Clinical trial NCT03685591
Conditions: Breast Neoplasms Prostate Neoplasms Neoplasms, Squamous Cell Melanoma Mesothelioma Pancreatic Neoplasms Colorectal Neoplasms Carcinoma, Renal Cell Liver Neoplasms
Keywords: efficacy safety pharmacokinetics dose escalation dose expansion open-label TGFb transforming growth factor beta breast cancer prostate cancer CRPC metastatic advanced adenocarcinoma
Sponsor: Pfizer
Start date: 2018-10-04; Completion date: 2022-03-30
Enrollment: 49 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1 dose escalation and expansion study evaluating safety, tolerability and pharmacokinetics of PF-06952229 in adult patients with advanced solid tumors.

Detailed description:
This is a Phase 1, open label, multi center, multiple dose, dose escalation and expansion, safety, tolerability, PK, and pharmacodynamics study of PF 06952229 in previously treated patients with advanced or metastatic cancers that may have high TGFbeta signatures and EMT expression.

The study includes Parts 1A and 1B, which are dose-escalation for monotherapy and combination therapy with enzalutamide, respectively, and Parts 2A and 2B, which are dose expansion for monotherapy and combination therapy with enzalutamide, respectively.

Arms: arm 1: PF-06952229 at 20mg twice daily (BID) arm 2: PF-06952229 at 40 mg BID arm 3: PF-06952229 at 80 mg BID arm 4: PF-06952229 at 150 mg BID arm 5: PF-06952229 at 250 mg BID arm 6: PF-06952229 at 375 mg BID arm 7: PF-06952229 at 500 mg BID arm 8: PF-06952229 at 625 mg BID arm 9: PF-06952229 at 750 mg BID arm 10: PF-06952229 at 375 mg BID in combination with enzalutamide arm 11: PF-06952229 at 500 mg BID in combination with enzalutamide arm 12: PF-06952229 at 625 mg BID in combination with enzalutamide arm 13: PF-06952229 at 750 mg BID in combination with enzalutamide arm 14: PF-06952229 at recommended Phase 2 Dose BID arm 15: PF-06952229 at recommended phase 2 dose BID in combination with enzalutamide
Interventions: intervention 1: PF-06952229 intervention 2: Enzalutamide
Intervention descriptions: intervention 1: Oral 7 days on / 7 days off - 28 day cycles (Part 1) intervention 2: Prostate Cancer (Part 2). 160mg, capsules, orally, daily

Protocol documents:
Prot_000.pdf: 
PF-06952229
C3881001
Protocol Amendment 3, 07 May 2021
PFIZER CONFIDENTIAL
Page 1
A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING 
SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06952229 IN 
ADULT PATIENTS WITH ADVANCED SOLID TUMORS
Investigational Product Number:
PF-06952229
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
TBD
Protocol Number:
C3881001
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Document History
Document
Version Date
Summary of Changes and 
Rationale
Amendment 3
07 May 2021
The overall rationale for the 
amendment is to revise inclusion 
and exclusion criteria in Part 1B  
(combination dose escalation) to 
enroll a patient population more 
reflective of the real world and to 
incorporate the administrative 
changes to ensure consistency 
throughout the protocol. 

For Part 1B: the inclusion 
criteria was revised to remove 
the requirements regarding 
prior docetaxel and abiraterone 
therapy, and disease 
progression as measured by 
RECIST v1.1, the appearance 
of 2 or more new bone lesions 
per Prostrate Cancer Working 
Group 2 PCWG2 (PCWG2),  
or rising prostate specific 
antigen (PSA) per PCWG2. 
This allows safety, tolerability, 
and pharmacokinetic (PK) 
assessment in a broader study 
population. 

Combination Dose Escalation 
Phase: histological or 
cytological diagnosis of 
metastatic castration-resistant 
prostate cancer (mCRPC). 
(Castration is defined as 
having a serum testosterone 
less than 50 ng/dL, due to 
medical or surgical castration),
patients who are intolerant to 
standard treatment, resistant to 
standard therapy, or refuse 
standard therapy.


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• For Part 1B: exclusion of 
patients treated with current or 
prior enzalutamide within 
24 days prior to first dose. This 
allows adequate PK assessments 
of enzalutamide during the 
study. 
•
 
 
•
 
 
 
 
 
 
 
 
 
 
• SOA (Part 2B): Administration 
of PF-0695229 in clinic on 
Cycle 1 Day 2 and Cycle 1 
Day 21 were added, as PK 
collections are performed during 
these visits. 
•
SOA (Part 1B): 
Electrocardiogram (ECG) 
measurements were added on 
Cycle 1 Day 2 and Cycle 1 
Day 15 to coincide with  
on-site PF-0695229 
administration.
•
SOA (Part 2B): ECG 
measurements were added on 
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Cycle 1 Day 2 (predose) and 
Cycle 1 Day 21 (predose), and 
Cycle 1 D15 and Cycle 1 D21 
(2 hours +/- 15 minutes 
postdose) to coincide with 
on-site PF-0695229 
administration.
Due to emerging data, the use of 
proton pump inhibitors (PPIs) 
during the study was revised.  
Patients currently on PPIs should 
be switched to antacids or 
H2-Receptor antagonists 14 days 
prior to Cycle 1 Day 1 and 
should abstain from PPI use 
throughout the study. 
SOA: Urine phosphate 
collections were removed, as 
serum phosphorus is collected.
Clarified the start of study entry 
is Cycle 1 Day 1.
Minor editorial changes were 
made throughout the document.
Amendment 2
24 August 2020
The study design was amended 
to add a dose expansion for the 
monotherapy (Part 2A), and to 
further define the dose escalation 
and expansion for PF-06952229 
in combination with 
enzalutamide in patients with 
mCRPC (Part 1B and Part 2B).
Based on clinical data from Part 
1A, the study design was 
amended to focus on patients 
with mCRPC.  The combination 
of PF-06952229 with palbociclib 
or the combination of 


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PF-06952229 with letrozole in 
patients with metastatic breast 
cancer was removed.  
Pregnancy testing was removed 
from Part 1B – Combination 
Dose Escalation, Part 2A 
Monotherapy Dose Expansion, 
and Part 2B – Combination Dose 
Expansion since these parts of 
the study will only apply to male 
patients.
Based on the revised study 
design, the total study sample 
size of approximately 90 patients 
is planned: Part 1A –
Monotherapy Dose Escalation 
N40, Part 1B Combination 
Dose Escalation N20, Part 2A –
Monotherapy Dose Expansion 
N=10, and Part 2B –
Combination Dose Expansion 
N=20. 
An additional dose level of 
750 mg BID was added to the 
protocol in relevant sections. 
Due to the updated study design 
and study population, the 
objectives and endpoints are 
divided into Parts 1A, 1B, 2A, 
and 2B to reflect the updated 
study design.
Individual Schedule of Activities 
were updated for Part 1A, 
Part 1B, Part 2A, and Part 2B for 
clarity.
The inclusion and exclusion 
criteria for Part 1B, Part 2A, and 


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Part 2B were updated to enroll 
mCRPC patients who had failed 
prior docetaxel and abiraterone 
based on the CARD trial (doi: 
10.1056/NEJMoa1911206).
It was clarified that enzalutamide 
is considered an Investigation 
Medicinal Product for this study. 
Additional information was 
added to Section 5.4.3 
(Enzalutamide Administration), 
Section 5.4.5 (Dosing 
Interruptions), Section 5.4.6 
(Dose Delays), and Section 5.4.7 
(Dose Reductions).  Reference to 
the SPC for enzalutamide was 
removed throughout the 
protocol.
Tumor assessments for mCRPC 
was changed from PCWG3 to 
PCWG2 based on the CARD 
trial. 
Clinical PK and Clinical Safety 
data for PF-06952229 were 
added in Section 1.2.6 and
Section 1.2.7, respectively.
Because alkaline phosphatase 
testing is not available in many 
centers, as it is not typically used 
to manage patients to 
differentiate liver disease vs 
bone metastasis.  The schedule 
was reduced to C1D1 and as 
clinically indicated in order 1) to 
provide a baseline for each 
patient and 2) to provide sites 
with the ability to interpret such 


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assays as needed for clinical 
management.
• Specified that serum phosphorus 
and urine phosphate should be 
collected during Blood 
Chemistry and Urinalysis, 
respectively.
• Blood collection for RNA was 
removed from all parts of the 
study.
• PK 
 collection timepoints 
were updated for Parts 1B, 2A, 
and 2B.
•
 
 
• Collection of the Gleason Score 
was added to the SoA for Part 
2A and Part 2B.
• In Section 3.1.2.1, it was 
clarified that the Accelerated 
Titration Design will only be 
used during the starting doses for 
Part 1A – Monotherapy Dose 
Escalation. Throughout the 
protocol it was clarified that Part 
1B – Combination Dose 
Escalation will use the mTPI 
design.
• Intra-patient dose escalation 
during the Accelerated Titration 
Design portion of the study was 
removed.
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It was clarified that during the 
28-day cycle, PF-06952229 
dosing is 7 days on followed by 
7 days off in the Study Design.
Figure 1 was updated to include 
both canonical and non-
canonical TGFsignaling 
pathways.
General updates to the protocol 
template were incorporated.
Appendix 7 was updated to 
reflect Prostate Cancer Working 
Group 2.
Appendix 8 was added to 
provide alternative study 
measures during public 
emergencies.
Appendix 9 was added to list 
prohibited drugs having the 
potential for DDI.  Lists of 
conmeds with potential DDI 
were removed from Section 5.7.
The Summary of Changes was 
reorganized to list the most 
recent amendment first.
General formatting and copy 
editing were performed 
throughout the protocol.
Amendment 1
30 October 2019
Addition of MRI of brain at 
Screening and every 8 weeks.
Adjustment of tumor assessment 
schedule for all patients to every 
8 weeks.


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Summary of Changes and 
Rationale
Addition of timepoints for Blood 
Chemistry, Coagulation and 
Urinalysis in Schedule of 
Activities.
Edit to anticoagulation 
medication exclusion criteria.
Edit to Exclusion criteria 
regarding brain metastases.
Addition of exclusion criteria for 
patients with history of clinically 
significant bleeding.
Addition of exclusion criteria for 
tumors that compress or invade 
major blood vessels.
Addition of exclusion criteria for 
patients with a history of central 
nervous system metastases.
Edit to Patient Compliance 
Section 5.2.
Addition of text in Section 5.7 
Concomitant Treatments.
Addition of discontinuation for 
patients who experience 
hemorrhages during trial 
participation.
Addition of 12-hour PK 
timepoint to Part 1, and Part 2 
combination A and B; Schedule 
of Activities.
Addition of exclusion criteria for 
liver metastases at baseline that 
are likely to bleed; Section 4.2.


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Version Date
Summary of Changes and 
Rationale
Update to statistical 
considerations, Section 3.1.2.2 
Acceleration Phase with 
Intrapatient Escalation.
Addition of Study Stopping and 
Patient Discontinuation, 
Section 5.4.10.
Original protocol
13 July 2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................17
LIST OF FIGURES .................................................................................................................17
APPENDICES .........................................................................................................................18
PROTOCOL SUMMARY.......................................................................................................19
STUDY OBJECTIVES AND ENDPOINTS...........................................................................20
STUDY DESIGN.....................................................................................................................24
STUDY TREATMENTS.........................................................................................................26
DATA ANALYSIS/STATISTICAL METHODS...................................................................26
SCHEDULE OF ACTIVITIES................................................................................................28
1. INTRODUCTION ...............................................................................................................56
1.1. Mechanism of Action/Indication.............................................................................56
1.2. Background and Rationale ......................................................................................56
1.2.1. TGFβ...........................................................................................................56
1.2.2. Tumors and Combination Therapies ..........................................................57
1.2.2.1. Metastatic Castration-Resistant Prostate Cancer (mCRPC)......58
1.2.3. Nonclinical Pharmacology..........................................................................58
1.2.4. Nonclinical Pharmacokinetics ....................................................................59
1.2.5. Nonclinical Safety ......................................................................................60
1.2.6. Clinical Pharmacokinetics ..........................................................................62
1.2.7. Clinical Safety ............................................................................................62
1.3. Starting Dose Rationale...........................................................................................62
1.3.1. Intermittent Dosing Schedule Rationale.....................................................62
1.4. PF-06952229 Rationale for Development...............................................................63
1.5. Study Rationale .......................................................................................................63
1.5.2. Rationale for Safety Monitoring Plan.........................................................64
1.5.2.1. Cardiac Disorders......................................................................64
1.5.2.2. Hepatobiliary Disorders ............................................................65
1.5.2.3. Metabolism and Nutrition Disorders.........................................65
1.5.2.4. Musculoskeletal and Connective Tissue Disorders...................65
1.5.2.5. Respiratory, Thoracic and Mediastinal Disorders.....................65
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1.6. Overview of Enzalutamide......................................................................................66
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................67
3. STUDY DESIGN.................................................................................................................71
3.1. Study Overview.......................................................................................................71
3.1.1. Part 1 Dose Escalation................................................................................73
3.1.1.1. Part 1A – Single Agent PF-06952229 in 
Advanced/Metastatic Solid Tumors ..................................................73
3.1.1.2. Starting Dose.............................................................................73
3.1.1.3. Criteria for Dose Escalation ......................................................73
3.1.1.4. Standard (mTPI) Escalation Phase............................................75
3.1.1.5. Part 1B – PF-06952229 in Combination With 
Enzalutamide in mCRPC...................................................................75
3.1.2. Part 2 Dose Expansion................................................................................76
3.1.2.1. Part 2A – Single Agent PF-06952229 in mCRPC ....................76
3.1.2.2. Part 2B – PF-06952229 in Combination with 
Enzalutamide in mCRPC...................................................................76
3.2. DLT Definition........................................................................................................76
3.3. MTD Definition.......................................................................................................78
3.4. Recommended Phase 2 Dose (RP2D) Definition ...................................................78
4. PATIENT ELIGIBILITY CRITERIA.................................................................................79
4.1. Inclusion Criteria.....................................................................................................79
4.2. Exclusion Criteria....................................................................................................82
4.3. Lifestyle Requirements ...........................................................................................86
4.4. Sponsor’s Qualified Medical Personnel..................................................................87
5. STUDY TREATMENTS.....................................................................................................87
5.1. Allocation to Treatment ..........................................................................................88
5.2. Patient Compliance .................................................................................................88
5.3. Investigational Product Supplies.............................................................................89
5.3.1. Dosage Form(s) and Packaging..................................................................89
5.3.1.1. Enzalutamide.............................................................................89
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5.3.2. Preparation and Dispensing........................................................................89
5.4. Administration.........................................................................................................89
5.4.1. PF-06952229...............................................................................................89
5.4.2. Food Requirements.....................................................................................90
5.4.2.1. Food Requirements 
...........90
5.4.3. Enzalutamide Administration.....................................................................91
5.4.4. Recommended Dose Modifications............................................................91
5.4.5. Dosing Interruptions...................................................................................92
5.4.6. Dose Delays................................................................................................93
5.4.7. Dose Reductions.........................................................................................94
5.4.8. Study Stopping Rules and Patient Discontinuation....................................97
5.5. Investigational Product Storage ..............................................................................98
5.6. Investigational Product and Study Treatment Accountability ................................99
5.6.1. Destruction of Investigational Product Supplies ........................................99
5.7. Concomitant Treatment(s).......................................................................................99
5.7.1. Proton-Pump Inhibitors ..............................................................................99
5.7.2. Antacids or H2-Receptor Antagonists......................................................100
5.8. Other Anti-tumor/Anti-Cancer or Experimental Drugs ........................................100
5.9. Supportive Care.....................................................................................................100
5.9.1. Hematopoietic Growth Factors.................................................................100
5.9.2. Anti-Diarrheal, Anti-Emetic Therapy.......................................................101
5.9.3. Anti-Inflammatory Therapy......................................................................101
5.9.4. Corticosteroids..........................................................................................101
5.9.5. Surgery......................................................................................................101
6. STUDY PROCEDURES ...................................................................................................101
6.1. Screening...............................................................................................................101
6.2. Study Period ..........................................................................................................101
6.3. Follow-up ..............................................................................................................102
6.4. Patient Withdrawal................................................................................................102
7. ASSESSMENTS................................................................................................................104
7.1. Safety Assessment.................................................................................................104
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7.1.1. Pregnancy Testing ....................................................................................105
7.1.2. Adverse Events.........................................................................................105
7.1.3. Laboratory Safety Assessment .................................................................105
7.1.4. Vital Signs and Physical Examination......................................................106
7.1.5. (12-Lead) Electrocardiogram....................................................................106
7.2. Echocardiogram ....................................................................................................107
7.3. Pharmacokinetics Assessments.............................................................................107
7.3.1. Plasma for PK analysis of PF-06952229..................................................107
7.3.2. Urine for Analysis of PF-06952229 Concentrations ................................108
7.6. Additional Research ..............................................................................................112
7.7. Imaging Assessments ............................................................................................112
7.8. Tumor Response Assessments ..............................................................................112
7.8.1. Image Acquisition Parameters..................................................................114
7.8.2. Soft Tissue Disease Assessment...............................................................114
7.8.3. Bone Scan Assessment .............................................................................114
7.8.4. Central Independent Radiology Facility (IRF).........................................114
8. ADVERSE EVENT REPORTING....................................................................................115
8.1. Requirements.........................................................................................................115
8.1.1. Additional Details on Recording Adverse Events on the CRF.................117
8.1.2. Eliciting Adverse Event Information........................................................117
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal Section) ..........................................................................117
8.1.4. Time Period for Collecting AE/SAE Information....................................117
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................117
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............118
8.1.5. Causality Assessment ...............................................................................118
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................118
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8.2. Definitions.............................................................................................................118
8.2.1. Adverse Events.........................................................................................118
8.2.2. Abnormal Test Findings ...........................................................................119
8.2.3. Serious Adverse Events ............................................................................120
8.2.4. Hospitalization..........................................................................................120
8.3. Severity Assessment..............................................................................................122
8.4. Special Situations ..................................................................................................122
8.4.1. Potential Cases of Drug-Induced Liver Injury..........................................122
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................124
8.4.2.1. Exposure During Pregnancy (EDP) ........................................124
8.4.2.2. Exposure During Breastfeeding ..............................................125
8.4.2.3. Occupational Exposure ...........................................................125
8.4.3. Medication Errors .....................................................................................126
8.4.3.1. Medication Errors Definition ..................................................126
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................126
9.1. Analysis Sets .........................................................................................................127
9.2. Statistical Methods and Properties ........................................................................128
9.2.1. Statistical Methods for Dose Escalation...................................................128
9.2.2. Statistical Methods for Determining the MTD.........................................129
9.3. Efficacy Analysis ..................................................................................................130
9.4. Analysis of Pharmacokinetics 
........................................130
9.4.1. Analysis of Pharmacokinetics...................................................................130
9.4.1.1. Single-Dose and Steady-State 
PF-06952229 Pharmacokinetic Analysis ........................................130
9.5. Safety Analysis......................................................................................................132
9.5.1. Analysis of the Primary Endpoint.............................................................132
9.5.2. Analysis of Secondary Safety Endpoints..................................................132
9.5.3. Electrocardiogram.....................................................................................132
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9.6. Sample Size Determination...................................................................................133
9.6.1. Part 1.........................................................................................................133
9.6.2. Part 2.........................................................................................................134
9.7. Data Monitoring Committee .................................................................................134
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................135
11. DATA HANDLING AND RECORD KEEPING ...........................................................135
11.1. Case Report Forms/Electronic Data Record .......................................................135
11.2. Record Retention.................................................................................................136
12. ETHICS............................................................................................................................136
12.1. Institutional Review Board/Ethics Committee....................................................136
12.2. Ethical Conduct of the Study ..............................................................................137
12.3. Patient Information and Consent.........................................................................137
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................138
13. DEFINITION OF END OF TRIAL.................................................................................138
13.1. End of Trial in All Participating Countries .........................................................138
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................138
15. PUBLICATION OF STUDY RESULTS........................................................................138
15.1. Communication of Results by Pfizer ..................................................................138
15.2. Publications by Investigators ..............................................................................139
16. REFERENCES ................................................................................................................141


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LIST OF TABLES
Table 1.
PF-06952229 Dose Levels........................................................................74
Table 2.
mTPI Dose Decision Rules.......................................................................75
Table 3.
Dose Modifications for PF-06952229 - Related Toxicity........................95
Table 4.
Nausea, Vomiting, or Diarrhea, Cardiac Toxicity Dose 
Modification Guidance .............................................................................97
Table 5.
Summary of Tumor Biopsy Requirements for C3881001......................109
LIST OF FIGURES
Figure 1.
Canonical and Non-Canonical TGFβ signaling10.....................................56
Figure 2.
Study Schema ...........................................................................................73


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APPENDICES
Appendix 1. ABBREVIATION LIST ...................................................................................145
Appendix 2. Detailed Dose Escalation/De-Escalation Scheme for mTPI design..................151
Appendix 3. Bone Marrow Reserve in Adults.......................................................................154
Appendix 4. ECOG Performance Status................................................................................156
Appendix 5. Bone Scan Assessment Form............................................................................157
Appendix 6. Response Evaluation Criteria In Solid Tumors (RECIST) v 1.1 ......................160
Appendix 7. Prostate Cancer Working Group 2 (PCWG2) – Soft Tissue Response 
Criteria....................................................................................................164
Appendix 8. Alternative Measures During Public Emergencies ...........................................169
Appendix 9. Prohibited Concomitant Medications Which May Result in Drug-Drug 
Interaction (DDI) ....................................................................................172
Appendix 10. Additional Clinical Safety Data ......................................................................174


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PROTOCOL SUMMARY 
Background and Rationale
TGFβ
Elevated TGFexpression by tumor and stromal cells in the tumor microenvironment, and 
activation of TGFreceptor intracellular signaling is observed in many cancers.  Activated 
TGFR1 phosphorylates the signaling intermediate proteins termed mothers against 
decapentaplegic homolog 2 and 3 (SMAD2 and SMAD3), which assemble into complexes 
with SMAD4, and translocate to the nucleus, where they regulate the expression of TGFβ
target genes.  In addition, non-SMAD signaling may also be initiated downstream of TGFβ
receptors, which can lead to the activation of various pathways such as 
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), c-jun N-terminal kinase (JNK), 
p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase (ERK) 
mitogen-activated protein kinase (MAP). 
The activation of the TGFpathway in cancer cells can induce epithelial to mesenchymal 
transition (EMT) in which epithelial cells lose their apico-basal polarity and cell-cell 
adhesion, to become highly migratory mesenchymal cells, leading to metastasis.  In addition, 
EMT has been linked to tumor cell evasion of immune surveillance.  TGFβ has been shown 
to be a potent immunosuppressive agent on both innate and adaptive immune cells, including 
dendritic cells, macrophages, natural killer (NK) cells, and CD4+ and CD8+ T cells.  
Conversely, TGFβ plays a key role stimulating the differentiation of immune-suppressive 
regulatory T (Treg) cells.  Finally, inhibition of the TGFR1 pathway in preclinical models 
has led to tumor growth inhibition.
Tumors and Combination Therapies
High TGFsignatures and EMT expression are found in a variety of tumors, including 
metastatic breast cancer, metastatic castration-resistant prostate cancer (mCRPC), squamous 
cell cancer of the head and neck, melanoma, mesothelioma, metastatic pancreatic cancer, 
colorectal cancer, renal cell carcinoma, and hepatocellular cancer.  These tumor types will be 
investigated in Part 1A of this protocol, a dose exploration of PF-06952229.  Subsequent 
investigations in Part 1B, Part 2A, and Part 2B of the protocol will be undertaken in a more 
targeted subset of tumors, selected based on nonclinical data, preliminary Part 1A data, and 
unmet medical need.  The monotherapy expansion (Part 2A) and combination portion of this 
clinical trial in Part 1B and Part 2B will focus on treatment of mCRPC. 


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STUDY OBJECTIVES AND ENDPOINTS
Part 1A - PF-06952229 Single Agent Dose Escalation Phase in Patients With 
Advanced/Metastatic Tumors.
Primary Objective(s):
Primary Endpoint(s):
•
To assess safety and tolerability at increasing 
dose levels of PF-06952229 in patients with 
advanced/metastatic tumors.
•
To determine MTD and RP2D of 
PF-06952229 as a single agent.
•
First-cycle DLTs.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the single and multiple dose PK of 
PF-06952229 when given as a single agent.
•
To evaluate preliminary anti-tumor activity of 
PF-06952229 when given as a single agent.
•
To evaluate preliminary biochemical responses 
as a measure of anti-tumor activity of 
PF-06952229
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
PSA50 Response Rate for prostate cancer 
patients.
•
Response assessment will be based on PCWG2 
for prostate cancer and RECIST 1.1 for other 
tumor types.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 1B - Dose Escalation of PF-06952229 in Combination With Enzalutamide in 
Patients with mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To assess safety and tolerability at increasing 
dose levels of PF-06952229 in combination with 
enzalutamide in patients with mCRPC.
•
To determine MTD and RP2D of 
PF-06952229 in combination with enzalutamide 
in patients with mCRPC.
•
First cycle DLTs in combination with 
enzalutamide for mCRPC.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the single and multiple dose PK of 
PF-06952229 when given in combination with 
enzalutamide.
•
To evaluate preliminary anti-tumor activity of 
PF-06952229 when given in combination with 
enzalutamide. 
•
To evaluate preliminary biochemical responses as 
a measure of anti-tumor activity of PF-06952229 
when given in combination with enzalutamide.
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
PSA50 Response Rate
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2A - PF-06952229 Single Agent Dose Expansion Phase in mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To confirm safety and tolerability of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To estimate efficacy of PF-06952229 at the 
estimated RP2D in patients with mCRPC.
•
To confirm the RP2D of PF-06952229 as a single 
agent.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
•
PSA50 Response Rate. 
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To estimate additional efficacy of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the single and multiple dose 
PK of PF-06952229 when given as a single 
agent.
•
To evaluate immune cells in paired pre and post 
treatment tumor biopsies (where available).
•
ORR based on PCWG2 and RECIST 1.1. and 
time to event endpoints (DoR, PFS, OS, TTP, 
TTR).
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
Assessment of levels of intra-tumor T cells (eg, 
CD8 IHC); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2B - Dose Expansion of PF-06952229 in Combination With Enzalutamide in 
Patients With mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To confirm PF-06952229 safety profile in 
combination with enzalutamide at the estimated 
RP2D in patients with mCRPC.
•
To estimate efficacy of PF-06952229 in 
combination with enzalutamide at the estimated 
RP2D in patients with mCRPC.
•
To confirm the RP2D of PF-06952229 in 
combination with enzalutamide in patients with 
mCRPC.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
•
PSA50 Response Rate. 
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To estimate additional efficacy of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the PK of PF-06952229 when 
given in combination with enzalutamide.
•
To evaluate immune cells in paired pre and post 
treatment tumor biopsies (where available).
•
ORR based on PCWG2 and RECIST 1.1. and 
time to event endpoints (DoR, PFS, OS, TTP, 
TTR).
•
Pharmacokinetic parameters of PF-06952229 
(in at least 8 subjects).
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
Peak and trough concentrations at selected 
cycles.
•
Assessment of levels of intra-tumor T cells (eg, 
CD8 IHC);
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY DESIGN
Study Overview
This is a Phase 1, open-label, multi-center, multiple-dose, dose-escalation and expansion, 
safety, tolerability, PK, and PD study of PF-06952229 in previously treated patients with 
advanced or metastatic cancers that may have high TGFβ signatures and EMT expression. 
The study includes Parts 1A and 1B, which are dose-escalation cohorts, and Parts 2A and 2B, 
which are dose expansion cohorts.  The primary objectives for Part 1A are to assess the 
safety and tolerability of PF-06952229 administered as a single agent and to determine 
maximum tolerated dose (MTD).  The primary objectives for Part 1B are to assess the safety 
and tolerability of PF-06952229 administered with enzalutamide and to determine MTD.  
The primary objectives for Part 2A are to confirm PF-06952229 safety and tolerability, 
estimate the single agent efficacy of PF-06952229 and determine a recommended Phase 2 
dose (RP2D).  The primary objectives of Part 2B are to confirm the safety profile of PF-
06952229 combined with enzalutamide, estimate the efficacy of PF-06952229 combined 
with enzalutamide and determine a RP2D for the combination.
Part 1A is a sequential single-agent dose-escalation conducted in patients with advanced or 
metastatic solid tumors who have failed standard-of-care treatment or for whom no 
standard-of-care exists.  Successive cohorts of patients are to receive escalating doses of 
PF-06952229 on an outpatient basis starting from 20 mg BID, which is based on non-clinical 
data.  Nine candidate dose levels are planned using an Accelerated Titration Design (ATD) 
until reaching 250 mg BID, after which the design will revert to modified target probability 
interval (mTPI).  The highest tested dose will not exceed 800 mg BID.  If an MTD is not 
observed during the 28-day safety window, additional dose levels may be considered based 
on PK, safety, tolerability, 
 assessments.  Based on PK and safety, 
additional patients can be added to a dose lower than the MTD and also may be moved 
forward to monotherapy expansion.
Part 1B is a dose-escalation of PF-06952229 in the combination of enzalutamide conducted 
in patients who were previously treated with metastatic castration-resistant prostate cancer 
(mCRPC).  The starting dose of PF-06952229 will be the MTD or maximum administered 
dose (MAD) of Part 1A.  Based on evolving PK, PD, and safety profiles, assessed in Part 1A, 
Part 1B may commence before reaching the MTD, and will follow an mTPI design.  The 
maximum PF-06952229 dose for the combination escalation may be higher than the 
monotherapy MTD due to the potential DDI between enzalutamide and PF-06952229, but 
not higher than 800 mg BID.
Part 2A and Part 2B are expansion cohorts for monotherapy and combination therapy, 
respectively, in patients with previously treated mCRPC.  
To assess baseline TGFβ related biomarker signatures that may correlate with clinical 
efficacy, all patients enrolled in Part 1 will be required to provide a recent archival tumor 
sample or to undergo a fresh pre-treatment biopsy if archival samples are unavailable prior to 
trial treatment.  
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Part 2 patients are required to provide either a recent archival tumor biopsy or, for all patients 
in Part 2A and from approximately 10 patients in Part 2B, mandatory de novo biopsies.  
Mandatory de novo pre-treatment and on-treatment tumor biopsies may not be required 
where it is determined that it is not medically feasible (such as constituting unacceptable 
medical risks).  However, this would require agreement of Investigator and Sponsor.
The biomarker studies will be used to help understand the in vivo mechanism of action of the 
agent(s) studied as well as potential mechanisms of resistance.  The studies may help in the 
future development of PF-06952229 as a single agent, or in combination with other 
compounds, and may provide information on tumor sub-types that may respond to the 
Investigational Product.
Approximately 90 patients are to be enrolled in this study.  The total sample size may vary 
depending on the number of the dose levels with patients enrolled and the actual number of 
patients at each dose level.  A maximum sample size of 40 patients may be needed to 
establish and confirm MTD in Part 1A, and approximately 20 patients may be needed for 
Part 1B.  A maximum of 10 and 20 patients are planned for the expansion cohorts in Part 2A 
and Part 2B, respectively. 
All patients:
1. Will undergo up to 4 weeks of screening prior to study entry, ie, Cycle 1 Day 1.
2. Will receive doses of PF-06952229, administered orally on 28-day cycle, 7 days on, 7 
days off, up to 2 years.  Any additional treatment with PF-06952229 beyond 2 years 
shall be discussed and approved by the Sponsor. 
3. Treatment with investigational product (IP) will continue until disease progression, 
patient refusal, or unacceptable toxicity occurs, whichever occurs first.  However, 
patients who demonstrate clinical benefit (despite radiographic progression) with 
manageable toxicity and are willing to continue receiving the investigational product 
will be given the opportunity to continue treatment upon agreement between 
investigator and sponsor.
4. Will undergo a follow-up visit approximately 4 weeks after the last dose for AE and 
serious adverse event (SAE) collection.
The proposed doses, schedule(s), and PK and PD time points may be reconsidered and 
amended during the study based on the emerging safety and PK and PD data. 


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Study Schema
 
STUDY TREATMENTS
For this study, the Investigational Medicinal Products are PF-06952229 and enzalutamide. 
Refer to the respective IBs for further information on PF-06952229 and enzalutamide.  
DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
Statistical Methods and Properties
Statistical Methods for Dose Escalation
This study contains 2 parts, dose escalation with PF-06952229 alone in patients with 
advanced/metastatic solid tumors (Part 1A) and in combination with enzalutamide in patients 
with mCRPC (Part 1B), followed by a monotherapy dose expansion (Part 2A) and 
combination dose expansion of PF-06952229 with enzalutamide in patients with mCRPC 
(Part 2B).
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Part 1A and 1B Dose Escalation
The dose escalation in Part 1A will start with Accelerated Titration Design (ATD) as 
proposed by Simon et al (Journal of the National Cancer Institute, Vol. 89, No. 15, August 6, 
1997).  Part 1A will have an initial accelerated phase followed by a standard (mTPI) 
escalation phase.  Part 1 B will follow a standard mTPI design.  During the accelerated phase 
in Part 1A, initial cohorts to contain a minimum of one patient until the first instance of 
first-cycle CTCAE grade 2 toxicity.   
Statistical Methods for Determining the MTD 
This study contains dose escalations with single agent and single agent in combination with 
enzalutamide (Part 1A and Part 1B, respectively) and dose expansions with single agent and 
single agent in combination with enzalutamide (Part 2A and Part 2B, respectively).  Part 1B, 
Part 2A and Part 2B will include previously treated patients with mCRPC.  Part 1A and Part 
1B will determine the MTD in sequential dose escalation cohorts for monotherapy and 
combination therapy, respectively. 
The dose finding process in the current study is designed to establish the MTD defined as the 
highest dose that yields a target of approximately 27.5% probability of DLT and considers 
equivalent doses that yield probability of DLT in the interval (Equivalence Interval) of 
(22.5%, 32.5%), provided the DLT rate for cardiac toxicity does not exceed 10%.  The 
27.5% target was chosen based on safety considerations.  The prior distribution of DLT is set 
as a beta (0.5, 0.5) and the threshold probability for early termination and dose exclusion is 
set to 0.95 as suggested in the original mTPI method.4 Similarly, doses with an incidence of 
DLT, eg, 4 out of 10, or apparently higher than 32.5% cannot be selected as MTD, even 
though it might be allowed by the mTPI method.
Cohorts of patients could receive doses already tested but a dose that is associated with
decision to “dose de-escalate, unacceptable toxicity” cannot be revisited and no more patients
should be treated at this dose or higher doses for the remainder of the trial.
The maximum sample size for Part 1A is approximately 40 patients for the monotherapy 
dose escalation, approximately 20 patients for the Part 1B combination escalation, 
approximately 10 patients for Part 2A monotherapy expansion, and approximately 20 
patients for Part 2B combination expansion.  Actual sample size will depend on the 
underlying dose toxicity profile and variability in actual data realization.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments section of the 
protocol for detailed information on each assessment required for compliance with the protocol.  The investigator may schedule visits 
(unplanned visits) in addition to those listed in the Schedule of Activities table in order to conduct evaluations or assessments required 
to protect the well-being of the patient. 
SCHEDULE OF ACTIVITIES PART 1A- Monotherapy Dose Escalation 
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)1
Active Treatment Phase†- One 
Cycle = 28 days
End of Treatment/ Withdrawal24
Post-Treatment Follow-Up25
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 
1
Day 
7
Day 
15
Day 
1
Da
y 7
Informed consent2
X
Medical/Oncological history3
X
Physical examination4
X
X
Abbreviated physical 
examination4
X
X
X
X
X
X
Baseline signs and symptoms5
X
X
Height
X
Weight
X
X
X
X
Vital signs6
X
X6
X
X
X6
X
X
ECOG Performance Status7
X
X
X
X
X
Laboratory
Hematology8
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
Coagulation10
X
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Pregnancy test11
X
X
X
X
Viral disease screening11
X
Contraception check14
X
X
X
X
X
12-lead ECG15
X
See Pharmacokinetic, ECG, 
 Sampling Schedule for Part 1A
Echocardiogram16
X
Cycle 3 Day 1 and every other cycle
Troponin I + BNP17
X
X 
X
X
X 
X
Alk phos fractionation18
X
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SCHEDULE OF ACTIVITIES PART 1A- Monotherapy Dose Escalation 
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)1
Active Treatment Phase†- One 
Cycle = 28 days
End of Treatment/ Withdrawal24
Post-Treatment Follow-Up25
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 
1
Day 
7
Day 
15
Day 
1
Da
y 7
Registration and Treatment 
Registration19
X
PF-0695222920
◄--►
Orally twice daily (BID) on Days 
1-7 and 15-21 of each Cycle
Disease assessments
CT/MRI Scans21
X
See footnote for frequency of scans
X
99Tc Bone scan (for CRPC 
and symptomatic other 
patients)21
X
X
X
Tumor markers
(CA 15-3 and CEA for breast 
cancer; PSA for prostate 
cancer)21
X
X
X
X
Other clinical assessments
Serious and non-serious 
adverse event monitoring22
X
◄--►
Concomitant treatment(s)23
X
◄--►
Survival Follow-Up26
X
Abbreviations: ◄--►= ongoing/continuous event; BID = twice daily; C = cycle; CA 125 = cancer antigen 125; CA 15-3 = cancer antigen 15-3; carcinoembryonic antigen = 
CEA; Day = D; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; CT = computed tomography; LHRH = luteinizing hormone 
releasing hormone; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment.
•
After Cycle 1, Day 1, tests and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for 
holidays, vacations and other administrative reasons.
•
For Pharmacokinetics and additional sampling requirements, please see Pharmacokinetic, ECG, 
 Sampling Schedule for Part 1A below.
a.
Patients must maintain their original dosing schedule (7 days on, 7 days off) regardless of dose reductions or holds.  To accommodate the dosing schedule, visit 
windows are not allowed into the “drug off” periods due to safety concerns; however, 2 day windows are allowed during the “drug on” period.
†Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  On mornings where patients are in the clinic, they will 
be instructed to hold their morning (or afternoon as applicable) dose, which will be administered by study staff onsite on clinic days.  Acceptable time windows for performing 
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SCHEDULE OF ACTIVITIES PART 1A- Monotherapy Dose Escalation 
Protocol Activity
Screening
(28 days 
prior to 
enrollment)1
Active Treatment Phase†- One 
Cycle = 28 days
End of Treatment/ Withdrawal24
Post-Treatment Follow-Up25
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 
1
Day 
7
Day 
15
Day 
1
Da
y 7
each assessment are described in the column headers.  One cycle consists of 28 days.  Day 1 of any cycle visit should coincide with the day the PF-06952229 treatment 
begins.  If there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again.  The active 
treatment phase is ongoing as long as the patient is receiving PF-06952229.
Study entry is Cycle 1 Day 1.
1.
Screening: To be obtained within 28 days prior to study entry.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Medical/Oncologic History: Includes history of disease process (eg, staging) (active or resolved) and concurrent illness.  Includes prior treatments and any current 
medical treatments for any condition.
4.
Physical Examination: Physical examinations (PEs) may be performed within 48 hours prior to a scheduled visit.  A full physical examination is required at Screening 
and abbreviated PEs should be performed as appropriate at each visit where complete physical examinations are not required.  For both full and abbreviated exams, patient 
should be assessed for evidence of bleeding (eg, bruising, petechiae, or hematomas).  No need to repeat PE if baseline assessment is within 96 hours on Cycle 1 Day 1.
5.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry.
6.
Vital Signs: Includes temperature, sitting or semi-recumbent (same position must be used throughout the study and documented in source notes) blood pressure (BP), pulse 
rate (PR, to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (at rest and after exertion).  On Day 1 of each cycle, vital signs should be 
measured prior to dosing (predose); BP, and PR will be repeated 1 hour after dosing.  The time window for Vital Signs will match the allowable window for PK and ECGs.
7.
ECOG Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendices.
8.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 72 hours prior to that date.  Assessments performed on Cycle 2 
Day 1 (C2D1) and each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments section for Laboratory Tests list.
9.
Blood Chemistry: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date (with the exception of serum creatinine which must be 
performed within 72 hours of C1D1).  See Assessments section for Laboratory Tests list.  (Testosterone to be performed at Screening for mCRPC patients only.)  Note that 
chemistries performed require serum phosphorus measurements.
10. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  See Assessments section for Laboratory Tests list. 
11. Urinalysis: Dipstick is acceptable at Screening, during trial conduct, and at the End of Treatment visit.  At Screening, if dipstick shows urine protein ++ or above, perform 
24-hour urine protein test.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  See Assessments section for Laboratory Tests list. 
12. Pregnancy Test: described in the Pregnancy Testing section.  From Cycle 3 onward, pregnancy testing will be performed every other cycle.
13. Viral Disease Screening: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti HBc), (HbcAb), hepatitis B surface antibody (anti HBs), hepatitis C 
virus antibodies (HCVAb), and human immunodeficiency virus testing (HIV) to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
14. Contraceptive Check (frequency to match that of pregnancy tests): Male patients who are able to father children and female patients who are of childbearing potential 
will need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception.  The Investigator or his or her designee will discuss with the 
patient the need to use 2 highly effective contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
Investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.


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SCHEDULE OF ACTIVITIES PART 1A- Monotherapy Dose Escalation 
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)1
Active Treatment Phase†- One 
Cycle = 28 days
End of Treatment/ Withdrawal24
Post-Treatment Follow-Up25
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 
1
Day 
7
Day 
15
Day 
1
Da
y 7
15. Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  ECGs will be collected at times specified in the Pharmacokinetic, ECG 
 
Sampling Schedule of Activities for Part 1A. 
16. Echocardiogram: Echo to be done once patient is confirmed to meet all other inclusion requirements, beginning Cycle 3 Day 1 pre-dose and every other cycle.  A ±7 day 
window will be applied.
17. Troponin I and BNP: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  Will be performed per the SOA and will be repeated 
if abnormal and clinically significant.
18. Alk Phos Fractionation: Obtain alkaline phosphatase (ALP) fractionation (bone, liver) per the SOA and as clinically indicated.  With each ALP increase in AE grade level 
once at the grade level, fractionation will be obtained and appropriate clinical evaluation will be conducted to determine the suitability of the patient continuation in the 
trial.
19. Registration: Patient number and dose level allocation assigned by Pfizer Inc. 
20. Study Treatment: PF-06952229 will be administered orally for 7 days on, 7 days off, during a 28 day cycle. Day 1 safety laboratory tests must be reviewed by the 
Investigator prior to dosing at the beginning of each cycle for dosing confirmation.  Patients will self dose as described above, with the exception of doses that will be 
administered on site.  Patients must maintain their original dosing schedule regardless of dose reductions or holds.  Patients will be required to return all bottles of 
PF-06952229 as well as the completed patient diary for drug accountability. For a minimum of the first 2 cycles, patients will be contacted by site personnel on drug start 
and stop days to ensure compliance to the study drug schedule.  On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at 
home).
21. Tumor Assessments: Tumor assessments will include CT or MRI of chest, abdomen and pelvis, and MRI of the brain.  If a brain MRI is medically contraindicated, a CT 
scan with contrast (unless contrast is medically contraindicated) may be performed, however the same modality should be used on an individual patient throughout the 
study.  Other disease sites may be imaged if disease is suspected.  Tumor assessments will be performed at Screening and every 8 weeks (±7 days) for the first year, then 
every 12 weeks (±7 days) Bone scans will be performed as medically indicated.  Patients who are found to have hemorrhage in other organs will discontinue treatment with 
PF-06952229 and enter the follow-up portion of the trial.  Tc-99m bone scans (required for CRPC at baseline) will be performed at baseline if disease is suspected and on 
study as appropriate to follow disease.  The frequency of CA-15-3 assessments should match the frequency of other tumor assessments.  Tumor assessments with continue 
until radiographically and/or clinically (ie, for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment discontinuation (for patients 
continuing treatment beyond RECIST defined disease progression), initiation of new anticancer therapy or discontinuation of patient from overall study participation (eg, 
death, patient's request, lost to follow-up), whichever occurs first.  Given the exploratory nature of the study, confirmation of response (complete response (CR)/partial 
response (PR)) is preferred (see RECIST version 1.1).  Tumor assessments should be repeated at the end of study visit if more than 6 weeks have passed since the last 
evaluation.  Patients should have a confirmatory scan for PD and can remain on trial if they are receiving clinical benefit upon discussion with investigator and sponsor 
MD.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  FDG-PET will be performed per standard of care. 
Bone Scans for mCRPC: 99mTc-methylene diphosphonate radionuclide bone scintigraphy should be performed every 8 weeks for first 24 weeks, then every 12 weeks 
(up to 2 years), then every 16 to 24 weeks (± 14 days).  Changes in lesions that are considered metastatic on bone scintigraphy should be followed and assessed serially 
using a bone scan assessment form (see Appendices).  mCRPC Only: Prostate specific antigen (PSA) assessment to be performed on Screening (for historical progression 
per Prostate Working Group 2), C1D1 (-14 days) and Day 1 of Cycle 4, 7, 10 and every 2nd cycle thereafter as well as the End of Treatment visit.  Please see Appendix for 
Prostate Cancer Working Group 2 (PCWG2) - Soft Tissue Response Criteria.
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SCHEDULE OF ACTIVITIES PART 1A- Monotherapy Dose Escalation 
Protocol Activity
Screening
(28 days 
prior to 
enrollment)1
Active Treatment Phase†- One 
Cycle = 28 days
End of Treatment/ Withdrawal24
Post-Treatment Follow-Up25
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 
1
Day 
7
Day 
15
Day 
1
Da
y 7
22. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 5.0.  The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time 
the patient provides informed consent through and including a minimum of 28 calendar days after the last investigational product administration.  If the patient begins a 
new anticancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
23. Concomitant Treatments: All concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF including supportive care drugs, eg, 
anti-emetic treatment and prophylaxis, radiotherapy on study is permitted (eg, skeletal administration for CRPC, drugs used to treat adverse events or chronic diseases, and 
non-drug supportive interventions [eg, infusions]).
24. End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of 
any new anti-tumor therapy.  Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks [as applicable] for 
disease assessments).
25. Post Treatment Follow-Up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant 
medications, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity and for confirmation of contraception use.  Patients 
continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, 
in the clinical judgment of the investigator, that no further improvement is expected. 
26. Survival Follow-Up: Subsequent to the follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the entire 
study (2 years after last patient first treatment).  If the patient is seen in the clinic during the window of time that a scheduled telephone call is to be made to collect survival 
data, then the clinic visit may replace the survival telephone call.


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Pharmacokinetic, ECG, 
 Sampling Schedule for Part 1A – Monotherapy Dose Escalation
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 7
Day 15
Day 1
Day 7
Day 7
Dose of PF-06952229 in clinic1
X
X
X
X
X
X
Meal administration2
X
Pharmacokinetics (PK) 
Predose (if dosing day)
X
X
X
X
X
X
X
0.5 hours (±5 min)
X
X
X
1 hour (±10 min)
X
X
X
2 hours (±15 min)
X
X
X
4 hours (±25 min)
X
X
X
6 hours (±40 min)
X
X
X
12 hours (-180 min)
X
X
X
12-Lead ECG3
0
X
X
X
X
X
X
X
2 hours (±15 min)
X
X
4 hours (±25 min)
X
X
 
 
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Page 34
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 7
Day 15
Day 1
Day 7
Day 7
Dose of PF-06952229 in clinic1
X
X
X
X
X
X
Meal administration2
X
Pharmacokinetics (PK) 
Abbreviations: PK = pharmacokinetic; 
; EOT = End of Treatment; 
1.
Dose of PF-06952229 in Clinic: On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
 
 
 
 
 
3.
Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be 
performed approximately 2 minutes apart to determine mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution.  When 
coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the blood sample is 
collected at the nominal time.  If the mean QTcF is prolonged (≥45 msec from the baseline or >500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
  
 
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SCHEDULE OF ACTIVITIES PART 1B – Combination Dose Escalation
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2
Day 
7
Day 
10b
Day 
15
Day 
21c
Day 
1
D
ay 
7
Informed consent2
X
Medical/Oncological history3
X
Physical examination4
X
X
Abbreviated physical examination4
X
X
X
X
X
X
Baseline signs and symptoms5
X
Height
X
Weight
X
X
X
X
Vital signs6
X
X6
X
X
X6
X
X
ECOG Performance status7
X
X
X
X
X
Laboratory
Hematology8
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
Coagulation10
X
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Viral disease screening12
X
Contraception check13
X
X
X
X
X
12-lead ECG14
X
See Pharmacokinetic, ECG 
 Sampling Schedule for Part 1B
Echocardiogram15
X
X 
X
Troponin I + BNP16
X
X
X
X
X 
X
Alk Phos fractionation17
X
Registration and Treatment 
Registration18
X
PF-0695222919
◄--►
Orally twice daily (BID) on Days 1-7 and 15-21 of each Cycle
Enzalutamide19
◄--►
Orally QD as continuous daily dosing
Tumor assessments
CT/MRI Scans20
X
See footnote for frequency of scans
X
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SCHEDULE OF ACTIVITIES PART 1B – Combination Dose Escalation
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2
Day 
7
Day 
10b
Day 
15
Day 
21c
Day 
1
D
ay 
7
Tumor markers
PSA for prostate cancer20
X
X
X
X
 
 
 
Other clinical assessments
Serious and non-serious adverse 
event monitoring21
X
◄--►
Concomitant treatment(s)22
X
◄--►
Survival Follow-Up25
X
Abbreviations: ◄--►= ongoing/continuous event; BID = twice daily; C = cycle; Day = D; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
end of treatment; CT = computed tomography; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment.
•
After Cycle 1, Day 1, tests and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for 
holidays, vacations and other administrative reasons.
•
For Pharmacokinetics and additional sampling requirements, please see Pharmacokinetic, ECG, 
 Sampling Schedule for Part 1B Table below.
a.
Patients must maintain their original dosing schedule (7 days on, 7 days off) regardless of dose reductions or holds.  To accommodate the dosing schedule, visit 
windows are not allowed into the “drug off” periods due to safety concerns; however, 2 day windows are allowed during the “drug on” period. 
b.
Day 10 assessments are only performed in Cycle 2.
c.
Day 21 assessments are only performed in Cycle 1.
†Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  On mornings where patients are in the clinic, they will 
be instructed to hold their morning (or afternoon as applicable) dose, which will be administered by study staff onsite on clinic days.  Acceptable time windows for performing 
each assessment are described in the column headers.  One cycle consists of 28 days.  Day 1 of any cycle visit should coincide with the day the PF-06952229 treatment 
begins.  If there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again.  The active 
treatment phase is ongoing as long as the patient is receiving PF-06952229.
Study entry is Cycle 1 Day 1.
1.
Screening: To be obtained within 28 days prior to study entry.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Medical/Oncologic History: Includes history of disease process (eg, staging) (active or resolved) and concurrent illness.  Includes prior treatments and any current 
medical treatments for any condition.
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SCHEDULE OF ACTIVITIES PART 1B – Combination Dose Escalation
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2
Day 
7
Day 
10b
Day 
15
Day 
21c
Day 
1
D
ay 
7
4.
Physical Examination: Physical examinations (PEs) may be performed within 48 hours prior to a scheduled visit.  A full physical examination is required at Screening 
and abbreviated PEs should be performed as appropriate at each visit where complete physical examinations are not required.  For both full and abbreviated exams, patient 
should be assessed for evidence of bleeding (eg, bruising, petechiae, or hematomas).  No need to repeat PE if baseline assessment is within 96 hours on Cycle 1 Day 1.
5.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry.
6.
Vital Signs: Includes temperature, sitting or semi-recumbent (same position must be used throughout the study and documented in source notes) blood pressure (BP), pulse 
rate (PR, to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (at rest and after exertion).  On Day 1 of each cycle, vital signs should be 
measured prior to dosing (predose), BP, and PR will be repeated 1 hour after dosing.  The time window for Vital Signs will match the allowable window for PK and ECGs.
7.
ECOG Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendices.
8.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 72 hours prior to that date.  Assessments performed on Cycle 2 
Day 1 (C2D1) and each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments section for Laboratory Tests list.
9.
Blood Chemistry: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date (with the exception of serum creatinine which must be 
performed within 72 hours of C1D1).  See Assessments section for Laboratory Tests list.  Note that chemistries performed require serum phosphorus measurements.
10. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  See Assessments section for Laboratory Tests list.  
11. Urinalysis: Dipstick is acceptable at Screening, during trial conduct, and the End of Treatment visit.  At Screening, if dipstick shows urine protein ++ or above, perform 
24-hour urine protein test.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  See Assessments section for Laboratory Tests list.  
.
12. Viral Disease Screening: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti HBc), (HbcAb), hepatitis B surface antibody (anti HBs), hepatitis C 
virus antibodies (HCVAb), and human immunodeficiency virus testing (HIV) to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
13. Contraceptive Check: Male patients who are able to father children need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception.  
The Investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods consistently and correctly and document such 
conversation in the patient’s chart.  In addition, the Investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient’s partner.
14. Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  ECGs will be collected at times specified in Pharmacokinetic, ECG, 
 
Sampling Schedule for Part 1B. 
15. Echocardiogram: Echo to be done once patient is confirmed to meet all other inclusion requirements, beginning Cycle 3 Day 1 predose and every 2 cycles for 6 months, 
then every 3 cycles. A ±7 day window will be applied.
16. Troponin I and BNP: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  Will be performed per the SOA and will be repeated 
if abnormal and clinically significant.
17. Alk Phos Fractionation: Obtain alkaline phosphatase (ALP) fractionation (bone, liver) per the SOA and as clinically indicated.  With each ALP increase in AE grade level 
once at the grade level, fractionation will be obtained and an appropriate clinical evaluation will be conducted to determine the suitability of the patient continuation in the 
trial.
18. Registration: patient number and dose level allocation assigned by Pfizer Inc. 
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SCHEDULE OF ACTIVITIES PART 1B – Combination Dose Escalation
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2
Day 
7
Day 
10b
Day 
15
Day 
21c
Day 
1
D
ay 
7
19. Study Treatment: PF-06952229 will be administered orally for 7 days on, 7 days off, during a 28 day cycle.  Day 1 safety laboratory tests must be reviewed by the 
Investigator prior to dosing at the beginning of each cycle for dosing confirmation.  For Part 1B mCRPC patients will receive PF-06952229 in combination with 
enzalutamide.  Patients will self dose as described above, with the exception of doses that will be administered on site.  Patients must maintain their original dosing 
schedule regardless of dose reductions or holds.  Patients will be required to return all bottles of PF-06952229 as well as the completed patient diary for drug 
accountability.  On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
20. Tumor Assessments: Tumor assessments will include CT or MRI of chest, abdomen and pelvis, and MRI of the brain.  If a brain MRI is medically contraindicated, a CT 
scan with contrast (unless contrast is medically contraindicated) may be performed, however the same modality should be used on an individual patient throughout the 
study.  Other disease sites may be imaged if disease is suspected.  Tumor assessments will be performed at Screening and every 8 weeks (±7 days) for the first year, then 
every 12 weeks (±7 days).  Bone scans will be performed as medically indicated.  Tc-99m bone scans (required for CRPC at baseline) will be performed at baseline if 
disease is suspected and on study as appropriate to follow disease.  Patients who are found to have hemorrhage in other organs will discontinue treatment with PF-
06952229 and enter the follow-up portion of the trial. Tumor assessments with continue until radiographically and/or clinically (ie, for photographed or palpable lesions) 
documented PD as per RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond RECIST defined disease progression), initiation of new 
anticancer therapy or discontinuation of patient from overall study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  Given the 
exploratory nature of the study, confirmation of response (complete response (CR)/partial response (PR)) is preferred (see RECIST version 1.1).  Tumor assessments 
should be repeated at the end of study visit if more than 6 weeks have passed since the last evaluation.  Patients should have a confirmatory scan for PD and can remain on 
trial if they are receiving clinical benefit upon discussion with investigator and sponsor MD.  Tumor assessments should be fixed according to the calendar, regardless of 
treatment delays.  FDG-PET will be performed per standard of care.
Bone Scans for mCRPC: 99mTc-methylene diphosphonate radionuclide bone scintigraphy should be performed every 8 weeks for first 24 weeks, then every 12 weeks 
(up to 2 years), then every 16 to 24 weeks (±14 days).  Changes in lesions that are considered metastatic on bone scintigraphy should be followed and assessed serially 
using a bone scan assessment form (see Appendices).
Prostate specific antigen (PSA) assessment to be performed on Screening (for historical progression per Prostate working Group 2), C1D1 (-14 days) and Day 1 of Cycle 
4, 7, 10 and every 3rd cycle thereafter as well as the End of Treatment visit.  Please see Appendix for Prostate Cancer Working Group 2 (PCWG2)- Soft Tissue Response 
Criteria.
21. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the NCI CTCAE version 5.0.  The time period for actively eliciting and 
collecting AEs and SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and including a minimum of 
28 calendar days after the last investigational product administration.  If the patient begins a new anticancer therapy, the period for recording non-serious AEs on the CRF 
ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must still be reported to Pfizer Safety and recorded on the 
CRF, irrespective of any intervening treatment.
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SCHEDULE OF ACTIVITIES PART 1B – Combination Dose Escalation
Protocol Activity
Screening
(28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2
Day 
7
Day 
10b
Day 
15
Day 
21c
Day 
1
D
ay 
7
22. Concomitant Treatments: All concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF including supportive care drugs, eg, 
anti-emetic treatment and prophylaxis, radiotherapy on study is permitted (eg, skeletal administration for CRPC), drugs used to treat adverse events or chronic diseases, 
and non-drug supportive interventions (eg, infusions).
23. End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of 
any new anti-tumor therapy.  Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks as applicable for 
disease assessments).
24. Post Treatment Follow-Up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant 
medications, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point 
following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that 
no further improvement is expected.
25. Survival Follow-Up: Subsequent to the follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the entire 
study (2 years after last patient first treatment).  If the patient is seen in the clinic during the window of time that a scheduled telephone call is to be made to collect survival 
data, then the clinic visit may replace the survival telephone call.


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Page 40
Pharmacokinetic, ECG,
 Sampling Schedule for Part 1B - Combination Dose Escalation with 
Enzalutamide 
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 2
Day 7
Day 15
Day 21
Day 1
Day 2
Day 7
Day 10 
(-24hrs)
Day 7
Dose of 
PF-06952229 in clinic1
X*
X
X
X
X
X*
X
X
X
Pharmacokinetics (PK)
Predose (if dosing day)
N, E
N
N, E
N
N, E
N, E
N
N
N
N
N
0.5 hours (±5 min)
N
N
N
1 hour (±10 min)
N
N
N
2 hours (±15 min)
N
N
N
4 hours (±25 min)
N
N
N
6 hours (±40 min)
N
N
N
12 hours (-180 min)
N
N
N
12-Lead ECG2
0
X
X
X
X
X
X
X
X
X
2 hours (±15 min)
X
X
4 hours (±25 min)
X
X
 
 
 
 
 
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Page 41
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 2
Day 7
Day 15
Day 21
Day 1
Day 2
Day 7
Day 10 
(-24hrs)
Day 7
 
 
 
 
 
Abbreviation: PK = pharmacokinetic;
; EOT = End of Treatment; N=PF-06952229; E=Enzalutamide; 
 
* On Day 1 of Cycle 1 and Cycle 2 only a single dose of PF-06952229 to be given to evaluate PF-06952229 PK sampling up to 24 hr time point (ie, pre-dose on Day 2 of 
Cycle 1 and Cycle 2)
1.
Dose of PF-06952229 in Clinic: On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
2.
Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be 
performed approximately 2 minutes apart to determine mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution.  When 
coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to blood sample collection, such that the blood 
sample is collected at the nominal time.  If the mean QTcF is prolonged (≥45 msec from the baseline or >500 msec), the ECGs should be re-evaluated by a qualified person 
at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
 
 
 
 
 
 
 
 
 
 
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SCHEDULE OF ACTIVITIES PART 2A – Monotherapy Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatmen
t Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 7
Day 
10b
Day 
15
Day 
1
Day 
7
Informed consent2
X
Medical/Oncological history3
X
Physical examination4
X
X
Abbreviated physical examination4
X
X
X
X
X
X
Baseline signs and symptoms5
X
Height
X
Weight
X
X
X
X
Vital signs6
X
X6
X
X
X6
X
X
ECOG Performance status7
X
X
X
X
X
Laboratory
Hematology8
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
Coagulation10
X
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Viral disease screening12
X
Contraception check13
X
X
X
X
X
12-lead ECG14
X
See Pharmacokinetic, ECG 
 Sampling Schedule for Part 2A
Echocardiogram15
X
X 
X
Troponin I + BNP16
X
X
X
X
X 
X
Alk Phos fractionation17
X
Registration and Treatment 
Registration18
X
PF-0695222919
◄--►
Orally twice daily (BID) on Days 1-7 and 15-21 of each 
Cycle
Tumor assessments
CT/MRI Scans20
X
See footnote for frequency of scans
X
Tumor markers
X
X
X
X
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SCHEDULE OF ACTIVITIES PART 2A – Monotherapy Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatmen
t Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 7
Day 
10b
Day 
15
Day 
1
Day 
7
(PSA and Gleason Score for prostate 
cancer)20
 
 
Other clinical assessments
Serious and non-serious adverse event 
monitoring21
X
◄--►
Concomitant treatment(s)22
X
◄--►
Survival Follow-Up25
X
Abbreviations: ◄--►= ongoing/continuous event; BID = twice daily; C = cycle; Day = D; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
end of treatment; CT = computed tomography; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment.
•
After Cycle 1, Day 1, tests administrative reasons.
•
For and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for holidays, vacations and other 
Pharmacokinetics and additional sampling requirements, please see Pharmacokinetic, ECG,
 Sampling Schedule for Part 2A Table below.
a.
Patients must maintain their original dosing schedule (7 days on, 7 days off) regardless of dose reductions or holds.  To accommodate the dosing schedule, visit 
windows are not allowed into the “drug off” periods due to safety concerns; however, 2 day windows are allowed during the “drug on” period. 
b.
Day 10 assessments are only performed in Cycle 2
†Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  On mornings where patients are in the clinic, they will 
be instructed to hold their morning (or afternoon as applicable) dose, which will be administered by study staff onsite on clinic days.  Acceptable time windows for performing 
each assessment are described in the column headers.  One cycle consists of 28 days.  Day 1 of any cycle visit should coincide with the day the PF-06952229 treatment 
begins.  If there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again.  The active 
treatment phase is ongoing as long as the patient is receiving PF-06952229.
Study entry is Cycle 1 Day 1.
1.
Screening: To be obtained within 28 days prior to study entry.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Medical/Oncologic History: Includes history of disease process (eg, staging) (active or resolved) and concurrent illness.  Includes prior treatments and any current medical 
treatments for any condition.
4.
Physical Examination: Physical examinations (PEs) may be performed within 48 hours prior to a scheduled visit.  A full physical examination is required at Screening and 
abbreviated PEs should be performed as appropriate at each visit where complete physical examinations are not required.  For both full and abbreviated exams, patient 
should be assessed for evidence of bleeding (eg, bruising, petechiae, or hematomas).  No need to repeat PE if baseline assessment is within 96 hours on Cycle 1 Day 1.
5.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry.
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SCHEDULE OF ACTIVITIES PART 2A – Monotherapy Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatmen
t Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 7
Day 
10b
Day 
15
Day 
1
Day 
7
6.
Vital Signs: Includes temperature, sitting or semi-recumbent (same position must be used throughout the study and documented in source notes) blood pressure (BP), pulse 
rate (PR, to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (at rest and after exertion).  On Day 1 of each cycle, vital signs should be 
measured prior to dosing (predose), BP, and PR will be repeated 1 hour after dosing.  The time window for Vital Signs will match the allowable window for PK and ECGs.
7.
ECOG Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendices.
8.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 72 hours prior to that date.  Assessments performed on Cycle 2 
Day 1 (C2D1) and each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments section for Laboratory Tests list.
9.
Blood Chemistry: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date (with the exception of serum creatinine which must be 
performed within 72 hours of C1D1).  See Assessments section for Laboratory Tests list.  Note that chemistries performed require serum phosphorus measurements.
10. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  See Assessments section for Laboratory Tests list.
11. Urinalysis: Dipstick is acceptable at Screening, during trial conduct, and the End of Treatment visit.  At Screening, if dipstick shows urine protein ++ or above, perform 
24-hour urine protein test.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  See Assessments section for Laboratory Tests list.  
12. Viral Disease Screening: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti HBc), (HbcAb), hepatitis B surface antibody (anti HBs), hepatitis C 
virus antibodies (HCVAb), and human immunodeficiency virus testing (HIV) to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
13. Contraceptive Check: Male patients who are able to father children need to affirm that they meet the criteria for correct use of 2 of the selected methods of contraception.  
The Investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods consistently and correctly and document such 
conversation in the patient’s chart.  In addition, the Investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient’s partner.
14. Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  ECGs will be collected at times specified in Pharmacokinetic, ECG, 
 
Sampling Schedule for Part 2A. 
15. Echocardiogram: Echo to be done once patient is confirmed to meet all other inclusion requirements, beginning Cycle 3 Day 1 predose and every 2 cycles for 6 months, 
then every 3 cycles. A ±7 day window will be applied.
16. Troponin I and BNP: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  Will be performed per the SOA and will be repeated if 
abnormal and clinically significant.
17. Alk Phos Fractionation: Obtain alkaline phosphatase (ALP) fractionation (bone, liver) per the SOA and as clinically indicated.  With each ALP increase in AE grade level 
once at the grade level, fractionation will be obtained and an appropriate clinical evaluation will be conducted to determine the suitability of the patient continuation in the 
trial.
18. Registration: patient number and dose level allocation assigned by Pfizer Inc. 
19. Study Treatment: PF-06952229 will be administered orally for 7 days on, 7 days off, during a 28 day cycle.  Day 1 safety laboratory tests must be reviewed by the 
Investigator prior to dosing at the beginning of each cycle for dosing confirmation.  Patients will self dose as described above, with the exception of doses that will be 
administered on site.  Patients must maintain their original dosing schedule regardless of dose reductions or holds.  Patients will be required to return all bottles of 
PF-06952229 as well as the completed patient diary for drug accountability.  On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, 
not at home).
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SCHEDULE OF ACTIVITIES PART 2A – Monotherapy Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatmen
t Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 7
Day 
10b
Day 
15
Day 
1
Day 
7
20. Tumor Assessments: Tumor assessments will include CT or MRI of chest, abdomen and pelvis, and MRI of the brain.  If a brain MRI is medically contraindicated, a CT 
scan with contrast (unless contrast is medically contraindicated) may be performed, however the same modality should be used on an individual patient throughout the 
study.  Other disease sites may be imaged if disease is suspected.  Tumor assessments will be performed at Screening and every 8 weeks (±7 days) for the first year, then 
every 12 weeks (±7 days).  Bone scans will be performed as medically indicated.  Tc-99m bone scans (required for CRPC at baseline) will be performed at baseline if 
disease is suspected and on study as appropriate to follow disease.  Patients who are found to have hemorrhage in other organs will discontinue treatment with PF-06952229 
and enter the follow-up portion of the trial. Tumor assessments with continue until radiographically and/or clinically (ie, for photographed or palpable lesions) documented 
PD as per RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond RECIST defined disease progression), initiation of new anticancer 
therapy or discontinuation of patient from overall study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  Given the exploratory nature of 
the study, confirmation of response (complete response (CR)/partial response (PR)) is preferred (see RECIST version 1.1).  Tumor assessments should be repeated at the 
end of study visit if more than 6 weeks have passed since the last evaluation.  Patients should have a confirmatory scan for PD and can remain on trial if they are receiving 
clinical benefit upon discussion with investigator and sponsor MD.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  FDG-PET 
will be performed per standard of care.
Bone Scans for mCRPC: 99mTc-methylene diphosphonate radionuclide bone scintigraphy should be performed every 8 weeks for first 24 weeks, then every 12 weeks (up 
to 2 years), then every 16 to 24 weeks (±14 days).  Changes in lesions that are considered metastatic on bone scintigraphy should be followed and assessed serially using a 
bone scan assessment form (see Appendices).
Prostate specific antigen (PSA) assessment to be performed on Screening (for historical progression per Prostate Cancer Working Group 2), C1D1 (-14 days) and 
Day 1 of Cycle 4, 7, 10 and every 3rd cycle thereafter as well as the End of Treatment visit.  Please see Appendix for Prostate Cancer Working Group 2 (PCWG2)- Soft 
Tissue Response Criteria.
Gleason Score should be collected at diagnosis. 
21. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 5.0.  The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the 
patient provides informed consent through and including a minimum of 28 calendar days after the last investigational product administration.  If the patient begins a new 
anticancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
22. Concomitant Treatments: All concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF including supportive care drugs, eg, 
anti-emetic treatment and prophylaxis, radiotherapy on study is permitted (eg, skeletal administration for CRPC), drugs used to treat adverse events or chronic diseases, and 
non-drug supportive interventions (eg, infusions).
23. End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of 
any new anti-tumor therapy.  Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks as applicable for 
disease assessments).
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SCHEDULE OF ACTIVITIES PART 2A – Monotherapy Dose Expansion
Protocol Activity
Screening
(28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatmen
t Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 7
Day 
10b
Day 
15
Day 
1
Day 
7
24. Post Treatment Follow-Up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant 
medications, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point 
following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that 
no further improvement is expected.
25. Survival Follow-Up: Subsequent to the follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the entire 
study (2 years after last patient first treatment).  If the patient is seen in the clinic during the window of time that a scheduled telephone call is to be made to collect survival 
data, then the clinic visit may replace the survival telephone call.


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Pharmacokinetic, ECG, 
 Sampling Schedule for Part 2A – Monotherapy Dose Expansion
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 7
Day 15
Day 1
Day 7
Day 10 (-24hrs)
Day 7
Dose of PF-06952229 in clinic1
X
X
X
X
X
X
Pharmacokinetics (PK)
Predose (if dosing day)
X
X
X
X
X
X
X
X
0.5 hours (±5 min)
X
X
1 hour (±10 min)
X
X
2 hours (±15 min)
X
X
4 hours (±25 min)
X
X
6 hours (±40 min)
X
X
12 hours (-180 min)
X
X
Urine for PF-06952229 PK2
X
12-Lead ECG3
0
X
X
X
X
X
X
X
2 hours (±15 min)
X
X
4 hours (±25 min)
X
X
 
 
 
  
 
 
 
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Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 7
Day 15
Day 1
Day 7
Day 10 (-24hrs)
Day 7
Dose of PF-06952229 in clinic1
X
X
X
X
X
X
Pharmacokinetics (PK)
Abbreviation: PK = pharmacokinetic; 
; EOT = End of Treatment; 
1.
Dose of PF-06952229 in Clinic: On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
2.
Urine for PF-06952229 PK: Optional – See Section 7.3.2.
3.
Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be 
performed approximately 2 minutes apart to determine mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution.  When 
coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to blood sample collection, such that the blood 
sample is collected at the nominal time.  If the mean QTcF is prolonged (≥45 msec from the baseline or >500 msec), the ECGs should be re-evaluated by a qualified person 
at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
 
 
 
 
 
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SCHEDULE OF ACTIVITIES PART 2B – Combination Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2c
Day 7
Day 
10b
Day 
15
Day 
21c
Day 1
Day 7
Informed consent2
X
Medical/Oncological history3
X
Physical examination4
X
X
Abbreviated physical examination4
X
X
X
X
X
X
Baseline signs and symptoms5
X
Height
X
Weight
X
X
X
X
Vital signs6
X
X6
X
X
X6
X
X
ECOG Performance status7
X
X
X
X
X
Laboratory
Hematology8
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
Coagulation10
X
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Viral disease screening12
X
Contraception check13
X
X
X
X
X
12-lead ECG14
X
See Pharmacokinetic, ECG 
 Sampling Schedule for Part 2B
Echocardiogram15
X
X 
X
Troponin I + BNP16
X
X
X
X
X 
X
Alk Phos fractionation17
X
Registration and Treatment 
Registration18
X
PF-0695222919
◄--►
Orally twice daily (BID) on Days 1-7 and 15-21 of each Cycle
Enzalutamide19
◄--►
Orally QD as continuous daily dosing
Tumor assessments
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SCHEDULE OF ACTIVITIES PART 2B – Combination Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2c
Day 7
Day 
10b
Day 
15
Day 
21c
Day 1
Day 7
CT/MRI Scans20
X
See footnote for frequency of scans
X
Tumor markers
(PSA and Gleason Score for 
prostate cancer)20
X
X
X
X
 
 
 
Other clinical assessments
Serious and non-serious adverse 
event monitoring21
X
◄--►
Concomitant treatment(s)22
X
◄--►
Survival Follow-Up25
X
Abbreviations: ◄--►= ongoing/continuous event; BID = twice daily; C = cycle; Day = D; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
end of treatment; CT = computed tomography; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment.
•
After Cycle 1, Day 1, tests and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for 
holidays, vacations and other administrative reasons.
•
For Pharmacokinetics and additional sampling requirements, please see Pharmacokinetic, ECG, 
 Sampling Schedule for Part 2B Table below.
a.
Patients must maintain their original dosing schedule (7 days on, 7 days off) regardless of dose reductions or holds.  To accommodate the dosing schedule, visit 
windows are not allowed into the “drug off” periods due to safety concerns; however, 2 day windows are allowed during the “drug on” period. 
b.
Day 10 assessments are only performed in Cycle 2.
c.
Day 2 and Day 21 visit for first 8 subjects (min).
†Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  On mornings where patients are in the clinic, they will 
be instructed to hold their morning (or afternoon as applicable) dose, which will be administered by study staff onsite on clinic days.  Acceptable time windows for performing 
each assessment are described in the column headers.  One cycle consists of 28 days.  Day 1 of any cycle visit should coincide with the day the PF-06952229 treatment 
begins.  If there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again.  The active 
treatment phase is ongoing as long as the patient is receiving PF-06952229.
Study entry is Cycle 1 Day 1.
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SCHEDULE OF ACTIVITIES PART 2B – Combination Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2c
Day 7
Day 
10b
Day 
15
Day 
21c
Day 1
Day 7
1.
Screening: To be obtained within 28 days prior to study entry.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
3.
Medical/Oncologic History: Includes history of disease process (eg, staging) (active or resolved) and concurrent illness.  Includes prior treatments and any current medical 
treatments for any condition.
4.
Physical Examination: Physical examinations (PEs) may be performed within 48 hours prior to a scheduled visit.  A full physical examination is required at Screening and 
abbreviated PEs should be performed as appropriate at each visit where complete physical examinations are not required.  For both full and abbreviated exams, patient 
should be assessed for evidence of bleeding (eg, bruising, petechiae, or hematomas).  No need to repeat PE if baseline assessment is within 96 hours on Cycle 1 Day 1.
5.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry.
6.
Vital Signs: Includes temperature, sitting or semi-recumbent (same position must be used throughout the study and documented in source notes) blood pressure (BP), pulse 
rate (PR, to be recorded in the sitting position after 5 minutes of rest), and pulse oximetry (at rest and after exertion).  On Day 1 of each cycle, vital signs should be 
measured prior to dosing (predose), BP, and PR will be repeated 1 hour after dosing.  The time window for Vital Signs will match the allowable window for PK and ECGs.
7.
ECOG Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendices.
8.
Hematology: No need to repeat on Cycle 1 Day 1 (C1D1) if baseline assessment performed within 72 hours prior to that date.  Assessments performed on Cycle 2 
Day 1 (C2D1) and each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments section for Laboratory Tests list.
9.
Blood Chemistry: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date (with the exception of serum creatinine which must be 
performed within 72 hours of C1D1).  See Assessments section for Laboratory Tests list.  Note that chemistries performed require serum phosphorus measurements.
10. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  See Assessments section for Laboratory Tests list.
11. Urinalysis: Dipstick is acceptable at Screening, during trial conduct, and the End of Treatment visit.  At Screening, if dipstick shows urine protein ++ or above, perform 
24-hour urine protein test.  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  See Assessments section for Laboratory Tests list.  
12. Viral Disease Screening: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti HBc), (HbcAb), hepatitis B surface antibody (anti HBs), hepatitis C 
virus antibodies (HCVAb), and human immunodeficiency virus testing (HIV) to be conducted by local laboratory where required by local regulations or if warranted by 
patient history.
13. Contraceptive Check (frequency to match that of pregnancy tests): Male patients who are able to father children need to affirm that they meet the criteria for correct use 
of 2 of the selected methods of contraception.  The Investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods 
consistently and correctly and document such conversation in the patient’s chart.  In addition, the Investigator or his or her designee will instruct the patient to call 
immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or suspected in the patient’s partner.
14. Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  ECGs will be collected at times specified in Pharmacokinetic, ECG, 
 
Sampling Schedule for Part 2B. 
15. Echocardiogram: Echo to be done once patient is confirmed to meet all other inclusion requirements, beginning cycle 3 Day 1 predose and every 2 cycles for 6 months, 
then every 3 cycles. A ±7 day window will be applied.
16. Troponin I and BNP: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  Will be performed per the SOA and will be repeated if 
abnormal and clinically significant.
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SCHEDULE OF ACTIVITIES PART 2B – Combination Dose Expansion
Protocol Activity
Screening
(≤28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2c
Day 7
Day 
10b
Day 
15
Day 
21c
Day 1
Day 7
17. Alk Phos Fractionation: Obtain alkaline phosphatase (ALP) fractionation (bone, liver) per the SOA and as clinically indicated.  With each ALP increase in AE grade level 
once at the grade level, fractionation will be obtained and an appropriate clinical evaluation will be conducted to determine the suitability of the patient continuation in the 
trial.
18. Registration: patient number and dose level allocation assigned by Pfizer Inc. 
19. Study Treatment: PF-06952229 will be administered orally for 7 days on, 7 days off, during a 28 day cycle.  Day 1 safety laboratory tests must be reviewed by the 
Investigator prior to dosing at the beginning of each cycle for dosing confirmation.  For Part 2B mCRPC patients will receive PF-06952229 in combination with 
enzalutamide.  Patients will self dose as described above, with the exception of doses that will be administered on site.  Patients must maintain their original dosing schedule 
regardless of dose reductions or holds.  Patients will be required to return all bottles of PF-06952229 as well as the completed patient diary for drug accountability.  On days 
of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
20. Tumor Assessments: Tumor assessments will include CT or MRI of chest, abdomen and pelvis, and MRI of the brain.  If a brain MRI is medically contraindicated, a CT 
scan with contrast (unless contrast is medically contraindicated) may be performed, however the same modality should be used on an individual patient throughout the 
study.  Other disease sites may be imaged if disease is suspected.  Tumor assessments will be performed at Screening and every 8 weeks (±7 days) for the first year, then 
every 12 weeks (±7 days).  Bone scans will be performed as medically indicated.  Tc-99m bone scans (required for CRPC at baseline) will be performed at baseline if 
disease is suspected and on study as appropriate to follow disease.  Patients who are found to have hemorrhage in other organs will discontinue treatment with PF-06952229 
and enter the follow-up portion of the trial. Tumor assessments with continue until radiographically and/or clinically (ie, for photographed or palpable lesions) documented 
PD as per RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond RECIST defined disease progression), initiation of new anticancer 
therapy or discontinuation of patient from overall study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  Given the exploratory nature of 
the study, confirmation of response (complete response (CR)/partial response (PR)) is preferred (see RECIST version 1.1).  Tumor assessments should be repeated at the 
end of study visit if more than 6 weeks have passed since the last evaluation.  Patients should have a confirmatory scan for PD and can remain on trial if they are receiving 
clinical benefit upon discussion with investigator and sponsor MD.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  FDG-PET 
will be performed per standard of care.
Bone Scans for mCRPC: 99mTc-methylene diphosphonate radionuclide bone scintigraphy should be performed every 8 weeks for first 24 weeks, then every 12 weeks (up 
to 2 years), then every 16 to 24 weeks (±14 days).  Changes in lesions that are considered metastatic on bone scintigraphy should be followed and assessed serially using a 
bone scan assessment form (see Appendices).
Prostate specific antigen (PSA) assessment to be performed on Screening (for historical progression per Prostate working Group 2), C1D1 (-14 days) and Day 1 of Cycle 
4, 7, 10 and every 3rd cycle thereafter as well as the End of Treatment visit.  Please see Appendix for Prostate Cancer Working Group 2 (PCWG2)- Soft Tissue Response 
Criteria. 
Gleason Score should be collected at diagnosis.
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SCHEDULE OF ACTIVITIES PART 2B – Combination Dose Expansion
Protocol Activity
Screening
(28 days 
prior to 
enrollment)
1
Active Treatment Phase†- One Cycle = 28 days
End of 
Treatment/ 
Withdrawal23
Post-Treatme
nt 
Follow-Up24
Cycles 1 & 2
Cycles 3+
Visit Identifier
(Visit Window)a
Day 1
Day 
2c
Day 7
Day 
10b
Day 
15
Day 
21c
Day 1
Day 7
21. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 5.0.  The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the 
patient provides informed consent through and including a minimum of 28 calendar days after the last investigational product administration.  If the patient begins a new 
anticancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
22. Concomitant Treatments: All concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF including supportive care drugs, eg, 
anti-emetic treatment and prophylaxis, radiotherapy on study is permitted (eg, skeletal administration for CRPC), drugs used to treat adverse events or chronic diseases, and 
non-drug supportive interventions (eg, infusions).
23. End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of 
any new anti-tumor therapy.  Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks as applicable for 
disease assessments).
24. Post Treatment Follow-Up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant 
medications, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point 
following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that 
no further improvement is expected.
25. Survival Follow-Up: Subsequent to the follow-up period, overall survival (OS) follow-up will be conducted by telephone every 8 weeks (7 days) until end of the entire 
study (2 years after last patient first treatment).  If the patient is seen in the clinic during the window of time that a scheduled telephone call is to be made to collect survival 
data, then the clinic visit may replace the survival telephone call.


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Pharmacokinetic, ECG, 
 Sampling Schedule for Part 2B - Combination Dose Expansion
Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 
2**
Day 7
Day 15
Day 
21**
Day 1
Day 
2**
Day 7
Day 10 
(-24 hrs)
Day 7
Dose of PF-06952229 in clinic1
X*
X
X
X
X
X*
X
X
X
Pharmacokinetics (PK)
Predose (if dosing day)
N, E
N
N, E
N
N,E
N, E
N
N
N
N
N
First 8 
Patients only (min)
0.5 hours (±5 min)
N
N
N
1 hour (±10 min)
N
N
N
2 hours (±15 min)
N
N
N
N
N
N
First 8 Patients 
only (min)
4 hours (±25 min)
N
N
N
6 hours (±40 min)
N
N
N
12 hours (-180 min)
N
N
N
12-Lead ECG2
0
X
X
X
X
X
X
X
X
X
2 hours (±15 min)
X
X
X
X
 
 
 
 
 
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Visit Identifier
Screen
Cycle 1
Cycle 2
Cycle ≥3
EOT
Study Day
Day 1
Day 
2**
Day 7
Day 15
Day 
21**
Day 1
Day 
2**
Day 7
Day 10 
(-24 hrs)
Day 7
Abbreviation: PK = pharmacokinetic; 
; EOT = End of Treatment; N=PF-06952229; E=Enzalutamide; 
 
* On Day 1 of Cycle 1 and Cycle 2 only a single dose of PF-06952229 to be given to evaluate PF-06952229 PK sampling up to 24 hr time point (i.e. pre-dose on Day 2 of Cycle 
1 and Cycle 2).
** Day 2 and Day 21 visit for first 8 subjects (min).
1.
Dose of PF-06952229 in Clinic: On days of scheduled clinic visits, morning (AM) dosing should be undertaken in the clinic (ie, not at home).
2.
Triplicate 12-Lead ECG: The Screening ECG will be a single 12-lead ECG.  At all other times, at each time point, 3 consecutive 12-lead ECGs (triplicate) will be 
performed approximately 2 minutes apart to determine mean QTcF interval.  All 12-lead ECGs should be confirmed by a qualified person at the institution.  When 
coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to blood sample collection, such that the blood 
sample is collected at the nominal time.  If the mean QTcF is prolonged (≥45 msec from the baseline or >500 msec), the ECGs should be re-evaluated by a qualified person 
at the institution for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
 
 
 
 
 
 
 
 
 
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06952229 is an orally bioavailable small molecule inhibitor of the serine/threonine kinase 
receptor transforming growth factor beta receptor 1 (TGFR1).  This receptor has pleiotropic 
effects on a number of transforming growth factor beta receptor (TGF)-mediated signaling 
pathways that impact the growth and proliferation of malignancies.  In this clinical study, 
PF-06952229 is being investigated as monotherapy to treat patients diagnosed with 
advanced/metastatic solid tumor, and with metastatic castration-resistant prostate cancer 
(mCRPC) in Part 1A and Part 2A, respectively, and as combination therapy with 
enzalutamide to treat patients diagnosed with mCRPC in Part 1B and Part 2B. 
1.2. Background and Rationale
1.2.1. TGFβ
Elevated TGFexpression by tumor and stromal cells in the tumor microenvironment, and 
activation of TGFβ receptor intracellular signaling is observed in many cancers.8 Activated 
TGFR1 phosphorylates the signaling intermediate proteins termed mothers against 
decapentaplegic homolog 2 and 3 (SMAD2 and SMAD3), which assemble into complexes 
with SMAD4, and translocate to the nucleus, where they regulate the expression of TGFβ
target genes (Figure 1).  In addition, non-SMAD signaling may also be initiated downstream 
of TGFβ receptors, which can lead to the activation of various pathways such as 
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), c-jun N-terminal kinase (JNK), 
p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase (ERK) 
mitogen-activated protein kinase (MAP).9
Figure 1.
Canonical and Non-Canonical TGFβ signaling10


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The activation of the TGFpathway in cancer cells can induce epithelial to mesenchymal 
transition (EMT) in which epithelial cells lose their apico-basal polarity and cell-cell 
adhesion, to become highly migratory mesenchymal cells, leading to metastasis.  In addition, 
EMT has been linked to tumor cell evasion of immune surveillance.11 TGFβ has been shown 
to be a potent immunosuppressive agent on both innate and adaptive immune cells, including 
dendritic cells, macrophages, natural killer (NK) cells, and CD4+ and CD8+ T cells.  
Conversely, TGFβ plays a key role stimulating the differentiation of immune-suppressive 
regulatory T (Treg) cells.  Finally, inhibition of the TGFR1 pathway in preclinical models 
has led to tumor growth inhibition.
Patient stratification based on gene expression studies reveals elevated TGFpathway 
activation in cohorts with the worst prognosis.12 TGFexpression has been associated with 
poor prognosis in a number of cancers, eg, prostate17, colorectal13, pancreatic14, and lung.15  
The TGFpathway has also been described to play a key role in resistance to therapy.  
Patients with innate resistance to programmed death ligand 1 (PD-L1)/ programmed cell 
death 1 (PD-1) antibody treatment show elevated pre-treatment tumor TGFsignatures.23 In 
prostate cancer, TGFplasma levels strongly predict progression16,17 and androgen depleting 
therapies, including enzalutamide, induce expression of TGF-dependent genes, and promote 
EMT and bone metastasis in castration resistant prostate cancer.18 EMT has also been linked 
to chemotherapy resistance in colorectal cancer.19,20 Collectively these findings demonstrate 
key roles for TGFpathways in disease progression and resistance to therapy in a broad 
spectrum of tumors, and support inhibiting the TGFpathway for the treatment of cancer. 
1.2.2. Tumors and Combination Therapies
High TGFsignatures and EMT expression are found in a variety of tumors, including 
metastatic breast cancer21, metastatic castration-resistant prostate cancer (mCRPC)16,17, 
squamous cell cancer of the head and neck22, melanoma, mesothelioma, metastatic pancreatic 
cancer,23 colorectal cancer,24,25,26 renal cell carcinoma, and hepatocellular cancer.27,28 These 
tumor types will be investigated in Part 1A of this protocol, a dose exploration of 
PF-06952229.  Subsequent investigations in Part 1B, Part 2A, and Part 2B of the protocol 
will be undertaken in patients with mCRPC which was selected based on nonclinical data, 
unmet medical need, and preliminary Part 1A data.  
These preliminary data were noted in 1 patient who was treated with 8 previous regimens for 
mCRPC, was treated with PF-06952229 on 30 May 2019 where the patient was reported to 
have a PSA of 125.3 ng/ml and a soft tissue mass of 11 mm in its longest dimension.  By 13 
Nov 2019, PSA was reduced to 1.6 ng/ml and the soft tissue mass was reported as 8 mm.  By 
04 Mar 2020 the soft tissue lesion was reported to be 0 mm in its longest dimension with a 
subsequent PSA measurement of 0.477 ng/ml.  The patient continues to work, has an ECOG 
performance score of 1, and reports feeling well. 
Metastatic prostate cancer treated with androgen deprivation therapy (ADT) is associated 
with increased TGFsignaling.  Enzalutamide resistance in preclinical prostate cancer 
models show increased TGF, EMT, cell migration and proliferation.18,43  Therefore, this 


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provides the basis for further investigation of PF-06952229 in monotherapy and in 
combination with enzalutamide in mCRPC.  
1.2.2.1. Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Prostate cancer is the most common non cutaneous cancer in US men with an estimated 
164,000 new cases expected to be diagnosed in 2018.29 It is a slow growing disease which 
occurs in prostate gland of the male reproductive system.41 However some prostate tumors 
can grow relatively quickly and at a later stage of the disease, the cancer cells may 
metastasize to other parts of the body, particularly the bones and lymph nodes.  Treatment 
options for prostate cancer include surgery, radiation therapy, hormone therapy and 
chemotherapy.  Most hormone dependent cancers become resistant to treatment after one to 
three years and resume growth despite hormone therapy.42 These metastatic castration-
resistant prostate cancers respond poorly to reduction of available androgen/testosterone/
dihydrotestosterone (DHT) by either chemical or surgical means.
Metastatic progression, poor prognosis, and drug resistance in prostate cancer treated with 
androgen deprivation therapy (ADT) are associated with increased TGFsignaling.  
Enzalutamide resistance in preclinical prostate cancer models show increased TGF, EMT, 
cell migration and proliferation.18,43 TGFinhibition decreases TGF-induced EMT markers 
in prostate cancer cells.18 In addition enzalutamide in combination with galunisertib 
(TGFBRi) inhibits signaling pathway (pSMAD2/3) and tumor growth (along with reversing 
EMT) in a preclinical prostate cancer model.44 Based on these data, combining a TGF
inhibitor such as PF-06952229 with enzalutamide may be a beneficial treatment option for 
patients with mCRPC. 
1.2.3. Nonclinical Pharmacology
PF-06952229 is a selective TGFR1 inhibitor with minimal kinase inhibitory 
activity/binding to TGFR2.  It is a potent inhibitor of TGFR1 with an IC50 value of 0.8 nM 
as measured by a competition binding enzyme assay.  Consistent with TGFaction on 
immune cells, PF-06952229 inhibits TGF-induced SMAD2 phosphorylation (pSMAD2), a 
direct target of the TGFR1 pathway, across several species with average unbound 
IC50 values of 57 nM in human PBMC, 26 nM in Cynomolgus monkey PBMCs, 38 nM in rat 
splenocytes, and 16 nM in mouse splenocytes.  PF-06952229 also reverses TGF-mediated 
suppression of interleukin-2(IL-2) secretion, a marker of activation in human T cells with an 
EC50 value of 12 nM (unbound).  PF-06952229 also potently inhibits TGFinduced 
pSMAD2 in human MDA-MB-231 and mouse 4T1 breast cancer cell lines with IC50 values 
of 17 and 25 nM (unbound), respectively. 
In vivo, pSMAD2 acts as a responsive and predictive pharmacodynamic biomarker of 
TGFR1 inhibition in MC38 and 4T1 tumors.  Modeling of the 
pharmacokinetic/pharmacodynamic relationship in tumors derives an IC50 of 5-10 nM for 
inhibition of phosphorylation of SMAD2 in good agreement with the in vitro cell based 
potencies.  As a single agent, PF-06952229 showed no tumor growth inhibition (TGI) in the 
4T1 primary tumors, which are known to be refractory to various therapeutic agents.  


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However, PF-06952229 shows significant inhibition of spontaneous lung metastasis in this 
model that was associated with a decrease in EMT and increase in immune-activation gene 
signatures in the 4T1 primary tumors.
In the MC38 murine syngeneic colorectal tumor model, PF-06952229 shows dose-dependent 
TGI as a single agent.  No significant TGI activity (-3%) was observed relative to the vehicle 
treated group at a dose of 10 mg/kg twice daily (BID) (7 days on/7 days off) while 86% TGI 
relative to the vehicle treated group was observed at 30 mg/kg BID (7 days on/7 days off).  
The efficacious concentration (Ceff) of PF-06952229 was defined in the MC38 syngeneic 
tumor model as the average concentration resulting in statistically significant TGI in a 
monotherapy setting (30 mg/kg BID, 7 day on/7 day off regimen).  The average unbound 
plasma concentration at this dose was 23 nM. In addition, when PF-06952229 (7 days on/7 
days off regimen) was evaluated in combination with an anti-murine specific PD-1 antibody 
(PD-1, dosed at 5 mg/kg twice a week for 2 weeks) in the MC38 model, there was a strong 
combinatorial effect observed even at the lower dose of PF-06952229 (10 mg/kg BID 7 days 
on/7 days off).  The TGI relative to control treated animals of 10 mg/kg BID + PD-1 was 
88% and for 30 mg/kg BID + PD-1 was 99%. Based on these data and current literature, 
there is a rationale for combinations with PF-06952229 in the clinic.
1.2.4. Nonclinical Pharmacokinetics
The nonclinical pharmacokinetic/toxicokinetic, absorption, distribution, metabolism, and 
excretion (ADME) properties of PF-06952229 have been evaluated in vitro and in vivo to 
support nonclinical safety evaluations and to assess the potential relevance to humans.  The
oral pharmacokinetics (PK) of PF-06952229 in nonclinical species indicated moderate to 
high oral absorption and bioavailability.  Systemic exposure increased with dose in pivotal 
toxicity studies in rats and monkeys.  PF-06952229 was highly bound to plasma proteins 
across species and, in general, demonstrated limited distribution into red blood cells.  In vitro 
studies suggest PF-06952229 may be a substrate for the efflux transporters such as human 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The moderate to high 
bioavailability observed in nonclinical species indicate that oral absorption was not limited 
by these efflux transporters.
The primary clearance mechanism of PF-06952229 was cytochrome P450 (CYP) 
3A4-mediated metabolism (fm ~0.9), with limited to no renal or biliary excretion.  
Consequently, significant changes in PF-06952229 exposure are anticipated following 
co-administration with strong CYP3A4 inhibitors or inducers.  Following co-administration 
of PF-06952229 with  enzalutamide (a strong inducer of CYP3A) a 70% decrease 
(AUCR ~0.3) in PF-06952229 AUC was predicted.  No unique human metabolites were 
observed in vitro compared to metabolite profiling in rat.
Assessments based on in vitro drug-drug interaction (DDI) studies and the predicted systemic 
exposure in humans following the projected efficacious dose indicate a low potential for DDI 
due to PF-06952229-mediated inhibition of CYP 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 or 
uridine diphosphate-glucuronosyltransferase (UGT) 1A4, 1A6, 1A9, 2B7 and 2B15.  
However, PF-06952229 may have the potential to inhibit CYP3A (time-dependent) and 
UGT1A1 (reversible) at concentrations associated with the projected efficacious dose.  The 


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potential for DDI due to PF-06952229-mediated inhibition of organic anion-transporting 
polypeptides (OATP) 1B1 and 1B3, organic anion transporter (OAT) 1 and OAT3, organic 
cation transporter (OCT) 2, multi-antimicrobial extrusion protein (MATE) 1, and MATE2K 
is low.  However, PF-06952229 has the potential to inhibit intestinal P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP) at the projected efficacious dose.
In humans, the predicted plasma CL and Vss of PF-06952229 are 5 mL/min/kg and 3 L/kg 
respectively, providing an effective t½ of approximately 7 hours.  PF-06952229 is estimated 
to exhibit an oral bioavailability of approximately 65% and fraction absorbed × fraction 
escaping gut metabolism (Fa×Fg) of approximately 1.  Based on the predicted human PK 
parameters and the unbound efficacious concentration (Ceff) defined in the MC38 syngeneic 
tumor model, the efficacious oral dose of PF-06952229 in humans is projected to be 225 mg 
twice daily (BID).
1.2.5. Nonclinical Safety
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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•
Liver: Hepatocellular hemorrhage, necrosis and mixed cell infiltration in the liver 
with associated transaminase increases were observed at ≥10 mg/kg BID in the rat 
pivotal study; non-reversible in one female rat at the highest dose.
•
Skeletal System: Cartilage hypertrophy/dysplasia was observed in both rats and 
monkeys, across the exploratory and pivotal studies.  The findings were partially 
reversible in rat and reversible in monkey in pivotal studies.  The bone/cartilage 
findings are considered to be related to the primary pharmacology of PF-06952229, in 
growing animals with open growth plates and are not expected to be relevant for adult 
patients.
•
Lung: Minimal hemorrhage that was generally accompanied by minimal mixed cell 
inflammation was observed in the rat pivotal study at doses of PF-06952229 
≥5 mg/kg BID.
•
Other Findings: Among other findings consistently seen in rats and monkeys was 
decrease in plasma phosphorous at ≥10 mg/kg BID.
Rat was the more sensitive nonclinical species with respect to PF-06952229-related 
toxicities. Based on the pivotal studies, the STD10 and the HNSTD in rat and monkey at the 
end of the dosing period were 20 and 100 mg/kg BID, respectively.  Sex-combined, unbound 
systemic maximum plasma concentration (Cmax) and area under the concentration time 
profile from time 0 to 24 hours (AUC24) values at the STD10 in rat were 75.9 ng/mL 
(165 nM) and 873 ng·h/mL (1900 nM·h), respectively.  At the STD10 in rats, the Cmax and 
AUC24 exposure multiples are 42x and 39x, respectively to the predicted exposure at the 
starting dose of 20 mg BID.  Sex-combined, unbound systemic Cmax and AUC24 values at the 
HNSTD in monkey were 159 ng/mL (346 nM) and 2300 ng·h/mL (5010 nM·h), respectively.  
At the HNSTD in monkeys, the Cmax and AUC24 exposure multiples are 88x and 102x, 
respectively to the predicted exposure at the starting dose of 20 mg BID.
Based on published data, attenuation of TGFβ pathway in nonhealing wounds may contribute 
to the loss of tissue homeostasis, epidermal hyperproliferation, and the inability of 
keratinocytes to migrate and epithelialize a wound.  Therefore PF-06952229-mediated 
inhibition of TGFβR1 may have effects on wound healing.52
Overall, the nonclinical safety profile of this PF-06952229 has been adequately characterized 
to support progression into clinical trials in advanced cancer patients.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PF-06952229 may be found in the Investigator’s Brochure, which is the 
SRSD for this study. 
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1.2.6. Clinical Pharmacokinetics
Preliminary PF-06952229 concentration-time data is available from a total of 13 patients at 
dose levels of 20, 40, 80, 150, 250 and 375 mg BID as of 24 Jul 2019.  It should be noted that 
due to the limited number of patients, the overall PK interpretation should be considered 
preliminary.
Upon oral administration on an empty stomach, PF-06952229 appeared to be rapidly 
absorbed after first dose with the Cmax being achieved between 1 to 4 hours.  After reaching 
Cmax, PF-06952229 concentrations declined in a monophasic manner.  In general, there was a 
dose-dependent increase in PF-06952229 exposures over the studied dose range.  Additional 
information on clinical pharmacokinetics of PF-06952229 can be found in the Investigator’s 
Brochure.
1.2.7. Clinical Safety
Since the modification of the patient entry criteria that led to the lifting of the FDA partial 
clinical hold, no hemorrhagic events have been reported as of 19 Jun 2020.  For additional 
information on AEs reported as of 19 Jun 2020, please see Appendix 10. 
1.3. Starting Dose Rationale
The selection of the starting dose and regimen for this first-in-patient (FIP) study was based 
on the nonclinical toxicology and PK results, which are in accordance with the International 
Conference on Harmonization (ICH) S9 Guidance (October 2009) for the intended 
population.  Results from nonclinical toxicity studies indicate that the rat is the most sensitive 
species, and in the pivotal study the Severely Toxic Dose in 10% of animals (STD10) for 
PF-06952229 was at 20 mg/kg twice daily (BID).  Key findings in this study were the 
microscopic findings of hepatocellular hemorrhage, hepatocyte necrosis and mixed cell 
infiltration in the liver and elevated transaminases that were non-reversible in one female at 
20 mg/kg BID.  The human equivalent dose for the STD10 (20 mg/kg BID) dose in rat is 
approximately 194 mg BID (assuming a body weight of 60 kg).  Per ICH-S9 Guidance, 
one-tenth of the STD10 can be considered as the appropriate starting dose.  Given the 
predicted human disposition and half-life (t½) of approximately 7 hours, the starting dose has 
been selected to be 20 mg administered orally (PO) BID.  The human unbound steady-state 
Cav and Cmax of PF-06952229 at the proposed starting oral dose of 20 mg BID [daily (PO) 
40 mg/day] is projected to be 0.94 ng/mL (2.0 nM) and 1.8 ng/mL (3.9 nM), respectively.  
The respective margins relative to the STD10 of 20 mg/kg BID in rat are 39× and 42× for 
Cav and Cmax, respectively.  The respective margins relative to the highest non-severely toxic 
dose (HNSTD) of 100 mg/kg BID in monkey are 102× and 88× for Cav and Cmax, 
respectively.
1.3.1. Intermittent Dosing Schedule Rationale
PF-06952229 will be administered PO BID on a 7-day on/7-day off schedule in a 28-day 
cycle.  An intermittent dosing schedule was selected to mitigate the risk of potential 
cardiovascular toxicity based on the nonclinical cardiovascular findings observed with 
galunisertib, a dual inhibitor of TGFR1 and TGFR2 when dosed continuously50 and with 


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These effects were not observed in the 8-week pivotal study (8330539) up to 20 mg/kg BID 
on a 5-day on 5-day off dosing schedule (5 cycles+ 3 days, 28 total doses). 
 
 
 A 7-day on 7 day-off 
dosing schedule, as was used in the mouse MC38 efficacy study, resulted in a slightly lower 
dose intensity over 28 days compared to 5-day on 5-day off schedule used in pivotal 
toxicology study, but with approximately similar predicted TGI.  Based on ICH S9 Guidance, 
a nonclinical treatment schedule of 5- or 7-day on and 5- or 7-day off, alternating weeks (2-
dose cycles), would support a clinical dosing schedule of 7 days on and 7 days off.  
Following consideration of all available data and practical considerations, a 7-day on 7-day 
off intermittent dosing schedule was selected for the FIP study.  Depending on the observed 
half-life, alternative dosing schedules may be considered, if deemed appropriate according to 
the aforementioned guidance and supported by available toxicology and clinical data.  
Modifications the current schedule would be implemented through a protocol amendment.
1.4. PF-06952229 Rationale for Development 
The TGFβ signaling pathway is associated with the invasive and metastatic process, 
resistance to immunotherapy, targeted therapy, and conventional chemotherapy.  
PF-06952229 is a potent, small molecule inhibitor of TGFβ signaling pathways and may 
overcome these treatment failures.  Based on these and other characteristics, PF-06952229, in 
combination with other oncology and immuno-oncology drugs is anticipated to be 
efficacious in resistant and/or relapsed TGFβ/EMT-dependent cancers. 
1.5. Study Rationale
TGFβ pathways play key roles in disease progression and resistance to therapy in a broad 
spectrum of tumors, supporting its inhibition for the treatment of cancer.28  High TGFβ
signatures and EMT expression are found in a variety of tumors making them promising 
targets for treatment with a TGFβ inhibitor in combination with either oncology or 
immuno-oncology drugs and may be particularly efficacious in resistant and/or relapsed 
TGFβ/EMT-dependent cancers.  Based on published nonclinical data and Part 1A 
preliminary data from this study, this clinical trial will focus on treatment of mCRPC 
(Section 1.2). 
Early human data have been generated for PF-06952229. Observations of bleeding events 
that resulted in an FDA partial clinical hold, led to mitigations being put in place within the 
study that included additional requirements for MRI brain scans, enrollment exclusions, and 
patient and study discontinuation criteria. Except for an observation of bleeding events that 
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resulted in the partial clinical hold and which to date have not recurred, the toxicity profile of 
PF-06952229 has been acceptable.  
Additionally, published clinical data utilizing other inhibitors of this target (TGFβR1) 
support the safety and pharmacology.  Based on the current available clinical data, TGFβ
inhibitors have been generally safe and well-tolerated on an intermittent dosing schedule 
(14 days on and 14 days off) in a number of small Phase 1 trials44,46,47 and one Phase 
2 trial.48 The most data available are from the galunisertib (LY2157299) program in which 
the notable Grade 3 or higher treatment-related adverse events (AE)s were: 1) in Phase 1 and 
2 studies in patients with advanced solid tumors and glioblastoma, decreased platelet, 
neutrophil, lymphocyte or white blood cell (WBC) counts were the most common, with rare 
cases (generally 1 case) of central nervous system (CNS) ischemia, thrombosis/embolism, 
dyspnea, febrile neutropenia44,48 2) in Phase 1 studies of Japanese patients with advanced 
solid tumors or pancreatic cancer, decreased neutrophil or white blood cell counts were most 
common with rare cases (generally 1 case) of biliary tract infection, duodenal ulcer, 
hypophosphatemia, increased lipase, sepsis, small intestinal hemorrhage, cholecystitis, 
duodenal stenosis, and hepatobiliary disorders.46,47 Of particular importance, no cardiac 
untoward events were observed in these studies, which included a thorough cardiac 
evaluation based on an array of clinical cardiac assessments.  (See IB for more details.)  
Clinical efficacy data available on TGFβ inhibitors are quite limited and it is premature to 
determine the potential for efficacy at this time. 
 
 
 
 
 
 
  
 
 
 
 
 
1.5.2. Rationale for Safety Monitoring Plan 
1.5.2.1. Cardiac Disorders
Valvulopathy – Inhibition of the TGFβ pathways was associated in galunasertib nonclinical 
studies with a number of cardiac toxicities that were characterized by aneurysms and 
valvulopathy with associated degenerative and inflammatory changes.50 
 
 
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 In addition, only patients with stable cardiac disease will 
be enrolled and monitored with periodic assessments of vital signs, electrocardiograms 
(ECGs), cardiac biomarkers (troponin, high-sensitivity C-reactive protein [hs-CRP], brain 
natriuretic peptide [BNP]), and Doppler echocardiography.  Patients with any Grade 3 
treatment-related cardiac event will be discontinued from the trial. 
1.5.2.2. Hepatobiliary Disorders
Transaminasemia – Elevated transaminases with associated hepatocyte necrosis were 
observed in rat at the STD10 in the pivotal PF-06952229 toxicology study.  At the highest 
non-severely toxic dose (HNSTD) in monkey, there were minimal reversible alanine 
transaminase (ALT) elevations (<2-fold) without associated microscopic findings.  To 
mitigate potential hepatoxicity, standards adapted from the Food and Drug Administration 
(FDA)’s DILI guidance (July 2009) for patient exclusion, hepatic monitoring and 
discontinuation criteria are incorporated into the protocol.
1.5.2.3. Metabolism and Nutrition Disorders
Hypophosphatemia – Decreased serum phosphate was observed in the PF-06952229 
nonclinical toxicology studies.  The relevance of this finding in adults is unclear and 
substantive changes in serum phosphorus are not anticipated in the population to be enrolled 
in this clinical trial.  Nevertheless, to mitigate any potential risk, serum phosphate will be 
included with requisite serum chemistry monitoring and regularly assessed throughout the 
study.  Any confirmed treatment-related Grade 3 hypophosphatemia that does not resolve to 
baseline will result in dose modification or discontinuation from the trial.
1.5.2.4. Musculoskeletal and Connective Tissue Disorders
Bone/Skeletal disorders - Physeal and cartilage hypertrophy observed in the PF-06952229 
toxicology studies is thought to be due to primary pharmacology of drug on bone physiology 
and in growing animals with open growth plate.  Therefore, this finding is not anticipated 
since substantive bone remodeling is not expected in adults.  Nevertheless, during the trial,
with each Common Terminology Criteria for AE (CTCAE) grade level increase in total 
alkaline phosphatase, bone and liver fractionation will be obtained and an appropriate clinical 
evaluation will be conducted to determine the suitability of the patient continuation in the 
trial.
1.5.2.5. Respiratory, Thoracic and Mediastinal Disorders
Minimal hemorrhage in the lung that was generally accompanied by minimal mixed cell 
inflammation was observed in the rat pivotal study at PF-06952229 doses ≥10 mg/kg/day.  
There was no effect on respiratory function in the single dose safety pharmacology study in 
rats at 40 mg/kg.  During the clinical trial, respiratory AEs and CT/MRI findings will be 
monitored closely, and an appropriate clinical evaluation will be conducted to determine the 
suitability of the patient continuation in the trial.
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1.6. Overview of Enzalutamide
Enzalutamide will be provided by Pfizer as capsules for oral administration.  More detailed 
information about the known and expected benefits and risks and reasonably expected AEs 
of enzalutamide may be found in the Investigator’s Brochure, which is the SRSD for this 
study. 
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2. STUDY OBJECTIVES AND ENDPOINTS
Part 1A - PF-06952229 Single Agent Dose Escalation Phase in Patients With 
Advanced/Metastatic Tumors.
Primary Objective(s):
Primary Endpoint(s):
•
To assess safety and tolerability at increasing 
dose levels of PF-06952229 in patients with 
advanced/metastatic tumors.
•
To determine MTD and RP2D of 
PF-06952229 as a single agent.
•
First-cycle DLTs.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the single and multiple dose PK of 
PF-06952229 when given as a single agent.
•
To evaluate preliminary anti-tumor activity of 
PF-06952229 when given as a single agent.
•
To evaluate preliminary biochemical responses 
as a measure of anti-tumor activity of 
PF-06952229
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
PSA50 Response Rate for prostate cancer 
patients.
•
Response assessment will be based on PCWG2 
for prostate cancer and RECIST 1.1 for other 
tumor types.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 1B - Dose Escalation of PF-06952229 in Combination With Enzalutamide in 
Patients with mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To assess safety and tolerability at increasing 
dose levels of PF-06952229 in combination with 
enzalutamide in patients with mCRPC.
•
To determine MTD and RP2D of 
PF-06952229 in combination with enzalutamide 
in patients with mCRPC.
•
First cycle DLTs in combination with 
enzalutamide for mCRPC.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To evaluate the single and multiple dose PK of 
PF-06952229 when given in combination with 
enzalutamide.
•
To evaluate preliminary anti-tumor activity of 
PF-06952229 when given in combination with 
enzalutamide. 
•
To evaluate preliminary biochemical responses as 
a measure of anti-tumor activity of PF-06952229 
when given in combination with enzalutamide.
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
PSA50 Response Rate
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2A - PF-06952229 Single Agent Dose Expansion Phase in mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To confirm safety and tolerability of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To estimate efficacy of PF-06952229 at the 
estimated RP2D in patients with mCRPC.
•
To confirm the RP2D of PF-06952229 as a single 
agent.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
•
PSA50 Response Rate. 
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To estimate additional efficacy of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the single and multiple dose 
PK of PF-06952229 when given as a single 
agent.
•
To evaluate immune cells in paired pre and post 
treatment tumor biopsies (where available).
•
ORR based on PCWG2 and RECIST 1.1. and 
time to event endpoints (DoR, PFS, OS, TTP, 
TTR).
•
Pharmacokinetic parameters of PF-06952229.
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
Assessment of levels of intra-tumor T cells (eg, 
CD8 IHC); 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2B - Dose Expansion of PF-06952229 in Combination With Enzalutamide in 
Patients With mCRPC
Primary Objective(s):
Primary Endpoint(s):
•
To confirm PF-06952229 safety profile in 
combination with enzalutamide at the estimated 
RP2D in patients with mCRPC.
•
To estimate efficacy of PF-06952229 in 
combination with enzalutamide at the estimated 
RP2D in patients with mCRPC.
•
To confirm the RP2D of PF-06952229 in 
combination with enzalutamide in patients with 
mCRPC.
•
AEs as graded by NCI CTCAE version 5.0.
•
Laboratory abnormalities as graded by NCI 
CTCAE version 5.0.
•
PSA50 Response Rate. 
•
Response assessment will be based on PCWG2 
and RECIST 1.1.
Secondary Objective(s): 
Secondary Endpoint(s): 
•
To estimate additional efficacy of 
PF-06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the PK of PF-06952229 when 
given in combination with enzalutamide.
•
To evaluate immune cells in paired pre and post 
treatment tumor biopsies (where available).
•
ORR based on PCWG2 and RECIST 1.1. and 
time to event endpoints (DoR, PFS, OS, TTP, 
TTR).
•
Pharmacokinetic parameters of PF-06952229 
(in at least 8 subjects).
o
Single Dose (SD) - Cmax, Tmax, AUClast, and 
as data permit, AUCinf, CL/F, Vz/F, and t1/2. 
o
Multiple Dose (MD) - Css,max, Tss,max, 
AUClast, Css,min, and as data permit CLss/F, 
Vss/F, t1/2, and Rac (AUClast /AUClast).
•
Peak and trough concentrations at selected 
cycles.
•
Assessment of levels of intra-tumor T cells (eg, 
CD8 IHC);
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label, multi-center, multiple-dose, dose-escalation and expansion, 
safety, tolerability, PK, and PD study of PF-06952229 in previously treated patients with 
advanced or metastatic cancers that may have high TGFβ signatures and EMT expression. 
The study includes Parts 1A and 1B, which are dose-escalation cohorts, and Parts 2A and 2B, 
which are dose expansion cohorts.  The primary objectives for Part 1A are to assess the 
safety and tolerability of PF-06952229 administered as a single agent and to determine 
maximum tolerated dose (MTD).  The primary objectives for Part 1B are to assess the safety 
and tolerability of PF-06952229 administered with enzalutamide and to determine MTD.  
The primary objectives for Part 2A are to confirm PF-06952229 safety and tolerability, 
estimate the single agent efficacy of PF-06952229 and determine a recommended Phase 2 
dose (RP2D).  The primary objectives of Part 2B are to confirm the safety profile of PF-
06952229 combined with enzalutamide, estimate the efficacy of PF-06952229 combined 
with enzalutamide and determine a RP2D for the combination.
Part 1A is a sequential single-agent dose-escalation conducted in patients with advanced or 
metastatic solid tumors who have failed standard-of-care treatment or for whom no 
standard-of-care exists.  Successive cohorts of patients are to receive escalating doses of 
PF-06952229 on an outpatient basis starting from 20 mg BID, which is based on non-clinical 
data.  Nine candidate dose levels are planned using an Accelerated Titration Design (ATD) 
until reaching 250 mg BID, after which the design will revert to modified target probability 
interval (mTPI).  The highest tested dose will not exceed 800 mg BID.  If an MTD is not 
observed during the 28-day safety window, additional dose levels may be considered based 
on PK, safety, tolerability, 
 assessments.  Based on PK and safety, 
additional patients can be added to a dose lower than the MTD and also may be moved 
forward to monotherapy expansion.
Part 1B is a dose-escalation of PF-06952229 in the combination with enzalutamide 
conducted in patients who were previously treated for metastatic castration-resistant prostate 
cancer (mCRPC).  The starting dose of PF-06952229 will be based on safety, PK, and 
potential efficacy, but will not exceed the MTD or MAD of Part 1A.  Because of the 
potential DDI between enzalutamide and PF-06952229, the maximum PF-06952229 dose for 
the combination may be higher than the monotherapy MTD, but not higher than 800 mg 
BID..  Based on evolving PK, PD, and safety profiles, assessed in Part 1A, Part 1B may 
commence before reaching the MTD in Part 1A, and will follow an mTPI design.  The 
maximum PF-06952229 dose for the combination escalation may be higher than the 
monotherapy MTD due to the potential DDI between enzalutamide and PF-06952229, but 
not higher than 800 mg BID.
Part 2A and Part 2B are expansion cohorts for monotherapy and combination therapy, 
respectively, in patients with previously treated mCRPC.  
To assess baseline TGFβ related biomarker signatures that may correlate with clinical 
efficacy, all patients enrolled in Part 1 will be required to provide a recent archival tumor 
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sample or to undergo a fresh pre-treatment biopsy if archival samples are unavailable prior to 
trial treatment.  
Part 2 patients are required to provide either a recent archival tumor biopsy or, for all patients 
in Part 2A and from approximately 10 patients in Part 2B, mandatory de novo biopsies.  
Mandatory de novo pre-treatment and on-treatment tumor biopsies may not be required 
where it is determined that it is not medically feasible (such as constituting unacceptable 
medical risks).  However, this would require agreement of Investigator and Sponsor.
The biomarker studies will be used to help understand the in vivo mechanism of action of the 
agent(s) studied as well as potential mechanisms of resistance.  The studies may help in the 
future development of PF-06952229 as a single agent, or in combination with other 
compounds, and may provide information on tumor sub-types that may respond to the 
Investigational Product.
Approximately 90 patients are to be enrolled in this study.  The total sample size may vary 
depending on the number of the dose levels with patients enrolled and the actual number of 
patients at each dose level.  A maximum sample size of 40 patients may be needed to 
establish and confirm MTD in Part 1A, and approximately 20 patients may be needed for 
Part 1B.  A maximum of 10 and 20 patients are planned for the expansion cohorts in Part 2A 
and Part 2B, respectively. 
All patients:
1. Will undergo up to 4 weeks of screening prior to study entry ie, Cycle 1 Day 1.
2. Will receive doses of PF-06952229, administered orally on 28-day cycle, 7 days on, 7 
days off, for up to 2 years.  Any additional treatment with PF-06952229 beyond 
2 years shall be discussed and approved by the Sponsor. 
3. Treatment with investigational product (IP) will continue until disease progression, 
patient refusal, or unacceptable toxicity occurs, whichever occurs first.  However, 
patients who demonstrate clinical benefit (despite radiographic progression) with 
manageable toxicity and are willing to continue receiving the investigational product 
will be given the opportunity to continue treatment upon agreement between 
investigator and sponsor.
4. Will undergo a follow-up visit approximately 4 weeks after the last dose for AE and 
serious adverse event (SAE) collection.
The proposed doses, schedule(s), and PK and PD time points may be reconsidered and 
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Figure 2.
Study Schema
 
3.1.1. Part 1 Dose Escalation
3.1.1.1. Part 1A – Single Agent PF-06952229 in Advanced/Metastatic Solid Tumors
Part 1A is a sequential single-agent dose-escalation conducted in patients with advanced or 
metastatic solid tumors who have failed standard-of-care treatment or for whom no 
standard-of-care exists. 
3.1.1.2. Starting Dose
The starting dose of PF-06952229 will be 20 mg given twice daily (BID) orally as a regimen 
of 7 days on/7 days off in 28- day cycles.  The rationale for selecting this starting dose is 
provided in Section 1.3.
3.1.1.3. Criteria for Dose Escalation
The initial dose escalation in Part 1A begins with an accelerated titration design followed by 
a standard escalation phase that will use a modified target probability interval (mTPI) 
approach.  Initial dose levels for Part 1A are provided in Table 1 and intermediate dose levels 
may be considered if needed. 
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Table 1.
PF-06952229 Dose Levels
DOSE LEVEL (DL)*
DOSE
Percent Increase From Previous Dose
DL -1
10 mg BID
-
DL 1** Starting dose
20 mg BID
-
DL 2
40 mg BID
100%
DL 3
80 mg BID
100%
DL 4
150 mg BID
88%
DL 5
250 mg BID
66%
DL 6
375 mg BID
50%
DL 7
500 mg BID
33%
DL 8
625 mg BID
25%
DL 9 
750 mg BID
16.7%
*The proposed doses, schedule(s), and PK time points may be reconsidered or amended during the study based on the 
emerging safety and PK data. Intermediate doses may be considered when deemed necessary based on on-going 
evaluation of safety and toxicity data.  
**Starting dose DL1.  De-escalation to a lower dose level (DL-1) may be considered if DLT(s) at the starting dose are 
observed (see Table 2 on mTPI Dose Decision Rules).
In principle, all patients must be evaluated for a minimum DLT observation period of 
28 days.  However, if a patient discontinues close to Day 28 for reasons other than toxicity 
and due to an evident non drug-related event, the patient may be deemed evaluable for safety 
if safety assessments have been unremarkable and the investigator and sponsor’s medical 
monitor both agree that the patient is evaluable for DLT safety observation. 
The dose escalation in the study will stop if any of the following criteria is met:

Approximately 40 patients have been achieved in Part 1A monotherapy dose 
escalation, or approximately 20 patients have been achieved in Part 1B combination 
dose escalation;

6 - 12 patients have been enrolled at a dose level that is predicted to be the MTD per
the mTPI method;

All dose levels explored appear to be overly toxic, and the MTD cannot be
determined.
3.1.1.3.1. Acceleration Phase 
The dose escalation in Part 1A – Monotherapy Dose Escalation will use the Accelerated 
Titration Design (ATD) as proposed by Simon7 followed by a standard escalation phase that 
will use a mTPI approach.  During the accelerated phase, initial cohorts will contain a 
minimum of 1 patient until the first instance of first-course CTCAE clinically significant 
grade 2 toxicity (as agreed upon by investigator and sponsor).  With the occurrence of 
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that dose.  If these 2 patients do not develop CTCAE grade 2 toxicity then the accelerated 
phase of the study with a minimum of 1 patient cohort will be continued.  The dose 
escalations in this phase are in increments of approximately 80 - 100%, until reaching 
250 mg BID, after which the design will revert to a standard escalation approach (mTPI) in 
order to obtain more comprehensive PK data.  The accelerated phase will revert to standard 
escalation (see below for underlying methodology) if there is a second occurrence of 
first-course cycle CTCAE grade 2 or first instance of first-course cycle DLT. 
3.1.1.4. Standard (mTPI) Escalation Phase
The proposed mTPI method for this protocol includes stopping rules and dose 
escalation/finding criteria which prevent the target DLT rate to reach 33% for determining 
the MTD.  Targeting a DLT rate of 27.5% and an acceptable DLT interval (22.5% to 32.5%) 
will be utilized in both Parts 1A – Monotherapy Dose Escalation (beginning at Dose Level 5) 
and 1B – Combination Dose Escalation, and will also be used to monitor the DLTs so as not 
to cross toxicity boundaries in the expansion of a cohort.  At least 3 DLT-evaluable patients 
will be required for the dose escalation decision based on mTPI beginning at Dose Level 5.  
Note provided the DLT rate for cardiac toxicity does not exceed 10%.  The decision rules use 
a Beta (1,1) prior.
Table 2.
mTPI Dose Decision Rules
DLT
n=1
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
S
E
E
E
E
E
E
2
DU
D
D
S
S
S
S
S
S
S
E
3
DU
DU
D
D
S
S
S
S
S
S
4
DU
DU
DU
DU
D
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
6
DU
DU
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
Source: https://udesign.laiyaconsulting.com/
E: Escalate to the next higher dose; S: Stay at the same dose; D: De-escalate to the previous lower dose; DU: 
De-escalate to the previous lower dose and the current dose will never be used again in the trial.
3.1.1.5. Part 1B – PF-06952229 in Combination With Enzalutamide in mCRPC
Part 1B is a dose-escalation of PF-06952229 in combination with enzalutamide conducted in 
patients who were previously treated for mCRPC. The starting dose of PF-06952229 will be 
based on safety, PK, and potential efficacy, but will not exceed the MTD or MAD of Part 
1A.  Because of the potential DDI between enzalutamide and PF-06952229, the maximum 
PF-06952229 dose for the combination may be higher than the monotherapy MTD, but not 


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higher than 800 mg BID.  In addition to safety and tolerability, PF-06952229 PK exposure 
data may be reviewed for informed dose escalation. Based on evolving PK, PD and safety 
profiles, assessed in Part 1A, Part 1B may commence before reaching the MTD in Part 1A, 
and will follow an mTPI design as described in Section 3.1.1.4.
Enzalutamide (a CYP3A4 inducer) is predicted to decrease the PK of PF-06952229 (a 
CYP3A4 substrate) by 70% (Section 1.2.4).  PF-06952229 is not expected to impact the PK 
of enzalutamide, therefore a fixed dose of enzalutamide is 160 mg QD, administered on a 
continuous basis.  Dose modifications to enzalutamide will not be allowed during the DLT 
evaluation period.  
3.1.2. Part 2 Dose Expansion
3.1.2.1. Part 2A – Single Agent PF-06952229 in mCRPC
PF-06952229 will be evaluated as a monotherapy in patients with mCRPC in this dose 
expansion cohort.  An additional 10 patients will be enrolled to confirm the safety of the 
MTD determined in Part 1A (monotherapy dose escalation) and estimate the effect of anti-
tumor activity of PF-06952229 as a monotherapy in patients with mCRPC.
3.1.2.2. Part 2B – PF-06952229 in Combination with Enzalutamide in mCRPC
PF-06952229 will be evaluated in combination with enzalutamide in patients with mCRPC in 
this dose expansion cohort.  An additional 20 patients will be enrolled to confirm the safety 
of the MTD determined in Part 1B (combination dose escalation) and estimate the effect of 
anti-tumor activity of PF-06952229 in combination with enzalutamide in patients with 
mCRPC.  Enzalutamide will be administered per the protocol.  
3.2. DLT Definition
Severity of adverse events (AEs) will be graded according to CTCAE version 5.0.  For the 
purposes of dose escalation, any of the following AEs occurring in the first cycle of treatment 
(within 28 days of first dose or until the patient completes the first cycle of therapy if there 
are treatment delays) which are clinically significant will be classified as DLTs, unless there 
is a clear alternative explanation and agreed upon by investigator and sponsor (eg, clearly 
and incontrovertibly due to underlying disease/progression or extraneous cause) where there 
has been a clinically significant change from baseline:

Clinically important or persistent toxicities that are not included in the criteria below 
may be considered a DLT following review by Pfizer and the Investigators.  All 
DLTs need to represent a clinically significant shift from baseline.
Note: Labs must be repeated for confirmation.  Only the lab result requiring confirmation 
must be repeated, not the entire panel. 


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Hematologic:
Any treatment-related hematologic laboratory abnormality specifically defined as: 

Thrombocytopenia Grade 4 for 7 days, or Grade 3 or 4 associated with Grade 2 
clinically significant bleeding or requiring platelet transfusion (for bleeding events 
with no grading available clinically significant bleeding is defined as required 
hospitalization or urgent medical intervention);

Neutropenia Grade 4 for 7 days; Grade 3 neutropenia with infection; 

Anemia Grade 4, or Grade 3 requiring blood transfusion.
Nonhematologic:

Grade 3 toxicities that are considered clinically significant;

Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >3x the upper 
limit of normal (ULN) with bilirubin >2x the ULN without another explanation 
(eg, cholestasis) will be considered a DLT, ie, confirmed drug induced liver injury 
(DILI) meeting Hy’s law criteria;

Grade 3 nausea, vomiting or diarrhea that does not resolve within 4 days despite 
maximal supportive therapy.
Nonhematologic and Non-Hepatic:

Any toxicity causing greater than 2 weeks of dose delay is a DLT. Note: Patients 
deriving clinical benefit from study treatment who experience a DLT may continue 
on study at a reduced dose following recovery of the AE to Grade 0-1 or baseline, 
only after discussion between the investigator and sponsor;

Any toxicity preventing patients from receiving 75% of study drug during the DLT 
evaluation period is a DLT.
The following AEs will not be adjudicated as DLTs:

Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement;

Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor);

Any Grade 5 event clearly due to underlying disease or extraneous causes;

Isolated Grade 3 laboratory abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 


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72 hours of their onset at data cut off will not be taken into account for MTD 
determination including but not limited to:
•
Grade ≥3 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions;
•
Grade ≥3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.
•
A patient is classified as DLT-evaluable if he/she experiences a DLT or if he/she 
otherwise in the absence of a DLT receives at least 75% of the planned doses of each 
investigational product and has received all scheduled safety assessments during the 
DLT window.  If a patient fails to meet these criteria, he/she may be replaced. 
3.3. MTD Definition
A DLT rate of 27.5% with an equivalence interval of (22.5%, 32.5%) (note: provided the 
DLT rate for cardiac toxicity does not exceed 10%) will be utilized to estimate the MTD; 
patients will be enrolled in dose cohorts of 2-4 patients, and each patient will receive 
2 courses of PF-06952229 (7 days on, 7 days off) in a 28 day cycle.  Due to the discreteness 
of the dose levels and in the interest of the safety of patients, the estimated MTD is the 
highest tested dose level with DLT rate ≤approximately 32.5%.  The dose finding decision 
will be based on a 1-cycle (28 day) DLT observation period. 
At least 6 patients have been accumulated on a dose that can be predicted to be the MTD.
3.4. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further investigation based on Phase 1 dose escalation and 
expansion study results.  Based on the safety, tolerability, and PK/PD data from the Part 1A 
Monotherapy Dose Escalation cohorts, the single agent recommended dose for expansion 
will be selected as an estimate of monotherapy RP2D.  After expansion cohorts with larger 
sample size and sufficient data, the final RP2D will be made by the sponsor based on the 
recommendation from investigators and study team.  The determination of RP2D will be 
based on safety, tolerability, and early signs of clinical efficacy and benefit. 
Based on the safety, tolerability, and PK/PD data from Part 1B combination dose escalation, 
the combination recommended dose for expansion will be selected as an estimate of 
combination RP2D.  Similarly, the final combination RP2D will be determined after the 
combination expansion cohort.  Combination RP2D may be different from monotherapy 
RP2D due to potential overlap toxicity or DDI.
 
 
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4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:  
1. For Part 1A (monotherapy dose escalation phase): Histological or cytological 
diagnosis of a solid tumor that is advanced/metastatic, patients are intolerant to 
standard treatment, resistant to standard therapy or for which no standard therapy is 
available for the following tumor types: 
•
Breast cancer;
•
Prostate cancer (mCRPC - testosterone less than 50 ng/dL);
•
Squamous cell cancer of the head and neck;
•
Melanoma;
•
Mesothelioma;
•
Pancreatic cancer;
•
Colorectal cancer;
•
Renal cell carcinoma;
•
Hepatocellular cancer.
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2. For Part 1B (Combination Dose Escalation Phase): histological or cytological 
diagnosis of mCRPC (castration is defined as having a serum testosterone less than 
50 ng/dL due to medical or surgical castration), patients who are intolerant to 
standard treatment, resistant to standard therapy, or refuse to standard therapy.
3. Part  2A and Part 2B:  

Histologically or cytologically confirmed prostate adenocarcinoma metastatic 
disease.

Effective castration with serum testosterone levels 0.5 ng/mL (1.7 nmol/L).

Having received 3 or more cycles of prior docetaxel therapy (before or after 
abiraterone).

Having PD while receiving abiraterone acetate within 12 months of abiraterone 
treatment initiation (≤12 months).

Progressive disease (PD) by:
a.
Progression in measurable disease per RECIST 1.1 criteria.  Patient with 
measurable disease must have at least 1 lesion that can be accurately measured 
in at least 1 dimension (longest diameter to be recorded).  Each lesion must be 
at least 10 mm when measured by computed tomography (CT) (CT scan 
thickness no greater than 5 mm) or magnetic resonance imaging (MRI).  
Lymph nodes should be ≥15 mm in short axis.  As defined by PCWG2, if 
lymph node metastasis is the only evidence of metastasis, it must be ≥20 mm
in diameter when measured by spiral CT or MRI.  Previously irradiated 
lesions, primary prostate lesion, and bone lesions will be considered non-
measurable disease, or
b. Appearance of 2 or more new bone lesions (PCWG2).  They must be 
confirmed by other imaging modalities (CT; MRI) if ambiguous results, or
c.
Rising PSA defined (PCWG2) as at least 2 consecutive rises in PSA to be 
documented over a reference value (measure 1) taken at least 1 week apart.  
The first rising PSA (measure 2) should be taken at least 7 days after the 
reference value.  A third confirmatory PSA measure is required (second 
beyond the reference level) to be greater than the second measure and it must 
be obtained at least 7 days after the second measure.  If this is not the case, a 
fourth PSA measure is required to be taken and be greater than the second 
measure.  The third (or the fourth) confirmatory PSA should be taken within 4 
weeks prior to enrollment.  A PSA value of at least 2 ng/mL is required at 
study entry.

Prior abiraterone acetate must be stopped at least 2 weeks before study treatment.


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4. Patients must have recently obtained archival tumor tissue available for submission to 
the sponsor (except for Part 2A – monotherapy dose expansion).  Patients enrolled in 
Part 1 and Part 2 should have access to their archival formalin-fixed paraffin-
embedded material, collected within 6 months of screening, containing tumor that is 
of diagnostic quality and representative of their diagnosed malignancy or whenever 
possible, consent to undergo a biopsy during screening.  The sponsor should be 
contacted if obtaining a new biopsy is not medically feasible for approval to enroll, 
prior to initiating screening activities. 
5. Patients entering the study in the subgroup(s) requiring mandatory pre- and 
on-treatment tumor biopsies in Part 2A and 2B must have a tumor amenable to biopsy 
and consent to these planned biopsy procedures.  The sponsor should be contacted if 
obtaining a pre-treatment and on treatment biopsies is not medically feasible for 
approval to enroll, prior to initiating screening activities.
6. Age 18 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
8. Adequate bone marrow function (see Appendix 3), including:

Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;

Platelets 100,000/mm3 or 100 x 109/L;

Hemoglobin 9 g/dL.
9. Adequate renal function, including serum creatinine 1.5 x upper limit of normal 
(ULN) or estimated creatinine clearance 60 mL/min as calculated using the method 
standard for the institution.  In equivocal cases, a 24-hour urine collection test can be 
used to estimate the creatinine clearance more accurately.  
10. Adequate liver function, including:

Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome;

Aspartate and alanine aminotransferase (AST and ALT) 2.5 x ULN, 5.0 x ULN 
if there is liver involvement by the tumor;

Alkaline phosphatase 2.5 x ULN (5 x ULN in case of bone metastasis). 
11. Serum phosphate within normal range (if abnormal, must be nonclinically significant 
per the Investigator and approval for patient inclusion after agreement from sponsor.
12. Resolved acute effects of any prior therapy to baseline severity or CTCAE 
Grade 1 except for alopecia and those listed in the specific exclusion criteria.


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13. For Part 1A monotherapy dose escalation: serum pregnancy test (for females of 
childbearing potential) negative at screening.
14. For Part 1A monotherapy dose escalation: female patients of nonchildbearing 
potential must meet at least 1 of the following criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and must have a serum follicle-stimulating hormone (FSH) 
level confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential. 
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. 
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures. 
4.2. Exclusion Criteria
Patients with any of the characteristics/conditions listed below will not be included in the 
study:
Any labs may be repeated for confirmation.  Only the lab result requiring confirmation must 
be repeated, not the entire panel. 
1. For Parts 1B; current or prior treatment with enzalutamide within 24 days prior to 
first dose
1. For 2A and 2B:

Prior chemotherapy other than docetaxel for prostate cancer, except estramustine, 
adjuvant/neoadjuvant treatment completed 3 years ago;

Less than 28 days elapsed from prior treatment with chemotherapy, 
immunotherapy, radiotherapy, or surgery to the time of study enrollment.
2. Central Nervous System (CNS) metastases, carcinomatous meningitis, or 
leptomeningeal disease as indicated by baseline brain MRI (or CT with contrast if 
MRI is medically contraindicated), clinical symptoms, cerebral edema, and/or 
progressive growth.  If contrast is medically contraindicated, a non-contrast CT scan 
may be performed.


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3. Patients with a history of CNS metastases or cord compression.
4. Liver metastases at baseline as evidenced by CT scan or MRI that may be at risk for 
bleeding, such as those that are >1 cm,
5. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of 
life-threatening complications in the short term (including patients with massive 
uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and 
over 50% liver involvement).  Note: Patients with indwelling catheter for drainage, or 
requirement for drainage no more frequently than monthly will be allowed.
6. Any other active malignancy within 3 years prior to study entry, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
7. Patients with a history of clinically significant tumor bleeding (except for bleeding in 
a post-operative setting), coagulopathy or arterio-venous malformations (AVM) or 
aneurysms in the CNS, liver, lung or other major organ of the body.  Patients with 
known Osler-Weber-Rendu disease, Hemophilia A, Hemophilia B (Christmas 
Disease), Von Willibrand’s Disease, Factor 13 deficiency and Factor 7 deficiency, 
antibodies to Factors 8 and 7, history of other bleeding diatheses and abnormal INR 
values.   
8. Evidence of a tumor that compresses or invades major blood vessels or tumor 
cavitation that in the opinion of the investigator is likely to bleed.
9. Major surgery within 4 weeks prior to first dose.
10. Prior organ transplantation including heart and allogeneic stem-cell transplantation.
11. Radiation therapy within 4 weeks prior to study entry.  Note: Patients who have 
received radiotherapy must have recovered from any reversible side effects, such as 
nausea and vomiting. 
12. Last anti-cancer therapy including investigational drug(s) within 28 days (or 
5 half-lives, whichever is shorter) prior to study entry excluding hormonal therapy. 
13. Active and clinically significant bacterial, fungal, or viral infection, including known 
hepatitis B virus (HBV), known hepatitis C virus (HCV), known human 
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) 
- related illness.  In equivocal cases, with positive serology, those patients with a 
negative viral load are potentially eligible provided the other entry criteria are met.  
Note: Inclusion of patients with well controlled HIV, HBV or HCV can be discussed 
with sponsor on a case by case basis.

COVID-19/SARS-CoV2: Refer to Appendix 8 for further information. 


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14. Any of the following in the previous 6 months: myocardial infarction, congenital long 
QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular 
tachyarrhythmia and ventricular fibrillation), right bundle branch block and left 
anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure (New York Heart Association 
class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic 
pulmonary embolism; deep venous thrombosis (DVT); arterial occlusive disease; 
ongoing cardiac dysrhythmias of National Cancer Institute (NCI) CTCAE Grade 2, 
atrial fibrillation of any grade that is uncontrolled, or QTcF interval >470 msec at 
screening.  Note: There is an exception where a cardiac rhythm device/pacemaker is 
fitted and results in QTcF >470 msec.  
15. Anticoagulation therapy with heparin, low molecular weight heparin, vitamin K 
antagonists, anti-platelet agents, or factor Xa inhibitors throughout the study and for 
at least 28 days post the last dose of study treatment.  (If anticoagulation therapy is 
medically indicated on trial, patients should stop treatment with PF-06952229.  For 
those requiring temporary anticoagulant therapy, resumption of PF-06952229 
treatment may be permitted after discussion with the Sponsor.  In any other case, 
study treatment should be permanently discontinued, and the patient should enter the 
follow-up portion of the trial.)
16. Moderate or severe heart valve function defect including moderate or severe valve 
stenosis or regurgitation.
17. Evidence or history of septal aneurysm, other heart aneurysm, or any aneurysm of the 
major vessels.
18. Grade 3 cardiac troponin I at baseline.
19. Left ventricular ejection fraction (LVEF) of 50% or significant valvular 
regurgitation.
20. Hypertension that cannot be controlled by medications (>150/90 mmHg despite 
optimal medical therapy) or requiring more than 2 medications for adequate control.
21. Clinically significant non-healing or healing wounds.
22. For patients entering the combination with enzalutamide arm, history of seizures 
other than isolated febrile seizure in childhood.
23. Has a history of a cerebrovascular accident or transient ischemic attack less than 
6 months ago.
24. Known or suspected hypersensitivity to active ingredient/excipients of PF-06952229 
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25. Other acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
26. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
27. For Part 1A Monotherapy Dose Escalation: Pregnant female patients; breastfeeding 
female patients; fertile male patients and female patients of childbearing potential 
who are unwilling or unable to use 2 highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for at least 28 days after the 
last dose of investigational product. 
28. For Part 1B Combination Dose Escalation, Part 2A Monotherapy Expansion, and Part 
2B Combination Dose Expansion: fertile male patients and female partners of 
childbearing potential who are unwilling or unable to use 2 highly effective methods 
of contraception as outlined in this protocol for the duration of the study and for at 
least 28 days after the last dose for monotherapy (Part 2A) or for at least 3 months 
after the last dose for combination therapy (Part 1B and Part 2B).
29. Inability to consume or absorb study drug, including but not limited to: 

Active inflammatory gastrointestinal (GI) disease, known diverticular disease or 
previous gastric resection or lap-band surgery.  Impairment of gastro-intestinal 
function or GI disease that may significantly alter the absorption of PF-06952229, 
such as history of GI surgery with may result in intestinal blind loops and patients 
with clinically significant gastroparesis, short bowel syndrome, unresolved 
nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE 
Grade >1.
30. Current use or anticipated need for food or drugs that are known strong and moderate 
CYP3A4/5 inhibitors, including their administration within 10 days or 5 half-lives of 
the CYP3A4/5 inhibitor, whichever is longer, prior to first dose of investigational 
product.  A list of CYP3A4/5 inhibitors are provided in Appendix 9 (Section 5.7).
31. Current use or anticipated need for drugs that are known strong and moderate 
CYP3A4/5 inducers, including their administration within 10 days or 5 half-lives of 
the CYP3A4/5 inducer, whichever is longer, prior to the first dose of investigational 
product (See Section 5.7).  A list of CYP3A4/5 inducers is provided in Appendix 9.


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32. Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa 
B -ligand (RANK-L) targeted agents (for example, denosumab) <14 days prior to 
study entry, unless there is agreement with the medical monitor.
33. Active, known or suspected autoimmune diseases including inflammatory bowel 
disease (including ulcerative colitis and Crohn’s disease), rheumatoid arthritis, 
systemic progressive sclerosis, systemic lupus erythematosus (SLE), autoimmune 
vasculitis (eg, Wegener’s Granulomatosis), CNS or motor neuropathy considered to 
be of autoimmune origin (eg, Gullian-Barre Syndrome, Myasthenia Gravis, Multiple 
Sclerosis).
4.3. Lifestyle Requirements 
In this study, fertile male patients and female patients who are of childbearing potential will 
receive PF-06952229.  Patients who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must agree to use 2 methods of highly effective 
contraception throughout the study and for at least 28 days after the last dose of monotherapy 
(Part 1A and Part 2A) or for at least 3 months after the last dose of combination therapy (Part 
1B and Part 2B).  The investigator or his or her designee, in consultation with the patient, 
will confirm that the patient has selected 2 appropriate methods of contraception for the 
individual patient and his or her partner(s) from the list of permitted contraception methods 
(see below) and will confirm that the patient has been instructed in their consistent and 
correct use.  At time points indicated in the Schedule of Activities, the investigator or 
designee will inform the patient of the need to use 2 highly effective methods of 
contraception consistently and correctly and document the conversation, and the patient’s 
affirmation, in the patient’s chart.  In addition, the investigator or designee will instruct the 
patient to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the patient or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the post vasectomy ejaculate. 


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5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male patients must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of monotherapy (Part 1A and Part 2A), and for at least 3 months after the last dose of 
combination therapy (Part 2A and Part 2B).
Patients will be advised to report any reaction to sun exposed skin.  In addition, special 
precautions will be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity ultraviolet B (UVB) light sources such as 
tanning beds, tanning booths and sunlamps.  Patients should be encouraged to apply 
sunscreen/sunblock daily.
Patients should not eat or drink products containing grapefruit from 7 days prior to 
enrollment until end of the study or discontinuation.
4.4. 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 supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study 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 
patient’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 patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, Investigational Medicinal Product is defined as a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the Investigational Medicinal Products are PF-06952229 and enzalutamide. 


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Refer to the respective IBs for further information on PF-06952229 and enzalutamide.  
5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will
e-mail or fax a complete Registration Form to the designated sponsor study team member or 
designee.  The sponsor will assign a patient identification number and supply this number to 
the site.  The patient identification number will be used on all study-related documentation at 
the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:
•
Confirmation of the patient’s enrollment;
•
Specification of the dose level for that patient and;
•
Permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Patient Compliance
On PK clinic days, all doses of study treatments will be administered by the appropriately 
designated study staff at the investigational site.
Patients will be required to return all unused study treatment at the beginning of each cycle.  
The number of tablets/capsules returned by the patient will be counted, documented, and 
recorded.
On drug start and stop days, compliance telephone calls will occur for a minimum of the first 
2 cycles to ensure compliance to the study drug schedule.  Additionally, a patient diary will 
be provided to the patients to aid in patient compliance with the dosing instructions and used 
to support the accountability process.  The diary will be maintained by the patient to include 
missed or changed doses (PF-06952229 and enzalutamide, where applicable).  The number 
of PF-06952229 tablets remaining will be documented and recorded at each clinic visit or 
Day 1 of each cycle.  The patient diary may also be used to support this part of the 
accountability process. 
 
 
Enzalutamide will be administered in accordance with the protocol.  All PF-06952229 and 
enzalutamide administration will be documented on the corresponding investigational 
product administration case report form (CRF).  The information regarding diary completion, 
requirement to return all bottles and accountability documentation will also be performed on 
patients receiving enzalutamide (where applicable).
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5.3. Investigational Product Supplies 
PF-06952229 and enzalutamide will be supplied by Pfizer.  Study centers will receive 
PF-06952229 and enzalutamide (for Part 1B and Part 2B) prior to enrollment of the first 
patient.
The clinical site pharmacy will dispense the supply that is appropriate for the patient.
5.3.1. Dosage Form(s) and Packaging
PF-06952229 will be provided as tablets for oral administration.  The 5 mg, 25 mg, and 
125 mg tablets will be supplied in separate bottles and labeled according to local regulatory 
requirements.
5.3.1.1. Enzalutamide
Enzalutamide will be provided by Pfizer as capsules for oral administration.  The 
enzalutamide 40 mg capsules will be supplied in bottles and labeled according to local 
regulatory requirements.
5.3.2. Preparation and Dispensing
The study treatment should be dispensed at each visit per the schedule of treatment.  A 
qualified staff member will dispense the investigational product in the bottles provided, in 
quantities appropriate for the study visit schedule.  The patient/caregiver should be instructed 
to maintain the product in the bottle provided throughout the course of dosing, keep the 
investigational product away from children, and return the bottle to the site at the next study 
visit. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of all investigational agents or drugs used in this study, including but not limited to: 
PF-06952229 and enzalutamide.
Dose adjustments or discontinuations should be managed according to the 
Section 5.4.4 below.  However, per the investigator’s discretion, other dose adjustments may 
be discussed with the sponsor.
Any unused product or waste material should be disposed of in accordance with local 
requirements.
5.4. Administration
5.4.1. PF-06952229
Patients will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing.
PF-06952229 will be administered twice a day (BID) on an intermittent basis (7 days 
on/7 days off).  A cycle is defined as 28 days, regardless of missed doses or dose delays. 


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PF-06952229 will be administered orally on an empty stomach without adjustment for body 
size at every cycle, 
 
  No food or liquids other than water will be consumed for 2 hours before and 
1 hour following each dose throughout the study.
Patients should be instructed to take their medication at approximately the same time each 
day (approximately every 12 hours) and to not take more than the prescribed dose at any 
time. 
On days of scheduled clinic visits (see the Schedule of Activities for Parts 1 and 2), morning 
(AM) dosing of PF-06952229 should be undertaken in the clinic (ie, not at home).  On those 
days where the morning dose of PF-06952229 is held due to a specific study visit, the second 
BID dosing should be taken no sooner than 8 hours, and no later than 16 hours post the first 
BID dosing (allowable treatment window ±4 hours).  On Day 1 of Cycle 1 and Cycle 2 in 
Part 1B and Part 2B, only a single dose of PF-06952229 to be given to evaluate PF-06952229 
PK sampling up to 24 hr time point (ie, pre-dose on Day 2 of Cycle 1 and Cycle 2).
If a patient misses a dose by more than 4 hours, he/she must be instructed not to “make it up” 
but to resume the subsequent dose as prescribed. 
If a patient vomits 1 hour or more after taking a dose, he/she must be instructed not to “make 
it up” but to resume subsequent doses and site should discuss dosing with sponsor. 
If a patient inadvertently takes 1 extra dose during a day, the patient should not take the next 
dose of PF-06952229.
In Part 1B and Part 2B of the study, PF-06952229 is given in combination with enzalutamide 
in patients with mCRPC.  After an appropriate dose of PF-06952229 is selected in the 
combination dose escalation cohort (Part 1B), the combination will be tested in a dose 
expansion cohort (Part 2B) of enzalutamide and PF-06952229. 
A dosing diary will be given to the patient to support at-home dosing. 
5.4.2. Food Requirements 
5.4.2.1. Food Requirements 
Oral PF-06952229 will be administered BID with at least 8-oz (240 mL) of water on an 
empty stomach.  No food or liquids other than water will be consumed for at least 2 hours 
before and 1 hour following each dose throughout the study. 
 
 
 
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5.4.3. Enzalutamide Administration
Enzalutamide capsules are to be self-administered once daily on an outpatient basis and can 
be taken with or without food. 
Patients receiving enzalutamide should also receive a gonadotropin-releasing hormone 
(GnRH) analog concurrently or should have had bilateral orchiectomy.
If a patient misses a dose by more than 8 hours, he/she must be instructed not to “make it up” 
but to resume the subsequent dose as prescribed.  If a patient vomits 1 hour or more after 
taking a dose, he/she must be instructed not to “make it up” but to resume subsequent doses 
and site should discuss dosing with sponsor. 
A dosing diary will be given to the patient to support at-home dosing. 
5.4.4. Recommended Dose Modifications
Dose modifications for enzalutamide due to toxicity or intolerable side effects are described 
in Sections 5.4.5 and Section 5.4.6. 
Every effort should be made to administer PF-06952229 on the planned dose schedule 
(28-day cycle, 7 days on/7 days off).
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modifications should be based on the worst 
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toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom. 

No dose adjustments or reductions are allowed and patients are to discontinue the 
study treatment at any signs of medically significant cardiac toxicity.

Patients will continue to receive the reduced dose as a result of AEs even after 
toxicity recovery. 

Patients who experience a second discreet DLT-equivalent toxicity will be 
discontinued from the study unless they are expected to continue to receive clinical 
beneﬁt after discussion with the sponsor medical monitor or designee.

Despite dose reductions or delays of PF-06952229 the patient will retain the same 
28-day cycle of 7 days on and 7 days off.  Note: If a treatment interruption continues 
beyond Day 28 of the current cycle, then the day when treatment is restarted will be 
counted as Day 1 of the next cycle. 

In the case where a patient is at a dose level deemed to be above a safe level (MTD 
determined below this dose level) discussion between the Investigator and the 
sponsor to determine what is in the best interest of the patient.
Dose modifications may occur in one of three ways:

Within a cycle: dosing interruption until adequate recovery, and if required, dose 
reduction during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
5.4.5. Dosing Interruptions
Patients experiencing Grade 3 or 4 potentially PF-06952229 treatment related toxicity or 
intolerable Grade 2 toxicity despite supportive care should have their treatment interrupted.
Consider permanent discontinuation of study treatment for related Grade 4 AEs of any 
duration. An exception to this such as emesis, as well as clinically insignificant laboratory 
abnormalities that resolve within 3 days on optimum treatment should be discussed between 
the investigator and Pfizer or its delegate.
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. 


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Doses may be held for up to 2 weeks until toxicity resolution.  Depending on when the 
adverse event resolved, a treatment interruption may lead to the patient missing all 
subsequent planned doses within that same cycle or may even delay the initiation of the 
subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  Patients must maintain their original dosing schedule regardless of dose 
reductions or holds.  The need for a dose reduction at the time of treatment resumption 
should be based on dose reduction criteria, unless expressly agreed otherwise following 
discussion between the investigator and the sponsor.  If a dose reduction is applied in the 
same cycle, the patient may need to return to the clinic to receive new drug supply.
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting >4 weeks, treatment resumption will be decided in consultation 
with the sponsor. 
For enzalutamide, if a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect (at 
the PI’s discretion), withhold dosing for 1 week or until symptoms improve to ≤ Grade 2, 
then resume at the same or a reduced dose (120 mg or 80 mg).  Please contact Sponsor’s 
medical monitor for any questions. 
5.4.6. Dose Delays
Re-treatment following treatment interruption for PF-06952229 treatment-related toxicity or 
at the start of any new cycle may not occur until all of the following parameters have been 
met:

ANC 1,000/mm3; 

Platelets count 50,000/mm3; 

Non-hematologic toxicities have returned to baseline or Grade 1 severity (or at the 
investigator’s discretion, Grade 2 if not considered a safety risk for the patient).
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are met within 4 weeks of treatment interruption, PF-06952229 may be 
resumed.  Refer to the Dose Reductions section for AEs that require dose reduction at the 
time of treatment resumption. 
If these conditions are not met, treatment resumption must be delayed for up to a maximum 
of an additional 2 weeks.  If patients require discontinuation of PF-06952229 for more than 6 
weeks at any time during the study, then study treatment should be permanently discontinued 
unless the investigator’s benefit/risk assessment suggests otherwise after discussion with the 
sponsor’s medical monitor or designee.


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If a treatment interruption continues beyond Day 14 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle. 
If patients require discontinuation of study drug for more than 4 weeks at any time during the 
study, then study treatment should be permanently discontinued, unless the investigator’s 
benefit/risk assessment suggests otherwise and after discussion with the sponsor’s medical 
monitor.
For enzalutamide, if a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect (at 
the PI’s discretion), withhold dosing for 1 week or until symptoms improve to ≤ Grade 2, 
then resume at the same or a reduced dose (120 mg or 80 mg).  Please contact Sponsor’s 
medical monitor for any questions.
5.4.7. Dose Reductions
Following dosing interruption or cycle delay due to toxicity, the PF-06952229 dose may need 
to be reduced when treatment is resumed.
Dose reduction/discontinuation of PF-06952229 should be considered before or concurrently 
with enzalutamide (for patients receiving combination of PF-06952229 and enzalutamide).
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Patients experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the 
next lower dose level once recovery to Grade 1 or baseline is achieved within 2 weeks.
Dose reduction of PF-06952229 associated with treatment related toxicity by 1 and, if 
needed, 2 dose levels will be allowed depending on the type and severity of toxicity 
encountered.  Patients requiring more than 2 dose reductions will be discontinued from the 
treatment and entered into the follow-up phase, unless otherwise agreed between the 
investigator and the sponsor.  All dose modifications/adjustments must be clearly 
documented in the patient's source notes and case report form (CRF).
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Intrapatient dose 
re-escalation is not allowed.
Patients experiencing a DLT during the 28 day safety window and who in the judgment of 
the investigator and sponsor are benefiting from therapy may resume dosing at the next lower 
dose level once adequate recovery is achieved.
Hold PF-06952229 for related Grade 3 AEs with subsequent dose-reduction, if such AEs 
return to Grade 1 or baseline within two weeks.


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Exclusions to this include emesis, and clinically insignificant laboratory abnormalities that 
resolved within two days on optimum treatment and dose reduction may not be required.
Patients who require a treatment interruption >4 weeks should discontinue the study drug 
thought to be responsible for the treatment interruption.
Table 3.
Dose Modifications for PF-06952229 - Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Serum bilirubin 
(Guidance for 
non-Gilbert’s 
Syndrome patients.  
Agreement between 
sponsor and 
investigator is 
required for these 
patients).
Continue at 
the same 
dose level
Continue at 
the same 
dose level
When serum bilirubin 2 x 
ULN: 
Hold administration until 
recovery to Grade 0-1 within 
2 weeks, serum bilirubin 
<2 xULN or baseline and 
reduce by 1 dose level.
Discontinue dose if dose 
delay is more than 2 weeks.*
If toxicity reoccurs despite 
reduction, patient may be 
dose reduced again by 
another dose level upon 
recovery to Grade 0-1 or 
baseline within 2 weeks 
unless the patient is in the 
first dose group, then only 
1 dose reduction is allowed.
Prompt palliative measures 
are strongly encouraged (eg, 
anti-emetics).
Patients who experience 
related 
Grade 4 non- hematologic 
toxicities despite optimal 
medical intervention should 
be discontinued from the 
study. *
Thrombocytopenia
Continue at 
the same 
dose level.
Continue at 
the same 
dose level.
Hold PF-06952229 until 
platelets 75,000/mm3.
For platelet counts 
10,000 – 25,000/mm3, 
continue monitoring every 
3 days until recovery to 
25,000/mm3 (Grade 3 or 
less) within 2 weeks.  For 
platelet counts 
10,000/mm3 monitor daily 
until recovery to 
25,000/mm3 (Grade 3 or 
less) within 2 weeks.
Reduce PF-06952229 by 
1 dose level.
If toxicity reoccurs despite 
dose reduction, patient may 
either be held until recovery 
within 2 weeks and 
continuation at same dose, or 
undergo further dose 
reduction by another dose 
Consider Permanent 
discontinuation of study 
drugs for related Grade 
4 AEs of any duration.


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Table 3.
Dose Modifications for PF-06952229 - Related Toxicity
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
level unless the patient is in 
the first dose group, then only 
1 dose reduction is allowed.
Non-hematologic 
Continue at 
the same 
dose level.
Continue at 
the same 
dose level. 
Withhold dose until toxicity 
is Grade 1, or has returned 
to baseline, within 2 weeks 
then resume treatment at the 
same dose level or reduce the 
dose by 1 level at the 
discretion of the 
investigator.*
Permanent discontinuation 
of study drugs for related 
Grade 4 AEs of any 
duration. * (Exclusion to this 
discontinuation for emesis, 
and clinically insignificant 
laboratory abnormalities that 
resolve within two days on 
optimum treatment, 
additional exclusions will 
require agreement between 
the investigator and 
sponsor).
Hematologic
Continue at 
the same 
dose level.
Continue at 
the same 
dose level.
Withhold dose until toxicity 
is Grade 2, or has returned 
to baseline within 2 weeks, 
then resume treatment at the 
same dose level.**
Permanent discontinuation 
of study drugs for related 
Grade 4 AEs of any 
duration.**
(Exclusion to this will 
require agreement between 
the investigator and 
sponsor).
Acute reductions in 
hemoglobin
Mild 
symptoms; 
investigate 
for tumor 
hemorrhage 
or other 
sources of 
bleeding.
Moderate 
symptoms. 
For acute 
hemoglobin 
reduction   
≥2g/dL, 
hold dose 
and 
investigate
for tumor 
hemorrhage 
or other 
sources of 
bleeding.
For acute unexplained G 
3 anemia (hemoglobin <8.0 
g/dL), restore blood/blood 
volume and investigate for 
tumor hemorrhage or other 
sources of bleeding. 
Consider permanent 
discontinuation. Continuation 
will require agreement with 
Sponsor, hemoglobin 
>9.0 g/dL and complete 
resolution of the tumor 
hemorrhage/ bleeding event. 
For acute unexplained G 
4 anemia, replace 
blood/blood volume and 
investigate for tumor 
hemorrhage or other sources 
of bleeding. 
Permanent discontinuation 
of study drug.
*Patients may continue on trial if they are receiving clinical benefit after discussion between the investigator 
and sponsor.
**Cycle will not be extended to cover for the missing doses.


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Nausea, vomiting, or diarrhea should follow guidance for the below:
Table 4.
Nausea, Vomiting, or Diarrhea, Cardiac Toxicity Dose Modification 
Guidance
Initial management or low-grade symptoms
Follow-up or higher-grade symptoms
Dyspepsia
Consider starting or giving prescription antacids (not 
PPIs.
For Grade 2, consider dose interruption until 
dyspepsia back to baseline.  Can restart at starting 
dose or dose modify (eg, 1 level) depending on the 
severity of symptoms and other contributing factors.
Consider referral to gastroenterology for evaluation 
of Helicobacter pylori, possible endoscopy if 
Grade 2 symptoms persist despite appropriate 
therapy with antacids and dose interruption.
Diarrhea
Prescribe loperamide or diphenoxylate/atropine; 
begin if diarrhea Grade 1.
Grade 2: interrupt PF-06952229; restart when it is 
Grade 1 at same dose or at dose reduction, 
depending on severity of symptoms and other 
contributing factors.
Nausea/emesis
Pretreatment with antiemetics is not required for 
PF-06952229.
Patient education regarding this common side effect 
is essential, and prescriptions for prochlorperazine, 
5-HT3 antagonists, or other antiemetics of choice 
should be given along with instructions and 
indications for use if nausea/emesis is Grade 1.
Grade 2: interrupt PF-06952229; consider adding a 
second antiemetic per NCCN guidelines; restart 
PF-06952229 when it is Grade 1 at same dose or at 
a dose reduction based on the severity of symptoms.
Cardiac Toxicity
No dose adjustments or reductions are allowed, and 
patients are to discontinue the study treatment at any 
signs of medically significant cardiac toxicity.
For enzalutamide, if a patient experiences a ≥Grade 3 toxicity or an intolerable side effect (at 
the PI’s discretion), withhold dosing for 1 week or until symptoms improve to ≤Grade 2, 
then resume at the same or a reduced dose (120 mg or 80 mg). Please contact Sponsor’s 
medical monitor for any questions.
5.4.8. Study Stopping Rules and Patient Discontinuation
If the incidence of all bleeding events (all Grades) that are related to PF-06952229 is 
observed above 25%, the trial will be suspended.
All Grade 3 or Grade 4 bleeding events that are related to PF-06952229 will result in trial 
discontinuation for any patient who experience such clinical findings. 
Any subsequent Grade 3 or Grade 4 bleeding event that is related to PF-06952229 will 
trigger a full review of overall safety of PF-06952229 and an assessment of the benefit/risks 
of this molecule in the studied patient population.


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5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any marketed products, are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 


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5.6. Investigational Product and Study Treatment Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product and study treatment supplies.  All 
investigational products and study treatment will be accounted for using a drug 
accountability form/record.  All bottles of study treatments must be returned to the 
investigator by the patient at every visit and at the end of the trial.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician (including bisphosphonates or approved RANK ligand 
(RANK-L) targeted agents (for example, denosumab).
All concomitant treatments, blood products, as well as nondrug interventions received by 
patients from screening until the end of study visit will be recorded on the CRF.
Anticoagulation therapy with heparin, low molecular weight heparin, vitamin K antagonists, 
anti platelet agents, or factor Xa inhibitors is prohibited throughout the study and for at least 
28 days post the last dose of study treatment.  If anticoagulation therapy is medically 
indicated on trial, patients should stop treatment with PF-06952229.  For those requiring 
temporary anticoagulant therapy, resumption of PF-06952229 treatment may be permitted 
after discussion with the Sponsor.  In any other case, study treatment should be permanently 
discontinued, and the patient should enter the follow-up portion of the trial.
Because inhibition of CYP3A4/5 isoenzymes may increase PF-06952229 exposure leading to 
potential increases in toxicities, the use of known strong and moderate inhibitors are not 
permitted within 10 days or 5 half-lives of the CYP3A4/5 inhibitors, whichever is longer 
prior to the first dose of PF-06952229.  A list of CYP3A4/5 inhibitors is provided in 
Appendix 9. 
Because induction of CYP3A4/5 isoenzymes may decrease PF-06952229 exposure leading to 
potential decrease in efficacy, the use of strong or moderate CYP3A4/5 inducers is not 
permitted within 10 days  or 5 half-lives of CYP3A4/5 inducers, whichever is longer prior to 
the first dose of PF-06952229.  A list of CYP3A4/5 inducers is provided in Appendix 9. 
5.7.1. Proton-Pump Inhibitors
Acid reducing agents (ARAs) may decrease PF-06952229 absorption and exposure.  The 
potential impact to absorption and exposure may be the greatest with proton pump inhibitors 
(PPIs).  When possible patients who are currently taking PPIs should be switched to antacids 


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or H2-Receptor antagonists (see below) at least 14 days prior to Cycle 1 Day 1 and continue 
with these alternative ARAs throughout the study. 
In Part 1A, Part 1B, and Part 2B, if the patient starts the study treatment period currently 
taking a PPI, the dose and frequency should be recorded in the appropriate CRF page and the 
patient should maintain this treatment until after Cycle 2 Day 1 visit, to allow for more
accurate estimation of the impact of 
 enzalutamide (Part 1B, and Part 2B) 
on PF-06952229 exposure. If the patient stops or alters treatment with PPI during this period, 
this should be recorded in the CRF.
5.7.2. Antacids or H2-Receptor Antagonists 
Recommendations about the use of antacids or H2-receptor antagonists and PF-06952229 
dosing include the following (but are not limited to): cimetidine, famotidine, nizatidine, 
ranitidine.  If needed, administer H2-receptor antagonists with a staggered dosing regimen 
(twice daily).  The dosing of PF-06952229 should occur at least 10 hours after H2-receptor 
antagonist evening dose and 2 hours before the H2-receptor antagonist morning dose.  
However, if needed, local antacids should be given at least 2 hours before or at least 2 hours 
after PF-06952229 administration.
5.8. Other Anti-tumor/Anti-Cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the initiation of new concurrent vitamins or herbal supplements is 
not permitted unless discussed and agreed with the sponsor.
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
provided that the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In 
view of the current lack of data about the interaction of PF-06952229 with radiotherapy, 
PF-06952229 treatment should be interrupted during palliative radiotherapy, stopping 
14 days before and resuming treatment after recovery to baseline.
5.9. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines. 
Patients currently being treated with a gonadotropin-releasing hormone agonist (GnRH 
agonist) may continue treatment while on clinical study C3881001 as long as the GnRH 
agonist treatment has been well tolerated for at least 3 months prior to study entry.  If patients 
have had tolerability issues with GnRH agonists, such patients may be allowed to enroll with 
agreement of the Pfizer medical monitor.
5.9.1. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first 14 days of Cycle 1, but they may be used to treat treatment emergent neutropenia as 
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indicated by the current American Society of Clinical Oncology guidelines or the relevant 
full prescribing information for the growth factor.
Erythropoietin or other erythropoiesis stimulating agents (ESAs) may be used at the 
investigator’s discretion for the supportive treatment of anemia as described in current 
American Society of Clinical Oncology/American Society of Hematology guidelines or the 
relevant full prescribing information. 
5.9.2. Anti-Diarrheal, Anti-Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is not permitted in the first cycle.  
Primary prophylaxis in subsequent cycles is at the investigator’s discretion.  The choice of 
the prophylactic drug as well as the duration of treatment is up to the investigator with 
sponsor approval assuming there is no known or expected DDI and assuming the drug is not 
included in the Concomitant Treatment(s) section.
5.9.3. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected DDI and assuming the drug is not included in the Concomitant 
Treatment(s) section. 
5.9.4. Corticosteroids 
Chronic systemic corticosteroid use (prednisone >15 mg/day or equivalents) for palliative or 
supportive purposes is permitted.  However, corticosteroids use for a short duration (eg, 
15 mg/day of prednisone, for 2 weeks) as symptomatic treatment on individual basis may 
be considered after discussion with sponsor’s medical monitor or designee.  Acute 
emergency administration, topical applications, inhaled sprays, eye drops, or local injections 
of corticosteroids are allowed.
5.9.5. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-06952229 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06952229 is 
recommended at least 14 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-06952229 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES
6.1. Screening
For screening procedures see the Schedule of Activities and Assessments sections.
6.2. Study Period
For the treatment period procedures, see the Schedule of Activities and Assessments sections.


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6.3. Follow-up 
For follow-up procedures see the Schedule of Activities and Assessments sections.
6.4. Patient Withdrawal 
Withdrawal of Consent:
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information.  
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to Follow-Up:
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (Withdrawal 
from the Study Due to Adverse Events (see also the Patient Withdrawal Section) or 
behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given investigator site. 


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Patient may permanently discontinue study treatment (definitive discontinuation).  Reasons 
for definitive discontinuation of study treatment may include the following:

Objective disease progression; 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
Note that discontinuation of study treatment does not represent withdrawal from the study.  If 
study treatment is definitively discontinued, the patient will remain in the study to be 
evaluated for AEs.  See the Schedule of Activities for data to be collected at the time of 
discontinuation of study treatment and follow-up for any further evaluations that need to be 
completed.
In the event of discontinuation of study treatment, it must be documented on the appropriate 
CRF/in the medical records whether the patient is discontinuing further receipt of study 
treatment or also from study procedures, posttreatment study follow-up, and/or future 
collection of additional information.
A patient may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.


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At the time of discontinuing from the study, if possible, an end of treatment visit should be 
conducted.  See the Schedule of Activities 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 patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow-up with 
the patient regarding any unresolved AEs.
Subsequent to the follow-up period, overall survival (OS) follow-up will be conducted by 
telephone every 8 weeks (7 days) until end of the entire study (2 years after last patient first 
treatment).  If the patient is seen in the clinic during the window of time that a scheduled 
telephone call is to be made to collect survival data, then the clinic visit may replace the 
survival telephone call.
If the patient refuses further visits, the patient should continue to be followed for survival (if 
survival is a secondary endpoint) unless the patient withdraws consent for disclosure of 
future information or for further contact.  In this case, no further study-specific 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.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, serious AEs (SAEs), vital signs and 
physical examination, electrocardiogram (ECG [12-lead]), laboratory assessments, including 
pregnancy tests and verification of concomitant treatments.
For alternative safety assessment logistics during public emergencies such as the COVID-19 
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7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  For female patients of 
childbearing potential, 2 negative pregnancy tests are required before receiving
PF-06952229 (1 negative pregnancy test at screening and 1 at the baseline visit immediately 
before PF-06952229 administration).  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and the second negative pregnancy 
test result will then be required at the baseline visit and within 5 days after the first day of the 
menstrual period (counting the first day of the menstrual period as Day 1) before the patient 
may receive the PF-06952229.  In the absence of regular menstrual bleeding, the study 
candidate should have used 2 forms of contraception for at least 1 month before the second 
pregnancy test.  Pregnancy tests will also be repeated at every treatment cycle up to 
Cycle 3 and every other cycle thereafter during the active treatment period, and at the end of 
study treatment to confirm that the patient has not become pregnant during the study.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period and when potential pregnancy is otherwise suspected, and may be repeated 
if requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the patient will be 
withdrawn from administration of investigational product but may remain in the study.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
version 5.0) timing, seriousness, and relatedness.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analysed at local laboratories.
Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT
PT or INR
Urine dipstick for 
urine protein: If 
(greater than 1+), 
collect 24-hr and 
microscopic (Reflex 
Testing)
For female patients 
of childbearing 
potential, serum or 
urine 
Platelets
AST
PTT
WBC
Alk Phos
Absolute Neutrophils
Sodium
Absolute 
Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic (Reflex 
Testing)
SEROLOGY
Absolute Eosinophils
Chloride
Hepatitis B testing**
Absolute Basophils
Total calcium
Hepatitis C virus 
Antibodies**
Total bilirubin***
Human 
immunodeficiency 
virus (HIV)
BUN or Urea
Tumor markers: PSA 
for mCRPC 
Creatinine
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Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Glucose (nonfasted)
Albumin
Serum Phosphorus 
Alkaline 
phosphatase bone 
fraction
Troponin I and BNP
Alkaline 
phosphatase liver 
fraction
TSH at Screening 
only
Testosterone at 
Screening (mCRPC 
patients only) 
**Viral Disease Screening: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti HBc), (HbcAb), 
hepatitis B surface antibody (anti HBs), hepatitis C virus antibodies (HCVAb), and human immunodeficiency virus 
testing (HIV) to be conducted by local laboratory where required by local regulations or if warranted by patient history.
***For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, 
alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels.
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination to include weight, vital signs, assessment of ECOG 
performance status and height; height will be measured at Screening only.
7.1.5. (12-Lead) Electrocardiogram
Electrocardiogram (ECG): The Screening ECG will be a single 12-lead ECG.  Triplicate 
12-lead (with a 10-second rhythm strip) tracing will be used for all other ECGs.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  At each time point (see the Schedule of Activities), 3 consecutive ECGs will 
be performed at approximately 2 minutes apart to determine the mean QTcF interval.  If the 
mean QTcF is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate. 
If manual reading verifies a QTcF of >500 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 
potential to prolong the QTcF interval) should be performed. 
In addition, repeat ECGs should be immediately performed hourly for at least 3 hours until 
the QTcF interval falls below 501 msec.  If QTcF interval reverts to less than 501 msec, and 
in the judgment of the investigator(s) and sponsor is determined to be due to cause(s) other 
than investigational product, treatment may be continued with regular ECG monitoring.  If in 
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held until the QTcF interval decreases to 500 msec.  Patients will then restart the 
investigational product at the next lowest dose level. 
If the QTcF interval has still not decreased to 500 msec after 2 weeks, or if at any time a 
patient has a QTcF interval >515 msec or becomes symptomatic, the patient will be removed 
from the study.  Additional triplicate ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), then an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, plan the timing of ECG accordingly so that the PK 
collection afterwards can be around the intended time point. 
7.2. Echocardiogram 
Echocardiogram (Echo) will be evaluated in all patients.  The following parameters will be 
evaluated: ventricular function (including left ventricular ejection fraction [LVEF], end 
systolic volume [ESV] and end diastolic volume [EDV]), qualitative evaluation of chamber 
size, and wall motion.  A Doppler examination will be completed and should include an 
assessment of mitral valve, atria, right ventricle, tricuspid valve, aortic valve, pulmonic 
valve, great vessels, and pericardium.  Additional assessments will be per the study manual.
7.3. Pharmacokinetics Assessments
7.3.1. Plasma for PK analysis of PF-06952229
Blood samples (3 mL) to provide a minimum of 1.2 mL plasma for PK analysis will be 
collected into appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic 
acid (K2EDTA) as outlined in the Schedule of Activities.  The PK sampling schedule may be 
modified based on emerging PK data. 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs and the date and time of 
blood sample collection and of last dosing prior to PK collection documented on the CRF.
Where noted in the Schedule of Activities, blood samples for PF-06952229 concentrations 
will be collected at approximately the same time as other assessments such as 
, ECGs (first ECG then PK collection) and bone marrow 
aspirate collections etc, wherever possible. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  The exact time of the sample collection will always be noted on the CRF.  If a 
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scheduled blood sample collection cannot be completed for any reason, the missed sample 
time may be re-scheduled with agreement of the clinical investigator, patient, and sponsor.
PK samples will be assayed for PF-06952229 using a validated analytical method. 
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.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other
internal exploratory purposes.  These data will not be included in the Clinical Study Report 
(CSR).
7.3.2. Urine for Analysis of PF-06952229 Concentrations
In single agent dose expansion cohort (Part 2A), optional urine samples will be collected for 
12 hours (-3 hour window) after PF-06952229 morning dosing on Cycle 1, Day 7 to measure 
PF-06952229 concentrations, and thereby determine the renal elimination of PF-06952229 
from the body.  Urine will be collected on Cycle 1, Day 7 from selected patients over the 
following intervals: 0 to 4 hours, 4 to 8 hours, and 8 to 12 (-3 hour window) hours post the 
morning dose.  Patients will empty their bladder just prior to morning dosing on Cycle 1, 
Day 7. 
At the end of each urine collection period, the total volume will be measured and recorded.  
Voided urine should be collected in a container.  The urine will then be mixed thoroughly, 
and an aliquot will be withdrawn for the potential measurement of drug concentrations.  The 
sample must be processed and shipped as indicated in the instructions provided by the 
sponsor.  The urine samples will be assayed using a validated analytical method in 
compliance with Pfizer SOPs.
Samples collected for analyses of urine PF-06952229 concentration may also be used for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
exploratory purposes.  These data will not be included in the CSR.
 
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7.6. Additional Research
Unless prohibited by local regulations or IRB/EC decision, patients will be asked to indicate 
on the consent form whether they will allow their banked samples to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Patients need not provide additional biospecimens for the uses described in this section; 
 
  Patients may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
Details on processes for collection and shipment of these samples can be found in the Lab 
Manual.
7.7. Imaging Assessments 
Management of Incidental Findings
An incidental finding is one unknown to the patient that has potential health or reproductive 
importance, which is discovered unexpectedly in the course of a research study, but is 
unrelated to the purpose and beyond the aims of the study.
CT, MRI, and PET images may be reviewed by a central review facility.  The purpose of this 
review is to evaluate images for response.  Central image review is not a complete medical 
review of the patient.  If, during the central review process, an unexpected observation is 
identified and this finding could, in the opinion of the central reviewer, have a significant 
health or reproductive consequence, this finding may be shared with the study sponsor for 
disclosure to the principal investigator.  All follow-up testing and final diagnosis will be left 
to the discretion of the medical professionals at the site or those with an existing 
physician-patient relationship.  The principal investigator will be responsible for reporting 
any AEs identified from incidental findings as described in the Adverse Event Reporting
section.  Identification of such incidental findings during the central review process should 
not be expected, and the site maintains responsibility for performing a general safety review 
of all images as per site protocols. 
7.8. Tumor Response Assessments 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Assessments, or whenever disease 
progression is suspected (eg, symptomatic deterioration), at the time of withdrawal from 
treatment, if not done in the previous 6 weeks, after end of treatment for patients who did not 
end treatment due to disease progression, death, or withdrawal of consent. 
Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  
Note: Bone scan and soft-tissue disease assessment should continue according to this 
schedule irrespective of whether study treatment is delayed, missed, or discontinued until the 
earlier of initiation of subsequent systemic anticancer therapy or permanent loss to 
radiographic follow-up (including hospice admission).
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Tumor assessments will include CT or MRI of chest, abdomen and pelvis, and MRI of the 
brain.  If a brain MRI is medically contraindicated, a CT scan with contrast (unless contrast is 
medically contraindicated) may be performed, however the same modality should be used on 
an individual patient throughout the study.  Other disease sites may be imaged if disease is 
suspected.  Tumor assessments will be performed at Screening and every 8 weeks (7 days) 
for the first year, then every 12 weeks (7 days).  Bone scans will be performed as medically 
indicated.  Tc-99m bone scans (required for mCRPC at baseline) will be performed at 
baseline if disease is suspected and on study as appropriate to follow disease.  Patients who 
are found to have hemorrhage in other organs will discontinue treatment with PF-06952229 
and enter the follow-up portion of the trial.  After 2 years, tumor assessments should be 
performed every 4 months thereafter.  Given the exploratory nature of the study, 
confirmation of response (complete response (CR)/partial response (PR)) is preferred (see 
RECIST version 1.1).  Tumor assessments should be repeated at the end of study visit if 
more than 6 weeks have passed since the last evaluation.  Patients should have a 
confirmatory scan for PD and can remain on trial if they are receiving clinical benefit upon 
discussion with investigator and sponsor.  Tumor assessments should be fixed according to 
the calendar, regardless of treatment delays.
mCRPC Only: For mCRPC, prostate specific antigen (PSA) assessment should also be 
performed on Screening (for historical progression), C1D1 (-14 days) and Day 1 of Cycles 4, 
7, 10 and every 2nd cycle thereafter as well as the End of Treatment visit, and should be 
evaluated using Prostate Working Group 3 – Soft Tissue Response Criteria.  Patients should 
have a confirmatory scan for PD and should remain on trial if they are receiving clinical 
benefit (according to discussion with site investigator and sponsor).
Confirmation of response (CR/PR) with a second consecutive scan at least 4 weeks later is 
preferred.  Tumor assessments should be repeated at the End of Treatment visit if more than 
6 weeks have passed since the last evaluation.  CT or MRI scans should be completed before 
tumor biopsy samples are collected.  If a patient is classified as having progressive disease 
(PD) at a post-baseline tumor assessment, then confirmation of PD by a second consecutive 
scan at least 4 weeks later in the absence of rapid clinical deterioration is required. 
Radiographic assessments obtained per the patient’s standard of care prior to enrollment into 
the study do not need to be repeated and are acceptable to be used as baseline evaluation, if, 
(1) obtained within 28 days before C1D1 (standard of care imaging may be utilized prior to 
the 28 days after agreement between the sponsor and investigator), (2) performed using the 
method requirements (ie, RECIST v. 1.1), (3) the same technique/modality can be used to 
follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as 
standard of care is available in the patient’s source notes.  All patients’ files and radiologic 
images must be available for source verification and for potential peer review.  All study 
images may also be provided by the study site to an  independent radiology facility (IRF) for 
independent evaluation.  Analysis of tumor assessments for the purpose of this study will be 
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Bone scans must be acquired on all patients using Tc99- methylene diphosphonate (MDP)
tracer at screening and at subsequent post-baseline tumor assessments.
7.8.1. Image Acquisition Parameters 
The following image acquisition parameters must be recorded as applicable: tomographic 
slice thickness and reconstruction interval, pulse sequence, contrast agent (including brand 
name), contrast agent dose and route of administration, contrast agent injection start and stop 
times, and contrast agent injector type (eg, manual or power/auto injector).
7.8.2. Soft Tissue Disease Assessment
CT scans should include full coverage of chest, abdomen, and pelvis at all specified time 
points.  If MRI is performed for the abdomen and pelvis examinations, then at least a 
non-contrast CT chest must be performed as well.  The same method of radiological 
assessment must be used throughout the study.  In particular, the same modality and imaging 
protocol used at baseline should be used at all subsequent imaging time points (eg, if MRI is 
initially used, MRI should be utilized throughout the study).  For at least the baseline 
imaging examination, both pre-contrast CT (or MRI) scans of the abdomen (liver at 
minimum) and post-contrast CT (or MRI) scans of the chest, abdomen, and pelvis must be 
obtained.  For the abdomen and pelvis at least single-phase (equilibrium or IVC phase) 
should be obtained.  For all scheduled follow-up imaging examinations, post-contrast CT (or 
MRI) scans of the chest, abdomen, and pelvis must be obtained. 
For prostate cancer soft tissue disease response and progression will be defined per modified 
Prostate Cancer Working Group 2 (PCWG2) (See Appendices).
Note: Soft tissue disease progression does not warrant discontinuation of tumor assessments 
or study treatment.  Patients may continue on trial if they are receiving clinical benefit after 
discussion between the investigator and sponsor.
7.8.3. Bone Scan Assessment
Whole body anterior and posterior bone scans should be acquired using 25 mCi (10%) 
Tc99-MDP administered intravenously, with imaging performed 3 hours post-injection.  For 
all follow-up bone scans, the same dose of Tc99-MDP and the same delay from injection to 
scanning and bed speed must be used and be recorded on source documents. 
For patients with symptoms of spinal compression, MRI of the spine and base of the skull 
should also be performed. 
Worsening bone scan does not warrant discontinuation of bone scans or study treatment 
discontinuation. 
7.8.4. Central Independent Radiology Facility (IRF) 
An IRF may evaluate imaging studies and supportive clinical data in a central and
independent fashion.  The IRF will comprise board-certified radiologists and nuclear 
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responses.  Details regarding IRF member qualification, training, methods, procedures, and 
other issues relevant to IRF will be described in the IRF Charter. 
All radiological studies acquired at all scheduled time points and any additional 
(unscheduled) radiological images acquired to evaluate for potential metastatic disease may 
also be requested to be sent to the IRF or sponsor.  All scans sent to the IRF must be in 
original digital imaging and communications in medicine (DICOM) format.  Electronic 
transfer of scan files (via file transfer protocol [FTP], hypertext transfer protocol (HTTP), or 
similar means) is preferred, although transfer on physical media (such as digital versatile disc 
[DVD] or compact disc [CDs]) is acceptable.  For digital media, each disk should contain 
one time point for one patient.  The site is expected to maintain a copy of digital data for the 
retention period applicable to the protocol, Good Clinical Practices (GCP)s, and federal, 
international and/or state legal and medical requirements.  The sponsor and or designee will 
retain the media for the life of the study.
Note: In patients that show evidence of clinical benefit, PCWG2 advises continuing therapy 
in the case of an isolated PSA rise after an initial decline, until radiographic or clinical 
progression is manifest.  PCWG2 draws the distinction between documenting progression for 
consistency of reporting (eg, recording the date of documented progression in a site of 
disease such as a lymph node that is unlikely to adversely affect prognosis) versus the 
decision to stop therapy.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious AEs; and (3) exposure to the investigational product under study during 
pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
All (and EDP 
supplemental form for 
EDP)  
Note:  Include all SAEs 
associated with exposure 
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Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
Occupational exposure is not 
recorded.
breastfeeding. Include all 
AEs/SAEs associated 
with occupational 
exposure.
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this 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 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
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8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
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If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a patient during the active collection period, 
which begins after obtaining informed consent as described in Section 8.1.4, will be recorded 
on the AE section of the CRF.Follow-up by the investigator may be required until the event 
or its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;


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
Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be 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.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or;

Test result 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; and/or;

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.


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8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes then the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;


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
Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 5.0 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. 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 patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or (ALT) precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab 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 patient’s 
individual baseline values and underlying conditions.  Patients who present with the 


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following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients 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 patients 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:
o
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).
o
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).
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 patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 


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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.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy (EDP)
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 


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pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE [ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital (anomaly in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death)], then 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 includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient 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.


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8.4.3. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with 
an SAE
8.4.3.1. Medication Errors Definition
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study patient 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 medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.


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9.1. Analysis Sets
1. Safety analysis set.
The safety analysis set includes all enrolled patients who receive at least one dose of 
study treatment.
2. Full analysis set.
The full analysis set includes all enrolled patients.
3. Per protocol analysis set (evaluable for MTD).
The per-protocol analysis set includes all enrolled patients who receive at least one dose 
of study treatment and who do not have major treatment deviations during the first cycle.  
Patients with major treatment deviations during the first cycle of treatment are not
evaluable for the MTD assessment and will be replaced as needed to permit the MTD 
estimation.  Major treatment deviations include the failure to satisfy major entry criteria 
(eg, confirmation of the target disease; signed informed consent) or use of other
anticancer treatments during the active treatment period and disease follow-up phases 
other than as defined/allowed in this protocol.  Major treatment deviations will also 
include:

Administration of less than 70% of the planned number of doses of 
PF-06952229 (provided that the reduction in doses is not due to toxicity 
attributable to PF-06952229).

Administration of more than 110% of the planned number of doses of 
PF-06952229.
4. Modified Intent to Treat (mITT) Population.
The modified intent to treat (mITT) is the analysis population that will follow the ITT 
principle and include patients receiving at least 1 dose of investigational product with 
baseline assessment and at least 1 post baseline assessment, disease progression, or death 
before the first tumor assessment.  The mITT population will be used for analyses and to 
support conference presentations when the study is still ongoing.
5. PK analysis sets.
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.  The PK 
concentration population is defined as all enrolled patients who are treated and have at 
least 1 analyte concentration.


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9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation
This study contains 2 parts, dose escalation with PF-06952229 (Part 1A), followed by dose 
escalation for PF-06952229 in combination with enzalutamide (Part 1B), and dose expansion 
for PF-06952229 as a monotherapy (Part 2A) and combination dose expansion of 
PF-06952229 with enzalutamide in patients with mCRPC (Part 2B).
Part 1A Single Agent PF-06952229 and Part 1B PF-06952229 Plus Enzalutamide 
Combination Dose Escalation
The dose escalation in Part 1A will start with Accelerated Titration Design (ATD) as 
proposed by Simon et al (Journal of the National Cancer Institute, Vol. 89, No. 15, August 6, 
1997).  Part 1 will have an initial accelerated phase followed by a standard (mTPI) escalation 
phase.  During the accelerated phase, initial cohorts to contain a minimum of one patient 
until the first instance of first-cycle CTCAE grade ≥2 toxicity.  
The traditional mTPI design4 uses a Bayesian statistics framework and a beta/binomial 
hierarchical model to compute the posterior probability of 3 dosing intervals that reflect the 
relative difference between the toxicity rate of each dose level to the target rate (pT = 0.275).  
If the toxicity rate of the currently used dose level is far smaller than pT, the mTPI will 
recommend escalating the dose level; if it is close to target probability (pT), the mTPI will 
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level.  These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model.  The proposed mTPI method for 
this protocol includes stopping rules and dose escalation criteria, which prevents the target 
DLT rate to reach ≥33% for determining the MTD.  This proposed mTPI method is more 
conservative than the traditional TPI method.
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Therefore, the 
target interval for the DLT rate is (0.225, 0.325).
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
underdosing interval corresponds to a dose-escalation (E), overdosing corresponds to a dose 
de-escalation (D), and proper dosing corresponds to remaining at the current dose (R).  Given 
a dosing and a probability distribution, the unit probability mass (UPM) of that dosing 
interval is defined as the probability of a patient belonging to that dosing interval divided by 
the length of the dosing interval.  The mTPI design calculates the UPMs for the 3 dosing 
CCI


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intervals, and the one with the largest UPM informs the corresponding dose-finding decision, 
which is the dose level to be used for future patients.  For example, if the under-dosing 
interval has the largest UPM, the decision will be to escalate, and the next cohort of patients 
will be treated at the next higher dose level.  Ji et al. (2010)4 have demonstrated that the 
decision based on UPM is optimal in that it minimizes a posterior expected loss (ie, 
minimizes the chance of making a wrong dosing decision).
9.2.2. Statistical Methods for Determining the MTD 
This study contains dose escalation with single agent (Part 1A) in patients with advance or 
metastatic solid tumor, and a combination dose escalation with enzalutamide in previously 
treated patients with mCRPC (Part 1B).  Part 1A and Part 1B will determine the MTD/RP2D 
in sequential dose escalation cohorts. 
The dose finding process in the current study is designed to establish the MTD defined as the 
highest dose that yields a target of approximately 27.5% probability of DLT and considers 
equivalent doses that yield probability of DLT in the interval (Equivalence Interval) of 
(22.5%, 32.5%).  Note provided the DLT rate for cardiac toxicity does not exceed 10%.  The 
27.5% target was chosen based on safety considerations.  The prior distribution of DLT is set 
as a beta (0.5,0.5) and the threshold probability for early termination and dose exclusion is 
set to 0.95 as suggested in the original mTPI method (Ji et al., 2010).4  Similarly, doses with 
an incidence of DLT, eg, 4 out of 10, or apparently higher than 32.5% cannot be selected as 
MTD, even though it might be allowed by the mTPI method.
Cohorts of patients could receive doses already tested but a dose that is associated with
decision to “dose de-escalate, unacceptable toxicity” cannot be revisited and no more patients
should be treated at this dose or higher doses for the remainder of the trial.
The maximum sample size for Part 1A would be approximately N=40 for the monotherapy 
dose escalation and approximately N=20 for the combination dose escalation, but actual 
sample size will depend on the underlying dose toxicity profile and variability in actual data 
realization.
The study will continue accruing until one of the three stopping conditions below is 
triggered.

The maximum sample size has been achieved (approximately 40 patients in Part 1A 
monotherapy dose escalation, approximately 20 patients in Part 1B combination dose 
escalation, and 10 patients in Part 2A monotherapy dose expansion and 20 patients in 
Part 2B combination dose expansion);

6 - 12 patients that have been enrolled at a dose level that is predicted to be the MTD 
per the mTPI method;

All dose levels explored appear to be overly toxic, and the MTD cannot be
determined.


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Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the true Probability (DLT) is fairly low.  This could result in the 
estimated posterior DLT rate to exceed the targeted 27.5% very early in the trial.
The following table shows the probability of escalating to the next dose level for a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
greater than 90% probability of escalating.  Conversely, for a DLT that occurs with a rate of 
70%, the probability of escalating is 3%.  It is assumed that dose escalation occurs with either 
0/3 or 1/6 patients with DLTs.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
9.3. Efficacy Analysis
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response 
(and PSA50 response if prostate cancer patient).  In addition, progression date, death date, 
date of first response and last tumor assessment date, and date of last contact will be listed.  
Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), Time 
to Response (TTR), time to progression (TTP), duration of response (DoR), and 
PSA50 response rate for prostate cancer patients will be summarized and presented if data 
permits.  For these efficacy parameters, all dose levels and tumor types will be included for 
part 1 patients, for part 2 patients, summary will be for mCRPC patients.
The definition of each response category is provided in the Appendix for RECIST 1.1.
9.4. Analysis of Pharmacokinetics 
 
9.4.1. Analysis of Pharmacokinetics 
9.4.1.1. Single-Dose and Steady-State PF-06952229 Pharmacokinetic Analysis
Plasma PK parameters including the maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax), and area under the plasma concentration versus time 
curve (AUClast) for PF-06952229 will be estimated using noncompartmental analysis.  If data 
permit or if considered appropriate, area under the plasma concentration versus time curve 
from time 0 extrapolated to infinity (AUCinf), terminal elimination half-life (t1/2), apparent 
oral plasma clearance (CL/F), apparent volume of distribution (Vss/F or Vz/F), accumulation 
ratio (Rac) and linearity ratio (Rss) will be also estimated.  The single-dose and steady-state 
PK parameters will be summarized descriptively (n, mean, standard deviation, coefficient of 
variation [CV], median, minimum, maximum, geometric mean and its associated CV) by 
dose, cycle and day.
For PF-06952229 concentrations, concentrations will be summarized descriptively (n, mean, 
standard deviation, CV, median, minimum, maximum, geometric mean and its associated 
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CV) by dose, cycle, day and nominal time.  Individual patient and median profiles of the 
concentration-time data will be plotted by dose, cycle and day (single dose and steady state) 
using nominal times.  Individual and median profiles will be presented on both linear-linear 
and log-linear scales.
Dose normalized AUClast and Cmax will be plotted against dose (using a logarithmic scale) by 
cycle and day.  These plots will include individual patient values and the geometric means 
for each dose.  These plots will be used to help understand the relationship between the PK 
parameters and dose.
The observed accumulation ratio and the linearity ratio will be summarized descriptively.  
Each will be analyzed after natural log transformation using a one-way analysis of variance 
(ANOVA) with a single term for dose.  The means and 90% confidence intervals (CIs) 
obtained from the model will be back-transformed to provide means and 90% CIs for the 
accumulation and linearity ratios for each dose.
Trough concentrations will be plotted for each dose using a box-whisker plot by cycle and 
day within cycle in order to assess the attainment of steady state.
Urine PK parameters (Ae%, CLR) for PF-06952229 will also be estimated and summarized.
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
9.5.1. Analysis of the Primary Endpoint
DLT is a primary endpoint of the dose escalation components of the study.  The occurrence 
of DLTs observed in the dosing cohorts is used to estimate the MTD as described in the 
Study Design section.  Adverse Events constituting DLTs will be listed per dose level.
9.5.2. Analysis of Secondary Safety Endpoints
Adverse Events
AEs will be graded by the investigator according to the CTCAE version 5.0 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries 
will be on Treatment Emergent Adverse Events, those with initial onset or increasing in 
severity after the first dose of study treatment.  The number and percentage of patients who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1 and Cycles beyond 1).
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the distribution of 
laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
9.5.3. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on treatment ECG data.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
CCI


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safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate).  Data will be summarized and listed for QT, heart rate, RR and PR interval, 
QRS, QTcF (and other correction factors, eg, QTcB as appropriate).  Individual QT (all 
evaluated corrections) intervals will be listed.  The most appropriate correction factor will be
selected and used for the following analyses of central tendency and outliers and used for the 
study conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the absolute corrected QT interval and changes 
from baseline in corrected QT after treatment, dose and time point.  For each patient and by 
treatment, the maximum change from baseline will be calculated as well as the maximum 
post baseline interval across time points.  Categorical analysis will be conducted for the 
maximum change from baseline in corrected QT and the maximum post baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs on treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
9.6. Sample Size Determination
9.6.1. Part 1
In Part 1, patients will participate in a dose escalation phase aimed at estimating the MTD.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.
A maximum of 60 patients are expected to be enrolled in the dose escalation safety cohorts in 
Part 1, including approximately 40 patients for the monotherapy dose escalation and 
approximately 20 patients for the combination dose escalation.  The actual number of 
patients enrolled will depend on the tolerability of PF-06952229 and the number of dose 
levels required to identify the MTD/RP2D.  It is expected that the dose escalation process can 
be stopped and MTD declared with approximately 6 to 12 patients at the MTD dose.  As for 
the number of patients treated at each dose, it is expected to be at 1 to 4 patients for the doses 
actually studied.  However, since variable cohort size is allowed, the actual number of 
patients treated at each dose (including MTD) will vary from 1 to 12 patients.


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9.6.2. Part 2
For PF-06952229 single agent expansion in patients with mCRPC, the planned sample size 
of the expansion cohort is 10 based on clinical consideration.
PF-06952229 single agent in combination with enzalutamide for patients with metastatic 
castration-resistant prostate cancer (mCRPC), assuming a sample size of 20, and the 
observed PSA50 response is 60% (12/20), the Bayesian posterior probability to demonstrate 
that the "True PSA50 response" is greater than 37% is 98.15%.  Assuming 80% of the 
20 patients have measurable disease and are response evaluable (16 patients evaluable), and 
the observed ORR is 43.75% (7/16), the Bayesian posterior probability to demonstrate that 
the "True ORR" is greater than 30% is 86.89%.
All the Bayesian calculations above assume a non-informative Uniform (0,1) prior
9.7. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).  For the purpose of this 
protocol, Pfizer procedures for periodic safety review by a safety review team, comprised of 
the investigators and the sponsor, will be applied in order to review individual and summary 
data collected in the safety and clinical databases. 
Discussions between the investigators and the sponsor regarding safety will occur in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety profile 
and risk/benefit ratio and determine if further patient enrollment is appropriate.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected and/or secured in a locked room to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete,
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
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In most cases, the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.  The investigator 
must ensure that the records continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Patient Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable law.
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the patient’s personal 
data.  The investigator further must ensure that each study patient 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. 


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed [unless a waiver of 
informed consent has been granted by an IRB/EC].  The investigator will retain the original 
of each patient's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last patient last visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06952229 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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


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


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45.
Rodon et al, 2014; Clin Cancer Res; 21(3); 553–60.First-in-Human Dose Study of the 
Novel Transforming Growth Factor-b Receptor I Kinase.Inhibitor LY2157299 
Monohydrate in Patients with Advanced Cancer and Glioma.
46.
Fujiwara et al, 2015; Cancer Chemotherapy and Pharmacology; 76 (6), pp 1143–1152.
Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese 
patients with advanced solid tumors.
47.
Ikeda et al, 2017; Cancer Chemother Pharmacol 79(6):1169-1177.Phase 1b study of 
galunisertib in combination with gemcitabine in Japanese patients with metastatic or 
locally advanced pancreatic cancer.
48.
Brandes AA, Carpentier AF, Kesari S, et al. A Phase II randomized study of 
galunisertib monotherapy or galunisertib plus lomustine compared with lomustine 
monotherapy in patients with recurrent glioblastoma. Neuro-Oncology 2016; 
18(8):1146-56.
49.
http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table accessed on October 1,
2017.
 
 
 
52.
Ramirez, H., Patel, S. B., & Pastar, I. (2014). The Role of TGFβ Signaling in Wound 
Epithelialization. Advances in Wound Care, 3(7), 482–491. 
http://doi.org/10.1089/wound.2013.0466.
CCI


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Appendix 1. ABBREVIATION LIST
Abbreviation
Term
ADME
absorption, distribution, metabolism, and excretion
ADTs
androgen depleting therapies
AE
adverse event
Ae%
percent of the cumulative amount of unchanged drug excreted 
into the urine
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
anti HBc
hepatitis B core antibody
anti HBs
hepatitis B surface antibody
ANC
absolute neutrophil count
ANOVA
analysis of variance
ARA
acid reducing agent
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATD
Accelerated Titration Design
AUC24h
area under the concentration-time curve from time 0 to 
24 hours after dose
AUCinf
area under the plasma concentration versus time curve from 
time 0 extrapolated to infinity
AUClast
area under the plasma concentration versus time curve from 
0 to last
AUCss,
area under the plasma concentration curve at time of steady 
state
AUCsd,
area under the plasma concentration curve at standard 
deviation
BBS
Biospecimen Banking System
BID
twice daily
BNP
B-type natriuretic peptide
BP
blood pressure
BUN
blood urea nitrogen
C#D#
Cycle # Day #
CA 15-3
cancer antigen 15-3
Cavg
average concentration
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration, 
CD
compact disc
CD4
cluster of differentiation 4
CD8
cluster of differentiation 8
CDK
cyclin dependent kinase
CEA
carcinoembryonic antigen


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Abbreviation
Term
Ceff
effective concentration
CI
confidence interval
CK
creatine kinase
CLb
predicted blood clearance
CL/F
apparent clearance
CLss/F
steady state apparent clearance
CLR
renal clearance of the drug from plasma
CNS
central nervous system
COVID-19
coronavirus disease 2019
CR
complete response
CRF
case report form
CRPC
castration-resistant prostate cancer
CSA
clinical study agreement
CSR
clinical study report
Css,max
steady state maximum plasma concentration
Css,min
steady state minimum plasma concentration
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome 
DDI
drug-drug interaction
DHT
Dihydrotestosterone
DICOM
digital imaging and communications in medicine
DILI
drug-induced liver injury
DL
dose level
DLT
dose-limiting toxicity
DoR
duration of response
DRF
Dose-range finding
DVD
digital versatile disc
DVT
deep venous thrombosis
EC
ethics committee
EC50
concentration corresponding to 50% of the maximum effect
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EDV
end diastolic volume
Eg
for example
EMT
epithelial-to-mesenchymal transition
EOT
end of treatment
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Abbreviation
Term
ER
estrogen receptor
ERK
extracellular signal-regulated kinase
ESA
erythropoiesis stimulating agents
ESV
end systolic volume
EU
European Union
EudraCT
European Clinical Trials Database
F
Bioavailability (systemic availability of the administered dose)
Fa
fraction absorbed
FDA
Food and Drug Administration 
FDG
Fluorodeoxyglucose
FIH
first in human
FIP
First-in-patient
FSH
follicle-stimulating hormone
FTP
file transfer protocol
GCP
Good Clinical Practice
GI
Gastrointestinal
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
GnRH
gonadotropin-releasing hormone agonist
HBsAg
hepatitis B virus surface antigen
HbcAb
hepatitis B core antibody
HCVAb
hepatitis C virus antibodies
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
hERG
human ether à-go-go-related gene
HIV
human immunodeficiency virus
HNSCC
squamous cell cancer of the head and neck
HNSTD
highest non-severely toxic dose
HR
heart rate
HR+
hormone receptor positive
hs-CRP
high-sensitivity C-reactive protein
5-HT
5-hydroxytryptamine
HTTP
hypertext transfer protocol
IB
investigator’s brochure
IC50
50% inhibitive concentration
ICH
International Conference on Harmonisation
ID
Identification
Ie
that is
IHC
Immunohistochemistry
IL-2
Interleukin-2
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Abbreviation
Term
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IRF
independent radiology facility
IUD
intrauterine device
IVC
abdominal imaging at 60 to 70% after intravenous 
administration of contrast material
JNK
c-jun N-terminal kinase
Ka
absorption rate
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LHRH
luteinizing hormone releasing hormone
LVEF
left ventricular ejection fraction
MAP
mitogen-activated protein kinase
mBC
metastatic breast cancer
mCRPC
metastatic castration-resistant prostate cancer
mITT
modified intent to treat
mTPI
modified target probability interval
MD
multiple dose
MDP
methylene diphosphonate
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N/A
not applicable
NCA
non-compartmental analysis
NCCN
National Comprehensive Cancer Network
NCI 
National Cancer Institute 
NK
natural killer
OS
overall survival
ORR
objective response rate
PACL
Protocol Administrative Change Letter
PBPK
physiologically based pharmacokinetic
PI3K
phosphatidylinositol-4,5-bisphosphate 3-kinase
pT
target probability
PCD
primary completion date
PCWG2
Prostate Cancer Working Group 2
PD
pharmacodynamics; progressive disease
PD-1
programmed cell death
PD-L1
programmed death ligand - 1
PE
physical examination
PEG 400
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Abbreviation
Term
PET
positron emission tomography
PFS
progression-free survival
PD-L1/PD-1
programmed death-ligand 1/ programmed cell death protein 1
PI
principal investigator
PK
pharmacokinetic
PO
administered orally 
PPI
proton pump inhibitor
PR
pulse rate; partial response
PS
performance status
PSA
prostate specific antigen
pSMAD2
phosphorylated mothers against decapentaplegic homolog 2
PT
prothrombin time
PTT
partial thromboplastin time
QD
once daily
QT
time between the start of the Q wave and the end of the T wave
QTcF
Fridericia's QTc correction formula
QTcB
Bazett’s QTc correction 
Rac
accumulation ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RANK
Receptor activator of nucleus factor kappa B-ligand
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RR
respiratory rate
Rss
linearity ratio
RUQ
right upper quadrant
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2 
SCLC
small cell lung cancer
SLE
systemic lupus erythematosus
SOA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
STD
severely toxic dose
STD10
severely toxic dose in 10% of the animals
t½
terminal elimination half-life
TBili
total bilirubin
TBNK
T-cells, B-cells, Natural Killer cells
TDI
time dependent inhibition
TGF
transforming growth factor beta
TGFR1
transforming growth factor beta receptor 1


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Abbreviation
Term
TGI
tumor growth inhibition
Tmax
time to maximum plasma concentration
TME
tumor microenvironment
Tss,max
time to steady-state maximum plasma concentration
TTP
time to progression
TTR
time to response
ULN
upper limit of normal
UPM
unit probability mass
US
United States
USPI
United States Package Insert
UVB
ultraviolet B 
Vd/F 
apparent volume of distribution after non-intravenous 
administration
Vdss
steady-state volume of distribution
Vss/F
apparent volume of distribution at steady state after 
non-intravenous distribution
Vz/F
Apparent volume of distribution during terminal phase after 
non-intravenous administration
WBC
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Appendix 2. Detailed Dose Escalation/De-Escalation Scheme for mTPI design
DLT
n=1
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
S
E
E
E
E
E
E
2
DU
D
D
S
S
S
S
S
S
S
E
3
DU
DU
D
D
S
S
S
S
S
S
4
DU
DU
DU
DU
D
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
6
DU
DU
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
Source: https://udesign.laiyaconsulting.com/.
E: Escalate to the next higher dose; S: Stay at the same dose; D: De-escalate to the previous lower dose; DU: 
De-escalate to the previous lower dose and the current dose will never be used again in the trial.
Escalation/De-escalation algorithms for total number of patients treated at the current 
dose level (current and previous cohorts)

With 2 patients treated at current dose level:

0 DLT -> escalate;

1 DLT -> remain at the same dose;

2 DLTs -> de-escalate and consider current dose as intolerable.

With 3 patients treated at current dose level:

0 DLT -> escalate;

1 DLT -> remain at the same dose;

2 DLTs -> de-escalate;

3 DLTs -> de-escalate and consider current dose as intolerable.

With 4 patients treated at current dose level:

0 DLT -> escalate;

1 DLT -> remain at the same dose;


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
2 DLT -> de-escalate;

3-4 DLTs -> de-escalate and consider current dose as intolerable.

With 5 patients treated at current dose level:

0 DLT -> escalate;

1-2 DLTs -> remain at the same dose;

3 DLTs -> de-escalate;

4-5 DLTs -> de-escalate and consider current dose as intolerable.

With 6 patients treated at current dose level:

0 DLT -> escalate;

1-2 DLT -> remain at the same dose;

3 DLTs -> de-escalate;

4-6 DLTs -> de-escalate and consider current dose as intolerable.

With 7 patients treated at current dose level:

0-1 DLT -> escalate;

2-3 DLTs -> remain at the same dose;

4-7 DLTs -> de-escalate and consider current dose as intolerable.

With 8 patients treated at current dose level:

0-1 DLT -> escalate;

2-3 DLTs -> remain at the same dose;

4 DLTs -> de-escalate;

5-8 DLTs -> de-escalate and consider current dose as intolerable.

With 9 patients treated at current dose level:

0-1 DLT -> escalate;

2-4 DLTs -> remain at the same dose;


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
5-9 DLTs -> de-escalate and consider current dose as intolerable.

With 10 patients treated at current dose level:

0-1 DLT -> escalate;

2-4 DLTs -> remain at the same dose;

5 DLTs -> de-escalate;

6-10 DLTs -> de-escalate and consider current dose as intolerable.

With 11 patients treated at current dose level:

0-1 DLT -> escalate;

2-5 DLTs -> remain at the same dose;

6-11 DLTs -> de-escalate and consider current dose as intolerable.

With 12 patients treated at current dose level:

0-2 DLTs -> escalate;

3-5 DLTs -> remain at the same dose;

6-12 DLTs -> de-escalate and consider current dose as intolerable.


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Appendix 3. Bone Marrow Reserve in Adults 
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head :
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle:
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs: 
82.6
1 pair
10.2
All 0.4
4.1
2
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar):
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0


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Appendix 4. ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
5
Dead.
*As published in Am J Clin Oncol 5:649-655, 1982.


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Appendix 5. Bone Scan Assessment Form


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Appendix 6. Response Evaluation Criteria In Solid Tumors (RECIST) v 1.1
Adapted from Eisenhauer E.A., et al: New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions: Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm);

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray;

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper;

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions.
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline;

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions;

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.


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RECORDING TUMOR ASSESSMENTS
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If 2 target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used;

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the CRF (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION.
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.


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Target disease

Complete response: Complete disappearance of all target lesions with the exception 
of nodal disease.  All target nodes must decrease to normal size (short axis <10 mm).  
All target lesions must be assessed.

Partial response: Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  
All target lesions must be assessed.

Stable: Does not qualify for CR, PR, or progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.

Objective progression: 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.

Indeterminate: Progression has not been documented; and:

one or more target measurable lesions have not been assessed;

or assessment methods used were inconsistent with those used at baseline;

or one or more target lesions cannot be measured accurately (eg, poorly 
visible unless due to being too small to measure);

or one or more target lesions were excised or irradiated and have not 
reappeared or increased.
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of stable disease (SD) or PR in target disease, progression due to unequivocal 
increase in non-target disease should be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.


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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.
Subjective progression
Subjects requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.
Table 1.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New 
Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, Indeterminate, 
or Missing
No
PR
SD
Non-CR/Non-PD, Indeterminate, 
or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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Appendix 7. Prostate Cancer Working Group 2 (PCWG2) – Soft Tissue Response 
Criteria
Adapted from Scher H.I., et al: Design and End Points of Clinical Trials for Patients with 
Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the 
Prostate Cancer Clinical Trials Working Group.  J Clin Oncol. 26 (2008) 1148-1159.
And Eisenhauer E.A., et al: New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
Evidence of PD to Determine CRPC Eligibility
Patients being considered for trial entry should have evidence of disease progression by 
either PSA, RECIST, or bone scan to be eligible.
PSA: PSA evidence of disease progression based on the prostate cancer working group 
(PCWG) 2 criteria consist of a minimum PSA level 2.0 ng/ml that has risen on at least 
2 successive occasions, at least 1 week apart.  The reference value #1 is the last value before 
the rise in PSA was observed.  If the confirmatory PSA value (Figure 1, #3A) is greater than 
the screening value then progression by PSA is met and the patient is eligible for trial 
enrollment on the basis of PSA alone.  If the confirmatory PSA (Figure 1, #3B) value is less 
than the screening PSA (Figure 1, #2) value, then an additional test for rising PSA (#4) will 
be required to document progression before the patient can be enrolled.
Figure 1. Change in PSA
Target lesion/measurable disease: Patients are not required to have evidence of disease 
progression by measurable disease if they meet the criteria for disease progression on the 
basis of PSA or bone scan.  Evidence of nodal or visceral disease RECIST 1.1 progression 
however is sufficient for trial entry independent of PSA readings.  Because lymph nodes may 
be enlarged due to benign pathology, only lymph nodes that are ≥2.0 cm should be used for 
disease evaluation.


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Bone scan: Evidence of disease progression based on bone scan appearance is sufficient for 
trial entry independent of PSA readings.  If the appearance of the bone scan is the only 
indicator of progression, then there must be ≥2 new bone lesions compared with the prior 
bone scans.  If there is ambiguity about the appearance of the bony lesions such as traumatic 
in nature or secondary to a flare reaction, then it is recommended that an alternative imaging 
modality such as MRI or fine-cut CT be used to evaluate these lesions further.
CRITERIA FOR OUTCOME MEASURES:
Soft-tissue lesions: Use RECIST with caveats, 

Only report changes in lymph nodes that were ≥2.0 cm in diameter at baseline;

Record changes in nodal and visceral soft tissue sites separately;

Record complete elimination of disease at any site separately;

Confirm favorable change with second scan.
Bone: 

Record outcome as new lesion or no new lesions
Criteria for Evidence of Radiographic Progression
Bone disease will be assessed for progressive disease only by PCWG2.  The documentation 
required for the determination of radiographic progression is shown in the table below. 
Date 
Progression 
Detected[1]
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document 
Disease Progression on 
Confirmatory Scan
Week 9
Bone lesions: 2 or more 
new lesions compared to 
screening bone scan by 
PCWG2
Timing: At least 6 weeks 
after progression identified 
or at Week 16 visit[2]
2 or more new bone lesions on 
bone scan compared to 
Week 8 scan
Soft tissue lesions: 
Progressive disease on 
CT or MRI by RECIST 
v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression
Week 18 or 
later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to Week 8 bone 
scan
Timing: At least 6 weeks 
after progression identified 
or at next imaging time 
point[2]
Persistent or increase in 
number of bone lesions on 
bone scan compared to prior 
scan[3]
Soft tissue lesions: 
Progressive disease on 
CT or MRI by RECIST 
v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression 


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Date 
Progression 
Detected[1]
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document 
Disease Progression on 
Confirmatory Scan
[1]
Progression detected by bone scan at an unscheduled visit either before Week 8 or between 
scheduled visits will require a confirmatory scan at least 6 weeks later and should follow confirmation 
criteria outlined in the table for the next scheduled scan. 
[2]
Confirmation must occur at the next available scan. 
[3]
For confirmation, at least 2 of the lesions first identified as new must be present at the next available 
scan (confirmation scan).  
Disease progression in bone must be confirmed at least 6 weeks later, as per PCWG2.  See 
table below for the timing of confirmatory imaging requirements.
Confirmatory Imaging Requirements for Patients With CRPC Based on RECIST v1.1 and PCWG2
Disease Site
Response
Progression[1]
Soft tissue
Must be confirmed at least 
4 weeks later 
No confirmation required 
Bone
Not applicable
Must be confirmed at least 6 weeks 
later 
[1]
To inform permanent treatment discontinuation.


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Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No, 
including bone 
determination
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If there is a protocol deviation and a patient has been enrolled allows enrollment of patients 
with only non-target disease, the following table will be used:
Table 2.
Objective Response Status at Each Evaluation for Patients With 
Non-Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
Procedures for Assessing PSA Response/Progression Post Study Treatment
PSA measurements will be performed on C1D1 (14 days) and Day 1 of Cycle 4, 7, 10 and 
every third cycle thereafter, as well as at the End of Treatment visit.  Increases and decreases 
will be tracked in order to assess disease response.  The PSA readings on its own will not be 
used to define progression in this protocol.  PSA response and PSA progression will be 
defined according to the consensus guidelines of the PCWG2:

PSA partial response is defined as a ≥50% decline in PSA from Cycle 1 
Day 1 (baseline) PSA value.  This PSA decline much be confirmed to be sustained by 
a second PSA value obtained 4 or more weeks later.


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
PSA progression date is defined as the date that a ≥25% increase and an absolute 
increase of ≥2 ng/mL above the nadir is documented, which is confirmed by a second 
consecutive value obtained 4 or more weeks later.  The first PSA reading will be 
obtained at week 12. 


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Appendix 8. 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 in the US and other areas as applicable 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. 
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 the exclusion criterion # 13.  When the infection resolves, the patient may be considered 
for rescreening. 
Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow-up on the safety of study patients at scheduled visits per the Schedule of Activities or 
unscheduled visits.  Telehealth visits may be used to continue to assess patient 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 patient and the Investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring.  The following 
assessments must be performed during a telehealth visit:

Review and record study treatments(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to ADVERSE 
EVENT REPORTING.

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 patient is adhering to the contraception method(s) required in the protocol. 
Refer to Pregnancy Testing.
Study patients must be reminded to promptly notify site staff about any change in their health 
status.


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Alternative Facilities for Safety Assessments
Laboratory Testing
If a study patient is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital.  The 
safety laboratory evaluations included in Section 7.1.3 may be performed at a local 
laboratory. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results.  Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the patient’s source 
documents/medical records.  Relevant data from the local laboratory report should 
be recorded on the CRF.
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements.  The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF.  Confirm that the patient is adhering to the 
contraception method(s) required in the protocol.
Imaging
If the patient is unable to visit the study site for imaging assessment(s), the patient may visit 
an alternative facility to have the imaging assessment(s) performed.  Qualified study site 
personnel must order, receive, and review results. 
Electrocardiograms
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative 
facility to have the ECGs performed.  Qualified study site personnel must order, receive, and 
review results. 
Study Treatment
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study treatment must 
be considered.
PF-06952229 may be shipped by courier to study patient if permitted by local regulations and 
in accordance with storage and transportation requirements for the PF-06952229. Pfizer does 
not permit the shipment of PF-06952229 by mail.  The tracking record of shipments and the 
chain of custody of PF-06952229 must be kept in the patient’s source documents/medical 
records.


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The following is recommended for the administration of PF-06952229 for patients who have 
active confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion) SARS-CoV2 infection:

For symptomatic patients with active SARS-CoV2 infection, PF-06952229 should be 
delayed for at least 14 days from the start of symptoms.  This delay is intended to allow 
the resolution of symptoms of SARS-CoV2 infection.

Prior to restarting treatment, the patient should be afebrile for 72 hours, and 
SARS-CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 
72 hours.  Notify the study team when treatment is restarted.

Continue to consider potential DDIs as described in Concomitant Treatment(s) for any 
concomitant medication administered for treatment of SARS-CoV2 infection.
Patients receiving PF-06952229 in combination with enzalutamide in Part 1B, and Part 2B 
will follow the same procedures described in this section for enzalutamide. 
Home Health Visits
A home health care service will be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the patient’s location, rather than an in-person study visit at the site.  The following 
may be performed during a home health visit:

Adverse Event Checks
Adverse Events and Serious Adverse Events
If a patient has COVID-19 during the study, this should be reported as an adverse event (AE) 
or SAE and appropriate medical intervention provided.  Temporary discontinuation of the 
study treatment is medically appropriate until the patient has recovered from COVID-19.
It is recommended that the Investigator discuss temporary or permanent discontinuation of 
study treatment with the study medical monitor. 
Efficacy Assessments
The use of alternative measures for efficacy assessments needs to be approved by the study 
team.
Independent Oversight Committees
Not applicable.


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Appendix 9. Prohibited Concomitant Medications Which May Result in Drug-Drug 
Interaction (DDI)
This is not an all-inclusive list. Study personnel should stay current and consult with their 
pharmacy to exclude all concomitant medications that are CYP3A4/5 inhibitors or inducers.
Drug Category 
Drugs or Supplement
Required Washout Period 
Requirement
CYP3A4/3A5 
Inhibitor
VIEKIRA PAK 
Anti-HIV retroviral drugs 
containing ritonavir 
ritonavir 
cobicistat 
troleandomycin 
telaprevir 
itraconazole 
indinavir 
voriconazole 
mifepristone 
mibefradil 
clarithromycin 
posaconazole 
telithromycin 
grapefruit juice  
ceritinib 
conivaptan 
nefazodone 
nelfinavir 
saquinavir 
ribociclib 
idelalisib
boceprevir
Erythromycin
Fluconazole
Atazanavir
Darunavir 
Duvelisib
Diltiazem
Dronedarone
Crizotinib 
Fedratinib
Letermovir
Aprepitant
Lefamulin
Casopitant
Amprenavir
Faldaprevir
Imatinib
Verapamil
10 days 
or
5 half-lives
whichever is longer


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Drug Category 
Drugs or Supplement
Required Washout Period 
Requirement
Ravuconazole
Netupitant
Nilotinib
Istradefylline
Tofisopam
Cyclosporine
Ciprofloxacin
Voxelotor 
Isavuconazole
Cimetidine
fluvoxamine
CYP3A4/3A5 
Inducer
carbamazepine 
enzalutamide 
rifampicin
mitotane
avasimibe
rifapentine
apalutamide
ivosidenib
phenytoin
St John's Wort extract
phenobarbital
semagacestat
efavirenz
dabrafenib
cenobamate
lesinurad
bosentan
thioridazine
rifabutin
Lorlatinib
Nafcillin
talviraline
lopinavir
modafinil
etravirine
elagolix
lersivirine
telotristat ethyl
10 days 
or
5 half-lives
whichever is longer 
Note 1: Half-life refers to the half-life of the parent drug and its metabolites, which are 
inhibitors or inducers. The longest half-life should be used to calculate the period necessary 
to washout a medication prior to the first dose of study treatment.


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Appendix 10. Additional Clinical Safety Data
The data below are from the Part 1A of the Study C3881001 clinical database as of 19 Jun 
2020.  These data are preliminary and may change.  At that time 27 subjects were reported to 
have been screened and 20 subjects were shown to have been enrolled.  The tumor types 
enrolled were prostate cancer (11 subjects), pancreatic cancer (3 subjects), colon 
cancer/colorectal cancer (2 subjects), squamous cell head and neck cancer/squamous cell 
tongue cancer (2 subjects), breast cancer (1 subject), and mesothelioma (1 subject).  One 
subject each was enrolled in the 20, 40, 80 and 150 mg BID accelerated titration cohorts.  Six 
subjects in the 250 mg BID cohort and 3 patients in the 375 BID mg cohort were enrolled 
prior to a partial clinical hold implemented in July 2019 when 2 subjects experienced Grade 
3 events of hepatic hemorrhage (250 mg BID cohort) and intracranial tumor hemorrhage 
(375 mg BID cohort).  Two additional subjects (1 each) with epistaxis and oral hemorrhage 
were also reported.  Subsequently, study entry criteria were modified to reduce the risks of 
bleeding in a protocol amendment.  As of the 19 Jun 2020 database version, no additional 
AEs of bleeding episodes have been reported.
One hundred and nineteen AEs were reported in 20 patients. Of the 119 AEs, 

Ninety-one AEs were either Grade 1 or 2 in 17 patients. 

The most frequency reported AEs (≥3 subjects) were nausea or worsening nausea (5 
subjects), cough (4 subjects), anorexia (4 subjects), nasal drainage or congestion (4 
subjects), nasal congestion or intermittent nasal congestion (4 subjects), abdominal pain, 
or abdominal/right upper quadrant (RUQ) pain (3 subjects), vomiting (3), anemia, or 
intermittent anemia (3 subjects), dyspnea (3 subjects), fatigue, or worsening fatigue (3 
subjects) and headache (3 subjects).Twenty-five Grade 3 AEs were reported in 14 
patients.
o
3 AEs (anemia, intracranial tumor hemorrhage, and intrahepatic hemorrhage, each 
in 1 patient) were reported as attributed to PF-06952229 by the investigators. Of 
note, no additional hemorrhagic events have been reported following the 
modifications made to study entry criteria.
o
21 Grade 3 AEs considered unrelated to PF-06952229 were reported in 13 
patients: 3 events of abdominal/abdominal RUQ pain, 2 events of hyponatremia, 2 
events of anemia/worsening anemia, 2 events of constipation, 2 events of nausea, 
vomiting and dehydration, and 1 episode each of pneumonia, pulmonary 
embolism, musculoskeletal weakness left side, left hip pain, hyperbilirubinemia, 
hyperglycemia, increased ALT, increased AST, hypotension, and dysphagia.
o
1 Grade 3 AE (fatigue) was reported and the relationship to PF-06952229 has not 
been reported.

Two Grade 4 AEs (sepsis and acute respiratory failure) were reported in 2 patients; both 
of which were deemed to be unrelated to PF-06952229.


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
One Grade 5 AE was reported due to death due to tumor progression.  
Serious AEs of intracranial tumor hemorrhage, intrahepatic hemorrhage, and anemia reported 
in 1 patient each were considered related to PF-06952229 by the investigators.  Serious AEs 
not related to PF-06952229 were death due to tumor progression, oral hemorrhage, acute 
respiratory failure, sepsis, abdominal pain, pneumonia, anemia, hyponatremia, constipation, 
pulmonary embolism, left hip pain, and nausea/vomiting/dehydration.  Each serious, 
unrelated AE was reported for 1 patient each.

SAP_001.pdf: 
Protocol C3881001 (PF-06952229) Statistical Analysis Plan
PFIZERCONFIDENTIAL
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Protocol C3881001
A PHASE 1 DOSE ESCALATION STUDY EVALUATING SAFETY,
TOLERABILITY AND PHARMACOKINETICS OF PF-06952229 IN ADULT
PATIENTS WITH ADVANCED SOLID TUMORS
Statistical Analysis Plan
(SAP)
Version:
Amendment 1
Author:
(
)
Date:   
20-May-2022
PPD
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS .................11
3.1. Primary Endpoint(s) ................................................................................................11
3.2. Secondary Endpoint(s) ............................................................................................11
3.4. Covariates................................................................................................................12
4. ANALYSIS SETS ...............................................................................................................13
4.1. Full Analysis Set .....................................................................................................13
4.2. Safety Analysis Set..................................................................................................13
4.3. ‘PER PROTOCOL’ Analysis Set (evaluable for MTD) .........................................13
4.4. Modified Intent to Treat (mITT) Population...........................................................13
4.5. PK Analysis Set.......................................................................................................13
4.7. Treatment Misallocations........................................................................................14
4.8. Protocol Deviations.................................................................................................14
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Statistical Hypotheses .............................................................................................14
5.2. Statistical Decision Rules........................................................................................14
5.2.1. Dose Escalation ..........................................................................................14
5.2.2. MTD Determination ...................................................................................15
5.2.3. Sample Size Determination ........................................................................16
5.3. General Methods .....................................................................................................17
5.3.1. Analyses for Time to Event Data................................................................17
5.3.2. Analyses for Binary Data............................................................................17
5.3.3. Analyses for Continuous Data....................................................................17
5.4. Methods to Manage Missing Data ..........................................................................17
5.4.1. Missing Dates .............................................................................................17
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5.4.2. Efficacy Analysis........................................................................................18
5.4.3. Pharmacokinetics........................................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................19
6.1. Standard Analyses...................................................................................................19
6.2. Analysis of Primary Endpoint.................................................................................21
6.2.1. DLT (Part 1 and Part 2) ..............................................................................21
6.2.2. Safety Endpoints (Part 1 and Part 2)...........................................................21
6.3. Analysis for Secondary Endpoints ..........................................................................22
6.3.1. Efficacy Endpoints Analysis.......................................................................22
6.3.2. Pharmacokinetics Analyses ........................................................................24
6.6. ECHO, ECG and Vital Sign Data Analysis ............................................................26
7. INTERIM ANALYSES.......................................................................................................28
8. REFERENCES ....................................................................................................................29
9. APPENDICES .....................................................................................................................30
9.1. Details of Definitions of Endpoints.........................................................................30
9.2. Time to Event Data Analysis Censoring Rules.......................................................33
9.3. Categorical Classes for ECG and Vital Signs .........................................................34
9.4. RECIST 1.1 Tumor Assessment Criteria ................................................................35
9.5. Prostate Cancer Working Group 2 (PCWG2) – Soft Tissue Response Criteria .....41
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LIST OF TABLES
Table 1.
Progression Free Survival and Duration of Response..............................33
Table 2.
Time to Progression..................................................................................33
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................10
Figure 2.
Change in PSA..........................................................................................41


Protocol C3881001 (PF-06952229) Statistical Analysis Plan
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Page 5
1. VERSION HISTORY
Version
Section
Update
Amendment 1
All
Texts taken directly from the protocol are made 
italicized
Updated per Protocol Amendment 3
2. INTRODUCTION
This analysis plan is meant to supplement the C3881001 study protocol. In this document, 
any text taken directly from the protocol is italicized.  Any deviations from this analysis plan 
will be described in the Clinical Study Report (CSR). This SAP is based on Protocol
Amendment 3 dated May 7, 2021.
2.1. Study Objectives
Part 1A
Primary Objectives
•
To assess safety and tolerability at increasing dose levels of PF 06952229 in patients 
with advanced/metastatic tumors
•
To determine MTD and RP2D of PF 06952229 as a single agent.
Secondary Objectives
•
To evaluate the single and multiple dose PK of PF 06952229 when given as a single 
agent.
•
To evaluate preliminary anti tumor activity of PF 06952229 when given as a single 
agent.
•
To evaluate preliminary biochemical responses as a measure of anti tumor activity of 
PF 06952229.
 
 
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Part 1B
Primary Objectives
•
To assess safety and tolerability at increasing dose levels of PF 06952229 in 
combination with enzalutamide in patients with mCRPC.
•
To determine MTD and RP2D of PF 06952229 in combination with enzalutamide in 
patients with mCRPC.
Secondary Objectives
•
To evaluate the single and multiple dose PK of PF 06952229 when given in 
combination with enzalutamide.
•
To evaluate preliminary anti tumor activity of PF 06952229 when given in 
combination with enzalutamide. 
•
To evaluate preliminary biochemical responses as a measure of anti tumor activity of 
PF 06952229 when given in combination with enzalutamide.
 
 
 
 
 
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Part 2A
Primary Objectives
•
To confirm safety and tolerability of PF 06952229 at the estimated RP2D in patients 
with mCRPC.
•
To estimate efficacy of PF 06952229 at the estimated RP2D in patients with mCRPC.
•
To confirm the RP2D of PF 06952229 as a single agent.
Secondary Objectives
•
To estimate additional efficacy of PF 06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the single and multiple dose PK of PF 06952229 when given as a 
single agent.
•
To evaluate immune cells in paired pre and post treatment tumor biopsies (where 
available).
 
 
 
 
Part 2B
Primary Objectives
•
To confirm PF 06952229 safety profile in combination with enzalutamide at the 
estimated RP2D in patients with mCRPC.
•
To estimate efficacy of PF 06952229 in combination with enzalutamide at the 
estimated RP2D in patients with mCRPC.
•
To confirm the RP2D of PF 06952229 in combination with enzalutamide in patients 
with mCRPC.
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Secondary Objectives
•
To estimate additional efficacy of PF 06952229 at the estimated RP2D in patients 
with mCRPC.
•
To further evaluate the PK of PF 06952229 when given in combination with 
enzalutamide.
•
To evaluate immune cells in paired pre and post treatment tumor biopsies (where 
available).
 
 
 
 
2.2. Study Design
This is a Phase 1, open label, multi center, multiple dose, dose-escalation and expansion, 
safety, tolerability, PK, 
 study of PF-06952229 in previously treated patients with
advanced or metastatic cancers that may have high TGFβ signatures and EMT expression.
The study includes Parts 1A and 1B, which are dose-escalation cohorts, and Parts 2A and 
2B, which are dose expansion cohorts.  The primary objectives for Part 1A are to assess the 
safety and tolerability of PF-06952229 administered as a single agent and to determine 
maximum tolerated dose (MTD).  The primary objectives for Part 1B are to assess the safety 
and tolerability of PF-06952229 administered with enzalutamide and to determine MTD.  
The primary objectives for Part 2A are to confirm PF-06952229 safety and tolerability, 
estimate the single agent efficacy of PF-06952229 and determine a recommended Phase 2 
dose (RP2D).  The primary objectives of Part 2B are to confirm the safety profile of PF-
06952229 combined with enzalutamide, estimate the efficacy of PF-06952229 combined with 
enzalutamide and determine a RP2D for the combination.
Part 1A is a sequential single-agent dose-escalation conducted in patients with advanced or 
metastatic solid tumors who have failed standard of care treatment or for whom no standard 
of care exists.  Successive cohorts of patients are to receive escalating doses of PF-06952229 
on an outpatient basis starting from 20 mg BID, which is based on non-clinical data.  Nine 
candidate dose levels are planned using an Accelerated Titration Design (ATD) until 
reaching 250 mg BID, after which the design will revert to modified target probability 
interval (mTPI).  The highest tested dose will not exceed 800 mg BID.  If an MTD is not 
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observed during the 28 day safety window, additional dose levels may be considered based 
on PK, safety, tolerability, 
 assessments.  Based on PK and safety, 
additional patients can be added to a dose lower than the MTD and also may be moved 
forward to monotherapy expansion.
Part 1B is a dose-escalation of PF-06952229 in the combination of enzalutamide conducted 
in patients who were previously treated with metastatic castration-resistant prostate cancer 
(mCRPC).  The starting dose of PF-06952229 will be the MTD or maximum administered 
dose (MAD) of Part 1A.  Based on evolving PK, 
and safety profiles, assessed in Part 1A, 
Part 1B may commence before reaching the MTD, and will follow an mTPI design.  The 
maximum PF-06952229 dose for the combination escalation may be higher than the 
monotherapy MTD due to the potential DDI between enzalutamide and PF-06952229, but 
not higher than 800 mg BID.
Part 2A and Part 2B are expansion cohorts for monotherapy and combination therapy, 
respectively, in patients with previously treated mCRPC.  
To assess baseline TGFβ related biomarker signatures that may correlate with clinical 
efficacy, all patients enrolled in Part 1 will be required to provide a recent archival tumor 
sample or to undergo a fresh pre treatment biopsy if archival samples are unavailable prior 
to trial treatment.  
Part 2 patients are required to provide either a recent archival tumor biopsy or, for all 
patients in Part 2A and from approximately 10 patients in Part 2B, mandatory de novo 
biopsies.  Mandatory de novo pre-treatment and on-treatment tumor biopsies may not be 
required where it is determined that it is not medically feasible (such as constituting 
unacceptable medical risks).  However, this would require agreement of Investigator and 
Sponsor.
See Figure 1 for the study schema.                                                                                                                       
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Figure 1.
Study Schema
 
All patients:
1.
Will undergo up to 4 weeks of screening prior to study entry, ie, Cycle 1 Day 1.
2.
Will receive doses of PF 06952229, administered orally on 28 day cycle, 7 days on, 7    
days off, up to 2 years.  Any additional treatment with PF 06952229 beyond 2 years shall be 
discussed and approved by the Sponsor. 
3.
Treatment with investigational product (IP) will continue until disease progression, 
patient refusal, or unacceptable toxicity occurs, whichever occurs first.  However, patients 
who demonstrate clinical benefit (despite radiographic progression) with manageable 
toxicity and are willing to continue receiving the investigational product will be given the 
opportunity to continue treatment upon agreement between investigator and sponsor.
4.
Will undergo a follow up visit approximately 4 weeks after the last dose for AE and 
serious adverse event (SAE) collection.
The proposed doses, schedule(s), and PK 
 time points may be reconsidered and 
amended during the study based on the emerging safety and PK 
 data. 
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3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoint(s)
Part 1 

First cycle Dose Limiting Toxicities (DLTs). The specific definition of DLT is 
provided in the study protocol.

Adverse events (as graded by National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0).
Part 2 

First cycle Dose Limiting Toxicities (DLTs) in combination with enzalutamide for 
CRPC and palbo/letrozole for HR+ BC.

Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
version 5.0), timing, seriousness, and relationship to study therapy.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE version 5.0), and timing.
3.2. Secondary Endpoint(s) 
Parts 1 and 2

Pharmacokinetic parameters of PF-06952229.

Single Dose (SD) Cmax, Tmax, AUClast, and as data permit, AUCinf, CL/F, Vz/F, and t1/2. 

Multiple Dose (MD) Css,max, Tss,max, AUClast, Css,min, and as data permit CLss/F, Vss/F, 
t1/2, and Rac (AUClast/AUClast).

Objective Response Rate (ORR). PSA50 Response Rate for prostate cancer patients 
only.

Time to event endpoints (Duration of Response (DOR), Progression Free Survival 
(PFS), Overall Survival (OS), Time to Progression (TTP), Time to Response (TTR).

For prostate cancer patients, response assessment will be based on Prostate Cancer 
Response criteria (PCWG2).  For other tumor types, response will be assessed using 
the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). 


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3.4. Covariates
Biomarker data may be considered as covariates in PK and anti-tumor efficacy exploratory 
analyses. Covariates may also be considered when exploring QTc and PK relationship.
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4. ANALYSIS SETS
4.1. Full Analysis Set
The full analysis set includes all enrolled patients. This is equivalent to the ITT
(intent-to-treat) population.
4.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.
4.3. ‘PER PROTOCOL’ Analysis Set (evaluable for MTD)
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study treatment and who do not have major treatment deviations during the first cycle.  
Patients with major treatment deviations during the first cycle of treatment are not evaluable 
for the MTD assessment and will be replaced as needed to permit the MTD estimation.  
Major treatment deviations include the failure to satisfy major entry criteria 
(eg, confirmation of the target disease; signed informed consent) or use of other anticancer 
treatments during the active treatment period and disease follow up phases other than as 
defined/allowed in this protocol.  Major treatment deviations will also include:
•
Administration of less than 70% of the planned number of doses of PF-06952229 
(provided that the reduction in doses is not due to toxicity attributable to 
PF-06952229).
•
Administration of more than 110% of the planned number of doses of PF-06952229. 
4.4. Modified Intent to Treat (mITT) Population
The modified intent to treat (mITT) is the analysis population that will follow the ITT 
principle and include patients receiving at least 1 dose of investigational product with 
baseline assessment and at least 1 post baseline assessment, disease progression, or death 
before the first tumor assessment.  The mITT population will be used for analyses and to 
support conference presentations when the study is still ongoing.
4.5. PK Analysis Set
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.  The PK 
concentration population is defined as all enrolled patients who are treated and have at least 
1 analyte concentration.
 
 
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4.7. Treatment Misallocations
Subjects who receive the wrong initial dose for whatever reason will be analyzed according 
to the initial dose actually received. Subjects who receive the wrong dose after the initial 
dose will be analyzed according to the initial dose received.
4.8. Protocol Deviations
The determination of protocol deviations (PDs) and important protocol deviations (IPDs) will 
follow Pfizer standard operating procedures. A full list of PDs, IPDs, and IPDs that are 
excluded from Per-protocol analysis will be determined prior to the database release and be 
included in the CSR.
5. GENERAL METHODOLOGY AND CONVENTIONS
This is an open-label dose escalation study and the data will be continuously monitored 
during the study. No formal interim analysis is planned for this study.  
5.1. Statistical Hypotheses
There are no statistical hypotheses.  
5.2. Statistical Decision Rules
5.2.1. Dose Escalation
The dose escalation in Part 1A will start with Accelerated Titration Design (ATD) as 
proposed by Simon et al 2.  Part 1 will have an initial accelerated phase followed by a 
standard (mTPI) escalation phase.  During the accelerated phase, initial cohorts to contain a 
minimum of one patient until the first instance of first-cycle CTCAE grade ≥2 toxicity.  
The traditional mTPI design5 uses a Bayesian statistics framework and a beta/binomial 
hierarchical model to compute the posterior probability of 3 dosing intervals that reflect the 
relative difference between the toxicity rate of each dose level to the target rate (pT = 0.275).  
If the toxicity rate of the currently used dose level is far smaller than pT, the mTPI will 
recommend escalating the dose level; if it is close to target probability (pT), the mTPI will 
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level.  These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model.  The proposed mTPI method for 
this protocol includes stopping rules and dose escalation criteria, which prevents the target 
DLT rate to reach ≥33% for determining the MTD.  This proposed mTPI method is more 
conservative than the traditional TPI method.
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Therefore, the 
target interval for the DLT rate is (0.225, 0.325).


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The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
underdosing interval corresponds to a dose-escalation (E), overdosing corresponds to a dose 
de-escalation (D), and proper dosing corresponds to remaining at the current dose (R).  
Given a dosing and a probability distribution, the unit probability mass (UPM) of that dosing 
interval is defined as the probability of a patient belonging to that dosing interval divided by 
the length of the dosing interval.  The mTPI design calculates the UPMs for the 3 dosing 
intervals, and the one with the largest UPM informs the corresponding dose-finding decision, 
which is the dose level to be used for future patients.  For example, if the under-dosing 
interval has the largest UPM, the decision will be to escalate, and the next cohort of patients 
will be treated at the next higher dose level.  Ji et al. (2010) 5 have demonstrated that the 
decision based on UPM is optimal in that it minimizes a posterior expected loss (ie, 
minimizes the chance of making a wrong dosing decision).
5.2.2. MTD Determination
This study contains dose escalation with single agent (Part 1A) in patients with advance or 
metastatic solid tumor, and a combination dose escalation with enzalutamide in previously 
treated patients with mCRPC (Part 1B).  Part 1A and Part 1B will determine the MTD/RP2D
in sequential dose escalation cohorts.
The dose finding process in the current study is designed to establish the MTD defined as the 
highest dose that yields a target of approximately 27.5% probability of DLT and considers 
equivalent doses that yield probability of DLT in the interval (Equivalence Interval) of 
(22.5%, 32.5%).  Note the DLT rate for cardiac toxicity should not exceed 10%.  The 27.5% 
target was chosen based on safety considerations.  The prior distribution of DLT is set as a 
beta (0.5,0.5) and the threshold probability for early termination and dose exclusion is set to 
0.95 as suggested in the original mTPI method (Ji et al., 2010).5  Similarly, doses with an 
incidence of DLT, eg 4 out of 10, or apparently higher than 32.5% cannot be selected as 
MTD, even though it might be allowed by the mTPI method.
Cohorts of patients could receive doses already tested but a dose that is associated with
decision to “dose de-escalate, unacceptable toxicity” cannot be revisited and no more 
patients should be treated at this dose or higher doses for the remainder of the trial.
The maximum sample size for Part 1A would be approximately N=40 for the monotherapy 
dose escalation and approximately N=20 for the combination dose escalation, but actual 
sample size will depend on the underlying dose toxicity profile and variability in actual data 
realization.
The study will continue accruing until one of the three stopping conditions below is 
triggered.

The maximum sample size has been achieved (approximately 40 patients in Part 1A 
monotherapy dose escalation, approximately 20 patients in Part 1B combination dose 
escalation, and 10 patients in Part 2A monotherapy dose expansion and 20 patients 
in Part 2B combination dose expansion);


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
6 - 12 patients that have been enrolled at a dose level that is predicted to be the MTD 
per the mTPI method;

All dose levels explored appear to be overly toxic, and the MTD cannot be
determined.
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the true Probability (DLT) is fairly low.  This could result in the 
estimated posterior DLT rate to exceed the targeted 27.5% very early in the trial.
The following table shows the probability of escalating to the next dose level for a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
greater than 90% probability of escalating.  Conversely, for a DLT that occurs with a rate of 
70%, the probability of escalating is 3%.  It is assumed that dose escalation occurs with 
either 0/3 or 1/6 patients with DLTs.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
5.2.3. Sample Size Determination
Part 1 
In Part 1, patients will participate in a dose escalation phase aimed at estimating the MTD.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.
A maximum of 60 patients are expected to be enrolled in the dose escalation safety cohorts in 
Part 1, including approximately 40 patients for the monotherapy dose escalation and 
approximately 20 patients for the combination dose escalation.  The actual number of 
patients enrolled will depend on the tolerability of PF 06952229 and the number of dose 
levels required to identify the MTD/RP2D.  It is expected that the dose escalation process 
can be stopped and MTD declared with approximately 6 to 12 patients at the MTD dose.  As 
for the number of patients treated at each dose, it is expected to be at 1 to 4 patients for the 
doses actually studied.  However, since variable cohort size is allowed, the actual number of 
patients treated at each dose (including MTD) will vary from 1 to 12 patients.
Part 2
For PF 06952229 single agent expansion in patients with mCRPC, the planned sample size 
of the expansion cohort is 10 based on clinical consideration.
PF 06952229 single agent in combination with enzalutamide for patients with metastatic 
castration resistant prostate cancer (mCRPC), assuming a sample size of 20, and the 
observed PSA50 response is 60% (12/20), the Bayesian posterior probability to demonstrate 
that the "True PSA50 response" is greater than 37% is 98.15%. Assuming 80% of the 20 
patients have measurable disease and are response evaluable (16 patients evaluable), and 


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the observed ORR is 43.75% (7/16), the Bayesian posterior probability to demonstrate that 
the "True ORR" is greater than 30% is 86.89%.
All the Bayesian calculations above assume a non informative Uniform (0,1) prior.
5.3. General Methods
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan,
if any additional exploratory analyses are found to be necessary, the analyses and the reasons 
for them will be detailed in the clinical study report (CSR).
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration in the first cycle. All data will 
be categorized based on the scheduled visit at which it was collected.  These visit designators 
are predefined values that appear as part of the visit tab in the eCRF.
5.3.1. Analyses for Time to Event Data
Time to event endpoints in this study may include progression-free survival (PFS), duration 
of response (DOR), time to response (TTR), time to progression (TTP), and overall survival 
(OS). These endpoints will be summarized using the Kaplan-Meier method6 and displayed 
graphically when appropriate. Median event times and 2-sided 95% confidence intervals for 
time-to-event endpoint (Brookmeyer and Crowley, 1982)7 will be provided.
5.3.2. Analyses for Binary Data
Binary endpoints in this study include ORR, complete response (CR), and partial response 
(PR). Response assessment will be based on PCWG2 for prostate cancer patient, and will 
use RECIST 1.1 for other tumor types. If deemed necessary disease control rate (ie, DCR, 
which is defined as the proportion of patients that achieved CR, or PR, or stable disease) may 
also be calculated for Part 2. Descriptive statistics along with the corresponding 2-sided 
95% confidence intervals using an exact method will be provided for these endpoints.
5.3.3. Analyses for Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values, will be provided for continuous endpoints.
5.4. Methods to Manage Missing Data
5.4.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the calculation
results in a negative time duration (eg, date of onset cannot be prior to day one date). In this
case, the date resulting in 0 time duration will be used. Pfizer standards are also used if both 
month and day are missing (Jan 1 unless negative time duration).  This excludes the 
pharmacokinetic, ECG,
 analyses, which will only use the actual date 
collected or if date not available deem the data missing.
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5.4.2. Efficacy Analysis
For the time-to-event endpoints, the missing data handling method will be censoring. 
Censoring rules for time-to-event endpoints are detailed in Section 9.2.
5.4.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ
(ie, lower limit of quantification) will be replaced with the value for the LLQ).
Deviations, missing concentrations and anomalous values
Patients who experience events that may affect their PK (eg, incomplete dosing) may be 
excluded from the PK analysis.
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
subjects. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a subject’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a subject 
discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing.
If an individual subject has a known biased estimate of a PK parameter, this will be footnoted 
in summary tables and will not be included in the calculation of summary statistics or 
statistical analyses.


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6. ANALYSES AND SUMMARIES
For efficacy related endpoints in this study, the following analysis plan may be implemented
if the data is sufficient. For tumor response assessment, PCWG2 will be used for prostate 
cancer patient and RECIST 1.1 will be used for other tumor types. 
Endpoint
Part 2
ORR 
Both
PFS 
Unconfirmed*
DOR 
Both
TTP
Unconfirmed*
TTR
Both
Note: “Both” in the above table represents both unconfirmed and confirmed tumor assessments. 
*: Confirmation for progressed disease is not applicable in RECIST 1.1.
In the “unconfirmed” analyses (ie, tumor response or progression without confirmation
required), all tumor assessments data will be included for analyses. Specifically, regardless if 
a patient’s tumor response or progression is subsequently confirmed or not, the patient data 
will all be included in the “unconfirmed” analyses. This is a more comprehensive analysis
where tumor confirmation is not required and not taken into account. For example in the 
ORR analysis, if a patient achieved CR or PR, regardless it is subsequently confirmed or not, 
the patient will be included in the numerator.  
In the “confirmed” analyses (ie, tumor response with confirmation required), only those 
tumor assessments data that’s subsequently confirmed by a consecutive tumor scan will be 
considered as a “success” or “event” and be included for analyses as appropriate. For 
example, in the ORR analysis, a patient will only be counted in the numerator (the “success”) 
if the tumor response (CR or PR) is subsequently confirmed. If a patient’s tumor response is 
not subsequently confirmed, the patient will still be included in the denominator (the 
population set) but will not be included in the numerator (the “success”). 
6.1. Standard Analyses
Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.
Subject discontinuation from treatment and study will be tabulated and listed separately with 
their reason for discontinuation.  The Safety Analysis Set will be used.
Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, and primary diagnosis will be tabulated and listed. For ECOG 
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performance status a shift table (worst post-baseline vs baseline may be produced). The 
Safety Analysis Set will be used.
Treatment Administration/Compliance
Listings and tables by dose level will be provided. Cycle length is 28 days (±2 days) for 
oral administration. Day 1 of a cycle is the first date of dose within that cycle. The safety
analysis set will be used.
Dose modifications may occur in the following ways:

Cycle delay—Day 1 of current cycle starts later than 28 (+2) days from Day 1 of the
previous cycle (only applies to cycle 2 and above), will be used in determining cycle 
delay. For example, after cycle 1 ended for a patient in Part 1, a new cycle didn’t start 
until 28 (+2) days after (but before 56 days after) cycle 1 day 1, the newly started 
cycle will be considered as cycle 2, and cycle 2 is considered delayed.

Cycle skip – Day 1 of current cycle starts later than 56 (+4) days from Day 1 of the 
previous cycle (only applies to cycle 2 and above). For example, After cycle 1 ended 
for a patient in Part 2, a new cycle didn’t start until 56 (+4) days after cycle 1 day 1, 
the newly started cycle will be considered as cycle 3, and cycle 2 is considered 
skipped for this patient. 

Dose reduction— a decrease in the administered total daily dose (non-zero) compared
to the planned total daily dose upon enrollment. If in the CRF the prescribed dose 
unit is mg/kg, but the actual dose is in mg the actual dose mg/kg should be calculated
considering the body weight of the patient at that visit. Intrapatient dose reductions
are not permitted during the study unless, in discussion with the sponsor, a dose level 
is deemed beyond the determined MTD.

Dose interruption – a skip in the planned administered daily dose upon enrollment. It 
includes missed dose and the dose with 0 administered collected on the CRF.  
The following will be summarized for each dose level:

Number of subjects;

Number of cycles per subject

Number (%) of subjects with cycle delays and cycle skips;

Number (%) of subjects with dose interruptions;

Number (%) of subjects with dose reductions;

Number (%) of each reason (drug related AE vs AE vs. Other) for cycle delays, dose
interruptions and dose reductions;

Time on treatment (median, range).


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
Number of cycles before 1st delay (median, range);

Number of cycles before 1st reduction (median, range);

Number of cycles before 1st interruption (median, range).
The following will be summarized for cumulative dose by dose level and cycle:

Summary statistics (mean, median, standard deviation and range) of cumulative dose 
and percent of starting dose (compared to Day 1 dose of each cycle).
Listings by subject (ordered by dose level): start date and stop date of each dosing period 
within each cycle (including records with 0 mg), administered total daily dose for each 
period, any missed doses with unknown dates (Y/N), number of missed doses with unknown 
dates, reason for any dosing changes.
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose, 
administered total dose, percentage of planned dose, dose delay (yes/no), dose reduction 
(yes/no), and dose interruption (yes/no).
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary. Listings of prior, concomitant, and
further therapies will be provided separately.
6.2. Analysis of Primary Endpoint
6.2.1. DLT (Part 1 and Part 2)
Dose Limiting Toxicity is the primary endpoint of the dose escalation phase of the study, 
which will be summarized by dose level using the Per Protocol Analysis Set for patients in 
the dose escalation portion of the study.  A listing of the DLTs will also be provided.  If 
necessary, a summary and listing of the DLT by malignancy may be provided using the Per 
Protocol Analysis Set for patients in the MTD expansion portion of the study.
6.2.2. Safety Endpoints (Part 1 and Part 2) 
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE 
version 5.0 and coded using the MedDRA.8  The focus of AE summaries will be on 
Treatment Emergent Adverse Events (TEAE), which is defined as any adverse event that 
occurs after the beginning of the study treatment (on or after Study Day 1) or any pre-
existing adverse event that worsens after the beginning of the study treatment and at least 28 
days after final dose of study treatment or start of new anticancer therapy (whichever comes 
first). The number and percentage of patients who experienced any AE, serious AE (SAE), 
treatment related AE, and treatment related SAE will be summarized according to worst
toxicity grades.  The Safety Analysis Set will be used.  Part 1 and Part 2 data will be 


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summarized separately and may also be pooled together for analysis. Pfizer standard on 
safety data reporting will be followed.
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities
(including liver function test) will be summarized according to worst toxicity grade observed 
for each laboratory test for overall and each dose.  The analyses will summarize laboratory 
tests both in the entire study period and by cycle (Cycle 1 and Cycles beyond 1). Shift tables 
will be provided to examine the distribution of laboratory abnormalities. The Safety 
Analysis Set will be used.
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal high/low or not done.
6.3. Analysis for Secondary Endpoints
6.3.1. Efficacy Endpoints Analysis
ORR, as assessed using PCWG2 for prostate cancer and RECIST version 1.1 for other tumor 
types,is a key efficacy endpoint. The following analyses will be performed in the mITT 
population by tumor type and pooled: 
The ORR, along with other efficacy analyses will be performed in the mITT population. Part 
1 and Part 2 data will be summarized separately, and may also be pooled together for 
analysis if deemed necessary.  Specifically, the key tables in Part 2 include:
1. ORR by visit: investigator provided tumor response CR, PR, and CR+PR will be 
presented by descriptive statistics (frequency and percentage) and 95% confidence 
interval.
2. Best overall response of CR, PR, and CR+PR. This will include best overall response 
derivation without confirmation and with confirmation. Descriptive statistics 
(frequency and percentage) and 95% confidence interval will be provided. 
Tumor response data in Part 1, Part 2 and across the two Parts may be summarized with 
descriptive statistics (frequency and percentage) in the following groups by visit and then 
best overall response across all visits:

Overall summary for all doses and all tumor types;

By tumor type regardless of dose;

By dose regardless of tumor type;

By dose and tumor type if data permit.


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Summary tables of best overall response rate, PFS, OS, DOSD, and DOR may be provided 
by the groups aforementioned when deemed necessary (eg, if there are ≥5 patients in a 
specific group). 
In addition, PSA50 Response Rate defined as ≥50% PSA reduction from baseline assessed 
by PCWG2 for prostate cancer patients will be summarized similarly as ORR. See 
Section 9.5 for more details on PSA measurement.
Efficacy listings (tumor measurements listings and tumor response listings) will be provided 
that include the investigator provided tumor measurement data, tumor response, best overall 
response, first CR/PR date, last date with CR or PR, most recent date without progression, 
progression date, death date, and last tumor assessment date, etc. 
Endpoint
Analysis Set
Statistical Method
Model/Covariates/Strata Missing Data
Overall response
mITT
Exact CI
See aforementioned
summary descriptions on 
data pooling
across dose and tumor 
type
Observed case
Overall Survival
ITT
Kaplan-Meier
See aforementioned
summary descriptions on 
data pooling
across dose and tumor 
type
Censored at last 
visit
Progression Free 
Survival (PFS)
mITT
Kaplan-Meier
See aforementioned
summary descriptions on 
data pooling 3721
across dose and tumor 
type
Censored per 
Section 9.2
Time to 
Progression (TTP)
and Time to 
Response (TTR)
mITT
Kaplan-Meier
See aforementioned
summary descriptions on 
data pooling
across dose and tumor 
type
Censored per 
Section 9.2
Duration of 
Response (DOR)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions on 
data pooling
across dose and tumor 
type
Censored per 
Section 9.2
Swimmer plot for individual clinical response and time on treatment, waterfall plot for 
individual tumor size percent change from baseline, and spider plot for individual tumor size 
percent change from baseline over time may be presented if needed. The following table 
provides an overview of the efficacy analysis if the data is sufficient.


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6.3.2. Pharmacokinetics Analyses
The concentration-time data of PF-06952229 will be summarized by descriptive statistics 
(n, mean, standard deviation, coefficient of variation, median, minimum, maximum, and
geometric mean) according to dosing cohort and time for each part of the study. In addition,
the concentration-time data from Part 2 dose expansion will also be summarized by
descriptive statistics according to tumor type.
The actual time of sample collection will be used in PK parameter calculation.  In the event 
that the actual sampling time is not available, the nominal time may be used if there is no
evidence that the actual sampling time deviates substantially from the nominal time.
Presentation of PF- PF-06952229 concentration-time data
The concentration-time data of PF-06952229 will be presented as below:

a listing of all concentrations by cohort, subject ID and nominal time.  The
concentration listing will also include the actual times. Deviations from the nominal 
time will be given in a separate listing.

a summary of concentrations by cohort and nominal time, where the summary 
statistics will include n, mean, standard deviation, median, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of
quantification.

for the concentration-time data after the 1st (C1D1) and 7th dose (C1D7), median 
concentration-time plots (on both linear and semi-log scales) against nominal time 
postdose by cohort (all cohorts on the same plot per scale, based on the summary of 
concentrations by cohort and time postdose).
For drug concentration summary statistics, median and mean plots by sampling time, the 
nominal PK sampling time will be used; for individual subject plots by time, the actual PK 
sampling time will be used, with the pre-dose time set to zero.
Calculation of PF-06952229 PK parameters
For patients enrolled in the dose escalation stage of the study, the individual 
concentration-time data of PF-06952229 during Cycle 1 and Cycle 2 will be analyzed 
separately by non-compartmental methods to estimate the PK parameters.  The PK 
parameters estimated will include Cmax, Tmax, and AUClast (AUCtau at steady state).  If data 
permit or if considered appropriate, t1/2, CL/F, Vd/F (orVss/F at steady state), and 
accumulation ratio (Rac) will also be estimated.  The PK parameters will be summarized 
descriptively by dose level and cycle.
Additionally, for Part 1, dose-normalized AUClast and Cmax will be plotted against dose (using 
a logarithmic scale) by cycle.  These plots will include individual patient values and the 
geometric means for each dose.  These plots will be used to help understand the relationship 
between the PK parameters and dose.


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For patients enrolled in Part 2 of the study, trough concentrations of PF-06952229 will be 
summarized descriptively by cycle and by tumor type.
PK parameters will be calculated using standard non-compartmental methods:
Parameter 
State
Method of Determination
AUCtau
sd, ss 
Linear/Log trapezoidal method
AUClast
sd,ss 
Linear/Log trapezoidal method 
AUCinfa
sd 
AUClast + (Clast*/kel), where Clast* is the predicted 
serum concentration at the last quantifiable time 
point estimated from the log-linear regression 
analysis.
Cmax
sd, ss 
Observed directly from data 
Tmax
sd, ss 
Observed directly from data as time of first occurrence
CL/F
sd, ss 
Dose/AUCinf for sda
Dose/AUCtau for ss
Vd/F
sd, ss
Dose/(AUCinf *kel) for sd
Dose/(AUCτ * kel) for ss
Vss/Fa
sd, ss 
CL * MRT, where MRT is the mean residence time 
adjusted for the duration of
infusion
t½a
sd
Loge(2)/kel, where kel is the terminal phase rate 
constant calculated by a linear
regression of the log-linear concentration timecurve.
a if data permit; sd: single dose; ss: steady-state
 
 
 
 
 
 
 
 
 
 
 
CCI


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6.6. ECHO, ECG and Vital Sign Data Analysis
The analysis of Echocardiogram (Echo) will be based on the Safety Analysis Set. A 
clinically significant asymptomatic cardiac event or the LVEF abnormality is defined as an 
absolute decline in LVEF from baseline of more than 15 points and to a value that is below 
the institution’s lower limit of normal.  Descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be used to summarize the LVEF change from 
baseline. Shift tables will also be provided for LVEF abnormality at baseline vs. on 
treatment (yes, no, not done: (n, %).
The analysis of ECG results will be based on patients in the Safety Analysis Set with baseline 
and on-treatment ECG data, and will follow the ICH E14 guidance on the clinical evaluation 
of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.9
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.
Interval measurements from repeated ECGs will be included in the outlier analysis as 
individual values obtained at unscheduled time points.
QT intervals will be corrected for HR (QTc) using standard correction factors [ie, Fridericia’s 
(default correction), Bazett’s, and possibly a study specific factor, as appropriate]. QTcF 
interval will be calculated using the Friderica formula, as follows:
QTcF=   QT
3 RR


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Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, QTcF (and/or 
QTcB if deemed appropriate by overall, and by dose group.  Individual QT (all evaluated 
corrections) intervals will be listed by study arm time and dose.  The most appropriate 
correction factor will be selected and used for the following analyses of central tendency and 
outliers and used for the study conclusions.  Descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be used to summarize the absolute corrected QT 
interval and changes from baseline in corrected QT after treatment by study arm dose and 
time point.  For each patient and by treatment, the maximum change from baseline will be 
calculated as well as the maximum post-baseline interval across time points.  Categorical 
analysis will be conducted for the maximum change from baseline in corrected QT and the 
maximum post- baseline QT interval.
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE version 4.03 Grade. Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: 
(n, %).
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline may be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
Changes from baseline for the ECG parameters QT interval, heart rate (HR), QTc interval, 
PR interval and QRS interval will be summarized by treatment and visit. Categorical data 
analysis will follow Section 9.3.
If more than one ECG is collected at a nominal time post dose (for example, triplicate 
ECGs), the mean of the replicate measurements will be used to represent a single observation 
at that time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, 
but the mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing 
will be described in a safety section of the study report in order to place the ≥500 msec value 
in appropriate clinical context. However, values from individual tracings within triplicate 
measurements that are ≥500 msec will not be included in the categorical analysis unless the 
average from the triplicate measurements is also ≥500 msec. Changes from baseline will be 
defined as the change between QTc post dose from the time-matched average of the pre-dose 
triplicate values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a PK/PD 
relationship is found, the impact of subject factors (covariates) on the relationship will be 
examined.


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7. INTERIM ANALYSES
There is no formal interim analysis planned in this study. 
A final analysis will be performed when all the patients are enrolled and have completed 
their scheduled tumor assessments.  
This is an open label study. The Pfizer study team will review safety, immunogenicity, 
 and other data throughout the study.
CCI


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8. REFERENCES
1.
C3881001 Protocol Amendment 3, May 7, 2021.
2.
Simon R, Freidlin B, Rubinstein L, et al. Accelerated titration designs for phase I 
clinical trials in oncology. J Natl Cancer Inst 1997; 89(15):1138-47.
3.
Palbociclib Summary of Product Characteristics. 
https://www.medicines.org.uk/emc/product/4449/smpc accessed 30 April 2018.
4.
Letrozole Summary of Product Characteristics. 
https://www.medicines.org.uk/emc/product/4686/smpc/history accessed 30 April 2018.
5.
Y Ji, P Liu, Y Li, and BN Bekele. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials, 7:653 663, 2010.
6.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.  J Am
Stat Assoc 1958; 53:457-481.
7.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time.
Biometrics 1982; 38:29-41.
8.
NCI Common Terminology Criteria for Adverse Events v5.0 (CTCAE). 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf.
9.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic
potential for non-antiarrhythmic drugs. CHMP/ICH/2/04.
10.
E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J.
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R.
Kaplan, D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009)
228-247.


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9. APPENDICES
9.1. Details of Definitions of Endpoints
DLT Definition
Severity of adverse events (AEs) will be graded according to CTCAE version 5.0.  For the
purposes of dose escalation, any of the following AEs occurring in the first cycle of treatment 
(within 28 days of first dose or until the patient completes the first cycle of therapy if there 
are treatment delays) which are clinically significant will be classified as DLTs, unless there 
is a clear alternative explanation and agreed upon by investigator and sponsor (eg, clearly 
and incontrovertibly due to underlying disease/progression or extraneous cause) where there 
has been a clinically significant change from baseline:

Clinically important or persistent toxicities that are not included in the criteria below 
may be considered a DLT following review by Pfizer and the Investigators.  All 
DLTs need to represent a clinically significant shift from baseline.
Note: Labs must be repeated for confirmation.  Only the lab result requiring confirmation 
must be repeated, not the entire panel. 
Hematologic:
Any treatment-related hematologic laboratory abnormality specifically defined as: 

Thrombocytopenia Grade 4 for ≥7 days, or Grade 3 or 4 associated with ≥Grade 2
clinically significant bleeding or requiring platelet transfusion (for bleeding events 
with no grading available clinically significant bleeding is defined as required 
hospitalization or urgent medical intervention);

Neutropenia Grade 4 for ≥7 days; Grade ≥3 neutropenia with infection; 

Anemia Grade 4, or Grade 3 or 4 requiring blood transfusion.
Nonhematologic:

Grade 3 toxicities that are considered clinically significant;

Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >3x the upper
limit of normal (ULN) with bilirubin >2x the ULN without another explanation 
(eg, cholestasis) will be considered a DLT, ie, confirmed drug induced liver injury 
(DILI) meeting Hy’s law criteria;

Grade 3 nausea, vomiting or diarrhea that does not resolve within 4 days despite 
maximal supportive therapy.


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Nonhematologic and Non-Hepatic:

Any toxicity causing greater than 2 weeks of dose delay is a DLT. Note: Patients 
deriving clinical benefit from study treatment who experience a DLT may continue 
on study at a reduced dose following recovery of the AE to Grade 0-1 or baseline, 
only after discussion between the investigator and sponsor;

Any toxicity preventing patients from receiving 75% of study drug during the DLT 
evaluation period is a DLT.
The following AEs will not be adjudicated as DLTs:

Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement;

Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor);

Any Grade 5 event clearly due to underlying disease or extraneous causes;

Isolated Grade 3 laboratory abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset at data cut off will not be taken into account for MTD 
determination including but not limited to:

Grade 3 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions;

Grade 3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.

A patient is classified as DLT-evaluable if he/she experiences a DLT or if he/she 
otherwise in the absence of a DLT receives at least 75% of the planned doses of each 
investigational product and has received all scheduled safety assessments during the 
DLT window.  If a patient fails to meet these criteria, he/she may be replaced. 
MTD Definition
A DLT rate of 27.5% with an equivalence interval of (22.5%, 32.5%) (note: provided the 
DLT rate for cardiac toxicity does not exceed 10%)  will be utilized to estimate the MTD; 
patients will be enrolled in dose cohorts of 2-4 patients, and each patient will receive 
2 courses of PF-06952229 (7 days on, 7 days off) in a 28 day cycle.  Due to the discreteness 
of the dose levels and in the interest of the safety of patients, the estimated MTD is the 
highest tested dose level with DLT rate ≤approximately 32.5%.  The dose finding decision 
will be based on a 1-cycle (28 day) DLT observation period. 
At least 6 patients have been accumulated on a dose that can be predicted to be the MTD.


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Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further investigation based on Phase 1 study results.  If the 
MTD proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D.  Further experience with the MTD may 
result in a RP2D dose lower than the MTD.


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9.2. Time to Event Data Analysis Censoring Rules
Table 1.
Progression Free Survival and Duration of Response
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive, on treatment2 and no Progression Date of last objective tumor assessment
Censored
Progression Documented on or 
between scheduled tumor assessments
prior to treatment discontinuation2
Date of first objective tumor assessment 
showing objective progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor assessment 
prior to discontinuation2
Censored
Treatment discontinuation due to 
toxicity or other reason
Date of last objective tumor assessment 
prior to discontinuation2
Censored
Death prior to first planned tumor 
assessment
Date of death
Death (Event)
Death without objective progression 
prior to treatment discontinuation2
Date of death
Death (Event)
Death or progression after 2 or more 
missed tumor assessments
Date of last objective tumor assessment 
prior to the event
Censored
1.
For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
2.
Or within 28 days of discontinuation of treatment.
Table 2.
Time to Progression
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive, on treatment2 and no Progression Date of last objective tumor assessment
Censored
Progression Documented on or 
between scheduled tumor assessments 
prior to treatment discontinuation2
Date of first objective tumor assessment 
showing objective progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor assessment 
prior to discontinuation2
Censored


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Table 2.
Time to Progression
Situation
Date of Progression/Censoring1
Outcome
Treatment discontinuation due to 
toxicity or other reason
Date of last objective tumor assessment 
prior to discontinuation2
Censored
New anticancer treatment <28 days
after discontinuation of treatment 
without progression
Date of last objective tumor assessment 
prior to new anticancer treatment
Censored
Death prior to first planned tumor 
assessment
Start date (C1D1)
Censored
Death without objective progression
prior to treatment discontinuation2
Date of last objective tumor assessment 
prior to death
Censored
Progression after 2 or more missed 
tumor assessments
Date of last objective tumor assessment 
prior to the event
Censored
1.
For censoring date, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
2.
Or within 28 days of discontinuation of treatment.
Censoring rules for DOR will be the same as for PFS.
9.3. Categorical Classes for ECG and Vital Signs 
Categories for QTcB and QTcF
QTcB/QTcF 
(ms)
max. ≤450
450< max. ≤480
480< max.≤500
max. >500
QTcB/QTcF (ms) 
increase from 
baseline
max. <30
30≤max. <60
max. ≥60
Categories for PR and QRS
PR (ms)
max ≥300
PR (ms) increase from 
baseline
Baseline
>200 and max. ≥25% increase
Baseline ≤200 and max. ≥50% increase
QRS (ms)
max ≥200
QRS (ms)
Baseline
Baseline ≤100
increase from
>100 and
and max. ≥50%
baseline
max. ≥25%
increase
increase


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Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) change from baseline
max. decrease
≥30
max. increase
≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) change from baseline
max. decrease
≥20
max. increase
≥20
Supine pulse rate (bpm)
min. <40
max. >120
9.4. RECIST 1.1 Tumor Assessment Criteria
Adapted from E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. 
Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.10
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below:
Measurable Lesions
Lesions that can be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice
thickness no greater than 5 mm).

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot
be accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
Non-measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a ≥10 but <15 mm short axis) as well as truly non-measurable lesions. 
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam and not measurable by reproducible imaging techniques.
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed.


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Special Considerations Regarding Specific Lesions
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such as CT
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be
considered as malignant lesions (neither measurable nor non-measurable) since they
are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for
selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other
loco-regional therapy, are usually not considered measurable unless there has been
demonstrated progression in the lesion.
Solitary lesions:
If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and
representative of all involved organs should be identified as target lesions and measured and
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for
accurate repetitive measurements (either by imaging techniques or clinically).


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The longest diameter will be recorded for each target lesion. The sum of the longest
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment.
One exception to the above described approach is related to pathological lymph nodes. 
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥15 mm by CT scan is met. Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller 
of these measures is the short axis.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
Definition of Tumor Response
Target Lesions
Response in target lesions is defined as follows:

Complete Response (CR): disappearance of all target lesions.

Partial Response (PR): at least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): at least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum
must also demonstrate an absolute increase of at least 5 mm.  The appearance of one 
or more new lesions is also considered a sign of progression.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.


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When nodal disease is included in the sum of target lesions and the nodes decrease to
‘normal’ size (<10 mm), they may still have a measurement reported on scans.  This
measurement should be recorded even though the nodes are normal in order not to overstate
progression should it be based on increase in size of the nodes.  As noted earlier, this means
that patients with CR may not have a total sum of ‘zero’ on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and
instead should be assessed only qualitatively at the time points specified in the protocol.
Response in non-target lesions is defined as follows:
Complete Response (CR): Disappearance of all non-target lesions and normalization
of tumor marker level.  All lymph nodes must be non-pathological in size
(<10 mm short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or
maintenance of tumor marker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
(Note: the appearance of one or more new lesions is also considered progression).
Cytology, histology
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens
during treatment can be considered if the measurable tumor has met criteria for response or
stable disease in order to differentiate between response or stable disease and progressive 
disease.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF. Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF.
New Lesions
The appearance of new malignant lesions indicates PD.  New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan.


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The use of FDG-PET is sometimes reasonable to complement a CT scan assessment of a PD 
(particularly for possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up.

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.
Determination of Overall Response by the RECIST 1.1 Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in the 
following table.
Response Evaluation Criteria in Solid Tumors by RECIST 1.1
Target Lesions
Non-target 
Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.


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Best overall response
The best overall response is defined according to the tumor response along the study. 
Complete or partial responses may be claimed only if the criteria for each are met at a 
following time point as specified in the protocol (generally 4 weeks later).  In this 
circumstance, the best overall response can be interpreted as the following table.
Best Overall Response When Confirmation of CR and PR Required
Overall response
First time point
Overall response
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for
SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original
CR should be changed to PR and the best response is PR.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner 


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similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
9.5. Prostate Cancer Working Group 2 (PCWG2) – Soft Tissue Response Criteria
Adapted from Scher H.I., et al: Design and End Points of Clinical Trials for Patients with 
Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the
Prostate Cancer Clinical Trials Working Group.  J Clin Oncol. 26 (2008) 1148-1159.
And Eisenhauer E.A., et al: New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
Evidence of PD to Determine CRPC Eligibility
Patients being considered for trial entry should have evidence of disease progression by 
either PSA, RECIST, or bone scan to be eligible.
PSA: PSA evidence of disease progression based on the prostate cancer working group 
(PCWG) 2 criteria consist of a minimum PSA level 2.0 ng/ml that has risen on at least 
2 successive occasions, at least 1 week apart.  The reference value #1 is the last value before 
the rise in PSA was observed.  If the confirmatory PSA value (Figure 2, #3A) is greater than 
the screening value then progression by PSA is met and the patient is eligible for trial 
enrollment on the basis of PSA alone.  If the confirmatory PSA (Figure 2, #3B) value is less 
than the screening PSA (Figure 2, #2) value, then an additional test for rising PSA (#4) will 
be required to document progression before the patient can be enrolled.
Figure 2.
Change in PSA


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Target lesion/measurable disease: Patients are not required to have evidence of disease 
progression by measurable disease if they meet the criteria for disease progression on the 
basis of PSA or bone scan.  Evidence of nodal or visceral disease RECIST 1.1 progression 
however is sufficient for trial entry independent of PSA readings.  Because lymph nodes may 
be enlarged due to benign pathology, only lymph nodes that are ≥2.0 cm should be used for 
disease evaluation.
Bone scan: Evidence of disease progression based on bone scan appearance is sufficient for 
trial entry independent of PSA readings.  If the appearance of the bone scan is the only 
indicator of progression, then there must be ≥2 new bone lesions compared with the prior 
bone scans.  If there is ambiguity about the appearance of the bony lesions such as traumatic 
in nature or secondary to a flare reaction, then it is recommended that an alternative imaging 
modality such as MRI or fine-cut CT be used to evaluate these lesions further.
CRITERIA FOR OUTCOME MEASURES:
Soft-tissue lesions: Use RECIST with caveats, 

Only report changes in lymph nodes that were ≥2.0 cm in diameter at baseline;

Record changes in nodal and visceral soft tissue sites separately;

Record complete elimination of disease at any site separately;

Confirm favorable change with second scan.
Bone:

Record outcome as new lesion or no new lesions
Criteria for Evidence of Radiographic Progression
Bone disease will be assessed for progressive disease only by PCWG2.  The documentation 
required for the determination of radiographic progression is shown in the table below. 
Date 
Progression 
Detected[1]
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document Disease 
Progression on Confirmatory 
Scan
Week 9
Bone lesions: 2 or more 
new lesions compared to 
screening bone scan by 
PCWG2
Timing: At least 6 weeks 
after progression identified 
or at Week 16 visit[2]
2 or more new bone lesions on 
bone scan compared to 
Week 8 scan
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression
Week 18 or 
later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to Week 8 bone 
scan
Timing: At least 6 weeks 
after progression identified 
or at next imaging time 
point[2]
Persistent or increase in number 
of bone lesions on bone scan 
compared to prior scan[3]


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Date 
Progression 
Detected[1]
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document Disease 
Progression on Confirmatory 
Scan
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression 
[1]
Progression detected by bone scan at an unscheduled visit either before Week 8 or between scheduled 
visits will require a confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in 
the table for the next scheduled scan. 
[2]
Confirmation must occur at the next available scan. 
[3]
For confirmation, at least 2 of the lesions first identified as new must be present at the next available 
scan (confirmation scan).  
Disease progression in bone must be confirmed at least 6 weeks later, as per PCWG2.  See 
table below for the timing of confirmatory imaging requirements.
Confirmatory Imaging Requirements for Patients With CRPC Based on 
RECIST v1.1 and PCWG2
Disease Site
Response
Progression[1]
Soft tissue
Must be confirmed at least 
4 weeks later 
No confirmation required 
Bone
Not applicable
Must be confirmed at least 6 weeks 
later 
[1]
To inform permanent treatment discontinuation.
Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No, 
including bone 
determination
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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If there is a protocol deviation and a patient has been enrolled allows enrollment of patients 
with only non-target disease, the following table will be used:
Objective Response Status at Each Evaluation for Patients With Non-Target Disease 
Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
Procedures for Assessing PSA Response/Progression Post Study Treatment
PSA measurements will be performed on C1D1 (±14 days) and Day 1 of Cycle 4, 7, 10 and 
every third cycle thereafter, as well as at the End of Treatment visit. Increases and decreases 
will be tracked in order to assess disease response.  The PSA readings on its own will not be 
used to define progression in this protocol.  PSA response and PSA progression will be 
defined according to the consensus guidelines of the PCWG2:

PSA partial response is defined as a ≥50% decline in PSA from Cycle 1 
Day 1 (baseline) PSA value.  This PSA decline much be confirmed to be sustained by 
a second PSA value obtained 4 or more weeks later.

PSA progression date is defined as the date that a ≥25% increase and an absolute 
increase of ≥2 ng/mL above the nadir is documented, which is confirmed by a second 
consecutive value obtained 4 or more weeks later.  The first PSA reading will be 
obtained at week 12.