Clinical trial NCT04299048
Conditions: Cachexia Non-Small-Cell Lung Cancer Pancreatic Cancer Colorectal Cancer
Keywords: cachexia, non-small cell lung cancer, pancreatic cancer colorectal cancer, weight loss, anorexia, muscle loss, fatigue
Sponsor: Pfizer
Start date: 2020-11-17; Completion date: 2022-03-30
Enrollment: 11 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Study to assess the safety and tolerability of repeated doses of an investigational new drug in patients with cancer and cachexia.

Detailed description:
This 12-week open-label study will explore how PF-06946860 is tolerated, the effects of the study drug, the best dose for treatment and how participants with non-small cell lung, pancreatic or colorectal cancer and cachexia feel after receiving repeated subcutaneous dosing. During the 12-week treatment period, study drug will be administered subcutaneously every 3 weeks for a total of 5 doses. There is a 12-week follow-up period following the last dose of study drug. Additional assessments include:

* body weight measurements
* blood pressure and heart rate measurements
* Lumbar Skeletal Muscle Index (LSMI) by CT scan
* Blood samples:

  * to evaluate safety,
  * to measure the amount of the study drug in the blood,
  * to evaluate if the study drug causes an immune response,
  * to examine the effects of the study drug on levels of a specific cytokine,
  * and for exploratory samples for bio banking.
* Measure the impact of the study drug on appetite, nausea, vomiting, fatigue, physical function, and health-related quality of life with questionnaires.
* Measure the impact of study drug on physical activity using wearable digital sensors.
* To evaluate the effect of study drug on ability to complete anti-tumor treatment and survival in participants with cancer and cachexia.
* To evaluate tumor size.

Arms: arm 1: subcutaneous injection
Interventions: intervention 1: PF-06946860
Intervention descriptions: intervention 1: subcutaneous injection

Protocol documents:
Prot_000.pdf: 
PF-06946860
Protocol C3651009
Final Protocol Amendment 1, 08 February 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1B, 12-WEEK, OPEN-LABEL STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS
FOLLOWING REPEATED SUBCUTANEOUS ADMINISTRATIONS OF 
PF-06946860 IN PATIENTS WITH CANCER AND CACHEXIA
Investigational Product Number:
PF-06946860
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
C3651009
Phase:
1b
Short Title: Study to Assess Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics following Repeated Subcutaneous Administrations of PF-06946860 in 
Patients with Cancer and Cachexia
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
08 February 2021
The rationale for this amendment overall is 
to streamline participant workflow, 
minimize participant testing burden, and 
include more cancer populations. The 
rationale for other changes are based upon 
completion of the C3651001 and 
C3651002 CSRs, incorporate PACL items, 
incorporate protocol template items and 
correction of spelling errors.  The updates 
are as follows:
Addition of pancreatic and colorectal 
cancer throughout the protocol.
Removal of DXA scan as a study 
procedure noted throughout protocol.
Removal of PROs 
 
from Cohort 2 noted throughout protocol.
Added flexibility for CT scan timing noted 
in SoA.
Updates from current IB (Section 2.2) and 
added 6-month nonclinical monkey data to 
Section 2.2.3.
Schema-updated based upon changes to the 
procedures and SoA.
SoA: 
•
Added a second screening GDF-15 
samples to allow analysis using the 
internal Pfizer assay(s). The additional 
sample will serve as a baseline prior to 
standard-of-care anti-tumor therapy for 
patients who enter the study at the 
second cycle of standard of care
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anti-tumor therapy.
•
Added an immunogenicity sample at 
Week 15 since this is the end of the 
dosing interval after the last dose of 
PF-06946860.
•
Changed V13 from an at-home visit to 
a clinic visit with additional procedures 
noted in SOA and increased visit 
window from ±1 to ±3 days.
•
Added safety labs and pregnancy test to
V14 noted in SOA.
•
Added pregnancy test to V15 noted in 
SoA.
•
 
 
Section 2.2.2:
•
Statement regarding the low risk of 
developing ADA was removed as ADA 
data from C3651001 and C3651002 are 
presented in Section 2.2.4.
Section 2.2.4: 
•
Updated based on emerging data from 
C3651001 and C3651002.
Section 3: 
•
PK endpoint has been updated to 
trough concentrations (Ctrough) of 
PF-06946860 as this is a PK parameter 
of interest. 
Section 4.3: 
•
Updated based on updated PK/PD 
modeling and simulation results. Safety 
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margin updated based on 6-month 
monkey toxicology data. 

Clarified if a different dosing frequency 
is selected for Cohort 2, this will be 
implemented via a protocol 
amendment.
Section 5: 

Inclusion Criterion # 3 modified for 
additional cancer types.

Inclusion Criterion # 6 modified for 
allowable therapies.

Inclusion Criterion # 8-minor 
corrections.

Exclusion Criterion #1-clarification of 
excluded cancer types.

Exclusion Criterion #2-updated for 
clarity.

Exclusion Criterion # 3-added for 
clarification of radiation therapy.

Exclusion Criterion # 13-removed
second bullet.

Exclusion Criterion # 15-removed.
Added the following sections to align with 
the updated protocol template: 
Sections 8.3.6, Section 8.3.7, 8.3.8 and 
8.3.8.1.
Section 8.0:

Blood volume increased based on
additional samples for safety, biobank 
and internal assay.


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Final Protocol Amendment 1, 08 February 2021
PFIZER CONFIDENTIAL
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Section 8.4: 

Overdose updated based on updated 
PK/PD simulation results and NOAEL
from 6-month monkey toxicology 
study. Definition of overdose for this 
study was redefined based on 
operational considerations. 
Sections 8.5, 8.6 and 8.9:

Updated per updated protocol template 
text. 

Section 8.6 updated per SOA. 
Section 8.8.1:

Updated Prep B2 and Prep 1.5 sample 
descriptions for clarity.
Appendix 10.4: 

Updated contraception requirements 
per emerging PK data from C3651001.
Updated protocol to include PACL items:

A pre-dose PK sample will also be 
collected on Day 1 in addition to the 
post-dose PK sample.

Radiation as primary SOC is not 
permitted (allowed for metastases for 
palliative care)

Inclusion Criterion # 6-Paclitaxel or 
nab-paclitaxel is permitted as an 
allowable therapy. Therefore, the 
allowable therapies are a platin + 
pemetrexed ± pembrolizumab or a 
platin + nab paclitaxel or paclitaxel
± pembrolizumab as first or second line 
therapy.
Original protocol
27 November 2019
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
1. PROTOCOL SUMMARY...................................................................................................12
1.1. Synopsis ..................................................................................................................12
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................17
2.1. Study Rationale .......................................................................................................17
2.2. Background .............................................................................................................18
2.2.1. Nonclinical Pharmacology..........................................................................18
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................18
2.2.3. Nonclinical Safety ......................................................................................19
2.2.4. Clinical Overview.......................................................................................19
2.2.4.1. Summary of Safety Data ...........................................................20
2.2.4.2. Summary of Pharmacokinetics..................................................20
2.2.4.3. Summary of Pharmacodynamics...............................................20
2.2.4.4. Summary of Immunogenicity....................................................22
2.3. Benefit/Risk Assessment.........................................................................................22
3. OBJECTIVES AND ENDPOINTS.....................................................................................22
4. STUDY DESIGN.................................................................................................................24
4.1. Overall Design.........................................................................................................24
4.2. Scientific Rationale for Study Design.....................................................................25
4.3. Justification for Dose ..............................................................................................27
4.4. End of Study Definition ..........................................................................................28
5. STUDY POPULATION......................................................................................................29
5.1. Inclusion Criteria.....................................................................................................29
5.2. Exclusion Criteria....................................................................................................31
5.3. Lifestyle Considerations..........................................................................................33
5.3.1. Contraception..............................................................................................33
5.4. Screen Failures ........................................................................................................33
6. STUDY INTERVENTION..................................................................................................34


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6.1. Study Intervention(s) Administered........................................................................34
6.1.1. Administration............................................................................................35
6.2. Preparation/Handling/Storage/Accountability ........................................................35
6.2.1. Preparation and Dispensing........................................................................36
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................36
6.3.1. Allocation to Investigational Product .........................................................36
6.4. Study Intervention Compliance...............................................................................37
6.5. Concomitant Therapy..............................................................................................37
6.6. Dose Modification...................................................................................................37
6.7. Intervention After the End of the Study..................................................................38
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................38
7.1. Discontinuation of Study Intervention ....................................................................38
7.1.1. Criteria for Discontinuation........................................................................38
7.2. Participant Discontinuation/Withdrawal from the Study........................................38
7.3. Lost to Follow-up....................................................................................................39
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................40
8.1. Efficacy Assessments..............................................................................................41
8.1.1. Body Weight...............................................................................................41
8.1.2. Imaging Assessment...................................................................................41
8.1.2.1. CT Scan.....................................................................................41
8.1.3. Patient-Reported Outcomes (Cohort 1) ......................................................42
8.1.3.2. Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE™).............43
8.1.3.3. Patient’s Global Impression of Severity (PGI-S)......................44
8.1.3.4. Patient’s Global Impression of Change (PGI-C).......................44
8.1.3.5. PROMIS – Fatigue (version 7a)................................................44
8.1.3.6. PROMIS – Physical Function (version 8c)...............................44
8.1.3.7. Functional Assessment of Anorexia-Cachexia Therapy 
(FAACT) ...........................................................................................45
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8.2. Safety Assessments .................................................................................................45
8.2.1. Physical Examinations................................................................................46
8.2.2. Eastern Cooperative Oncology Group (ECOG) .........................................46
8.2.3. Vital Signs ..................................................................................................46
8.2.4. Electrocardiograms.....................................................................................46
8.2.5. Clinical Safety Laboratory Assessments ....................................................47
8.2.6. Pregnancy Testing ......................................................................................48
8.3. Adverse Events and Serious Adverse Events..........................................................48
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......48
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................49
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................49
8.3.2. Method of Detecting AEs and SAEs ..........................................................50
8.3.3. Follow-up of AEs and SAEs.......................................................................50
8.3.4. Regulatory Reporting Requirements for SAEs...........................................50
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................51
8.3.5.1. Exposure During Pregnancy......................................................51
8.3.5.2. Exposure During Breastfeeding ................................................51
8.3.5.3. Occupational Exposure .............................................................51
8.3.6. Cardiovascular and Death Events...............................................................51
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................51
8.3.8.1. Lack of Efficacy........................................................................52
8.3.9. Medical Device Deficiencies......................................................................52
8.3.10. Medication Errors.....................................................................................52
8.4. Treatment of Overdose............................................................................................53
8.5. Pharmacokinetics ....................................................................................................53
8.6. Pharmacodynamics of GDF-15...............................................................................54
8.7. Genetics...................................................................................................................55
8.7.1. Specified Genetics ......................................................................................55
8.7.2. Banked Biospecimens for Genetics............................................................55
8.8. Biomarkers ..............................................................................................................55


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8.8.1. Banked Biospecimens for Biomarkers .......................................................56
8.9. Immunogenicity Assessments.................................................................................56
8.10. Health Economics .................................................................................................57
9. STATISTICAL CONSIDERATIONS ................................................................................57
9.1. Estimands and Statistical Hypotheses.....................................................................57
9.2. Sample Size Determination.....................................................................................57
9.3. Populations for Analysis .........................................................................................58
9.4. Statistical Analyses .................................................................................................58
9.4.1. Efficacy Analyses .......................................................................................58
9.4.2. Safety Analyses ..........................................................................................58
9.4.2.1. Electrocardiogram Analyses......................................................59
9.4.3. Pharmacokinetic Analyses..........................................................................59
9.4.4. Other Analyses............................................................................................60
9.4.4.1. Pharmacodynamic Analyses .....................................................60
9.4.4.2. Immunogenicity Analyses.........................................................60
9.5. Interim Analyses .....................................................................................................60
9.5.1. Data Monitoring Committee.......................................................................60
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................61
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............61
10.1.1. Regulatory and Ethical Considerations ....................................................61
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................61
10.1.2. Financial Disclosure .................................................................................62
10.1.3. Informed Consent Process ........................................................................62
10.1.4. Data Protection .........................................................................................63
10.1.5. Dissemination of Clinical Study Data ......................................................63
10.1.6. Data Quality Assurance ............................................................................65
10.1.7. Source Documents....................................................................................66
10.1.8. Study and Site Closure..............................................................................66
10.1.9. Publication Policy.....................................................................................67
10.1.10. Sponsor’s Qualified Medical Personnel .................................................68


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10.2. Appendix 2: Clinical Laboratory Tests .................................................................69
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................70
10.3.1. Definition of AE .......................................................................................70
10.3.2. Definition of SAE.....................................................................................71
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................73
10.3.4. Reporting of SAEs....................................................................................76
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................77
10.4.1. Male Participant Reproductive Inclusion Criteria....................................77
10.4.2. Female Participant Reproductive Inclusion Criteria.................................77
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................78
10.4.4. Contraception Methods.............................................................................79
10.5. Appendix 5: Genetics............................................................................................82
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........83
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................85
10.9. Appendix 9: Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events PATIENT (PRO-CTCAE™)..................88
10.10. Appendix 10: Patient’s Global Impression of Severity (PGI-S).........................89
10.11. Appendix 11: Patient’s Global Impression of Change (PGI-C)..........................90
10.12. Appendix 12: PROMIS – Fatigue (version 7a)...................................................91
10.13. Appendix 13: PROMIS – Physical Function (version 8c) ..................................92
10.14. Appendix 14: Functional Assessment of Anorexia-Cachexia Therapy 
(FAACT) ...................................................................................................................93
10.16. Appendix 16: ECOG Performance Status...........................................................97
10.17. Appendix 17: RECIST 1.1 Tumor Assessment Criteria RECIST 
(Response Evaluation Criteria In Solid Tumors) version 1.1 Guidelines .................98
10.18. Appendix 18: Modification of Diet in Renal Disease Equation........................103
10.19. Appendix 19: Proposed Chronology of Procedures..........................................104
10.20. Appendix 20: Alternative Measures During Public Emergencies.....................107
10.20.1. Eligibility..............................................................................................107
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10.20.2. Home Health Visits...............................................................................107
10.20.3. Adverse Events and Serious Adverse Events.......................................107
10.21. Appendix 21: Abbreviations .............................................................................108
11. REFERENCES ................................................................................................................112
LIST OF TABLES
 
 
Table 2.
Patient Reported Outcomes for Cohort 1..................................................43
Table 3.
Protocol-Required Safety Laboratory Assessments .................................69
Table 4.
Objective Response Status at each Evaluation.......................................102
Table 5.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only ...............................................................................102
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Not Applicable.
1.2. Schema
The following schema applies to Cohort 1.
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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 


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Visit Identifier
Screeninga
Treatment
EOT
Follow Upb
ET
Visit Number
v1
v2
v3
v4
v5
v6
v7
v8
v9
v10
v11
v12
v13
v14
v15
Study Week (relative to Day 1)
w1
w2
w3
w4
w5
w6
w9
w12
w13
w14
w15
w18
w24
Study Day (relative to Day 1 dosing)
-28 to -1
1
8
15
22
29
36
43
64
85
92
99
106
127
169
Visit Window (days)
±1
±1
±3
±1
±1
±3
±3
±3
±1
±1
±3
±7
±7
Clinic Visit
X
X
X
X
X
X
X
X
X
X
At-Home Visitc
X
X
X
X
X
X
Informed Consent and Registration
X
Review of Eligibility Criteria
X
X
Medical History and Demography
X
Record Prior or Concomitant treatments
X
X
X
X
X
X
X
X
X
X
Monitor Serious/nonserious AEsd
X
X
→
→
X
→
→
X
X
X
→
→
X
X
X
X
Review contraception use 
X
X
X
X
X
X
X
X
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
X
Weight (+ Height at Screening only)
X
X
X
X
X
X
X
X
X
X
Supine vital signsf
X
X
X
X
X
X
X
X
X
X
Supine standard 12-Lead ECGg
X
X
X
X
X
X
X
X
X
X
CT scan
Xh,i
Xh,i
Xh,i,j
Xj
ECOG Performance
X
X
X
X
X
X
Randomization 
X
Administration of IP (PF-06946860, SC)l
X
X
X
X
X
Anti-tumor therapy prescribed per SoCm
X
→
→
→
→
→
→
→
→
Safety Labs (Blood and Urine):
X
X
X
X
X
X
X
X
X
X
Pregnancy Test for females (Blood and/or Urine)n
X
X
X
X
X
X
X
X
X
X
GDF-15 blood levels (Roche assay)o
X
GDF-15 blood levels (Internal assay(s))o,p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PF-06946860 serum PKp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity (ADA/NAb)p
X
X
X
X
X
X
X
X
X
X
Prep D1 banked biospecimenq
X
Prep B1.5 & B2 banked biospecimenq
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes (At home) (Cohort 1 
only)r
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes (At clinic) (Cohort 1 
only)s
X
X
X
X
X
X
X
 
Please see next page for table footnotes.  Abbreviations: see Appendix 21: Abbreviations.
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a.
CT scan, 
and PROs (Cohort 1) are performed during the screening period to determine baseline values, but do not need to be
reviewed to determine eligibility.
b.
Follow-up visits: Number, length, and frequency of follow-up visits may be modified based on emerging data.
c.
At-Home visits: The blood sampling to be conducted at these visits is intended to be done at home by a visiting health care professional for the participant’s 
convenience, but blood sampling may be conducted at the clinic, at the discretion of the participant or investigator. If the participant will be coming to the 
clinic for clinical care on a day that a home visit is scheduled, the procedures for that visit can be performed at the clinic; and this will not be a protocol 
deviation.
d.
AEs will be queried at each clinic visit using open-ended and nonleading verbal questioning of the participant.  Any spontaneously reported AEs noted 
during the home visits will be captured.
e.
Full physical exam will be conducted at Screening.  Abbreviated physical exams planned at all other clinic visits, however full exams may be performed 
for findings during previous exam, new/open AEs, or at investigator discretion.
f.
Triplicate blood pressure and pulse rate will be measured on Day 1; single blood pressure and pulse rate for all other clinic visits. See Section 8.2.3.
g.
Triplicate ECGs on Day 1; single ECG for all other clinic visits. See Section 8.2.4.
h.
CT scan: If a CT scan was performed within 3 weeks prior to the Screening visit and meets the quality and anatomical requirements, then a CT scan at 
screening is not needed. If a CT scan is being performed at the Week 6 or Week 12 visit as part of the standard of care, then an additional CT scan is not 
needed as long as CT quality matches the requirements outlined in the imaging guidelines. The RECIST 1.1 categorization is to be entered in the CRF after 
each scan. See Section 8.1.2.
i.
CT scans can be done within ± 14 days of the Week 6 visit and within 7 days after the last dose of IP administration at the Week 12 visit.
j.
CT scan: To be completed at the ET visit if a CT scan has not been completed in the prior 6 weeks.  However, a CT scan at the ET visit is not needed if the 
ET is before Week 4 or if a CT scan was performed at Week 12.
 
 
l.
PF-06946860 dosing can be initiated at the start of the first or second cycle of the standard of care anti-tumor therapy.  If the standard of care anti-tumor 
therapy is to be administered on the same day of dosing with PF-06946860, the IP will be the first drug administered during the clinic visit and must be 
given at least 0.5h prior to administration of SOC anti-tumor therapy.  If SoC anti-tumor therapy is paused, adjusted or discontinued during the 12 week 
treatment period, this would not be considered a protocol deviation. PF-06946860 administration is to continue as prescribed by the protocol. 
m. The SoC anti-tumor therapy may continue beyond the study 12-week PF-06946860 treatment period according to the SOC anti-tumor therapy for each 
cancer type and the treating physician’s clinical judgment; this would not be considered a protocol deviation.
n.
Blood and/or Urine pregnancy test may be performed at the discretion of the PI.
o.
Two GDF-15 samples will be collected at Screening. One sample will be tested using the Roche GDF-15 assay for determination of enrollment eligibility.  
Another sample will be analyzed using the internal Pfizer GDF-15 assay(s).
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p.
GDF-15, PK and Immunogenicity blood samples will be collected as described in Section 10.19.  On dosing days (Day 1, Weeks 3, 6, 9, and 12), these 
blood samples will be collected prior to PF-06946860 administration (ie, pre-dose). Additionally, on Day 1 and Week 12, post-dose blood samples will be 
collected, one for PK and one for GDF-15 at each visit.  These post-dose blood samples will be collected at a minimum of 3h post PF-06946860 
administration or at a maximum by the end of the clinic visit.
q.
Prep D1, B1.5 and B2 banked biospecimen samples collected during clinic visits will be collected prior to PF-06946860 administration. For Prep D1, if
not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a 
participant visit.
r.
During Cohort 1, participants will be provided with a hand-held device at the Screening visit once the informed consent document is signed and available 
eligibility criteria are confirmed for completion of 
 at home for daily completion between Screening and 
Week 18, with a target of at least 7 consecutive days prior to Day 1. The hand-held device is to be returned at Week 18. 
 for details related to specific timing refer to Table 2.  If the participant early terminates prior to Week 18, the hand-held device is to be 
returned to the site. and for details related to specific timing refer to Table 2.  If the participant early terminates prior to Week 18, the hand-held device is to 
be returned to the site.
s.
At each clinic visit during Cohort 1, participants will complete questionnaires on a separate electronic device (tablet) available at the site.  The devices will 
prompt the participant to complete the appropriate questionnaire(s). For additional details refer to Section 8.1.3 and for details related to specific timing 
refer to Table 2.  If the participant early terminates prior to Week 18, the hand-held device is to be returned to the site.
 
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2. INTRODUCTION
Cachexia is a metabolic disorder and comorbidity that occurs with several chronic diseases 
including cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic 
kidney disease (CKD).  Cachexia manifests as marked involuntary body weight loss, muscle 
atrophy, and reduced appetite, progressing to significant functional impairment and increased 
risk of death.
The cytokine growth differentiation factor 15 (GDF-15), also known as Macrophage 
Inhibitory Cytokine 1 (MIC-1), is a member of the transforming growth factor beta (TGF) 
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;1 and during 
pregnancy it is highly expressed by placental trophoblast.2 GDF-15 is also secreted by tumor 
cells, macrophages and damaged cells.3-7  In several chronic conditions such as cancer, heart 
failure, COPD, and CKD, circulating GDF-15 concentrations are markedly elevated 
compared to healthy levels.8-11  Elevated GDF-15 is associated with weight loss/cachexia in 
cancer12-15 and also heart failure16,17 patients.  In addition, elevated circulating GDF-15 levels 
are associated with poor outcomes and survival in many cancers, heart failure, CKD and 
COPD.18-24  In rodents and non-human primates, GDF-15 induces anorexia and weight 
loss25-29 by acting through the glial cell-derived neurotrophic factor (GDNF) family receptor 
alpha-like (GFRAL).  Furthermore, increased GDF-15 levels are associated with cachexia in 
mouse tumor models, and inhibition of GDF-15 reverses weight loss and improves survival.14
GFRAL is a transmembrane protein with a short cytoplasmic domain lacking any signaling 
function and requires the tyrosine kinase co-receptor RET for signaling. Its expression is 
largely restricted to the area postrema and the nucleus tractus solitarius. Signaling is 
mediated via dimers of circulating GDF-15 binding to a co-receptor complex composed of 
2 GFRAL molecules and 2 RET molecules leading to an activated pentameric activated 
receptor complex.26-29
PF-06946860 is a recombinant humanized monoclonal antibody (immunoglobulin gamma-1 
with kappa light chains [IgG1κ]) directed against GDF-15.  This anti-GDF-15 humanized 
monoclonal antibody (mAb) binds to the GDF-15 protein preventing its interaction with 
GFRAL.  It is anticipated that binding of the mAb to circulating GDF-15 will prevent its 
interaction with the GFRAL receptors and promote appetite and increase body weight in 
patients with cachexia. 
2.1. Study Rationale 
Non-Small Cell Lung Cancer (NSCLC) is a common type of cancer with a high prevalence 
of cachexia.30 NSCLC has been observed to be associated with elevated circulating GDF-15 
levels and this elevated concentration of GDF-15 correlates with lower body weight.13
Therefore, it is hypothesized that cachexia in NSCLC is largely mediated via GDF-15 and 
that suppression of GDF-15 in these patients may lead to improvement in serious aspects of 
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Similar observations have been made in other cancers. In colorectal cancer, elevations in 
GDF-15 have been reported as compared to levels in healthy individuals, and higher 
elevation correlated with lower survival.31,32 Elevated GDF-15 has also been reported in 
patients with pancreatic cancer.8 Animal and clinical data suggest that GDF-15 is a key 
driver of cachexia in cancer, and cachexia in pancreatic cancer has been shown to correlate 
with decreased survival.33
This study is intended to obtain safety, tolerability, pharmacokinetic (PK) and
pharmacodynamic (PD) data following administration of PF-06946860 to a limited number 
of participants in the target patient population, prior to exposure to a larger group of patients
with cancer and cachexia.  
2.2. Background
A summary of relevant, currently available data is provided in this protocol.  Additional
detail, and further information for this compound, may be found in the investigator’s
brochure (IB). 
2.2.1. Nonclinical Pharmacology
PF-06946860 is a potent and highly selective binder of human GDF-15 compared to 10 other 
human transforming growth factor beta (TGF) family members.  In vitro binding, to 
fragment crystallizable gamma (Fc) receptors, was not observed, suggesting low potential to 
cause antibody dependent cell-mediated cytotoxicity (ADCC). However, PF-06946860
elicited relatively low binding to C1q, suggesting that the potential for 
complement-dependent cytotoxicity (CDC) cannot be ruled out. PF-06946860 did not cause 
cytokine release in human whole blood.
Consistent with the literature25-29 exogenously administered mouse and human GDF-15 
caused weight loss (both lean mass and fat mass) in mice, and administration of 
PF-06946860 reversed these observations. In a variety of GDF-15 secreting mouse tumor 
models (HT-1080, PA0165, NSX-26115 and RENCA), tumor implantation induced a 
cachectic phenotype that was either prevented or reversed by administration of PF-06946860.  
Treatment with PF-06946860 also consistently increased survival compared to control 
groups. Taken together, the data suggest that PF-06946860 has the potential to be a 
treatment for GDF-15 related cancer cachexia in humans.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Details of the nonclinical PK of PF-06946860 are provided in the IB Section 5.2.  The PK of 
PF-06946860 in mouse was consistent with that for a typical human immunoglobulin G1 
(IgG1) mAb.  After weekly subcutaneous (SC) administration of PF-06946860 to mice and 
monkeys in repeat dose toxicity studies, there were no apparent sex related differences in 
systemic exposures, and accumulation was observed.  After repeat dosing, mean systemic 
exposures increased in a less than dose proportional manner in mice and an approximately 
dose proportional manner in monkeys.  PF-06946860 did not induce inflammatory cytokine 
release in vitro, therefore it is not expected to affect the PK of small molecule drugs either 


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via cytokine mediated effects on CYP enzymes or transporters.  PF-06946860 is expected to 
undergo both non-specific proteolytic elimination and target-mediated elimination.  As such, 
concomitant medications and/or disease states, that alter the expression of GDF-15, may 
potentially impact the elimination of PF-06946860. 
2.2.3. Nonclinical Safety
PF-06946860 was administered weekly in SC studies for 13 weeks (3 months) to mice, and 
for 3- and 6-months to cynomolgus monkeys, followed by a recovery phase of approximately 
2 and 3 months, respectively.  
No adverse effects were observed in any of the toxicity studies conducted with PF-06946860.
The cardiovascular and renal systems, and hematology parameters were identified as 
potential nonadverse targets. Cardiovascular and renal observations were predominantly
related to lower group mean organ weights but were nonadverse based on the small 
magnitude, lack of macroscopic, microscopic and functional correlates, and/or clinical 
sequelae. Hematology findings consisted of nonadverse increases in red blood cell mass
parameters.  Serum chemistry findings consisted of nonadverse increases in serum 
triglyceride concentration.  Other nonadverse findings related to administration of 
PF-06946860 included small magnitude alterations in clinical chemistry parameters, minor 
decreases in organ weights, zymogen granule depletion in the pancreas, minimal increases in 
locomotor activity in mice, and microscopic findings (mononuclear cell infiltrates of choroid 
plexus and glomerulus) considered secondary to antidrug antibodies (ADA) and immune 
complex disposition in monkeys. Nearly all of the dosing phase findings in both species 
reversed by the end of the recovery phase. 
The no-observed-adverse-effect levels (NOAELs) were the highest doses tested in the 
3-month study in mice 
 and the 3-month 
 and 6-month 
(20 mg/kg/week) studies in monkeys.  Systemic exposures of total PF-06946860 (maximum
observed concentration [Cmax], average concentration [Cav] and area under the curve from the 
time of dose administration up to 168 hours [AUC168H]) at the NOAEL in the 3-month mouse 
study were 3190 μg/mL, 2010 μg/mL and 337,000 μg•h/mL, respectively. Systemic 
exposures of total PF-06946860 (Cmax, Cav, and AUC168H) at the NOAEL in monkeys were 
5520 μg/mL, 4340 μg/mL and 729,000 μg•h/mL, respectively, in the 3-month study and 
964 μg/mL, 827 μg/mL and 139,000 μg•h/mL, respectively, in the 6-month study.
2.2.4. Clinical Overview
PF-06946860 has been evaluated in 2 completed Phase 1 single dose studies in healthy 
participants, C3651001 and C3651002.  Clinical data from the completed studies are 
provided in the IB for PF-06946860.
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2.3. Benefit/Risk Assessment
This study is designed primarily to assess safety, tolerability, pharmacokinetics and 
pharmacodynamics of PF-06946860 in participants with non-small cell lung cancer, 
pancreatic cancer or colorectal cancer and cachexia.
The available clinical data show the single dosing of PF-06946860, in healthy participants, to 
be safe and well tolerated.  Efficacy has not yet been studied in humans.
Based upon pre-clinical data, it is possible that dosing with PF-06946860 will improve 
participants appetite and support maintenance of body weight; and there may be mitigation of 
the anorexia and emetogenic effect of platinum-based chemotherapy.
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06946860 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 PF-06946860 may be found in the investigator’s brochure (IB), 
which is the single reference safety document (SRSD) for this study.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To characterize the safety and tolerability of repeated 
subcutaneous administrations of PF-06946860 to 
participants with NSCLC, pancreatic cancer or colorectal
cancer and cachexia.
•
Incidence of treatment emergent adverse events 
(AEs and SAEs), safety laboratory tests, vital 
signs (blood pressure and pulse rate) and 
standard ECG parameters (heart rate, QT, QTcF, 
PR and QRS intervals).
Secondary: 
Secondary: 
•
To characterize unbound (free) and total PK of 
PF-06946860 administered to participants with NSCLC,
pancreatic cancer or colorectal cancer and cachexia.
•
Serum unbound and total trough concentrations 
(Ctrough) of PF-06946860 at Weeks 3, 6, 9, 12,
and 15.
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Tertiary/Exploratory:
Tertiary/Exploratory: 
•
To evaluate the immunogenicity profile of PF-06946860 
in participants with NSCLC, pancreatic cancer or
colorectal cancer and cachexia.
•
Incidence of ADA and NAb, if applicable.
•
To characterize the effect of repeated administrations of 
PF-06946860 on circulating GDF-15 concentrations in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Serum concentrations of total and, if feasible, 
unbound GDF-15 at time points specified in the 
schedule of activities (SoA).
•
To evaluate the effect of PF-06946860 on Lumbar 
Skeletal Muscle Index (LSMI) measured by CT scan in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Change from baseline LSMI measured by CT 
scan at time points specified in the schedule of 
activities (SoA). 
•
To evaluate the effect of PF-09646860 on body weight in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Change from baseline body weight at time points 
specified in the schedule of activities (SoA).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE)
selected items in participants with NSCLC, pancreatic 
cancer or colorectal cancer and cachexia.
•
Change from baseline scores for selected 
PRO-CTCAE items at time points specified in 
Table 2.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
fatigue as measured by the PROMIS-Fatigue
questionnaire in participants with NSCLC, pancreatic 
cancer or colorectal cancer and cachexia.
•
Change from baseline score for
PROMIS-Fatigue at time points specified in 
Table 2.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
physical function as measured by the PROMIS-Physical 
Function questionnaire in participants with NSCLC,
pancreatic cancer or colorectal cancer and cachexia.
•
Change from baseline score for
PROMIS-Physical Function at time points 
specified in Table 2.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
HRQoL as measured by FAACT in participants with 
NSCLC, pancreatic cancer or colorectal cancer and 
cachexia.
•
Change from baseline FAACT total and 
sub-scale scores at time points specified in 
Table 2.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) in participants with 
•
Change from baseline PGI-S at time points 
specified in Table 2.
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NSCLC, pancreatic cancer or colorectal cancer and 
cachexia.
•
PGI-C at time points specified in Table 2.
 
 
 
 
 
 
 
 
•
To evaluate the effect of PF-06946860 on ability to 
complete anti-tumor treatment as originally prescribed 
in participants with NSCLC, pancreatic cancer or
colorectal cancer and cachexia.
•
Number and % of participants completing 
anti-tumor treatment as originally prescribed.
•
To evaluate the effect of PF-06946860 on participant 
survival in participants with NSCLC, pancreatic cancer or
colorectal cancer and cachexia.
•
Number and % of participants alive at last 
subject last visit (LSLV).
•
To evaluate tumor burden in participants with NSCLC,
pancreatic cancer or colorectal cancer and cachexia.
•
The RECIST 1.1 categorization using CT scan at 
time points specified in the schedule of activities 
(SoA). 
•
To enable exploratory research through collection of 
banked biospecimens, unless prohibited by local 
regulations or ethics committee decision.
•
Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1b, open-label study in participants with advanced metastatic NSCLC,
pancreatic cancer or colorectal cancer and cachexia, and elevated circulating GDF-15 
concentrations. Baseline GDF-15 levels will be assessed at screening to determine eligibility 
for participation.
Following the 28-day screening period to confirm eligibility, the study will consist of a 
treatment period of 12weeks and a follow-up period of 12weeks.  The total duration of 
participation in this study is approximately 24 weeks (not including the screening period).
During the 12-week treatment period in Cohort 1, participants will receive a total of 5 doses 
of PF-06946860, administered subcutaneously (SC), every 3 weeks (Q3W).  
This study will consist of up to 2 cohorts.  In each study cohort, approximately 8 participants
will be enrolled such that approximately 6 evaluable participants complete the study.
Participants who discontinue prior to completion of the study may be replaced, at the 
discretion of the investigator and sponsor.  It is planned that the 2 cohorts will be enrolled 
sequentially and will follow similar schedules of activity.  The optional Cohort 2 may be 
conducted at the discretion of the Sponsor, with data emerging from Cohort 1 informing the 
dose level and/or frequency to be administered in Cohort 2 (see Section 4.3).  
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Based on emerging data, the dose, schedule, length and number of follow-up visits required 
may be adjusted; in this case, details will be provided to the investigator in writing or via a 
protocol amendment, as appropriate, prior to initiation of the cohort.
4.2. Scientific Rationale for Study Design
The purpose of this study is to evaluate the safety, tolerability, PK, PD and immunogenicity 
of PF-06946860 following repeated SC administrations to adult patients with advanced 
metastatic NSCLC, pancreatic cancer or colorectal cancer and cachexia, with elevated 
concentrations of circulating GDF-15. 
Elevated concentrations of circulating GDF-15 have been reported in literature12-15, in 
patients experiencing weight loss with a variety of tumor types (including lung cancer) and a 
greater magnitude of elevation was associated with worse survival. Biospecimens from 
healthy adults34 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.  These 
patients were mostly Caucasian, aged 29-90, and had an approximate ratio of 40%:
60% females to males.  The sample set of 739 apparently healthy volunteers were 
predominantly Caucasian, aged 20-79 and equally distributed males and females. Analysis 
of both the cancer and healthy sample sets using the Roche Elecsys assay,34 confirmed 
literature reported elevations in GDF-15 concentrations in NSCLC, pancreatic cancer, and 
colorectal cancer 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 degree of GDF-15 
elevation necessary for inclusion in this study. GDF-15 concentrations above the 95th
percentile of GDF-15 concentrations reported in these healthy subjects will be considered 
elevated (≥
).  
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 data35 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, 
pancreatic cancer, and colorectal cancer, 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. 
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Study C3651009 represents the first administration of PF-06946860 in patients with cancer
and cachexia.  As such, an open-label design and a small sample size have been implemented
in order to transparently establish an initial assessment of clinical safety, PK, PD and 
immunogenicity of this novel therapy.
A treatment duration of 12 weeks is consistent with available pre-clinical toxicology 
coverage and to support development of PF-06946860 in subsequent Phase 2 studies.  A 
treatment duration of 12 weeks should provide sufficient safety information to inform 
subsequent PF-06946860 Phase 2 studies.  After the 12-week treatment period, participants 
will be followed up for 12 weeks post last dose. Based on the preliminary population PK/PD 
simulation results, it is anticipated that at 12 weeks post last dose of 
 PF-06946860
the unbound PF-06946860 concentrations will be below the level that would be expected to 
fully suppress GDF-15.
PF-06946860 will be dosed via subcutaneous injections, every 3 weeks. However, the 
dosing frequency in Cohort 2 may be adjusted based upon emerging data from Cohort 1.
In addition to the characterization of safety, tolerability, PK, PD and immunogenicity of 
PF-06946860, this study will include exploratory assessment of key parameters needed in 
future studies to characterize the efficacy of PF-06946860. Cachexia is characterized by 
involuntary anorexia and weight loss, involving skeletal muscle mass depletion. Therefore,
body composition via CT-scan derived lumbar skeletal index will be measured. In addition 
to lumbar skeletal muscle index, assessment of the impact of PF-06946860 on other aspects 
of cachexia, 
will be studied. These will be 
measured through the use of electronic Patient Reported Outcome (ePRO) instruments 
administered to patients at home and during clinic visits. These initial exploratory data will 
be collected during Cohort 1 and will be used to start the process of validation of these 
instruments for use in the clinical development in the target population (cancer patients with 
cachexia). Validation of these instruments in early studies will enable a better assessment of 
the effect of PF-06946860 on how patients feel. 
 
 
 
 
 
 
The baseline assessments for the CT scan-derived LSMI, 
 and PROs will be
performed during the screening period, but do not need to be reviewed to determine 
eligibility.
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PF-06946860 dosing can be initiated at the start of a participant’s first or second cycle of 
standard of care anti-tumor therapy. Flexibility in the initiation of PF-06946860 is intended 
to minimize any interference with the evaluation, diagnosis, and/or initiation of standard of 
care anti-tumor therapy.  
At the present time, embryo-fetal developmental toxicology studies with PF-06946860 have 
not been conducted.  Consequently, to prevent pregnancy, the protocol includes contraceptive 
provisions for both male and female participants (see Section 5.3.1 and Appendix 4
Section 10.4.4).
Banked biospecimens will be collected for exploratory 
pharmacogenomic/genomic/biomarker analyses and retained in the Biospecimen Banking 
System (BBS), which makes it possible to better understand the investigational product’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.
4.3. Justification for Dose
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last follow up visit.
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The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  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. Male or female participants ≥18 years of age (or the minimum country-specific age of 
consent if >18), at screening.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2).
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Documented histologic or cytologic diagnosis of advanced metastatic NSCLC, 
advanced/unresectable pancreatic cancer, or metastatic colorectal cancer by American 
Joint Committee on Cancer (AJCC) criteria
4. Cachexia, defined using Fearon’s criteria:36
•
Body Mass Index (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; or
If medical record documentation is unavailable, patient’s report will suffice to 
estimate involuntary body weight loss.
5. Serum GDF-15 levels of ≥
(as measured using the Investigational Use Only
Roche Elecsys GDF-15 assay34) at screening.
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6. Participants considered eligible for systemic anti-cancer treatment/therapy at the time 
of screening, who:

Are diagnosed with advanced metastatic NSCLC who will be treated with: 

A platinum + pemetrexed ± pembrolizumab; or 

A platinum + nab paclitaxel or paclitaxel ± pembrolizumab; or 

Pembrolizumab alone.

Are diagnosed with advanced/unresectable pancreatic cancer who will be treated 
with:

FOLFIRINOX; or

Nab-Paclitaxel + Gemcitabine;

Gemcitabine.

Are diagnosed with metastatic colorectal cancer who will be treated with:

FOLFOX +/- Biologic (Bevacizumab or Cetuximab/Panitumumab); or

FOLFIRI +/- Biologic (Bevacizumab or Cetuximab/Panitumumab); or

FOLFOXIRI +/- Biologic (Bevacizumab or Cetuximab/Panitumumab); or

Pembrolizumab for MSI-H.

Will be entering the study at the first or second cycle of their current course of 
anti-cancer treatment/therapy. 
Note: Other therapies can be considered upon discussion with the Pfizer medical 
monitor.
7. Adequate liver function as evidenced by liver enzymes, including:

Total serum bilirubin ≤1.5 x upper limit of normal (ULN) unless the participant 
has documented Gilbert syndrome;

Aspartate and Alanine aminotransferase (AST and ALT) ≤2.5 x ULN; 
≤5.0 x ULN if there is liver involvement by the tumor; 

Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone metastasis). 


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8. Adequate renal function, including creatinine ≤2 mg/dL, or Glomerular Filtration 
Rate (GFR) ) ≥30 mL/minute/1.73 m2 as calculated by the modification of diet in 
renal disease (MDRD) equation37 (Appendix 18).
Weight: Not Applicable (N/A)
Informed Consent:
9. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1.
All other forms of cancers not specified in Inclusion Criterion #3 unless currently 
considered cured (>5 years without evidence of recurrence).
2. Participants with known symptomatic brain metastases requiring steroids. 
Participants with asymptomatic or previously diagnosed brain metastases are eligible 
if they have completed their treatment and have recovered from the acute effects of 
radiation therapy or surgery prior to screening, have discontinued corticosteroid 
treatment for these metastases and are neurologically stable for at least 4 weeks
(requires magnetic resonance imaging [MRI] confirmation) prior to randomization.  
3. Planned radiation therapy as part of the primary anti-tumor therapy regimen.  
However, localized radiation therapy for symptomatic relief is permitted and if this
becomes necessary after randomization, it will not be a reason for discontinuation.
4. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
5. Active hepatitis B virus (HBV) or hepatitis C virus (HCV).
6. Confirmed positive test for human immunodeficiency virus (HIV).
7. Current active reversible causes of decreased food intake, as determined by the 
Investigator. These causes may include, but are not limited to:


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
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 3 or 4 oral mucositis;

NCI CTCAE Grade 3 or 4 Gastrointestinal (GI) disorders [nausea, vomiting, 
diarrhea, and constipation];

mechanical obstructions making patient unable to eat.
8. Receiving tube feedings or parenteral nutrition (either total or partial) at the time of 
Screening.
9. Undergoing major surgery (central venous access placement and tumor biopsies are 
not considered major surgery) within 4 weeks prior to randomization. Patient must be 
well recovered from acute effects of surgery prior to screening. Patient should not 
have plans to undergo major surgical procedures during the study.
10. Severe gastrointestinal disease (including esophagitis, gastritis, malabsorption).
11. History of gastrectomy.
12. Cachexia caused by other reasons, as determined by the investigator, including, but 
not limited to: 

Severe COPD requiring use of home O2;

New York Heart Association (NYHA) class III-IV heart failure;

Acquired Immunodeficiency Syndrome (AIDS).
13. Any of the following in the previous 6 months: myocardial infarction, congenital long 
QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular 
tachyarrhythmia and ventricular fibrillation), unstable angina, coronary/peripheral 
artery bypass graft, symptomatic congestive heart failure (CHF, New York Heart 
Association class III or IV), cerebrovascular accident, transient ischemic attack, or 
symptomatic pulmonary embolism or other clinical significant episode of thrombo 
embolic disease. 

Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) CTCAE 
Grade ≥2. 
Prior/Concomitant Therapy:
14. Actively receiving a concurrent investigational agent or previous administration with 
an investigational drug within 30 days (or as determined by the local requirement) or 
5 half-lives preceding the first dose of investigational product used in this study 
(whichever is longer).


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Prior/Concurrent Clinical Study Experience:
15. Enrollment in a previous study with PF-06946860.
Diagnostic Assessments:
16. Elevated blood pressure that cannot be controlled by medications 
(eg, >150/90 mmHg) despite optimal medical therapy.
Other Exclusions:
17. Woman who is pregnant or breast-feeding.
18. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the , the investigator or designee will 
inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).


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Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
Intervention Name
PF-06946860
PF-06946860
ARM Name
PF-06946860 Cohort 1
PF-06946860 Cohort 2 
Type
Biologic
Biologic
Dose Formulation
Solution for injection
Solution for injection
Unit Dose Strength(s)
 and diluent
TBD 
Dosage Level(s)
 Q3W
TBD 
Route of Administration
Subcutaneous 
Subcutaneous 
Investigational Medicinal Product (IMP) 
and Noninvestigational Medicinal 
Product (NIMP)
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)
Not applicable
Not applicable
CCI
CCI


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6.1.1. Administration
During all clinic visits, the dose of investigational product must be administered in the office 
by study personnel.  PF-06946860 is to be administered first, followed by any 
premedications administered at the clinic (eg, antihistamine, anti-inflammatory agent, or pain 
reliever) and then the standard of care prescribed anti-tumor therapy. If the standard of care
anti-tumor therapy is to be administered on the same day of dosing with PF-06946860, 
PF-06946860 will be the first drug administered during the clinic visit and must be given at 
least 0.5h prior to administration of the standard of care anti-tumor therapy. If the standard 
of care anti-tumor therapy is paused, adjusted or discontinued during the 12-week treatment 
period, this would not be considered a protocol deviation. PF-06946860 administration is to 
continue as prescribed by the protocol.  The standard of care anti-tumor therapy may either 
be shorter or may continue beyond the study 12 week PF-06946860 treatment period 
according to the standard of care anti-tumor therapy for each cancer type and the treating 
physician’s clinical judgment; this would not be considered a protocol deviation. Similarly, 
adjustments to the standard of care anti-tumor therapy dose or duration, including treatment 
holidays are at the discretion of the PI. 
Premedication is permitted for all participants, consistent with institutional guidelines, and 
may include an antihistamine, anti-inflammatory agent, or pain reliever.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. 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 temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions will be accounted for using an investigational product accountability 
form/record.  
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the investigational product (IP) manual.


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5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. See the IP manual for storage conditions of the study intervention.
8. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, 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.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual.
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.
6.2.1. Preparation and Dispensing
Investigational Product, PF-06946860 (
), and diluent (depending upon the dose)
will be used to prepare doses for administration.  See the IP manual for instructions on how 
to prepare the investigational product for administration.  Investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
This is an open-label study; however, the specific investigational product dispensed to the 
participant will be assigned using an interactive response technology (IRT) system 
(interactive Web-based response [IWR]). The site will contact the IRT prior to the start of 
investigational product administration for each participant.  The site personnel (study 
coordinator or specified designee) will be required to enter or select information including 
but not limited to the user’s identification (ID) and password, the protocol number, and the 
CCI


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participant number.  The site personnel will then be provided with a treatment assignment, 
randomization number, and dispensable unit (DU) or container number when investigational 
product 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. The site will 
record the investigational product assignment on the applicable case report form, if required.  
Investigational product will be dispensed at the clinic study visits as summarized in the SoA. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.
6.5. Concomitant Therapy
Participants may be entering the study at the first or second cycle of their current course of 
standard of care anti-tumor therapy. Participants will receive standard of care anti-tumor 
therapy as described in the Inclusion criteria (See Section 5.1) and will receive any other 
supportive treatments or interventions as indicated by standard of care for their clinical 
condition. 
Hormonal contraceptives, that meet the requirements of this study, are allowed to be used in 
participants who are women of childbearing potential (WOCBP) (see Appendix 4).
Concomitant treatment considered necessary for the participant’s well-being may be given at 
discretion of the treating physician.  
All concomitant treatments, blood products, as well as nondrug interventions 
(eg, paracentesis) received by participants from screening until the end of study visit will be 
recorded on the case report form (CRF) with indication, daily dose, and start and stop dates 
of administration.  All participants will be questioned about concomitant treatment at each 
clinic visit. 
Treatments taken within the 28 days before the first dose of IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as a concomitant 
treatment.
6.6. Dose Modification
There is no dose modification of PF-06946860 anticipated for a given participant in this 
study.


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6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue 
investigational product. If investigational product is permanently discontinued, the 
participant will remain in the study for follow up. Note that discontinuation of 
investigational product does not represent withdrawal from the study.
If a safety or tolerability concern arises, in particular if not responsive to symptomatic
management, dosing with IP may be stopped in an individual participant at investigator 
discretion.
Any participant who prematurely withdraws after being randomized and during active study 
intervention, (Day 1 through Week 12) should return for an early withdrawal visit and then 
enter into the follow-up period.
See Section 1.3 for data to be collected at the time of intervention discontinuation and
follow-up and for any further evaluations that need to be completed.
7.1.1. Criteria for Discontinuation 
Discontinuation of IP must occur for a participant meeting any of the following conditions: 

Criteria for a potential Hy’s law case are met (see Appendix 6).

Intent to become pregnant or pregnancy confirmed by serum beta human chorionic
gonadotropin (-hCG) testing.
7.2. Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor.


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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.
If a participant withdraws from the study, he/she 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) for 
disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;


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
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Refer to Appendix 19 for a 
proposed chronology of procedures. Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
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 may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
Any changes in the timing or addition of time points (eg, additional follow up visits) 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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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 individual participants in this study is approximately 
490 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 60 consecutive 
days.
8.1. Efficacy Assessments
The following procedures will be conducted as part of exploratory assessments.
8.1.1. Body Weight
Weight will be recorded using a calibrated scale (with the same scale used if possible for the 
duration of the study) reporting weight in either pounds (lb.) or kilograms (kg), and accuracy 
to the nearest 0.2 lb. (or 0.1 kg); ie, the device must be able to distinguish a difference 
between 150.4 lb. (68.4 kg) versus 150.2 lb. (68.3 kg).  The scale must be placed on a stable, 
flat surface.
Weight measurement should be taken under the following conditions:

After void of urine;

After removal of shoes, bulky layers of clothing and jackets so that only light clothing 
remains;

While remaining still during the measurement.
8.1.2. Imaging Assessment
8.1.2.1. CT Scan
CT scans will be acquired throughout the study to monitor the tumor burden and evaluate the 
Lumbar Skeletal Muscle Index, in addition to other potential exploratory muscle quality 
parameters.  The standard process to obtain serial CT scans will be outlined in an Image 
Acquisition Manual.  The sites will be provided with guidance on obtaining CT images of the 
chest, abdomen, and pelvis that meet the quality requirement of this study.  
If a CT scan was performed within 3 weeks prior to the Screening visit and meets the quality 
and anatomical requirements, then a CT scan at screening is not needed. If a CT scan was 
not performed prior to Screening, a CT scan should be performed after other eligibility 
criteria (such as medical history, diagnosis) have been confirmed.  The CT scan may be 
performed without receipt of safety laboratory and GDF-15 sample results.  If a CT scan is 
being performed at the Week 6 or Week 12 visit as part of the standard of care, then an 


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additional CT scan is not needed as long as CT scan quality matches the requirements 
outlined in the Image Acquisition Manual.
Monitoring of the tumor burden will be performed by the local imaging site following 
standard RECIST 1.1 criteria (outlined in Appendix 17). The RECIST 1.1 categorization is 
to be entered in the CRF after each scan.
CT scans will also be required to be sent to a central imaging review facility for evaluation of
the Lumbar Skeletal Muscle Index and exploratory measures of muscle quality.  Central 
image review is not a complete medical review of the participant and will not include any 
tumor assessments.  If, during the central review process, an unexpected observation is 
identified and this finding could, in the opinion of the central reviewer, have a significant 
health or reproductive consequence, this finding may be shared with the study sponsor for 
disclosure to the principal investigator (PI).  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.  Identification of 
such incidental findings during the central review process should not be expected, and the 
site maintains responsibility for performing a general safety review of all images as per site 
protocols.
8.1.3. Patient-Reported Outcomes (Cohort 1)
All patient-reported outcome (PRO) assessments are implemented on an ePRO device 
(hand-held device for home use and tablet for clinic use) and completed by study participants 
at home, or at the clinic, following a schedule of assessments as per the SoA and Table 2. 
Every effort should be made to have the study participant complete all patient-reported 
outcome assessments before any other clinical assessments that take place at the clinical site.  
The site user guide will be provided separately.


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Table 2.
Patient Reported Outcomes for Cohort 1
Patient Reported Outcome (PRO) 
Measure Planned
Frequency
Assessment
Number of 
Questions
Completion 
Time
 
 
 
 
 
PRO-CTCAE selected items: taste 
change, decreased appetite, fatigue, 
nausea, vomiting
Conducted at clinic visits on Day 1 
(Baseline), Week 3, Week 6, Week 9, 
Week 12 and Week 18
At the clinic
9
~3 minutes
Patient Global Impression of Severity 
(PGI-S) 
(1 item: appetite) 
Conducted at clinic visits on Day 1 
(Baseline), Week 3, Week 6, Week 9, 
Week 12 and Week 18
1
Patient Global Impression of Change 
(PGI-C) 
(2 items: appetite and fatigue)
Conducted at clinic visits on Week 12 
and Week 18
2
PROMIS-Fatigue 7a (“Past 7 days” 
recall version)
Conducted at clinic visits on Day 1 
(Baseline), Week 6, Week 12, and 
Week 18 
7
~14 minutes
PROMIS-Physical Function 8c 
(no recall version)
Conducted at clinic visits on Day 1 
(Baseline), Week 6, Week 12, and 
Week 18
8
FAACT
Conducted at clinic visits on Day 1 
(Baseline), Week 6, Week 12, and 
Week 18
39
 
 
 
 
 
8.1.3.2. Patient-Reported Outcomes Version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE™)
Initiated and sponsored by the US National Cancer Institute, the PRO-CTCAE (Appendix 9) 
is a patient-reported outcome measure developed to evaluate symptomatic toxicity in patients 
enrolled in cancer clinical trials. It was designed to complement the Common Terminology 
Criteria for Adverse Events (CTCAE), the standard lexicon for investigator or 
clinician-reported adverse events in cancer trials. The PRO-CTCAE item library is 
composed of 124 self-report items reflecting 78 symptomatic adverse events drawn from the 
CTCAE arranged by organs and systems. Each adverse event is assessed relative to one or 
more attributes that include the presence/absence/amount (P), frequency (F), severity (S), and 
interference (I) with usual or daily activities. PRO-CTCAE provides a systematic yet 
flexible tool for descriptive reporting of symptomatic treatment side effects in cancer clinical 
trials. PRO-CTCAE data will be collected and analyzed and reported separately from 
CTCAE AE data and will not be reconciled with each other. Adverse events for this study 
will be assessed, recorded, and reported in the standard manner with investigators using 
CTCAE.
CCI
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From the 78 symptomatic adverse events, the following were selected to be administered in 
the study, each with a 7-day recall period: taste changes (S), decreased appetite (S and I), 
nausea (S and F), vomiting (S and F), fatigue (S and I).
8.1.3.3. Patient’s Global Impression of Severity (PGI-S)
The Patient’s Global Impression of Severity (PGI-S) (Appendix 10) is a single item measure 
that asks the study participants to evaluate their current severity of lack of appetite on a 
5-point verbal response scale that ranges from “None” to “Very severe”.
The PGI-S is recommended by Food and Drug Administration (FDA) for use as an anchor 
measure to generate an appropriate threshold that represents meaningful within-individual
change in the target patient population. 
8.1.3.4. Patient’s Global Impression of Change (PGI-C)
The PGI-C (Appendix 11) is a single item measure that asks study participants to rate the 
overall change in their level of appetite and fatigue since they started the study on a 7-point 
verbal rating scales 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. 
8.1.3.5. PROMIS – Fatigue (version 7a)
The PROMIS Fatigue 7a (Appendix 12) 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.
8.1.3.6. PROMIS – Physical Function (version 8c)
The PROMIS Physical Function short form 8C (Appendix 13) 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.


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8.1.3.7. Functional Assessment of Anorexia-Cachexia Therapy (FAACT)
The Functional Assessment of Anorexia-Cachexia Therapy (FAACT) (Appendix 14)
measures combines the Functional Assessment of Cancer Therapy - General (FACT-G) core 
instrument and anorexia and cachexia subscale (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 
Functional Assessment of Anorexia-Cachexia Therapy (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. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements, imaging and other safety assessments may be obtained at any time 
during the study as part of standard of care or to assess any perceived safety concerns.
Injection site reactions will be assessed as part of standard safety/AE monitoring.  Additional 
assessments may be conducted at investigator discretion and/or until any symptoms resolve.  
Injection site reactions may include but are not limited to: erythema, induration, ecchymosis, 
pain, and pruritus.  The size and severity of injection site reactions will be assessed and 
documented.  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.
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In addition to the safety monitoring as detailed in the SoA, safety monitoring for this 
open-label Phase 1b study will include monthly reviews of all available data to screen for 
trends in AEs, vital signs, ECGs and safety laboratories.
8.2.1. 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. and weight will also be measured and recorded, (height will be 
measured at screening only).
An abbreviated physical examination will be focused on general appearance, the respiratory 
and cardiovascular systems, and subject-reported symptoms.
A full physical examination will be conducted at screening only; Abbreviated physical exams 
planned at all other clinic visits, however full exams may be performed for findings during 
previous exam, new/open AEs, or at investigator discretion.  Investigators should pay special 
attention to clinical signs related to previous serious illnesses.
8.2.2. Eastern Cooperative Oncology Group (ECOG)
Assessment of ECOG performance status (see Appendix 16) may be conducted by a 
physician, trained physician's assistant, or nurse practitioner as acceptable according to local 
regulation.
8.2.3. Vital Signs
Blood pressure and pulse rate will be assessed at times specified in the SoA.
Blood pressure and pulse rate measurements will be assessed supine with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. On Day 1, blood pressure and pulse rate will be measured in triplicate,
approximately 2 to 4 minutes apart.  The average of these triplicate measurements collected 
prior to dosing on Day 1, will serve as each participant’s baseline value. At all other visits, a 
single measurement will be collected.  Blood pressure and pulse rate measurements should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions 
(eg, television, cell phones).
8.2.4. Electrocardiograms
Standard 12-Lead ECGs should be collected at times specified in the SoA section of this
protocol. All scheduled ECGs should be performed after the participant has rested quietly 
for at least 10 minutes in a supine position. Participants should be in a quiet environment and 
not speak during the resting period or measurement.


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On Day 1, triplicate standard 12-lead ECGs will be obtained approximately 2 to 4 minutes 
apart.  The average of the triplicate ECG measurements collected prior to dosing on Day 1 
will serve as each participant’s baseline value. At all other visits, a single standard 12-lead
ECG will be collected. To ensure safety of the participants, a qualified individual at the 
investigator site will make comparisons to baseline measurements.  Additional ECG 
monitoring will occur if a) any postdose QTc interval is increased by ≥60 msec from the 
baseline and is >470 msec; or b) an absolute QTc value is ≥500 msec for any scheduled 
ECG.  If either of these conditions occurs, then a single ECG measurement must be repeated 
at least hourly until QTc values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement. In addition, if verified QTc values continue to exceed the 
criteria above, immediate correction for reversible causes including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the corrected 
QT (Fridericia method) (QTcF) interval should be performed.  A cardiologist should be 
consulted if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study 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 medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.


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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Urine pregnancy tests will be provided by the central lab. 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 PF-06946860.  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 institutional 
review boards (IRBs)/ethics committees (ECs) or if required by local regulations.  If a urine 
test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required.  In such cases, the participant must be excluded if the serum pregnancy result is 
positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). AEs will be assessed based on 
CTCAE 5.0.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of up to the time of the final planned follow-up visit, after the last administration 
of the investigational product.


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Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
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 definitively 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 AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Forms.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment. Note that a switch to a commercially available version of the study intervention is 
considered as a new anticancer therapy for the purposes of SAE reporting.
8.3.1.2. 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 8.3.1, 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.
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period. Note that a switch to a 
commercially available version of the study intervention is considered as a new anticancer 
therapy for the purposes of SAE reporting.


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


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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until approximately 
130 days that is at least 5 terminal half-lives after the last dose.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.


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8.3.8. Adverse Events of Special Interest
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4.  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.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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8.4. Treatment of Overdose
Based on preliminary population PK/PD simulations, doses greater than approximately
11,000 mg, administered when exposure is expected to be at steady state, are projected to
result in exposure exceeding the NOAEL from the 6-month toxicology study in monkeys
(Section 2.2.3). The definition of overdose for this trial is based on the operational aspects of 
the protocol design. Given the nature of this study (ie, subcutaneous dose administered in the 
clinic), and the allowed visit window, an overdose will be defined as more than 2 doses of 
PF-06946860 
 SC administered in a period of 3 weeks.
There is no specific treatment for an overdose of PF-06946860, and the sponsor recommends 
general supportive medical care as clinically indicated.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06946860 (whichever 
is longer).  The duration of monitoring required will be provided by the sponsor.
3. Obtain blood samples for PK, PD and/or immunogenicity analysis approximately 
5-7 days from the date of the last dose of study intervention if requested by the 
medical monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood for PK samples will be drawn from the arm contralateral to any drug infusion.
Blood samples of approximately 6 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of serum unbound and total concentrations of PF-06946860, 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 times may change; the
actual date and time (24-hour clock time) of each sample will be recorded.
All efforts will be made to obtain the samples at the exact nominal time relative to dosing.  
Collection of samples within the protocol-allowed visit window (±1, ±3, ±7 days, as defined 
in the SoA) will not be captured as protocol deviation, as long as the exact time of the 
collection is noted on the source document and the CRF. 
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The blood sampling to be conducted during the at home visits (per SoA) is intended to be 
done at home by a visiting health care professional for the participant’s convenience, but 
blood sampling may be conducted at the clinic, at the discretion of the participant or 
investigator
Samples will be used to evaluate the PK of PF-06946860. Samples collected for analysis of 
PF-06946860 serum concentration 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 bioanalytical methods, or for other internal exploratory purposes.  Any such 
data generated may not be included in the CSR.
Genetic analyses will not be performed on PK samples unless consent for this was included 
in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of serum unbound and total concentrations of 
PF-06946860 will be analyzed using validated analytical methods 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.
8.6. Pharmacodynamics of 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 GDF-15, and if feasible, unbound 
GDF-15 at time points 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 times may change; the actual date and time 
(24-hour clock time) of each sample will be recorded.
All efforts will be made to obtain the samples at the exact nominal time relative to dosing.  
Collection of samples within the protocol-allowed visit window (±1, ±3, ±7 days, as defined 
in the SoA) will not be captured as protocol deviation, as long as the exact time of the 
collection is noted on the source document and the CRF.  
The blood sampling to be conducted during the at home visits (per SoA) is intended to be 
done at home by a visiting health care professional for the participant’s convenience, but 
blood sampling may be conducted at the clinic, at the discretion of the participant or 
investigator.
As part of understanding the PD of the study intervention, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes.  


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At screening, 2 GDF-15 samples will be collected. One GDF-15 sample will be analyzed 
using the IUO Roche Elecsys GDF-15 assay, for determination of enrollment eligibility. 
This assay will be validated in a CLIA accredited central laboratory. The second screening 
sample will be analyzed using the internal Pfizer GDF-15 assay(s). 
All serum PD samples will be analyzed for total GDF-15 and, if feasible, unbound GDF-15, 
using validated analytical methods in compliance with applicable SOPs.
PD samples collected in this study may also be analyzed using the Roche assay and/or a 
fit-for-purpose validated analytical method in compliance with applicable SOPs. These data 
may be included in the CSR, if deemed appropriate. 
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.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for deoxyribonucleic acid (DNA) isolation Prep D1 will be 
collected as local regulations and IRBs/ECs allow.
Banked biospecimens may be used for research related to drug response and cachexia.  
Genes and other analytes (eg, proteins, ribonucleic acid (RNA), nondrug metabolites) may be 
studied using the banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other
diseases and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked biospecimens. 
The optional additional research does not require the collection of any further 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. Biomarkers
There are no additional biomarkers planned for this study aside from GDF-15.


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8.8.1. Banked Biospecimens for Biomarkers
A 10-mL whole blood sample for serum (Prep B2) and a 6-mL whole blood sample for 
plasma (Prep B1.5) will be collected as local regulations and IRB/ECs allow.
Banked biospecimens may be used for research related to drug response and cachexia.  
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked samples to also be 
used to design and conduct research in order to gain a further understanding of other diseases 
and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
the study even if they do not agree to the additional research on their banked samples.  The 
optional additional research does not require the collection of any further 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. 
8.9. Immunogenicity Assessments
Blood samples of approximately 6 mL, to provide a minimum of 2 mL of 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, to evaluate safety or efficacy aspects related to
concerns arising during or after the study, and/or evaluation of the bioanalytical method, or 
for other internal exploratory purposes. These data will be used for internal exploratory 
purposes and may not be included in the CSR.
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.
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 
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.


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8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
There are no statistical hypotheses or estimands for this study.
9.2. Sample Size Determination
A sample size of approximately 6 participants per cohort has been chosen based on the need 
to minimize first exposure to patients of a new chemical entity and the requirement to 
provide adequate safety, tolerability and PK/PD assessment.  Approximately 8 participants
will be assigned to the investigational product such that approximately 6 evaluable 
participants complete the study, per cohort. 
The additional second cohort may be included if needed to meet study objectives, as 
informed by data emerging from this study.
Participants who discontinue prior to completion of the study may be replaced, at the 
discretion of the sponsor.


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9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled/Randomly 
assigned to 
investigational product
"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.  
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
Evaluable
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product
Safety
All participants randomly assigned to investigational product
and who take at least 1 dose of investigational product
PK
All randomized participants who received a dose of 
PF-06946860 and in whom at least 1 serum concentration 
value is reported
PD
All randomized participants who received a dose of 
PF-06946860 and in whom at least 1 serum GDF-15 
concentration is reported
Immunogenicity
All randomized participants who received a dose of 
PF-06946860 and in whom at least 1 ADA result is reported 
Efficacy
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in 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. Details of the analysis of all 
exploratory/tertiary endpoints will be described in the SAP.
9.4.1. Efficacy Analyses
Analyses of the exploratory efficacy assessments defined in Section 8.1 will be described in 
the SAP. These analyses will be performed on the efficacy population.
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.


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AEs, ECGs, blood pressure (BP), pulse rate and safety laboratory data will be reviewed and 
summarized on an ongoing basis during the study to evaluate the safety of participants. Any 
clinical laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will 
be described.  Safety data will be presented in tabular and/or graphical format and 
summarized descriptively, where appropriate.
Medical history and physical examination, collected during the course of the study, will be
considered source data and will not be required to be reported, unless otherwise noted. 
However, any untoward findings identified on physical and/or neurological examinations 
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE. 
9.4.2.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by time (and cohort, if applicable).
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated (by cohort, if applicable): 
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>470-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.4.3. Pharmacokinetic Analyses
All PK analyses will be performed on the PK population.
The serum concentration of unbound and total PF-06946860 will be presented in tabular 
and/or graphical format and summarized descriptively, where appropriate. Serum unbound 
and total Ctrough will be summarized by time (and cohort, if applicable).  No formal inferential
statistics will be applied to the pharmacokinetic data.  Details of planned analyses will be 
given in the SAP.
Additional PK, or population PK analyses may be performed if deemed appropriate, and will 
not be included in the CSR.


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9.4.4. Other Analyses 
Demographic data, GDF-15 concentration, height, weight, CT scan, ECOG, 
, PROs (Cohort 1) and AEs, collected at screening, may be reported.  Other data 
collected at screening, that are used for inclusion/exclusion criteria, such as laboratory data, 
ECGs and vital signs, will be considered source data, and will not be required to be reported, 
unless otherwise noted.
9.4.4.1. Pharmacodynamic Analyses
All PD analyses will be performed on the PD population. 
The serum concentration of total GDF-15 and, if feasible, unbound GDF-15, will be 
presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.  Details of planned analyses will be given in the SAP.
Additional PD, and/or population PK/PD, analyses may be performed if deemed appropriate, 
and will not be included in the CSR.
9.4.4.2. Immunogenicity Analyses
Immunogenicity analyses will be performed on the Immunogenicity population.
Incidence of ADA and NAb, if applicable, will be summarized. The number of 
ADA-positive and NAb-positive participants will be summarized by time, if appropriate. 
Potential impact of ADA and/or NAb on PK, PD and safety may be assessed, if appropriate.  
Details of planned analyses will be given in the SAP.
9.5. Interim Analyses
As this is an open-label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating PK/PD modelling, 
and/or supporting clinical development.
A formal interim analysis may be performed to assess PK, PD and/or safety. Interim analysis 
results may be used for internal business decisions regarding future study planning. If a 
formal interim analysis is conducted, details of the timing, objectives, decision criteria (if 
applicable) and analyses will be documented in an internal charter or in the final SAP.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
CCI


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


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


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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide 
this separate signature.
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 shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  
Policy 0070 applies to new marketing authorization applications submitted via the 
centralized procedure since 01 January 2015 and applications for line extensions and for new 
indications submitted via the centralized procedure since 01 July 2015.


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Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the study 
monitoring plan (SMP).
The sponsor or designee is responsible for the data management of this study, including 
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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in the SMP.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.


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


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10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand (SToD) 
system.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns.
Table 3.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea and Creatininea
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
CRP
Pre-albumin
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyb
Pregnancy test (-hCG)c
At screening only:
FSHd
Hepatitis B surface antigen
Hepatitis C antibody
HIV
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide;
CRP = C-reactive protein; FSH = follicle-stimulating hormone; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
MDRD = Modification of diet in renal disease; pH = power of hydrogen;qual = qualitative; RBC = red blood 
cell; WBC = white blood cell. 
a.Glomerular Filtration Rate (GFR) will be calculated using the modification of diet in renal disease 
(MDRD) equation.
b. Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
c. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
institutional review board/ethics committee (IRB/EC).  Serum or urine -hCG for female participants of 
childbearing potential.
d. For confirmation of postmenopausal status only.
Investigators must document their review of each laboratory safety report.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 


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the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.


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d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with
Common Terminology Criteria for Adverse Events (CTCAE) Grade 5 (see the 
Assessment of Intensity section).

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient 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.


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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)
Note: Include all SAEs 
associated with exposure 
during pregnancy or
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.  

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 


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exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 


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information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such 
an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form 
(see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 22 weeks after the last dose of study intervention, 
which corresponds to the time needed to eliminate study intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
least 22 weeks after the last dose of study intervention, which corresponds to the time 
needed to eliminate any study intervention(s). 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. 


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


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


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Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred. In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman 
(eg, a participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.5. Appendix 5: 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.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome 
(as appropriate).

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06946860 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 clinical study report (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:

Samples for banking (see Section 8.7.2 and 8.8.1) will be stored indefinitely or 
other period as per local requirements. 

Participants may withdraw their consent for the storage and/or use of their banked 
biospecimens 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. 

Banked biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank. 


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


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT and TBili for suspected cases of
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) atrioventricular (AV) block of 
>30 seconds’ duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 


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<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.9. Appendix 9: Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events PATIENT (PRO-CTCAE™)


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10.10. Appendix 10: Patient’s Global Impression of Severity (PGI-S)


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10.11. Appendix 11: Patient’s Global Impression of Change (PGI-C)


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10.12. Appendix 12: PROMIS – Fatigue (version 7a)


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10.13. Appendix 13: PROMIS – Physical Function (version 8c)


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10.14. Appendix 14: Functional Assessment of Anorexia-Cachexia Therapy (FAACT)


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10.16. Appendix 16: ECOG Performance Status


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10.17. Appendix 17: RECIST 1.1 Tumor Assessment Criteria RECIST (Response 
Evaluation Criteria In Solid Tumors) version 1.1 Guidelines
Adapted from Eisenhauer E.A., et al.38
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.
a.
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).
b. Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
c.
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
d. 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.
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.


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
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 
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’).


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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.
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended 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 4.
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 5 will be used:
Table 5.
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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10.18. Appendix 18: Modification of Diet in Renal Disease Equation
GFR (mL/min/1.73m2) = 175 x standardized Scr-1.154 x age-0.203 x 1.212 [if black] x 0.742 [if female].


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10.19. Appendix 19: Proposed Chronology of Procedures
Other procedures listed in the SoA may be conducted after the procedures listed below as per 
site discretion to allow for flexibility of participant care. For the procedures described below, 
where multiple procedures are scheduled at the same timepoint(s) relative to dosing, the 
below chronology of events should be adhered to, where possible. 
Note: All samples collected are to be processed and shipped according to the lab manual.
Screening: 

Patient signature on current IRB/RC approved informed consent form MUST be 
obtained prior to performing any study-related procedures, see Section 10.1.3.

Patient Reported Outcomes (see Section 8.1.3 (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment (see 
Section 8.2.3 and Section 8.2.4).

Blood samples for safety (see Section 8.2.5) and PD (GDF-15, Section 8.6) are to be 
collected after assessment of supine standard 12-lead ECG and vital signs.  
Day 1:

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment, and, where 
applicable, prior to dosing (see Section 8.2.3 and Section 8.2.4).

Pre-dose blood samples for safety (see Section 8.2.5), PK (see Section 8.5), PD 
(GDF-15, see Section 8.6), immunogenicity (see Section 8.9), and banked 
biospecimens (see Section 8.7.2 and Section 8.8.1) are to be collected after 
assessment of supine standard 12-lead ECG and vital signs.

Dosing: Administration of Investigational Product (PF-06946860) must be given at 
least 0.5h prior to administration of SoC anti-tumor therapy.

Post-dose blood samples for PK (see Section 8.5) and PD (GDF-15, see Section 8.6)
will be collected at a minimum of 3h post PF-06946860 administration or at a
maximum by the end of the clinic visit. 
Weeks 1 and 13:
Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).


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Blood samples for PK (see Section 8.5), PD (GDF-15, see Section 8.6) and banked
biospecimens (see Section 8.8.1).
Week 2:
Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).
Blood samples for PK (see Section 8.5), PD (GDF-15, see Section 8.6) and immunogenicity
(see Section 8.9).
Weeks 3, 6 and 9: 

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment and, where 
applicable, prior to dosing (see Section 8.2.3 and Section 8.2.4).

Pre-dose blood samples for safety (see Section 8.2.5), PK (see Section 8.5), PD 
(GDF-15, See Section 8.6), immunogenicity (see Section 8.9) and banked 
biospecimens (see Section 8.8.1) are to be collected after assessment of supine
standard 12-lead ECG and vital signs.

Dosing: Administration of Investigational Product (PF-06946860) must be given at 
least 0.5h prior to administration of standard of care anti-tumor therapy.
Weeks 4, 5 and 14:

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Blood samples for PK (see Section 8.5) and PD (GDF-15, see Section 8.6).
Week 12: 

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment and, where 
applicable, prior to dosing (see Section 8.2.3 and Section 8.2.4).

Pre-dose blood samples for safety (see Section 8.2.5), PK (see Section 8.5), PD 
(GDF-15, See Section 8.6), immunogenicity (see Section 8.9) and banked 
biospecimens (see Section 8.8.1), are to be collected after assessment of supine 
standard 12-lead ECG and vital signs.

Dosing: Administration of Investigational Product (PF-06946860) must be given at 
least 0.5h prior to administration of standard of care anti-tumor therapy.


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
Post-dose blood samples for PK (see Section 8.5) and PD (GDF-15, see Section 8.6), 
will be collected at a minimum of 3h post PF-06946860 administration or at a 
maximum by the end of the clinic visit. 
Weeks 15, 18 and 24: 

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment and, where 
applicable, prior to dosing (see Section 8.2.3 and Section 8.2.4).

PK (see Section 8.5), PD (GDF-15, see Section 8.6), immunogenicity (see 
Section 8.9) and banked biospecimens (see Section 8.8.1) are to be collected after
assessment of supine standard 12-lead ECG and vital signs.

Early Termination

Patient Reported Outcomes (see Section 8.1.3) (Cohort 1 only).

Supine standard 12-lead ECG: obtain prior to vital signs assessment and, where 
applicable, prior to dosing (see Section 8.2.3 and Section 8.2.4).

Blood samples for safety (see Section 8.2.5), PK (see Section 8.5), PD (GDF-15, see 
Section 8.6), immunogenicity (see Section 8.9) and banked biospecimens (see 
Section 8.8.1) are to be collected after assessment of supine standard 12-lead ECG 
and vital signs.


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10.20. Appendix 20: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
10.20.1. Eligibility
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive viral test 
result for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. 
10.20.2. Home Health Visits
A home health care service will be utilized to facilitate scheduled visits per the Schedule of 
Activities.  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:

The use of the home-health visit could be extended to include specimen collection for 
PK, PD and ADA during the follow-up visits.
10.20.3. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) 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.
If a participant is confirmed to have active SARS-CoV2 infection and if alteration of the 
planned anti-tumor regimen is deemed necessary, the study medical monitor should be 
consulted regarding how to manage the study treatment, including potential temporary or 
permanent discontinuation of the study treatment.


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10.21. Appendix 21: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Abs
Absolute
ACS
anorexia and cachexia subscale
ADA
antidrug antibodies
ADCC
antibody dependent cell-mediated cytotoxicity
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC168H
area under the curve from the time of dose administration up to 
168 hours
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
BBS
Biospecimen Banking System
-hCG
beta human chorionic gonadotropin
BLQ
Below the limit of quantification
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
Cav
average concentration
CDC
complement dependent cytotoxicity
CFR
Code of Federal Regulations
CHF
Congestive heart failure
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CL/F
apparent clearance of drug from eg, plasma
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COPD
Chronic obstructive pulmonary disease
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein


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Abbreviation
Term
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CT scan
Computed tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
ECL
electrochemiluminescent
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic CRF
EDP
exposure during pregnancy
EMA
European Medicines Agency
Emax
maximal effect
EOT
End of Treatment
ePRO
electronic Patient Reported Outcome
ET 
Early Termination
EU
European Union
EudraCT
European Clinical Trials Database
FAACT
Functional Assessment of Anorexia-Cachexia Therapy
FACT-G
Functional Assessment of Cancer Therapy - General
Fc
fragment crystallizable gamma 
FDA
Food and Drug Administration
FIH
first in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GDF-15
growth differentiation factor 15
GDNF
glial cell-derived neurotrophic factor
GFR
Glomerular Filtration Rate
GFRAL
glial cell-derived neurotrophic factor (GDNF) family receptor 
alpha- like
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HRQoL
Health Related Quality of Life


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Abbreviation
Term
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IgG1
immunoglobulin gamma-1 
IgG1κ
immunoglobulin gamma-1 with kappa light chains
IND
investigational new drug 
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUO
Investigational Use Only
IUS
Intrauterine hormone-releasing system
IV
intravenous
IWR
interactive Web-based response
LBBB
left bundle branch block
LFT
liver function test
LSMI
Lumbar Skeletal Muscle Index
LSLV
last subject last visit 
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MIC-1
Macrophage Inhibitory Cytokine 1
MRI
magnetic resonance imaging
MSD
Meso Scale Discovery
MSI-H
metastatic microsatellite instability-high
N/A
not applicable
NAb
neutralizing antibodies
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NRS
numerical rating scale
NSCLC
non-small cell lung cancer
NOAEL
no-observed-adverse-effect level
NYHA
New York Heart Association
PCD
primary completion date
PD
pharmacodynamic(s)
PGI-C
Patient Global Impression of Change


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Abbreviation
Term
PGI-S
Patient Global Impression of Severity
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PR
pulse rate
PRO-CTCAE
Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events
PROMIS
Patient-Reported Outcomes Measurement Information System
PT
prothrombin time
PVCs
premature ventricular complexes
Q1W
administered every week
Q2W
administered every 2 weeks
Q3W
administered every 3 weeks
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RET
rearranged during transfection
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SMP
study monitoring plan
SoA
schedule of activities
SoC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
t½
terminal elimination half-life
TBili
total bilirubin
TEAE
treatment emergent adverse event
TGF
transforming growth factor beta
Tmax
time for Cmax
TMDD
target-mediated drug disposition
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
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Martinez, C.H., Freeman, C.M., Nelson, J.D., et al., GDF-15 plasma levels in chronic 
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25.
Johnen, H., Lin, S., Kuffner, T., et al., Tumor-induced anorexia and weight loss are 
mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med, 2007. 13(11): 
1333-40.
26.
Mullican, S.E., Lin-Schmidt, X., Chin, CN., et al., GFRAL is the receptor for GDF15 
and the ligand promotes weight loss in mice and nonhuman primates. Nat Med, 2017. 
23(10): 1150-1157.
27.
Emmerson, P.J., Wang, F., Du, Y., et al., The metabolic effects of GDF15 are mediated 
by the orphan receptor GFRAL. Nat Med, 2017. 23(10): 1215-1219.
28.
Yang, L., Chang, CC, Sun, Z., et al., GFRAL is the receptor for GDF15 and is required 
for the anti-obesity effects of the ligand. Nat Med, 2017. 23(10): 1158-1166.
29.
Hsu JY, Crawley S, Chen M, et al. Non-homeostatic body weight regulation through a
brainstem-restricted receptor for GDF15. Nature 2017; 550(7675): 255-9.
30.
Dewys, W. D., et al., Prognostic effect of weight loss prior to chemotherapy in cancer 
patients. The American Journal of Medicine, 1980. 69(4): 491-497.
31.
Li, C, Wang X, Casal I, et al. Growth differentiation factor 15 is a promising diagnostic 
and prognostic biomarker in colorectal cancer. JCellMol Med. 2016; 20(8): 1420-6.
32.
Jakubowska, K, Pryczynicz A, Dymicka-Piekarska V, et al. The growth differentiation 
factor-15 (GDF-15) can be useful in the detection of distant metastases in sera of 
colorectal cancer patients. Prog Health Sci. 2016; 6(1): 40-8.
33.
Bachmann, J, Heiligensetzer M, Krakowski-Roosen H, et al. Cachexia worsens 
prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg. 2008;12(7): 
1193-201.
34.
Elecsys® GDF-15 package insert (2017). Documentation Roche Diagnostics, Bâle.
35.
Altena, R., Rudolf SN Fehrmann, 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 10, no. 1 (2015): 
e0115372.
36.
Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: 
an international consensus. Lancet Oncol 2011;12(5):489-95.


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37.
Levey AS, Coresh, J, Greene, T, et al.  Using Standardized Serum Creatinine Values in 
the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular 
Filtration Rate. Ann Intern Med. 2006;145:247-254.
38.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J of Cancer 2009; 45(2): 228-47.
39.
Rochette L, Zeller M, Cottin Y, et al. Insights into mechanisms of GD15 and receptor 
GFRAL: Therapeutic targets. Trends Endocrinol Metab. 2020 Dec;31(12):939-951.

SAP_001.pdf: 
Protocol C3651009 (PF-06946860) Statistical Analysis Plan
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Protocol C3651009
A PHASE 1B, 12-WEEK, OPEN-LABEL STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS 
FOLLOWING REPEATED SUBCUTANEOUS ADMINISTRATIONS OF PF-
06946860 IN PATIENTS WITH CANCER AND CACHEXIA
Statistical Analysis Plan 
(SAP)
Version:
4
  
Date:
16 March 2022  
NOTE: Italicized text within this document has been taken verbatim from the Protocol
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.1.1. Adverse Events.............................................................................................9
3.1.2. Laboratory Data............................................................................................9
3.1.3. Vital Signs ....................................................................................................9
3.1.4. Electrocardiogram (ECG)...........................................................................10
3.2. Secondary Endpoint(s) ............................................................................................10
3.3. Other Endpoint(s)....................................................................................................10
3.3.1. Immunogenicity (ADA, NAb)....................................................................10
3.3.2. Pharmacodynamics (GDF-15)....................................................................11
3.3.3. Efficacy.......................................................................................................11
3.3.4. Patient-Reported Outcomes (PRO).............................................................11
3.3.4.2. PRO CTCAE Items ...................................................................12
3.3.4.3. PROMIS Fatigue – Short Form 7a............................................12
3.3.4.4. PROMIS Physical Function – Short Form 8c ...........................12
3.3.4.5. FAACT Total and Sub Scale Scores.........................................13
3.3.4.6. PGI-S.........................................................................................13
3.3.4.7. PGI-C ........................................................................................13
3.3.6. Completion of Anti-Tumor Treatment .......................................................15
3.3.7. Number and % of Participants Alive at LSLV...........................................15
3.3.8. RECIST 1.1 Categorization........................................................................15
3.4. Baseline Variables...................................................................................................15
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3.5. Safety Endpoints .....................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.2. General Methods .....................................................................................................16
5.2.1. Analyses for Continuous Endpoints ...........................................................16
5.2.2. Analyses for Categorical Endpoints ...........................................................16
5.3. Methods to Manage Missing Data ..........................................................................17
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint(s) ................................................................................................17
6.1.1. Adverse Events...........................................................................................17
6.1.2. Laboratory Data..........................................................................................17
6.1.3. Vital Signs ..................................................................................................17
6.1.4. Electrocardiogram (ECG)...........................................................................18
6.2. Secondary Endpoint(s) ............................................................................................18
6.3. Other Endpoint(s)....................................................................................................19
6.3.1. Immunogenicity (ADA, NAb)....................................................................19
6.3.2. Pharmacodynamics (GDF-15)....................................................................19
6.3.3. Analysis of PK and PD Data by Immunogenicity Status ...........................20
6.3.4. Efficacy.......................................................................................................20
6.3.5. Patient-Reported Outcomes (PRO).............................................................21
6.3.5.2. PRO CTCAE Items ...................................................................21
6.3.5.3. PROMIS Fatigue.......................................................................22
6.3.5.4. PROMIS Physical Function ......................................................22
6.3.5.5. FAACT Total and Sub Scale Scores.........................................22
6.3.5.6. PGI-S.........................................................................................22
6.3.5.7. PGI-C ........................................................................................22
6.3.7. Completion of Anti-Tumor Treatment .......................................................23
6.3.8. Number and % of Participants Alive at LSLV...........................................23
6.3.9. RECIST 1.1 Categorization........................................................................23
6.4. Subset Analyses.......................................................................................................23
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6.5. Baseline and Other Summaries and Analyses.........................................................23
6.5.1. Baseline Summaries....................................................................................23
6.5.2. Study Conduct and Participant Disposition................................................23
6.5.3. Demographic Data......................................................................................24
6.5.4. Banked Biospecimens.................................................................................24
6.5.5. Concomitant Medications and Nondrug Treatments..................................24
6.5.6. Treatment Compliance................................................................................24
6.6. Safety Summaries and Analyses .............................................................................24
7. INTERIM ANALYSES.......................................................................................................24
7.1. Introduction .............................................................................................................24
7.2. Interim Analyses and Summaries............................................................................24
8. REFERENCES ....................................................................................................................24
9. APPENDICES .....................................................................................................................25
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
LIST OF FIGURES
No table of figures entries found.
APPENDICES
Appendix 1. Data Derivation Details.......................................................................................25
Appendix 1.1. PROMIS Score Conversion Tables..................................................................25
Appendix 1.2. FAACT Scoring Guidelines.............................................................................26
Appendix 2. Definitions of Immunogenicity Terms................................................................29
Appendix 3. Data Set Descriptions..........................................................................................30
Appendix 4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....31
Appendix 5. Example SAS Code.............................................................................................32
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1.0
02 Mar 2020
Original 
27 Nov 2019
PACL
11 Feb 2020
N/A
N/A
2.0 
26 May 2021
Amendment 1
08 Feb 2021
Protocol 
amendment
• Updated verbatim protocol wording throughout
• Removed DXA throughout, as per protocol
• Updated wording throughout to reflect removal of 
 PROs in Cohort 2
• Updated all timepoints to reflect new SoA
• ‘Free’ replaced with ‘unbound’ throughout for both 
PK and PD endpoints
• Sections 3.1.3 and 3.1.4: Removed max. vitals 
decrease/increase over first 12 weeks, as not
required
• Section 3.2 and 3.3: Additional wording added for 
clarification
• Section 3.3.2: Calculations included for change 
from baseline, relative change from baseline,
duration of suppression, maximum concentration 
and time to maximum concentration
• Section 3.3.4: Wording simplified
• Section 6.2: Added/removed some PK outputs
• Section 6.3.1: Added/removed some 
immunogenicity outputs
• Section 6.3.2: Additional wording added for 
clarification; Added some additional outputs; 
Analysis added for relative change from baseline 
GDF-15
• Section 6.3.3: Additional wording added for 
clarification
• Section 6.3.4: Wording simplified
• Section 6.3.5: Wording simplified
• Section 7.2: Added further wording to describe 
interim analysis 
• Appendix 2: Added additional wording for 
immunogenicity terms
3
21 Oct 2021
Amendment 1
08 Feb 2021
Requirement 
for additional 
output for 
POM 
declaration
Findings 
during BDRs
• Updated protocol title to match amendment 1
• Sections 3.2 and 6.2: Added clarification for Ctrough
• Sections 3.3.2 and 6.3.2: Added percent change 
from baseline; Changed summaries to be based on 
percent change from baseline.  Removed duration of 
suppression of GDF-15 and reference to Emax and 
Tmax.
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• Sections 3.3.3 and 6.3.4: Added percent change 
from baseline for body weight
• Section 6.1.1: Replaced ‘severity’ with ‘grade’ in 
description of TEAE table in second paragraph
• Sections 6.1.3 and 6.1.4: Combined individual and 
mean plots
• Section 6.1.4: Corrected endpoint for >500msec 
listing (QT rather than QTcF) 
• Section 6.2: Added individual concentrations (and 
removed quartiles/sd) to median and mean trough 
concentration plots
• Section 6.3.2: Added individual concentrations (and 
removed quartiles) to median concentration plots
• Section 6.3.4: Removed absolute summary and plot.  
Added summaries and plots for % change from 
baseline body weight; Additional analysis of body 
weight change from baseline
• Section 6.3.5: Added change from baseline figures 
for select PROs
 
• Section 6.5.1: Added clarification on baseline data 
for summary
• Appendix 5: Added example SAS code for 
additional body weight analysis
 
4
16 Mar 2022
N/A
Additional 
PRO analysis
required for 
clinical 
development
• Section 3.3.3: Corrected formatting 
• Sections 3.3.4.5 and 6.3.5.5: Added FAACT-5IASS 
calculation and analysis
• Appendix 3: Additional dataset specified
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3651009.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary: 
Primary: 
•
To characterize the safety and tolerability of repeated 
subcutaneous administrations of PF-06946860 to 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Incidence of treatment emergent adverse events 
(AEs and SAEs), safety laboratory tests, vital 
signs (blood pressure and pulse rate) and 
standard ECG parameters (heart rate, QT, 
QTcF, PR and QRS intervals).
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Secondary: 
Secondary: 
•
To characterize free and total PK of PF-06946860 
administered to participants with NSCLC, pancreatic 
cancer or colorectal cancer and cachexia.
•
Serum unbound and total trough concentrations 
(Ctrough) of PF-06946860 at Weeks 3, 6, 9, 12,
and 15..
Tertiary/Exploratory: 
Tertiary/Exploratory: 
•
To evaluate the immunogenicity profile of PF-06946860 in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Incidence of ADA and NAb, if applicable.
•
To characterize the effect of repeated administrations of 
PF-06946860 on circulating GDF-15 concentrations in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Serum concentrations of total and, if feasible,
unbound GDF-15 at time points specified in the
schedule of activities (SoA) in the protocol.
•
To evaluate the effect of PF-06946860 on Lumbar Skeletal 
Muscle Index (LSMI) measured by CT scan in participants 
with NSCLC, pancreatic cancer or colorectal cancer and 
cachexia.
•
Change from baseline LSMI measured by CT 
scan at time points specified in the schedule of 
activities (SoA) in the protocol. 
•
To evaluate the effect of PF-09646860 on body weight in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Change from baseline body weight at time points 
specified in the schedule of activities (SoA) in the 
protocol.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) 
selected items in participants with NSCLC, pancreatic 
cancer or colorectal cancer and cachexia.
•
Change from baseline scores for selected 
PRO-CTCAE items at time points specified in 
Table 2 in the protocol.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
fatigue as measured by the PROMIS-Fatigue questionnaire 
in participants with NSCLC, pancreatic cancer or 
colorectal cancer and cachexia.
•
Change from baseline score for 
PROMIS-Fatigue at time points specified in 
Table 2 in the protocol.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
physical function as measured by the PROMIS-Physical 
Function questionnaire in participants with NSCLC, 
pancreatic cancer or colorectal cancer and cachexia.
•
Change from baseline score for 
PROMIS-Physical Function at time points 
specified in Table 2 in the protocol.
•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
HRQoL as measured by FAACT in participants with 
NSCLC, pancreatic cancer or colorectal cancer and 
cachexia.
•
Change from baseline FAACT total and 
sub-scale scores at time points specified in Table 
2 in the protocol.
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•
Cohort 1 only: To evaluate the effect of PF-06946860 on 
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) in participants with 
NSCLC, pancreatic cancer or colorectal cancer and 
cachexia.
•
Change from baseline PGI-S at time points 
specified in Table 2 in the protocol.
•
PGI-C at time points specified in Table 2 in the 
protocol.
 
 
 
 
 
 
 
 
•
To evaluate the effect of PF-06946860 on ability to 
complete anti-tumor treatment as originally prescribed in 
participants with NSCLC, pancreatic cancer or colorectal 
cancer and cachexia.
•
Number and % of participants completing 
anti-tumor treatment as originally prescribed.
•
To evaluate the effect of PF-06946860 on participant 
survival in participants with NSCLC, pancreatic cancer or 
colorectal cancer and cachexia.
•
Number and % of participants alive at last 
subject last visit (LSLV). 
•
To evaluate tumor burden in participants with NSCLC, 
pancreatic cancer or colorectal cancer and cachexia.
•
The RECIST 1.1 categorization using CT scan at 
time points specified in the schedule of activities
(SoA) in the protocol. 
•
To enable exploratory research through collection of 
banked biospecimens, unless prohibited by local 
regulations or ethics committee decision.
•
Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
There are no estimands for this study.
2.2. Study Design
This is a Phase 1b, open-label study in participants with advanced metastatic NSCLC ,
pancreatic cancer or colorectal cancer and cachexia, and elevated circulating GDF-15 
concentrations, that are eligible for treatment with platinum-based systemic anti-tumor 
therapy.  Baseline GDF-15 levels will be assessed at screening to determine eligibility for 
participation.
Following the 28-day screening period to confirm eligibility, the study will consist of a 
treatment period of 12weeks and a follow-up period of 12weeks.  The total duration of 
participation in this study is approximately 24 weeks (not including the screening period). 
During the 12-week treatment period in Cohort 1, participants will receive a total of 5 doses 
of PF-06946860, administered subcutaneously (SC), every 3 weeks (Q3W).  
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This study will consist of up to 2 cohorts.  In each study cohort, approximately 8 participants 
will be enrolled such that approximately 6 evaluable participants complete the study.  
Participants who discontinue prior to completion of the study may be replaced, at the 
discretion of the investigator and sponsor.  It is planned that the 2 cohorts will be enrolled 
sequentially and will follow similar schedules of activity.  The optional Cohort 2 may be 
conducted at the discretion of the Sponsor, with data emerging from Cohort 1 informing the 
dose level and/or frequency to be administered in Cohort 2.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Incidence of treatment emergent adverse events (AEs and SAEs), safety laboratory tests, vital 
signs (blood pressure and pulse rate) and standard ECG parameters (heart rate, QT, QTcF, 
PR and QRS intervals).
3.1.1. Adverse Events
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 
dosing day and time/start time, if collected, but before the last dose plus the lag time will be 
flagged as TEAEs.  The algorithm will not consider any events that started prior to the first 
dose date.
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
3.1.2. Laboratory Data
Safety laboratory tests (hematology, chemistry, urine testing and other clinical laboratory 
tests) will be performed on Day 1 and Weeks 3, 6, 9, 12, 15, 18 and 24.
To determine if there are any clinically significant laboratory abnormalities, the safety tests 
will be assessed against the criteria specified in the sponsor reporting standards. The 
assessment will take into account whether each participant’s baseline test result is within or 
outside the laboratory reference range for the particular laboratory parameter. 
Baseline for all laboratory measurements is defined as the last result prior to dosing on Day 
1.
3.1.3. Vital Signs
Vital sign measurements (blood pressure and pulse rate) will be taken on Day 1 and Weeks 3, 
6, 9, 12, 15, 18 and 24. 
Baseline is defined as the average of the triplicate measurements prior to dosing on Day 1. 
Changes from baseline for supine systolic and diastolic blood pressure and pulse rate will be 
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The maximum decrease from baseline, over all measurements taken post-dose, will be 
calculated for supine systolic and diastolic blood pressures. The maximum increase from 
baseline, over all measurements taken post-dose, will be calculated for supine pulse rate.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase.  In such an instance, the minimum decrease should be 
taken. Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a participant does not show a 
decrease, the minimum increase should be taken.
3.1.4. Electrocardiogram (ECG)
Standard 12-lead ECG (including heart rate, QT, QTcF, PR and QRS interval) will be 
obtained on Day 1 and Weeks 3, 6, 9, 12, 15, 18 and 24. 
Baseline is defined as the average of the triplicate results prior to dosing on Day 1.
Change from baseline for heart rate, QT, QTcF, PR and QRS interval will be calculated for 
each post baseline timepoint.
The maximum absolute value (post-dose) and the maximum increase from baseline over all 
measurements taken post-dose will be calculated for QTcF, PR and QRS.
The maximum increase from baseline will be calculated by first subtracting the baseline value 
from each post-dose measurement to give the change from baseline.  The maximum of these 
values over the respective period will then be selected, except in the case where a participant
does not show an increase.  In such an instance, the minimum decrease should be taken.
3.2. Secondary Endpoint(s)

Serum unbound and total trough concentrations (Ctrough) of PF-06946860 at Weeks 3, 6, 
9, 12 and 15.
Serum concentrations of unbound and total PF-06946860 will be collected both pre- and 
post-dose on Day 1 and at Week 12, pre-dose only at Weeks 3, 6 and 9, and additionally at 
Weeks 1, 2, 4, 5, 13, 14, 15, 18 and 24.
Trough concentrations (Ctrough) are defined as the samples measured pre-dose at Weeks 3, 6, 
9 and 12, and at Week 15. Dose normalized Ctrough will also be calculated, if appropriate.
3.3. Other Endpoint(s)
3.3.1. Immunogenicity (ADA, NAb)

Incidence of ADA and NAb, if applicable.
ADA and NAb, if applicable, will be assessed on Day 1 and Weeks 2, 3, 6, 9, 12, 15, 18 and 
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Baseline is defined as the pre-dose result on Day 1.
3.3.2. Pharmacodynamics (GDF-15)
•
Serum concentrations of total and, if feasible, unbound GDF-15 at time points specified 
in the schedule of activities (SoA) in the protocol.
Serum concentrations of total and, if feasible, unbound GDF-15 will be measured both pre-
and post-dose on Day 1 and Week 12, pre-dose only at Weeks 3, 6 and 9, and additionally at 
Weeks 1, 2, 4, 5, 13, 14, 15, 18 and 24.
Baseline is defined as the pre-dose result on Day 1.  Trough timepoints are pre-dose at 
Weeks 3, 6, 9 and 12, and Week 15. 
Change from baseline, relative change from baseline (i.e. post-dose / baseline) and percent 
change from baseline for total and, if feasible, unbound GDF-15, will be calculated for each 
post baseline timepoint. The maximum, maximum percent change from baseline and time to 
maximum, for total GDF-15 may also be calculated for each participant.
3.3.3. Efficacy
•
Change from baseline LSMI measured by CT scan at time points specified in the schedule 
of activities (SoA) in the protocol.
Lumbar Skeletal Muscle Index (LSMI), measured by CT Scan, will be collected at Screening 
(Baseline) and Weeks 6 and 12. Change from baseline will be calculated for each post 
baseline timepoint.
•
Change from baseline body weight at time points specified in the schedule of activities 
(SoA) in the protocol.
Body Weight will be collected on Day 1 (Baseline) and Weeks 3, 6, 9, 12, 15, 18 and 24.
Change from baseline and percent change from baseline will be calculated for each post 
baseline timepoint.
3.3.4. Patient-Reported Outcomes (PRO) 
PRO data will be collected for Cohort 1 only.
 
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3.3.4.2. PRO CTCAE Items
•
Change from baseline scores for selected PRO-CTCAE items at time points specified in 
Table 2 in the protocol.
Data will be collected on Day 1 (Baseline) and Weeks 3, 6, 9, 12 and 18 using a 5-point 
scale.
Change from baseline will be calculated for each post baseline timepoint.
3.3.4.3. PROMIS Fatigue – Short Form 7a
•
Change from baseline score for PROMIS-Fatigue at time points specified in Table 2 in 
the protocol.
Data will be collected on Day 1 (Baseline) and Weeks 6, 12, and 18 using a 5-point scale.
The PROMIS Fatigue Short Form 7a has seven questions, each with five response options 
ranging in value from 1 to 5. A total raw score will be calculated as the sum of the responses
to all seven questions. 
The total raw score will then be translated into a T-score for each participant using the 
Fatigue 7a Short Form score conversion table, provided in Appendix 1.1. The T-score 
rescales the raw score into a standardized score with a mean of 50 and a standard deviation 
(SD) of 10. 
Change from baseline for PROMIS-Fatigue T-score will be calculated for each post baseline 
timepoint.
3.3.4.4. PROMIS Physical Function – Short Form 8c
•
Change from baseline score for PROMIS-Physical Function at time points specified in 
Table 2 in the protocol.
Data will be collected on Day 1 (Baseline) and Weeks 6, 12, and 18 using a 5-point scale.
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The PROMIS Physical Function Short Form 8c has eight questions each with five response 
options ranging in value from 1 to 5.  A total raw score will be calculated as the sum of the 
responses to all eight questions. 
The total raw score will then be translated into a T-score for each participant using the 
Physical Function 8c Short Form score conversion table, provided in Appendix 1.1. The T-
score rescales the raw score into a standardized score with a mean of 50 and a standard 
deviation (SD) of 10. 
Change from baseline for PROMIS-Physical Function T-score will be calculated for each 
post baseline timepoint.
3.3.4.5. FAACT Total and Sub Scale Scores

Change from baseline FAACT total and sub-scale scores at time points specified in Table 
2 in the protocol.
Data will be collected on Day 1 (Baseline) and Weeks 6, 12, and 18 using a 5-point scale.
See Appendix 1.2 for FAACT scoring guidelines showing the calculation of FAACT 
subscales and two total scores. 
Additionally, FAACT-5IASS (FAACT 5-item Anorexia Symptoms Subscale) will be 
calculated (using only items C6, ACT6, ACT7, ACT10 and ACT3, and a similar scoring 
system as for the other sub-scales): -  
1.
Add up the scores (with or without reversing)
2.
Multiply by 5
3.
Divide by the number of items answered
Change from baseline for FAACT total scores and subscales (including 5IASS) will be 
calculated for each post baseline timepoint.
3.3.4.6. PGI-S

Change from baseline PGI-S at time points specified in Table 2 in the protocol.
Data will be collected on Day 1 (Baseline) and Weeks 3, 6, 9, 12 and 18 using a 5-point 
scale.
Change from baseline will be calculated for each post baseline timepoint.
3.3.4.7. PGI-C

PGI-C at time points specified in Table 2 in the protocol.
Data will be collected at Weeks 12 and 18 using a 7-point scale.
Categories will be combined to produce a 5-point scale as defined below:-


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Category
Definition
Much Better
1
Somewhat Better
2-3
No Change
4
Somewhat Worse
5-6
Much Worse
7
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
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3.3.6. Completion of Anti-Tumor Treatment
•
Number and % of participants completing anti-tumor treatment as originally prescribed.
Information regarding each participant’s anti-tumor treatment (e.g. change of dose) will be 
collected.  
3.3.7. Number and % of Participants Alive at LSLV
•
Number and % of participants alive at last subject last visit (LSLV). 
Any deaths during the study will be collected.  
3.3.8. RECIST 1.1 Categorization
•
The RECIST 1.1 (overall) categorization using CT scan at time points specified in the 
schedule of activities (SoA) in the protocol.
Data will be collected at Screening (Baseline) and Weeks 6 and 12. 
3.4. Baseline Variables
N/A
3.5. Safety Endpoints
See Section 3.1 for details.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
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Population
Description
Enrolled/Randomly
assigned to
investigational product
“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.
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
Evaluable
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product
Safety
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product
PK
All randomized participants who received a dose of 
PF-06946860 and in whom at least 1 serum concentration 
value is reported
PD
All randomized participants who received a dose of 
PF-06946860 and in whom at least 1 serum GDF-15 
concentration is reported
Immunogenicity
All randomized participants who received a dose of 
PF-06946860 with at least 1 ADA result reported 
Efficacy
All participants randomly assigned to investigational product 
and who take at least 1 dose of investigational product
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There is no statistical hypothesis testing planned for this study and no statistical decision 
rules will be applied.
5.2. General Methods
Unless otherwise stated, all summaries and plots will be presented by treatment, if
appropriate.
5.2.1. Analyses for Continuous Endpoints
Unless otherwise stated, continuous variables will be presented using summary statistics: 
number of observations, arithmetic mean, standard deviation, median, minimum and 
maximum values.
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.


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5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. 
In all PD data presentations (except listings), BLQ concentrations will be set to the lower 
limit of quantification (LLOQ).  
In listings, BLQ values will be reported as “<LLOQ”, where LLOQ will be replaced with the 
value for the LLOQ.
For PK and PD summary tables and plots of mean/median profiles, statistics will be 
calculated having set concentrations to missing if one of the following cases is true: -
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist/statistician.
 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Adverse Events
Adverse events will be summarised by treatment and overall and in accordance with sponsor 
reporting standards using the safety population defined in Section 4. 
Incidence and CTCAE grade of treatment emergent adverse event (TEAE) tables will 
additionally be produced (‘All causality’ and ‘Treatment related’, separately) to summarise 
the total number of adverse events by preferred term, which will be reported by treatment and 
overall.
6.1.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment, in accordance with the sponsor 
reporting standards using the safety population defined in Section 4. Baseline is as defined in 
Section 3.1.2.
6.1.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarised by treatment and time point, according to sponsor 
reporting standards using the safety population defined in Section 4. Baseline is as defined in 
Section 3.1.3. 
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Individual plots of change from baseline systolic and diastolic blood pressure and pulse rate, 
versus time, will be produced with all participants on the same plot, paged by treatment. 
Separate colours will be used for each participant with a black solid line added for the 
mean.Maximum decrease from baseline  for supine systolic and diastolic blood pressures and
maximum increase from baseline for supine pulse will be summarised by treatment, 
according to sponsor reporting standards.
Maximum absolute values and changes from baseline for supine vital signs will also be 
summarised descriptively by treatment using categories as defined in Appendix 4. Numbers
and percentages of participants meeting the categorical criteria will be provided. All planned 
and unplanned post dose time points will be counted in these categorical summaries. All 
values meeting the criteria of potential clinical concern will be listed.
6.1.4. Electrocardiogram (ECG)
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarised by treatment and time point using sponsor reporting standards using the safety 
population defined in Section 4. Tables will be paged by parameter. Baseline is as defined in 
Section 3.1.4. 
Individual plots of change from baseline QT, heart rate and QTcF, versus time, will be 
produced with all participants on the same plot, paged by treatment. Separate colours will be 
used for each participant with a black solid line added for the mean.Maximum increase from 
baseline for QTcF will be summarised by treatment, according to sponsor reporting 
standards. 
Maximum absolute values and changes from baseline for QTcF, PR and QRS will also be 
summarised descriptively by treatment using categories as defined in Appendix 4. Numbers 
and percentages of participants meeting the categorical criteria will be provided. All planned 
and unplanned postdose timepoints will be counted in these categorical summaries. All 
values meeting the criteria of potential clinical concern will be listed. 
Listings of participants with any single post dose value > 500 msec will also be produced for 
QT.
6.2. Secondary Endpoint(s)
Presentations for serum unbound and total PF-06946860 concentrations for participants in 
the PK population (as defined in Section 4) will include: -

A listing of all concentrations sorted by dose, participant ID, and nominal time point.  
The concentration listing will also include the actual times.  

Individual concentration-time plots (semi-log scale) by dose using actual time post first 
dose.  There will be separate spaghetti plots for each dose.   All timepoints will be 
included and trough timepoints may be highlighted, e.g. using symbols.

A summary of all concentrations by dose and nominal time point, where the set of 
statistics will include n, mean, standard deviation, coefficient of variation (CV, %), 


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median, minimum, maximum and the number of concentrations at or above the lower 
limit of quantification (NALQ).

A summary of Ctrough and dose normalized Ctrough, if appropriate, by dose and nominal 
time point, where the set of statistics will include n, arithmetic mean,  standard deviation, 
CV (%), median, geometric mean, geometric CV (%), Q1, Q3, minimum, maximum, and 
NALQ.

Median concentration-time plot (semi-log scale, all timepoints) by dose using nominal 
time (all doses on the same plot).

Median trough concentration-time plot (linear scale) by dose using nominal time (all 
doses on the same plot), individual concentrations may be included.

Mean trough concentration-time plot (linear scale) by dose using nominal time (all doses 
on the same plot), individual concentrations may be included. 
No formal inferential statistics will be applied to the pharmacokinetic data. 
Additional PK analyses may be performed if deemed appropriate, and may not be included in 
the CSR.
6.3. Other Endpoint(s)
6.3.1. Immunogenicity (ADA, NAb)
Immunogenicity analyses will be performed on the immunogenicity analysis set defined in 
Section 4. Definitions for ADA and NAb terms are defined in Appendix 2. Immunogenicity 
analyses will include: -  

A listing of ADA and NAb results for all participants and if appropriate, a listing of ADA 
and NAb data, including onset, titer, and if appropriate, duration (number of days 
participant is ADA positive or NAb positive) for all ADA-positive participants.  

A summary of the incidence of ADA and NAb by dose and all doses combined.

A summary of the percentage of participants who are ADA positive and NAb positive by
time and by dose and all doses combined. The cumulative % of ADA-positive and NAb-
positive participants may also be be included.

If appropriate, spaghetti plots of individual participant ADA and NAb titer by dose

If appropriate (e.g. the number of ADA-positive participants for each dose is ≥3), a 
summary of ADA and NAb titer by time for each dose. 
6.3.2. Pharmacodynamics (GDF-15)
All PD analyses will be performed on the PD population as defined in Section 4. Baseline is 
as defined in Section 3.3.2.
Presentations for total and/or unbound (as data permit) GDF-15 concentrations will include: -

A listing of all concentrations (absolute values, change from baseline, relative change 
from baseline and percent change from baseline) sorted by treatment (dose), participant 
ID and nominal time point.  The listing will also include the actual times. The maximum, 


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maximum percent change from baseline and time to maximum, for total GDF-15 may 
also be included.

Individual concentration-time plots (for absolute values and percent change from 
baseline) by treatment using actual time.  There will be separate spaghetti plots for each 
treatment. All timepoints will be included and trough timepoints may be highlighted, e.g. 
using symbols.

A summary of concentrations (absolute values and percent changes from baseline) by 
treatment and nominal time point, where the set of statistics will include n, mean, 
standard deviation, CV (%), minimum, Q1, median, Q3, maximum, and geometric mean, 
geometric CV (%)and NALQ (for absolute values only). 

Median concentration-time plot (for absolute values and percent change from baseline) 
by treatment using nominal time (all treatments on the same plot), individual 
concentrations may be included on the plot.

A summary of the maximum, maximum percent change from baseline and time to 
maximum, for total GDF-15 may be produced.
Relative change from baseline (i.e. post-dose / baseline) unbound GDF-15 concentration at 
Week 4 may also be modelled (as data permit), if appropriate.  The analysis will be 
performed on the log scale using an analysis of covariance with log baseline and treatment as 
fixed terms in the model.  Back transformed least squares means (and 80% confidence 
intervals) will be obtained for each treatment. Plots of these back-transformed LS means
(including 80% CIs) will also be produced (all treatments on the same plot with different 
colours/symbols for each treatment).  The relative changes will be presented as percent 
change from baseline ([relative change from baseline -1]*100).  
If this analysis is deemed inappropriate (e.g. due to a large number of data below the level of 
quantification), the analysis may not be performed, or may be replaced by an alternative 
analysis.
Additional PD, and/or population PK/PD, analyses may be performed if deemed 
appropriate, and will not be included in the CSR.
6.3.3. Analysis of PK and PD Data by Immunogenicity Status
If appropriate, the additional analyses below may be performed: -

Spaghetti plots of unbound and total PF-06946860 concentrations by ADA and NAb 
status 

Spaghetti plots of total and unbound (as data permit) GDF-15 concentrations by ADA 
and NAb status

Individual plots of unbound and total PF-06946860 concentration, total and unbound (as 
data permit) GDF-15 concentration, ADA and NAb titer in ADA-positive participants.
6.3.4. Efficacy
Changes from baseline in LMSI (measured by CT scan) and body weight, and percent 
change from baseline (for body weight only), will be summarised descriptively by treatment


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(if appropriate) and timepoint, as described in Section 5.2.1, using the efficacy population
defined in Section 4. Baseline is as defined in Section 3.3.3. 
Individual plots of change from baseline, and percent change from baseline (for body weight 
only), versus time will be produced with all participants on the same plot, paged by treatment
(if appropriate). Separate colours will be used for each participant with a black solid line 
added for the mean.
Change from baseline body weight will be analyzed using a mixed effects repeated measures 
model including subject as a random term, and baseline, nominal time (as a factor) and 
baseline-by-nominal-time interaction as fixed terms in the model.  Treatment and treatment-
by-nominal-time interaction will also be include as fixed terms in the model, if appropriate
(see Appendix 5 for example SAS code). A compound symmetry covariance matrix will be 
fitted to the repeated times within subject (other covariance matrices will be considered if 
necessary, e.g. compound symmetry with heterogeneity; additionally it may be necessary to 
restrict the timepoints included in the model, e.g. up to Week 12 only).  Least squares (LS) 
means, standard errors and 90% confidence intervals will be obtained for each treatment at 
each time point. A plot of the LS means (including 90% CIs) will also be produced over 
time (all treatments on the same plot with different colours/symbols for each treatment).
 
 
 
 
 
These analyses of change from baseline body weight may not be included in the CSR.
6.3.5. Patient-Reported Outcomes (PRO) 
Summaries will be produced using the efficacy population defined in Section 4.
 
 
 
 
6.3.5.2. PRO CTCAE Items
Changes from baseline for the PRO CTCAE will be summarised by time point as described 
in Section 5.2.2.  Baseline is as defined in Section 3.3.4.2.
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6.3.5.3. PROMIS Fatigue
Changes from baseline for the PROMIS Fatigue T-score will be summarised by time point as 
described in Section 5.2.1.  Baseline is as defined in Section 3.3.4.3.
An individual plot of change from baseline T-score will be produced with all participants on 
the same plot, paged by treatment. Separate colours will be used for each participant with a 
black solid line added for the mean. These plots may not be included in the CSR.
6.3.5.4. PROMIS Physical Function
Changes from baseline for the PROMIS Physical Function T-score will be summarised by 
time point as described in Section 5.2.1.  Baseline is as defined in Section 3.3.4.4.
An individual plot of change from baseline T-score will be produced with all participants on 
the same plot, paged by treatment. Separate colours will be used for each participant with a 
black solid line added for the mean. These plots may not be included in the CSR.
6.3.5.5. FAACT Total and Sub Scale Scores
Changes from baseline for the FAACT total scores and subscales (including the 5IASS) will 
summarised by time point as described in Section 5.2.1. Baseline is as defined in Section 
3.3.4.5.
For the ACS, 5IASS, FACT-G total and FAACT total scores, individual plots of change from 
baseline will be produced with all participants on the same plot, paged by score treatment. 
Separate colours will be used for each participant with a black solid line added for the mean.
These plots may not be included in the CSR.
6.3.5.6. PGI-S
Changes from baseline for the PGI-S will be summarised by time point as described in 
Section 5.2.2. Baseline is as defined in Section 3.3.4.8.
An individual plot of change from baseline will be produced with all participants on the same 
plot, paged by treatment. Separate colours will be used for each participant with a black solid 
line added for the mean. These plots may not be included in the CSR.
6.3.5.7. PGI-C
Absolute values for PGI-C on the 5-point scale will be summarised by time point as 
described in Section 5.2.2.
An individual plot of absolute values will be produced with all participants on the same plot, 
paged by treatment. Separate colours will be used for each participant with a black solid line 
added for the mean. These plots may not be included in the CSR.


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6.3.7. Completion of Anti-Tumor Treatment
The number and % of participants completing anti tumor treatment as originally prescribed
will be presented by treatment using the efficacy population defined in Section 4.
6.3.8. Number and % of Participants Alive at LSLV
The number and % of participants alive at LSLV will be presented by treatment using the 
efficacy population defined in Section 4.
6.3.9. RECIST 1.1 Categorization 
The RECIST 1.1 categorization will be summarised by treatment and time point as described 
in Section 5.2.2 using the efficacy population defined in Section 4.
6.4. Subset Analyses
No subset analyses will be performed.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
A baseline table (or separate tables, as required) will be produced, by treatment and overall,
summarising the following baseline data (if available): type of cancer; stage of cancer; 
duration of cancer; serum GDF-15 at screening; chemotherapy treatment as described in 
Sections 5.2.1 or 5.2.2 (as appropriate).
6.5.2. Study Conduct and Participant Disposition
Participant evaluation groups will show participant disposition for each phase of the study 
(screening, open-label treatment and follow-up) and will additionally show which 
participants were analysed for efficacy, PK, PD, immunogenicity as well as for safety. 
Frequency counts and percentages will be supplied for participant discontinuation(s) by 
treatment.  Data will be reported in accordance with the sponsor reporting standards.
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6.5.3. Demographic Data
Demographic data (age, gender, race, ethnicity, weight, body mass index and height) will be 
summarised by treatment and overall (if applicable) in accordance with the sponsor reporting 
standards. 
6.5.4. Banked Biospecimens
Banked biospecimens will be collected and retained for future analyses, but will not be 
analyzed specifically for this study and will not be included in the CSR.
6.5.5. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported 
according to current sponsor reporting standards. 
6.5.6. Treatment Compliance
A summary table of treatment compliance will be produced according to current sponsor 
reporting standards.
6.6. Safety Summaries and Analyses
See Section 6.1 for details.
7. INTERIM ANALYSES
7.1. Introduction
As this is an open-label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating PK/PD modeling, 
and/or supporting clinical development.
A formal interim analysis may be performed to assess PK, PD and/or safety. Interim analysis
results may be used for internal business decisions regarding future study planning.  If a 
formal interim analysis is conducted, details of the timing, objectives, decision criteria (if
applicable) and analyses will be documented in an internal charter or in the final SAP.
7.2. Interim Analyses and Summaries
If an interim analysis is performed, a subset of the analyses outlined in Section 6 will be 
produced, e.g. for safety (e.g. AE’s, SAE’s, deaths, labs, vitals, ECG, Resist), PK/PD ,
ADA/NAb, baseline, participant disposition and demographic data.  
8. REFERENCES
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9. APPENDICES
Appendix 1. Data Derivation Details
Appendix 1.1. PROMIS Score Conversion Tables
                   
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Appendix 1.2. FAACT Scoring Guidelines
FAACT Scoring Guidelines (Version 4) – Page 1
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
    number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FAACT). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________
   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
             Divide by number of items answered: ________=  PWB subscale score
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=  SWB subscale score
Score range: 0-28
Score range: 0-28
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EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
            Divide by number of items answered: ________=  EWB subscale score
FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=  FWB subscale score
Score range: 0-24
Score range: 0-28
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Subscale
         Item Code       Reverse item?            Item response        
Item Score
ANOREXIA
C6
0
+
________
=________
CACHEXIA
ACT1
0
+
________
=________
SUBSCALE
ACT2
4
-
________
=________
   (ACS)
ACT3
4
-
________
=________
     
ACT4
4
-
________
=________
      
ACT6
4
-
________
=________
      
ACT7
4
-
________
=________
      
ACT9
4
-
________
=________
      
O2
4
-
________
=________
      
ACT10
4
-
________
=________
      
ACT11
4
-
________
=________
      
ACT13
0
+
________
=________
              Sum individual item scores:________  
                   Multiply by 12: ________
            Divide by number of items answered: ________=  AC subscale score
To Derive a FACT-G total score:
        __________ + __________ + __________ + __________=________=  FACT-G Total score
        (PWB score)    (SWB score)   (EWB score)  (FWB score)
To Derive a FAACT total score:
              _________ + __________ + __________ + __________ + __________ =________=  FAACT Total score
                            (PWB score)  (SWB score)   (EWB score)  (FWB score)   (ACS score)
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring Guidelines in the manual or on-line at 
www.facit.org.
Score range: 0-108
Score range: 0-156
Score range: 0-48
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Appendix 2. Definitions of Immunogenicity Terms
ADA evaluable population
All participants with ≥ 1 post-treatment ADA result. 
NAb evaluable population 
ADA-positive participants with ≥ 1 post-treatment NAb result, plus all ADA-negative participants. An ADA-positive participant without any post-treatment NAb data is 
excluded from the analysis population. 
Treatment-induced ADA 
Baseline ADA titer is missing or negative and participant has ≥ 1 post-treatment positive ADA titer. 
Treatment-boosted ADA
Baseline ADA titer is positive and participant has a ≥ 4-fold dilution increase in ADA titer from baseline in ≥ 1 post-treatment sample. 
ADA-positive participant
A participant with ≥ 1 treatment-induced or treatment-boosted ADA response.    
ADA-negative participant
An ADA evaluable participant without treatment-induced or treatment-boosted ADA response. Participant either has (1) all ADA-negative results throughout the study or (2) 
is ADA positive at baseline but did not become treatment-boosted post dose. 
ADA incidence
The percent of ADA-positive participants. 
Treatment-induced NAb 
Baseline NAb titer is missing or negative or ADA-negative and participant has ≥ 1 post-treatment positive NAb titer.
Treatment-boosted NAb
Baseline NAb titer is positive and participant has a ≥ 4-fold dilution increase in NAb titer from baseline in ≥ 1 post-treatment sample. 
NAb-positive participant
An ADA-positive participant with ≥ 1 treatment-induced or treatment-boosted NAb response.  For ADA-positive (treatment-boosted) participants, participant is NAb 
positive only if the participant has ≥1 treatment-induced or treatment-boosted NAb response at the visit where the participant has a treatment-boosted ADA response. For 
visits where the participant did not show a boosted ADA response, the participant is classified as NAb-negative for the visit even if the participant has post-treatment 
positive NAb titer for that visit.     
NAb-negative participant
A NAb evaluable participant who is either (1) an ADA-negative participant or (2) an ADA-positive participant without treatment-induced or treatment-boosted NAb 
response (i.e. participant has all NAb-negative results throughout the study or participant is NAb positive at baseline but did not become treatment-boosted post dose). 
NAb incidence
The percent of NAb-positive participants. 
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Appendix 3. Data Set Descriptions
To explore the data further separate SAS datasets and .csv files will be provided by the 
clinical programmer to the statistician.
Four datasets are to be created (all are to include participant ID, treatment and time point):
•
PROs (2 datasets) to include all endpoints in Section 3.3.4 at all time points. Two 
datasets:
o
one for weekly data to include baseline, absolute and change from baseline for 
all questions and total / T-scores (where applicable). 
 
 
An additional .xlsx dataset will be provided by the clinical programmer to the statistician, 
ordered by participant and timepoint, with columns for the following endpoints: -
•
Participant ID
•
Age
•
Gender
•
Roche GDF-15 (at screening)
•
Timepoint
•
Absolute and change from baseline Pfizer total and unbound GDF-15
•
Absolute and change from baseline body weight
•
RECIST categorization
 
•
Absolute and change from baseline PGI-S (appetite)
•
Absolute PGI-C (appetite and fatigue)
•
Absolute and change from baseline PRO-CTCAE items (taste change, decreased 
appetite, fatigue, nausea, vomiting)
•
Absolute and change from baseline FAACT-AS
•
Absolute and change from baseline FAACT-5IASS
•
Absolute and change from baseline PROMIS Fatigue T-score
•
Absolute and change from baseline PROMIS Physical function T-score
CCI
CCI
CCI


Protocol C3651009 (PF-06946860) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 31
Appendix 4. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Absolute value of QTcF (msec)
470 and 480
>480 and 500
>500
Increase from baseline in QTcF (msec)
30 and 60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase from baseline
Baseline >200 and max. ≥25% 
increase
Baseline ≤200 and max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) increase from baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed.


Protocol C3651009 (PF-06946860) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 32
Appendix 5. Example SAS Code
proc mixed data = dataset;
  class subject time treat;
  model cfb = base treat time treat*time base*time / solution ddfm = 
kr residual;
  repeated time / subject = subject type = cs r rcorr;
  lsmeans treat*time / diff cl alpha=0.1;
run;
quit;


Protocol C3651009 (PF-06946860) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 33
 
 
 
 
 
 
 
 
 
CCI