr e at m e nt, irr e s p e cti v e of a n y n e g ati v e s a m pl e s 
i n b et w e e n.
I n d et er mi n at e A D A 
A n A D A -p o siti v e s u bj e ct w h o i s n ot p er si st e nt or tr a n si e nt.
Tr a n si e nt N A b
A N A b -p o siti v e s u bj e ct wit h ( 1) a tr e at m e nt -i n d u c e d or tr e at m e nt-b o o st e d N A b s a m pl e d et e ct e d 
o nl y at 1 s a m pli n g ti m e ( e x cl u di n g t h e l a st ti m e p oi nt) p o st -tr e at m e nt, or ( 2) tr e at m e nt-i n d u c e d or 
tr e at m e nt-b o o st e d N A b s a m pl e s d et e ct e d at ≥ 2 ti m e p oi nt s w h er e t h e fir st a n d l a st p o siti v e 
s a m pl e s (irr e s p e cti v e of a n y n e g ati v e s a m pl e s i n b e t w e e n) ar e s e p ar at e d b y < 1 6 w e e k s, a n d t h e 
s u bj e ct’ s l a st s a m pl e i s N A b n e g ati v e or A D A n e g ati v e.  
P er si st e nt N A b
A N A b -p o siti v e s u bj e ct wit h fir st a n d l a st p o siti v e N A b s a m pl e s (tr e at m e nt -i n d u c e d or tr e at m e nt-
b o o st e d) d et e ct e d o v er a p eri o d of ≥ 1 6 w e e k s p o st -tr e at m e nt, irr e s p e cti v e of a n y n e g ati v e s a m pl e s 
i n b et w e e n. 
I n d et er mi n at e N A b
A N A b -p o siti v e s u bj e ct w h o i s n ot p er si st e nt or tr a n si e nt. 
N ot e: D ur ati o n of r e s p o n s e ( p er si st e nt, tr a n si e nt or i n d et er mi n at e), o n -tr e at m e nt a n d off-tr e at m e nt d efi niti o n s ar e o nl y 
a p pli c a bl e t o A D A ( or N A b) -p o siti v e s u bj e ct s.
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 8 of 6 0
A p p e n di x 8. Li st o f A b br e vi ati o n s
A b br e vi ati o n
T er m
A C S
a n or e xi a a n d c a c h e xi a s u b s c al e
A D A
a nti -dr u g a nti b o di e s
A E
a d v er s e e v e nt
A N C O V A
a n al y si s of c o v ari a n c e
a u
ar bitr ar y u nit s
B D R
bli n d e d d at a r e vi e w
B L Q
b el o w t h e li mit of q u a ntit ati o n
B MI
b o d y  m a s s i n d e x
B P
bl o o d pr e s s ur e
b p m
b e at s p er mi n ut e
c al
c al ori e s
C F B
c h a n g e fr o m b a s eli n e
CI
c o nfi d e n c e i nt er v al
c m
c e nti m etr e s
C R C
c ol or e ct al c a n c er
C R C S D
c a n c er r el at e d c a c h e xi a s y m pt o m  di ar y
C R P
C- r e a cti v e pr ot ei n
C S R
cli ni c al st u d y r e p ort
C T
c o m p ut e d t o m o gr a p h y
C tr o u g h
tr o u g h c o n c e ntr ati o n
C V
c o effi ci e nt of v ari ati o n
df
d e gr e e s of fr e e d o m
dif T ar g et
t h e diff er e n c e i n r e s p o n s e b et w e e n t h e hi g h e st d o s e a n d pl a c e b o
d L
d e cilitr e s
d T ar g et
t h e hi g h e st d o s e
E 0
pl a c e b o eff e ct
E C G
el e ctr o c ar di o gr a m
E D 5 0
d o s e pr o d u ci n g 5 0 % of t h e m a xi m al eff e ct
E C O G P S
E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at u s
E m a x
m a xi m al eff e ct
E W B
e m oti o n al w ell -b ei n g
F A A C T
F u n cti o n al A s s e s s m e nt of A n or e xi a -C a c h e xi a T h er a p y
F A A C T -5I A S S
F u n cti o n al A s s e s s m e nt of A n or e xi a/ C a c h e xi a T h er a p y 5 -it e m A n or e xi a S ym p t o m 
S c al e
F A A C T -A C S
F u n cti o n al A s s e s s m e nt of A n or e xi a -C a c h e xi a T h er a p y - a n or e xi a a n d c a c h e xi a 
s u b s c al e
F A C T- G
F u n cti o n al A s s e s s m e nt of C a n c er T h er a p y - G e n er al
F D A
F o o d a n d Dr u g A d mi ni str ati o n
F W B
f u n cti o n al w ell-b ei n g
G D F -1 5
gr o wt h diff er e nti ati o n f a ct or 1 5
H R
h e art r at e
H R Q o L
h e alt h- r el at e d q u alit y of lif e
C R P
C- r e a cti v e pr ot ei n
H U
H o u n sfi el d u nit s
I-A E
i m m u n o g e ni c a d v er s e e v e nt
I R C
i n d e p e n d e nt r e vi e w c o m mitt e e
I P
i n v e sti g ati o n al pr o d u ct
I S R
i nj e cti o n sit e r e a cti o n
I V
i ntr a v e n o u s
k g
kil o gr a m
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 5 9 of 6 0
A b br e vi ati o n
T er m
L 5 hr
a v er a g e a cti vit y c o u nt s f or t h e l e a st a cti v e 5 h o ur s of t h e d a y
l b
l o w er b o u n d
L L Q
l o w er li mit of q u a ntit ati o n
L S
l e a st-s q u ar e s
L S MI
l u mb ar s k el et al m u s cl e i n d e x
m
m e tr e s
M 1 0 hr
a v er a g e a cti vit y c o u nt s f or t h e m o st a cti v e 1 0 h o ur s of t h e d a y
M 1 5 m i n s
m a xi m u m  1 5 mi n ut e s of a cti vit y l e v el
M 6 m i n
m a xi m u m  d ail y 6 mi n ut e s of a cti vit y
M 6 0 m i n s
m a xi m u m  6 0 mi n ut e s of a cti vit y l e v el
M e d D R A
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s
m g
mi lli gr a ms
mi n( s)
mi n ut e( s)
m L
mi llilitr e s
m m H g
mi lli metr e s of m er c ur y
M M R M
mi x e d m o d el wit h r e p e at e d m e a s ur e s
m s e c / m s
mi lli s e c o n d s
M V P A
m o d er at e t o vi g or o u s p h y si c al a cti vit y ti m e
n
n u m b er
N/ A
n ot a p pli c a bl e
N A b
n e utr ali zi n g a nti b o di e s
N D
n ot d o n e
n g
n a n o gr a m s
N L R
n e utr o p hil -l ym p h o c yt e r ati o
N R S
n u m eri c al r ati n g s c al e
N S
n o s a m pl e
N S C L C
n o n -s m all -c ell l u n g c a n c er
O L T
o p e n -l a b el tr e at m e nt
P 5 0
t h e pr e di ct e d E D 5 0 f or t h e c o m p o u n d
P A N C
p a n cr e ati c c a n c er
P C D
pri m ar y  c o m pl eti o n d at e
P D
p h ar m a c o d y n a mi c( s)
P GI - C
P ati e nt Gl o b al I m pr e s si o n of C h a n g e
P GI - S
P ati e nt Gl o b al I m pr e s si o n of S e v erit y
P K
p h ar m a c o ki n eti c( s)
P L R
pl at el et -l ym p h o c yt e r ati o
P R
i nt er v al i n m s of t h e P R p orti o n of t h e E C G
P R O A C C - 1
P ati e nt R e p ort e d O ut c o m e s a n d A cti vit y i n C a n C er
P R O MI S
P ati e nt -R e p ort e d O ut c o m e s M e a s ur e m e nt I nf or m ati o n S y st e m
P T
pr ef err e d t er m
P W B
p h y si c al w ell -b ei n g
Q 1
fir st q u artil e
Q 3
t hir d q u artil e
Q 4 W
e v er y f o ur w e e k s
Q C
q u alit y c o ntr ol
Q O L
q u alit y of lif e
Q Q
q u a ntil e -q u a ntil e
Q R S
i nt er v al i n m s of t h e Q R S p orti o n of t h e E C G
Q T
i nt er v al i n m s of t h e Q T p orti o n of t h e E C G
Q T c F
c orr e ct e d Q T ( Fri d eri ci a m et h o d)
R E CI S T
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m o ur s
s
s e c o n d s
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)


Pr ot o c ol C 3 6 5 1 0 0 3 ( Po n s e gr o m a b ) St ati sti c al A n al y si s Pl a n
P FI Z E R C O N FI D E N TI A L 
D M B 0 2 -G S O P -R F 0 2 8. 0 St ati sti c al A n al y si s Pl a n T e m pl at e
T M F D o c I D: 9 8. 0 3
P a g e 6 0 of 6 0
A b br e vi ati o n
T er m
S A E
s eri o u s a d v er s e e v e nt
S A P
st ati sti c al a n al y si s pl a n
S C
s u b c ut a n e o u s 
S D
st a n d ar d d e vi ati o n
S E
st a n d ar d err or
S M Q
st a n d ar di s e d M e d D R A q u er y
S O P
st a n d ar d o p er ati n g pr o c e d ur e
S V
s cr e e ni n g vi sit
S W B
s o ci al/f a mil y w ell -b ei n g
T N M
T u m o r ( T), n o d e ( N), a n d m e t a st a si s ( M) c a n c er st a gi n g
T E A E
tr e at m e nt-e m er g e nt a d v er s e e v e nt
T E S A E
tr e at m e nt-e m er g e nt s eri o u s a d v er s e e v e nt
u b
u p p er b o u n d
0 9 0 1 7 7 e 1 a 0 5f 7 b 8 e\ A p pr o v e d\ A p pr o v e d O n: 0 7- A pr- 2 0 2 4 0 7: 0 3 ( G M T)