Clinical trial NCT04803305
Conditions: Non-small Cell Lung Cancer Pancreatic Cancer Colorectal Cancer Prostate Cancer Breast Cancer Ovarian Cancer Loss of Appetite Fatigue Cachexia Anorexia
Keywords: cancer, anorexia, cachexia, weight loss, loss of appetite, fatigue
Sponsor: Pfizer
Start date: 2021-05-11; Completion date: 2022-08-09
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Study to compare the effects of the investigational new drug (PF-06946860) and a placebo on appetite and to find out how participants with advanced cancer and anorexia feel after receiving repeated subcutaneous (SC-injected under the skin) doses.

Detailed description:
A 6 week double blind study to compare the effects of the investigational new drug (PF-06946860) and a placebo on appetite and to find out how participants with advanced cancer and anorexia feel after receiving repeated doses injected under the skin (subcutaneously).

During the initial 6-week treatment period (Part A), a total of 2 doses of study drug or placebo will be administered 3 weeks apart. Each dose contains two injections. Part B is an optional 18-week open-label treatment period where up to 7 doses of study drug may be administered. Part B does not include placebo.

Assessments include:

* Measure the impact of the study drug on appetite, fatigue, and pain questionnaires
* Body weight measurements
* Blood samples to evaluate safety and additional endpoints including the amount of the study drug in the blood and the effects of the study drug on levels of a specific cytokine.

Arms: arm 1: subcutaneous injection arm 2: subcutaneous injection
Interventions: intervention 1: PF-06946860 intervention 2: Placebo for PF-06946860
Intervention descriptions: intervention 1: subcutaneous injection intervention 2: subcutaneous injection

Protocol documents:
Prot_000.pdf: 
PF-06946860
Protocol C3651010
Final Protocol Amendment 2, 08 October 2021
PFIZER CONFIDENTIAL
Page 1
A 6-WEEK, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN STUDY TO 
ASSESS THE EFFECT OF REPEATED SUBCUTANEOUS ADMINISTRATION OF
PF-06946860 ON APPETITE IN PARTICIPANTS WITH ADVANCED CANCER 
AND ANOREXIA, FOLLOWED BY AN 18-WEEK OPEN-LABEL TREATMENT
PERIOD
Study Intervention Number:
PF-06946860
Study Intervention Name:
Not Applicable (N/A)
US IND Number:
EudraCT Number:
Not Applicable (N/A)
Protocol Number:
C3651010
Phase:
1b
Short Title: Study to Assess the Effect of PF-06946860 on Appetite Following 
Subcutaneous Administration to Patients With Anorexia and Advanced Cancer
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 C3651010
Final Protocol Amendment 2, 08 October 2021
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 2
08 October 2021
The overall rationale for this amendment is to 
provide modifications and clarifications to the 
below select entry criteria and associated 
concomitant therapy requirements.  

Section 5.1: Inclusion criterion # 2: 
clarification of description of cancer 
diagnosis.

Section 5.1: Inclusion criterion # 3: 
clarification of treatment options.

Section 5.2: Exclusion criterion # 1: removed
for simplification.

Section 5.2: Exclusion criterion # 9 (# 8 in 
Protocol Amendment 2): clarification of HIV
diagnosis.

Section 5.2: Exclusion criterion # 13 (#12 in 
Protocol Amendment 2) and Section 6.5: 
clarification of description of treatments for 
anorexia, weight loss or cachexia and minor 
update to sentence structure describing 
‘stable”.

Section 5.2: Exclusion criterion # 15 (# 14 in 
Protocol Amendment 2) and Section 6.5: 
updates on the use of glucocorticoid therapy 
based on the current standard of care 
regimens common in the patient population
and timing given the primary endpoint and 
minor update to sentence structure describing 
‘stable”.

Section 5.2: Exclusion criterion # 16 (#15 in 
Protocol Amendment 2) and Section 6.5: and 
minor update to sentence structure describing 
‘stable”.


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Final Protocol Amendment 2, 08 October 2021
PFIZER CONFIDENTIAL
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
Section 5.2: Exclusion criterion # 20 (# 19 in 
Protocol Amendment 2) minor clarification to 
add “x” to “Inclusion of participants with 
alkaline phosphatase >3 ULN may be 
acceptable if they are deemed medically 
stable and fit for the study by both 
investigator and sponsor medically qualified 
personnel.”  
Additional updates and clarifications were made 
to the following sections: 

Schedule of activities: footnote “i” was added 
to the Qualitative Phone Interview 
(participant) at the Week 4 and Early
Term/Discontinuation visits for flexibility. 

Sections 2.2.2.2 and 2.2.2.3: updated per the 
finalized supplemental CSRs for C3651001 
and C3651002.

Section 6.1.1: updated to include details of 
investigational product dosing details and 
administration timing.

Section 9.5: added clarifying text to the 
interim analysis.

Appendix 13: Abbreviations.
Amendment 1
22 June 2021
The overall rationale for this amendment is to 
provide modifications and clarifications to the 
following exclusion criteria:

Section 5.2: Exclusion criterion # 7: 
clarification of description and timing ascites 
symptoms.

Section 5.2: Exclusion criterion # 15 and 
Section 6.5: updates based on the current 
standard of care regimens common in the 
patient population.


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Final Protocol Amendment 2, 08 October 2021
PFIZER CONFIDENTIAL
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
Section 5.2: Exclusion criterion # 17: Updated 
to clarify that receipt of at least one dose of 
PF-06946860 is exclusionary.

Section 5.2: Exclusion criterion #20: updated 
to reflect variability of typical baseline levels 
observed in patient population with advanced 
cancer.
Additional updates based on the final 6-month 
NHP study report and minor edits for consistency 
and to improve readability as follows:

SOA: footnote k: PD in footnote changed to 
GDF-15Section 2.2.1.3: NOAEL Cmax, Cav
and AUC168H values updated to reflect final 
6-month NHP study report.  Corresponding 
changes made to safety margins in Table 1
and overdose text in Section 8.4.

Section 2.2.2.2: minor update in the text 
describing the total PF-06946860 PK.

Section 2.2.2.3: baseline GDF-15 
concentration updated from median to 
geometric mean to be consistent with 
reporting standards for the data that will be 
included in the supplemental Clinical Study 
Reports for completed Phase 1 studies.

Section 4.3: description of dose rationale 
simplified by deleting repetitive text.

Section 6.1.1: guidance provided on timing of 
IP dosing relative to standard of care 
treatment, if applicable. 

Section 8.5: administrative clarification: 

On dosing days, pre-dose PK sample will 
be collected prior to IP administration. 

Section 8.6.1: administrative clarifications: 


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Protocol C3651010
Final Protocol Amendment 2, 08 October 2021
PFIZER CONFIDENTIAL
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
The actual date and time (24 hour clock 
time) of each sample will be recorded.

On dosing days, pre-dose GDF-15 sample
will be collected prior to IP 
administration.

Section 10.4.4 Highly Effective Methods That 
are User Dependent

Removal of “injectable” under Combined 
(estrogen and progestogen containing)
hormonal contraception associated with 
inhibition of ovulation required template 
update.
The following items noted in the Protocol 
Administrative Change Letter dated 09 March 
2021 have also been incorporated.

Modification to Exclusion criterion # 1, 
Schedule of Activities Footnote ‘j’, 
Section 8.1.1.5 Qualitative Phone Interviews, 
Section 8.6.1 GDF-15, Section 10.13. 
Appendix 13: Abbreviations.
Original 
protocol
18 December 2020
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
clarification letter.


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Final Protocol Amendment 2, 08 October 2021
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
1. PROTOCOL SUMMARY...................................................................................................12
1.1. Synopsis ..................................................................................................................12
1.2. Schema ....................................................................................................................18
1.3. Schedule of Activities .............................................................................................19
2. INTRODUCTION ...............................................................................................................22
2.1. Study Rationale .......................................................................................................22
2.2. Background .............................................................................................................23
2.2.1. Nonclinical Overview.................................................................................23
2.2.1.1. Nonclinical Pharmacology........................................................23
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism........................23
2.2.1.3. Nonclinical Safety.....................................................................23
2.2.2. Clinical Overview.......................................................................................24
2.3. Benefit/Risk Assessment.........................................................................................26
2.3.1. Risk Assessment.........................................................................................27
2.3.2. Benefit Assessment.....................................................................................28
2.3.3. Overall Benefit/Risk Conclusion................................................................28
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................28
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Population...................................................................................................32
4.2.2. Duration of Dosing .....................................................................................33
4.2.3. Endpoints and Procedures...........................................................................33
4.2.3.1. Participant Input into Design.....................................................34
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4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION......................................................................................................36
5.1. Inclusion Criteria.....................................................................................................36
5.2. Exclusion Criteria....................................................................................................38
5.3. Lifestyle Considerations..........................................................................................41
5.3.1. Contraception..............................................................................................41
5.4. Screen Failures ........................................................................................................41
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................42
6. STUDY INTERVENTION..................................................................................................42
6.1. Study Intervention(s) Administered........................................................................42
6.1.1. Administration............................................................................................43
6.2. Preparation/Handling/Storage/Accountability ........................................................43
6.2.1. Preparation and Dispensing........................................................................44
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................44
6.3.1. Allocation to Study Intervention ................................................................44
6.3.2. Breaking the Blind......................................................................................45
6.4. Study Intervention Compliance...............................................................................45
6.5. Concomitant Therapy..............................................................................................45
6.5.1. Rescue Medicine.........................................................................................47
6.6. Dose Modification...................................................................................................47
6.7. Intervention After the End of the Study..................................................................47
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................47
7.1. Discontinuation of Study Intervention ....................................................................47
7.2. Participant Discontinuation/Withdrawal From the Study.......................................48
7.2.1. Withdrawal of Consent...............................................................................48
7.3. Lost to Follow-up....................................................................................................49
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................49
8.1. Efficacy Assessments..............................................................................................50
8.1.1. Patient Reported Outcomes ........................................................................50


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8.1.1.1. Cancer-Related Cachexia Symptom Assessment –
Appetite .............................................................................................50
8.1.1.2. Cancer-Related Cachexia Symptom Assessment – Fatigue......51
8.1.1.3. PROMIS Pain 1a .......................................................................51
8.1.1.4. Patient Global Impression of Change (PGI-C) .........................51
8.1.1.5. Qualitative Phone Interviews ....................................................51
8.2. Safety Assessments .................................................................................................51
8.2.1. Physical Examinations................................................................................52
8.2.2. Clinical Safety Laboratory Assessments ....................................................52
8.2.3. Pregnancy Testing ......................................................................................52
8.3. Adverse Events and Serious Adverse Events..........................................................53
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.3.2. Method of Detecting AEs and SAEs ..........................................................54
8.3.3. Follow-up of AEs and SAEs.......................................................................54
8.3.4. Regulatory Reporting Requirements for SAEs...........................................55
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................55
8.3.5.1. Exposure During Pregnancy......................................................55
8.3.5.2. Exposure During Breastfeeding ................................................57
8.3.5.3. Occupational Exposure .............................................................57
8.3.6. Cardiovascular and Death Events...............................................................57
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.3.8. Adverse Events of Special Interest.............................................................58
8.3.8.1. Lack of Efficacy........................................................................58
8.3.9. Medical Device Deficiencies......................................................................58
8.3.10. Medication Errors.....................................................................................58
8.4. Treatment of Overdose............................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.6. Pharmacodynamics..................................................................................................60


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8.6.1. GDF-15.......................................................................................................60
8.6.2. Body Weight...............................................................................................61
8.7. Genetics...................................................................................................................62
8.7.1. Specified Genetics ......................................................................................62
8.7.2. Banked Biospecimens for Genetics............................................................62
8.8. Biomarkers ..............................................................................................................62
8.8.1. Specified Gene Expression (RNA) Research .............................................62
8.8.2. Specified Protein Research.........................................................................62
8.8.3. Specified Metabolomic Research ...............................................................62
8.9. Immunogenicity Assessments.................................................................................62
8.10. Health Economics .................................................................................................63
9. STATISTICAL CONSIDERATIONS ................................................................................63
9.1. Estimands and Statistical Hypotheses.....................................................................63
9.1.1. Estimands....................................................................................................63
9.2. Sample Size Determination.....................................................................................65
9.3. Analysis Sets ...........................................................................................................66
9.4. Statistical Analyses .................................................................................................67
9.4.1. General Considerations...............................................................................67
9.4.1.1. Analyses for Continuous Endpoints..........................................67
9.4.2. Primary Endpoint(s)....................................................................................67
9.4.3. Secondary Endpoint(s)................................................................................68
9.4.4. Tertiary/Exploratory Endpoint(s) ...............................................................68
9.4.5. Other Analyses............................................................................................68
9.5. Interim Analyses .....................................................................................................69
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............69
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................70
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............70
10.1.1. Regulatory and Ethical Considerations ....................................................70
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................70
10.1.2. Financial Disclosure .................................................................................71


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10.1.3. Informed Consent Process ........................................................................71
10.1.4. Data Protection .........................................................................................72
10.1.5. Dissemination of Clinical Study Data ......................................................72
10.1.6. Data Quality Assurance ............................................................................74
10.1.7. Source Documents....................................................................................75
10.1.8. Study and Site Start and Closure ..............................................................75
10.1.9. Publication Policy.....................................................................................76
10.1.10. Sponsor’s Qualified Medical Personnel .................................................77
10.2. Appendix 2: Clinical Laboratory Tests .................................................................78
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................79
10.3.1. Definition of AE .......................................................................................79
10.3.2. Definition of SAE.....................................................................................80
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................82
10.3.4. Reporting of SAEs....................................................................................85
10.4. Appendix 4: Contraceptive Guidance ...................................................................86
10.4.1. Male Participant Reproductive Inclusion Criteria....................................86
10.4.2. Female Participant Reproductive Inclusion Criteria.................................86
10.4.3. Woman of Childbearing Potential ............................................................87
10.4.4. Contraception Methods.............................................................................88
10.5. Appendix 5: Genetics............................................................................................89
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........90
10.7. Appendix 7: Cancer-Related Cachexia Symptom Assessment – Appetite...........92
10.8. Appendix 8: Cancer-Related Cachexia Symptom Assessment – Fatigue.............93
10.9. Appendix 9: PROMIS Pain 1a ..............................................................................94
10.10. Appendix 10: Patient Global Impression of Change...........................................95
10.11. Appendix 11 Study Conduct ...............................................................................96
10.11.1. Telehealth Visits.....................................................................................96
10.11.2. Nutritional Advice Consult.....................................................................96
10.11.3. Home Health Visits.................................................................................96
10.12. Appendix 12 Alternative Measures During Public Emergencies........................97
10.12.1. Eligibility................................................................................................97


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10.12.2. Adverse Events and Serious Adverse Events.........................................97
10.13. Appendix 13: Abbreviations ...............................................................................98
11. REFERENCES ................................................................................................................102
LIST OF TABLES
 
 
Table 2.
Protocol-Required Safety Laboratory Assessments .................................78
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Study to Assess the Effect of PF-06946860 on Appetite Following 
Subcutaneous Administration to Patients with Anorexia and Advanced Cancer.
Background and Rationale
Cachexia, or anorexia-cachexia syndrome, 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 is multifactorial, 
and is characterized by loss of appetite, weight, and skeletal muscle, leading to fatigue, 
functional impairment, increased treatment-related toxicity, poor quality of life, and reduced 
survival.  Anorexia is a key component of the cachectic phenotype.1 A meta-analysis of 
30 randomized controlled trials from the European Organisation for Research and Treatment 
of Cancer (EORTC) showed that loss of appetite correlates with poor survival in cancer 
patients with advanced disease.2
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;3 and during 
pregnancy it is highly expressed by placental trophoblast.4 GDF-15 is also secreted by tumor 
cells, macrophages and damaged cells.5-8 In several chronic conditions such as cancer, heart 
failure, COPD, and CKD, circulating GDF-15 concentrations are markedly elevated 
compared to healthy levels.9-12
Elevated GDF-15 is associated with weight loss and anorexia-cachexia in patients with 
cancer.13-16 It is hypothesized that anorexia-cachexia in patients with cancer is largely 
mediated via GDF-15 and that suppression of GDF-15 in these patients may lead to 
improvement in serious aspects of their disease such as anorexia leading to unintended 
weight loss, fatigue and impaired mobility.  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 receptor.  It is anticipated that
PF-06946860, therefore, has the potential to promote appetite, mitigate fatigue, and 
ameliorate the malaise and weight loss associated with cachexia in advanced cancer.
The primary purpose of this study is to assess the effect of repeated subcutaneous 
administration of PF-06946860 on appetite in participants with advanced cancer, anorexia 
and elevated circulating GDF-15 levels. The study will also assess secondary and 
exploratory endpoints including fatigue, safety and body weight. 


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Objectives, Estimands and Endpoints
Part A
Objectives
Endpoints
Estimands
Primary

To evaluate the early effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at Week 4. 

Estimand 1 (similar to 
“hypothetical”) is intended to 
provide a population level 
estimate of the treatment effect on 
the change from baseline Appetite 
score for PF-06946860 compared 
to placebo in all evaluable 
participants under the scenario of 
no discontinuation of study 
intervention and without the 
potential confounding effects of 
prohibited medications, regardless 
of the participants’ compliance 
with dosing (ie, using the 
Censored analysis set).
Secondary

To evaluate the effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at Weeks 1, 2, 3, 5 and 6. 

Estimand 1, as above.

To evaluate the effect of 
PF-06946860 compared to 
placebo on fatigue in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment-Fatigue 
score, at Weeks 1, 2, 3, 4, 5 and 6. 

Estimand 2 (similar to 
“hypothetical”) is intended to 
provide a population level estimate 
of the treatment effect on the 
change from baseline Fatigue score 
for PF-06946860 compared to 
placebo in all evaluable participants 
under the scenario of no 
discontinuation of study 
intervention and without the 
potential confounding effects of 
prohibited medications, regardless 
of the participants’ compliance 
with dosing (ie, using the Censored 
analysis set).

To characterize the safety and 
tolerability of repeated 
subcutaneous administrations of 
PF-06946860 compared to 
placebo in participants with 
anorexia and advanced cancer.

Incidence of adverse events and
laboratory abnormalities, in Part 
A of the study.

There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data 
standards, as applicable.


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Objectives
Endpoints
Estimands
Tertiary/Exploratory: 

To evaluate the effect of 
PF-06946860 compared to 
placebo on body weight in 
participants with anorexia and 
advanced cancer.

Change from baseline in body 
weight, at Weeks 3, 4 and 6.

N/A

To explore the relationship 
between pain and appetite and 
fatigue in participants with 
anorexia and advanced cancer.

Change from baseline score for 
patient reported 7-day recall 
PROMIS-Pain 1a, Cancer-Related 
Cachexia Symptom Assessment-
Fatigue score and Cancer-Related 
Cachexia Symptom 
Assessment-Appetite score at 
Weeks 1, 2, 3, 4, 5 and 6.

N/A

To assess patient global 
impression of change of 
appetite and fatigue in 
participants with anorexia and 
advanced cancer.

PGI-C (appetite), at Weeks 4 
and 6.

PGI-C (fatigue), at Weeks 4 
and-6.

N/A

To characterize the unbound and 
total PK of PF-06946860 
administered in participants with 
anorexia and advanced cancer.

Serum unbound and total 
concentrations of PF-06946860,
on Day 1 and Weeks 3, 4 and 6.

N/A

To characterize the effect of 
PF-06946860 administration on 
circulating GDF-15
concentrations in participants 
with anorexia and advanced 
cancer.

Serum concentrations of total 
GDF-15; and if feasible, unbound 
GDF-15, on Day 1 and Weeks 3, 
4 and 6.

N/A

To assess the immunogenicity
of PF-06946860 administered in 
participants with anorexia and 
advanced cancer.

Incidence of ADA and, if 
applicable, NAb, in Part A of the 
study.

N/A


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Part B 
In addition, the following objectives will be evaluated using data from Part B, as data permit:
Objectives
Endpoints
Estimands
Tertiary/Exploratory:

To assess appetite in participants with 
anorexia and advanced cancer, during 
the open-label treatment period.

Change from baseline for patient 
reported 7-day recall Cancer-Related 
Cachexia Symptom 
Assessment-Appetite score, weekly 
from Week 7 to 24. 

N/A

To assess fatigue in participants with 
anorexia and advanced cancer, during 
the open-label treatment period.

Change from baseline for patient 
reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment-Fatigue 
score, weekly from Week 7 to 24.

N/A

To characterize the safety and 
tolerability of repeated subcutaneous 
administrations of PF-06946860 in 
participants with anorexia and advanced 
cancer, during the open-label treatment 
period.

Incidence of adverse events and 
laboratory abnormalities, in Part B of 
the study.

There are no defined 
estimands for these 
endpoints and they 
will be analyzed using 
Pfizer data standards, 
as applicable.

To assess body weight in participants 
with anorexia and advanced cancer, 
during the open-label treatment period.

Change from baseline in body weight, 
at Weeks 12, 15, 18, 21 and 24.

N/A

To explore the relationship between
pain and appetite/fatigue in participants 
with anorexia and advanced cancer, 
during the open-label treatment period.

Change from baseline score for patient 
reported 7-day recall PROMIS-Pain 1a,
Cancer-Related Cachexia Symptom 
Assessment-Fatigue score and Cancer-
Related Cachexia Symptom 
Assessment–Appetite score, weekly 
from Week 7 to 24.

N/A

To assess patient global impression of 
change of appetite and fatigue in 
participants with anorexia and advanced 
cancer, during the open-label treatment 
period.

PGI-C (appetite), at Week 24.

PGI-C (fatigue), at Week 24.

N/A

To characterize the unbound and total 
PK of PF-06946860 administered in 
participants with anorexia and advanced 
cancer, during the open-label treatment 
period.

Serum unbound and total concentrations 
of PF-06946860, at Weeks 12, 18 
and 24.

N/A

To characterize the effect of 
PF-06946860 administration on 
circulating GDF-15 concentrations in 
participants with anorexia and advanced 
cancer, during the open-label treatment 
period.

Serum concentrations of total GDF-15; 
and if feasible, unbound GDF-15, at 
Weeks 12, 18 and 24.

N/A


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Objectives
Endpoints
Estimands

To assess the immunogenicity of 
PF-06946860 administered in 
participants with anorexia and advanced 
cancer, during the open-label treatment 
period.

Incidence of ADA and, if applicable, 
NAb, in Part B of the study.

N/A
Overall Design
This is a Phase 1b study in patients with advanced cancer, anorexia and elevated circulating 
GDF-15 levels. The study will be conducted in 2 parts. The initial 6-week treatment period 
will be a randomized, double-blind, placebo-controlled, parallel group study. Participants 
who meet the entry criteria will be randomized to study drug (PF-06946860 or placebo).  The 
6-week double-blind dosing period will consist of a total of 2 SC doses, administered 
3 weeks apart (Q3W).  The 6-week double-blind treatment period will be followed by 
optional open-label treatment (OLT) with PF-06946860 of up to 18 weeks. 
Potential participants will attend at least 2 clinic visits (Screening and Randomization) with 
the investigator. The Screening visit will occur no more than 28 days and no less than 
5 days, prior to Randomization. The 5-day minimum duration between Screening and 
Randomization visits will ensure that all necessary data (including GDF-15 level) are 
available to inform the investigator’s assessment of eligibility. 
All study visits following Randomization may be conducted by a visiting Health Care 
Professional (HCP) at the patient’s home. During selected home-HCP visits, the investigator 
will conduct Telehealth consults with the participant in order to assess patient safety. Should 
the participant elect, at Randomization, to have all subsequent Part A study visits carried out 
at the investigator site rather than at home, this preference may be accommodated. 
During the Week 4 TeleHealth consult, the investigator and participant will decide whether 
to continue with the optional open-label treatment period. Participants opting to continue to 
the OLT period will receive their first dose of open-label PF-06946860 at the Week 6 visit, 
coinciding with the last visit of the double-blind portion of the study. The participant and 
investigator may select to have study visits for Part B conducted at home or in-clinic.
Follow-up contact with all participants (whether participating in the 6-week double-blind 
only, or the OLT period) will be scheduled to occur at least 28 days and up to 35 days after 
the last administration of blinded IP. For study Part A, this contact may be done via a phone 
call, telehealth, at home or in the clinic, per investigator judgement. For study part B, a 
home-HCP + TeleHealth (or in-Clinic) visit will be conducted. Additional follow-up may be 
conducted for safety evaluation, at the discretion of the investigator.


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Number of Participants
Approximately 40 participants will be randomly assigned to investigational product such that 
approximately 30 evaluable participants complete the 6-week double-blind portion of the 
study. 
The study will be randomized in approximately a 2:1 ratio (27 active: 13 placebo).
Intervention Groups and Duration
Intervention Name
PF-06946860
Placebo
ARM Name
PF-06946860 Double-Blind Treatment 
followed by Open-Label Treatment
Placebo Double-Blind Treatment followed by 
Open-Label Treatment
Type
Biologic
Placebo
Dose Formulation
Solution for injection
Solution for injection
Unit Dose Strength(s)
 
Placebo
Dosage Level(s)
Placebo Q3Weeks
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
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Refer to Section 9.
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1.2. Schema
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1.3. Schedule of Activities
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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Screening
Part A: Double-Blind
Part B: Open-Label
Part A: 
Follow-upb
Part B: 
Follow-
upc
Early Term/
Discontinuation
Visit Identifier
Abbreviations, see Appendix 13
v1
v2
v3
v4
v5
v6
v7
v8
v9
v10
v11
v12
v13
Study Week (relative to Day 1)
Rand
wk3
wk4a,b wk6 wk9 wk12 wk15 wk18 wk21 wk24
Study Day (relative to Day 1 dosing)
-28 to -5 Day 1
22
29
43
64 
85
106
127
148
169
50 
197
Visit Window (days)
±1
±1
±1
±3
±3
±3
±3
±3
±3
+7
+7
Clinic Visit  
X
X
Telehealth Visitd
X
X
X
X
X
X
X
X
X
At-Home/Residential Care Facility Home-HCP 
Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Informed Consent and Registration
X
Informed consent (caregiver)e
X
Review of Eligibility Criteria
X
X
Randomization
X
Administration of blinded PF-06946860/placebo
X
X
Administration of open-label PF-06946860
X
X
X
X
X
X
X
Medical History, Demography and Height
X
Record Prior or Concomitant treatments
X
X
→
→
→
→
→
→
→
→
→
X
X
X
Monitor Serious/nonserious AEs
X
X
→
→
→
→
→
→
→
→
→
X
X
X
Review contraception use 
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination (Height at Screening only)f
X
X
X
X
PRO (weekly) 7-day recall: appetite, fatigue, paing
X
Xh
→
→
→
→i
→i
→i
→i
→i
→i
Xi
Xi
X
PRO PGI-C: appetite and fatigue 
X
X
Xi
X
Qualitative Phone Interview (participant)j
Xi
Xi
Xi
Qualitative Phone Interview (care giver)e,j
X
X
Weight + Body Composition via BIA (BIA not at 
Screen)
X
Xh
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
X
Blood and Urine samples: Clinical Lab Tests, 
Table 2
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test for female participants of 
childbearing potential (Blood and/or Urine)
X
X
X
X
X
X
Blood sample for GDF-15k
X
X
X
X
X
Xi
Xi
Xi
Xi
Xi
X
Blood sample for PF-06946860 PKk
X
X
X
X
Xi
Xi
Xi
Xi
Xi
X
Blood sample for immunogenicity (ADA and NAb)k
X
X
X
Xi
Xi
Xi
Xi
Xi
X
Prep D1.5 banked biospecimen (serum)k,l
X


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a.
The investigator and participant must decide at the Week 4 visit if they wish to continue to the open-label treatment period.
b.
Participants not continuing to Part B only. Follow-up contact 28 to 35 days from final dose of study drug.  May occur via Clinic or TeleHealth+home-HCP visit, per 
PI judgement.
c.
Participants continuing to Part B only. Follow-up contact 28 to 35 days from final dose of study drug. May occur via Clinic or TeleHealth+home-HCP visit, per 
PI judgement. 
d.
Participant and investigator may elect to have all post-randomization study visits for Part A conducted at-home or at clinic. A selection should be made, and efforts made, to 
have all Part A visits conducted using the same paradigm (home or clinic). If the participant chooses to do a visit at the clinic, the Telehealth visit will not be implemented.
Additional Telehealth visits, home-HCP visits or phone calls may be scheduled, as needed per PI judgement. If operationally feasible, a nutritional consult via telehealth with 
a central vendor will be scheduled by the participant within the first 7 days after randomization.
e.
This would only occur if a caregiver was available and willing to participate, and if the participant was in agreement with the caregiver completing the caregiver interview.
f.
A full physical examination will be conducted at Screening.  A symptom-directed PE may be conducted at any time during the study and/or at end of study as judged 
necessary by the investigator (eg, to assess previous findings or to assess ongoing/open AEs).
g.
PRO (weekly) 7-day recall: appetite, fatigue, pain refers to the Cancer-Related Cachexia Symptom assessments for appetite and fatigue and the PROMIS pain assessment.
h.
Devices (eg, weighing scales and ePRO) required for study procedures will be used at Day 1 clinic visit, and provided to participant for at-home use, as applicable. 
i.
Every effort must be made to conduct procedures as specified, however if this becomes infeasible due to progression or complications of underlying disease, non-completion 
will not be considered a protocol deviation as long as the participant’s safety was preserved. Collection of safety samples should be prioritized.
j.
Phone Interview will be conducted by central vendor within the 10 days following the Week 4 visit (ie, Day 29-39), or at early termination, if feasible. For Part B, a second 
participant interview will be conducted at week 12 ±10 days, or at early termination, if feasible.
k.
On dosing days, blood samples for PK, GDF-15, immunogenicity and banked biospecimens will be collected prior to treatment administration.
l.
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.


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2. INTRODUCTION
Cachexia, or anorexia-cachexia syndrome, 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 is multifactorial, 
and is characterized by loss of appetite, weight, and skeletal muscle, leading to fatigue, 
functional impairment, increased treatment-related toxicity, poor quality of life, and reduced 
survival.  Anorexia is a key component of the cachectic phenotype.1 A meta-analysis of 
30 randomized controlled trials from the European Organization for Research and Treatment 
of Cancer (EORTC) showed that loss of appetite correlates with poor survival in cancer 
patients with advanced disease.2
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;3 and during 
pregnancy it is highly expressed by placental trophoblast.4  GDF-15 is also secreted by tumor 
cells, macrophages and damaged cells.5-8 In several chronic conditions such as cancer, heart 
failure, COPD, and CKD, circulating GDF-15 concentrations are markedly elevated 
compared to healthy levels.9-12  Elevated GDF-15 is associated with weight loss and 
anorexia-cachexia in patients with cancer.13-16 In addition, elevated circulating GDF-15 
levels are associated with poor outcomes and survival in many cancers, heart failure, CKD 
and COPD.17-23  In rodents and non-human primates, GDF-15 induces anorexia and weight 
loss24-28 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  
It is hypothesized that anorexia-cachexia in patients with cancer is largely mediated via 
GDF-15 and that suppression of GDF-15 in these patients may lead to improvement in 
serious aspects of their disease such as anorexia leading to unintended weight loss, fatigue 
and impaired mobility.
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 receptor. It is anticipated that PF-06946860, therefore, has the potential to promote 
appetite, mitigate fatigue, and ameliorate the malaise and weight loss associated with 
cachexia in advanced cancer.
2.1. Study Rationale 
The primary purpose of this study is to assess the effect of repeated subcutaneous 
administration of PF-06946860 on appetite in participants with advanced cancer, anorexia 
and elevated circulating GDF-15 levels. The study will also assess secondary and 
exploratory endpoints including fatigue, safety and body weight. 


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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 Overview
2.2.1.1. 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 literature24-28 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.
2.2.1.2. Nonclinical Pharmacokinetics and Metabolism
Details of the nonclinical PK of PF-06946860 are provided in the IB.  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 is not expected to affect the PK of 
small molecule drugs either 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.
2.2.1.3. 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. 


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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 
934 μg/mL, 786 μg/mL and 132,000 μg•h/mL, respectively, in the 6-month study.
2.2.2. Clinical Overview
PF-06946860 has been evaluated in two completed Phase 1 single dose studies (C3651001 
and C3651002) in healthy participants. A multiple dose Phase 1 study (C3651009) in cancer 
patients with cachexia is ongoing; no data from this ongoing study are currently available.  
Clinical data from the completed studies are provided in the IB for PF-06946860. 
2.2.2.1. Safety
 
 
 
 
 
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2.3. Benefit/Risk Assessment
The C3651010 study is designed primarily to assess the effect of PF-06946860 on appetite, 
fatigue and safety in a population with advanced cancer and anorexia.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06946860 may be found in the investigator’s brochure (IB), which is the 
single reference safety document (SRSD) for this study. 
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
No potential risks of clinical significance have been 
identified to date.
Summary of Data/Rationale for Risk
Assessment of risk is based on nonclinical toxicology 
studies up to 6 months in duration with no findings 
identified as adverse, and the results of 2 completed 
single dose administration studies in healthy 
participants show only mild AEs, no adverse trends in 
laboratory, ECG or vital signs safety monitoring and 
no SAEs.
Mitigation Strategy
Standard safety monitoring for a biological 
investigational product, including ADA/NAb 
monitoring will continue to be implemented. 
Study Intervention(s) PF-06946860 
Potential risks associated with PF-06946860 include 
the following: 
1.
Injection site reactions.
2.
This will be the first administration of 
PF-06946860 to patients with a variety of 
cancer types and that may be receiving a variety 
of anti-tumor therapies. Therefore, this will be 
the first clinical experience to assess safety in 
this context.
Single doses of PF-06946860 were well-tolerated by 
study participants when administered subcutaneously 
at 0.1 to 300 mg in 2 completed Phase 1 studies.  All 
AEs reported across the 2 completed studies were 
mild. The risk of injection site reaction is not 
anticipated to be elevated beyond that expected with 
any subcutaneously administered treatment. 
Eligibility criteria have been selected to 
ensure that only appropriate participants, who 
are not at apparent increased risk, are included 
in the study (see Section 5).
Adverse events and clinical laboratory results 
will be monitored on an ongoing basis.
Injection site reactions will be monitored, and 
injections sites rotated.
Use of a placebo arm. 
Use of a placebo arm represents a risk of lack of 
benefit for those not receiving active therapy. As 
there are no data on efficacy yet, this risk cannot be 
assessed. 
As the endpoint under evaluation (appetite) is 
anticipated to change rapidly, the study has 
been designed with a short duration (6 weeks), 
and with the potential for participation in an 
optional OLT Part B where all participants 
would receive PF-06946860. 
The study has also been designed with, a 
2:1 randomization ratio, in order to increase 
participants’ chances of receiving active 
therapy.


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2.3.2. Benefit Assessment
The available clinical data, summarized in Section 2.2.2, show that a single dose of 
PF-06946860 as high as 300 mg SC in healthy participants is safe and well tolerated.  
Efficacy has not yet been studied in humans.
Based upon nonclinical data, it is hypothesized that dosing with PF-06946860 will improve 
participants appetite and support maintenance of body weight. 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.
There are currently no approved therapies for cachexia.  It is estimated that 50-80%29 of 
patients with advanced malignant cancer suffer with cachexia which results in worse 
outcomes.  Therefore, the development of PF-06946860 for the treatment of cachexia may 
satisfy an area of high unmet need.
2.3.3. Overall Benefit/Risk Conclusion
Considering all available clinical and nonclinical data, the benefit-risk profile of 
PF-06946860 is favorable and supports continued clinical development. 
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Part A
Objectives
Endpoints
Estimands
Primary

To evaluate the early effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at Week 4. 

Estimand 1 (similar to 
“hypothetical”) is intended to 
provide a population level estimate 
of the treatment effect on the 
change from baseline Appetite 
score for PF-06946860 compared 
to placebo in all evaluable 
participants under the scenario of 
no discontinuation of study 
intervention and without the 
potential confounding effects of 
prohibited medications, regardless 
of the participants’ compliance 
with dosing (ie, using the Censored 
analysis set).
Secondary

To evaluate the effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at Weeks 1, 2, 3, 5 and 6. 

Estimand 1, as above.


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Objectives
Endpoints
Estimands

To evaluate the effect of 
PF-06946860 compared to 
placebo on fatigue in 
participants with anorexia and 
advanced cancer.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment-Fatigue 
score, at Weeks 1, 2, 3, 4, 5 and 6. 

Estimand 2 (similar to 
“hypothetical”) is intended to 
provide a population level estimate 
of the treatment effect on the change 
from baseline Fatigue score for 
PF-06946860 compared to placebo 
in all evaluable participants under 
the scenario of no discontinuation of 
study intervention and without the 
potential confounding effects of 
prohibited medications, regardless of 
the participants’ compliance with 
dosing (ie, using the Censored 
analysis set).

To characterize the safety and 
tolerability of repeated 
subcutaneous administrations 
of PF-06946860 compared to 
placebo in participants with 
anorexia and advanced cancer.

Incidence of adverse events and 
laboratory abnormalities, in Part A
of the study.

There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data standards,
as applicable.
Tertiary/Exploratory: 

To evaluate the effect of 
PF-06946860 compared to 
placebo on body weight in 
participants with anorexia and 
advanced cancer.

Change from baseline in body 
weight, at Weeks 3, 4 and 6.

N/A

To explore the relationship 
between pain and appetite and 
fatigue in participants with 
anorexia and advanced cancer.

Change from baseline score for 
patient reported 7-day recall 
PROMIS-Pain 1a, Cancer-Related 
Cachexia Symptom 
Assessment-Fatigue score and 
Cancer-Related Cachexia 
Symptom Assessment-Appetite 
score at Weeks 1, 2, 3, 4, 5 and 6.

N/A

To assess patient global 
impression of change of 
appetite and fatigue in 
participants with anorexia and 
advanced cancer.

PGI-C (appetite), at Weeks 4 
and 6.

PGI-C (fatigue), at Weeks 4 and 6.

N/A

To characterize the unbound 
and total PK of PF-06946860 
administered in participants 
with anorexia and advanced 
cancer.

Serum unbound and total 
concentrations of PF-06946860, on 
Day 1 and Weeks 3, 4 and 6.

N/A

To characterize the effect of 
PF-06946860 administration 
on circulating GDF-15
concentrations in participants 
with anorexia and advanced 
cancer.

Serum concentrations of total 
GDF-15; and if feasible, unbound 
GDF-15, on Day 1 and Weeks 3, 4 
and 6.

N/A


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Objectives
Endpoints
Estimands

To assess the 
immunogenicity of 
PF-06946860 administered in 
participants with anorexia and 
advanced cancer.

Incidence of ADA and, if 
applicable, NAb, in part A of the 
study.

N/A
Part B 
In addition, the following objectives will be evaluated using data from Part B, as data permit:
Objectives
Endpoints
Estimands
Tertiary/Exploratory:

To assess appetite in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

Change from baseline for patient 
reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, weekly from Week 7 to 24. 

N/A

To assess fatigue in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

Change from baseline for patient 
reported 7-day recall Cancer-
Related Cachexia Symptom 
Assessment–Fatigue score, weekly 
from Week 7 to 24.

N/A

To characterize the safety and 
tolerability of repeated 
subcutaneous administrations 
of PF-06946860 in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

Incidence of adverse events and 
laboratory abnormalities, in Part B 
of the study.

There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data standards, 
as applicable.

To assess body weight in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

Change from baseline in body 
weight, at Weeks 12, 15, 18, 21 
and 24.

N/A

To explore the relationship 
between pain and 
appetite/fatigue in participants 
with anorexia and advanced 
cancer, during the open-label
treatment period.

Change from baseline score for 
patient reported 7-day recall 
PROMIS-Pain 1a, Cancer-Related 
Cachexia Symptom 
Assessment-Fatigue score and 
Cancer-Related Cachexia 
Symptom Assessment-Appetite 
score, weekly from Week 7 to 24.

N/A

To assess patient global 
impression of change of 
appetite and fatigue in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

PGI-C (appetite), at Week 24.

PGI-C (fatigue), at Week 24.

N/A


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Objectives
Endpoints
Estimands

To characterize the unbound 
and total PK of PF-06946860 
administered in participants 
with anorexia and advanced 
cancer, during the open-label
treatment period.

Serum unbound and total 
concentrations of PF-06946860, at 
Weeks 12, 18 and 24.

N/A

To characterize the effect of 
PF-06946860 administration 
on circulating GDF-15
concentrations in participants 
with anorexia and advanced 
cancer, during the open-label
treatment period.

Serum concentrations of total 
GDF-15; and if feasible, unbound 
GDF-15, at Weeks 12, 18 and 24.

N/A

To assess the 
immunogenicity of 
PF-06946860 administered in 
participants with anorexia and 
advanced cancer, during the 
open-label treatment period.

Incidence of ADA and, if 
applicable, NAb, in Part B of the 
study.

N/A
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1b study in patients with advanced cancer, anorexia and elevated circulating 
GDF-15 levels with the primary purpose of assessing the effect of PF-06946860 
administration on anorexia. 
The study will be conducted in 2 parts. The initial 6-week treatment period will be a 
randomized, double-blind, placebo-controlled, parallel group study. Participants who meet 
the entry criteria will be randomized to study drug (PF-06946860 or placebo).  The 6-week 
double-blind period will consist of a total of 2 SC doses, administered 3 weeks apart (Q3W).  
The 6-week double-blind treatment period will be followed by optional open-label treatment 
(OLT) with PF-06946860 of up to 18 weeks; the total duration of treatment would, therefore, 
be up to 24 weeks. 
Potential participants will attend 2 clinic visits (Screening and Randomization) with the 
investigator. The Screening visit will occur no more than 28 days and no less than 5 days, 
prior to Randomization. The 5-day minimum duration between Screening and 
Randomization visits will ensure that all necessary data (including GDF-15 level) are 
available to inform the investigator’s assessment of eligibility. 
All study visits following Randomization may be conducted by a visiting Health Care 
Professional (HCP) at the patient’s home. During selected home-HCP visits, the investigator 
will conduct periodic Telehealth consults with the participant in order to assess patient safety
(See Appendix 11 Study Conduct). Should the participant elect, at Randomization, to have 


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all subsequent Part A study visits carried out at the investigator site rather than at home, this 
preference may be accommodated. 
During the Week 4 TeleHealth consult, the investigator and participant will decide whether 
to continue with the optional open-label treatment period. Participants opting to continue to 
the OLT period will receive their first dose of open-label PF-06946860 at the Week 6 visit, 
coinciding with the last visit of the double-blind portion of the study. The participant and 
investigator may select to have study visits for Part B conducted at home or in-clinic.
Follow-up contact with all participants (whether participating in the 6-week double-blind 
only, or the OLT period) will be scheduled to occur at least 28 days and up to 35 days after 
the last administration of IP. For study Part A, this contact may be done via a phone call, 
telehealth, at home or in the clinic, per investigator judgement. For study part B, a
home-HCP+TeleHealth (or in-Clinic) visit will be conducted. Additional follow-up may be 
conducted for safety evaluation, at the discretion of the investigator.
4.2. Scientific Rationale for Study Design
The primary purpose of this study is to assess the effect of repeated subcutaneous 
administrations of PF-06946860 on appetite in patients with advanced cancer, anorexia and 
elevated circulating GDF-15 levels. The study will also assess secondary and exploratory 
endpoints including fatigue, safety, body weight, immunogenicity, PK and PD. 
4.2.1. Population
As described in Section 2, it is hypothesized that anorexia-cachexia in patients with advanced 
cancer is largely mediated via GDF-15, and that suppression of GDF-15 in these patients 
may lead to improvement in serious aspects of their disease including appetite. This study, 
therefore, intends to enroll patients with advanced cancer, anorexia and elevated GDF-15 
levels. 
Across malignancies, cachexia is highly prevalent, impacting approximately half of patients 
with advanced cancer, including those solid tumor types selected for inclusion in this study. 
Elevated levels of circulating GDF-15 have been reported in literature in patients with a 
variety of tumor types experiencing anorexia and weight loss.  Biospecimens from healthy 
adults30 and patients with cancer (from both external commercial biorepositories and an 
internal study) were analyzed for GDF-15 levels. The cancer sample set contained 
399 NSCLC, 116 pancreatic cancer, 157 colorectal cancer, 136 prostate cancer, 112 ovarian 
cancer and 144 breast cancer patients. These patients were mostly Caucasian, aged 29-90, 
and had an approximate ratio of 40%: 60% females to males (excluding breast and ovarian 
[100% female] and prostate [100% male]).  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,30 confirmed literature-reported elevations in GDF-15 levels in cancer patients when
compared to healthy subjects (elevations ranging from 2-fold [prostate and breast cancer] to 
5-fold [pancreatic cancer]).  An adhoc analysis of NSCLC patients from an internal Pfizer 
study demonstrated that higher GDF-15 levels were associated with a reduction in body 


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weight.  These data were used to determine the degree of GDF-15 elevation necessary for 
inclusion in this study. GDF-15 levels above the 95th percentile of GDF-15 concentrations 
reported in these healthy subjects will be considered elevated 
. 
In order to appropriately enroll patients who may be expected to derive benefit from 
treatment with PF-06946860, severity of anorexia (See Section 8.1.1.1) will be assessed at 
Screening and prior to Randomization using a self-reported questionnaire.  Impaired appetite 
will be a requirement for inclusion into this study. 
Studies to evaluate the development toxicity of PF-06946860 have not been conducted.
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.2.2. Duration of Dosing 
The double-blind portion of this study (Part A) will be 6 weeks in duration. This is 
anticipated to be sufficient to detect an effect on the primary endpoint, appetite, while 
minimizing the required duration of study participation. 
All participants completing the 6-week double-blind portion of the study will be given the 
option of receiving open-label PF-06946860 during study Part B. As efficacy has not yet 
been studied in a clinical setting, participation in study Part B will be optional with the 
purpose of providing continued access to participants who are deriving or may derive benefit
(based on their own perception, along with that of their investigator).
The total duration of dosing with PF-06946860 in this study will be up to 24 weeks, as 
supported by completed nonclinical toxicity studies (Section 2.2.1).
4.2.3. Endpoints and Procedures
The key objectives of this study are to assess the effect of PF-06946860 on serious aspects of 
disease, anorexia and fatigue, in this population. The primary objective of the study is to 
assess the early effect of PF-06946860 on appetite, this will be evaluated at Week 4. This 
Week 4 timepoint is intended to reflect the initial anticipated symptomatic change, while 
minimizing potential impact of any early termination in this fragile population. An 
additional assessment of appetite and fatigue endpoints across the entire 6-week double-blind
period will be conducted. As the severity of pain may influence a participant’s level of 
appetite, patient reported data on pain may be used as part of exploratory analyses. Appetite, 
fatigue and pain will be assessed weekly via questionnaires completed by the patient (see 
Section 8.1.1.3). A small number of fit-for-purpose questions has been selected to minimize 
patient burden. Additionally, phone interviews will be conducted with the patient and a 
caregiver, if feasible. This will allow a qualitative assessment of the overall
participant/caregiver experience (see Section 8.1.1.5).
Participant safety will be monitored primarily via clinical laboratory test and adverse event 
monitoring with a combination of in-clinic, home-HCP and TeleHealth visits. To 
supplement the standard clinical safety laboratory tests assessed at this stage of development, 
CRP, albumin and pre-albumin will be included as measures of nutritional status. 
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As an amelioration of anorexia can be expected to precede improvement in body weight, an 
exploratory assessment of change in weight will be included in this study, see Section 8.6.2. 
The electronic scales, provided to each participant for use from the randomization visit 
onward, will also provide data on body composition as part of the same body weight 
measurement procedure. Given the prevalence of edema in this population, the data may be
used as part of exploratory analyses.
As PF-06946860 is a monoclonal antibody, immunogenicity samples will be collected for the 
determination of ADA and NAb, if applicable.
Sparse PF-06946860 and GDF-15 concentrations will be measured in this study to (1) assess 
PF-06946860 exposure in this population; (2) understand the range of baseline GDF-15
values and variability in this population; and (3) provide preliminary information on the 
magnitude of GDF-15 response after PF-06946860 treatment. 
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.
4.2.3.1. Participant Input into Design
Twelve patients and caregivers were interviewed in order to better understand what 
symptoms are most burdensome to patients and what might impact their decision to 
participate in a clinical study.  All patients had cancer (prostate, non-small cell lung, 
colorectal or pancreatic cancers) and had experienced significant unintentional weight loss 
and other symptoms of cachexia.  
Patient input was valuable in informing key outcomes. Of greatest interest were improved 
appetite and reduced fatigue, supporting the choice of appetite as the primary endpoint for 
the study. 
Patients and caregivers also provided input on the study design which triggered incorporation 
of options to potentially enhance patient participation and retention, and highlighted the 
following additional considerations which are anticipated to be of value to patients: 

Option for home/tele-visits with physician or in-person physician appointments where 
feasible through double-blind portion of the study.

Nutritional consultations eg, via TeleHealth. This will be included, if operationally 
feasible. 

Confirmed the importance to patients of including the option to receive open-label 
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•
Patients emphasized the significance of having their overall experiences with the 
study treatment heard by the Sponsor. This led to the incorporation of qualitative 
phone interviews in order to facilitate a more holistic assessment.
•
Highlighted the value of appropriate training, including to home HCPs, on important 
aspects of the disease and the potential social and psychological impact. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
.
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4.4. End of Study Definition
A participant is considered to have completed the study if he/she has either completed Part A 
(including follow-up), or has completed Part A and has entered, and completed, the OL 
extension Part B.
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 the following criteria apply:
Age and Sex:
1. Male or female participants ≥18 (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) participants.
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Type of Participant and Disease Characteristics:
2. Documented diagnosis of non-small cell lung, pancreatic, colorectal, prostate, breast 
or ovarian cancer which, in the treating oncologist’s assessment, is considered 
advanced, for example:
•
Unresectable Stage III or IV non-small cell lung cancer.
•
Locally advanced or metastatic pancreatic adenocarcinoma.
•
Metastatic or recurrent colorectal cancer.
•
Metastatic prostate cancer.
•
Metastatic or recurrent breast cancer.
•
Refractory ovarian cancer.
3. Meets any of the following criteria at Randomization:
i.
Not currently receiving antineoplastic therapy. This may be, for example, a 
patient who: 
•
Has chosen not to receive further therapy, for example for quality of life 
reasons;
•
Is not indicated for future antineoplastic therapy or has exhausted all treatment 
options;
•
Has stable disease where no antineoplastic therapy is judged to be necessary;
•
Is taking a break between antineoplastic treatments, where the break has 
begun at least 4 weeks prior to Randomization and is anticipated to be longer 
than the 6-week duration of the double-blind portion of this study.
If such a patient has recently completed a course of antineoplastic therapy, the 
last dose of that therapy should be at least 4 weeks prior to Randomization
(see Section 6.5).
ii.
Patients on standard of care systemic antineoplastic therapy or treatment without 
curative intent, (see Section 6.5).
4. Anorexia as defined by a score 
 in the Cancer-Related Cachexia Symptom 
Assessment-Appetite 7-day recall scale (see Appendix 7) at Screening and
Randomization.
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5. Serum GDF-15 levels of 
 (as measured using the Investigational Use Only 
Roche Elecsys GDF 15 assay)30 at Screening.
6. Participants who are assessed by the investigator to be able to participate for the 
double-blind treatment period of 6 weeks. In the investigator’s judgement, the 
participant should be anticipated to be able to comply with all scheduled visits, 
treatment plan, laboratory tests, lifestyle considerations, and other study procedures 
during the double-blind portion of the study. 
In cases where the investigator is not the treating oncologist, the oncologist’s 
assessment of the potential participant’s suitability for inclusion must also be 
considered. 
Informed Consent:
7. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
8. Willing to comply with all scheduled visits, treatment plan, laboratory tests, 
contraception guidelines, and other study procedures for at least the 6-week 
double-blind treatment period.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Receiving tube feedings or parenteral nutrition (either total or partial) at the time of 
Screening or Randomization.
2. Current active reversible causes of decreased food intake, as determined by the 
Investigator.  These causes may include, but are not limited to:
•
Mechanical obstructions making patient unable to eat;
•
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 3 or 4 oral mucositis.
3. Unresolved acute effects of any prior therapy, or uncontrolled symptoms (eg, pain, 
diarrhea) at Randomization that in the judgement of the PI makes the participant 
unsuitable for the study. For example, uncontrolled pain may be indicated by a recent 
(eg, within past 15 days) change in opioid treatment. 
4. Current, severe gastrointestinal disease (including esophagitis, gastritis, 
malabsorption) at Randomization.
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5. History of gastrectomy.
6. Persistent symptoms due to ascites at randomization, unresponsive to clinically 
indicated interventions.
7. 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 Screening.  
Note that if radiation therapy becomes necessary for treatment of brain metastases or 
palliative treatment after Randomization, this will not be a reason for discontinuation.
8. Participants with active, uncontrolled bacterial, fungal, or viral infection, including 
but not limited to HBV, HCV, HIV or participants with known AIDS-related illness. 
9. Undergoing major surgery (central venous access placement and tumor biopsies are 
not considered major surgery) within 4 weeks prior to first dose of investigational 
product.  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. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
Part A Double-Blind treatment period only:
11. Initiation of new systemic antineoplastic therapy (eg, chemotherapy, immunotherapy) 
within the 4 weeks prior to the first dose of investigational product or planning to 
initiate antineoplastic therapy during the 6-week double-blind portion of the study. 
12. Initiation of new treatment prescribed or self-administered and known to have an 
impact on anorexia, weight loss or cachexia, including but not limited to mirtazapine, 
olanzapine, cannabinoids, within the 4 weeks prior to the first dose of investigational 
product or during the 6-week double-blind portion of the study; stable (ie, no 
significant change to dosage or frequency of administration in prior 4 weeks) therapy 
is permissible. See Section 6.5 Concomitant Therapy for details. 


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13. Radiation therapy other than localized palliative treatment (eg, pain management for 
bone metastases) within the 3 weeks prior to the first dose of investigational product 
or during the 6-week double-blind portion of the study.
14. Initiation of new treatment with systemic glucocorticoids within the 4 weeks prior to 
the first dose of investigational product or during the 6-week double-blind portion of 
the study; stable (ie, no significant change to dosage or frequency of administration in 
prior 4 weeks) steroid therapy eg, dexamethasone as part of pre-medication or daily 
oral prednisone is permissible. See Section 6.5 Concomitant Therapy for details. 
15. Initiation of megestrol acetate within the 2 weeks prior to the first dose of 
investigational product or during the 6-week double-blind portion of the study; stable 
(ie, no significant change to dosage or frequency of administration in prior 2 weeks) 
therapy is permissible. See Section 6.5 Concomitant Therapy for details.
Part B Open-Label treatment period: there are no restrictions on initiation of new therapy 
or changes to existing therapy during open-label treatment.
Prior/Concurrent Clinical Study Experience:
16. Received previous treatment with at least one dose of PF-06946860.
17. 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).
Diagnostic Assessments:
18. Positive urine drug screen for illicit drugs at Screening, with the exception of 
cannabinoids per Prior/Concomitant Therapy criteria number 12 above. Results may 
be confirmed by a single repeat, if necessary. In addition, drugs which have been 
medically prescribed and reported to the investigator at the Screening visit may be 
permitted, if judged appropriate by the investigator and permitted by the Sponsor. 
Prescribed pain medications (eg, opioids, morphine, hydrocodone) do not need be 
cleared with the Sponsor.  
19. Inadequate liver function at Screening as evidenced by any 1 of the following, which 
may be confirmed by a single repeat, if necessary: 

Total serum bilirubin >1.5 x upper limit of normal (ULN) unless the participant 
has documented Gilbert syndrome;

Aspartate (AST) and/or Alanine aminotransferase (ALT) >3 x ULN; >5.0 x ULN 
if there is liver involvement by the tumor; 


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
Alkaline phosphatase >3 x ULN. Inclusion of participants with alkaline 
phosphatase >3 x ULN may be acceptable if they are deemed medically stable 
and fit for the study by both investigator and sponsor medically qualified 
personnel. 
20. Inadequate renal function at Screening, including creatinine >2 mg/dL, or calculated 
Glomerular Filtration Rate (GFR) <30 mL/minute/1.73 m2 as calculated by the 
modification of diet in renal disease (MDRD) equation.31 Result may be confirmed 
by a single repeat, if necessary.
Other Exclusions:
21. Woman who is pregnant or breast-feeding.
22. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
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 SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. This includes participants 
who consent and do not meet eligibility criteria as well as those who are not randomized for 
administrative reasons (eg, screening window has expired, delays in IP shipping, cohort 
filled). A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the CONSORT publishing requirements and 
to respond to queries from regulatory authorities.  Minimal information includes 
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Individuals who qualify for this study but are not randomized for administrative reasons, may 
be re-screened. Individuals who do not meet the criteria for participation in this study may 
be re-screened once if, in the judgement of the investigator, the reason for initial ineligibility
is considered to be resolved, or there has been a change in eligibility status.  
For individuals who are re-screening for any reason, all screening procedures must be 
repeated and the participant assigned a new SSID.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration 
Not Applicable.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-06946860.
6.1. Study Intervention(s) Administered
Intervention Name
PF-06946860
Placebo
ARM Name
PF-06946860 Double-Blind Treatment 
followed by Open-Label Treatment
Placebo Double-Blind Treatment followed by 
Open-Label Treatment
Type
Biologic
Placebo
Dose Formulation
Solution for injection
Solution for injection
Unit Dose Strength(s)
 
Placebo
Dosage Level(s)
Placebo Q3Weeks
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
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6.1.1. Administration
Each dose of investigational product must be administered by appropriately qualified health 
care personnel (whether administered at home or in a clinic setting).  During the double-blind 
portion (Part A) of the study, investigational product will be administered at a dose of 
 or placebo Q3W SC for a total of 2 doses (6 weeks). If the participant continues to 
the optional OLT period (Part B), up to 7 additional doses of PF-06946860 
 
will be administered starting at the Week 6 visit (for participants entering the OLT period). 
Each dose is comprised of two 1 mL SC injections which are to be administered 
consecutively.  For participants who are receiving standard of care systemic antineoplastic 
treatment, premedication is permitted consistent with institutional guidelines, and, unless 
specifically noted in Section 6.5, may include an antihistamine, anti-inflammatory agent, or 
pain reliever.  In such cases, PF-06946860 is to be administered first, followed by any
required premedications. If the standard of care systemic antineoplastic treatment is to be 
administered on the same day of dosing with study drug (PF-06946860 or placebo in Part A 
or PF-06946860 in Part B), where feasible, the study drug will be administered prior to the 
standard of care antineoplastic treatment.   
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. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff or designated healthcare personnel 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 temperatures since 
previously documented for all site storage locations upon return to business.
3. 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.  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.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
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6. 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), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All study intervention that is 
administered at home by the designated healthcare personnel, both used and unused, 
must be returned to the investigator by the designated healthcare personnel.  Returned 
study intervention must not be redispensed to the participants.
7. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
Investigational Product, PF-06946860 
and placebo will be prepared by 
qualified personnel according to the IP manual.  The study intervention will be administered 
in a blinded fashion to the participants in Part A and open-label in Part B.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(IWR).  The site personnel (study coordinator or specified designee) will be required to enter 
or select information including, but not limited to, the user’s ID and password, the protocol 
number, and the participant number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and DU or container number when study 
intervention is being supplied via the IRT system.  The IRT system will provide a 
confirmation report containing the participant number, randomization number, and DU or 
container number assigned.  The confirmation report must be stored in the site’s files. 
Study intervention will be administered at the study visits 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.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
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6.3.2. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and CRF.
Part A of this study is participant- and Investigator-blinded and Sponsor-open.  Part B of the 
study will be open to the participant, Investigator, and Sponsor or Sponsor-designate 
personnel responsible for study monitoring activities (including all site monitoring activities).
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
The study intervention will be administered to participants directly by an appropriately 
qualified individual.  The date and time of each dose administered will be recorded in the 
source documents and recorded in the CRF.  The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by designated healthcare
personnel if the study intervention is administered at the participant’s home or a member of 
the study site staff other than the person administering the study intervention if the study 
intervention is administered at the clinic. 
Deviation(s) from the protocol-specified dosage regimen should be recorded in the CRF.
A record of the number of the study drug (Investigational Product, PF-06946860 
 or placebo vials) administered to each participant must be maintained and 
reconciled with study intervention and compliance records.  Intervention start and stop dates, 
including dates for intervention delays and/or missed doses, will also be recorded in the CRF.
6.5. Concomitant Therapy
The date and time of administration of any background and/or concomitant therapies as well 
as the name and dosage regimen must be recorded.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
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Prohibited in the 4 weeks prior to first dose of IP and during Part A

Initiation of new systemic antineoplastic therapy (eg, chemotherapy, 
immunotherapy) within the 4 weeks prior to the first dose of investigational product
or planning to initiate antineoplastic therapy during the 6-week double-blind portion 
of the study. 

If a participant has recently completed a course of antineoplastic therapy, the last 
dose of that therapy should be at least 4 weeks prior to Randomization.

Initiation of new treatment prescribed or self-administered and known to have an 
impact on anorexia, weight loss or cachexia, including but not limited to 
mirtazapine, olanzapine, cannabinoids, within the 4 weeks prior to the first dose of 
investigational product or during the 6-week double-blind portion of the study; stable 
(ie, no significant change to dosage or frequency of administration in prior 4 weeks) 
therapy is permissible. 

Initiation of new treatment with systemic glucocorticoids is prohibited within the 
4 weeks prior to the first dose of investigational product or during the 6-week 
double-blind portion of the study; stable (ie, no significant change to dosage or 
frequency of administration in prior 4 weeks) steroid therapy eg, dexamethasone as 
part of pre-medication or daily oral prednisone is permissible. 
While use of glucocorticoids for antiemetic prophylaxis as part of standard of care 
treatment protocols is permitted under conditions described here, every effort should 
be made not to administer such medications within the 7 days prior to the Day 1 and 
Week 4 PRO assessments (see Section 8.1.1).
Inhaled or topical steroid use is not restricted.
Prohibited in the 3 weeks prior to first dose of IP and during Part A

Radiation therapy other than localized palliative care (eg, pain management for 
bone metastases) within the 3 weeks prior to the first dose of investigational product 
or during the 6-week double-blind portion of the study.
Prohibited in the 2 weeks prior to first dose of IP, and during Part A

Initiation of megestrol acetate within the 2 weeks prior to the first dose of 
investigational product or during the 6-week double-blind portion of the study; stable 
(ie, no significant change to dosage or frequency of administration in prior 2 weeks) 
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Open-Label treatment period:

There are no restrictions on initiation of new therapy, or changes to existing therapy,
during the open-label treatment part of the study.
6.5.1. Rescue Medicine
There is no specific rescue therapy to reverse AEs observed with PF-06946860. There is no 
approved medication to treat anorexia associated with cancer-cachexia. Standard medical 
supportive care must be provided to manage any AEs or changes to underlying symptoms. 
Note that, following the 6-week double blind portion of the study, there are no 
protocol-specified restrictions on concomitant medications (see Section 6.5).
6.6. Dose Modification
There is no dose modification of PF-06946860 anticipated for a given participant in this 
study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants following Part B 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 study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

Progression of underlying disease such that the investigator no longer considers 
participation appropriate, or of potential benefit to the participant.

Hospitalization that in the opinion of the investigator would render continued 
participation unfeasible.
Note that discontinuation of investigational product does not represent withdrawal from the 
study. If investigational product is permanently discontinued, the participant will remain in 
the study for follow up.  See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
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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.
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 7.2.1) 
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.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with 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 study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
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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/attend a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment.  The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether 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 
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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it 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. For 
selected procedures which are not feasible due to progression or complications of underlying 
disease, as indicated in the SoA, non-completion will not be considered a protocol deviation 
as long as the participant’s safety was preserved. In all cases, collection of safety data should 
be prioritized.
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 
220 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
8.1.1. Patient Reported Outcomes
All patient-reported outcome (PRO) assessments are completed electronically by study 
participants at home, or at the clinic, following a schedule of assessments as per the SoA.  
Every effort should be made to have the study participant complete all patient-reported 
outcome assessments before any other clinical assessments that take place during a study 
visit.  
The PRO/eCOA Training Manual will be provided separately.
8.1.1.1. Cancer-Related Cachexia Symptom Assessment – Appetite
The Cancer-Related Cachexia Symptom Assessment-Appetite (Appendix 7) is a self-reported 
questionnaire that measures the severity of anorexia.  It was developed based on qualitative 
research with patients as well as review of literature and other existing relevant measures.  
The measure consists of 1 question that asks study participants to rate their appetite over the 
past 7 days from 0-“no appetite” to 10-“very good appetite”.


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8.1.1.2. Cancer-Related Cachexia Symptom Assessment – Fatigue
The Cancer-Related Cachexia Symptom Assessment-Fatigue (Appendix 8) is a self-reported 
questionnaire that measures the severity of fatigue.  It was developed based on qualitative
research with patients as well as review of literature and other existing relevant measures.  
The measure consists of 1 question that asks study participants to rate their fatigue over the 
past 7 days from 0-“no fatigue” to 10-“worst possible fatigue”.
8.1.1.3. PROMIS Pain 1a
While not considered an efficacy endpoint, the severity of pain may influence a participant’s 
level of appetite.  The PROMIS Pain 1a (Appendix 9) is a self-reported measure that assesses 
the intensity of the participant’s pain in the past 7 days from 0-“no pain” to 10-“worst 
imaginable pain”. These data may be used as part of exploratory analyses.
8.1.1.4. Patient Global Impression of Change (PGI-C)
The PGI-C (Appendix 10) is a measure consisting of 2 questions that asks study participants 
to rate the overall change in their symptoms of appetite and fatigue since they started the 
study on a 7 point verbal rating scales that ranges from “Much better” to “Much worse”.
8.1.1.5. Qualitative Phone Interviews
Qualitative interviews will be conducted with the participant by telephone at times indicated 
in the SoA. Additionally, where a caregiver is available and willing to participate, similar 
qualitative phone interviews may be conducted with a caregiver, as indicated in the SoA.
Note that both the participant and their caregiver must provide consent (Appendix 1) for the
caregiver to participate in the phone interviews. 
Interviews will be conducted by trained moderators and are anticipated to be approximately 
30 minutes in duration. Using the transcripts and interviewer field notes, dominant trends 
will be identified in each interview and compared across all the interviews to describe the 
participant/caregiver experience with a focus on the themes or patterns in the way the 
treatment experience is described, and the importance of any improvements reported. 
Following the analysis, a comprehensive summary report that fully describes the study 
objectives, methods, participants and results of the qualitative interviews will be prepared
and will not be reported in the CSR.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
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 


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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.
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 be conducted at Screening and will include, at a minimum, 
assessments of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph 
nodes, and gastrointestinal, musculoskeletal, and neurological systems. Height will also be 
measured and recorded at Screening only.
Symptom-directed assessments may be carried out by acceptably trained HCP (eg, RN at
Home-HCP visits), if necessary. 
8.2.2. 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. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or 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.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.3. 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.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced prior the participant’s receiving the study intervention.  Pregnancy tests will also 


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be done whenever 1 menstrual cycle is missed during the active treatment period (or when 
potential pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may 
also be repeated if requested by IRBs/ECs or if required by local regulations.  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 the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. 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 study intervention), through and including a 
minimum of up to the time of the final planned follow-up visit, after the last administration 
of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.


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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 the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and 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 Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
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.
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. 


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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, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention 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
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by eg, skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by eg, skin contact then exposes his female partner prior to or around 
the time of conception.


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The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 
5 terminal half-lives after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 


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Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An 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, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  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.


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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
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 study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention 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 study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
Based on preliminary population PK/PD simulation, doses greater than approximately 
 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 2.2.1.3).  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 participant’s home by a trained healthcare provider, and the allowed visit window, an 
overdose will be defined as more than 2 doses of PF-06946860
 administered in a 
period of 3 weeks.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
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. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain blood samples for PK, PD, and/or immunogenicity analyses within 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).
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.
CCI
CCI


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8.5. Pharmacokinetics 
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 date and time (24-hour 
clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  On dosing 
days, predose PK sample will be collected prior to IP administration. Collection of samples 
within the protocol-allowed visit window (±1, ±3 or +7 days, as defined in SoA) will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF.
Samples will be used to evaluate the PK of PF-06946860. Samples collected for analyses of 
PF-06946860 concentrations may also be used to evaluate safety or efficacy aspects related 
to concerns arising during or after the study, and/or evaluation of bioanalytical methods, or 
for other internal exploratory purposes.
Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of serum 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.
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
8.6. Pharmacodynamics
8.6.1. GDF-15
Blood samples of approximately 6 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of serum concentrations of total 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 
date and time (24-hour clock time) of each sample will be recorded.


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The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  On dosing 
days, predose GDF-15 sample will be collected prior to IP administration. Collection of
samples within the protocol-allowed visit window (±1, ±3 or +7 days, as defined in SoA) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF.
Samples collected for PD analyses may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, and/or evaluation of bioanalytical 
methods, or for other internal exploratory purposes.
At Screening, serum GDF-15 concentrations will be measured using the IUO Roche Elecsys 
GDF-15 assay, which will be validated in a CLIA accredited central laboratory.  Post 
Screening, serum samples will be analyzed for total GDF-15 and, if feasible, unbound 
GDF-15, using validated analytical methods in compliance with applicable SOPs. In 
addition, screening samples may also be analyzed in these methods for exploratory purposes.
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
GDF-15 concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
8.6.2. Body Weight
At Screening, body weight will be recorded using a calibrated scale at the investigator site. 
Any scale used during the study must report weight in either pounds (lb) or kilograms (kg), 
and be accurate 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.
At the Randomization visit, an electronic scale will be provided to the participant for their 
use (at home) for the remainder of the study. Where possible, the same scale should be used 
for all body weight measurements from the Randomization visit onward. 
Weight measurements should be taken under the following conditions, where feasible:

After void of urine;

After removal of shoes, socks, bulky layers of clothing and jackets so that only light 
clothing remains; 


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
While remaining still during the measurement.
During each weight measurement from Randomization onward, and using electronic scale 
provided to the participant, body composition data (including total body water, fat mass and 
fat-free mass, if possible) will be captured via bioelectrical impedance analysis (BIA), as 
feasible.  
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 2-mL blood sample optimized for DNA isolation Prep D1.5 will be collected as local 
regulations and IRBs/ECs allow.
Banked Biospecimens may be used for research related to the study intervention(s) and 
anorexia/cachexia.  Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the banked 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 (described in 
Section 8.6).
8.8.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study.
8.8.2. Specified Protein Research 
Specified protein research is not included in this study.
8.8.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.9. Immunogenicity Assessments
Blood samples of approximately 6 mL, to provide a minimum of 2 mL serum, will be 
collected for determination of ADA and NAb as specified in the SoA.  Instructions for the 
collection and handling of biological samples will be provided in the laboratory manual or by 
the sponsor.  The actual date and time (24-hour clock time) of each sample will be recorded.


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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 bioanalytical methods, or for 
other internal exploratory purposes.
Genetic analyses will not be performed on these serum samples unless consent for this was 
included in the informed consent.  Participant confidentiality will be maintained.
Samples 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.
Immunogenicity information that may unblind the study will not be reported to investigator 
sites or blinded personnel until the study has been unblinded.
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 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
9.1.1. Estimands
Estimand related to the appetite primary objective: 
Estimand 1 (similar to “hypothetical”) is intended to provide a population level estimate of 
the treatment effect on the change from baseline Appetite score for PF-06946860 compared 
to placebo in all evaluable participants under the scenario of no discontinuation of study 
intervention and without the potential confounding effects of prohibited medications, 
regardless of the participants’ compliance with dosing (ie, using the Censored analysis set).

Population: Patients with advanced cancer, anorexia and elevated circulating GDF-15 
levels.


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
Variable: Change from baseline for the patient reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment-Appetite score at Week 4.

Intercurrent Events: 
a.
Discontinuation of study intervention - Data collected after a participant has 
discontinued study intervention will be censored and treated as missing data.
b. Prohibited medications - Data collected after a participant has received prohibited 
medications, that would modulate the primary endpoint, will be censored and 
treated as missing data.  The list of concomitant medications will be reviewed 
prior to database lock to determine which would be classed as “prohibited” for 
this estimand.
c.
Inadequate compliance - Data collected after a participant has missed a dose will 
be censored and treated as missing data.
Missing data due to censoring, study withdrawal or other reasons, are assumed to 
be missing at random.

Population level summary: Difference in mean change from baseline for the patient 
reported 7-day recall Cancer-Related Cachexia Symptom Assessment-Appetite score
at Week 4 between PF-06946860 and placebo.
This estimand will similarly be applied to the appetite secondary objective (ie, change from 
baseline at Weeks 1, 2, 3, 5 and 6).
Alternative estimands for the primary objective may be used in order to examine the 
robustness of the results and will be detailed in the SAP.
Estimand related to the fatigue secondary objective: 
Estimand 2 will be similar to Estimand 1, except for the following: 

Variable: Change from baseline for the patient reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment-Fatigue score at Weeks 1, 2, 3, 4, 5 and 6.

Population level summary: Difference in mean change from baseline for the patient 
reported 7-day recall Cancer-Related Cachexia Symptom Assessment-Fatigue score 
at Week 4 between PF-06946860 and placebo.
Estimands related to the safety and tolerability secondary objective: 
There are no defined estimands for the incidence of treatment emergent adverse events and 
laboratory abnormalities, and these endpoints will be analyzed using Pfizer data standards as 
applicable.


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Estimands related to tertiary/exploratory objectives: 
Tertiary/exploratory endpoints may be analyzed using similar estimands or analyzed in a 
descriptive manner without reference to an estimand.  Other supporting estimands may be 
used for some of the primary and secondary endpoints as a means to examine the robustness 
of results, compare to available literature and/or be used for future study planning as needed.  
Details of these estimands and analyses will be presented in the SAP.
9.2. Sample Size Determination
A sufficient number of participants will be screened to achieve approximately 40 participants 
(approximately 27 participants in the PF-06946860 200 mg Q3W arm and 13 participants in 
the placebo arm) randomly assigned to study intervention in approximately a 2:1 ratio.  This 
is expected to ensure completion of Part A of the study of approximately 30 evaluable 
participants (approximately 20 PF-06946860: 10 placebo), assuming a discontinuation rate of 
25%.  There is no required sample size for Part B of the study.
The study sample size has been chosen to provide sufficient data for an initial assessment of 
efficacy in the population for facilitating internal decision making and may be used for future 
study planning.  Completion of 30 participants, with a 2:1 ratio, gives acceptable Operating 
Characteristics in that: 

The probability of achieving statistical significance (at the 5% significance level, 
using a 1-sided t-test) for a true effect of 4 versus placebo for the patient reported 
7-day recall Cancer-Related Cachexia Symptom Assessment-Appetite score (ranging 
0-10) at 4 weeks is approximately 80%.

An observed effect of 2.7 versus placebo for the patient reported 7-day recall 
Cancer-Related Cachexia Symptom Assessment-Appetite score at 4 weeks should 
achieve statistical significance (at the 5% significance level, using a 1-sided test).
A conservative estimate of the between-subject standard deviation for the change from 
baseline in the patient reported 7-day recall Cancer-Related Cachexia Symptom 
Assessment-Appetite score of 4.2 has been used.  This estimate was based on the observed 
variability of a similar appetite scale in a double-blind controlled clinical trial assessing the 
effect of megestrol acetate on appetite in patients with far-advanced cancer.32
Evaluable participants are defined as in Section 9.3. 
Participants who withdraw from the study will not be replaced.


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9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"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 study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the randomized study 
intervention.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
Defined Analysis Set
Description
Censored
For participants who discontinue study intervention, receive 
prohibited medication and/or miss a dose, all observations 
post-discontinuation, post-medication or post-missed dose will 
be censored and treated as missing data.
PK
All participants randomly assigned to study intervention and 
who take at least 1 dose of PF-06946860 and in whom at least 
1 PK concentration value is reported.
PD
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 PD (GDF-15) concentration value is reported.
Immunogenicity
All participants randomly assigned to study intervention and 
who take at least 1 dose of PF-06946860 and in whom at least 
1 ADA result is reported.


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9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.  
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.4.1. General Considerations
For objectives relating to Part A of the study, each treatment arm (PF-06946860 or placebo) 
will be reported separately through the 6-week double-blind treatment period only (including 
follow-up for any participants not continuing onto Part B of the study).
9.4.1.1. Analyses for Continuous Endpoints 
The mixed effects repeated measures (MMRM) model will include participant as a random 
term, and baseline, time (as a factor), baseline-by-time interaction, treatment and 
treatment-by-time interaction as fixed terms in the model.  An unstructured covariance 
matrix will be fitted to the repeated times within subject (other covariance matrices will be 
considered if necessary), and the Kenward-Roger approximation will be used for estimating 
degrees of freedom.  Additional terms may be fitted in the model (eg, cancer type, 
PROMIS-Pain 1a change from baseline score), as appropriate.
9.4.2. Primary Endpoint(s)
Change from baseline for patient reported 7-day recall Cancer-Related Cachexia Symptom 
Assessment–Appetite score will be analyzed using Estimand 1 and an MMRM model (as per 
Section 9.4.1.1). The MMRM model will be fitted to the change from baseline at all 
post-treatment timepoints up to Week 6 using the Censored analysis set. Least squares 
means (and 90% CIs) and mean differences versus placebo (and 90% CIs), at Week 4, will be 
provided.  No adjustments will be made for multiplicity.


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9.4.3. Secondary Endpoint(s)
Endpoint
Statistical Analysis Methods
Change from baseline for patient reported 
7-day recall Cancer-Related Cachexia 
Symptom Assessment-Appetite score, at 
Weeks 1, 2, 3, 5 and 6. 
Results related to this endpoint will be 
obtained from the Primary Analysis model
above.  
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs), at 
each week, will be provided.  No adjustments 
will be made for multiplicity.
Change from baseline for patient reported 
7-day recall Cancer-Related Cachexia 
Symptom Assessment-Fatigue score, at 
Weeks 1, 2, 3, 4, 5 and 6. 
Change from baseline for patient reported 
7-day recall Cancer-Related Cachexia 
Symptom Assessment–Fatigue score will be 
analyzed using Estimand 2 and an MMRM 
model (as per Section 9.4.1.1).  The MMRM 
model will be fitted to the change from 
baseline at all post-treatment timepoints up to 
Week 6 using the Censored analysis set. 
Least squares means (and 90% CIs) and mean 
differences versus placebo (and 90% CIs), at 
each weeks, will be provided.  No adjustments 
will be made for multiplicity.
Incidence of adverse events and 
laboratory abnormalities, in Part A of the 
study.
All safety analyses will be performed on the 
safety population. The safety data will be 
summarized in accordance with Pfizer Data 
Standards. All safety data will be summarized 
descriptively through appropriate data 
tabulation, descriptive statistics, categorical 
summaries, and graphical presentations, as 
appropriate. 
9.4.4. Tertiary/Exploratory Endpoint(s)
Details on the analyses of Tertiary/Exploratory endpoints will be described in the SAP.
9.4.5. Other Analyses
Selected data collected at Screening may be reported. These data include demographic data, 
prior and concomitant medications, GDF-15 levels, height, weight and appetite score. In 
addition, a subset of medical history data will be reported; this will include primary cancer 
diagnosis and staging at time of screening, date of initial diagnosis, body weight history 


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(eg, weight 6 months ago or ‘usual’ weight prior to current cancer diagnosis), where feasible.  
Other data collected at screening that are used for inclusion/exclusion criteria, such as 
laboratory data, will be considered source data, and will not be required to be reported, unless 
otherwise noted.
As permitted by data, and determined by the sponsor, the PK/PD relationship between serum 
PF-06946860 concentration and the effect on primary, secondary and/or tertiary endpoints 
may be explored using a population PK/PD approach. The population PK/PD analysis, if 
conducted, will be reported in a separate report. 
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
9.5. Interim Analyses
As this is a sponsor-open 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 efficacy and/or safety. Interim 
analysis results may be used for internal business decisions regarding future study planning, 
conducting a sample size re-estimation, adapting the study, or stopping for futility.  If a 
formal interim analysis is conducted, details of the timing, objectives, decision criteria and 
analyses will be documented in an internal charter or in the final SAP.
Following completion of Part A, the data will be analyzed, and a report written.  The results 
of Part A will not be used to make any changes to the design or conduct of Part B.  
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use an internal review committee (IRC) or a data monitoring committee 
(DMC).


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor 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 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 study 
intervention, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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10.1.2. Financial Disclosure
Investigators and sub investigators 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.  The participant or his/her legally authorized representative should be given sufficient 
time and opportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.


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Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional
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 specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional 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 will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. 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 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 SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
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 corresponding study results are
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 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.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make 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.


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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 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. 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 eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the SMP.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;


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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. 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 the 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).
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
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 issues.
Table 2.
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 and creatinine
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
Microscopya

Pregnancy test (β-hCG)c
At screening only:

FSHb

Urine drug screening

Hepatitis B surface antigen

Hepatitis C antibody

HIV
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC.  Serum or urine -hCG for female participants of childbearing potential.
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.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

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.


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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 
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 


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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.
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 
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 


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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.
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 CT 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 study intervention 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 study 
intervention 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 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.


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
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 
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.


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
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 IB and/or product 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 study intervention caused the 
event, then the event will be handled as “related to study intervention” 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 providers.

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.


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
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
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 
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 reproductive safety risk of the 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), preferably with a low user dependency, 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 reproductive 
safety risk of the study intervention(s).  If a highly effective method that is user 
dependent is chosen, a second effective method of contraception, as described below, 
must also be used.  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, 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 reproductive safety risk of the 
study intervention(s) In addition, a second effective method of contraception, as 
described below, must be used.  The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention.


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The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
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 no menses for 12 months without an 
alternative medical cause. In addition, a

high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 

Female 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
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
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.
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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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to 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 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 will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their 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 DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede 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, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
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 samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: Cancer-Related Cachexia Symptom Assessment – Appetite


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10.8. Appendix 8: Cancer-Related Cachexia Symptom Assessment – Fatigue


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10.9. Appendix 9: PROMIS Pain 1a


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10.10. Appendix 10: Patient Global Impression of Change


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10.11. Appendix 11 Study Conduct
10.11.1. Telehealth Visits
Telehealth visits may be conducted during this study and used to assess participant safety and 
collect data points. Telehealth includes the exchange of healthcare information and services 
via telecommunication technologies (eg, audio, video, video-conferencing software) 
remotely, allowing the participant and the investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring. Assessments to 
be performed during a telehealth visit are outlined in the SoA, and may include:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact.  Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.11.2. Nutritional Advice Consult
If operationally feasible, a nutritional consult with a registered dietician via telehealth with a 
central vendor will be scheduled by the participant within the first 7 days after 
randomization.
10.11.3. Home Health Visits
A home health care service may 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. Additional 
details will be provided separately. 


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10.12. Appendix 12 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). 
10.12.1. 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 test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per protocol language regarding eligibility exclusions due to infection. 
10.12.2. 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 event (SAE) and appropriate medical intervention provided. The 
participant should be discontinued from the study. Study treatment should continue unless 
the investigator/treating physician is concerned about the safety of the participant, in which 
case temporary or permanent discontinuation may be required. It is recommended that the 
investigator discuss permanent discontinuation of study intervention with the study medical 
monitor. 


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10.13. Appendix 13: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Term
Abs
absolute
ADA
antidrug antibodies
ADCC
antibody dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse events of special interest
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 concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from 0 to time of last 
measurable concentration
AUC
area under the concentration-time curve from 0 to time t
AV
atrioventricular
BBS
Biospecimen Banking System
-hCG
Beta-human chorionic gonadotropin
BIA
bioelectrical impedance analysis
BUN
blood urea nitrogen
Cav or Cavg
average concentration
CDC
complement-dependent cytotoxicity
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CL/F
apparent clearance of drug from eg, plasma
CLIA
clinical laboratory improvement amendments
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events


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Term
CYP
cytochrome P450      
DC
discontinuation
DCT
data collection tool
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
EDP
exposure during pregnancy
EMA
European Medicines Agency
Emax
maximal effect
EORTC
European Organisation for Research and Treatment of Cancer
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
Fc
fragment crystallizable gamma
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
family receptor alpha-like
GGT
gamma-glutamyl transferase
HBV
hepatitis B virus
HCP
Health Care Professional
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ID
identification
IgG1
immunoglobulin G1
IgG1κ
immunoglobulin gamma-1 with kappa light chains
IMP
investigational medicinal product
IND
investigational new drug


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Term
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUO
investigational use only
IWR
interactive Web-based response
LBBB
left bundle branch block
LFT
liver function test
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
MMRM
mixed-effect model repeated measure
MRI
magnetic resonance imaging
msec
millisecond
N/A
not applicable
NAb
neutralizing antibodies
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NSCLC
non-small cell lung cancer
OL
open-label
OLT
open-label treatment
PD
pharmacodynamic(s)
PE
physical examination
PGI-C
patient global impression of change
PI
principal investigator
PK
pharmacokinetic(s)
PRO
patient reported outcome
PROMIS
Patient-Reported Outcomes Measurement Information System
PT
prothrombin time
PVC
premature ventricular contraction/complex
Q3W
3 weeks apart
Qual
qualitative
RBC
red blood cell
RN
registered nurse
RNA
ribonucleic acid


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Term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SMP
study monitoring plan
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SSID
single subject identifier
SToD
study team on demand
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal phase half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TGF
transforming growth factor beta
Tmax
time to reach Cmax
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman/women of childbearing potential


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25.
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.
26.
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.
27.
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.
28.
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.
29.
Von Haeling S, Anker MS, Anker SD. Prevalence and clinical impact of cachexia in 
chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J Cachexia 
Sarcopenia Muscle. 2016 Dec; 7(5): 507–509. doi: 10.1002/jcsm.12167. 
30.
Elecsys® GDF-15 package insert (2017). Documentation Roche Diagnostics, Bâle.
31.
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(4): 247-54.
32.
De Conno F, Martini C, Zecca E, et al. Megestrol acetate for anorexia in patients with 
far-advanced cancer: a double-blind controlled clinical trial. Eur J Cancer. 1998 Oct;
34(11):1705-9.

SAP_001.pdf: 
Protocol C3651010 (PF-06946860) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3651010
A 6-WEEK, RANDOMIZED, DOUBLE BLIND, SPONSOR-OPEN STUDY TO 
ASSESS THE EFFECT OF REPEATED SUBCUTANEOUS ADMINISTRATION OF
PF-06946860 ON APPETITE IN PARTICIPANTS WITH ADVANCED CANCER 
AND ANOREXIA, FOLLOWED BY AN 18-WEEK OPEN-LABEL TREATMENT 
PERIOD
Statistical Analysis Plan 
(SAP)
Version:
1  
Date:
13 Apr 2021
NOTE: Italicized text within this document has been taken verbatim from the Protocol.


Protocol C3651010 (PF-06946860) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Estimand(s).....................................................................................7
2.1.2. Secondary Estimand(s).................................................................................8
2.1.3. Additional Estimand(s).................................................................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................11
3.1. Primary Endpoint(s) ................................................................................................11
3.2. Secondary Endpoint(s) ............................................................................................11
3.3. Other Endpoint(s)....................................................................................................11
3.4. Baseline Variables...................................................................................................13
3.5. Safety Endpoints .....................................................................................................13
3.5.1. Adverse Events...........................................................................................13
3.5.2. Laboratory Data..........................................................................................13
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Hypotheses and Decision Rules ..............................................................................14
5.2. General Methods .....................................................................................................14
5.2.1. Summary Analyses for Continuous Endpoints...........................................15
5.2.2. Summary Analyses for Categorical Endpoints...........................................15
5.2.3. Mixed Models Repeated Measures (MMRM) Analysis.............................15
5.3. Methods to Manage Missing Data ..........................................................................15
6. ANALYSES AND SUMMARIES ......................................................................................16
6.1. Primary Endpoint(s) ................................................................................................16
6.1.1. Change from baseline for patient reported 7-day recall Cancer-
Related Cachexia Symptom Assessment–Appetite score, at Week 4..............16


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Page 3
6.1.1.1. Main Analysis ...........................................................................16
6.1.1.2. Sensitivity/Supplementary Analyses.........................................17
6.2. Secondary Endpoint(s) ............................................................................................17
6.2.1. Change from Baseline for patient reported 7-day recall Cancer-
Related Cachexia Symptom Assessment-Appetite Score, at Weeks 1, 2, 
3, 5 and 6..........................................................................................................17
6.2.2. Change from Baseline for patient reported 7-day recall Cancer-
Related Cachexia Symptom Assessment-Fatigue Score, at Weeks 1, 2, 
3, 4, 5 and 6......................................................................................................17
6.2.3. Incidence of Adverse Events and Laboratory Abnormalities, in Part 
A of the Study..................................................................................................17
6.3. Other Endpoint(s)....................................................................................................17
6.3.1. Change from baseline in body weight, at Weeks 3, 4 and 6.......................17
6.3.2. Change from baseline score for patient reported 7-day recall 
PROMIS-Pain 1a at Weeks 1, 2, 3, 4, 5 and 6.................................................17
6.3.3. PGI-C (appetite), at Weeks 4 and 6............................................................18
6.3.4. PGI-C (fatigue), at Weeks 4 and 6..............................................................18
6.3.5. Serum unbound and total concentrations of PF-06946860, on Day 1 
and Weeks 3, 4 and 6.......................................................................................18
6.3.6. Serum concentrations of total GDF-15; and if feasible, unbound 
GDF-15, on Day 1 and Weeks 3, 4 and 6 ........................................................18
6.3.7. Incidence of ADA and, if applicable, NAb,in Part A of the study.............19
6.4. Subset Analyses.......................................................................................................20
6.5. Baseline and Other Summaries and Analyses.........................................................20
6.5.1. Baseline Summaries....................................................................................20
6.5.2. Study Conduct and Participant Disposition................................................20
6.5.3. Concomitant Medications and Nondrug Treatments..................................20
6.5.4. Population PK.............................................................................................21
6.5.5. Banked Biospecimens.................................................................................21
6.5.6. Qualitative Phone Interviews......................................................................21
6.6. Safety Summaries and Analyses .............................................................................21
6.6.1. Adverse Events...........................................................................................21
6.6.2. Laboratory Data..........................................................................................21
7. INTERIM ANALYSES.......................................................................................................21


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7.1. Introduction .............................................................................................................21
7.2. Interim Analyses and Summaries............................................................................22
8. REFERENCES ....................................................................................................................22
9. APPENDICES .....................................................................................................................23
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
LIST OF FIGURES
Figure 1
Schema......................................................................................................10
APPENDICES
Appendix 1. Statistical Methodology Details..........................................................................24
Appendix 2. Definitions of Immunogenicity Terms................................................................25
Appendix 3. List of Abbreviations...........................................................................................26


Protocol C3651010 (PF-06946860) Statistical Analysis Plan
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Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
Version 1 / 
13APR2021
Original
18DEC2020
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Part A of Study C3651010 (including follow-up 
for Part A if a participant does not continue to Part B of the study).  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.  The 
methodology for summary and statistical analyses of the data collected in Part B of the study 
will be detailed in a supplemental SAP.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary

To evaluate the early effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for 
patient reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at week 4. 

Estimand 1 (similar to “hypothetical”) 
is intended to provide a population 
level estimate of the treatment effect on 
the change from baseline Appetite 
score for PF-06946860 compared to 
placebo in all evaluable participants 
under the scenario of no 
discontinuation of study intervention 
and without the potential confounding 
effects of prohibited medications, 
regardless of the participants’ 
compliance with dosing (i.e. using the 
Censored analysis set)
Secondary

To evaluate the effect of 
PF-06946860 compared to 
placebo on appetite in 
participants with anorexia and 
advanced cancer.

Change from baseline for 
patient reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment–Appetite 
score, at weeks 1, 2, 3, 5 and 
6. 
Estimand 1, as above


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Objectives
Endpoints
Estimands

To evaluate the effect of 
PF-06946860 compared to 
placebo on fatigue in 
participants with anorexia and 
advanced cancer.

Change from baseline for 
patient reported 7-day recall 
Cancer-Related Cachexia 
Symptom Assessment-Fatigue 
score, at weeks 1, 2, 3, 4, 5 
and 6. 

Estimand 2 (similar to “hypothetical”) 
is intended to provide a population 
level estimate of the treatment effect on 
the change from baseline Fatigue score 
for PF-06946860 compared to placebo 
in all evaluable participants under the 
scenario of no discontinuation of study 
intervention and without the potential 
confounding effects of prohibited 
medications, regardless of the 
participants’ compliance with dosing 
(i.e. using the Censored analysis set)

To characterize the safety and 
tolerability of repeated 
subcutaneous (SC)
administrations of PF-
06946860 compared to 
placebo in participants with 
anorexia and advanced 
cancer.

Incidence of adverse events 
(AE) and laboratory 
abnormalities, in Part A of the 
study.

There are no defined estimands for 
these endpoints and they will be 
analyzed using Pfizer data standards, 
as applicable.
Tertiary/Exploratory: 

To evaluate the effect of 
PF-06946860 compared to 
placebo on body weight in 
participants with anorexia and 
advanced cancer.

Change from baseline in body 
weight,at weeks 3, 4 and 6.

N/A

To explore the relationship 
between pain and 
appetite/fatigue in participants 
with anorexia and advanced 
cancer

Change from baseline score 
for patient reported 7-day 
recall PROMIS-Pain 1a, 
Cancer-Related Cachexia 
Symptom Assessment-Fatigue 
score and Cancer-Related 
Cachexia Symptom 
Assessment-Appetite score at 
Weeks 1, 2, 3, 4, 5 and 6.

N/A

To assess patient global 
impression of change (PGI-C) 
of appetite and fatigue in 
participants with anorexia and 
advanced cancer

PGI-C (appetite), at Weeks 4 
and 6.

PGI-C (fatigue), at Weeks 4 
and 6.

N/A

To characterize unbound and 
total pharmacokinetics (PK) of 
PF-06946860 administered in 
participants with anorexia and 
advanced cancer

Serum unbound and total 
concentrations of 
PF-06946860, on Day 1 and 
Weeks 3, 4 and 6.

N/A

To characterize the effect of
PF-06946860 administration
on circulating growth 
differentiation factor 15 
(GDF-15) concentrations in 

Serum concentrations of total 
GDF-15; and if feasible, 
unbound GDF-15, on Day 1 
and Weeks 3, 4 and 6.

N/A


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Objectives
Endpoints
Estimands
participants with anorexia and 
advanced cancer.

To assess the immunogenicity
of PF-06946860 administered 
in participants with anorexia 
and advanced cancer.

Incidence of antidrug 
antibodies (ADA) and, if
applicable, neutralizing 
antibodies (Nab), in part A of 
the study.

N/A
Additional tertiary/exploratory objectives will be evaluated using data from Part B of Study 
C3651010, as data permit.  These objectives are not addressed in this SAP but will be 
addressed in a supplemental SAP.
2.1.1. Primary Estimand(s)
Estimand related to the change from baseline for the patient reported 7-day recall Appetite
score (Part A): 
Estimand 1 (similar to “hypothetical”) is intended to provide a population level estimate of 
the treatment effect on the change from baseline Appetite score for PF-06946860 compared 
to placebo in all evaluable participants under the scenario of no discontinuation of study 
intervention and without the potential confounding effects of prohibited medications, 
regardless of the participants’ compliance with dosing (i.e. using the Censored analysis set).

Population: Patients with advanced cancer, anorexia and elevated circulating GDF-15 
levels.

Variable: Change from baseline for the patient reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment–Appetite score at Week 4.

Intercurrent Events: 
a) Discontinuation of study intervention – Data collected after a participant has 
discontinued study intervention will be censored and treated as missing data.
b) Prohibited medications – Data collected after a participant has received prohibited 
medications, that would modulate the primary endpoint, will be censored and treated 
as missing data.  The list of concomitant medications will be reviewed prior to 
database lock to determine which would be classed as “prohibited” for this estimand.
c) Inadequate compliance – Data collected after a participant has missed a dose will be 
censored and treated as missing data.
Missing data due to censoring, study withdrawal or other reasons, are assumed to be 
missing at random.

Population level summary:  Difference in mean change from baseline for the patient 
reported 7-day recall Cancer-Related Cachexia Symptom Assessment–Appetite score at 
Week 4 between PF-06946860 and placebo.
This estimand will similarly be applied to the change from baseline at Weeks 1, 2, 3, 5 and 6.


Protocol C3651010 (PF-06946860) Statistical Analysis Plan
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Page 8
2.1.2. Secondary Estimand(s)
Estimand related to the change from baseline for the patient reported 7-day recall Fatigue 
score (Part A): 
Estimand 2 will be similar to Estimand 1, except for the following: -

Variable: Change from baseline for the patient reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment–Fatigue score at Weeks 1, 2, 3, 4, 5 and 6.

Population level summary:  Difference in mean change from baseline for the patient 
reported 7-day recall Cancer-Related Cachexia Symptom Assessment–Fatigue score at 
Week 4 between PF-06946860 and placebo.
Estimands related to safety and tolerability: 
There are no defined estimands for the incidence of treatment emergent adverse events and 
laboratory abnormalities, and these endpoints will be analyzed using Pfizer data standards 
as applicable.
2.1.3. Additional Estimand(s)
Estimands related to tertiary/exploratory objectives: 
Tertiary/exploratory endpoints may be analyzed using similar estimands or analyzed in a 
descriptive manner without reference to an estimand.  Other supporting estimands may be 
used for some of the primary and secondary endpoints as a means to examine the robustness 
of results, compare to available literature and/or be used for future study planning as 
needed.  
Additional estimand related to the change from baseline for the patient reported 7-day recall 
Appetite score (Part A):
Estimand 3 (similar to “treatment policy”) may be used, dependant on the amount of 
censored data (based on a blinded review prior to database lock), to assess the robustness of 
the treatment effect on the primary endpoint.  It is intended to provide a population level 
estimate of the treatment effect on the change from baseline Appetite score for PF-06946860 
compared to placebo in all evaluable participants without regard to discontinuation of study 
intervention or administration of prohibited medications, regardless of the participants’ 
compliance with dosing (i.e. using the Complete analysis set).

Population: Patients with advanced cancer, anorexia and elevated circulating GDF-15 
levels.

Variable: Change from baseline for the patient reported 7-day recall Cancer-Related 
Cachexia Symptom Assessment–Appetite score at Week 4.

Intercurrent Events: 
a) Discontinuation of study intervention – All data collected, regardless of a 
participant’s discontinuation of study intervention, will be included in the analysis.
b) Prohibited medications – All data collected, regardless of a participant’s use of 
prohibited medications, will be included in the analysis.


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c) Inadequate compliance – All data collected, regardless of a participant’s compliance 
(i.e. missed doses), will be included in the analysis.

Population level summary:  Difference in mean change from baseline for the patient 
reported 7-day recall Cancer-Related Cachexia Symptom Assessment–Appetite score at 
Week 4 between PF-06946860 and placebo.
This estimand will similarly be applied to the change from baseline at Weeks 1, 2, 3, 5 and 6.
2.2. Study Design
This is a Phase 1b study in patients with advanced cancer, anorexia and elevated circulating 
GDF-15 levels with the primary purpose of assessing the effect of PF-06946860 
administration on appetite. 
The study will be conducted in 2 parts. The initial 6-week treatment period will be a 
randomized, double-blind, placebo-controlled, parallel group study. Participants who meet 
the entry criteria will be randomized to study drug (PF-06946860 or placebo).  The 6-week 
double-blind period will consist of a total of 2 SC doses, administered 3 weeks apart (Q3W).  
The 6-week double-blind treatment period will be followed by optional open-label treatment 
(OLT) with PF-06946860 of up to 18 weeks; the total duration of treatment would, therefore, 
be up to 24 weeks. 
Approximately 40 participants will be randomly assigned to investigational product such that
approximately 30 evaluable participants complete the 6-week double-blind portion of the
study.  The study will be randomized in approximately a 2:1 ratio (27 active: 13 placebo).
Potential participants will attend 2 clinic visits (Screening and Randomization) with the 
investigator. 
All study visits following Randomization may be conducted by a visiting Health Care 
Professional (HCP) at the patient’s home. Should the participant elect, at Randomization, to 
have all subsequent Part A study visits carried out at the investigator site rather than at 
home, this preference may be accommodated. 
During the week 4 TeleHealth consult, the investigator and participant will decide whether to 
continue with the optional open-label treatment period. Participants opting to continue to the 
OLT period will receive their first dose of open-label PF-06946860 at the week 6 visit, 
coinciding with the last visit of the double-blind portion of the study. 
Follow-up contact with all participants (whether participating in the 6-week double-blind 
only, or the OLT period) will be scheduled to occur at least 28 days and up to 35 days after 
the last administration of IP. For study Part A, this contact may be done via a phone call, 
telehealth or in the clinic. Additional follow-up may be conducted for safety evaluation, at 
the discretion of the investigator.


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Page 10
Figure 1
Schema
This SAP relates to the 6-week double blind (Part A) portion of the study.  
CCI
CCI


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Page 11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
For all endpoints, baseline is defined as the measurement taken on Day 1 (unless otherwise 
specified) or, if that is not available, the last-pre-dose measurement at screening will be used,
where appropriate.
For those participants continuing into Part B of the study, only data collected prior to dosing 
at Week 6 will be included in the summary and statistical analyses of Part A of the study.  
3.1. Primary Endpoint(s)
Change from baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment–Appetite score, at Week 4
The Cancer-Related Cachexia Symptom Assessment-Appetite is a self-reported questionnaire 
that measures the severity of anorexia.  It was developed based on qualitative research with 
patients as well as review of literature and other existing relevant measures.  The measure 
consists of 1 question that asks study participants to rate their appetite over the past 7 days 
from 0-“no appetite” to 10-“very good appetite”. The assessments will be completed 
electronically by study participants at home, or at the clinic.
3.2. Secondary Endpoint(s)
Change from baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment–Appetite score, at Weeks 1, 2, 3, 5 and 6 
See section 3.1.
Change from baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment-Fatigue score, at Weeks 1, 2, 3, 4, 5 and 6 
The Cancer-Related Cachexia Symptom Assessment-Fatigue is a self-reported questionnaire 
that measures the severity of fatigue.  It was developed based on qualitative research with 
patients as well as review of literature and other existing relevant measures.  The measure 
consists of 1 question that asks study participants to rate their fatigue over the past 7 days 
from 0-“no fatigue” to 10-“worst possible fatigue”.  The assessments will be completed 
electronically by study participants at home, or at the clinic.
Incidence of adverse events and laboratory abnormalities, in Part A of the study
See section 3.5.
3.3. Other Endpoint(s)
Change from baseline in body weight, at Weeks 3, 4 and 6


Protocol C3651010 (PF-06946860) Statistical Analysis Plan
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Page 12
Body weight will be recorded using an electronic scale (provided to the participant for their
use at home). During each weight measurement, from Randomization onward, body 
composition data (including total body water, fat mass and fat-free mass, if possible) will be 
captured via bioelectrical impedance analysis (BIA), as feasible.
Change from baseline score for patient reported 7-day recall PROMIS-Pain 1a at 
Weeks 1, 2, 3, 4, 5 and 6
The PROMIS Pain 1a is a self-reported measure that assesses the intensity of the 
participant’s pain in the past 7 days from 0-“no pain” to 10-“worst imaginable pain”. 
PGI-C (appetite), at Weeks 4 and 6 and PGI-C (fatigue) at Weeks 4 and 6
The PGI-C is a measure consisting of 2 questions that asks study participants to rate the 
overall change in their symptoms 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 (appetite and fatigue) categories will be combined to produce a 5-point scale as 
defined below:-
Category
Definition
Much Better
1
Somewhat Better
2-3
No Change
4
Somewhat Worse
5-6
Much Worse
7
Serum unbound and total concentrations of PF-06946860, on Day 1 and Weeks 3, 4 
and 6.
Serum concentrations of total GDF-15; and if feasible, unbound GDF-15, on Day 1 and 
Weeks 3, 4 and 6.
Relative change from baseline (i.e. post-dose / baseline) will be derived at each post-baseline 
timepoint.  
Incidence of ADA and, if applicable, NAb, in part A of the study.
Change from baseline in body composition endpoints, at Weeks 3, 4 and 6
During each weight measurement from Randomization onward, and using electronic scale
provided to the participant, body composition data (including total body water, fat mass and
fat-free mass, if possible) will be captured via bioelectrical impedance analysis (BIA), as
feasible.


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3.4. Baseline Variables
Not applicable.
3.5. Safety Endpoints
3.5.1. Adverse Events
An AE is considered treatment emergent (TEAE), relative to a given treatment, if the event 
starts during the effective duration of treatment, i.e. starting on, or after, the date and time of 
the first dose, but before the end of Part A (i.e. Week 6 for subjects continuing to Part B; or 
follow-up contact (28-35 days after last dose), for those subjects not continuing to Part B of 
the study)).
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited.
3.5.2. Laboratory Data
Safety laboratory tests (hematology, chemistry, urinalysis and other clinical laboratory tests) 
will be performed as described in the protocol.
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.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention 
"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 study intervention 
and who take at least 1 dose of study intervention.
Participants will be analyzed according to the randomized 
study intervention.


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Defined Analysis Set
Description
Censored
For participants who discontinue study intervention, 
receive prohibited medication and/or miss a dose, all 
observations post-discontinuation, post-medication or 
post-missed dose will be censored and treated as missing 
data.
Complete
For participants who discontinue study intervention, 
receive prohibited medication and/or miss a dose, all 
observations post-discontinuation, post-medication or 
post-missed dose will be included in the analysis set.
PK
All participants randomly assigned to study intervention 
and who take at least 1 dose of PF-06946860 and in whom 
at least 1 PK concentration value is reported.
Pharmacodynamic (PD)
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention and in 
whom at least 1 PD (GDF-15) concentration value is 
reported.
Immunogenicity
All participants randomly assigned to study intervention 
and who take at least 1 dose of PF-06946860 and in whom 
at least 1 ADA result is reported.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There are no formal hypothesis tests planned for this study and no statistical decision rules 
will be applied.
5.2. General Methods
The analyses related to the primary, secondary and exploratory endpoints will be based on 
the appropriate population for analysis (see Section 4).
Unless otherwise stated, all summaries and plots will be presented by treatment group.  The 
following treatment group labels (or similar) will be used: -
Safety
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention.  
Participants will be analyzed according to the product 
they actually received.


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Placebo
PF-06946860 
Q3W
5.2.1. Summary Analyses for Continuous Endpoints
Unless otherwise stated, continuous variables will be presented using summary statistics: 
number of observations, arithmetic mean, standard deviation (SD), median and range 
(minimum and maximum) values.  For endpoints to be analysed on the natural log scale
(loge), the geometric mean and geometric coefficient of variation (CV) will additionally be 
calculated.
5.2.2. Summary Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.
5.2.3. Mixed Models Repeated Measures (MMRM) Analysis
The mixed effects repeated measures (MMRM) model will include participant as a random 
term, and baseline, time (as a factor), baseline-by-time interaction, treatment and treatment-
by-time interaction as fixed terms in the model.  An unstructured covariance matrix will be 
fitted to the repeated times within subject (other covariance matrices will be considered if 
necessary, e.g. if convergence is not obtained or model fit is not adequate), and the Kenward-
Roger approximation will be used for estimating degrees of freedom.  Additional terms may be 
fitted in the model (e.g. cancer type, PROMIS-Pain 1a change from baseline score), as 
appropriate.
Least-squares (LS) means (and 90% CIs) and mean differences versus placebo (and 90% 
CIs), at each timepoint, will be provided.  Means and differences averaged over the 
timepoints may also be included.  No adjustments will be made for multiplicity.
Example SAS code is provided in Appendix 1.
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 PD data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to the lower limit of quantification (LLQ). 
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. 
In listings, BLQ values (for PK or PD) will be reported as “<LLQ”, where LLQ will be 
replaced with the value for the LLQ.
For PK and PD summary tables and plots of median profiles, statistics will be calculated 
having set concentrations to missing if one of the following cases is true:
CCI


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1. A concentration has been collected as ND (i.e. not done) or NS (i.e. 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
For all endpoints the analyses will be carried using the Censored Analysis Set, defined in 
Section 4, unless otherwise specified. Baseline is defined in Section 3.
6.1. Primary Endpoint(s)
6.1.1. Change from baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment–Appetite score, at Week 4.
6.1.1.1. Main Analysis
Absolute values and changes from baseline in the Cancer-Related Cachexia Symptom 
Assessment–Appetite score will be summarized descriptively by treatment group and 
timepoint, as described in Section 5.2.1.  Tables will present all data from the baseline and 
post-baseline timepoints (including follow-up for Part A for those participants that do not 
continue to Part B of the study).
The primary analysis will be an MMRM (as described in Section 5.2.3) applied to the change 
from baseline at Weeks 1, 2, 3, 4, 5 and 6, that will be used to estimate the treatment effect 
related to the primary Estimand 1 (as described in Section 2.1.1).
The following results from the above primary analysis will be plotted:

Profile plots of the LS Means (including 90% confidence intervals [CIs]) over time, with 
a separate line for each treatment group

Profile plots of the LS Mean differences to Placebo (including 90% CIs) over time
Standard SAS output will be provided to support the main statistical summary table for the 
secondary analysis model, but will not be included in the Clinical Study Report (CSR).
Statistical Model Diagnostics
The presence of outliers will be investigated for this analysis. An outlier will be defined as 
any response data value with a studentized (conditional) residual greater than 3, or less 
than -3. A listing will be presented of any participants meeting these criteria and will be 
included with standard SAS outputs. The assumptions of normality will be verified 
graphically using residual plots. For each fitted model, a set of conditional studentized 
residual plots will be produced, including residual plot, histogram of normality, quartile-
quartile (QQ) plot and summary of fit statistics. The residual plots will not be included in the 
clinical study report.
If there are outliers or major deviations from normality, then the effect of these on the 
conclusions may be investigated through alternative transformations and/or analyses 


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excluding outliers. Justification for any alternative to the planned analysis will be given in 
the report of the study.
6.1.1.2. Sensitivity/Supplementary Analyses
An additional exploratory analysis (for the primary endpoint only), examining the robustness 
of results for the primary endpoint, may be performed to estimate the treatment effect related 
to Estimand 3 (as described in Section 2.1.3). The same summaries and analysis as the main 
analysis (Section 6.1.1.1) will be performed and reported, but applied to the Complete 
Analysis Set (as described in Section 4).
6.2. Secondary Endpoint(s)
6.2.1. Change from Baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment-Appetite Score, at Weeks 1, 2, 3, 5 and 6
Summaries and analysis for Weeks 1, 2, 3, 5 and 6 of the Cancer-Related Cachexia Symptom 
Assessment-Appetite score will be presented as part of the primary analysis described in 
section 6.1.1.1.
6.2.2. Change from Baseline for patient reported 7-day recall Cancer-Related Cachexia 
Symptom Assessment-Fatigue Score, at Weeks 1, 2, 3, 4, 5 and 6
The Cancer-Related Cachexia Symptom Assessment-Fatigue score will be summarized and 
analysed in a similar way to the primary endpoint, as described in Section 6.1.1.1. 
6.2.3. Incidence of Adverse Events and Laboratory Abnormalities, in Part A of the 
Study
See section 6.6.
6.3. Other Endpoint(s)
6.3.1. Change from baseline in body weight, at Weeks 3, 4 and 6
Body weight will be summarized and analysed in a similar way to the primary endpoint, as 
described in Section 6.1.1.1.
Absolute values and changes from baseline in the body composition endpoints will be 
summarized descriptively by treatment group and timepoint, as described in Section 5.2.1.  
6.3.2. Change from baseline score for patient reported 7-day recall PROMIS-Pain 1a at 
Weeks 1, 2, 3, 4, 5 and 6
Absolute and change from baseline in the PROMIS-Pain 1a score will be summarized 
descriptively by treatment group and timepoint, as described in Section 5.2.1.
Scattter plots will be produced of the change from baseline PROMIS-Pain 1a score versus: -

Both the change from baseline Cancer-Related Cachexia Symptom Assessment-Appetite
and -Fatigue scores


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
The residuals from the MMRM analysis of both the change from baseline Cancer-Related 
Cachexia Symptom Assessment-Appetite and -Fatigue scores
Plots will be trellised by timepoint (with separate colours for each treatment group) and also 
produced with all timepoints on the same plot.  Y=X line and correlation coefficient will be 
included on the plots.
6.3.3. PGI-C (appetite), at Weeks 4 and 6
PGI-C (appetite) data will be summarized descriptively by treatment group and timepoint, as 
described in Section 5.2.2.
6.3.4. PGI-C (fatigue), at Weeks 4 and 6
PGI-C (fatigue) data will be summarized descriptively by treatment group and timepoint as 
described in 5.2.2.
6.3.5. Serum unbound and total concentrations of PF-06946860, on Day 1 and Weeks 3, 
4 and 6
PK analyses will be performed using the PK analysis set, as defined in Section 4.
Presentations for serum unbound and total concentrations of PF-06946860 will include: -

A listing of concentrations sorted by participant and timepoint

A summary of concentrations by timepoint, where the set of statistics will include n, 
arithmetric mean, SD, coefficient of variation (CV%), minimum, Q1, median, Q3, 
maximum, geometric mean, geometric CV%, and the number of concentrations above 
the LLQ

Individual concentration-time plots (on a linear scale) 

Median concentration-time plot (on a linear scale), Q1 and Q3 may be included

Mean (±SD) concentration-time plot (on a linear scale).
6.3.6. Serum concentrations of total GDF-15; and if feasible, unbound GDF-15, on Day 
1 and Weeks 3, 4 and 6
PD analyses will be performed using the PD analysis set, as defined in Section 4.
Presentations for total and, if feasible, unbound GDF-15 levels (as data permit) will include: -

A listing of concentrations sorted by treatment group, participant and timepoint. The 
listing will also include the relative change from baseline

A summary of concentrations (absolute values and relative changes from baseline) by 
treatment group and timepoint, where the set of statistics will include (as data permit) 
n, arithmetric mean, SD, CV%, minimum, Q1, median, Q3, maximum, geometric 
mean, geometric CV% and the number of concentrations above the LLQ (for absolute 
values only)

Individual concentration-time plots (for absolute values and relative change from 
baseline) by treatment group (on a linear scale). There will be separate spaghetti plots 
for each treatment group


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
Median concentrations-time plots (for absolute values and relative change from 
baseline) by treatment group (on a linear scale, all treatments on the same plot), Q1 
and Q3 may be included

Mean (±SD, if appropriate) concentrations-time plots (for absolute values and relative
change from baseline) by treatment group (on a linear scale, all treatments on the 
same plot).
In all presentations, the relative changes will be presented as percent change from baseline 
([relative change from baseline -1]*100).
Relative change from baseline (i.e. post-dose / baseline) unbound GDF-15 concentration may 
also be analysed in a similar way to the primary endpoint, as described in Section 6.1.1.1.  
Both the relative change and the baseline will be on the log scale.  LS means (and 80% CIs) 
and mean differences versus placebo (and 80% CIs) will be obtained for each treatment at 
each timepoint.  These will be back transformed prior to presentation to give relative changes 
from baseline, presented as percent change from baseline ([relative change from baseline -
1]*100) and ratios of relative changes from baseline, presented as percent change from 
placebo ([ratio of relative change from baseline -1]*100).  Plots of these back-transformed 
LS means and differences (including 80% CIs) will also be produced over time (all 
treatments on the same plot with different colours/symbols for each treatment). 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, may be simplified (e.g. fewer timepoints, 
different covariance matrix) or may be replaced by an alternative analysis.
6.3.7. Incidence of ADA and, if applicable, NAb,in Part A of the study
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 and titer for all ADA-positive participants  

A summary (both table and figure, if appropriate) of the overall incidence of ADA, 
incidence of NAb, as well as the percentage of participants who are ADA positive 
and NAb positive at each timepoint.
If appropriate (e.g. the number of ADA-positive participants is ≥3), the additional analyses 
below may be performed:

A spaghetti plot of individual participant ADA and NAb titer over time 

A summary of ADA and NAb titer by time

Analysis of unbound and total PF-06946860 concentration by ADA and NAb status. 
This may include summary tables and box and/or spaghetti plots of concentration data 
by ADA and NAb status


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
Analysis of unbound and/or total PF-06946860 concentration by ADA and NAb titer 
tertile which may include summary tables and box plots of concentration data by titer 
tertile 

Analysis of unbound and/or total GDF-15 concentration (as data permit) by ADA and 
NAb status which may include summary tables and box and/or spaghetti plots of 
concentration data by ADA and Nab status

Analysis of unbound and/or total GDF-15 concentration (as data permit) by ADA and 
NAb titer tertile which may include summary tables and a box plot of concentration 
data by titer tertile 

An individual plot of unbound and total PF-06946860 concentration, unbound and/or 
total GDF-15 concentration (as data permit), ADA and NAb titer in ADA-positive 
participants.
6.4. Subset Analyses
No subset analyses will be performed.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographic data, prior and concomitant medications, GDF-15 levels (at screening, using 
the Roche Elecsys assay), height, weight and appetite score at screening will be summarised.  
In addition, a subset of medical history data will be reported; this will include primary 
cancer diagnosis and staging at time of screening, date of initial diagnosis, body weight 
history (e.g., weight 6 months ago or ‘usual’ weight prior to current cancer diagnosis), 
where feasible. 
Other data collected at screening that are used for inclusion/exclusion criteria, such as 
laboratory data, will be considered source data, and will not be required to be reported, 
unless otherwise noted.
6.5.2. Study Conduct and Participant Disposition
Participant evaluation groups will show end of study participant disposition by treatment 
group and will show which participants were analyzed for efficacy (Censored and Complete 
Analysis sets) as well as for safety, PK, PD and immunogenicity.  Frequency counts and 
percentages will be supplied for participant discontinuation(s) by treatment group and 
overall.
Data will be reported in accordance with the sponsor reporting standards.
6.5.3. 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.


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6.5.4. Population PK
As permitted by data, and determined by the sponsor, the PK/PD relationship between serum 
PF-06946860 concentration and the effect on primary, secondary and/or tertiary endpoints 
may be explored using a population PK/PD approach. The population PK/PD analysis, if 
conducted, will be reported in a separate report. 
6.5.5. Banked Biospecimens
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned 
to be included in the CSR. 
6.5.6. Qualitative Phone Interviews
Qualitative interviews will be conducted with the participant and may additionally be 
conducted with the the caregiver.  A comprehensive summary report that fully describes the 
study objectives, methods, participants and results of the qualitative interviews will be 
prepared and will not be reported in the CSR.
6.6. Safety Summaries and Analyses
Analysis of adverse events and laboratory abnomatities will use the the Safety Analysis Set
defined in Section 4.
6.6.1. Adverse Events
Adverse events will be summarised by treatment group and overall, in accordance with 
sponsor reporting standards.  
6.6.2. Laboratory Data
Laboratory data will be listed and summarized by treatment group and overall, in accordance 
with the sponsor reporting standards.
7. INTERIM ANALYSES
7.1. Introduction
As this is a sponsor-open 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 efficacy and/or safety. Interim analysis 
results may be used for internal business decisions regarding future study planning or 
stopping for futility.  If a formal interim analysis is conducted, details of the timing, 
objectives, decision criteria and analyses will be documented in an internal charter or in the 
final SAP (via an amendment).
Following completion of Part A, the data will be analyzed, and a report written.  The results 
of Part A will not be used to make any changes to the design or conduct of Part B.  


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7.2. Interim Analyses and Summaries
N/A
8. REFERENCES
Not applicable.


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9. APPENDICES


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Appendix 1. Statistical Methodology Details
Example SAS code for MMRM Model:
proc mixed data = dataset method=reml;
class subject treatment time;
model cfb = treatment base time base*time time*treatment / ddfm=kr residual 
outp=resid_out;
repeated time /subject=subjid type = un;
lsmeans treatment*time/diff cl alpha=0.1;
ods output lsmeans=lsmeans_out;
ods output diffs=diffs_out;
run;


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Appendix 2. Definitions of Immunogenicity Terms
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 (a participant with ≥ 1 post-treatment ADA 
result ) 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
(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. List of Abbreviations
Abbreviation
Term
ADA
antidrug antibodies
AE
adverse event
BLQ
below the limit of quantitation
CI
confidence interval
CSR
clinical study report
CV
coefficient of variation
GDF-15
growth differentiation factor 15
HCP
Healthcare professional
LLQ
lower limit of quantitation
LS
least-squares
mg
milligrams
MMRM
mixed-effects model with repeated measures
N/A
not applicable
NAb
neutralizing antibodies
ND
not done
NS
no sample
OLT
open-label treatment
PD
pharmacodynamic(s)
PGI-C
Patient global impression of change
PK
pharmacokinetic(s)
PRO
patient-reported outcome
PROMIS
Patient-Reported Outcomes Measurement Information System
Q1
lower quartile
Q3
upper quartile
Q3W
3 weeks apart
QQ
quartile-quartile
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SC
subcutaneous
SD
standard deviation
SOP
standard operating procedure
TEAE
treatment-emergent adverse event