Clinical trial NCT03854227
Conditions: Advanced Solid Tumors Metastatic Solid Tumors
Sponsor: Pfizer
Start date: 2019-03-14; Completion date: 2022-04-27
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, open label, multi center, dose escalation and expansion, safety, tolerability, PK, and pharmacodynamics study of PF 06939999 in previously treated patients with advanced or metastatic cancer.

Detailed description:

Arms: arm 1: Participants will receive PF-06939999 orally at escalating doses in 28 day cycles on a continuous basis arm 2: Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis arm 3: Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis arm 4: Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis arm 5: Participants will receive PF-06939999 on a continuous basis in combination with docetaxel arm 6: Participants will receive PF-06939999 on a continuous basis at escalating doses in combination with docetaxel
Interventions: intervention 1: PF-06939999 dose escalation intervention 2: PF-06939999 monotherapy intervention 3: PF-06939999 in combination with docetaxel
Intervention descriptions: intervention 1: PF-06939999 orally at escalating doses on a continuous basis intervention 2: PF-06939999 at the recommended Phase 2 dose orally on a continuous basis intervention 3: PF-06939999 orally on a continuous basis in combination with docetaxel

Protocol documents:
Prot_000.pdf: 
PF-06939999
Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
PFIZER CONFIDENTIAL
Page 1
A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, 
AND PHARMACODYNAMICS OF ESCALATING DOSES OF PF-06939999 (PRMT5 
INHIBITOR) IN PARTICIPANTS WITH ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER, HEAD AND NECK SQUAMOUS CELL 
CARCINOMA, ESOPHAGEAL CANCER, ENDOMETRIAL CANCER, CERVICAL 
CANCER AND BLADDER CANCER
Investigational Product Number:
PF-06939999
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C3851001
Phase:
Phase 1 
Short Title: A phase 1, open‑label, dose escalation study of PF‑06939999 in participants
with selected advanced or metastatic solid tumors.
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.
P
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Document History
Document
Version Date
Summary of Changes and Rationale
Amentment 3
11 June 2020

Overarching rationale for Protocol 
Amendment 3: The C3851001 protocol 
is being amended to add Part 1B 
(PF-06939999 + docetaxel dose 
finding) and Part 2 (dose expansions) 
to the study to further evaluate the 
safety and tolerability of PF-06939999 
monotherapy at RP2D as well as 
preliminary clinical efficacy in 
advanced or metastatic NSCLC, 
urothelial carcinoma (bladder cancer) 
and HNSCC, and PF-06939999 in 
combination with docetaxel in 
NSCLC.  In addition, a food effect 
substudy has been added to assess the 
effect of food on the PK of 
PF-06939999.

Part 1B and Part 2 related changes and 
rationale: Provide study objectives, 
participant population 
(inclusion/exclusion criteria), study 
schema, protocol text, schedule of 
acitivies, PK/PD collection and 
statistical data analysis for Part 1B 
combination dose finding and Part 2 
expansion cohorts.

Update to Overall Design – Protocol 
Summary, Overall Design, 
Sections 1.1, 1.2, 4.1, 4.1.1, 4.3.2, 
9.2.1, 9.2.2, 10.9.2, and 10.9.3.  

Added Schedule of Activities (SOA) 
tables (including ECG, 
pharmacokinetic [PK], and biomarker 
sampling schedules) Added separate 
tables for Part 1B and Part 2 [including 
food effect substudy]) Section 1.3.


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Version Date
Summary of Changes and Rationale
•
Added Objectives and Endpoints for 
Part 1B and Part 2 Dose Expansion 
(including food effect substudy), 
Sections 1.1, 3, 9.2.2, and 9.4.4.1.2.
•
Revised inclusion criteria to include 
details for participants in Part 1B and 
Part 2 (NSCLC, urothelial carcinoma, 
HNSCC). Section 5.1.
•
Revised exclusion criterion # 17 to 
exclude participatns with history of 
hypersensitivity reactions to docetaxel 
or drugs formulated with polysorbate 
80.
•
Revised exlusion criterion # 18 
indicating that Participants with 
HNSCC requiring drug administration 
via NG tube are eligible if they meet 
other criteria.
•
Added to text to Sections 8.5.1, and 
8.5.2 to provide details for 
 
and PF-06939999 urine PK.
•
Added details for food requirements 
for participants in the food effect 
sub-study to assess the effect of food 
on the PK of PF-06939999. Section 
6.2.4.2.
•
Added patient reported outcomes as 
assessments in Part 2 for participants 
with NSCLC. Section 8.10.
Rationale: To assess the impact of 
PRMT5 on lung cancer symptoms.
•
Updated sample size determination 
text. Section 9.2.
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Version Date
Summary of Changes and Rationale
•
Updated statistical analyses sections. 
Sections 9.4, 9.4.1, 9.4.2, 9.4.4.1.1, 
9.4.4.1.2, 9.4.4.2. 9.4.4.3, 9.4.4.4, and 
Appendix 9.
•
Biomarker related changes and 
rationale: To optimize biomarker 
collection, timepoint and analysis to 
help clincial decision (PD biomarker) 
and potentially identify predictive 
biomarkers for patient selection; and 
remove suboptimal biomarker assay 
and anaylsis.
•
 
 
•
Biomarker sample collection: Section 
1.3 SoA, Table 2: 
•
Blood sample collection for 
RNAseq before starting treatment, 
while receiving treatment (Days 8 
and 15 on Cycle 1, Cycle 2 Day 1), 
and end of treatment (EoT).
Rationale: For pharmacodynamic 
(PD) biomarker analysis. 
•
Remove plasma 
 samples 
from 2 and 6 hour time points at 
Days 1 and 15; add EOT time point 
collection.
Rationale: Based on plasma
 
data obtained from cohorts 1-5 
during dose escalation study, there 
is no need to include those time 
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points. Added EOT time point to 
assess 
 rebound.
•
Added the strong recommendation 
for the collection of up to 5 on-
treatment de novo biopsies in each 
arm for Part 2 dose expansion 
cohorts if state, local, and 
institutional policies allow.
Rationale: To enable tumor PD 
biomarker analysis. 
•
 
 
 
•
Section 8.8.1. Revised first sentence by 
adding “and to assess PD activity of 
the tumor upon PF-06939999 
treatment” after treatment with study 
drugs.
•
Section 8.8.2. Deleted serum from 
section title. 
•
Section 8.9. Added clarifying language 
regarding who (investigators or 
qualified designees [Radiologist etc.]) 
will be evaluating tumor response.  
•
Added bullet to Appendix 5 for the 
collection of whole blood samples for 
DNA sequencing. 
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Summary of Changes and Rationale

Protocol text and definition related 
changes and rationale: To provide 
details and clarifications on protocol 
language and definition and add 
protocol text for Part 1B combination 
dose finding and Part 2 expansion 
cohorts.

Updated Section 2.  Summarized 
clinical data for PF-06939999 as of 
17 October 2019.

Clarified specific details on the RP2D 
definition in Section 4.3.5.

Minor updates to last sentence of 
Section 4.2.6. 

Updated end of study definition to 
increase clarity in Section 4.3.6.

Added details for study intervention 
administration. Section 6.1, 6.2, 6.2.1, 
6.2.2. 6.2.3, 6.2.4, 6.2.4.1, 6.2.4.3. 
Rationale: To provide specific details 
for study treatment administration 
(PF-06939999 and docetaxel) for each 
study part including the administration 
of PF-0693999 via nasogastric tube for 
participants unable to swallow whole 
tablets. 

Added details for allocation to 
investigational product for Part 2. 
Section 6.3.1.
Rationale: To provide instructions for 
the sites for Part 2 allocation using IRT 
system. 

Added text to allow for dexamethasone 
as a premedication for participants in 


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Part 1B and 2D receiving docetaxel. 
Section 6.5.1.
Rationale: In order to reduce the 
incidence and severity of fluid 
retention as well as the severity of 
hypersensitivity reactions per 
docetaxel approved label (USPI).

Edited/added dose modification, 
interruption, and dose reduction text 
for Cohorts 1B and 2D and for Grade 3 
toxicity (anemia) and 
thrombocytopenia (Table 14) 
Sections 6.6, 6.6.1, 6.6.2 and 6.6.3.
Rationale: To provide details for 
Parts 1B and Part 2. To specify the 
reduction of 1 dose level and clarify 
instructions for dose modification for 
Grade 3 thrombocytopenia for 
recurrent toxicity.

To comply with protocol template 
updates May 2020, Section 7.1 was 
updated to provide examples of 
specific reasons for discontinuation of 
study intervention and added 
instructional text in the event of 
discontinuation of study intervention. 

Appendix 2: Added RBC and MCV to 
hematology column and reticulocyte 
count and peripheral blood smear to 
serology column and included 
footnotes for each. Revised hepatitis B 
footnote (deleted non Hepatitis B text).

Updated adverse event, serious adverse 
event, medication error, and treatment 
of overdose language to align with the 


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May 2020 protocol template.  The 
following were updated: 

Section 8.3.1: Added paragraph 
describing SAE collection during the 
long-term follow-up period. Deleted 
“Medical occurrences that begin before 
the start of study intervention but after 
obtaining informed consent will be 
recorded on the Medical 
History/Current Medical Conditions 
section of the case report form (CRF), 
not the AE section”.

Section 8.3.1.2: Added text to first and 
second paragraph clarifying the active 
collection period as beginning after 
informed consent is obtained and that 
the investigator is to to record on the 
CRF all directly observed and all 
spontaneously reported AEs and SAEs 
reported by the participant.

Section 8.4: Updated reporting 
timeframe for overdose from 
“immediately” to “within 24 hours”.
Updated item 2. Laboratory 
abnormalities are to be monitored for 
for at least 5 half-lives or 28 calendar 
days after the overdose of 
PF-06939999 (whichever is longer be 
detected systemically (at least 
30 days).

Section 8.3.6: Updated the reporting 
timeframe for medication dosing erros 
from “immediately” to “within 
24 hours”.

Appendix 3.  Section 10.3.2: Added 
text regarding suspected transmission 


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via a Pfizer product of an infectious 
agent, pathogenic or non-pathogenic, is 
considered serious. Section 10.3.3: 
Added “All AEs/SAEs associated with 
exposure during pregnancy or 
breastfeeding” to the table in the 
recorded on the CRF column and 
‘Include all SAEs associated with 
exposure during pregnancy or 
breastfeeding. Include all AEs/SAEs 
associated with occupational exposure’ 
in the Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 Hours 
of Awareness column

Section 10.3.4. Deleted non-applicable 
text regarding the reporting of serious 
adverse events (SAEs) using an 
electronic data collection tool. 
Appendix 3, Section 10.3.4.  
Rationale: A CT SAE Report Form is 
being used in this study, not an 
electronic data collection tool.

Added Section 10.13 Appendix 13 to 
provide guidance during public 
emergencies, including the COVID-19 
pandemic. Added references to this 
appendix in Sections 5, 7.1.1, and 8.2. 
Incorporated language from Protocol 
Administrative Change Letter dated 
26 March 2020.

Aligned Section 9.5.1 data monitoring 
committee language to align with 
added text in protocol summary. 

Administrative changes or corrections
including updates to list of 


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abbreviations and references as 
applicable. Sections: global.
Amendment 2
16 December 2019

Changes to allow once a day (QD) 
dosing in the upcoming dose escalation 
cohorts: Section 1 protocol summary 
(1.1 synopsis, 1.2 study schema, 
1.3 SoA), 4.1 overall design, 
4.3 justification for dose.  
Rationale: To test additional dosing 
regimen (QD) for improving patient 
convenience and compliance. 

Changes Pharmacokinetic (PK) sample 
collection timepoints to capture trough 
concentrations for QD and BID dosing 
regimens: section 1.3 SoA table 2 (add 
Day 16 PK sample collection for QD 
dosing; add PK sample collection 
12 hours post dose on Day 1 and 
Day 15 for BID dosing). 
Rationale: To better characterize PK 
profiles for both QD and BID dosing 
regimens. 

Change biomarker sample collection: 
section 1.3 SoA table 2: 
a.
Delete whole blood for circulating 
tumor cell collection.
Rationale: The circulating tumor cell 
analysis assay was not sensitive and 
informative. 
b. Add blood sample collection for 
RNAseq before starting treatment, 
while receiving treatment (day 8 on 
cycle 1, 2 and 3, SoA table 2), and 
post treatment. 


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Summary of Changes and Rationale
Rationale: For splicing factor and 
biomarker analysisAdd 1 blood sample 
collection for plasma 
.
•
Rationale: To further characterize 
plasma 
 profiles at steady state.
•
Optional on-treatment biopsies for 
Part 1 dose escalation.
Amendment 1
15 January 2019 
•
Change in starting dose and maximum 
percent dose escalation increment –
Protocol Summary, Overall Design, 
Sections 1.1, 1.2, 1.3, 2.2.4, 4.1, 4.3, 
6.2.5, 9.4.1 and 10.9.2. 
•
Rationale – FDA request to change the 
starting dose to approximately 1/6 the 
HED of the HNSTD/NOAEL in dogs 
and a maximum dose escalation 
increment of 100%.
•
Update to Overall Design – Protocol 
Summary, Overall Design, Sections 
1.1, 1.2, 4.1, 4.3.2, 9.2.1 and 10.9.2.
•
Rationale – Increased number of 
cohorts and participants resulting from 
change in starting dose and maximum 
dose escalation increment of 100%.
•
Update to Section 1.2, Table 1 SOA 
and Table 2 PK//Biomarker Sampling 
Schedule.
Rationale – FDA request and other 
clarifications.
•
Removal of specific references to 
Part 2 (dose expansion) of the 
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study -Protocol Summary, Overall 
Design, Sections 1.1, 1.2, and 4.1.
Rationale – FDA request. 

Include solubility data at different pH 
levels and no anticipated impact in 
absorption – Sections 2.2.3. and 6.5.5.
Rationale – FDA request.

Updated safety margins – Sections 
2.2.4 and 4.3.1. 
Rationale – New starting dose.

Update to neutropenia DLT and dose 
reduction DLT added – Sections 4.3.3 
and 6.6.2.
Rationale – FDA request.

Update to inclusion 2 – Section 5.1.
Rationale – FDA request.

Exclusion of current use of strong P-gp 
or BCRP inhibitors and potential 
drug-drug interaction – Sections 5.2.
and 6.5.1.
Rationale – FDA request.

Update simulation of the BLRM model 
for new starting dose – Section 10.9.2.
Rationale – FDA request.

Administrative changes or corrections.
Original protocol
12 November 2018
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This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................21
1. PROTOCOL SUMMARY...................................................................................................22
1.1. Synopsis ..................................................................................................................22
1.2. Study Schema..........................................................................................................31
1.3. Schedule of Activities (SoA)...................................................................................32
2. INTRODUCTION ...............................................................................................................60
2.1. Study Rationale .......................................................................................................60
2.2. Background .............................................................................................................60
2.2.1. Protein Arginine Methyltransferase 5 (PRMT5)........................................60
2.2.1.1. Cellular Functions .....................................................................60
2.2.1.2. PRMT5 Dysregulation in Cancer..............................................61
2.2.1.3. Splicing Changes in Cancer ......................................................62
2.2.1.4. PRMT5 Inhibitor Activity in Splicing Factor Mutated 
Leukemia ...........................................................................................62
2.2.1.5. PRMT5 and NSCLC .................................................................63
2.2.1.6. Role of PRMT5 in Additional Solid Tumor Types...................63
2.2.1.7. PRMT5 Inhibitors in Treatment Resistant Disease...................63
2.2.2. Nonclinical Pharmacology..........................................................................64
2.2.3. Nonclinical Pharmacokinetics and Projection of Human 
Pharmacokinetics.............................................................................................65
2.2.4. Nonclinical Safety ......................................................................................66
2.2.5. Clinical Overview.......................................................................................68
2.3. Benefit/Risk Assessment.........................................................................................68
3. OBJECTIVES AND ENDPOINTS ....................................................................................69
4. STUDY DESIGN.................................................................................................................73
4.1. Overall Design.........................................................................................................73
4.1.1. Food-Effect Substudy.................................................................................76
4.2. Scientific Rationale for Study Design.....................................................................77
4.2.1. Non-Small Cell Lung Cancer (NSCLC).....................................................77
4.2.2. Head and Neck Squamous Cell Carcinoma (HNSCC)...............................78


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4.2.3. Esophageal Cancer......................................................................................78
4.2.4. Endometrial Cancer ....................................................................................78
4.2.5. Cervical Cancer ..........................................................................................79
4.2.6. Urothelial Carcinoma..................................................................................79
4.2.7. Drug Resistance..........................................................................................80
4.2.8. Background of Biomarker Assessments.....................................................80
4.2.9. Scientific Rationale for Biomarker Studies................................................81
4.3. Justification for Dose ..............................................................................................82
4.3.1. Starting Dose ..............................................................................................82
4.3.2. Criteria for Dose Escalation........................................................................83
4.3.3. Dose Limiting Toxicity Definition.............................................................85
4.3.4. Maximum Tolerated Dose Definition.........................................................86
4.3.5. Recommended Phase 2 Dose (RP2D) Definition.......................................86
4.3.6. End of Study Definition..............................................................................87
5. STUDY POPULATION......................................................................................................87
5.1. Inclusion Criteria.....................................................................................................87
5.2. Exclusion Criteria....................................................................................................91
5.3. Lifestyle Considerations..........................................................................................94
5.3.1. Photosensitivity...........................................................................................94
5.3.2. Contraception..............................................................................................94
5.4. Screen Failures ........................................................................................................95
6. STUDY INTERVENTION..................................................................................................95
6.1. Study Intervention(s) Administered........................................................................95
6.2. Preparation/Handling/Storage/Accountability ........................................................95
6.2.1. Preparation and Dispensing........................................................................97
6.2.2. Investigational Product Supplies ................................................................97
6.2.3. Dosage Form(s) and Packaging..................................................................97
6.2.4. Administration............................................................................................97
6.2.4.1. PF-06939999 Administration....................................................97
6.2.4.2. Food Requirements ...................................................................98
6.2.4.3. Docetaxel Administration .........................................................99


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6.3. Measures to Minimize Bias: Randomization and Blinding.....................................99
6.3.1. Allocation to Investigational Product .........................................................99
6.4. Study Intervention Compliance.............................................................................100
6.5. Concomitant Therapy............................................................................................101
6.5.1. Potential Drug-Drug Interactions .............................................................101
6.5.2. Other Anti-tumor/Anti-cancer or Experimental Drugs.............................102
6.5.3. Supportive Care ........................................................................................102
6.5.4. Hematopoietic Growth Factors.................................................................102
6.5.5. Acid Reducing Agents..............................................................................102
6.5.6. Anti-Diarrheal, Anti-Emetic Therapy.......................................................103
6.5.7. AntiInflammatory- Therapy......................................................................103
6.5.8. Corticosteroids..........................................................................................103
6.5.9. Surgery......................................................................................................103
6.6. PF-06939999 Dose Modification..........................................................................103
6.6.1. PF-06939999 Dosing Interruptions ..........................................................104
6.6.2. PF-06939999 Dose Reductions ................................................................104
6.6.3. Docetaxel Dose Modifications .................................................................108
6.7. Intervention After the End of the Study................................................................109
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.........................................................................109
7.1. Discontinuation of Study Intervention ..................................................................109
7.1.1. Temporary Discontinuation......................................................................110
7.1.2. Rechallenge...............................................................................................110
7.2. Participant Discontinuation/Withdrawal From the Study.....................................110
7.2.1. Withdrawal of Consent:............................................................................111
7.3. Lost to Follow-up..................................................................................................111
8. STUDY ASSESSMENTS AND PROCEDURES.............................................................112
8.1. Efficacy Assessments............................................................................................113
8.1.1. Safety Imaging Assessments ....................................................................113
8.2. Safety Assessments ...............................................................................................113
8.2.1. Physical Examinations..............................................................................113
8.2.2. Vital Signs ................................................................................................113


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8.2.3. Electrocardiograms...................................................................................114
8.2.4. Clinical Safety Laboratory Assessments ..................................................115
8.2.5. Pregnancy Testing ....................................................................................115
8.3. Adverse Events and Serious Adverse Events........................................................116
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.....116
8.3.1.1. Reporting SAEs to Pfizer Safety.............................................117
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF.................117
8.3.2. Method of Detecting AEs and SAEs ........................................................117
8.3.3. Follow-up of AEs and SAEs.....................................................................118
8.3.4. Regulatory Reporting Requirements for SAEs.........................................118
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................118
8.3.5.1. Exposure During Pregnancy....................................................118
8.3.5.2. Exposure During Breastfeeding ..............................................119
8.3.5.3. Occupational Exposure ...........................................................119
8.3.6. Medication Errors .....................................................................................119
8.4. Treatment of Overdose..........................................................................................120
8.5. Pharmacokinetics ..................................................................................................120
8.5.1. Plasma for analysis of PF-06939999 and docetaxel concentrations.........120
8.5.2. Urine for Analysis of PF-06939999 Concentrations ................................122
8.6. Pharmacodynamics................................................................................................122
8.7. Genetics.................................................................................................................122
8.7.1. Specified Genetics ....................................................................................122
8.7.2. Banked Biospecimens for Genetics..........................................................122
8.8. Biomarkers ............................................................................................................123
8.8.1. Archival/De Novo Tumor Biopsies..........................................................123
8.8.2. Whole Blood and Plasma..........................................................................123
8.9. Tumor Response Assessments ..............................................................................124
8.10. Patient Reported Outcomes.................................................................................124
8.11. Health Economics ...............................................................................................124
9. STATISTICAL CONSIDERATIONS ..............................................................................124
9.1. Statistical Hypothesis ............................................................................................125


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9.2. Sample Size Determination...................................................................................125
9.2.1. Part 1 Dose Escalation..............................................................................125
9.2.2. Part 2 Dose Expansion..............................................................................125
9.3. Populations for Analysis .......................................................................................125
9.4. Statistical Analyses ...............................................................................................126
9.4.1. Maximum Tolerated Dose Determination................................................126
9.4.2. Efficacy Analyses .....................................................................................128
9.4.3. Safety Analyses ........................................................................................128
9.4.3.1. Electrocardiogram Analyses....................................................129
9.4.3.2. Adverse Events........................................................................130
9.4.3.3. Laboratory Test Abnormalities ...............................................130
9.4.4. Other Analyses..........................................................................................130
9.4.4.1. Pharmacokinetic Analyses ......................................................130
9.4.4.2. Pharmacodynamic/Biomarker Analyses .................................131
9.4.4.3. Analysis of PRO data ..............................................................132
9.4.4.4. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling................132
9.5. Interim Analyses ...................................................................................................132
9.5.1. Data Monitoring Committee.....................................................................132
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................133
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............133
10.1.1. Regulatory and Ethical Considerations ..................................................133
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................133
10.1.2. Financial Disclosure ...............................................................................134
10.1.3. Informed Consent Process ......................................................................134
10.1.4. Data Protection .......................................................................................135
10.1.5. Dissemination of Clinical Study Data ....................................................135
10.1.6. Data Quality Assurance ..........................................................................137
10.1.7. Source Documents..................................................................................138
10.1.8. Study and Site Closure............................................................................138


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10.1.9. Publication Policy...................................................................................139
10.1.10. Sponsor’s Qualified Medical Personnel ...............................................139
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................141
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................143
10.3.1. Definition of AE .....................................................................................143
10.3.2. Definition of SAE...................................................................................144
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.....................146
10.3.4. Reporting of SAEs..................................................................................149
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..............................................................................................................150
10.4.1. Male Participant Reproductive Inclusion Criteria..................................150
10.4.2. Female Participant Reproductive Inclusion Criteria...............................150
10.4.3. Woman of Childbearing Potential (WOCBP) ........................................151
10.4.4. Collection of Pregnancy Information .....................................................153
10.5. Appendix 5: Genetics..........................................................................................155
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......156
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................158
10.7.1. Adverse Events and Serious Adverse Events.........................................160
10.8. Appendix 8: Country-Specific Requirements .....................................................161
10.8.1. France Contrat Unique............................................................................161
10.9. Appendix 9: Detailed Dose Escalation/De-escalation Scheme for BLRM 
Design......................................................................................................................162
10.9.1. Statistical Model.....................................................................................162
10.9.2. Prior Specifications for BID Regimen....................................................162
10.9.3. Prior Specifications for QD Regimen.....................................................164
10.9.4. Model description and prior specification for Part 1B ...........................166
10.10. Appendix 10: ECOG Performance Status.........................................................167
10.11. Appendix 11: RECIST (Response Evaluation Criteria In Solid Tumors) 
Version 1.1 Guidelines ............................................................................................168
10.12. Appendix 12: Bone Marrow Reserve in Adults................................................173
10.13. Appendix 13: Alternative Measures During Public Emergencies.....................175


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10.13.1. Eligibility..............................................................................................175
10.13.2. Telehealth Visits...................................................................................175
10.13.3. Laboratory Testing................................................................................176
10.13.4. Electrocardiograms...............................................................................176
10.13.5. Study Intervention ................................................................................176
10.13.6. Home Health Visits...............................................................................177
10.13.7. Efficacy Assessments ...........................................................................178
10.14. Appendix 14: Abbreviations .............................................................................179
11. REFERENCES ................................................................................................................184
LIST OF TABLES
Table 1.
Study Related Procedures: Part 1A (dose escalation PF-06939999 
monotherapy)............................................................................................33
Table 2.
Study Related Procedures: Part 1B (dose finding PF-06939999 + 
docetaxel)..................................................................................................37
Table 3.
Study Related Procedures: Part 2A, 2B, and 2C (dose expansion, 
monotherapy)............................................................................................41
Table 4.
Study Related Procedures: Part 2D (dose expansion, PF-06939999 
+ docetaxel) ..............................................................................................46
Table 5.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for 
Part 1A (dose escalation, PF-06939999 monotherapy) ............................50
Table 6.
ECG, Pharmacokinetic (PK) and Biomarker Sampling Schedule for 
Part 1B (dose finding, PF-06939999 + docetaxel) ...................................52
Table 7.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for 
Part 2A, Part 2B, and Part 2C (dose expansion, PF-06939999 
monotherapy) (except for food effect sub-study) .....................................54
Table 8.  Food Effect Sub-study Participants: ECG, Pharmacokinetic (PK), and 
Biomarker Sampling Schedule .................................................................56
Table 9.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for 
Part 2D (dose expansion, PF-06939999 + docetaxel) ..............................58
Table 10.
Provisional Dose Levels in Dose Escalation ............................................84
Table 11.
Provisional Dose Levels in Dose Escalation with Intermittent 
Dosing Regimen .......................................................................................84
Table 12.
PF-06939999 dose level (depending on RP2D decision).......................105


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Table 13.
Dose Modifications for PF-06939999 Related Toxicity:  
Nonhematologic......................................................................................106
Table 14.
Dose Modifications for PF-06939999 Related Toxicity: 
Hematologic............................................................................................107
Table 15.
Safety Laboratory Tests..........................................................................141
Table 16.
Prior Distribution for the Model Parameters (BID regimen)..................163
Table 17.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
PF-06939999 (BID regimen)..................................................................163
Table 18.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
PF-06939999 (QD regimen)...................................................................165
Table 19.
Objective Response Status at each Evaluation.......................................172
Table 20.
Objective Response Status at each Evaluation for Participants with 
Non-Target Disease Only .......................................................................172
LIST OF FIGURES
Figure 1.
PRMT5 methylosome complex regulates snRNP assembly ....................61
Figure 2.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
PF-06939999 with BID regimen (total daily dose) ................................164


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A phase 1, open‑label, dose escalation study of PF‑06939999 in participants
with selected advanced or metastatic solid tumors.
Rationale: PF-06939999 is a potent and selective small molecule inhibitor of protein 
arginine methyltransferase 5 (PRMT5), which is overexpressed in hematologic malignancies 
and solid tumors.  PRMT5 methylates multiple substrates with a variety of biological 
functions known to be dysregulated in cancer including transcription, cell signaling, 
messenger ribonucleic acid (mRNA) translation, deoxyribonucleic acid (DNA) damage, 
receptor trafficking, protein stability, and pre-mRNA splicing.  Proliferation of multiple 
cancer cell lines was reduced in response to treatment with PF-06939999 and this translated 
to robust tumor growth inhibition in vivo as a single agent.
This is a first-in-human clinical study of PF-06939999. The study is divided into 2 parts: 
dose escalation (Part 1) followed by dose expansion (Part 2). The purpose of Part 1 (dose 
escalation) is to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
escalating doses of PF-06939999 in participants with advanced or metastatic HNSCC, 
NSCLC, esophageal, endometrial, cervical, and bladder cancer and determine the maxium 
tolerable dose (MTD) and recommended dose for expansion (RP2D). The purpose of Part 2 
(dose expansion) is to further evaluate the safety and tolerability of PF-06939999 at RP2D as 
well as preliminary clinical efficacy in advanced or metastatic NSCLC, urothelial carcinoma 
(bladder cancer) and HNSCC.


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Part 1A Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:
•
To assess safety and tolerability at 
increasing dose levels of PF-06939999
in successive cohorts of participants
with selected advanced or metastatic 
solid tumors in order to estimate MTD 
or Maximum Administered Dose 
(MAD) and select the RP2D/schedule.
•
Dose Limiting Toxicities (DLTs).
•
Adverse Events (AEs) 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.
Secondary: 
Secondary: 
•
To characterize the single and multiple 
dose PK of PF-06939999 following 
oral administration.
•
To evaluate preliminary anti-tumor 
activity.
•
PK parameters of PF-06939999: Single 
Dose (SD) - Cmax, Tmax, AUClast, and as 
data permit, t1/2, AUCinf, CL/F, and 
Vz/F.
•
PK parameters of PF-06939999: 
Multiple Dose (MD) – Cmax,ss, Tmax,ss, 
AUCss,τ, and as data permit, CL/F, 
Vss/F, and Rac (AUCss,τ/AUCsd,τ).
•
Tumor response: Objective response rate 
(ORR) and duration of response (DoR), 
as assessed using the Response 
Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1) Section 10.11.
•
 
 
 
 
 
 
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Part 1B Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:
•
To assess safety and tolerability of 
PF-06939999 in combination with 
docetaxel in participants with locally
advanced or metastatic NSCLC to 
determine MTD and select the 
RP2D/schedule for combination.
•
DLTs.
•
AEs as characterized by type, frequency, 
severity (as graded by 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.
Secondary: 
Secondary: 
•
To characterize the single and multiple 
dose PK of PF-06939999 when 
administered in combination with 
docetaxel. 
•
To evaluate preliminary anti-tumor 
activity.
•
To evaluate overall survivial (OS).
•
PK parameters of PF-06939999: 
SD - Cmax, Tmax, AUClast, and as data 
permit, t1/2, AUCinf, CL/F, and Vz/F.
•
PK parameters of PF-06939999: MD –
C max,ss, Tmax,ss, AUCss,τ, and as data 
permit, CL/F, Vss/F, and Rac (AUCss,τ
/AUCsd,τ).
•
Tumor response: ORR,DoR, 
progression-free survival (PFS) and time 
to progression (TTP), as assessed using 
the Response Evaluation Criteria in 
Solid Tumors (RECIST, version 1.1) 
Section 10.11.
•
OS, proportion of participants alive at 6 
months, 1 year, and 2 years of 
PF-06939999 in combination with 
docetaxel.
•
 
 
 
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Part 2 Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:
•
To assess safety and tolerability of 
PF-06939999 monotherapy in 
participants with locally advanced or 
metastatic NSCLC, urothelial
carcinoma, or HNSCC and in 
combination with docetaxel in locally 
advanced or metastatic NSCLC.
•
AEs as characterized by type, frequency, 
severity (as graded by 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.
•
To estimate clinical efficacy by ORR
of PF-06939999 monotherapy in 
participants with NSCLC, urothelial 
carcinoma or HNSCC and in 
combination with docetaxel in 
NSCLC.
•
Best overall response (BOR) as assessed 
by investigators using the Response 
Evaluation Criteria in Solid Tumors 
(RECIST version 1.1) Section 10.11.
Secondary: 
Secondary: 
•
To further evaluate the PK of 
PF-06939999 as a single agent and in 
combination with docetaxel at the
respective RP2D. 
•
PK parameters of PF-06939999: Cmax, 
Tmax from single and multiple dose, and
Ctrough at selected timepoints.
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Objectives
Endpoints
•
To evaluate the effect of food on the 
PK of PF-06939999 (Part 2B).
•
To evaluate anti-tumor activity of 
PF-06939999 monotherapy in 
participants with locally advanced or 
metastatic NSCLC, urothelial 
carcinoma, or HNSCC and in 
combination with docetaxel in locally 
advanced or metastatic NSCLC.
•
To evaluate overall survival (OS).
•
PK parameters of PF-06939999 given 
with and without food: Cmax, Tmax, and 
AUClast.
•
Tumor response:Duration of response 
(DoR) progression free survival (PFS)
and time to progression (TTP) as 
assessed by investigators using the 
Response Evaluation Criteria in Solid 
Tumors (RECIST version 1.1) Section 
10.11 of PF-06939999 monotherapy and 
in combination with docetaxel. 
•
OS, proportion of participants alive at 6 
months, 1 year, and 2 years of 
PF-06939999 monotherapy and in 
combination with docetaxel.
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Design:
The study is divided into 2 parts: dose escalation (Part 1) followed by dose expansion 
(Part 2). The overall study design is depicted in the schema (Section 1.2). 
Part 1 dose escalation further divides into Part 1A and Part 1B. Part 1A contains dose 
escalation as a single agent in participants with locally advanced or metastatic head and neck 
squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), esophageal 
cancer, endometrial cancer, cervical cancer, or bladder cancer who are resistant or intolerant 
to standard therapy or for whom no standard therapy is available, to determine the MTD and 
RP2D. Part 1B contains dose finding of PF‑06939999 in combination with docetaxel in 
locally advanced or metastatic NSCLC. 
Part 1A (dose escalation) plans to enroll approximately 40 participants in different dose level 
cohorts.  Bayesian Logistic Regression Model (BLRM) was used to determine the maximum 
tolerable dose (MTD).  Participants have received escalating doses of PF-06939999 starting 
from 0.5 mg once daily. Dose limiting toxicities (DLT) were assessed during Cycle 1 (the 
first 28 days) to inform dose escalation and determine the MTD.  Cohort size was
approximately 3 participants, with at least 1 DLT-evaluable participant per cohort in the first 
3 cohorts and at least 2 DLT evaluable participants per cohort in the remaining cohorts.
For Part 1A, PF-06939999 was administered as a single agent, orally QD for the first cohort 
then BID or QD in 28 day cycles for subsequent cohorts on a continuous basis until disease 
progression, participant refusal, or unacceptable toxicity. The estimated length of treatment 
is approximately 2 years. Any additional treatment with PF-06939999 beyond 2 years shall 
be discussed and approved by the Sponsor. The actual number of participants enrolled in 
Part 1A depends on the tolerability of PF-06939999 and the number of dose levels required 
to identify the MTD and and recommended dose for expansion (RP2D). RP2D definition is 
provided in Section 4.2.9.  After the selecton of recommended dose for expansion (RP2D)
for monotherapy, Part 2 (dose expansion) will evaluate the safety and antitumor activity of 
PF-06939999 monotherapy at the single agent RP2D. Part 2 dose expansion will consist of 
3 monotherapy cohorts in locally advanced or metastatic NSCLC (Part 2A), urothelial 
cancinoma (Part 2B) and HNSCC (Part 2C) repspectively and 1 combination cohort with 
docetaxel in locally advanced or metastatic NSCLC (Part 2D). The participant population is 
briefly described below and detailed in the inclusion criteria (Section 5.1).
Monotherapy expansion cohorts Part 2A, 2B, and 2C:

Part 2A: Participants with NSCLC (n=20) who have progressed after at least 1 line of 
checkpoint inhibitors and 1 line of platinum based chemotherapy (2L+).

Part 2B: Participants with urothelial carcinoma (n=20) who have progressed after at 
least 1 line of standard of care systemic chemotherapy (cisplatin/carboplatin+ 
Gemcitabine; or methotrexate/vinblastine sulfate/doxorubicin hydrochloride/cisplatin 
[MVAC]) and checkpoint inhibitor (2L+).


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
Part 2C: Participants with HNSCC (n=20) who have progressed after at least 1 line of 
standard of care systemic chemotherapy and 1 line of checkpoint inhibitor (2L+).
The collection of on-treatment biopsies in up to 5 participants per arm is strongly 
recommended if state, local, and institutional policies allow.
Combination expansion cohort Part 2D (PF-06939999 in combination with docetaxel):

Part 2D: Participants with NSCLC (n=20) who have progressed after at least 1 line of 
checkpoint inhibitor and 1 line of platinum based chemotherapy (2L+).
Furthermore, the PF-06939999 in combination with docetaxel will be evaluated in locally 
advanced or metastatic NSCLC (Part 1B combination dose finding and Part 2D combination 
dose expansion). In Part 1B, the PF-06939999 in combination with docetaxel will be 
evaluated in participants with locally advanced or metastatic NSCLC who have progressed 
after at least 1 line of checkpoint inhibitor and platinum based chemotherapy (2L+). BLRM 
specifically designed for combinations and guided by EWOC principle will be used for dose 
finding. PF-06939999 may start at 1 dose level below single agent RP2D (RP2D-1) with 
fixed dose of docetaxel per standard of care. Dose limiting toxicities (DLT) will be assessed 
during the first 28 days to inform dose escalation and determine the MTD.  Cohort size will 
be approximately 3 participants with at least 3 DLT-evaluable participants. In addition, 
depending on the safety findings in Part 1A, and whether significant overlapping toxicities 
are expected in combination, the starting dose of PF-06939999 may be further escalated or 
de-escalated but will not exceed the single agent RP2D. It is anticipated that Part 1B will 
enroll approximately 6-9 participants.
Once the RP2D for the combination has been determined, additional NSCLC participants 
will be enrolled under Part 2D combination expansion cohort until a total of 20 participants 
have been evaluated at the combination RP2D (Part 1B participants dosed at the combination 
RP2D will be counted towards the total of 20 participants). The collection of on-treatment 
biopsies in up to 5 participants is strongly recommended if state, local, and institutional 
policies allow.
Food effect will be assessed in at least 6 participants (but no more than 15 participants) from
the urothelial carcinoma monotherapy cohort.
Approximately 80 participants are expected to be enrolled in Part 2.
All participants will undergo up to 28 days of screening prior to study entry. Eligible 
participants will then receive treatment with PF-06939999 for up to 2 years, or until disease 
progression, unacceptable toxicities, a decision by the participant (withdrawal of consent or 
no longer willing to participate), or investigator to discontinue treatment or study 
termination. Any additional treatment beyond 2 years shall be discussed and approved by the 
sponsor. At least 28 days and no more than 35 days after end of treatment all participants 
will complete a Safety follow up visit. Participants in Part 1B and Part 2 dose expansion 


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cohorts will be contacted by telephone every 12 weeks for survival data collection until end 
of trial (2 years from last participant first dose).
Data Monitoring Committee:
This is an open label non-randomized Phase 1 study. This study will not use a data 
monitoring committee (DMC).
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 participant enrollment is appropriate.
Statistical Methods:
Bayesian adaptive approach: The dose escalation in the Part 1A and Part 1B of the study will 
be guided by a Bayesian analysis of Cycle 1 dose limiting toxicity (DLT) data for 
PF‑06939999. Toxicity is modelled using 2-parameter logistic regression in Part 1A and 
5-parameter model specifically designed for combinations in Part 1B for the probability of a 
participant experiencing a DLT at the given dose.
Assessment of participant risk: After each cohort of participants, the posterior distribution for 
the risk of DLT for new participants at different doses of interest for PF-06939999 will be 
evaluated.  The posterior distributions will be summarized to provide the posterior 
probability that the risk of DLT lies within the following intervals: 
Under-dosing:
[0, 0.16]
Targeted dosing:
[0.16, 0.33]
Overdosing:
[0.33, 1]
The escalation with overdose control (EWOC) principle: Dosing decisions in both Part 1A 
and Part 1B are guided by the escalation with overdose control principal.1  A dose may only 
be used for newly enrolled participants if the risk of over-dosing at that dose is less than 
25%.
Prior distributions in Part 1A for BID regimen: Weekly informative prior distribution based 
on pre-clinical/expert opinion information will be chosen for the logistic parameters.
Prior distributions in Part 1A QD regimen: The data from BID regimen have been used to 
set up a meta-analystic prior (MAP) and a mixture of the MAP and weakly informative prior 
has been used for Part 1A QD regimen. Details are described in Appendix 10.9.


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Prior distributions in Part 1B: A meta-analytic-predictive (MAP) approach will be used to 
derive the prior distribution for model parameters used in Part 1B based on the data collected 
in Part 1A and original dose escalation studies of docetaxel. A full description of the 
application of the MAP approach to derive the prior distributions of the model parameters is 
given in Technical Supplement to Appendix 10.9.
Efficacy analysis:
Tumor response will be presented in the form of participant data listings that include, but are
not limited to tumor type, dose on Day 1, tumor response at each visit, and best overall 
response.  In addition, progression date, death date, date of first response and last tumor 
assessment date and date of last contact will be listed. Part 1B and Part 2: The Kaplan-Meier 
methods will be used to analyze all time to event endpoints. Proportion of participants alive 
at 6 months, 1 year, and 2 years will be also reported.
1.2. Study Schema


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1.3. Schedule of Activities (SoA)
Table 1provides an overview of the protocol visits and procedures for Part 1A (dose escalation PF-06939999 monotherapy). 
Table 2 provides an overview of the protocol visits and procedures for Part 1B (dose finding PF-06939999 + docetaxel).
Table 3 provides and overview of the protocol visits and procedures for Parts 2A, 2B, and 2C (dose expansion, PF-06939999 
monotherapy). 
Table 4 provides and overview of the protocol visits and procedures for Part 2D, (dose expansion, PF-06939999 + docetaxel). 
ECG, Pharmacokinetic (PK) and Biomarker Sampling Schedules
Table 5 provides an overview of the ECG, PK, and biomarker sampling schedule for Part 1A (dose escalation PF-06939999 
monotherapy). 
Table 6 provides an overview of the ECG, PK, and biomarker sampling schedule for Part 1B (dose finding, PF-06939999 + 
docetaxel). 
Table 7 provides an overview of the ECG, PK, and biomarker sampling schedule for Parts 2A, 2B, and 2C (dose expansion
PF-06939999 monotherapy) except for food effect sub-study.  
Table 8 provides and overview of the ECG, PK, and biomarker sampling schedule for the food effect sub-study participants. 
Table 9 provides and overview of the ECG, PK and biomarker sampling schedule for Part 2D (dose expansion PF-06939999 + 
docetaxel). 
Refer to Section 8 of the protocol for detailed information on each assessment required for compliance with the protocol for each 
study part. The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA tables, in order to conduct 
evaluations or assessments required to protect the well being of the participant.


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Table 1.
Study Related Procedures: Part 1A (dose escalation PF-06939999 monotherapy)
Screen1
(28 days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
End of 
Treatment 
(EOT)21
Safety follow-
Up visit22
Protocol Activity
Day 1
Day 2a
Day 8
Day 15
Day 16a
Day 22
Day 1
Day 15
Visit Window
±2 day
±2 day
±2 day
±2 days
±2 day
Informed Consent2
X
Medical History3
X
Physical Examination4
X
X
X
X
X
X
X
X
Baseline Signs and Symptoms5
X
Height
X
Weight
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
X
ECOG Performance Status7
X
X
X
X
Contraception check8
X
X
X
X
12-lead ECG
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1A
Laboratory Studies
Hematology9
X
X
X
X
X
X
X
X
X
Blood Chemistry10
X
X
X
X
X
X
X
X
X
Coagulation11
X
X
X
X
X
Urinalysis12
X
X
X
X
Pregnancy Test13
X
X
X
X
Viral disease screen [Hepatitis 
B, C, and HIV tests]14
X
Registration and Treatments
Registration15
X
PF-06939999 Treatment16
Day 1 to Day 28
Day 1 to Day 28
Tumor Assessments
CT or MRI Scans17
X
Every 8 weeks for the first 6 months, then every 12 weeks. See footnote 17


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Table 1.
Study Related Procedures: Part 1A (dose escalation PF-06939999 monotherapy)
Screen1
(≤28 days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
End of 
Treatment 
(EOT)21
Safety follow-
Up visit22
Protocol Activity
Day 1
Day 2a
Day 8
Day 15
Day 16a
Day 22
Day 1
Day 15
Visit Window
±2 day
±2 day
±2 day
±2 days
±2 day
Other Clinical Assessments
Serious and Non-serious 
Adverse Event Monitoring18
X
Concomitant Medications19
X
X
X
X
X
X
X
X
X
X
Archival or De Novo Tumor 
Biopsy20
X
Other Laboratory Assessments
Blood for Biomarker Analyses
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1A
Plasma for PF-06939999 PK 
and 
See Table 6 ECG, ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1A
Banked Biospecimen 
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1A
Serum for CA-125 [Cervical and 
Endometrial Cancer only]
X
X
28- to 35-day Follow-up
X
Abbreviations: ɦ ongoing/continuous event; C = Cycle; CT = computed tomography;CA-125 = cancer antigen 125 ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; 
Footnotes (Schedule of Activities) 
a.
Days 2 and 16 are Cycle 1 only to correspond with PK collection days for QD dosing regimen only.  No clinical assessments required.
1.
Screening: To be conducted within 28 days prior to treatment start. 
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
3.
Medical History: To include date of diagnosis and information on prior anti-tumor treatments, surgeries, radiotherapy and recurrence date.
4.
Physical Examination: Examination of major body systems including body weight. Height is measured at screening visit only. 
5.
Baseline Signs and Symptoms: Participants will be asked about any signs and symptoms experienced within 14 days prior to C1D1.  
6.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position or semi-recumbent position (however the 
position should be maintainted throughout the study) after approximately 5 minutes of rest.
7.
ECOG Performance Status: ECOG performance scale is available in Section 10.10 Appendix 10.
CCI
CCI


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8.
The participant will be informed of the need to use highly effective contraception consistently and correctly.  The conversation and participant’s affirmation 
will be documented in the participant’s chart.
9.
Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  The list of required laboratory tests is provided 
in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
10. Blood Chemistry: All chemistry laboratory tests included in Section 10.2 Table 15) are required at every protocol chemistry required time point.  No need to 
repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date.  During Cycle 1, liver function tests, creatinine and 
amylase/lipase must be checked on Days 8, 15 and 22 to assess for events qualifying as dose limiting toxicities (DLTs).  For participants with treatment 
emergent Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing should be undertaken, eg, every 2-3 days. 
11. Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed per the schedule of activities
and as clinically indicated after baseline.  The list of required laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests.
12. Urinalysis: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed as clinically indicated after 
baseline.  The list of required urine laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
13. Pregnancy Test: Pregnancy tests (serum/urine) for female participants of childbearing potential.  Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations.  FSH will be done at Screening only in females who are 
amenorrheic for at least 12 consecutive months.  See Section 8.2.5 Pregnancy Testing for further details.
14. Viral disease screening tests: Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Total Hepatitis B Core Ab (anti-HBc), Hepatitis B Surface Ab 
(anti-HBs) as clinically indicated IgM antibody to hepatitis B core antigen (IgM anti-HBc), HCV Ab, and HIV to be conducted by local laboratory where 
required by local regulations or if warranted by participant history.
15. Registration: Participant identification number and dose level allocation to be operated by the Sponsor (see Section 6.3.1 Allocation to Investigational 
Product). Allocation to Investigational Product).
16. PF-06939999 treatment: Initially PF-06939999 will be administered as a single agent, orally, once daily (QD) for the first cohort then twice a day (BID) or 
daily (QD) for all subsequent cohorts in 28 day cycles on a continuous basis.  Additional dosing frequency may be considered in the study if supported by 
emerging clinical data.  Treatment will continue until PD, unacceptable toxicity or participant refusal, whichever occurs first.  If PD occurs during treatment, 
continuation of study drug may continue, under the following conditions: (a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant 
toxicity; and (c) after discussion with the Sponsor.  The participant will be reminded not to take their morning dose at home on PK days, but to bring their 
bottle into clinic so that study drug may be administered after study visit assessments are completed, and PK samples have been collected.  
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites (eg, including CT or MRI of neck with contrast for HNSCC). CT 
or MRI scans are to be performed every 8 weeks for the first 6 months, then every 12 weeks until the end of the safety follow up visit or participant 
withdrawal from the study. Efficacy assessments start on Cycle 2 Day 28.  The allowable time window for disease assessments is ±7 days while on 
treatment and up to 7 days for screening (ie, the screening time window is up to 35 days prior to registration).  Brain CT or MRI scan for participants with 
known or suspected brain metastases; bone scan and/or bone X-rays for participants with known or suspected bone metastases.  Tumor assessment should be 
repeated at the end of treatment visit if more than 8 weeks have passed since the last evaluation.  When the study treatment is discontinued for reasons other 
than disease progression or participant refusal, participants will be followed and have tumor assessments performed every 8 weeks until (a) disease 
progression or death, (b) participant refusal or (c) start of another anti-cancer treatment, whichever occurs first.  Tumor assessments should be fixed 
according to the calendar, regardless of treatment delays. 


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18. Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent, which is obtained before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving investigational product), through and including a minimum of 28 calendar days after the last administration of the investigational 
product.  For participants who are screen failures, the active collection period ends when screen failure status is determined.  See Section 8.3.1.
19. Concomitant Medications: Concomitant medications and treatments must be recorded on the CRF.
20. Archival or de novo Tumor Biopsy: Tumor biospecimens from archival and/or de novo biopsies will be required at study entry.  Post-treatment biopsies are 
not required for Part 1.  A summary of planned analysis for core needle biopsies is provided in Section 8.8.1.
21. End of Treatment or for early discontinuation: Obtain these assessments if not completed in the last week.  Tumor assessment should be repeated at the end 
of treatment visit if more than 8 weeks have passed since the last evaluation.
22. Safety follow up visit: At least 28 days, and no more than 35 days after discontinuation of treatment, participants will return to undergo review of 
concomitant medications and assessment for resolution of any treatment related toxicity.  Participants continuing to experience toxicity 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.  
When the study treatment is discontinued for reasons other than disease progression or participant refusal, participants will be followed and have tumor 
assessments performed every 8 weeks until (a) disease progression or death, (b) participant refusal or (c) start of another anti-cancer treatment, (whichever 
occurred first).


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Final Protocol Amendment 3, 11 Jun 2020 
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Table 2.
Study Related Procedures: Part 1B (dose finding PF-06939999 + docetaxel)
Screen1
(28 days)
Cycle 1
(21 days)
Cycle 2
(21 days)
Subsequent 
Cycles
(21 Days per 
cycle)
End of 
Treatment 
(EOT)21
Safety 
Follow-
Up Visit22
Long-
Term 
Survival 
Follow-
up23
Protocol Activity
Day 1
Day 2
Day 8
Day 15
Day 16
Day 1
Day 8
Day 1
Visit Window
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Informed Consent2
X
Medical History3
X
Physical Examination4
X
X
X
X
X
X
X
X
X
Baseline Signs and 
Symptoms5
X
Height
X
Weight
X
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status7
X
X
X
X
X
Contraception check8
X
X
X
X
X
12-lead ECG
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1B
Laboratory Studies
Hematology9
X
X
X
X
X
X
X
X
X
Reticulocyte count9
X
X
X
Blood Chemistry10
X
X
X
X
X
X
X
X
X
Coagulation11
X
X
X
X
X
X
Urinalysis11
X
X
X
X
Pregnancy Test12
X
X
X
X
Viral disease screen 
Hepatitis B, C, and HIV 
tests]13
X
Registration and Treatments
Registration14
X


PF-06939999
Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
PFIZER CONFIDENTIAL
Page 38
Table 2.
Study Related Procedures: Part 1B (dose finding PF-06939999 + docetaxel)
Screen1
(≤28 days)
Cycle 1
(21 days)
Cycle 2
(21 days)
Subsequent 
Cycles
(21 Days per 
cycle)
End of 
Treatment 
(EOT)21
Safety 
Follow-
Up Visit22
Long-
Term 
Survival 
Follow-
up23
Protocol Activity
Day 1
Day 2
Day 8
Day 15
Day 16
Day 1
Day 8
Day 1
Visit Window
±2 days
±2 days
±2 days
±2 days
±2 days
±2 days
Docetaxel treatment15
X
X
X
PF-06939999 
Treatment16
Day 1 to Day 21
Day 1 to Day 21
Day 1 to Day 21
Tumor Assessments
CT or MRI Scans17
X
Every 6 weeks for the first 9 months, then every 12 weeks. See footnote 17
Other Clinical Assessments
Serious and Non-serious 
Adverse Event 
Monitoring18
X
Concomitant 
Medications19
X
X
X
X
X
X
X
X
Archival or De Novo 
Tumor Biopsy20
X
X (C3 only, 
optional)
Other Laboratory Assessments
Blood for Biomarker 
Analyses
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1B
Plasma for PF-06939999 
PK and 
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1B
Banked Biospecimen
See Table 6 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1B
Other Assessments
28- to 35-day Follow-up
X
Overall Survival
X
Footnotes (Schedule of Activities) 
1.
Screening: To be conducted within 28 days prior to treatment start. 
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
CCI


PF-06939999
Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
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Page 39
3.
Medical History: To include smoking, alcohol abuse (ETOH) and human papilloma virus (HPV) status, date of diagnosis or primary disease and information 
on prior anti-tumor treatments, surgeries, radiotherapy and recurrence date as as well as prior tumor genomic testing resport if available.
4.
Physical Examination: Examination of major body systems including body weight.  Height is measured at screening visit only. 
5.
Baseline Signs and Symptoms: Participants will be asked about any signs and symptoms experienced within 14 days prior to C1D1.  
6.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position or semi-recumbent position (however the 
position should be maintainted throughout the study) after approximately 5 minutes of rest.
7.
ECOG Performance Status: ECOG performance scale is available in Section 10.10 Appendix 10.
8.
The participant will be informed of the need to use highly effective contraception consistently and correctly.  The conversation and participant’s affirmation 
will be documented in the participant’s chart.
9.
Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. Grade ≥3 thrombocytopenia should trigger a 
blood smear for differential. Reticulocyte count should be performed per schedule of acitivity. In addition, Grade≥3 anemia should trigger a recticulcyte 
count if not done within 7 days. The list of required laboratory tests is provided in Section 10.2 Appendix 2. 
10. Blood Chemistry: All chemistry laboratory tests included in Section 10.2 Appendix 2 are required at every protocol chemistry required time point.  No need 
to repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date.  Liver function tests, creatinine and 
amylase/lipase must be checked on Cycle 1 Days 8 and,15 and on Cycle2 Days 1 and 8 to assess for events qualifying as  dose limiting toxicities (DLTs).  
For participants with treatment emergent Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing should be 
undertaken, eg, every 2-3 days.  Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be 
performed per the schedule of activities and as clinically indicated after baseline.  The list of required laboratory tests is provided in Section 10.2 Appendix 
2: Clinical Laboratory Tests.
11. Urinalysis: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed as clinically indicated after 
baseline.  The list of required urine laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
12. Pregnancy Test: Pregnancy tests (serum/urine) for female participants of childbearing potential.  Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations.  FSH will be done at Screening only in females who are 
amenorrheic for at least 12 consecutive months.  See Section 8.2.5 Pregnancy Testing for further details.
13. Viral disease screening tests: Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Total Hepatitis B Core Ab (anti-HBc), Hepatitis B Surface Ab 
(anti-HBs) as clinically indicated IgM antibody to hepatitis B core antigen (IgM anti-HBc), HCV Ab, and HIV to be conducted by local laboratory where 
required by local regulations or if warranted by participant history.
14. Registration: Participant identification number and dose level allocation to be operated by the Sponsor (see Section 6.3.1 Allocation to Investigational 
Product).
15. Docetaxel will be administered at 75 mg/m2 intravenously over 1 hour on Day 1 of each 21 day cycle until disease progression unacceptable toxicity or 
participant refusal, whichever occurs first,  All participants should be premedicated with oral corticosteroids such as dexamethasone 16 mg per day (eg, 8 mg 
BID) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions. Participants should be observed closely for hypersensitivity reactions, especially during the first and second infusions.
16. PF-06939999 treatment: Initially PF-06939999 will be administered as a single agent, orally, once daily (QD) or twice a day (BID) in 21 day cycles on a 
continuous basis.  Treatment will continue until PD, unacceptable toxicity or participant refusal, whichever occurs first.  If PD occurs during treatment, 
continuation of study drug may continue, under the following conditions: (a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant 
toxicity; and (c) after discussion with the Sponsor.  The participant will be reminded not to take their morning dose at home on PK days, but to bring their 
bottle into clinic so that study drug may be administered after study visit assessments are completed, and PK samples have been collected.  


PF-06939999
Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
PFIZER CONFIDENTIAL
Page 40
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites (eg, including CT or MRI of neck with contrast for HNSCC). CT 
or MRI scans are to be performed every 6 weeks for the first 9 months, then every 12 weeks until the end of safety follow up visit or participant withdrawal 
from the study. Efficacy assessments start on Cycle 2 Day 21.  The allowable time window for disease assessments is ±7 days while on treatment and up to 
7 days for screening (ie, the screening time window is up to 35 days prior to registration).  Brain CT or MRI scan for participants with known or suspected 
brain metastases; bone scan and/or bone X-rays for participants with known or suspected bone metastases.  Tumor assessment should be repeated at the end 
of treatment visit if more than 6 weeks have passed since the last evaluation.  When the study treatment is discontinued for reasons other than disease 
progression or participant refusal, participants will be followed and have tumor assessments performed every 8 weeks until (a) disease progression or death, 
(b) participant refusal or (c) start of another anti-cancer treatment, whichever occurs first.  Tumor assessments should be fixed according to the calendar, 
regardless of treatment delays. 
18. Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent, which is obtained before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving investigational product), through and including a minimum of 28 calendar days after the last administration of the investigational 
product.  For participants who are screen failures, the active collection period ends when screen failure status is determined.  See Section 8.3.1.
19. Concomitant Medications: Concomitant medications and treatments must be recorded on the CRF.
20. Archival or de novo Tumor Biopsy: Tumor biospecimens from archival and/or de novo biopsies will be required at study entry.  Post-treatment biopsies are 
not required for Part 1B. A summary of planned analysis for core needle biopsies is provided in Section 8.8.1.
21. End of Treatment or for early discontinuation: Obtain these assessments if not completed in the last week.  Tumor assessment should be repeated at the end 
of treatment visit if more than 8 weeks have passed since the last evaluation.
22. Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment, participants will return to undergo review of concomitant 
medications and assessment for resolution of any treatment related toxicity.  Participants continuing to experience toxicity 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.  When the study 
treatment is discontinued for reasons other than disease progression or participant refusal, participants will be followed and have tumor assessments 
performed every 8 weeks until (a) disease progression or death, (b) participant refusal or (c) start of another anti-cancer treatment, (whichever occurred first).
23. Long term survival follow up: Participants in Part 2 dose expansion cohorts will be contacted by telephone every 12 weeks for survival data collection until 
end of trial (2 years from last participant’s first dose).


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Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
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Page 41
Table 3.
Study Related Procedures: Part 2A, 2B, and 2C (dose expansion, monotherapy) 
Screen1
(28 days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
End of 
Treatment 
(EOT)22
Safety 
Follow-
Up Visit23
Long-Term 
Survival 
Follow-up24
Protocol Activity
Day 1
Day 8
Day 15
Day 16a
Day 17a
Day 22
Day 1
Day 15
Visit Window
±2 days
±2 days
±2 days
±2 days
±2 days
Informed Consent2
X
Medical History3
X
Physical Examination4
X
X
X
X
X
X
X
X
Baseline Signs and 
Symptoms5
X
Height
X
Weight
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
X
ECOG Performance Status7
X
X
X
X
NSCLC-SAQ and PGIS8
X
X
X(C2D1, 
and C4D1 
only)
X
Contraception check9
X
X
X
X
12-lead ECG
See Table 7 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule
See Table 8 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Parts 2A and 2B participants in the 
food effect assessment
Laboratory Studies
Hematology10
X
X
X
X
X
X
X
X
X
Reticulocyte count10
X
X
Blood Chemistry11
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
Urinalysis13
X
X
X
X
Pregnancy Test14
X
X
X
X
Viral disease screen Hepatitis 
B, C, and HIV tests]15
X
Registration and Treatments


PF-06939999
Protocol C3851001
Final Protocol Amendment 3, 11 Jun 2020 
PFIZER CONFIDENTIAL
Page 42
Table 3.
Study Related Procedures: Part 2A, 2B, and 2C (dose expansion, monotherapy) 
Screen1
(≤28 days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
End of 
Treatment 
(EOT)22
Safety 
Follow-
Up Visit23
Long-Term 
Survival 
Follow-up24
Protocol Activity
Day 1
Day 8
Day 15
Day 16a
Day 17a
Day 22
Day 1
Day 15
Visit Window
±2 days
±2 days
±2 days
±2 days
±2 days
Registration16
X
PF-06939999 Treatment17
Day 1 to Day 28
Day 1 to Day 28
Tumor Assessments
CT or MRI Scans18
X
Every 8 weeks for the first 12 months, then every 12 weeks. See footnote 18
X
Other Clinical Assessments
Serious and Non-serious 
Adverse Event Monitoring19
X
Concomitant Medications20
X
X
X
X
X
X
X
X
X
X
X
Archival or De Novo Tumor 
Biopsy21
X
X (C3 only 
from 5 
participants/
arm)
Other Laboratory Assessments
Blood for Biomarker 
Analyses
See Table 7 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule
See Table 8 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Parts 2A and 2B participants in the 
food effect assessment
Plasma for PF-06939999 PK 
and 
See Table 7 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule
See Table 8 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Parts 2A and 2B participants in the 
food effect assessment
Banked Biospecimen
See Table 7 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule
See Table 8 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Parts2A and 3B participants in the food 
effect assessment
Other Assessments
28- to 35-day Follow-up
X
Overal Survival 
X
CCI


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Final Protocol Amendment 3, 11 Jun 2020 
PFIZER CONFIDENTIAL
Page 43
Table 3.
Study Related Procedures: Part 2A, 2B, and 2C (dose expansion, monotherapy) 
Screen1
(≤28 days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
End of 
Treatment 
(EOT)22
Safety 
Follow-
Up Visit23
Long-Term 
Survival 
Follow-up24
Protocol Activity
Day 1
Day 8
Day 15
Day 16a
Day 17a
Day 22
Day 1
Day 15
Visit Window
±2 days
±2 days
±2 days
±2 days
±2 days
Abbreviations: ɦ ongoing/continuous event; C = Cycle; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
MRI = magnetic resonance imaging; 
Footnotes (Schedule of Activities) 
a.
Days 16 and 17 are displayed in the table for Cycle 1 only to correspond with PK collection days for participants in the food effect cohort only.  No clinical 
assessments required.
1.
Screening: To be conducted within 28 days prior to treatment start. 
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
3.
Medical History: To include smoking, alcohol abuse (ETOH) and human papilloma virus (HPV) status, date of diagnosis or primary disease and information 
on prior anti-tumor treatments, surgeries, radiotherapy and recurrence date as as well as prior tumor genomic testing resport if available.
4.
Physical Examination: Examination of major body systems including body weight.  Height is measured at screening visit only. 
5.
Baseline Signs and Symptoms: Participants will be asked about any signs and symptoms experienced within 14 days prior to C1D1.  
6.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position or semi-recumbent position (however the 
position should be maintainted throughout the study) after approximately 5 minutes of rest.
7.
ECOG Performance Status: ECOG performance scale is available in Section 10.10 Appendix 10.
8.
PROs: Only NSCLC participants (Parts 2A and, 2D) will complete the NSCLC-SAQ and the patient global impression of severity (PGIS).
9.
Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. Grade ≥3 thrombocytopenia should trigger a 
blood smear for differential. Reticulocyte count should be performed per schedule of acitivity. In addition, Grade ≥3 anemia should trigger a recticulcyte 
count if not done within 7 days. The list of required laboratory tests is provided in Section 10.2 Appendix 2 (Table 15). 
10. Blood Chemistry: All chemistry laboratory tests included in Section 10.2 Appendix 2 (Table 15) are required at every protocol chemistry required time 
point.  No need to repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date.  Liver function tests, creatinine 
and amylase/lipase must be checked on Cycle 1 Days 8 and,15 and on Cycle2 Days 1 and 8 to assess for events qualifying as dose limiting toxicities (DLTs).  
For participants with treatment emergent Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing should be 
undertaken, eg, every 2-3 days.  
11. Blood Chemistry: All chemistry laboratory tests included in Section 10.2 Appendix 2: Clinical Laboratory Tests (Table 15) are required at every protocol 
chemistry required time point.  No need to repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date.  During 
Cycle 1, liver function tests, creatinine and amylase/lipase must be checked on Days 8, 15 and 22 to assess for events qualifying as dose limiting toxicities 
(DLTs).  For participants with treatment emergent Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing 
should be undertaken, eg, every 2-3 days.
CCI


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Final Protocol Amendment 3, 11 Jun 2020 
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Page 44
12. Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed per the schedule of activities
and as clinically indicated after baseline.  The list of required laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests.
13. Urinalysis: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed as clinically indicated after 
baseline.  The list of required urine laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
14. Pregnancy Test: Pregnancy tests (serum/urine) for female participants of childbearing potential.  Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations.  FSH will be done at Screening only in females who are 
amenorrheic for at least 12 consecutive months.  Section 10.2 Appendix 2 Pregnancy Testing for further details.
15. Viral disease screening tests: Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Total Hepatitis B Core Ab (anti-HBc), Hepatitis B Surface Ab 
(anti-HBs) as clinically indicated IgM antibody to hepatitis B core antigen (IgM anti-HBc), HCV Ab, and HIV to be conducted by local laboratory where 
required by local regulations or if warranted by participant history.
16. Registration: Participant identification number and dose level allocation to be operated by the Sponsor (see Section 6.3.1 Allocation to Investigational 
Product).
17. PF-06939999 treatment: Initially PF-06939999 will be administered as a single agent, orally, once daily (QD) or twice a day (BID) in 28 day cycles on a 
continuous basis.  Treatment will continue until PD, unacceptable toxicity or participant refusal, whichever occurs first.  If PD occurs during treatment, 
continuation of study drug may continue, under the following conditions: (a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant 
toxicity; and (c) after discussion with the Sponsor.  The participant will be reminded not to take their morning dose at home on PK days, but to bring their 
bottle into clinic so that study drug may be administered after study visit assessments are completed, and PK samples have been collected.  
18. Tumor Assessments: Tumor assessments will include all known or suspected disease sites (eg, including CT or MRI of neck with contrast for HNSCC). CT 
or MRI scans are to be performed every 8 weeks for the first 12 months, then every 12 weeks until the end of safety follow up visit or participant withdrawal 
from the study. Efficacy assessments start on Cycle 2 Day 28.  The allowable time window for disease assessments is ±7 days while on treatment and up to 
7 days for screening (ie, the screening time window is up to 35 days prior to registration).  Brain CT or MRI scan for participants with known or suspected 
brain metastases; bone scan and/or bone X-rays for participants with known or suspected bone metastases.  Tumor assessment should be repeated at the end 
of treatment visit if more than 8 weeks have passed since the last evaluation.  When the study treatment is discontinued for reasons other than disease 
progression or participant refusal, participants will be followed and have tumor assessments performed every 8 weeks until (a) disease progression or death, 
(b) participant refusal or (c) start of another anti-cancer treatment, whichever occurs first.  Tumor assessments should be fixed according to the calendar, 
regardless of treatment delays. 
19. Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent, which is obtained before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving investigational product), through and including a minimum of 28 calendar days after the last administration of the investigational 
product.  For participants who are screen failures, the active collection period ends when screen failure status is determined.  See Section 8.3.1.
20. Concomitant Medications: Concomitant medications and treatments must be recorded on the CRF.
21. Archival or de novo Tumor Biopsy: Tumor biospecimens from archival and/or de novo biopsies will be required at study entry.  Post-treatment biopsies are 
not required for Part 2 but up to 5 participants from each study arm will be strongly recommended to provide de novo post-treatment tumor biopsies at cycle 
3 day 1 if state, local, and institutional policies allow. A summary of planned analysis for core needle biopsies is provided in Section 8.8.1.
22. End of Treatment or for early discontinuation: Obtain these assessments if not completed in the last week.  Tumor assessment should be repeated at the end 
of treatment visit if more than 8 weeks have passed since the last evaluation.


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23. Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment, participants will return to undergo review of concomitant 
medications and assessment for resolution of any treatment related toxicity. Participants continuing to experience toxicity 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.  When the study 
treatment is discontinued for reasons other than disease progression or participant refusal, participants will be followed and have tumor assessments 
performed every 8 weeks until (a) disease progression or death, (b) participant refusal or (c) start of another anti-cancer treatment, (whichever occurred first).
24. Long term survival follow up: Participants in Part 2 dose expansion cohorts will be contacted by telephone every 12 weeks for survival data collection until 
end of trial (2 years from last participant’s first dose).


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Table 4.
Study Related Procedures: Part 2D (dose expansion, PF-06939999 + docetaxel)
Screen1
(28 days)
Cycle 1
(21 days)
Subsequent 
Cycles
(21 Days per 
cycle)
End of 
Treatment 
(EOT)23
Follow-up24
Long-Term 
Survival 
Follow-up25
Protocol Activity
Day 1
Day 8
Day 15
Day 1
Visit Window
±2 day
±2 day
±2 days
Informed Consent2
X
Medical History3
X
Physical Examination4
X
X
X
X
X
X
X
Baseline Signs and Symptoms5
X
Height
X
Weight
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
ECOG Performance Status7
X
X
X
X
NSCLC-SAQ and PGIS8
X
X
X(C2D1, and 
C4D1 only)
X
Contraception check9
X
X
X
X
12-lead ECG
See Table 9 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2D
Laboratory Studies
Hematology10
X
X
X
X
X
X
X
Reticulocyte count10
X
X
Blood Chemistry11
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
Urinalysis13
X
X
X
X
Pregnancy Test14
X
X
X
X
Viral disease screen [Hepatitis 
B, C, and HIV tests]15
X
Registration and Treatments
Registration16
X
PF-06939999 Treatment17
Day 1 to Day 21
Day 1 to Day 21
Docetaxel treatment18
X
X


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Table 4.
Study Related Procedures: Part 2D (dose expansion, PF-06939999 + docetaxel)
Screen1
(≤28 days)
Cycle 1
(21 days)
Subsequent 
Cycles
(21 Days per 
cycle)
End of 
Treatment 
(EOT)23
Follow-up24
Long-Term 
Survival 
Follow-up25
Protocol Activity
Day 1
Day 8
Day 15
Day 1
Visit Window
±2 day
±2 day
±2 days
Tumor Assessments
CT or MRI Scans19
Every 6 weeks for the first 9 months, then every 12 weeks. See footnote
Other Clinical Assessments
Serious and Non-serious 
Adverse Event Monitoring20
Concomitant Medications21
X
X
X
X
X
X
X
Archival or De Novo Tumor 
Biopsy22
X
X
(C3 only)
Other Laboratory Assessments
Blood for Biomarker Analyses
See Table 9 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2D
Plasma for PF-06939999 PK 
and 
See Table 9 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2D
Banked Biospecimen 
See Table 9 ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2D
Other Assessments
28- to 35-day Follow-up
X
Overal Survival 
X
Abbreviations: → ongoing/continuous event; C = Cycle; CT = computed tomography;CA-125 = cancer antigen 125 ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; 
Footnotes (Schedule of Activities) 
1.
Screening: To be conducted within 28 days prior to treatment start. 
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
3.
Medical History: To include date of diagnosis and information on prior anti-tumor treatments, surgeries, radiotherapy and recurrence date as as well as prior 
tumor genomic testing resport if available.
4.
Physical Examination: Examination of major body systems including body weight. Height is measured at screening visit only. 
5.
Baseline Signs and Symptoms: Participants will be asked about any signs and symptoms experienced within 14 days prior to C1D1.  
6.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position or semi-recumbent position (however the 
position should be maintainted throughout the study) after approximately 5 minutes of rest.
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7.
ECOG Performance Status: ECOG performance scale is available in Section 10.10 Appendix 10.
8.
PROs: Only NSCLC participants (cohorts 2A, 2D) will complete the NSCLC-SAQ and the patient global impression of severity (PGIS). 
9.
The participant will be informed of the need to use highly effective contraception consistently and correctly.  The conversation and participant’s affirmation 
will be documented in the participant’s chart.
10. Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. Grade ≥ 3 thrombocytopenia should trigger a 
blood smear for differential. Reticulocyte count should be performed per schedule of acitivity. In addition, Grade≥ 3 anemia should trigger a recticulcyte 
count if not done within 7 days.The list of required laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
11. Blood Chemistry: All chemistry laboratory tests included in Section 10.2 Table 15) are required at every protocol chemistry required time point.  No need to 
repeat full blood chemistry on C1D1 if screening assessment performed within 7 days prior to that date. Liver function tests, creatinine and amylase/lipase 
must be checked on Cycle 1 Days 8 and 15, and on Cycle2 Days 1 and 8 to assess assess for events qualifying as dose limiting toxicities (DLTs).  For 
participants with treatment emergent Grade ≥3 AST/ALT, close clinical monitoring with an increased frequency of relevant blood testing should be 
undertaken, eg, every 2-3 days.  
12. Coagulation: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed per the schedule of activities
and as clinically indicated after baseline.  The list of required laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests.
13. Urinalysis: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  To be performed as clinically indicated after 
baseline.  The list of required urine laboratory tests is provided in Section 10.2 Appendix 2: Clinical Laboratory Tests. 
14. Pregnancy Test: Pregnancy tests (serum/urine) for female participants of childbearing potential.  Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations.  FSH will be done at Screening only in females who are 
amenorrheic for at least 12 consecutive months.  See Section 8.2.5 Pregnancy Testing for further details.
15. Viral disease screening tests: Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Total Hepatitis B Core Ab (anti-HBc), Hepatitis B Surface Ab 
(anti-HBs) as clinically indicated IgM antibody to hepatitis B core antigen (IgM anti-HBc), HCV Ab, and HIV to be conducted by local laboratory where 
required by local regulations or if warranted by participant history.
16. Registration: Participant identification number and dose level allocation to be operated by the Sponsor (see Section 6.3.1 Allocation to Investigational 
Product). 
17. PF-06939999 treatment: Initially PF-06939999 will be administered as a single agent, orally, once daily (QD) or twice a day (BID) in 21 day cycles on a 
continuous basis.  Treatment will continue until PD, unacceptable toxicity or participant refusal, whichever occurs first.  If PD occurs during treatment, 
continuation of study drug may continue, under the following conditions: (a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant 
toxicity; and (c) after discussion with the Sponsor.  The participant will be reminded not to take their morning dose at home on PK days, but to bring their 
bottle into clinic so that study drug may be administered after study visit assessments are completed, and PK samples have been collected.  
18. Docetaxel will be administered at 75 mg/m2 intravenously over 1 hour on Day 1 of each 21 day cycle until disease progression, unacceptable toxicity or 
participant refusal, whichever occurs first. All participants should be premedicated with oral corticosteroids such as dexamethasone 16 mg per day (eg, 8 mg 
BID) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions. Participants should be observed closely for hypersensitivity reactions, especially during the first and second infusions.


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19. Tumor Assessments: Tumor assessments will include all known or suspected disease sites (eg, including CT or MRI of neck with contrast for HNSCC). CT 
or MRI scans are to be performed every 6 weeks for the first 9 months, then every 12 weeks until the end of safety follow up visit or participant withdrawal 
from the study. Efficacy assessments start on Cycle 2 Day 21.  The allowable time window for disease assessments is ±7 days while on treatment and up to 
7 days for screening (ie, the screening time window is up to 35 days prior to registration).  Brain CT or MRI scan for participants with known or suspected 
brain metastases; bone scan and/or bone X-rays for participants with known or suspected bone metastases.  Tumor assessment should be repeated at the end 
of treatment visit if more than 6 weeks have passed since the last evaluation.  When the study treatment is discontinued for reasons other than disease 
progression or participant refusal, participants will be followed and have tumor assessments performed every 8 weeks until (a) disease progression or death, 
(b) participant refusal or (c) start of another anti-cancer treatment, whichever occurs first.  Tumor assessments should be fixed according to the calendar, 
regardless of treatment delays. 
20. Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each participant begins from the time the 
participant provides informed consent, which is obtained before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving investigational product), through and including a minimum of 28 calendar days after the last administration of the investigational 
product.  For participants who are screen failures, the active collection period ends when screen failure status is determined.  See Section 8.3.1.
21. Concomitant Medications: Concomitant medications and treatments must be recorded on the CRF.
22. Archival or de novo Tumor Biopsy: Tumor biospecimens from archival and/or de novo biopsies will be required at study entry.  Post-treatment biopsies are 
not required but up to 5 participants will be strongly recommended to provide on-treatment de novo tumor biopsy samples if state, local, and institutional 
policies allow.  A summary of planned analysis for core needle biopsies is provided in Section 8.8.1.
23. End of Treatment or for early discontinuation: Obtain these assessments if not completed in the last week.  Tumor assessment should be repeated at the end 
of treatment visit if more than 8 weeks have passed since the last evaluation.
24. Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment, participants will return to undergo review of concomitant 
medications and assessment for resolution of any treatment related toxicity.  Participants continuing to experience toxicity 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.  When the study 
treatment is discontinued for reasons other than disease progression or participant refusal, participants will be followed and have tumor assessments 
performed every 8 weeks until (a) disease progression or death, (b) participant refusal or (c) start of another anti-cancer treatment, (whichever occurred first).
25. Long term follow up: Participants in Part 2 dose expansion cohorts will be contacted by telephone every 12 weeks for survival data collection until end of 
trial (2 years from last participant’s first dose).


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Table 5.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 1A (dose escalation, PF-06939999 
monotherapy)
Screen
(≤28
days)
Cycle 1
(28 days)
Subsequent 
Cycles
(28 Days per 
cycle)
EOT
Protocol Activity
Day 1
Day 
2
Day 
8
Day 15
Day 
16
Day 
22
Day 1
Hours post dose*
Pre-
dose§
0.5
1
2
4
6
12
Pre-
dose
Pre-
dose§
Pre-
dose§
0.5
1
2
4
6
12
Pre-
dose
Pre-
dose§
Pre-dose§
Sample collection 
window†
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
±3h
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
±3h
Plasma for 
PF-06939999 PK1
X
X
X
X
X
X
X2
X
X
X
X
X
X
X
X3
X
X
X
 
only)
Triplicate ECGs5
X
X
X
X
X
X
X
(C2 and C3 
Day 1; and 
anytime if 
clinically 
indicated)
X
Whole Blood for 
RNA Sequencing 
Analysis6
X
X
X (C2 and C3 
only)
X
Whole Blood for 
Germline mutation7
X
Archival or De 
Novo Tumor 
Biopsy8
X
C3 only 
(optional)
Banked 
Biospecimen9
X
*Collection Time: Sampling times are related to morning dose.
†Sample collection windows: All sampling should be within the protocol specified window in the table above. 
§Pre-dose sample collection: Within 3 hours prior to the morning dose of PF-06939999.
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Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1A).
1.
Pharmacokinetics: Blood samples for determination of plasma PF-06939999 drug concentrations will be collected at the time points specified (NOTE: PK 
sampling time points may change, pending PK data from early dose levels, but the total number of samples will remain the same).  Additional PK blood 
samples may be collected at time of occurrence of unexpected or serious adverse events.  On days when participants require predose PK sampling 
assessments, the morning dose of PF-06939999 should be held (NOT taken) prior to the study visit.  On those days, the PF-06939999 morning dose can then 
be taken after the predose PK sampling is obtained. 
2.
Trough sample after single dosing: Only one sample will be collected. The sample will be collected on Day 1 (within 12±3 h from the Day 1 first dose and 
prior to Day 1 second dose) for BID dosing regimen or Day 2 (within 24±3 h from the Day 1 dose and prior to Day 2 dose) for QD dosing regimen. 
3.
Trough sample after multiple dosing: Only one sample will be collected. The sample will be collected on Day 15 (within 12±3 h from the Day 15 first dose 
and prior to Day 15 second dose) for BID dosing regimen or Day 16 (within 24±3 h from the Day 15 dose and prior to Day 16 dose) for QD dosing regimen.
4.
.
5.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc and QRS 
intervals.  During Cycles 2 and 3, ECGs will be performed on Day 1.  After Cycle 3, ECGs can be performed as clinically indicated and will be required at 
the EOT visit.  All ECG collection time points are with respect to PF-06939999 morning dosing.  When coinciding with blood sample draws for 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 QTc is prolonged 
(value of >480 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation; further guidance is provided in Section 8.2.3.
6.
Whole blood will be collected for whole transcriptome RNA sequencing analysis according to the Laboratory/Study Manual.
7.
Whole Blood for Germline mutation will be collected for whole genome sequencing.
8.
Archival or de novo tumor tissue biopsy: Required for assessing splicing factors, alternative RNA splicing patterns and/or immunohistochemistry (IHC). 
Blood DNA needed as normal reference.  Post-treatment Archival or de novo tumor tissue biopsy samples are optional but not required for Part 1.  Archival 
tumor tissue samples less than 6 months old are preferred but also accept older samples. 
9.
Banked Biospecimen: Blood samples for banked biospecimens Prep D1 (4 mL K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected at C1D1 (Pre-dose) as described in the Central Laboratory Manual.  Participants will be asked to indicate on the consent form whether they will 
allow this sample to be also used for the Optional Pharmacogenomic Research as described in the Section 10.5, Appendix 5.
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Table 6.
ECG, Pharmacokinetic (PK) and Biomarker Sampling Schedule for Part 1B (dose finding, PF-06939999 + 
docetaxel)
Screen
(≤28
days)
Cycle 1 (21 days)
Cycle 2 
(21 days)
Subsequent 
Cycles
(21 Days per 
cycle)
EOT 
Protocol Activity
Day 1
Day 
2
Day 
8
Day 15
Day 
16
Day 1
Day 1
Hours post dose*
Pre-
dose1
0.5
1
2
4
6
Pre-
dose
Pre-
dose1
Pre-
dose1
0.5
1
2
4
6
Pre-
dose
Pre-
dose1
1
Pre-dose
Sample collection 
window†
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
-5 
min
Plasma for 
PF-06939999 PK2
X
X
X
X
X
X
X3
X
X
X
X
X
X
X
X4
X
X
X
 
X
X
X5
Triplicate ECGs7
X
X
X
X
X
X
(C3 Day 1; 
and anytime 
if clinically 
indicated)
X
Whole Blood for RNA 
Sequencing Analysis8
X
X
X
X (C3 only)
X
Whole Blood for 
Germline mutation9
X
Archival or De Novo 
Tumor Biopsy10
X
C3 only 
(optional)
Banked Biospecimen11
X
*Collection Time: Sampling times are related to morning dose.
†Sample collection windows: All sampling should be within the protocol specified window in the table above. 
Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part 1B).
1.
Pre-dose sample collection: Within 3 hours prior to the morning dose of PF-06939999 (for PF-06939999 PK) or within 6 hours prior to the start of docetaxel 
infusion (for 
  
2.
Pharmacokinetics: Blood samples for determination of plasma PF-06939999 drug concentrations will be collected at the time points specified (NOTE: PK 
sampling time points may change, pending PK data from early dose levels, but the total number of samples will remain the same).  Additional PK blood 
samples may be collected at time of occurrence of unexpected or serious adverse events.  On days when participants require predose PK sampling 
assessments, the morning dose of PF-06939999 should be held (NOT taken) prior to the study visit.  On those days, the PF-06939999 morning dose can then 
be taken after the predose PK sampling is obtained. 
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3.
Trough sample after single dosing: The sample will be collected on Day 2 (within 24±3 h from the Day 1 dose and prior to Day 2 dose) for QD dosing 
regimen. 
4.
Trough sample after multiple dosing: The sample will be collected on Day 16 (within 24±3 h from the Day 15 dose and prior to Day 16 dose) for QD dosing 
regimen.
5.
The 1 hour sample for 
should be collected from the contra-lateral arm of docetaxel infusion within 5 minutes prior to the end of infusion.
6.
Blood for 
: Blood samples for determination of free 
 concentration will be measured at the time points specified.
7.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc and QRS 
intervals.  During Cycles 2 and 3, ECGs will be performed on Day 1.  After Cycle 3, ECGs can be performed as clinically indicated and will be required at 
the EOT visit.  All ECG collection time points are with respect to PF-06939999 morning dosing.  When coinciding with blood sample draws for 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 QTc is prolonged 
(value of >480 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation; further guidance is provided in Section 8.2.3.
8.
Whole blood will be collected for whole transcriptome 
 according to the Laboratory/Study Manual.
9.
Whole Blood for Germline mutation will be collected for whole genome sequencing.
10. Archival or de novo tumor tissue biopsy: Required for assessing splicing factors, alternative 
 and/or immunohistochemistry (IHC). 
Blood DNA needed as normal reference.  Post-treatment Archival or de novo tumor tissue biopsy samples are optional but not required for Part 1B.  
Archival tumor tissue samples less than 6 months old are preferred but also accept older samples. 
11. Banked Biospecimen: Blood samples for banked biospecimens Prep D1 (4 mL K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected at C1D1 (Pre-dose) as described in the Central Laboratory Manual.  Participants will be asked to indicate on the consent form whether they will 
allow this sample to be also used for the Optional Pharmacogenomic Research as described in the Section 10.5, Appendix 5.
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Table 7.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2A, Part 2B, and Part 2C (dose 
expansion, PF-06939999 monotherapy) (except for food effect sub-study)
Screen
(≤28
days)
Cycle 1
(28 days)
Subsequent Cycles
(28 Days per cycle)
EOT 
Protocol Activity
Day 1
Day 8
Day 15
Day 
22
Day 1
Hours post dose*
Pre-
dose1
0.5
1
2
4
Pre-
dose1
Pre-
dose1
0.5
1
2
4
Pre-
dose1
Pre-dose1
Sample collection 
window†
±3 min
±6 min
±12 
min
±24 
min
±3 min
±6 min
±12 
min
±24 
min
Plasma for 
PF-06939999 PK2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for 
PF-06939999 PK
Optional: See Section 8.5.2
Triplicate ECGs4
X
X
X
X
X
(C2 and C3 Day 1; 
and anytime if 
clinically indicated)
X
 
 
X
X
X
X (C2 only)
X
Whole Blood for 
Germline mutation6
X
Archival or De Novo 
Tumor Biopsy7
X
X (C3 only from 
5 participants/arm)
Banked Biospecimen8
X
*Collection Time: Sampling times are related to morning dose.
†Sample collection windows: All sampling should be within the protocol specified window in the table above. 
Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule).
1.
Pre-dose sample collection: Within 3 hours prior to the morning dose of PF-06939999.
2.
Pharmacokinetics: Blood samples for determination of plasma PF-06939999 drug concentrations will be collected at the time points specified (NOTE: PK 
sampling time points may change, pending PK data from early dose levels, but the total number of samples will remain the same).  Additional PK blood 
samples may be collected at time of occurrence of unexpected or serious adverse events.  On days when participants require predose PK sampling 
assessments, the morning dose of PF-06939999 should be held (NOT taken) prior to the study visit.  On those days, the PF-06939999 morning dose can then 
be taken after the predose PK sampling is obtained. 
3.
Blood for 
: Blood samples for determination of free 
 concentration will be measured at the time points specified.
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4.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc and QRS 
intervals.  During Cycles 2 and 3, ECGs will be performed on Day 1.  After Cycle 3, ECGs can be performed as clinically indicated and will be required at 
the EOT visit.  All ECG collection time points are with respect to PF-06939999 morning dosing.  When coinciding with blood sample draws for 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 QTc is prolonged 
(value of >480 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation; further guidance is provided in Section 8.2.3.
5.
Whole blood will be collected for whole transcriptome RNA sequencing analysis according to the Laboratory/Study Manual.
6.
Whole Blood for Germline mutation will be collected for whole genome sequencing.
7.
Archival or de novo tumor tissue biopsy: Required for assessing mutations in splicing factor genes, alternative RNA splicing patterns and/or 
immunohistochemistry (IHC) analysis. Blood DNA needed as normal reference.  Post-treatment Archival or de novo tumor tissue biopsy samples are not 
required but up to 5 participants from each study arm will be strongly recommended to provide de novo post-treatment tumor biopsies at cycle 3 day 1 if 
state, local, and institutional policies allow.  Archival tumor tissue samples less than 6 months old are preferred but also accept older samples. 
8.
Banked Biospecimen: Blood samples for banked biospecimens Prep D1 (4 mL K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected at C1D1 (Pre-dose) as described in the Central Laboratory Manual.  Participants will be asked to indicate on the consent form whether they will 
allow this sample to be also used for the Optional Pharmacogenomic Research as described in the Section 10.5, Appendix 5.


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Table 8. Food Effect Sub-study Participants: ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule
Screen
(≤28
days)
Cycle 1
(28 days)
Subsequent 
Cycles
(28 Days per 
cycle)
EOT
Protocol 
Activity
Day 
1
Day 
8
Day 15
Day 16
Day 
17
Day 
22
Day 1
Hours post 
dose*
Pre-
dose1
Pre-
dose1
Pre-
dose1
0.5
1
2
4
6
12
Pre-
dose1
0.5
1
2
4
6
12
Pre-
dose
Pre-
dose1
Pre-dose1
Sample 
collection 
window†
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
±3h
±3 
min
±6 
min
±12 
min
±24 
min
±36 
min
±3h
Plasma for 
PF-06939999 P
K2
X
X
X
X
X
X
X
X
X3
X
X
X
X
X
X
X4
X
X
X
 
 
Triplicate 
ECGs6
X
X
X
X
X
X
(C2 and C3 
Day 1; and 
anytime if 
clinically 
indicated)
X
 
 
X
X
X
X (C2 only)
X
Whole Blood 
for Germline 
mutation8
X
Archival or De 
Novo Tumor 
Biopsy9
X
X (C3 only 
from
5 participants
Banked 
Biospecimen10
X
X
X
*Collection Time: Sampling times are related to morning dose.
†Sample collection windows: All sampling should be within the protocol specified window in the table above. 
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Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule)
1.
Pre-dose sample collection: Within 3 hours prior to the morning dose of PF-06939999.
2.
Pharmacokinetics: Blood samples for determination of plasma PF-06939999 drug concentrations will be collected at the time points specified.  Additional 
PK blood samples may be collected at time of occurrence of unexpected or serious adverse events.  On days when participants require predose PK sampling 
assessments, the dose of PF-06939999 should be held (NOT taken) prior to the study visit.  On those days, the PF-06939999 dose will be taken after the 
predose PK sampling is obtained. 
3.
For BID dosing regimen only: The trough sample will be collected on Day 15 (within 12±3 h from the Day 15 first dose and prior to Day 15 second dose) 
for BID dosing regimen.
4.
Trough sample after Day 16 dosing: Only one sample will be collected. The sample will be collected on Day 16 (within 12±3 h from the Day 16 first dose 
and prior to Day 16 second dose) for BID dosing regimen or Day 17 (within 24±3 h from the Day 16 dose and prior to Day 17 dose) for QD dosing regimen.
5.
Blood for
: Blood samples for determination of free 
 concentration will be measured at the time points specified.
6.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc and QRS 
intervals.  During Cycles 2 and 3, ECGs will be performed on Day 1.  After Cycle 3, ECGs can be performed as clinically indicated and will be required at 
the EOT visit.  All ECG collection time points are with respect to PF-06939999 morning dosing.  When coinciding with blood sample draws for 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 QTc is prolonged 
(value of >480 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation; further guidance is provided in Section 8.2.3.
7.
Whole blood will be collected for whole transcriptome 
 according to the Laboratory/Study Manual.
8.
Whole Blood for Germline mutation will be collected for whole genome sequencing.
9.
Archival or de novo tumor tissue biopsy: Required for assessing mutations in splicing factor genes, alternative 
 and/or 
immunohistochemistry (IHC) analysis. Blood DNA needed as normal reference.  Post-treatment archival or de novo tumor tissue biopsy samples are not 
required but up to 5 participants will be strongly recommended to provide de novo post-treatment tumor biopsies at cycle 3 day 1 if state, local, and
institutional policies allow.  Archival tumor tissue samples less than 6 months old are preferred but older samples will also be accepted. 
10. Banked Biospecimen: Blood samples for banked biospecimens Prep D1 (4 mL K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected at C1D1 (Pre-dose) as described in the Central Laboratory Manual.  Participants will be asked to indicate on the consent form whether they will 
allow this sample to be also used for the Optional Pharmacogenomic Research as described in the Section 10.5, Appendix 5.
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Table 9.
ECG, Pharmacokinetic (PK), and Biomarker Sampling Schedule for Part 2D (dose expansion, PF-06939999 + 
docetaxel)
Scree
n
(≤28
days)
Cycle 1
(21 days)
Cycle 2
(21 days)
Subsequent Cycles
(21 Days per 
cycle)
EOT 
Protocol Activity
Day 1
Day 8
Day 15
Day 1
Day 1
Hours post dose*
Pre-
dose1
0.5
1
2
4
Pre-
dose1
Pre-
dose1
0.5
1
2
4
Pre-
dose1
1
Pre-dose1
Sample collection 
window†
±3 
min
±6 
min
±12 
min
±24 
min
±3 
min
±6 min
±12 min
±24 min
-5 
min
Plasma for 
PF-06939999 PK2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
X
X
X3
Triplicate ECGs5
X
X
X
X
X
X
(C3 Day 1; and 
anytime if 
clinically 
indicated)
X
 
 
X
X
X
X
X
Whole Blood for 
Germline 
mutation7
X
Archival or De 
Novo Tumor 
Biopsy8
X
X (C3 only from 
5 participants)
Banked 
Biospecimen9
X
*Collection Time: Sampling times are related to morning dose.
†Sample collection windows: All sampling should be within the protocol specified window in the table above. 
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Footnotes (Pharmacokinetic and Pharmacodynamic Sampling Schedule).
1.
Pre-dose sample collection: Within 3 hours prior to the morning dose of PF-06939999 (for PF-06939999 PK) or within 6 hours prior to the start of 
 
.  
2.
Pharmacokinetics: Blood samples for determination of plasma PF-06939999 drug concentrations will be collected at the time points specified (NOTE: PK 
sampling time points may change, pending PK data from early dose levels, but the total number of samples will remain the same).  Additional PK blood 
samples may be collected at time of occurrence of unexpected or serious adverse events.  On days when participants require predose PK sampling 
assessments, the morning dose of PF-06939999 should be held (NOT taken) prior to the study visit.  On those days, the PF-06939999 morning dose can then 
be taken after the predose PK sampling is obtained. 
3.
The 1 hour sample for 
 should be collected from the contra-lateral arm of docetaxel infusion within 5 minutes prior to the end of infusion.
4.
Blood for 
: Blood samples for determination of free 
 concentration will be measured at the time points specified.
5.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc and QRS 
intervals.  During Cycles 2 and 3, ECGs will be performed on Day 1.  After Cycle 3, ECGs can be performed as clinically indicated and will be required at 
the EOT visit.  All ECG collection time points are with respect to PF-06939999 morning dosing.  When coinciding with blood sample draws for 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 QTc is prolonged 
(value of >480 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation; further guidance is provided in Section 8.2.3.
6.
Whole blood will be collected for whole transcriptome RNA sequencing analysis according to the Laboratory/Study Manual.
7.
Whole Blood for Germline mutation will be collected for whole genome sequencing.
8.
Archival or de novo tumor tissue biopsy: Required for assessing mutations in splicing factor genes, alternative RNA splicing patterns and/or 
immunohistochemistry (IHC) analysis. Blood DNA needed as normal reference.  Post-treatment Archival or de novo tumor tissue biopsy samples are not 
required but up to 5 participants will be strongly recommended to provide de novo post-treatment tumor biopsies at cycle 3 day 1 if state, local, and 
institutional policies allow.  Archival tumor tissue samples less than 6 months old are preferred but also accept older samples. 
9.
Banked Biospecimen: Blood samples for banked biospecimens Prep D1 (4 mL K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected at C1D1 (Pre-dose) as described in the Central Laboratory Manual.  Participants will be asked to indicate on the consent form whether they will 
allow this sample to be also used for the Optional Pharmacogenomic Research as described in the Section 10.5, Appendix 5.
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2. INTRODUCTION
PF-06939999 is an orally available small molecule inhibitor of protein arginine 
methyltransferase 5 (PRMT5) that is investigated in participants with advanced or metastatic 
head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), 
esophageal, endometrial, cervical and bladder cancer.  
2.1. Study Rationale 
This is a first-in-human clinical study of PF-06939999. The study is divided into 2 parts: 
dose escalation (Part 1) followed by dose expansion (Part 2). The purpose of Part 1 (dose 
escalation) is to evaluate the safety, pharmacokinetics, and pharmacodynamics of escalating 
doses of PF-06939999 in participants with advanced or metastatic HNSCC, NSCLC, 
esophageal, endometrial, cervical, and bladder cancer and determine the maxium tolerable 
dose (MTD) and recommended dose for expansion (RP2D).
The purpose of Part 2 (dose expansion) is to further evaluate the safety and tolerability of 
PF-06939999 at RP2D as well as preliminary clinical efficacy in advanced or metastatic 
NSCLC, urothelial carcinoma (bladder cancer) and HNSCC.
2.2. Background
PF-06939999 is an orally available small molecule inhibitor of protein arginine 
methyltransferase 5 (PRMT5).  PRMT5 over-expression in hematologic malignancies and 
solid tumors promotes methylation of protein substrates that activate a variety of biological 
functions known to be dysregulated in cancer.  Inhibition of PRMT5 leads to growth arrest 
and cell death in tumors that harbor alterations in mRNA splicing pathways. PF-06939999
has potent cellular effects as measured by its ability to reduce 
 
levels of splicing regulators resulting in growth arrest in multiple hematologic and 
solid tumor cell lines. In this study PF-06939999 is being investigated in participants with 
advanced or metastatic HNSCC, NSCLC, esophageal, endometrial, cervical and bladder 
cancer.
2.2.1. Protein Arginine Methyltransferase 5 (PRMT5)
2.2.1.1. Cellular Functions
PRMT5 and binding partner MEP50 form the methylosome complex that utilizes 
S-adenosylmethionine to transfer methyl groups to arginine, catalyzing both mono- and 
symmetric di-methylation on substrate residues.  PRMT5 methylates multiple protein 
substrates involved in transcription, cell signaling, mRNA translation, DNA damage, 
receptor trafficking, protein stability, and pre-mRNA splicing.2
The most well studied of the PRMT5 substrates are the spliceosomal assembly proteins that 
regulate pre-mRNA splicing.  Mutations in splice sites, splicing factor mutations, and 
changes in splicing activity have been linked to cancer development and progression.3
PRMT5 symmetrically di-methylates proteins that regulate pre-mRNA splicing including 
spliceosomal proteins, SmD1, SmD3 and SmB/B.4 This methylation increases the affinity of 
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the Sm proteins for the tudor domain of the SMN1 protein, facilitating assembly of small 
nuclear ribonucleoprotein (snRNP) complexes for proper splice site recognition and 
recruitment of additional splicing factors. This is shown in Figure 1.  A conditional PRMT5 
knockout in mouse neural stem/progenitor cells (NPCs) highlights that PRMT5 function is 
necessary for proper splice site selection.5 PRMT5 genetic inhibition leads to increased 
intron retention and exon skipping in pre-mRNAs resulting in mRNA non-sense mediated 
decay or alteratively spliced mRNAs. These splicing alterations can reduce expression of 
proteins or generate alternative protein isoforms that function in cell cycle regulation, DNA 
replication and repair, and metabolism.5,6,7
Figure 1.
PRMT5 methylosome complex regulates snRNP assembly
Figure modified from (Neuenkirchen N 2008)8 to show PRMT5 complex methylates core spliceosomal proteins 
(SmD1, SmD3 and SmB) and aids in formation of mature U snRNPs through recruitment of the SMN complex.
2.2.1.2. PRMT5 Dysregulation in Cancer
Epigenetic dysregulation of cancer cell growth and survival pathways is a hallmark of both 
hematologic malignancies and solid tumors.  PRMT5 is an epigenetic regulator that is 
overexpressed in hematologic malignancies and solid tumors which has been associated with 
decreased patient survival.2,6 PRMT5 over-expression increases protein methylation on 
multiple substrates performing a variety of biological functions known to be dysregulated in 
cancer including transcription, cell signaling, mRNA translation, DNA damage, receptor 
trafficking, protein stability, and pre-mRNA splicing. Cancer cells are dependent on PRMT5 
enzymatic activity for growth as genetic inhibition or catalytic inhibition of PRMT5 blocks 
cancer cell proliferation.9
PRMT5 methylation of splicing proteins, including Sm proteins, leads to splicing changes in 
oncogenes and tumor suppressor genes that regulate cancer cell proliferation and survival.
Loss of PRMT5 activity induces alternative splicing changes with significant increases in 
levels of intron retention and exon skipping, primarily at sites with weak 5’ exon-intron 
junctions.5,7  These alternative splice variants may reduce expression of proteins or generate 
alternative protein isoforms with altered cellular functions.  One example of an alternative 


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splicing event induced by PRMT5 loss is skipping of exon 6 in the MDM4 gene, causing the 
transcript to go through nonsense mediated decay, leading to a decrease in MDM4 protein, 
and subsequent activiation of the p53 pathway.  In p53 wild-type lymphoma models, exon 
6 skipping in MDM4 was linked to the anti-proliferative activity of PRMT5 inhibitors.10
Other examples of alternative splicing events induced by PRMT5 loss or inhibition include 
genes involved in proliferation of cancer cells, such as: DVL1, MINK1, EP400, DDX51, 
ATR, RAC1 and CDC25B.6
2.2.1.3. Splicing Changes in Cancer
Recent high-throughput sequencing of human tumor tissue has identified  that perturbations 
in mRNA splicing represent a common feature of tumorigenesis. Tumors have up to 30% 
more alternative splicing events than normal samples, including cancer specific exon-exon 
junctions, and there are associations between somatic variants of splicing factors and 
alternative splicing events.12 The Cancer Genome Atlas (TCGA) identified recurrent somatic 
mutations and copy number alterations in 119 splicing factor genes, including genes
encoding the splicing factors SF3B1, U2AF1, SRSF2, FUBP1, ZRSR2, and RBM1017 in 
hematologic malignancies and solid tumors such as NSCLC, bladder, endometrial, 
esophageal, cervical, and HNSCC.  Stratification of 119 genes with recurrent mutations with 
known roles in RNA splicing, including known PRMT5 substrates, and those important in 
snRNP assembly and branch point recognition, enriches the incidence of splicing factor 
mutations in these tumor types to over 42% of the total participants. RNA sequencing data 
from participant samples harboring these somatic mutations has revealed that cancers 
demonstrate transcriptome-wide splicing alterations, including splicing of regulators of 
proliferation, angiogenesis and cell death.3
2.2.1.4. PRMT5 Inhibitor Activity in Splicing Factor Mutated Leukemia
Splicing factor SF3B1 is frequently mutated in leukemia and hotspot mutations in the HEAT 
domain are classified as gain of function.  Hotspot mutations in SF3B1 induce aberrant 3’ 
splice site selection by utilizing an alternative branch point to generate an increased number 
of mRNAs targeted for nonsense mediated decay.13 One example of these transcripts is 
ABCB7, a heme transporter and mediator of erythroid growth.  ABCB7 is down-regulated in 
refractory anemia with ring sideroblasts (RARS), a subtype of myelodyplastic syndrome 
(MDS) with over 80-90% incidence of SF3B1 hotspot mutations.13 A hematopoietic 
conditional heterozygous knock-in of SF3B1K700E in mice demonstrated impaired blood cell 
differentiation leading to anemia and myelodysplasia.14  HSPCs isolated from SF3B1+/K700E
mice also demonstrated increased sensitivity to spliceosome inhibitor, E7107, compared to 
wild–type cells.14 To assess whether splicing dysregulation caused by splicing factor 
mutations would lead to increased sensitivity to PRMT5 inhibitors, anti-proliferative activity 
of PF‑06939999 was tested in heterozygous SF3B1+/H662Q NALM-6 leukemia cells.  
Increased potency of PF-06939999 was observed in NALM-6 cells harboring the 
SF3B1+/H662Q mutation compared to the wild-type isogenic parental cell line with IC50 values 
of 4.05 nM and 13.41 nM respectively.  PF-06939999 also demonstrated strong anti-
proliferative activity in SF3B1 mutant MOLT-4 cells (IC50 = 0.381 nM), which translated to
in vivo efficacy of 96% tumor growth inhibition at 10 mg/kg once daily, at a Cav


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free = 23 nM and a 79 % reduction of the 
 biomarker.  PRMT5 inhibitors have also 
demonstrated increased sensitivity in leukemia mouse models with splicing factor SRSF2P95H
mutation compared to wild-type.15  
 
2.2.1.5. PRMT5 and NSCLC
PRMT5 is highly expressed in lung cancer cells where it has been identified to promote lung 
cancer cell growth and accelerated metastasis. NSCLC is dependent on PRMT5 enzymatic 
function for growth as both genetic inhibiton and small molecule inhibitors block 
proliferation of lung cancer cells.11 Splicing dysregulation has been well characterized as a 
molecular feature of NSCLC.3,17,19 Using analysis of TCGA data, the incidence of mutations 
in 119 splicing factors analyzed in 5171 NSCLC samples was 46%, one of highest 
percentages of all tumor types.  A panel of NSCLC cell lines (50% containing splicing factor 
mutations) were tested for anti-proliferative activity in response to PF-06939999.  IC50 
values for the splicing mutant cell lines were 50nM or lower, suggesting splicing 
dysregulation may increase sensitivity to PRMT5 inhibitors.  There exists a necessity to 
identify novel therapeutic modalities that target previously unrecognized molecular events 
that drive the aggressiveness of lung cancer. These data highlight the potential for 
PF-06939999 as an attractive therapeutic in NSCLC.
2.2.1.6. Role of PRMT5 in Additional Solid Tumor Types
Additional solid tumors with increased splicing dysregulation due to higher percentages of 
splicing factor mutations include: head and neck squamous cell carcinoma, cervical cancer, 
endometrial cancer, esophageal cancer, and bladder cancer.  Using analysis of TCGA data, 
the incidence of mutations in the 119 splicing factors described above were determined.  In 
bladder cancer, the incidence of splicing factor mutations was 51% in 1857 patients, 38% of 
1638 endometrial cancer patients, 42% of 604 cervical cancer patients, 44% of 1662 
esophageal cancer patients and 51% of 1587 head and neck cancer patients. These identified 
mutations may permit enhanced sensitivity to a PRMT5 inhibitor.  
2.2.1.7. PRMT5 Inhibitors in Treatment Resistant Disease
Development of drug resistance is a reality for many patients being treated with targeted 
agents.  Initial clinical response is strong, but development of resistance to these drugs is 
common, with relapse occurring as early as 2 months of treatment.16 Mechanisms tumors use 
to evade targeted therapies involve bypassing the targeted pathways by utilizing alternative 
signaling pathways, regulating gene expression and acquiring DNA mutations in oncogenic 
drivers.  PF-06939999 targets a unique PRMT5-driven cellular process, alternative splicing, 
which remains a vulnerability in cancer cells where resistance has emerged to chemotherapy, 
oncogenic driver mutation therapies, cell cycle inhibitors and immunotherapy.  PF-06939999
demonstrated efficacy in several drug resistant cell lines, suggesting combinations or later 
line therapy options in the clinic may be effective in multiple cancer indications. This 
provides the rationale for developing PF-06939999 in participants with advanced or 
metastatic cancers including HNSCC, NSCLC, esophageal cancer, endometrial cancer, 
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cervical cancer, and bladder cancer that are resistant to standard therapy or for whom no 
standard of therapy is available. 
2.2.2. Nonclinical Pharmacology
PF-06939999 is a potent and selective small molecule inhibitor with demonstrated 
biochemical and cellular activity against PRMT5. The biochemical potency was assessed 
using enzymatic assays performed using human full length PRMT5/MEP50 complex and
peptides based on the C-terminal GR rich region of SmD3.  The Ki value (concentration 
required to produce half maximum enzyme inhibition) is <50 pM, which is below the lower 
limits of quantitation for the assay. Selectivity of PF-06939999 at 10 μM was assessed in 
both protein methyltransferase and kinase selectivity panels and showed no activity above 
20% inhibition for all enzymes in both enzyme panels.
Cellular activity of PF-06939999 was measured by the reduction of its direct biomarker, 
 and anti-proliferative activity in cancer cells.  
PF-06939999 displayed potent inhibition of cellular activity in an 
 ELISA assay with 
an IC50 value of 0.417 nM.  Breadth of efficacy studies were done to assess anti-proliferative 
activity of PF-06939999 in cell lines representing multiple solid tumor indications with 
increased incidence of splicing dysregulation.  Anti-proliferative responses with differential 
sensitivity to PF-06939999 were observed in NSCLC, esophageal, endometrial, cervical, 
bladder and leukemia cell lines treated for 7 days.  In NSCLC, potency ranged from 
IC50 = 1.3 nM to 79.2 nM with many  sensitive cell models harboring mutations in splicing 
factors or demonstrating significant differences in alternative splicing patterns.  Additionally, 
PC-9 (an EGFR mutant NSCLC line) was evaluated for anti-proliferative effects, comparing 
the sensitivity of the parental cell line to one that had developed acquired resistant to specific 
EGFR inhibitors.  PF-06939999 demonstrated similar efficacy in parental (IC50 = 12.2 nM) 
and resistant cells (IC50 = 15.4 nM).  In bladder cancer cell lines, potency ranged from 
IC50 = 1 nM to 92 nM for anti-proliferation.  Esophageal cancer cell lines demonstrated a 
similar range of potency to other solid tumor cell lines with a potency range from 
IC50 = 8.96 nM to 131 nM.  Leukemia cell lines also had strong anti-proliferative activity in 
response to PF-06939999 treatment with IC50 values ranging from 0.6 nM to 116 nM and 
induction of apoptosis in several cell lines.
In vivo, PF-06939999 demonstrated significant tumor growth inhibition (TGI) relative to 
vehicle in xenograft studies representing NSCLC, bladder and esophageal cancer as a 
monotherapy. PF-06939999 showed significant tumor suppression as an orally administered 
single agent in the 2 splicing factor mutant NSCLC (A427 and NCI-H441) xenograft models.  
In the NCI-H441 (U2AF1S34F) model, PF-06939999 demonstrated dose dependent tumor 
growth inhibition (TGI) of 55.5% at 5 mg/kg BID, 14.9% at 3 mg/kg once daily, 46.6% at 
10 mg/kg once daily and 87.2% at 30 mg/kg once daily doses.  Modulation of 
 in the 
tumors was evaluated via ELISA at end of study with reductions compared to control from 
70.6% to 85.9% for the once daily doses.  PF-06939999 also demonstrated dose dependent 
TGI in the A427 (RBM10I348N) model, of 94.5% at 5 mg/kg BID, 32.4% at 3 mg/kg once 
daily, 76.2% at 10 mg/kg once daily and 102.3% at 30 mg/kg once daily doses.  Patient 
derived xenografts of bladder and esophageal cancer were evaluated for tumor growth 
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inhibition at 10 mg/kg or 30 mg/kg QD.  Significant tumor growth inhibition was observed in
6/7 bladder cancer xenografts and 7/13 esophageal cancer xenografts.  Body weight was 
maintained over the course of dosing.  Based on these data, there is pre-clinical rationale for 
the use of PF-06939999 as a single agent in the clinic for NSCLC, bladder cancer, 
esophageal cancer, and leukemia indications.
2.2.3. Nonclinical Pharmacokinetics and Projection of Human Pharmacokinetics
Details of the nonclinical ADME properties of PF-06939999 are provided in the 
Investigator's Brochure.  Briefly, PF-06939999 is predicted to have a human plasma 
clearance of 3.1 mL/min/kg, a steady-state volume of distribution of 1.6 L/kg, and a half-life 
of approximately 6 hours.  The oral bioavailability is predicted to be 50%. Stomach pH is 
not anticipated to impact oral absorption in the planned clinical dose range. Since 
PF-06939999 is a substrate for efflux transporters, there is the potential to observe variable 
nonlinear pharmacokinetics with over-proportional increases in exposure across doses due to 
saturation of efflux transporters.  Minimal accumulation (≤3x) was observed in rats and dogs 
after 15 weeks of once daily dosing.  PF-06939999 showed moderate plasma protein binding 
with unbound fractions in plasma of 0.1 to 0.2 across the species evaluated and partitioning 
of PF-06939999 into blood cells was modest with blood-to-plasma ratios of ≤1.4.  Brain 
penetration of PF-06939999 was limited in mice, with unbound brain to plasma 
concentration ratios of ≤0.1. Preliminary in vitro metabolism evaluation of PF-06939999
showed similar oxidative metabolite profiles across species with no evidence of human 
specific oxidative metabolites. PF-06939999 is expected to be primarily metabolized by 
cytochrome P450 (CYP) 3A4/5 (~70% of hepatic metabolism), with minor contributions 
from CYP1A2, CYP2C9, and CYP2D6.  Physiologically-based pharmacokinetic (PBPK) 
modeling suggested that the oral exposure of PF-06939999 at the predicted 
pharmacologically active dose (PAD) of 50 mg twice daily (BID) could increase by 2 to 
3-fold with coadministration of a strong CYP3A inhibitor and decrease by 50% to 70% with 
coadministration of a strong CYP3A inducer.  Based on the cumulative in vitro drug-drug 
interaction (DDI) data and projected total steady-state maximum systemic concentration 
(Cmax,ss) of 458 nM (53 nM unbound) in humans at the dose of 50 mg BID, PF-06939999 has 
a low risk to cause pharmacokinetic DDIs with compounds for which CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP3A, UGT1A1, UGT1A4, UGT1A6, UGT1A9, 
UGT2B7, UGT2B15 mediated metabolism constitutes the primary mechanism of clearance.  
PF-06939999 has a low potential to inhibit BCRP (systemic), MDR1/P-gp, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2, and MATE1 in humans at the dose of 50 mg BID.  
However, PF-06939999 may have the potential to inhibit CYP2D6, BCRP (intestinal), and 
OCT1 at clinically relevant concentrations.  PBPK modeling suggested that PF-06939999, at 
the predicted PAD of 50 mg BID, could increase the oral exposure of 
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2.2.4. Nonclinical Safety
The nonclinical safety profile of PF-06939999 was evaluated in vitro (off-target binding, 
hERG, genetic toxicity) and in vivo following oral administration of PF-06939999 to rats and 
dogs in nonpivotal and pivotal Good Laboratory Practice (GLP) toxicity studies of up to 
1-month in duration.  PF-06939999 was developed as a brain restricted compound.  The oral 
route of exposure with a continuous once daily dosing regimen was selected for in vivo 
studies since it is the intended route of administration in participants.
In vitro assays with PF-06939999 suggest minimal risk of off-target pharmacology or direct 
effects on ion channels or cardiac tissues at clinically relevant exposures.  PF-06939999 was 
not mutagenic in the in vitro bacterial reverse mutation assay and not clastogenic or 
aneugenic in an in vitro micronucleus assay in human lymphoblastoid TK6 cells.  
PF-06939999 may have potential risk for phototoxicity based on its UV absorption within the 
290-400 nm range, with a calculated molar extinction coefficient (MEC) >1000 Lmol-1cm-1.  
PF-06939999 will be evaluated for phototoxicity during exploratory development prior to 
any large-enrollment clinical trials (Phase 3). Developmental and reproductive toxicity 
studies have not been conducted with PF-06939999, the effects of PF-06939999 on sperm, a 
pregnancy, a fetus, or a nursing child are not known. Adverse effects on sperm, a pregnancy, 
a fetus, or a nursing child are common with oncology therapeutics and may result from 
exposure to PF-06939999.
In repeat dose 1-month GLP toxicity studies in rats and dogs, administration of PF-06939999
was not tolerated at the high doses of 30 and 0.3 mg/kg/day, respectively, with the declining 
clinical condition in both species being primarily ascribed to extensive and persistent adverse 
gastrointestinal effects.  The primary target organs identified in the pivotal toxicity studies in 
rats and dogs included:
Significant Non-Clinical Toxicities: 

Gastrointestinal (GI): clinical signs including liquid feces, dehydration, decreased 
body weight and food consumption, emesis (dog) and severely decreased activity.  
Microscopically GI findings were characterized by minimal to moderate degeneration
of crypt epithelium with regeneration throughout the entire GI tract.  GI findings were 
observed at the high doses of 30 mg/kg in rats (margin vs predicted exposure at the 
start dose is 1859x) and 0.3 mg/kg in dogs (margin vs predicted exposure at the start 
dose is 41.4x). GI findings in the dog defined the highest non-severely toxic dose 
(HNSTD). Reversibility was established for the PF-06939999-related GI changes in 
rats and dogs following a 1-month recovery period. The rat STD10 exposure equates 
to approximately 116 mg BID doses in humans, which is not anticipated to be 
explored in the clinic. Note: the PAD (pharmacologically active dose) is predicted to 
be 50mg BID. The GI toxicity observed may be anticipated to commence at human 
dose of approximately 3.5mg BID.


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
Bone Marrow: hematopoietic/myelosuppressive effects characterized by decreased 
red blood cell mass, platelets and WBCs; and microscopically evidenced by moderate 
to marked decreased cellularity of bone marrow was observed.  Bone marrow 
findings at ≥10 mg/kg (mid dose) in rats and were considered non-adverse until 
30mg/kg (exposure margin vs. predicted start dose is 1859x) and for dogs findings 
were non-adverse even at the highest dose level (at 0.3mg/kg exposure margin vs. 
predicted start dose is 41.4x). Reversibility was established for PF-06939999-related 
bone marrow changes in rats and dogs following a 1-month recovery period. The rat 
STD10 exposure equates to approximately 116 mg BID doses in humans, which is not 
anticipated to be explored in the clinic. Note: the PAD (pharmacologically active 
dose) is predicted to be 50mg BID. The bone marrow toxicity observed may be 
anticipated to commence at human dose of approximately 10mg BID.

Pancreatic: microscopic observations included moderate pancreas acinar cell necrosis 
and mild atrophy, inflammation/necrosis of pancreatic and peripancreatic adipose 
tissue with associated clinical pathology such as increases in amylase and lipase.  
Findings were observed in only one dog at the highest dose of 0.3mg/kg and in rats at 
doses ≥10mg/kg (adverse in both species, margins vs exposure at the start dose is 
41.4x in dogs, 464x in rats). The pancreatic effects in dogs also contributed to the 
HNSTD.  Reversibility was established for the PF-06939999-related pancreatic 
changes in rats and dogs following a 1-month recovery period. The rat STD10
exposure equates to approximately 116 mg BID doses in humans, which is not 
anticipated to be explored in the clinic. Note: the PAD (pharmacologically active 
dose) is predicted to be 50mg BID. The pancreatic toxicity observed may be 
anticipated to commence at a human dose of approximately 10mg BID.
Non-Significant Non-Clinical Toxicities:

Male reproductive: in the testis minimal to marked degeneration of seminiferous 
tubules; ≥10 mg/kg (mid dose); and epididymis minimal to moderate cell debris at 
≥0.3 mg/kg (high dose, dog only) and moderate reduced sperm count and single cell 
necrosis at 30 mg/kg (high dose, rat only).  PF-06939999-related male reproductive 
changes did not recover following a 1-month recovery period. These were considered 
clinically non-significant for an oncology subject population.

Additional target organs identified in the rat only included: bone (moderate to marked 
decreased trabecular bone/necrosis in the metaphysis, osteoblast degeneration, 
increased osteoclasts; ≥10 mg/kg) and pituitary (minimal to mild single cell necrosis, 
pars anterior (distalis); ≥10 mg/kg).  Reversibility was established for the 
PF-06939999-related bone and pituitary findings in rats following a 1-month recovery 
period. Bone effects on the open epiphyseal plate in rats would not be considered to 
represent a risk to adult participants with a closed growth plate.  Changes in the 
pituitary gland were minimal and nonadverse and only observed in a single species 
and were not associated with any functional alterations, thus the relationship of this 
finding to humans is unknown but likely minimal. These were considered clinically 
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The dog was identified as the most sensitive species to PRMT5-related toxicities.  The 
HNSTD (highest nonseverely toxic dose) in the pivotal 1-month toxicity study in dogs was 
0.1 mg/kg/day (total Cmax of 15 ng/mL and AUC24 of 175 ng*hr/mL,and unbound Cave of 
2.9 nM and Cmax of 5.9 nM).  The STD10 (severely toxic dose in 10% of rodents) in the 
pivotal 1-month toxicity study in rats was 10 mg/kg/day (total Cmax of 437 ng/mL and AUC24
of 4824 ng*hr/mL, and unbound Cave of 95 nM and Cmax of 206 nM).  At the 
HNSTD/NOAEL in the dog, safety margins over the unbound projected exposure at the 
0.5 mg QD human starting dose for Cave and Cmax are approximately 14.5 and 15.1, 
respectively.  At STD10 in rat, safety margins over the unbound projected exposure at the 
0.5 mg QD human starting dose for Cave and Cmax are approximately 475-x and 528-x. This 
justifies the starting dose of 0.5 mg QD which is one sixth the HNSTD/NOAEL in dogs.
The nonclinical safety findings related to oral administration of PF-06939999 represent 
toxicities that can be monitored and/or are considered clinically manageable or acceptable 
risks in the intended advanced cancer participant population.  Additional details of the 
nonclinical safety program and a complete list of all toxicity findings are provided in the 
current Investigator’s Brochure.
2.2.5. Clinical Overview
As of 17 October 2019, 7 participants were enrolled and dosed at 4 dose levels (0.5 mg QD, 
0.5 mg BID, 1 mg BID and 2 mg BID) in this study. Five of 7 particpants experienced at
least 1 treatment-emergent adverse event (TEAE). Most TEAEs were CTCAE Grade 1 or 2. 
One participant dosed at 1 mg BID experienced 2 CTCAE Grade 3 TEAEs of anemia and 
hypomagnesemia, resulting in a dose reduction to 0.5 mg BID.
Treatment related AEs include CTCAE Grade 3 anemia, and Grade 1 blood creatinine 
increased, dysgeusia, and hypomagneseamia (n=1 each).   
As of 17 October 2019, 1 participant experienced a treatment-emergent serious adverse event 
(SAE) of pneumonia, which was assessed as not related to PF-06939999. No particpants 
experienced treatment related SAEs. No participants were discontinued due to an AE. No 
participants experienced dose limiting toxicities (DLTs) or CTCAE Grade 4 or 5 TEAEs.
2.3. Benefit/Risk Assessment
This is the first-in-human clinical trial to evaluate PF-06939999. As of the data cut-off date 
of 17 October 2019, 7 participants have been enrolled and dosed in clinical study C3851001. 
Treatment related AEs include CTCAE Grade 3 Anemia, and Grade 1 blood creatinine
increased, dysgeusia and hypomagneseamia (n=1 each). No particpants experienced 
treatment related SAEs. No participants were discontinued due to an AE. No participants 
experienced dose limiting toxicities (DLTs) or CTCAE Grade 4 or 5 TEAEs.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PF-06939999 may be found in the investigator’s brochure, 
which is the single reference safety document (SRSD) for this study.
The SRSD for docetaxel is the Taxotere® USPI.17


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3. OBJECTIVES AND ENDPOINTS 
Part 1A Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:

To assess safety and tolerability at 
increasing dose levels of PF-06939999
in successive cohorts of participants
with selected advanced or metastatic 
solid tumors in order to estimate MTD 
or Maximum Administered Dose 
(MAD) and select the RP2D/schedule.

Dose Limiting Toxicities (DLTs).

Adverse Events (AEs) 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.
Secondary: 
Secondary: 

To characterize the single and multiple 
dose PK of PF-06939999 following 
oral administration. 

To evaluate preliminary anti-tumor 
activity.

PK parameters of PF-06939999: Single 
Dose (SD) - Cmax, Tmax, AUClast, and as 
data permit, t1/2, AUCinf, CL/F, and 
Vz/F.

PK parameters of PF-06939999: 
Multiple Dose (MD) - Cmax,ss, Tmax,ss , 
AUCss,, and as data permit, CL/F, 
Vss/F, and Rac (AUCss,/AUCsd,).

Tumor response: Objective response rate 
(ORR) and duration of response (DoR), 
as assessed using the Response 
Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1) Section 10.11.


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•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1B Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:
•
To assess safety and tolerability of 
PF-06939999 in combination with 
docetaxel in participants with locally
advanced or metastatic NSCLC to 
determine MTD and select the 
RP2D/schedule for combination.
•
DLTs.
•
AEs as characterized by type, frequency, 
severity (as graded by 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.
Secondary: 
Secondary: 
•
To characterize the single and multiple 
dose PK of PF-06939999 when 
administered in combination with 
docetaxel. 
•
PK parameters of PF-06939999: 
SD - Cmax, Tmax, AUClast, and as data 
permit, t1/2, AUCinf, CL/F, and Vz/F.
•
PK parameters of PF-06939999: 
MD - Cmax,ss, Tmax,ss, AUCss,τ , and as data 
CCI
CCI


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Objectives
Endpoints
•
To evaluate preliminary anti-tumor 
activity.
•
To evaluate overall survivial (OS).
permit, CL/F, Vss/F, and Rac (AUCss,τ
/AUCsd,τ).
•
Tumor response: ORR,DoR, 
progression-free survival (PFS) and time 
to progression TTP, as assessed using 
the Response Evaluation Criteria in 
Solid Tumors (RECIST, version 1.1) 
Section 10.11.
•
OS, proportion of participants alive at 6 
months, 1 year, and 2 years of 
PF-06939999 in combination with 
docetaxel.
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Part 2 Objectives and Endpoints: 
Objectives
Endpoints
Primary:
Primary:

To assess safety and tolerability of 
PF-06939999 monotherapy in 
participants with locally advanced or 
metastatic NSCLC, urothelial
carcinoma, or HNSCC and in 
combination with docetaxel in locally 
advanced or metastatic NSCLC.

AEs as characterized by type, frequency, 
severity (as graded by 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.

To estimate clinical efficacy by ORR
of PF-06939999 monotherapy in 
participants with NSCLC, urothelial 
carcinoma or HNSCC and in 
combination with docetaxel in 
NSCLC.

Best overall response (BOR) as assessed 
by investigators using the Response 
Evaluation Criteria in Solid Tumors 
(RECIST version 1.1) Section 10.11.
Secondary: 
Secondary: 

To further evaluate the PK of 
PF-06939999 as a single agent and in 
combination with docetaxel at the
respective RP2D. 

To evaluate the effect of food on the 
PK of PF-06939999 (Part 2B).

To evaluate anti-tumor activity of 
PF-06939999 monotherapy in 
participants with locally advanced or 
metastatic NSCLC, urothelial 
carcinoma, or HNSCC and in 
combination with docetaxel in locally 
advanced or metastatic NSCLC.

To evaluate overall survival (OS).

PK parameters of PF-06939999: Cmax, 
Tmax from single and multiple dose, and 
Ctrough at selected timepoints.

PK parameters of PF-06939999 given 
with and without food: Cmax, Tmax, and 
AUClast.

Tumor response:Duration of response 
(DoR) progression free survival (PFS) 
and time to progression (TTP) as 
assessed by investigators using the 
Response Evaluation Criteria in Solid 
Tumors (RECIST version 1.1) 
Section 10.11 of PF-06939999 
monotherapy and in combination with 
docetaxel. 

OS, proportion of participants alive at 
6 months, 1 year, and 2 years of 
PF-06939999 monotherapy and in 
combination with docetaxel.


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Objectives
Endpoints
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, multi-center, dose escalation and dose expansion study to 
assess the safety, PK, PD, and anti-tumor activity of PF-06939999 as a single agent and in 
combination in participants with locally advanced or metastatic selected solid tumor 
indications.
The overall study design is depicted in the schema below. The study is divided into 2 parts, 
dose escalation (Part 1) followed by dose expansion (Part 2). Part 1 dose escalation further 
divides into Part 1A and 1B. Part 1A contains dose escalation as a single agent in 
participants with locally advanced or metastatic head and neck squamous cell carcinoma 
(HNSCC), non-small cell lung cancer (NSCLC), esophageal cancer, endometrial cancer, 
cervical cancer, or bladder cancer who are resistant or intolerant to standard therapy or for 
whom no standard therapy is available, to determine the MTD and RP2D. Part 1B contains 
CCI


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dose finding of PF‑06939999 in combination with docetaxel in locally advanced or 
metastatic NSCLC.
Part 1A (dose escalation) is anticipated to have approximately 9 cohorts and expected to 
enroll approximately 40 participants. A Bayesian Logistic Regression Model (BLRM) was
used to determine the MTD. Participants received escalating doses of PF-06939999 starting 
from 0.5 mg QD. Dose limiting toxicities (DLT) were assessed at the end of Cycle 1 
(28 days) to inform dose escalation and determine the MTD. Cohort size was approximately 
3 participants, with at least 1 DLT-evaluable participant per cohort at the first 3 dose levels
and at least 2 DLT-evaluable participants per cohort in the remaining cohorts. PF-06939999
was administered as a single agent, orally, once daily during the first cohort, twice a day 
(BID) or once a day (QD) for subsequent cohorts in 28 day cycles on a continuous basis until 
disease progression, participant refusal, or unacceptable toxicity. If the clinical PK and 
pharmacodynamic data support the feasibility of QD dosing regimen, QD will be tested for 
better participant compliance and convenience. Other dosing regimens (eg, a regimen with 
dose interruptions to allow recovery from certain adverse events) may be considered in the 
study if further supported by emerging clinical data.  The estimated length of treatment is 
approximately 2 years. Any additional treatment beyond 2 years shall be discussed and 
approved by the Sponsor. The proposed treatment schedule(s) and PK time points may be
reconsidered and amended during the study based on the emerging safety and PK data. The 
actual number of participants enrolled will depend on the tolerability of PF-06939999 and the 
number of dose levels required to identify the MTD and recommended dose for expansion 
(RP2D). RP2D definition is provided in Section 4.3.5.


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After the selection of recommended dose for expansion (RP2D) for monotherapy, Part 2
(dose expansion) will evaluate the safety and antitumor activity of PF-06939999 
monotherapy at the single agent RP2D in 3 expansion cohorts: locally advanced or metastatic 
NSCLC (Part 2A, 20 participants), urothelial carcinoma (Part 2B, 20 participants) and 
HNSCC (Part 2C, 20 participants). The collection of on-treatment biopsies in up to 
5 participants per arm is strongly recommended if state, local, and institutional policies 
allow.
Furthermore, the PF-06939999 in combination with docetaxel will be evaluated in locally 
advanced or metastatic NSCLC (Part 1B combination dose finding and Part 2D combination 
dose expansion). In part 1B, the PF-06939999 in combination with docetaxel will be 
evaluated in participants with locally advanced or metastatic NSCLC who have progressed 
after at least 1 line of checkpoint inhibitor and platinum based chemotherapy (2L+). BLRM 
specifically designed for combinations guided by EWOC principle will be used for dose 
finding. PF-06939999 may start at 1 dose level below single agent RP2D (RP2D-1) with 
fixed dose of docetaxel per standard of care. In addition, depending on the safety findings in 
Part 1A, and whether significant overlapping toxicities are expected in combination, the 
starting dose of PF-06939999 may be further escalated or de-escalated but will not exceed 
the single agent RP2D. Participants will be enrolled in cohorts of approximately 
3 paticipants of whom at least 3 will be DLT evaluable. It is anticipated that approximately 
6-9 participants will be enrolled in Part 1B. 
Once the RP2D for the combination has been determined, additional NSCLC participants 
will be enrolled under Part 2D combination expansion cohort until a total of 20 participants 
have been evaluated at the combination RP2D (Part 1B participants dosed at the combination 
RP2D will be counted towards the total of 20 participants). The collection of on-treatment 
biopsies in up to 5 participants per arm is strongly recommended if state, local, and 
institutional policies allow.
Approximately 80 participants are expected to be enrolled in Part 2. The participant
population is briefly described below and detailed in inclusion criteria (Section 5).
Monotherapy expansion cohorts Parts 2A, 2B, and 2C:

Part 2A: Participants with NSCLC (n=20) who have progressed after at least 1 line of 
checkpoint inhibitors and 1 line of platinum based chemotherapy (2L+).

Part 2B: Participants with urothelial carcinoma (n=20) who have progressed after at 
least 1 line of standard of care systemic chemotherapy (cisplatin/carboplatin+ 
Gemcitabine; or methotrexate/vinblastine sulfate/doxorubicin hydrochloride/cisplatin 
[MVAC]) and checkpoint inhibitor (2L+).

Part 2C: Participants with HNSCC (n=20) who have progressed after at least 1 line of 
standard of care systemic chemotherapy and 1 line of checkpoint inhibitor (2L+).


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Combination expansion cohort Part 2D (PF-06939999 in combination with docetaxel):

Part 2D: Participants with NSCLC (n=20) who have progressed after at least 1 line of 
checkpoint inhibitor and 1 line of platinum based chemotherapy (2L+).

All participants in Part 1 and Part 2:

Will undergo up to 28 days of screening prior to study entry.

Will receive doses of PF-06939999, administered orally continuously on 28 day 
cycles up to 2 years (for combination with docetaxel, 21 day cycle is used to be 
consistent with docetaxel dosing schedule).  Any additional treatment with 
PF-06939999 beyond 2 years shall be discussed and approved by the Sponsor. 

Treatment with investigational product (IP) will continue until disease progression, a 
decision by the participant (withdrawal of consent or no longer willing to participate),
or investigator , or unacceptable toxicity, whichever occurs first.  

Will undergo a Safety follow up visit at least 28 days but no more than 35 days after 
end of treatment.

In addition, participants in Part 1B and Part 2 dose expansion cohorts will be 
contacted by telephone every 12 weeks for survival data collection until end of trial 
(2 years from last participant first dose).

A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the schedule of 
activities, including overall survial (OS). OS follow up should not continue after end 
of the study (Section 4.3.6).
4.1.1. Food-Effect Substudy
The effect of food on the PK of PF-06939999 at the recommended Phase 2 dose and regimen 
(BID or QD) will be assessed in at least 6 participants (but no more than 15 participants)
from Part 2B, to inform whether PF-06939999 can be administered without food restriction 
in subsequent clinical trials. A fixed sequence one-way cross-over design will be utilized to 
assess the PK of PF-06939999 under the fasted and fed conditions on Cycle 1 Day 15 and 
Day 16, respectively, following repeated dosing under empty stomach condition (no food or 
liquids other than water will be consumed for 2 hours before and 1 hour following each 
dose).
With the exception of the study visits for food effect assessment (Cycle 1 Day 15 and 
Day 16), participants will receive continuous oral doses of PF-06939999 (QD or BID) under 
an empty stomach condition (ie, no food or liquids other than water will be consumed for 
2 hours before and 1 hour following each dose).  On Cycle 1 Day 15, participants will 
receive an oral dose of PF-06939999 under the fasted condition (overnight fasting of at least 


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10 hours; water permitted). On Cycle 1 Day 16, participants will receive another oral dose 
of PF-06939999 with a high-fat, high-calorie meal (breakfast) following 10-hour overnight 
fasting (water permitted). Serial PK samples will be collected after each dose on Day 15 and 
Day 16 per the Schedule of Activities. Subsequently, participants will receive the remaining 
drug treatment under an empty stomach condition. Participants who have had a gastrectomy 
or have dietary or other restrictions that preclude a 10- hour overnight fast (water permitted) 
or consumption of the high fat, high calorie meal will not be required to participate in this 
assessment.
Details regarding PF-06939999 administration and food requirements for participants in the 
the food-effect assessment are provided in Section 6.2.4.2.2.
4.2. Scientific Rationale for Study Design
4.2.1. Non-Small Cell Lung Cancer (NSCLC)
About 80-85% of lung cancers are histologically classified as NSCLC, which includes 
2 major sub-types: 1) non-squamous carcinoma (including adenocarcinoma, large-cell 
carcinoma (rare), and other cell types) and 2) squamous cell (epidermoid) carcinoma.22  The 
5-year survival rate of metastatic NSCLC is 4%.23
For the majority of participants diagnosed with advanced-stage NSCLC without targetable 
genetic aberrations, platinum-based doublet chemotherapy (ChTx) has been the standard of 
care (SOC) for over 30 years. With the exception of bevacizumab,24,25 and despite extensive 
study of multiple targeted and cytotoxic agents, addition of a third agent to platinum-doublet 
chemotherapy has not been shown to improve progression-free survival (PFS) or overall 
survival (OS) over platinum-doublet chemotherapy alone in randomized studies.26 Targeting 
driver mutations responsible for tumor progression (EGFR receptor and the EML4-ALK 
receptor) is modestly effective; however resistance to these therapies inevitably ensues.27,28,29
Checkpoint inhibitors including anti-PD-1 and anti-PD-L1 have recently approved as 1L and 
2L treatment regimens in metastatic NSCLC.30,31,32  Unfortunately, only a sub-group of these 
participants responds and shows long-term survival to these therapies indicating that a 
significant unmet medical need exists for NSCLC participants as the majority do not respond 
to checkpoint inhibitors.  
PRMT5 is highly expressed in lung cancer cells, where it has been identified to promote lung 
cancer growth and also accelerate metastasis.  NSCLC is dependent on PRMT5 enzymatic 
function for growth as both genetic inhibiton and small molecule inhibitors block 
proliferation of lung cancer cells.  NSCLC models have demonstrated strong anti-tumor
responses to PF-06939999.  Splicing dysregulation has been well characterized as a 
molecular feature of NSCLC.3,17,19  Computational analysis identified specific splicing factor 
mutations enriched in NSCLC cell lines sensitive to PF-06939999, including RBM10 
mutation or loss and U2AF1 mutations.  Based on the rationale in Section 2.2.1.5 this tumor 
type is selected for Part 1 (Dose Escalation) and Part 2 (Dose Expansion). 


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4.2.2. Head and Neck Squamous Cell Carcinoma (HNSCC)
Head and neck squamous cell carcinoma (HNSCC) represents a heterogenous disease entity, 
which encompasses a variety of tumors originating in the lip/oral cavity, hypopharynx, 
nasopharynx or larynx with differences in epidemiology, etiology and therapeutic approach.  
It is the sixth most common malignancy worldwide, accounting for approximately 6% of all 
cases and is responsible for an estimated 1-2% of all cancer deaths.20  HNSCC has been 
historically associated with tobacco and alcohol use; however, in the past decade, infection 
with high-risk human papillomaviruses (HPV) and especially type 16 has been implicated in 
the pathogenesis of a subset of HNSCCs, mainly those arising from the oropharynx.20,21 For 
recurrent/metastatic disease (R/M), cytotoxic-based chemotherapy remains the standard 
therapeutic option and median survival of participants with palliative chemotherapy alone 
ranges from 6-10 months.  Checkpoint inhibitors pembrolizumab and nivolumab are also 
established in the treatment paradigm for metastatic disease.20,21  However, limited overall 
survival and toxicities with standard of care agents highlight the unmet medical need for 
enhanced treatment options in HNSCC.  PRMT5 is frequently expressed in this disease and 
analysis of TCGA data uncovered an incidence of splicing factor mutations of 51% 
(119 genes analyzed), hence HNSCC was selected for Part 1 (Dose Escalation) and Part 2 
(Dose Expansion) of this study since these tumors may be sensitive to PRMT5 inhibition.17  
4.2.3. Esophageal Cancer 
Esophageal carcinoma is the eighth most common cancer and the sixth most common cause 
of cancer related deaths worldwide.33,34  Despite many advances in diagnosis and treatment, 
the 5-year survival rate for all participants diagnosed with esophageal cancer ranges from 
15-20%.35 The 2 most common histological types of esophageal carcinoma include 
squamous cell carcinomas and adenocarcinoma. Current treatment options include 
multimodality therapy -mainstays of current treatment include  surgery, radiation and 
chemotherapy. With increasing clinical experience, biomarker analyses, and improvements 
in preclinical models, the potential role of immunotherapy in esophageal cancers is emerging 
with checkpoint inhibitors such as CTLA-4, PD-1 and PD-L1 which are currently 
underway.36 However, advanced esophageal cancers carry a poor prognosis with limited 
therapeutic options, and few major therapeutic advances.  PRMT5 is overexpressed in 
esophageal cancer. Using TCGA analysis, the incidence of mutation in 119 splicing factors 
analyzed in esophageal cancer samples was 44%, hence this tumor type was selected for 
Part 1 (dose escalation) of the study.
4.2.4. Endometrial Cancer
Endometrial cancer is the most common gynecologic malignancy in the developed world. In 
2016, 60,050 women were diagnosed with endometrial cancer in the US and there were over 
10,000 deaths due to this disease.37 Endometrial cancer is a heterogenous malignancy with 
very different prognoses: Endometroid cancer (type 1 endometrial cancer) accounts for 85% 
of all endometrial cancers and has a good prognosis. Serous carcinomas and clear cell 
carcinomas (CCC) are traditionally designated nonendometrioid carcinomas (type II 
endometrial cancers) and are very aggressive tumors.37 At the time of diagnosis, 67% of 
women have disease confined to the uterus and an associated 5-year survival rate of 95%. In 


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contrast, the 8% of participants with distant metastases at the time of diagnosis have a 5-year 
survival rate of 17% and face cytotoxic chemotherapy (primarily taxanes, anthracyclines and 
platinum drugs) with limited responses. A triplet regimen of paclitaxel, doxorubicin and 
cisplatin (TAP) in participants with advanced and recurrent endometrial cancers has an ORR 
of 57% and median OS of 15.3 months and is associated with chemotherapy related 
toxicities.38 Hormonal therapy is better tolerated but results in response rates between 18% 
and 34%. With taxanes alone showing response rates of greater than 20% in select 
participants (taxane-naïve) with recurrent disease, effective second line therpaeutic 
approaches are warranted in this participant population.38 Phase I trials testing 
immunotherapy agents in endometrial cancer are ongoing and have demonstrated 
encouraging immunologic responses but few clinical responses in heavily pretreated 
participants with advanced disease, making this an area of high unmet medical need.38
PRMT5 is expressed in endometrial cancer. Using TCGA analysis, the incidence of 
mutation in 119 splicing factors analyzed in endometrial cancer samples was 38%, hence this 
tumor type was selected for the Part 1 (dose escalation) portion of the study. 
4.2.5. Cervical Cancer 
Cervical cancer is the second most commonly diagnosed cancer and the third leading cause 
of cancer death among females in less developed countries. Early-stage cervical cancer can 
be cured with surgery, while concurrent chemoradiation is the treatment of choice for locally 
advanced stages. Participants with recurrent or metastatic cancers have limited treatment 
options: the use of cisplatin-based chemotherapy regimens is the first-line treatment for 
advanced cervical cancer. However, it has low response rates (20%), short median PFS 
(2.8-3.2 months) and OS (6.2-8.0 months).39 Recently, bevacizumab has been approved in 
combination with chemotherapy as first-line therapy, with a statistically significant OS 
improvement as compared with chemotherapy alone.40 No validated treatment options exist 
beyond first-line treatment regimens. Chemotherapy is associated with substantial toxicity 
and poor efficacy with a median overall survival of 7 months. New effective treatment 
options are therefore needed in this setting.  PRMT5 is expressed in cervical cancer. Using 
TCGA analysis, the incidence of mutation in 119 splicing factors analyzed in cervical cancer 
samples was 42%, hence this tumor type was selected in Part 1 (dose escalation) of the study.
4.2.6. Urothelial Carcinoma
Urothelial carcinoma (bladder cancer) is the second most common genitourinary malignant 
disease in the USA. Risk factors include genetic and molecular abnormalities, chemical or 
environmental exposures and chronic irritation. More than 90% of bladder cancers are 
transitional cell carcinomas, 5% are squamous cell carcinomas, and less than 2% are 
adenocarcinomas.41  Cisplatin-based chemotherapies have been the SOC for metastatic 
bladder cancer for over 30 years and is the first-line treatment for advanced tumors sensitive 
to platinum salts however, long-term responses are rare and relapses often occur within 
3 months of the end of chemotherapy. Additionally, almost half of the participants are not 
eligible for first-line cisplatin-containing chemotherapy, with no clear SOC, but 
carboplatin-based regimens (gemcitabine-carboplatin) or single agent therapies are 
considered acceptable.  As second-line therapy, only vinflunine is approved in Europe with a 


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overall survival (OS) of 6.9 months and taxanes are used in the U.S.(paclitaxel response rates 
5-10% with median OS of 6.5-7.2 months).42 Better response rates (15-60%) but higher 
toxicity rates with multidrug combinations including taxanes are available in the U.S.
Recently, clinical trials are evaluating checkpoint inhibitors as frontline therapy for cisplatin 
eiligible and ineligible participants. However, a large majority of participants do not respond 
to anti-PD(L)1 drugs as monotherapy making this an area of high unmet medical need for 
combination IO treatments and novel therapeutic options such as PF-06939999.42,43  PRMT5 
is expressed in this disease, and bladder cancer models have demonstrated strong anti-tumor
responses to PF-06939999.  Using TCGA analysis, the incidence of  mutation in 119 splicing 
factors analyzed in bladder cancer samples was 51%, hence this tumor type was selected for 
Part 1 (dose escalation) and Part 2 (dose expansion) of the study.
4.2.7. Drug Resistance
Development of drug resistance is a reality for many participants being treated with targeted 
agents.  Initial clinical response is strong, but development of resistance to these drugs is 
common, with relapse occurring as early as 2 months of treatment.16 Mechanisms tumors use 
to evade targeted therapies involve bypass of the targeted pathways by utilizing alternative 
signaling pathways, regulating gene expression and acquiring DNA mutations in oncogenic 
drivers.  PF-06939999 targets a unique PRMT5-driven cellular process, alternative splicing, 
which remains a vulnerability in cancer cells where resistance has emerged to chemotherapy, 
oncogenic driver mutation therapies, cell cycle inhibitors and immunotherapy.  PF-06939999
demonstrated efficacy in several drug resistant cell lines, suggesting combinations or later 
line therapy options in the clinic may be effective in multiple cancer indications. This 
provides additional rationale for developing PF-06939999 in participants with advanced or 
metastatic HNSCC, NSCLC, esophageal, endometrial, cervical and bladder cancer that are 
resistant to standard therapy or for whom no standard of therapy is available in Part 1.
4.2.8. Background of Biomarker Assessments 
The objectives of the biomarker assessments is to (1) provide insight into the 
pharmacological effects of PF-06939999 by measuring 
 
 levels on target proteins such as SmD1, SmD3 and SmB/B’ prior to treatment, 
during treatment, and upon progression when appropriate samples are available; and (2) test 
the hypothesis of a participant selection strategy by retrospectively assessing mutations in 
splicing factor genes, aberrant splicing patterns and 
 
 PRMT5 inhibitor activity on the pharmacodynamic (PD) 
biomarker was originally assessed by measuring decreases in 
level detected by an 
in-cell ELISA and more recently by a flow-based assay utilizing a pan-
antibody 
(CST #13222), but will be replaced by a plasma-based liquid chromatography-mass 
spectrometry (LC/MS) assay. The biomarker assessments may contribute to confirming 
target exposure/engagement, determining PD effects and identifying those participants who 
are most likely to benefit from treatment.
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Since cancer types included in Part 1 Dose Escalation of this study are solid tumors, an 
immunohistochemistry (IHC) assay for 
 will be developed for participants 
who provide both pre- and post-treatment tumor samples. Easily accessible biomarkers such 
as those which can be detected in peripheral blood are always desirable options if available. 
Recent cell culture and mouse tumor model studies indicated that PF-06939999 could reduce 
more than 50% of supernatant and plasma free 
 respectively; whereas no 
change in the relevant control asymmetric dimethyl arginine (ADMA) level was detected, 
manifesting the specificity of PF-06939999. Furthermore, a correlation was observed 
between plasma 
 and the tumor volume in a mouse tumor model (data not 
shown), raising the possibility of utilizing free plasma 
 concentration as a PD and 
even a response predictive biomarker. A measurement of free 
 or plasma by 
an aforementioned LC/MS44 assay has been developed to enable PD biomarker analysis in a 
non-invasive way with the possibility of monitoring pre- and post-treatment samples at 
multiple time points. Since PRMT5 activity was shown to be associated with both adaptive 
and innate immune responses, peripheral blood RNA profiling will be performed for 
identifying potential PD biomarkers and for additional 
 purposes such as MoA (eg 
activation of CD8 T cell activity) or/and safety analysis (eg, identification of any 
toxicity-related gene signature). 
As previously stated, cancer cell lines carrying splicing factor mutations are more sensitive to 
PRMT5 inhibitors; for example, NSCLC cell lines with hotspot splicing factor mutations are 
more sensitive to PF-06939999 than those without mutation, and a participant stratification 
strategy based on these observations was therefore proposed accordingly. Splicing factor 
mutations will be assessed by using either a targeted sequencing approach or by whole 
exome sequencing (WES) focusing on the recently identified 119 splicing factor genes.45 A
recent TCGA publication reported that tumors have up to 30% more alternative splicing 
events than normal tissue, and there are associations between somatic variants of splicing 
factors and alternative splicing events.12 Therefore an effort will be made to identify 
common splicing variant events from tumor cell line data and to look for landmark splice 
variants in TCGA data with the expectation that a small set of alternatively spliced variants 
only detectable in PRMT5 sensitive tumors may be found to serve as predictive biomarkers. 
The results may help in the future development of PF-06939999 as a single agent, or in 
combination with other compounds, and may provide information on specific participant 
populations that may respond to the Investigational Product.
4.2.9. Scientific Rationale for Biomarker Studies
Biomarker studies will be used to help understand the in vivo mechanism of action of the 
agent(s) in this trial as well as identify potential mechanisms of resistance. 
Splicing factor mutations in archived or fresh biopsied tumor tissues will be analyzed 
retrospectively.  In addition, this study will also evaluate and attempt to identify predictive 
molecular targets/signatures in vivo.  Sample collection details for these studies can be found 
in the SoA.
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4.3. Justification for Dose
4.3.1. Starting Dose
The rationale for the starting dose in this study is based on all available nonclinical data 
including PK, pharmacodynamics, efficacy in xenograft mouse models, and toxicity 
observed in rat and dog. The goals of selecting the starting dose were: to identify a dose that 
is expected to have pharmacologic effects and is reasonably safe to use; and to minimize 
exposure to subtherapeutic doses. 
As described in Section 2.2.3, predicted CLp and Vss of PF‑06939999 in humans were 
3.1 mL/min/kg and 1.6 L/kg, respectively. The projected human effective half-life is 
approximately 6 hours, which was the rationale for the intial evaluation of the twice daily 
(BID) dose regimen following the first cohort receiving a once daily (QD) dose regimen.
Preliminary data (PK, PD, safety) from early cohorts of the study suggested that a QD dose 
regimen may also be feasible and will be evaluated for better participant compliance and 
convenience in subsequent dose escalation cohorts.   
Based on the PK/PD modeling in xenograft models with Pfeiffer (lymphoma) and SW1990 
(pancreatic cancer) cell lines, the pharmacologically active dose (PAD) was predicted to be 
50 mg BID, and corresponds to the tumor stasis concentration in these models and 
approximately 90% inhibition of 
 in the tumor. Using the MOLT4 (leukemia) 
xenograft model as representing sensitization to PRMT5 inhibition in a tumor with splicing 
factor mutation, the tumor stasis concentration was approximately 10-fold lower, suggesting 
the PAD may be lower in tumor indications with increased incidence of splicing 
dysregulation.
In the pivotal study the HNSTD and NOAEL of PF-06939999 in dog was 0.1 mg/kg/day, 
based on GI and hematologic toxicities. The toxicities which led to the determination of 
HNSTD are considered to be reversible and monitorable in humans. Similar GI toxicities 
occurred in rats at the highest dose of 30 mg/kg/day, and the middle dose of 10 mg/kg/day 
was determined to be the STD10.  
Using a body surface area scaling approach, the human equivalent dose (HED) for the 
HNSTD/NOAEL (0.1 mg/kg once daily) dose in dog is approximately 3.2 mg/day (assuming 
a body weight of 60 kg). The HED for STD10 in rat is approximately 100 mg/day.  
Therefore, the dog is considered the most sensitive species and is used for setting the starting 
dose in humans.  Based on the lowest available tablet strength (0.5 mg), the proposed starting 
dose is 0.5 mg po once daily (QD), or approximately one sixth the HED of the 
HNSTD/NOAEL in dogs. This starting dose is projected to result in less than 20% 
 
inhibition based on translational PK/PD modeling and is considered reasonably safe given 
the predicted toxicities described above. 
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The human unbound steady-state Cave and Cmax of PF-06939999 at the starting dose is 
projected to be 0.2 nM and 0.39 nM, respectively, resulting in an approximate 14.5-x and 
15.1-x margin relative to the observed unbound Cave (2.9 nM) and Cmax (5.9 nM) at 
HNSTD/NOAEL in dog, (po 0.1 mg/kg/day), and approximately 475-x and 528-x relative to 
the unbound Cave (95 nM) and Cmax (206 nM) at STD10 in rat. The projected exposures at the 
starting dose could be considered a conservative estimate as they do not incorporate impact 
of efflux by P-gp and BCRP, which could result in exposures lower than predicted, thereby 
leading to a larger margin relative to HNSTD.
The starting dose will be 0.5 mg given orally QD on a continuous basis in 28 day cycles. 
Subsequent cohorts will utilize a BID or QD dosing regimen on a continuous basis. Other 
dosing regimens, eg, intermittent dosing (such as 3 weeks on 1 week off), may also be 
considered in the study if supported by emerging clinical data.
4.3.2. Criteria for Dose Escalation
A 2-parameter Bayesian Logistic Regression Model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used in dose escalation in Part 1A and 
5-parameter model specifically developed for combinations will be used for Part 1B dose 
finding. See 10.9 for more details on the model used in Part 1A and Technical Supplement 
to Section 10.9 for more details of the model used in Part 1B.  Using DLT data at all tested 
dose levels and pre-specified prior distribution of model parameters, posterior probabilities of 
probability of having a DLT falling into 3 dosing intervals (underdosing, target dosing, 
overdosing) will be calculated for all dose levels.  A dose may only be used for newly 
enrolled participants in Part 1A and Part 1B if the risk of excessive toxicity (toxicity higher 
than 0.33 at that dose is less than 25%).
If intermediate dose levels are used, all the dose levels selected for administration will 
satisfy EWOC principle, ie, risk of over-dosing at this dose is predicted to be less than 25%. 
Final selection of the dose for the next cohort will be made based on all the available toxicity 
information (including adverse events which are not DLTs), PK, PD, and other relevant data 
as well as predictions of toxicity levels using BLRM.
The provisional dose levels to be evaluated are listed in Table 10.


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Table 10.
Provisional Dose Levels in Dose Escalation
Cohort
Total Daily Dose 
(mg)
Regimen
Maximal % 
increasea
DL1 (starting dose)
0.5
QD (0.5 mg)
-
DL2
1
BID (0.5 mg)
100%
DL3
2
BID (1 mg)
100%
DL4
4
BID (2 mg)
100%
DL5
8
BID (4 mg)
100%
DL6
16
BID (8 mg)
100%
DL7 
<32
QD or BID (TBDb)
100%
DL8 and beyond 
TBDb
QD or BID (TBDb)
100%
a. Calculated based on total daily dose (mg/day).
b. To be determined. 
Note: Alternative dosing may be evaluated based on evolving PK and safety data.
A maximum of 100% increment may be used in both Part 1A and Part 1B, given that the 
predicted human toxicities based on toxicities observed in both animal species are considered 
monitorable and reversible; however a smaller increment may be used based on review of 
data available from prior cohorts. Dose escalation cohorts may remain with the same 
regimen (QD or BID) or proceed to a different dosing regimen (eg, from BID to QD) 
compared to that for the previous dose level. However, within a given cohort, all participants 
should be tested either QD or BID but not both. The maximal dose increment will be 
calculated based on total daily dose regardless of the dosing regimen. The decision for 
testing a different dosing regimen in subsequent cohorts will be based on evaluation of 
available PK, PD, and safety data. Dose escalation utilizing continuous dosing will stop 
when stopping criteria are met (see Section 9.4.1). For individual participants, interchanging 
QD and BID dosing regimen during treatment is not allowed. 
If warranted, an intermittent dosing schedule may be used to mitigate toxicities observed in 
this first in human study.  In such case, participants may for example receive PF-06939999
administered orally BID or QD for 21 days on followed by 7 days off. The intermittent dose 
escalation schedule will begin at the MTD based on escalation using a continuous dosing 
regimen, and will proceed towards determination of MTD of the intermittent schedule (see 
Table 11).
Table 11.
Provisional Dose Levels in Dose Escalation with Intermittent 
Dosing Regimen
Cohort
Dose [mg/BID]
Maximal % increase
Starting dose (DL1)
X
-
DL2
≤2x
100%
DL3
≤4x
100%
DL4*
≤8x
100%
*Higher dose levels might be tested if warranted. Abbreviations: DL = dose level; x = the maximum tolerated 
dose determined from the escalation under continuous dosing regimen.


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Intrapatient dose escalation will not be allowed in any regimen.
4.3.3. Dose Limiting Toxicity Definition
Participants who discontinue treatment before completing Cycle 1 or receive less than 75% 
of the planned doses for reasons other than treatment-related toxicity (eg, missed 
appointments, misplaced investigational product supplies, development of rapidly 
progressing disease) might be replaced. 
For the purpose of dose escalation, the DLT observation period will be the first cycle of 
treatment (within 28 days of the first dose) in each participant including the Day 29 
laboratory assessments (for example, for PF-06939999 monotherapy with 28-day cycle, day 
29 laboratory assessments should be Cycle 2 Day 1 laboratory assessments).  Significant 
adverse events considered to be related to the investigational product or treatment under 
investigation that occurs after the DLT observation period will be reviewed in context of all 
safety data available.  That review may result in re-evaluation of the dosing level or regimen.
Severity of adverse events (AEs) will be graded according to CTCAE version 5.0.  
Hematologic Dose-Limiting Toxicities:
Any Grade 4 hematologic AE is a DLT with the following clarifications:
1. Grade 4 neutropenia regardless of intervention is a DLT.
2. Febrile neutropenia (defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.5°C [101.3°F] or a temperature of ≥38°C [100.4°F] sustained for 
more than 1 hour) is a DLT.
3. Grade 3 neutropenia with infection is a DLT. 
4. Grade 3 thrombocytopenia with ≥ Grade 2 clinically significant bleeding (defined as 
hospitalization or urgent medical intervention for atypical bleeding sites) is a DLT.
5. Grade 3 anemia requiring blood transfusion is a DLT.
Non Hematologic Dose-Limiting Toxicities: 
Any Grade ≥3 non-hematologic adverse events (AEs) is a DLTs with the following 
clarifications:
1. Grade 3 nausea/vomiting or diarrhea lasting ≥4 days after treatment with adequate 
antiemetics or other supportive care is a DLT.
2. Confirmed drug induced liver injury (DILI) meeting Hy's law criteria is a DLT.


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3. For participants with Grade 2 hepatic transaminase or alkaline phosphatase levels at 
baseline as a result of liver metastasis or bone metastasis, a hepatic transaminase or 
alkaline phosphatase level >10 times the upper limit of normal will be considered a 
DLT.
4. Clinically important or persistent toxicities that are not included in the above criteria 
may be considered a DLT following review by Pfizer and the investigators. All 
DLTs need to represent a clinically significant shift from baseline.
Any toxicity causing greater than 2 weeks of dose delay is a DLT.  Note: Participants
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 1 or baseline, only after discussion 
between the Investigator and Sponsor.
Any dose reduction due to an adverse event (per protocol) during the first cycle will be 
qualified as the participant experiencing DLT.
The following AEs will not be adjudicated as DLTs:

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.
4.3.4. Maximum Tolerated Dose Definition
Maximum tolerated dose (MTD) is defined as a dose with probability of a DLT from the 
target toxicity interval.  The target interval for the DLT rate is defined as (0.16,0.33).
For any given participant that is on‑treatment at dose levels that are subsequently considered 
to be above the MTD, the option to dose reduce will be discussed.  If a participant tolerated 
the above MTD dose level well and is benefiting from therapy, continuation of treatment at 
the above MTD dose level will require re‑consenting.
4.3.5. 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 Part 1A dose 
escalation, 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 sponsor based on the recommendation from investigators and 
study team. The determination of RP2D will be based on safety, tolerability, and early sign 
of clinical efficacy and benefit. Based on the safety, tolerability, and PK/PD data from Part 
1B combination dose finding, the combination recommended dose for expansion will be 
selected as an estimate of combination RP2D. Similarly, the final combination RP2D will be 
determined after combination expansion cohort. Combination RP2D may be different from 
monotherapy RP2D due to potential overlap toxicity or drug-drug interaction. 


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4.3.6. End of Study Definition
The end of the study is defined as two years after last participant first visit.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
During COVID-19 pandemic, please refer to Appendix 13 (Section 10.13) for additional 
eligibilities.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Females and/or male participants age 18 years.

Refer to Section 10.4 Appendix 4 for reproductive criteria for male 
(Section 10.4.1) and female (Section 10.4.2) participants.  
2. For Part 1 dose escalation participants must have histological or cytological diagnosis 
of a solid tumor that is advanced/metastatic, participants are intolerant to standard 
treatment or resistant to standard therapy* for the following tumor types: 

NSCLC;

HNSCC;

Esophageal;

Endometrial;

Cervical;

Bladder.

*Intolerance or progression on prior therapies must be documented for study 
enrollment.


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3. For Part 2 single agent dose expansion, NSCLC participants:

Histologically or cytologically confirmed, locally advanced or metastatic NSCLC
including squamous cell carcinoma or adenocarcinoma;

For NSCLC without available 1L targeted therapies (EGFR, ALK, ROS1, BRAF 
and NTRK negative), 2L+ NSCLC who have progressed after at least 1 line of
checkpoint inhibitors (CPI) and 1 line of platinum based chemotherapy regimen 
given together or sequentially in the metastatic setting;

For NSCLC with available 1L targeted therapies (EGFR, ALK, ROS1, BRAF or 
NTRK posivite), 2L+ NSCLC who have progressed after at least 1 line of targeted 
therapies;

Should receive no more than 3 lines of systemic therapies in metastatic setting;

Radiographic progression during or after the most recent treatment. 
4. For Part 2 combination with docetaxel expansion, NSCLC participants:

Histologically or cytologically confirmed, locally advanced or metastatic NSCLC 
including both squamous cell carcinoma and adenocarcinoma;

For NSCLC without available 1L targeted therapies (EGFR, ALK, ROS1, BRAF 
and NTRK negative), 2L+ NSCLC who have progressed after at least 1 line of 
checkpoint inhibitors (CPI) and 1 line of platinum based chemotherapy regimen 
given together or sequentially in the metastatic setting;

For NSCLC with available 1L targeted therapies (EGFR, ALK, ROS1, BRAF or 
NTRK posivite), 2L+ NSCLC who have progressed after at least 1 line of targeted 
therapies;

Have not been treated with taxane chemotherapy (docetaxel or palclitaxel) in 
locally advanced or metastatic setting;

Should receive no more than 2 lines of systemic therapies in metastatic setting;

Radiographic progression during or after the most recent treatment. 
5. For Part 2 urothelial carcinoma participants:

Histologically or cytologically confirmed, locally advanced or metastatic 
urothelial carcinoma of the bladder, renal pelvis, ureter or urethra;


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
2L+ urothelial cancinoma who have progressed after at least 1 line of standard of 
care chemotherapy (cisplatin/carboplatin+ Gemcitabine; or MVAC) and 1 line of 
checkpoint inhibitor in the metastatic setting;

Should receive no more than 3 lines of systemic therapies in metastatic setting;

Radiographic progression during or after the most recent treatment.
6. For Part 2 HNSCC participants:

Histologically or cytologically confirmed locally advanced or metastatic HNSCC;

2L+ HNSCC who have progressed after at least 1 line of standard of care 
systemic chemotherapy and one line of checkpoint inhibitors in the metastatic 
setting;

Should receive no more than 3 lines of systemic therapies in metastatic setting;

Radiographic progression during or after the most recent treatment. 
7. A mandatory archived formalin fixed- paraffin embedded (FFPE) tumor tissue block 
must be provided. If an archived FFPE tissue is not available, a de novo (ie, fresh) 
tumor sample should be obtained in accordance with local institutional practice for 
tumor biopsies.  
8. Participants must have at least 1 measurable lesion (not previously irradiated) as 
defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1, 
Section 10.11) that has not been previously irradiated.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
10. Adequate Bone Marrow Function, 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. Limited transfusions to reach this value are allowed, after 
discussion with the sponsor’s medical monitor.  There should not be a chronic 
need for transfusions in the recent (approximately 3 month) past.


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11. Adequate Renal Function, including:
Serum creatinine 1.5 x upper limit of normal (ULN) or Estimated creatinine 
clearance 50 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;
Estimated creatinine clearance 40 mL/min for participants with urothelial
carcinoma. 
12. Adequate Liver Function, including:
For Part 1A, 2A, 2B and 2C monotherapy
Total serum bilirubin 1.5 x upper limit of normal (ULN) for PF-06939999 
monotherapy (unless the partipant 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) for PF-06939999 monotherapy; 
AST and ALT 1.5 x ULN for PF-06939999 in combination with docetaxel;
For Part 1B and 2D in combination with Docetaxel
Total bilirubin ULN for PF-06939999 in combination with docetaxel;
Aspartate and Alanine aminotransferase (AST and ALT) 1.5 x ULN; alkaline 
phosphatase (ALP) 2.5 x ULN for PF-06939999 in combination with docetaxel. 
13. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 
except for AEs not constituting a safety risk by investigator judgment. Participants
with hypothyroidism of hypopituitarism resulting from immunotherapy on stable 
hormone replacement therapy and participants with adrenal insufficiency receiving 
doses <15 mg/day of prednisone equivalents are eligible.
14. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures. 
15. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Part 1 – Dose Escalation Monotherapy 
1. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth.  Participants with a history of 
CNS metastases or cord compression are eligible if they have been definitively 
treated (eg, radiotherapy, stereotactic surgery), have discontinued corticosteroid 
treatment (except for adrenal replacement therapy) for these metastases for at least 
4 weeks, and are clinically stable for 3 months (requires MRI confirmation) with no 
evidence of progression at time of study enrollment. 
2. Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk 
of life threatening complications in the short term (including participants with 
massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary 
lymphangitis, and over 50% liver involvement).  Note: Participants with indwelling 
catheter for drainage, or requirement for drainage no more frequently than monthly 
will be allowed.
3. Participants with any other active malignancy within 3 years prior to enrollment, 
except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in 
situ.
4. Major surgery within 4 weeks prior to study entry.
5. Radiation therapy within 4 weeks prior to study entry. 
6. Systemic anti-cancer therapy within 4 weeks prior to study entry (6 weeks for 
mitomycin C or nitrosoureas).  If the last immediate anti-cancer treatment contained 
an antibody based agent(s) (approved or investigational), then an interval of 28 days 
or 5 half lives (whichever is shorter) of the agent(s) prior to receive the 
investigational product treatment is required. 
7. Prior irradiation to >25% of the bone marrow (see Section 10.12 Appendix 12: Bone 
Marrow Reserve in Adults).


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8. Participants with active, uncontrolled bacterial, fungal, or viral infection, including 
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.  HIV 
seropositive subjects who are healthy and low risk for -AIDS related outcomes could 
be considered eligible.  Eligibility criteria for -HIV positive- subjects should be 
evaluated and discussed with sponsor’s medical monitor, and will be based on current 
and past CD4 and Tcell counts, history (if any) of -AIDS defining- conditions (eg, 
opportunistic infections), and status of HIV treatment. Also the potential for drug 
drug interactions will be taken into consideration.  In equivocal cases, with positive 
serology, those participants with a negative viral load are potentially eligible provided 
the other entry criteria are met.  Note: Inclusion of participants with well controlled 
HIV, HBV or HCV can be discussed with the sponsor on a case by case basis.
9. Bleeding esophageal or gastric varices <2 months prior to informed consent 
document (ICD) date.
10. Unmanageable ascites (limited medical treatment to control ascites is permitted, but 
all participants with ascites require review by the sponsor’s medical monitor). 
11. Baseline 12-lead electrocardiogram (ECG) that demonstrates clinically relevant 
abnormalities that may affect participant safety or interpretation of study results 
(eg, baseline corrected QT [QTc] interval >470 msec, complete left bundle branch 
block [LBBB], signs of an acute or indeterminate-age myocardial infarction, ST-T 
interval changes suggestive of active myocardial ischemia, second- or third-degree 
atrioventricular [AV] block, or serious bradyarrhythmias or tachyarrhythmias).  If the 
baseline uncorrected QT interval is >470 msec, this interval should be rate-corrected 
using the Fridericia method and the resulting QTcF should be used for decision 
making and reporting.  The average of the triplicate QTc or QRS values should be 
used to determine the participant’s eligibility. If the average QTc exceeds 470 msec, 
or the average QRS exceeds 120 msec, the participant is not eligible. 
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding participants.  Cases must be discussed in detail with 
the sponsor’s medical monitor to judge eligibility. 
12. Therapeutic anticoagulation. However, low molecular weight heparin, vitamin K 
antagonists or factor Xa inhibitors may be allowed following discussion with the 
Sponsor.
13. Any of the following in the previous 6 months: myocardial infarction, congenital long 
QT syndrome, Torsade de Pointes, clinically significant arrhythmias (including 
sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior 
hemiblock, bifascicular block, unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (CHF, New York Heart Association class 
III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic 
pulmonary embolism or other clinical significant episode of thrombo embolic disease.  


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Ongoing cardiac dysrhythmias of National Cancer Institute (NCI) CTCAE Grade ≥2, 
atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial 
fibrillation).  Subjects with cardiac rhythm device/pacemaker must be discussed in 
detail with sponsor’s medical monitor to judge eligibility.  
14. Hypertension that cannot be controlled by medications (>150/90 mmHg despite 
optimal medical therapy) or requiring more than 2 medications for adequate control.
15. Participants with intolerance to or who have had a severe (Grade 3) allergic or 
anaphylactic reaction to any of the substances included in the investigational product 
(excluding excipients).
16. Participation in other studies involving investigational drug(s) within 28 days prior to 
first dosing.  Note: Participation in long term follow up of other studies is allowed if 
no procedures which may interfere with the interpretation of study results will be 
performed.
17. Known or suspected hypersensitivity to PF-06939999. For PF-06939999 in 
combination with docetaxel, history of hypersensitivity reactions to docetaxel or to 
drugs formulated with polysorbate 80 is also excluded.
18. Inability to consume or absorb study drug, including but not limited to: Active 
inflammatory gastrointestinal (GI) disease, known diverticulitis or previous gastric 
resection or lap-band surgery.  Impairment of gastro-intestinal function or GI disease 
that may significantly alter the absorption of PF-06939999 tablets, such as history of 
GI surgery with may result in intestinal blind loops and participants with clinically 
significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active 
inflammatory bowel disease or diarrhea of CTCAE Grade >1. Participants with 
HNSCC requiring drug administration via NG tube are eligible if they meet other 
criteria. 
19. Current use or anticipated need for food or drugs that are known strong and/or 
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 (Strong CYP3A4/5 inhibitors: eg, grapefruit juice or 
grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), ketoconazole, 
miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, 
indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, 
lopinavir, troleandomycin, mibefradil, and conivaptan; Moderate CYP3A4/5 
inhibitors: eg, erythromycin, verapamil, atazanavir, delavirdine, fluconazole, 
darunavir, diltiazem, aprepitant, imatinib, tofisopam, ciprofloxacin, and cimetidine).
20. Current use or anticipated need for drugs that are known strong/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 (Strong CYP3A4/5 inducers: eg, phenobarbital, rifampin, phenytoin, 


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carbamazepine, rifabutin, rifapentin, clevidipine, St. John’s Wort; Moderate 
CYP3A4/5 inducers: eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). 
21. Current use or anticipated need for drugs that are known P-glycoprotein (P-gp) or 
BCRP inhibitors, including their administration within 7 days of the P-gp or BCRP
inhibitor prior to the first dose of investigational product. P-gp inhibitors may include 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, 
lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, 
tipranavir or verapamil. BCRP inhibitors may include curcumin, cyclosporine A, and
eltrombopag.
22. Serum or urine pregnancy test (for females of childbearing potential) positive at 
screening.
23. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study. 
24. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
5.3. Lifestyle Considerations 
The following guidelines are provided.
5.3.1. Photosensitivity
Participants 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 
participants’ exposure to light including sunlight, and high intensity ultraviolet B (UVB) 
light sources such as tanning beds, tanning booths and sunlamps.  Participants should be 
encouraged to apply sunscreen/sunblock daily and to wear clothing that covers areas of 
exposed skin when outdoors during daylight hours. 
5.3.2. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods 
(Section 10.4 Appendix 4) and will confirm that the has been instructed in its consistent and 
correct use.  At time points indicated in the schedule of activities (SoA), the investigator or 
designee will inform the participant of the need to use highly effective contraception 


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consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 
1 of the selected methods of contraception).  In addition, the investigator or designee will 
instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial, who 
do not meet 1 or more criteria required for participation in the trial during the screening 
procedures and are not subsequently assigned to the study intervention.  A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).  It should be stated if this information will be captured in the case report form (CRF) 
or elsewhere.
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened.  Rescreened participants should be assigned a different participant number as for 
the initial screening.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
For this study, the investigational product is PF-06939999.
Participants enrolled in Parts1A, 2A, 2B, and 2C will receive PF-06939999 orally daily on a 
continuous basis as monotherapy in 28 day cycles.
Participants enrolled in Parts 1B and 2D will receive PF-06939999 orally on a continuous 
basis in combination with docetaxel given on Day 1 of each 21-day cycle until disease 
progression, unacceptable toxicity, or participant refusal, whichever occurs first.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored- shipments. 


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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All study 
interventions will be accounted for using an investigational product accountability 
form/record.  Participant will return all empty containers and unused product to the 
investigator.
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels.  
7. Site staff will instruct participants on the proper storage requirements for take
home- study intervention. 
8. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion.  Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation.  Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site in the IP manual.
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.


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6.2.1. Preparation and Dispensing
The investigational product (PF-06939999) 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 
participant/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 investigational agents.
For Part 1B and 2D PF-06939999, docetaxel will be used in accordance with the US Package 
Insert (USPI).
6.2.2. Investigational Product Supplies
PF-06939999 will be supplied by Pfizer.  The clinical sites will receive PF-06939999 prior to 
enrollment of the first participant.
The clinical site pharmacy will dispense the supply that is appropriate for the participant.
Docetaxel is commercially available and will be supplied by the clinical sites as standard of 
care and reimbursed by the participant’s insurance. Pfizer will reimburse the cost of 
docetaxel for participants who do not have insurance. 
6.2.3. Dosage Form(s) and Packaging
PF-06939999 will be provided as tablets for oral administration. The 0.5 mg, 1 mg and
5 mg, will be supplied in separate bottles and labeled according to local regulatory 
requirements.
Docetaxel is commercially available and will be used in accordance with the US Package 
Insert (USPI).
6.2.4. Administration
6.2.4.1. PF-06939999 Administration
Participants will swallow the investigational product whole, and will not manipulate 
(eg, crush) or chew the investigational product prior to swallowing. Participants who are 
unable to swallow whole tablets may dissolve their dose in oral syringe(s) as outlined in the 
IP manual to allow for suspension administration either orally or via an NG tube.
PF-06939999 will be administered orally initially QD, then BID or QD for subsequent 
cohorts on a continuous basis. If supported by emerging data, alternative intermittent dosing 
regimen may be considered.  For monotherapy cohorts, a cycle is defined as continuous 
dosing of 28 days, regardless of missed doses or dose delays. For Cohorts 1B and 2D 


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(PF-06939999 in combination with docetaxel) a cycle is defined as 21 days to be consistent 
with docetaxel treatment cycles and dosing schedule. 
For the BID dosing regimen, on days where the morning dose of PF-06939999 is held due to 
a specific study visit, the second dose on that day should be taken no sooner than 8 hours, 
and no later than 16 hours post the first dose on that day (allowable treatment window 
±4 hours). For once daily dosing regimen, the allowable treatment window is ±4 hours. 
PF-06939999 will be administered orally on an empty stomach without adjustment for body 
size at every cycle. Participants should be instructed to take their medication at 
approximately the same time each day and to not take more than the prescribed dose at any 
time. If a participant misses a dose or day of treatment, they must be instructed not to “make 
it up” but to resume subsequent doses as prescribed. In addition, if a participant vomits any 
time after taking a dose; they must be instructed not to “make it up” but to resume 
subsequent doses as prescribed. Lastly, if a participant inadvertently takes 1 extra dose 
during a day, the participant should not take the next dose of PF-06939999.
Investigational product (PF-06939999) tablets can also be dissolved into a suspension which 
can be administrated orally or via nasogastric (NG) tube if needed. Detailed instructions for 
suspension preparation and administration are provided in the IP manual.
On Cycle 1 Day 15 and Day 16, Part 2 participants participating in the food effect assessment 
will receive PF-06939999 under fasted and fed conditions, respectively, at the site, and have 
blood samples collected for PK characterization.  
A dosing diary will be given to the participant to support at-home dosing.
6.2.4.2. Food Requirements
6.2.4.2.1. Food Requirements (Except for the Food-Effect Cohort)
Oral PF-06939999 will be administered QD or BID with at least 8-oz (240 mL) of water or 
as a suspension for participants who are unable to swallow tablets.  Investigational product is 
to be administered on an empty stomach, no food or liquids other than water will be 
consumed for 2 hours before and 1 hour following each dose throughout the study.  These 
fasting requirements may be removed (via a letter to the investigators) if the data from the 
food-effect study (that will be performed in Part 2) indicate that there is not a substantial 
effect of food on the bioavailability of PF-06939999. 
6.2.4.2.2. Food Requirements for the Food-Effect Sub-study
For all participants participating in the food-effect substudy (to be evaluated in at least 
6 participants in Part 2B dose expansion), PF-06939999 will be administered under the fasted 
and fed conditions on Cycle 1 Day 15 and Day 16, respectively, and under empty stomach 
condition (see Section 6.2.4.2.1) for the remaining portion of the study. 


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Cycle 1 Day 15 (Fasted condition): PF-06939999 will be administered, following an 
overnight fast of at least 10 hours, with 8 ounces (240 mL) of water. No food will be 
allowed for an additional 4 hours post dose. Water will be allowed ad libitum except for 
1 hour before and 1 hour after drug administration.
Cycle 1 Day 16 (Fed condition): Following overnight fasting of at least 10 hours, a test 
breakfast meal (described below) will be provided and must be consumed over 30 minutes.  
PF-06939999 will be administered with approximately 8 ounces (240 ml) of water
30 minutes after the start of the meal. No additional food will be allowed until at least 
4 hours post-dose. Water will be allowed ad libitum except for 1 hour before and 1 hour 
after drug administration.
The test meal to be consumed will be a high-fat (approximately 50% of total caloric content 
of the meal) and high-calorie (approximately 800-1000 calories) meal. This test meal should 
derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively. An example test meal would be 2 eggs fried in butter, 2 strips of bacon (may be 
replaced with ham and cheese of similar caloric content), 2 slices of toast with butter, 
4 ounces of hash brown potatoes, and eight ounces of whole-fat milk. Substitutions to this 
test meal can be made after discussion with the sponsor, as long as the meal provides a 
similar amount of calories from protein, carbohydrate, and fat and has comparable meal 
volume and viscosity (if substitutions are made, the contents of the meal will be documented 
by a dietitian or designate to confirm it matches the Food and Drug Administration [FDA] 
requirements for protein, carbohydrate and fat described above). However, it is understood 
that some participants may not be able to consume the entire meal. Study staff should record 
the percent of the test meal consumeed and the time it took to be consumed.
6.2.4.3. Docetaxel Administration
For participants in Parts 1B and 2D, docetaxel will be administered at 75 mg/m2
intravenously over 1 hour on Day 1 of each 21 day cycle until disease progression,
unacceptable toxicity, or participant refusal, whichever occurs first.  All participants should 
be premedicated with oral corticosteroids such as dexamethasone 16 mg per day (eg, 8 mg 
BID) for 3 days starting 1 day prior to docetaxel administration in order to reduce the 
incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.  
Participants should be observed closely for hypersensitivity reactions, especially during the 
first and second infusion.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Eligible participants will be enrolled to receive PF-06939999 in an open-label, unblinded 
manner. In Part 1, participants will be successively assigned to the next available treatment 
slot. Dose level allocation will be performed by the sponsor after participants have given 
their written informed consent and have completed the necessary baseline assessments.  The 
site staff will e-mail a complete Registration Form to the designated sponsor study team 
member or designee.  The sponsor will assign a participant identification number and supply 


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this number to the site.  The participant identification number will be used on all study
related- documentation at the site.
No participant shall receive investigational product until the investigator or designee has 
received the following information in writing from the sponsor:

Confirmation of the participant’s enrollment;

Specification of the dose level for that participant; and 

Permission to proceed with dosing the participant.

In Part 2, allocation of participants to treatment groups will proceed through the use 
of an IRT system (IWR).  The site personnel (study coordinator or specified designee) 
will be required to have an active or valid account and password with the IRT system, 
enter or select information including but not limited to the users ID and password, 
protocol number, specific protocol entrance criteria indicated in the system and the 
participant number.  The site personnel will then be provided with, at a minimum, a 
treatment assignment, randomization number, and DU or container number when 
study intervention is being supplied via the IRT system.  The IRT system will provide 
a confirmation report containing the participant number, randomization number, and 
DU or container number assigned.  The confirmation report must be stored in the 
site’s files.  
Study interventions will be dispensed at the study visits as summarized in the SoA.  
Returned PF-06939999 must not be redispensed to the participants.
The study‑specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
6.4. Study Intervention Compliance
Participant compliance with investigational product will be assessed at each visit.  
Compliance will be assessed by direct questioning, counting returned tablets/capsules, and 
review of the participant diary.  Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF.
All investigational products will be distributed to the participant by the appropriately 
designated study staff at the investigational site.  Participants will be required to return all 
unused study treatment at the beginning of each cycle.  The number of tablets returned by the 
participant will be counted, documented, and recorded.


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A participant diary will be provided to the participants to aid in compliance with the dosing 
instructions.  The diary will be maintained by the participant to include missed or changed 
PF-06939999 doses.  Participants will be required to return all bottles of PF-06939999 every 
cycle.  The number of PF-06939999 tablets remaining will be documented and recorded at 
each clinic visit or Day 1 of each cycle.  The participant diary may also be used to support 
this part of the PF-06939999 accountability process via a discussion between the study site 
staff and the participant. Discrepancies will be documented on the appropriate eCRF.
6.5. Concomitant Therapy
Concomitant treatment considered necessary for the participant’s well-being may be given at 
discretion of the treating physician.  
All concomitant treatments, blood products, as well as nondrug interventions received by 
participants from screening until the end of study visit will be recorded on the CRF.
6.5.1. Potential Drug-Drug Interactions
All concomitant treatments that have a clinically significant potential drug interaction must 
be approved by the sponsor at study entry. Because inhibition of CYP3A4/5 isoenzymes 
may increase PF-06939999 exposure leading to potential increases in toxicities, the use of 
known strong and/or moderate inhibitors is not permitted within 10 days or 5 half-lives of the 
CYP3A4/5 inhibitors, whichever is longer, prior to the first dose of investigational product.
Strong CYP3A4/5 inhibitors may include grapefruit juice or grapefruit/grapefruit related 
citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, 
and conivaptan.  Moderate CYP3A4 inhibitors may include erythromycin, verapamil, 
atazanavir, fluconazole, darunavir, diltiazem, delavirdine, aprepitant, imatinib, tofisopam, 
ciprofloxacin, and cimetidine. 
Because induction of CYP3A4/5 isoenzymes may decrease PF-06939999 exposure leading to 
potential decrease in efficacy, the use strong/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 investigational product. Strong CYP3A4/5 inducers may include phenobarbital, 
rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John’s Wort.  
Moderate CYP3A4/5 inducers may include bosentan, efavirenz, etravirine, modafinil, and 
nafcillin. For Part 1B and Part 2D only, participants are allowed to receive dexamethasone (a 
moderate CYP3A4 inducer) for a limited duration as a premedication for docetaxel as 
indicated in Section 6.2.4.3.
Concomitant use of PF-06939999 and a CYP2D6 substrate may increase the exposure of the 
CYP2D6 substrate.  CYP2D6 substrates of a narrow therapeutic index, may include 
thioridazine. Therefore, caution is warranted if coadministration of PF-06939999 with these 
and other CYP2D6 substrates occurs.


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Because inhibition of P-glycoprotein (P-gp) or BCRP transporters may increase 
PF-06939999 exposure leading to potential increases in toxicities, the use of known 
inhibitors is not permitted within 7 days of P-gp or BCRP inhibitors prior to the first dose of 
investigational product. P-gp inhibitors may include amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, 
saquinavir, telaprevir, tipranavir or verapamil. BCRP inhibitors may include curcumin, 
cyclosporine A, and eltrombopag.
Concomitant use of PF-06939999 and a substrate of the BCRP, or OCT1 transporters may 
increase the exposure of a substrate for the transporter.  Therefore, caution is warranted if 
coadministration of PF-06939999 with BCRP, or OCT1 substrates occurs.
6.5.2. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while participants are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not 
permitted.
6.5.3. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to the specific supportive care product Prescribing 
Information or the current American Society of Clinical Oncology (ASCO) guidelines. 
6.5.4. Hematopoietic Growth Factors
The use of granulocyte colony stimulating factors is permitted in this study.  However, 
primary prophylactic use of granulocyte colony stimulating factors is not permitted during 
the first 28 days (DLT assessment period), but they may be used during this time to treat 
treatment emergent neutropenia.  The use of these factors is as indicated by the current 
American Society of Clinical Oncology (ASCO) guidelines.  Erythropoietin may be used at 
the investigator’s discretion for the supportive treatment of anemia. 
6.5.5. Acid Reducing Agents
The solubility PF-06939999 was greater than 2 mg/mL in the range from pH 7.0 to pH 1.1 
(Section 2.2.3). Therefore, pH is not anticipated to impact oral absorption in the planned 
clinical dose range and acid reducing agents are permitted, including:

H2-Receptor Antagonists (H2RAs) for symptomatic treatment of gastrointestinal 
disorder (including, but not limited to famotidine, ranitidine, nizatidine, cimetidine);

Local antacids for symptomatic treatment of gastrointestinal disorder (eg, 
aluminum/calcium hydroxide, aluminum/calcium carbonate, bismuth subsalicylate);

Acid reducing agents (including proton pump inhibitors) can be used for symptomatic 
treatment of gastrointestinal disorder.


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6.5.6. Anti-Diarrheal, Anti-Emetic Therapy 
Primary prophylaxis beyond the first cycle 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 drugdrug- interaction and 
assuming the drug is not included in Section 6.5.1 Potential Drug-Drug Interactions.
6.5.7. AntiInflammatory- Therapy
Antiinflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in Section 
6.5.1 Potential Drug-Drug Interactions. 
6.5.8. Corticosteroids 
Chronic systemic corticosteroid use (prednisone >15 mg/day or equivalents) for palliative or 
supportive purposes is not permitted.  However, corticosteroid use for a short duration (eg, 
≥15 mg/day of prednisone, for 2 weeks) as symptomatic treatment on an individual basis 
may be considered after discussion with the sponsor’s medical monitor or designee. For 
adrenal insufficiency replacement therapy, doses <15 mg/day will be allowed. Acute 
emergency administration, topical applications, inhaled sprays, eye drops, or local injections 
of corticosteroids are allowed.
6.5.9. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-06939999 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06939999 is 
recommended at least 7 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-06939999 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6.6. PF-06939999 Dose Modification 
Every effort should be made to administer PF-06939999 on the planned dose and schedule.  
In the event of significant toxicity, dosing may be interrupted and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed (and attribution for the combination treatment – use if a combination is to 
be tested).  Participants are to be instructed to notify investigators at the first occurrence of 
any adverse symptom. 
For Cohorts 1B and 2D, docetaxel dose modifications should be performed in accordance 
with the approved labeling (See Section 6.6.3).


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6.6.1. PF-06939999 Dosing Interruptions
Participants experiencing Grade 3-4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care should have PF-06939999 interrupted. Appropriate 
followup- assessments should be done until adequate recovery occurs as assessed by the 
investigator.  Doses may be held up to 4 weeks until toxicity resolution.  
Doses omitted for toxicity are not replaced within the same cycle.  The need for a dose 
reduction at the time of treatment resumption should be based on the criteria defined in 
Section 6.6.2, unless expressly agreed otherwise following discussion between the 
investigator and the sponsor.  If a dose reduction is applied in the same cycle, the participant
will need to return to the clinic to receive new drug supply.
Retreatment following treatment interruption for -treatment related- toxicity may not occur 
until all of the following parameters have been met:

ANC 1,000/mm3 for PF-06939999 monotherapy; ANC 1,500/mm3for 
PF-06939999 in combination with docetaxel; 

Platelets count 50,000/mm3;

Nonhematologic 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 participant).
If a treatment interruption 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-06939999 may be 
resumed.  Refer to Section 6.6.2 for adverse events requiring dose reduction at the time of 
treatment resumption. 
If participants require interruption of PF-06939999 due to treatment related toxicity 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 after 
discussion with the Sponsor’s medical monitor. 
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.  
6.6.2. PF-06939999 Dose Reductions
Following dosing interruption due to toxicity, the PF-06939999 dose may need to be reduced 
when treatment is resumed. Any dose reduction due to an adverse event (per protocol)
during the first cycle will be qualified as participant experiencing DLT. 


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No specific dose adjustments are recommended for Grade 1/2 treatment related- toxicity.  
However, investigators should always manage their participants according to their medical 
judgment based on the particular clinical circumstances.
Participants 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.
Dose reduction of PF-06939999 by 1 and, if needed, 2 previously studied dose levels will be 
allowed depending on the type and severity of toxicity encountered. If previously studied 
dose levels are incomplete for QD schedule, the table below should be considered as a 
general recommendation. In addition, dose reduction to intermittent dose level can be 
considered for individual participants based on the type and severity of the toxicities after 
agreement between the investigator and the sponsor. Participants 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 participant's source notes and 
CRF. 
Table 12.
PF-06939999 dose level (depending on RP2D decision)
Starting Dose
8 mg QD
6 mg QD
4 mg QD
- 1
6 mg QD
4 mg QD
2 mg QD
- 2
4 mg QD
2 mg QD
1 mg QD
- 3
Discontinue
Discontinue
Discontinue
Once a dose has been reduced for a given participant, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Intrapatient dose 
re-escalation is not allowed.
For Part 1 dose escalation, participants experiencing a DLT may resume dosing at the next 
lower dose level (if applicable) once adequate recovery is achieved, and if in the opinion of 
the investigator and the sponsor, the participant is benefiting from therapy.  In some cases, 
participants 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.  
For both Part 1 dose escalation and part 2 dose expansion, recommended dose reductions for 
PF-06939999 non-hematologic related toxicity are described in Table 13.


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Table 13.
Dose Modifications for PF-06939999 Related Toxicity: 
Nonhematologic  
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Nonhematologic
Continue at 
the same 
dose level.
Continue at the same 
dose level. 
Hold 
PF-06939999 until 
toxicity is Grade ≤1, 
or has returned to 
baseline, within 4 
weeks and 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 drug for 
related Grade 4 
adverse events of 
any duration.**
Pancreatitis
Continue at 
the same 
dose level.
For Grade 2 
pancreatitis, hold 
PF-06939999 until 
toxicity is resolved, 
then reduce the dose 
by 1 level. 
For Grade 3 
pancreatitis, consider 
discontinuation 
(continuation requires 
sponsor approval).*
Permanent 
discontinuation of 
study drug for 
related Grade 4 
adverse events of 
any duration.**
Diarrhea
Continue at 
the same 
dose level.
For persistent Grade 2 
diarrhea may consider 
to interrupt dosing, 
then restart at the 
same dose after 
toxicity is Grade ≤1.  
If a Grade 2 diarrhea 
caused weight loss, or 
other severe 
symptoms, discuss 
with sponsor and 
consider to reduce the 
dose by 1 level.
For Grade 3 diarrhea, 
hold PF-06939999
until toxicity is 
Grade ≤1, or has 
returned to baseline, 
then consider reducing
the dose by 1 level.
Permanent 
discontinuation of 
study drug for 
related Grade 4 
adverse events of 
any duration.**
* Participants may continue on trial if they are receiving clinical benefit after discussion between the 
investigator and sponsor.
** Exclusion: Nausea, vomiting, or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy to 
require dose modification. Grade 3 or 4 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions. Grade 3 or 4 amylase and/or 
lipase must be accompanied by signs or symptoms or radiological evidence of pancreatitis.  
For both Part 1 dose escalation and Part 2 dose expansion, recommended dose reductions for 
PF-06939999 hematologic related toxicity are described in Table 14.


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Table 14.
Dose Modifications for PF-06939999 Related Toxicity: Hematologic  
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Anemia
Continue 
at the 
same 
dose 
level.
Continue 
at the 
same dose 
level.
Hold PF-06939999 until 
toxicity is Grade ≤2, or 
has returned to baseline,
and then reduce the dose 
by one level.

If toxicity 
reoccurs despite 
dose reduction, 
PF-06939999
may be held 
until recovery, 
then consider 
reducing the 
dose by one 
level.
Consider permanent 
discontinuation of study 
drug for related Grade 
4 adverse events of any 
duration. (Continuation will 
require agreement between 
the investigator and 
sponsor).*
Neutropenia
Continue 
at the 
same 
dose 
level.
Continue 
at the 
same dose 
level.
Hold PF-06939999 until 
toxicity is Grade ≤2, or 
has returned to baseline, 
then resume treatment at 
the same dose level.

If toxicity 
reoccurs despite 
dose reduction, 
PF-06939999
may be held 
until recovery or 
ANC >1500 
cells/mm3, then
consider 
reducing the 
dose by one 
level.

G-CSF for 
treatment are 
permitted based 
on Investigator 
judgment. 
Consider permanent 
discontinuation of study 
drug for related Grade 4 
adverse events of any 
duration. (Continuation will 
require agreement between 
the investigator and 
sponsor).*  
G-CSF for treatment are 
permitted based on 
Investigator judgement.


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Table 14.
Dose Modifications for PF-06939999 Related Toxicity: Hematologic  
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Thrombocytopenia
Continue 
at the 
same 
dose 
level.
Continue 
at the 
same dose 
level.
Hold PF-06939999 until 
platelets ≥75,000/mm3. 
and then reduce the dose 
by one level. 
If toxicity reoccurs 
despite dose reduction, 
hold PF-06939999 up to 
4 weeks until recovery 
and then reduce the dose 
by another dose level.
Consider permanent 
discontinuation of study 
drug for related Grade 
4 adverse events of any 
duration. (Continuation will 
require agreement between 
the investigator and 
sponsor).*
For platelet counts 
10,000 – 25,000/mm
3, 
monitor every 3 days until 
recovery to >25,000/mm3
For platelet counts 
≤10,000/mm3 monitor daily 
until recovery to 
>25,000/mm3. 
Reduce PF-06939999 by 
1 dose level. 
If toxicity reoccurs despite 
dose reduction, hold
PF-06939999 until recovery 
and either continue at the 
same dose with increased 
monitoring, or further dose 
reduce by another dose level 
(for participants is in the 
first dose group, only 1 dose 
reduction is allowed).
* Participants may continue on trial if they are receiving clinical benefit after discussion between the 
investigator and sponsor. Withhold dose until toxicity is Grade ≤2, or has returned to baseline after agreement 
with sponsor resume treatment at a reduced dose level.
6.6.3. Docetaxel Dose Modifications
Hypersensitivity reactions (characterized by generalized rash/erythema, hypotension and/or 
bronchospasm, or anaphylaxis) require immediate discontinuation of the docetaxel 
administration infusion and administration of appropriate therapy. 
Participants dosed at 75 mg/m2 who experience either febrile neutropenia, neutrophils 
<500 cells/mm3 for more than 1 week, nadir platelet count <25,000 cells/mm3, severe or 
cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during 
docetaxel treatment should have treatment withheld until resolution of the toxicity and then 


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resumed at 65 mg/m2. For participants requiring further dose reduction, a dose of 
65 mg/m2.is recommended.
Participants who develop ≥grade 3 peripheral neuropathy should have docetaxel treatment 
discontinued entirely.(ref USPI).
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation).  Reasons for definitive discontinuation of study 
intervention may include the following:

Objective disease progression;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Participant refused further treatment;

Study terminated by sponsor;

Death.
If investigational product is permanently discontinued, the participant will remain in the 
study for further evaluation.  See the SoA for data to be collected at the time of 
discontinuation of study intervention.
Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for survival.  See the SoA for data to be collected at the time of discontinuation 
of study intervention and follow-up for any further evaluations that need to be completed.


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In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Temporary Discontinuation 
Participants who discontinue treatment due to disease progression that is subsequently 
determined to have been based on equivocal radiological findings, may resume treatment 
after discussion with the Sponsor’s medical monitor. 
See Appendix 13 for guidance for participants with active or presumed SARS-CoV2 
infection.
7.1.2. Rechallenge
Participants who meet criteria for treatment discontinuation due to toxicity should not be 
rechallenged, unless the investigator’s benefit/risk assessment suggests otherwise after 
discussion with the Sponsor’s medical monitor.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  
The Early Discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding 
their reason for withdrawal.  The participant will be permanently discontinued both from the 
study intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.


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If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent: 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.


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
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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8.1. Efficacy Assessments
Anti-tumor activity will be assessed through radiological tumor assessments conducted as 
specified in the schedule of activities. Assessment of response will be made using RECIST 
version 1.1 (see Section 10.11, Appendix 11: RECIST for details) by investigators or 
qualified designees (radiologist, etc.).
8.1.1. Safety Imaging Assessments 
Unscheduled CT/MRI chest and abdomen with contrast should be obtained for all suspected 
cases of pancreatitis.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs 
and physical examination, electrocardiogram (12-lead ECG), laboratory assessments, 
including pregnancy tests and verification of concomitant treatments.  
During COVID-19 pandemic, please refer to Appendix 13 (Section 10.13) for safety and 
efficacy assessments.
8.2.1. Physical Examinations
Participants will have a physical examination to include weight, vital signs, assessment of 
ECOG performance status and height; height will be measured at screening only.
Findings should be recorded in the source documents, and any change from baseline 
considered by the investigator to be clinically significant should be recorded as an adverse 
event in the CRF.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2. Vital Signs
Oral temperature, pulse rate, and blood pressure (BP) will be assessed.


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Blood pressure and pulse rate measurements will be assessed in a sitting or semi-recumbent 
position (however the position should be maintainted throughout the study) with a 
completely automated device.  Manual techniques will be used only if an automated device is 
not available.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
rate and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute).  The average of the 3 blood pressure readings will 
be recorded on the CRF.
8.2.3. Electrocardiograms
Standard 12-Lead ECGs utilizing limb leads (with a 10-second rhythm strip)  should be 
collected at times specified in the Section 1.3 of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex.  
All scheduled ECGs should be performed after the participant has rested quietly for at least 
10 minutes in a supine position. At each time point (see Table 5, Table 6, and Table 7), 
3 consecutive ECGs will be performed at approximately 2 minutes apart to determine the 
mean QTcF interval.  After Cycle 3, ECGs can be performed as clinically indicated.  All 
ECG collection time points are with respect to PF-06939999 morning dosing. When 
coinciding with blood sample draws for PK, ECG assessment should be performed prior to 
blood sample collection, such that the blood sample is collected at the nominal time.  To 
ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Additional ECG monitoring will occur if a) the 
mean value from the triplicate measurements for any postdose QTcF interval is increased by 
60 msec from the baseline and is >450 msec; or b) an absolute QTcF value is 500 msec for 
any scheduled ECG. If either of these conditions occurs, then a single ECG measurement 
must be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.  In addition, if verified QTcF values 
continue to exceed the criteria above, immediate correction for reversible causes including 
electrolyte abnormalities, hypoxia and concomitant medications for drugs with the potential 
to prolong the QTcF interval should be performed.
If the QTcF interval reverts to less than the treshhold criteria listed above, and in the 
judgment of the investigator(s) and sponsor, it is determined that the cause(s) of QTcF 
prolongation is something other than investigational product, treatment may be continued 
with regular ECG monitoring.  If in that timeframe the QTcF intervals rise above the 
threshold values, the investigational product will be held until the QTc interval decreases to 
below the threshold values.  Participants will then restart the investigational product at the 
next lowest dose level.  If the QTcF interval has still not decreased to <480 msec after 
2 weeks, or if at any time a participant has a QTcF interval >500 msec or becomes 


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symptomatic, the participant discontinuation will be discussed with the Sponsor.  Additional 
triplicate ECGs may be performed as clinically indicated.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
If a participant experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event. 
ECG values of potential clinical concern are listed in Section 10.7 Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Section 10.2 Appendix 2: Clinical Laboratory Tests for the list of clinical safety 
laboratory tests to be performed and the SoA for the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Section 10.2 Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.5. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in women of childbearing potential 
(WOCBP) at the times listed in the SoA.  Following a negative pregnancy test result at 


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screening, appropriate contraception must be commenced and a second negative pregnancy 
test result will be required at the baseline visit prior to the participant’s receiving the 
PF-06939999.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed 
during the active treatment period (or when potential pregnancy is otherwise suspected) and 
at the end of the study.  Pregnancy tests may also be repeated if requested by institutional 
review boards (IRBs)/ethics committees (ECs) or if required by local regulations.  If a urine 
test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required.  In such cases, the participant must be excluded if the serum pregnancy result is 
positive. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue 
PF-06939999 (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days, except as indicated below, after the last administration of the 
investigational product.
During the long-term follow-up period in this study for survival, only SAEs will be actively 
elicited and collected after completion of the active collection period described above. The 
SAEs identified during long-term follow-up will be reported to Pfizer Safety on the CT SAE 
Report Form only if considered reasonably related to the study intervention.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.


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Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Section 10.3 Appendix 3.  The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3
Appendix 3: Adverse Events.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
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8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in in Section 10.3, Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 30 days after the 
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If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report Form 
to Pfizer Safety Within 24 Hours of 
Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.


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Such medication errors occurring to a study patie are to be captured on the medication error
page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified -within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-06939999 greater than the daily dose assigned will be 
considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of PF-06939999 (whichever 
is longer).
3. Obtain a blood sample for PK analysis within 30 days from the date of the last dose 
of study intervention if requested by the medical monitor (determined on a 
case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
8.5.1. Plasma for analysis of PF-06939999 and docetaxel concentrations
Blood samples of approximately 3 mL, to provide a minimum of 1 mL of plasma, will be 
collected for measurement of plasma concentrations of PF-06939999 as specified in the
Schedule of Activities (SoA). For Part 1B and Part 2D only, approximately 3 mL of blood 
samples (to provide a minimum of 1 mL of plasma) will be collected for measurement of 


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plasma concentrations of docetaxel as specified in the Schedule of Activities (SoA).
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor.  The actual date and time (24-hour clock time) of each 
sample will be recorded.
For Part 1B and Part 2D, the 1 hour samples for 
 should be collected from the 
contra-lateral arm of docetaxel infusion within 5 minutes of completing the infusion.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from participants 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.
All efforts will be made to obtain the samples at the exact nominal time relative to dosing.  
Samples collected within the windows specified in the Schedule of Activities (SoA) will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and data collection tool (eg, CRF).  
Samples collected for analyses of plasma PF-06939999 concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanalytical method, or for other 
 
 These data will not be included in the Clinical Study Report (CSR).
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.
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of PF-06939999 will be 
analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs). Samples collected for measurement of plasma concentrations 
of docetaxel will be analyzed only if there is a need of docetaxel concentration data to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. If 
analyzed, a validated analytical method in compliance with applicable SOPs will be used and 
the data will be included in the CSR.
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8.5.2. Urine for Analysis of PF-06939999 Concentrations
In single agent dose expansion cohorts (Part 2A or Part 2C), urine samples will be collected 
for 1 dosing interval after PF-06939999 morning dosing on Cycle 1, Day 15 to measure 
PF-06939999 concentrations, and thereby determine the renal elimination of PF-06939999 
from the body. Urine will be collected on Cycle 1, Day 15 from selected participants over 
6-hour intervals (every 6 hours for 24 hours starting from the morning dose for QD; 0 to 
6 hours and 6 to 12 hours post the morning dose for BID). Participants will empty their 
bladder just prior to morning dosing on Cycle 1, Day 15. 
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-06939999 concentration may also be used for 
metabolite identification and/or evaluation of the bioanalytical method, or for other internal 
 purposes. These data will not be included in the CSR.
8.6. Pharmacodynamics
Pharmacodynamic (PD) parameters will be evaluated in this study.  See Section 8.8.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected as local 
regulations and IRBs/ECs allow.  
Banked biospecimens may be used for research related to drug response and the cancer under 
study. Genes and other analytes (eg, proteins, ribonucleic acid [RNA], nondrug metabolites) 
may be studied using the banked samples.
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other 
diseases and to advance science, including development of other medicines for participants.  
This component of the sampling banking is optional for participants; they may still 
participate in the study even if they do not agree to the additional research on their banked 
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biospecimens.  The optional additional research does not require the collection of any further 
samples. 
See Section 10.5, Appendix 5 for information reagarding genetic research. Details on 
processes for collection and shipment of these samples can be found in the Laboratory 
Manual.
8.8. Biomarkers
Biospecimens collected for pharmacodynamic and other biomaker assessments will include 
peripheral blood, and tumor tissues which will be used to analyze protein/amino acid 
derivatives as well as DNA and RNA for achieving planned biomarker objectives. Refer to 
the schedule of activities for sample collection time points and Study/Laboratory Manual for 
sample processing and shipping. The following biospecimen types are planned to be 
collected in support of study objectives. Additional biospecimens collected over the course 
of participant disease management may be submitted for biomarker analyses. 
8.8.1. Archival/De Novo Tumor Biopsies
Tumor biospecimens from archival and/or de novo biopsies will be used to analyze candidate 
nucleic acid and protein biomarkers for their ability to identify those participants who are
most likely to benefit from treatment with the study drugs and to assess PD activity of the 
tumor upon PF-06939999 treatment. Biomarkers may include, but are not limited to target 
expression, nucleic acid analyses, as well as cell types and constituents of the tumor 
microenvironment (TME). Additional information on tissue collection procedures can be 
found in the Laboratory/Study Manual.
8.8.2. Whole Blood and Plasma
Peripheral blood and derivatives (eg, plasma) will be used to analyze nucleic acids and amino 
acid derivatives to support study objectives. Examples may include free plasma 
, cell 
free DNA (cfDNA) and gene expression analysis. Peripheral blood DNA sequencing will be 
used as normal control for identifying somatic mutations found in tumor samples and 
 
 will be used to identify potential PD and other 
 biomarkers. 
Additional analyses may be warranted based on emerging data. Note that plasma levels of 
 has been shown to be a predictor of renal and cardiovascular outcome in chronic 
kidney disease26 in clinical settings which could facilitate the assay development.
See Section 10.5, Appendix 5 for information regarding genetic research.  Details on 
processes for collection and shipment of these samples can be found in the Laboratory 
Manual.
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8.9. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  For participants with 
known computed tomography contrast allergy, a non contrast computed tomography of the 
chest with contrast enhanced abdominal and pelvic MRI can be used.  The same imaging 
technique used to characterize each identified and reported lesion at baseline will be 
employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the schedule of activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
treatment (if not done in the previous 6 weeks).  Assessment of response will be made using 
RECIST version 1.1 (see Section 10.11 Appendix 11) by investigators or qualified designees 
(Radiologist etc.).
All participant files and radiologic images must be available for source verification and for 
potential peer review.  
8.10. Patient Reported Outcomes 
Two PRO instruments will administered to participants with NSCLC in Part 2 of the study 
(Part 2A and 2D): (1) 7-item NSCLC-SAQ assessing key lung cancer symptoms of cough, 
pain, dyspnea, fatigue, and loss of appetite, and (2) 1-item PGIS to assess meaningful change 
in lung cancer symptoms. Both questionnaires will be administered at BL, 1-week, 1-month, 
3-month, and EOT.
The purpose of the NSCLC-SAQ to assess the impact of PRMT5 on NSCLC symptoms and 
the PGIS will be used as an anchor to assess Meaningful Within-Patient Change (MW-PC) in 
NSCLC symptoms. The MW-PC is one of PRO statistical tests required by the FDA, as 
specified in the Patient-Focused Drug Development Guidance. Both the NSCLC-SAQ and 
PGIS from this trial will provide “early signals” on the impact of PRMT5 and guide endpoint 
development for upcoming pivotal trials. A separate Ad Hoc Analysis Plan will highlight the 
details of PRO analyses. 
8.11. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  
The data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, 
pharmacokinetic and biomarker measurements.


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9.1. Statistical Hypothesis
There will be no hypothesis testing in this study.
9.2. Sample Size Determination
The total number of participants for Part 1 is estimated to be approximately 40 (15 to 50).
Subsequent participants will enter a Part 2, aimed at evaluating safety and anti-tumor activity 
of PF-06939999 at the RP2D. Approximately 80 participants are expected to be enrolled into 
Part 2.
9.2.1. Part 1 Dose Escalation
According to stopping criteria for dose escalation, approximately 15–50 participants will be 
enrolled in the Part 1 dose escalation portion of the study, however the total number of 
participants will depend on the number of dose levels needed to determine the MTD and 
number of participants evaluable for DLT at each dose level. It is envisioned that overall 
sample size for Part 1A will be approximately 40 participantsPart 1B is expected to have 
6-9 participants enrolled.
9.2.2. Part 2 Dose Expansion
Part 2 (dose expansion) will enroll participants in 3 non-randomized monotherapy cohorts 
and 1 combination with Docetaxel cohort to further evaluate safety and preliminary 
antitumor activity of the compound at the RP2D corresponding to monotherapy and 
combination respectively. The Participants from Part 1 who were treated at the dose level 
selected for Part 2 and fulfilling Part 2 inclusion/exclusion criteria might be counted towards 
the sample size of Part 2 at the corresponding indication. 
Each of the Parts 2A, 2B, 2C, and 2D will enroll approximately 20 participants. Sample size 
of 20 participants is chosen from practical considerations.
9.3. Populations for Analysis
1. Full analysis set.
The full analysis set includes all enrolled participants.
2. Safety analysis set. 
The safety analysis set includes all enrolled participants who receive at least 1 dose of
study treatment.
3. Per protocol analysis set (evaluable for MTD).
The per protocol analysis set includes all enrolled participants who had at least 1 dose 
of study treatment and either experienced DLT or do not have major treatment 
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4. Modified Intent to Treat (mITT) set.
The modified intent to treat (mITT) is the analysis population that will follow the ITT 
principle and include participants receiving at least 1 dose of study medication with 
baseline assessment and at least 1 post baseline assessment, disease progression, or 
death before the first tumor assessment.  The mITT population may be used for 
interim analysis and conference presentations when the study is still ongoing.
5. PK analysis sets.
The PK parameter analysis population is defined as all enrolled participants treated 
who do not have protocol deviations influencing PK assessment, and have sufficient 
information to estimate at least 1 of the PK parameters of interest.
The PK concentration population is defined as all enrolled participants who are 
treated and have at least 1 analyte concentration.
6. Response Evaluable Set.
The response evaluable population will include all participants who received at least 
1 dose of study treatment and had baseline disease assessment or measurable disease 
at baseline, if applicable and at least 1 post baseline disease assessment.
7. PD/Biomarker analysis set(s).
The PD/Biomarker analysis population is defined as all enrolled participants with at 
least 1 of the PD/Biomarkers evaluated at pre and/or post dose.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Maximum Tolerated Dose Determination
Determination of MTD will be performed using a Per-protocol analysis set (evaluable for 
MTD).
Bayesian adaptive approach:
The dose escalation in the Part 1A and Part 1B of the study will be guided by a Bayesian 
analysis of Cycle 1 dose limiting toxicity (DLT) data for PF-06939999.  Toxicity is modelled 
using 2-parameter logistic regression for the probability of a participant experiencing a DLT 
at the given dose in Part 1A and a 5-parameter model specifically developed for 
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Assessment of participant risk:
After each cohort of participants, the posterior distribution for the risk of DLT for new 
partcipants at different doses of interest for PF-06939999 will be evaluated.  The posterior 
distributions will be summarized to provide the posterior probability that the risk of DLT lies 
within the following intervals: 
Under-dosing:
[0, 0.16]
Targeted dosing:
[0.16, 0.33]
Overdosing:
[0.33, 1]
The escalation with overdose control (EWOC) principle:
Dosing decisions in Part 1A and Part 1B are guided by the escalation with overdose control 
principal.1 A dose may only be used for newly enrolled participants if the risk of excessive 
toxicity at that dose is less than 25%.
Prior distributions in Part 1A for BID regimen:
Weekly informative prior distribution based on pre-clinical/expert opinion information will 
be chosen for the logistic parameters, see Section 10.9, Appendix 9.
Prior distributions in Part 1A QD regimen: The data from BID regimen have been used to 
set up a meta-analystic prior (MAP) and a mixture of the MAP and weakly informative prior 
has been used for Part 1A QD regimen. 
Prior distributions in Part 1B: A meta-analytic-predictive (MAP) approach will be used to 
derive the prior distribution for model parameters used in Part 1B based on the data collected 
in Part 1A and original dose escalation studies of Docetaxel. A full description of the 
application of the MAP approach to derive the prior distributions of the model parameters is 
given in Technical Supplement to Appendix 10.9.
Starting doses in Part 1A and Part 1B:
The Part 1A starting dose is 0.5 mg/QD.  For this dose the prior risk of overdosing is 6.4%, 
which satisfies the EWOC criterion.  A full assessment of the prior risk to participants is 
given in Section 10.9, Appendix 9.
The starting dose in Part 1B will be a PF-06939999 RP2D-1 with fixed dose of docetaxel per 
standard of care. In addition, depending on the safety findings in Part 1A, and whether 
significant overlapping toxicities are expected in combination, the starting dose of 
PF-06939999 may be further modified but will not exceed the single agent RP2D.
Stopping criteria in Part 1A and Part 1B: 
The maximum number of participants in dose escalation part of the trial was set to 50.  The 
trial will be stopped when the following criteria are met:
•
At least 6 participants have been treated at the recommended MTD.
•
The dose ݀ሚsatisfies 1 of the following conditions:


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•
The probability of target toxicity at dose ݀ሚexceeds 50%, 
ie, Pr(0.16 ≤ߨௗ෨<0.33)≥50%.
•
A minimum of 15 participants have been treated in the trial.
9.4.2. Efficacy Analyses
Response Evaluable Set will be used for all response related analyses including ORR, DOR,
PFS, and OS. Tumor response will be presented in the form of participant data listings that 
include, but are not limited to tumor type, dose on Day 1, tumor response at each visit, and 
best overall response.  In addition, progression date, death date, date of first response and last 
tumor assessment date and date of last contact will be listed.
Part 1and Part 2: Progression date, death date, date of first response and last tumor
assessment date and date of last contact will be listed. The definition of each response 
category is provided in Section 10.11 Appendix 11 (RECIST v1.1). The proportion of 
participants with response will be presented for each dose level. Details of analysis will be 
included in Statistical Analysis plan.
Part 2: The Kaplan-Meier methods will be used to analyze all time to event endpoints.
Median PFS and median OS (both if reached) will be reported. Proportion of participants
alive at 6 mo, 1 year, and 2 years will be also presented. Efficacy data of participants from 
Part 1B who are dosed at the level selected for Part 2 and satisfy inclusion/exclusion criteria 
of the corresponding Part 2 cohort will be used in efficacy analysis conducted for that Part 2 
cohort. Details of these endpoint analyses methods will be included in the Statistical 
Analysis Plan.
PFS is defined as the time from start date to date of first documentation of progression, or 
death due to any cause. Progression is defined as the appearance of local, regional or distant
disease of the same type after complete response or progression of pre-existing lesions. 
Itdoes not include second primary malignancies of unrelated types.
OS is defined as the time from start date to date of first documentation of death due to any 
cause.
9.4.3. Safety Analyses
All safety analyses will be performed on the safety population.
Summaries and analyses of safety parameters will include all participants in the safety 
analysis set.
AEs, ECGs, BP, PR, continuous cardiac monitoring, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants.  Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical 
concern will be described.  Safety data will be presented in tabular and/or graphical format
and summarized descriptively, where appropriate.


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Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted. However, any untoward findings identified on physical 
examinations conducted during the active collection period will be captured as AEs, if those 
findings meet the definition of an AE.  Data collected at screening that are used for 
inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, will be 
considered source data, and will not be required to be reported, unless otherwise noted.  
Demographic data collected at screening will be reported.
9.4.3.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
The mean of the replicate measurements (eg, triplicate ECGs obtained) will be used to 
represent a single observation at that time point.  If any of the 3 individual ECG tracings has 
a QTc value >500 msec, but the mean of the triplicates is not >500 msec, the data from the 
participant’s individual tracing will be described in a safety section of the clinical study 
report (CSR) 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 the postdose 
QTc value and the average of the predose 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 participant factors (covariates) on the relationship will be examined.
The analysis of ECG results will be based on participants in the safety analysis set with 
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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 (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (HR) (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, HR, RR interval, PR interval (PR), 
QRS, QTcF (and other correction factors, eg, QTcB as appropriate), and dose.  Individual QT 
(all evaluated corrections) intervals will be listed by time and dose.  The most appropriate 
correction factor depending on HR (default QTcF) 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 dose and time point.  Details of additional analysis (if any) will be 
specified in SAP.
9.4.3.2. Adverse Events
AEs will graded by the investigator according to the CTCAE version 5.0 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  Adverse event data will be 
reported in tables and listings.  Summaries of adverse event by mapped terms, appropriate 
thesaurus level, toxicity grade, and seriousness and relationship to study treatment will be 
presented, as well as summaries of adverse events leading to death and premature withdrawal 
from study treatment.  The number and percentage of participants 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). Listings of DLTs and deaths will be provided.
9.4.3.3. Laboratory Test Abnormalities
The number and percentage of participants 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).  For laboratory tests without CTCAE grade definitions, 
results will be categorized as normal, abnormal, or not done. 
9.4.4. Other Analyses 
9.4.4.1. Pharmacokinetic Analyses
9.4.4.1.1. Single dose and Steady‑State PF-06939999 pharmacokinetic Analysis
Plasma concentrations of PF-06939999 will be summarized descriptively (n, mean, standard 
deviation, coefficient of variation [CV], median, minimum, maximum, geometric mean and 
its associated CV) by dose, cycle, day and nominal time.  


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Individual participant plasma PF-06939999 concentration-time data within a dose interval 
after Cycle 1 Day 1 and Cycle 1 Day 15 will be analyzed using noncompartmental methods 
to determine single- and multiple- dose PK parameters.  Single-dose PK parameters to be 
estimated will include the maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax), and area under the plasma concentration versus time curve (AUC) from 
time 0 to the last sampling time point within the dose inveral (AUClast), and if data permit, 
AUC from time 0 extrapolated to infinity (AUCinf), terminal elimination half life (t1/2), 
apparent oral plasma clearance (CL/F), and apparent volume of distribution (Vss/F or Vz/F). 
Multiple-dose PK parameters to be estimated will include steady state Cmax (Cmax,ss), Tmax, 
AUC within 1 dose interval (AUCtau,ss), minimum plasma concentration (Cmin,ss), steady-state 
CL/F (CLss/F), and if data permit, apparent volume of distribution (Vss/F), t1/2, and 
accumulation ratio (Rac).  The single dose and steady state PK parameters will be 
summarized descriptively (n, mean, standard deviation, coefficient of variation, median, 
minimum, maximum, geometric mean and its associated coefficient of variation) by dose 
level, cycle and day.
Dose normalized AUCinf (AUCτ at steady state), AUClast and Cmax for PF-06939999 in 
plasma will be plotted against dose (using a logarithmic scale) by cycle and day.  These plots 
will include individual participant values and the geometric means for each dose. 
For Part 1B and Part 2D, if the samples collected for measurement of plasma concentrations 
of docetaxel are analyzed (see Section 8.5.1), these plasma docetaxel concentrations will be 
summarized descriptively (n, mean, standard deviation, CV, median, minimum, maximum, 
geometric mean and its associated CV) by cycle, day and nominal time.
Urine PF-06939999 concentrations will be summarized by descriptive statistics (n, mean, 
standard deviation, CV, median, minimum, maximum, geometric mean and its associated 
CV). Renal clearance will be estimated if data permit.
Metabolite Profiling
Plasma metabolite profiling will be summarized in a separate report and not included in the 
CSR.
9.4.4.1.2. Effect of Food on PF-06939999 Pharmacokinetics
The effect of food will be assessed based on AUClast and Cmax by determining the ratios 
(fed/fast) of geometric means of these PK parameters and the 90% confidence intervals for 
the ratios.
9.4.4.2. Pharmacodynamic/Biomarker Analyses 
For PD samples including tumor 
IHC and plasma 
 summary statistics (eg, the 
mean and standard deviation, median, and minimum/maximum levels) will be determined at 
baseline and post-treatment.  Further analysis will be specified in SAP. 
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Clinically relevant and interpretable biomarker assessments generated for Primary and 
Secondary objectives will be summarized in the CSR.  Other biomarker data might be 
summarized in a separate technical document.
9.4.4.3. Analysis of PRO data
Patient reported outcome data in the form of NSCLC-SAQ and PGIS will be presented as 
participant data listings that include, but are not limited to participant demographics, dose on 
Day 1, outcomes metrics, and change from baseline in corresponding parameter. Additional 
analytic details will be highlighted in the SAP as well as a separate PRO Analysis Plan. All 
PRO results will be summarized as a separate document.
9.4.4.4. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling 
Population PK assessment may be conducted with plasma PF-06939999 concentrations from 
all participants using the nonlinear mixed effect modeling approach in accordance with 
regulatory guidance. Subjects who provide at least 1 post dose drug concentration 
measurement and have no major protocol deviations influencing the PK assessment will be 
included in the population PK analysis. The population PK analysis will estimate typical 
value and variability for parameters including absorption rate constant (Ka), CL/F, and 
volume of distribution (Vd/F). Also, the influence of selected potential covariates on the PK 
parameters will be explored; the potential covariates to be explored will include selected 
demographics and participant characteristics (eg, body weight, sex, age).
The population PK model may be further combined with data on biomarkers and relevant 
efficacy and safety endpints for population PK/PD analysis. The population PK and PK/PD 
analysis, if performed, will be reported in a Population Modeling and Analysis Report 
(PMAR), separate from the clinical study report of this study.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study.  As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or supporting clinical development.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
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 participant enrollment is appropriate.


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


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
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A copy of the ICD(s) must be provided to the participant.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional 
 research.  The investigator or authorized designee will 
explain to each participant the objectives of the 
 research.  Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period.  A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for 
 
research.  Participants who decline to participate in this optional research will not provide 
this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
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 participants) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the
purposes of “bona-fide scientific research” that contribute to the scientific understanding of 
the disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations.  CSRs will have personally identifiable 
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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the Site 
Monitoring Plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 


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investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Source data includes medical records, clinical laboratory reports, radiology reports or other 
sources per site practices.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;


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
Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first.  
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements.  
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 


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participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of this 
protocol.  Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated values.  
These additional tests would not require additional collection of blood.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any perceived safety 
concerns.
Table 15.
Safety Laboratory Tests
Hematology
Chemistry
Serology
Coagulation
Urinalysis
Pregnancy 
Test
Hemoglobin*
ALT
HBV*
PT
Urine dipstick 
for urine 
blood or 
leukocyte 
esterase: If 
positive 
perform
microscopy
(Reflex 
Testing).
For female 
participants of 
childbearing 
potential, serum 
or urine.
Platelets*
AST
HCV Ab*
PTT
WBC
Bicarbonate
HIV
Absolute 
Neutrophils
CRP
Reticulocyte 
count**
Absolute 
Lymphocytes
Alk Phos
Peripheral 
blood 
smear**
Absolute 
Monocytes
Sodium
Absolute 
Eosinophils
Potassium
Absolute 
Basophils
Magnesium
Urine dipstick 
for urine 
protein: If 
positive 
perform
microscopy
(Reflex 
Testing).
Tumor 
Markers 
CA-125 for 
participants
with cervical or 
endometrial 
cancer only.
RBC
Chloride
MCV
Total calcium
Total 
bilirubin***
Total Protein
BUN or Urea
Creatinine
Uric Acid
Glucose 
(nonfasted)
LDH
Albumin
Phosphorus or 
Phosphate
Amylase
Lipase
Triglycerides
Abbreviations: Alk Phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CRP = C-reactive protein; HBV = hepatitis B; HCV = hepatitis C; IFNγ = interferon-gamma; 
IL = interleukin; INR = International Normalized; LDH = lactate dehydrogenase; MCV = mean corpuscular volume 
PTT = partial thromboplastin time; RBC = red blood cells; TNF= Tumor necrosis factor- alpha; WBC = white blood cells.
* Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Total Hepatitis B Core Ab (anti-HBc), Hepatitis B Surface
Ab (anti-HBs) as clinically indicated IgM antibody to hepatitis B core antigen (IgM anti-HBc), HCV Ab (also known As 
Hepatitis C Antibody). 
** Grade ≥3 thrombocytopenia should trigger a blood smear for differential. Reticulocyte count should be performed per 
schedule of acitivity. In addition, Grade≥ 3 anemia should trigger a recticulcyte count if not done within 7 days.


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*** 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. 
Investigators must document their review of each laboratory safety report.


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


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


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


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


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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

An event is defined as “serious” when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.
Grade
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Assessment of Causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.


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


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 90 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate study intervention(s) plus an additional 90 days 
(a spermatogenesis cycle): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR

Must agree to use contraception/barrier as detailed below: 

Agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

Use of an additional highly effective contraceptive method with a failure rate of <1% 
per year as described below in Section 10.4.4 for a female partner of childbearing 
potential. 

Male participants should be advis ed of the benefit for a female partner to use a highly 
effective method of contraception, as a condom may break or leak when having 
sexual intercourse with a WOCBP who is not currently pregnant.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any study intervention(s).  The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
OR


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
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with high user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate any study intervention(s). In 
addition, a second effective method of contraception, as described below, must be 
used. The investigator should evaluate the effectiveness of the contraceptive method 
in relationship to the first dose of study intervention. 
OR

Is a WOCBP and is abstinent from heterosexual intercourse during the entire period 
of risk associated with the study intervention.  The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and be the preferred and 
usual lifestyle of the participant.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
10.4.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.  
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.


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Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female.

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;


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
Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.

Effective Methods
3. Male or female condom with or without spermicide.
4. Cervical cap, diaphragm, or sponge with spermicide.
5. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
10.4.4. Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.5. Appendix 5: Genetics
Use/Analysis of DNA:

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease.  Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06939999 or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary, or may be used for internal decision making without 
being included in a study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for banking (see Section 8.7.2) will be stored indefinitely or other period 
as per local requirements. 

Participants may withdraw their consent for the storage and/or use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.

Banked biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.

Additional whole blood samples will be collected (see Table 5, Table 6, Table 7, 
Table 8, and Table 9) for DNA sequencing to detect germline mutations to serve as a 
control for somatic mutation analysis. This analysis is independent of the genetic 
analyses as stated above.


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a 
participant presents with clinical signs/symptoms, such LFT results should be managed and 
followed as described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory 
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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


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


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


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10.7.1. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. 
See Section 7.1.1 for temporary discontinuation of the study intervention.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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10.8. Appendix 8: Country-Specific Requirements
10.8.1. France Contrat Unique
1. GCP Training 
Before enrolling any participants, the investigator and any subinvestigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer.  Any investigators who later join 
the study will do the same before performing study-related duties.  For studies of 
applicable duration, the investigator and subinvestigators will complete Pfizer GCP 
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
2. Investigational Product 
No participants or third-party payers will be charged for investigational product.
3. Urgent Safety Measures 
In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
4. Termination Rights 
Pfizer retains the right to discontinue development of PF-06939999 at any time.
The investigator agrees to abide by the ethical principles set forth in the World Health 
Organization’s Guiding Principles for Human Cell, Tissue and Organ Transplantation 
(WHA63.22) (http://www.who.int/transplantation/en/) with regard to the study.


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10.9. Appendix 9: Detailed Dose Escalation/De-escalation Scheme for BLRM Design
This appendix provides the details of the statistical model, the description of prior 
distribution. The results of the Bayesian analyses and respective dosing decisions for some 
hypothetical data scenarios, and a simulation study of the operating characteristics of the 
model could be found in the separate Technical supplement to this appendix.  
10.9.1. Statistical Model
Let ߨሺ݀ሻbe the risk of DLT for PF-06939999 given as a single agent at dose ݀. The 
dose-DLT model is logistic:
logit ൫ߨሺ݀ሻ൯ൌlogሺߙሻ൅ߚlogሺ݀݀∗
⁄
ሻ
݀∗=50 mg/BID or 100 mg total daily dose and used to scale the doses of PF-06939999.  
Hence, ߙ(>0) are the PF-06939999 odds of a DLT at ݀∗; and ߚ(>0) is the increase in the 
log-odds of a DLT by a unit increase in log-dose.
10.9.2. Prior Specifications for BID Regimen
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the parameters logሺߙሻand logሺߚሻ. A weakly informative prior 
was used as there were no relevant human historical DLT data available. It was assumed that 
model parameters will follow a bivariate normal (BVN) distribution
(log(α), log(β)) ⁓ N2(μ, Σ)
with prior means μ ൌሺμଵ, μଶሻ, and prior covariance matrix S composed of standard 
deviations σଵ, σଶand correlation ρ. It was assumed that
ሺμଵ, μଶ, σଵ, σଶ, ρሻൌሺlogitሺ݌∗ሻ, 0, 2, 1, 0ሻ
Here, ݌∗is the anticipated DLT rate at the scaling dose ݀∗. It was assumed based on 
pre-clinical data that DLT rate at 50 mg/BID dose was 0.33.
This prior is considered to be weakly informative (Neuenschwander et al. 2014).
The prior distributions of the model parameters are provided in Table 16 illustrates the 
resulting prior distribution of DLT rate derived from the prior given in Table 17 and rounded 
to 3 decimal points.  Based on the available information the starting dose of 
PF-06939999 = 0.5 mg/QD satisfies the EWOC criteria.


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Table 16.
Prior Distribution for the Model Parameters (BID regimen)
PF-06939999 single agent parameters: BVN weakly informative prior
Parameters
Means
Standard 
deviations
Correlation
ሺlogሺαሻ, logሺβ ሻሻ
-0.708,0
2, 1
0
Table 17.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for PF-06939999
(BID regimen)
PF-06939999 dose
Prior probabilities that DLT 
rate is in the interval:
Mean
SD
Quantiles
Total 
(mg/day)
BID (mg)
am/pm
[0, 0.16)
[0.16, 
0.33)
[0.33,1]
2.5%
50%
97.5%
0.5
0.5/0
0.885
0.051
0.064
0.062
0.151
0.000
0.002
0.607
1
0.5/0.5
0.864
0.060
0.076
0.073
0.164
0.000
0.003
0.658
2
1/1
0.838
0.069
0.093
0.087
0.179
0.000
0.006
0.710
4
2/2
0.803
0.082
0.115
0.106
0.196
0.000
0.012
0.756
8
4/4
0.757
0.096
0.147
0.131
0.216
0.000
0.024
0.804
16
8/8
0.691
0.119
0.190
0.167
0.239
0.000
0.048
0.853
32
16/16
0.593
0.149
0.258
0.220
0.264
0.000
0.097
0.896
60
30/30
0.466
0.172
0.362
0.295
0.288
0.002
0.188
0.931
120
60/60
0.270
0.174
0.556
0.438
0.313
0.013
0.398
0.973
Abbreviations: BID = twice daily; SD = standard deviation


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Figure 2.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for PF-06939999
with BID regimen (total daily dose)
10.9.3. Prior Specifications for QD Regimen
The data from BID regimen and original weakly informative prior were used to set up a prior 
for QD regimen.  The MAP prior was used to borrow the information form the BID regimen.  
However, to safeguard against unwarranted use of historical information a mixture prior is 
recommended which is adopted in this study.  Then a mixture of weakly informative prior 
and MAP prior was used with mixing probabilities 0.2 and 0.8 respectively. 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫logሺߙ∗ሻ, logሺߚ∗ሻ൯for the part of the study with the QD regimen using DLT data from the 
BID regimen. It was assumed that model parameters will follow a bivariate normal (BVN) 
distribution
൫݈݋݃ሺߙ∗ሻ, ݈݋݃ሺߚ∗ሻ൯หߤ, ߰~ BVNሺߤ, ߰ሻ
The parameter ߤൌሺߤଵ, ߤଶሻis the mean for the logistic parameters, and ߰is the 
between-regimen covariance matrix.  Covariance matrix ߰is defined by the standard 
deviations ሺτଵ, τଶሻ, and correlation ρ . More details of the MAP prior derivation are 
described in Technical supplement to this appendix.  
The MAP prior takes the following form
ሺߤଵ, ߤଶ, τଵ, τଶ, ߩሻൌሺ1.13, െ0.12, 1.55, 0.65, 0.72ሻ.
Then a robust prior is achieved via the following mixture 0.8 ܰଶሺߤ, ߰ሻெ஺௉൅
0.2 ܰଶሺߤ, Σሻௐ௘௔௞


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The entire prior distributions of the model parameters are provided in which illustrates the 
resulting prior distribution of DLT rate derived. 
Table 18.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for 
PF-06939999 (QD regimen)
PF-06939999 
dose
Prior probabilities that DLT rate is 
in the interval
Mean
SD
Quantiles
Total (mg/day)
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
0.5
0.907
0.066
0.027
0.055
0.100
0.000
0.016
0.343
1
0.858
0.097
0.044
0.075
0.117
0.000
0.029
0.421
2
0.781
0.145
0.074
0.103
0.138
0.000
0.051
0.510
4
0.665
0.205
0.130
0.146
0.165
0.000
0.089
0.604
8
0.510
0.254
0.235
0.210
0.195
0.000
0.155
0.703
12
0.407
0.266
0.327
0.260
0.215
0.000
0.211
0.761
16
0.335
0.260
0.405
0.303
0.228
0.000
0.262
0.804
32
0.196
0.195
0.609
0.425
0.259
0.004
0.421
0.891
64
0.128
0.122
0.750
0.556
0.283
0.020
0.603
0.958
128
0.075
0.090
0.834
0.666
0.282
0.059
0.749
0.991
Abbreviations: QD = once daily; SD = standard deviation


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Figure 3.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for PF-06939999
(total daily dose, QD regimen)
10.9.4. Model description and prior specification for Part 1B
Details of model specification for combination with Docetaxel are presented in Technical 
supplement to this Appendix. Details of selected priors will be finalized when DLT data for 
Part 1A becomes available.
References
1.
Neuenschwander B, Matano A, Tang Z, Roychoudhury S, Wandel S and Bailey S. A 
Bayesian Industry Approach to Phase I Combination Trials in Oncology. In Statistical 
Methods in Drug Combination Studies. Zhao W and Yang H (eds), Chapman & 
Hall/CRC, 2014.
2.
Schimidli, H., Gsteiger, S., Roychoudhury, S., O'Hagan, A., Spiegelhalter, D., & 
Neuenschwander, B. (2014). Robust Meta-Analytic-Predictive Priors in CLinical Trials 
with Historical Control Information. Biometrics, 70, 1023--1032.


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10.10. Appendix 10: 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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10.11. Appendix 11: RECIST (Response Evaluation Criteria In Solid Tumors) Version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
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 [based on Prostate Cancer Working Group 3 (PCWG3) criteria]: Bone 
disease is defined as present or absent and will be followed as non-target lesions. 

Previous local treatment: A previously irradiated lesion (or lesion patiented to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If 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 case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target 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 (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate: Progression has not been 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. 


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Subjective progression
Participants requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 


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Table 19.
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
Table 20.
Objective Response Status at each Evaluation for Participants with Non-
Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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10.12. Appendix 12: 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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10.13. Appendix 13: Alternative Measures During Public Emergencies
The alternative study procedures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix is currently in effect applies 
for the COVID-19 pandemic 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).
Notify Pfizer when conditions have returned to business as usual.
10.13.1. Eligibility
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per exclusion criterion #8.  When the infection resolves, the patient may be considered for re-
screening.
10.13.2. 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 participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, 
video-conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit:

Review and record PF-06939999 administration, including compliance and missed 
doses as detailed in the SOA.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.  

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Contraception check as detailed in the SOA. Confirm that the participant is adhering 
to the contraception method(s) required in the protocol.

Review and record contraceptive method and results of pregnancy testing. Refer to 
Appendix 4 and Section 10.13.3 of this appendix regarding pregnancy tests

Provide instructions for laboratory testing and radiological assessments as described 
in Section 10.13.3 and 10.13.7.


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
Review and record safety and efficacy result if applicable 
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.13.3. Laboratory Testing
If a study participant 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 
following safety laboratory evaluations may be performed at a local laboratory:

Hematology;

Blood chemistry;

Coagulation;

Urinalysis;

Pregnancy test.
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 
participant’s source documents/medical records. Relevant data from the local laboratory 
report should be recorded on the CRF. 
If a participant 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 participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. 
10.13.4. Electrocardiograms
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. 
10.13.5. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.


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PF-06939999 may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the
PF-06939999. Pfizer does not permit the shipment of PF-06939999 by mail. The tracking 
record of shipments and the chain of custody of PF-06939999 must be kept in the 
participant’s source documents/medical records. Study participants must provide their verbal 
consent to allow the site to provide their contact details to a courier for the purpose of 
shipping PF-06939999 to them. The verbal consent should be documented in the source 
documents/medical records. Administration of docetaxel must be performed in person at the 
Study site. 
Ongoing participants who have active [confirmed (positive by regulatory authority-approved 
test) or presumed (test pending/clinical suspicion)] SARS-CoV2 infection, should follow the 
treatment guidelines:

For symptomatic participants with active SARS-CoV2 infection, investigational 
treatment should be delayed for at least 14 days from start of symptoms.  This delay 
is intended to allow resolution of symptoms of SARS-CoV2 infection

Prior to restarting treatment, the participant should be afebrile for 72 hours and 
SARS-CoV2-related symptoms should have recovered to ≤Grade 1 for a minimum of 
72 hours.  Please inform the study team when treatment is restarted.
See Section 7.1.1.
Continue to consider potential drug-drug interactions as described in Section 6.5.1 for any 
concomitant medication administered for treatment of SARS-CoV2 infection.
10.13.6. Home Health Visits
A home health care service may be considered to facilitate scheduled visits per the Schedule 
of Activities only after Sponsor’s approval. Home health visits include a healthcare provider 
conducting an in-person study visit at the participant’s location, rather than an in-person 
study visit at the site. The following may be performed during a home health visit:

Physical Exams;

Vital Signs (including height and weight);

Safety laboratory blood draws (including hematology, blood chemistry, coagulation);

Urinalysis;

Blood draw for PK and PD;

ECGs, if available;


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
Also all assessments included in Telehealth Visits (Section 10.13.2).
10.13.7. Efficacy Assessments
If the participant is unable to visit the study site for radiological tumor assessments, the 
participant may visit an alternative facility to have these assessments performed as described 
in the SOA. Qualified study site personnel must order, receive, and review results. 


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10.14. Appendix 14: Abbreviations
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
Anti-HBc
hepatitis B core antibody(ies)
Anti-HBs
Hepatitis B Surface antibody(ies)
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUClast
AUC from time 0 to the last sampling time point within the dose 
inveral
AUCinf
AUC from time 0 extrapolated to infinity
AUCsd,τ
is the single-dose AUC within one dose interval
AUCtau,ss
AUC within one 1 dose interval
AV
Atrioventricular
BBS
Biospecimen Banking System
BID
twice daily
BLRM
Bayesian Logistic Regression Model
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
BVN
bivariate normal
C1D1
Cycle 1 Day 1
C2D1
Cycle 2 Day 1
C4D1
Cycle 4 Day 1
CCC
clear cell carcinoma
CFR
Code of Federal Regulations
ChTx
platinum-based doublet chemotherapy
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
Oral plasma clearance
CLss/F
steady state CL/F
Cmax
maximum observed concentration
Cmax,ss
steady state Cmax
Cmin
minimum plasma concentration
Cmin,ss
steady state Cmin 
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials


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Abbreviation
Term
COV
cornonavirus
CPI
checkpoint inhibitors 
CR
complete response
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CTC
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough conentration
CV
coefficient of variation
DDI
drug-drug interations
DILI
drug-induced liver injury
DLBCL
diffuse large b-cell lymphoma
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DU
dispensable unit
EC
ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDP
exposure during pregnancy
EGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
end of treatment
ETOH
Ethanol
EU
European Union
EudraCT
European Clinical Trials Database
EWOC
escalation with overdose control
FDA
Food and Drug Adminsitration
FFPE
formalin fixed  paraffin embedded
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimuating factor
GGT
gamma-glutamyl transferase
GI
gastrointestinal 
GLP
Good Laboratory Practice
H2RA
H2 – receptor antagonist
HBcAb
hepatitis B core antibody


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Abbreviation
Term
HbsAg 
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papilloma virus
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
IC₅₀
half maximal inhibitory concentration 
ICD
informed consent document
ICH
International Council for Harmonisation
IEC
Institutional Ethics Committee 
IFN
interferon-gamma
IgM
Immunoglobulin M 
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IP manual
investigational product manual
IRB
institutional review board
IRT
Interactive Response Technology
ITT
intention-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWR
Interactive Web Response 
Ka
absorption rate constant
K2 EDTA
dipotassium ethylenediaminetetraacetic acid
LBBB
left bundle branch block
LDH
lactate dehydrogenase
LFT
liver function test
MAD
maximum administered dose
Map
meta-analytic-predictive
MCV
mean corpuscular volume
MD
multiple dose
MEC
molar extinction coefficient
MedDRA
Medical Dictionary for Regulatory Activities
MDS
myelodyplastic syndrome
mITT
modified intent to treat
MRI
magnetic resonance imaging
MTD
maximum tolerated dose


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Abbreviation
Term
MVAC
methotrexate/vinblastine sulfate/doxorubicin 
hydrochloride/cisplatin)
MW-PC
Meaningful Within-Patient Change 
N/A
not applicable
NCI
National Cancer Institute
NG
nasogastric 
NHL
non-Hodgkins lymphoma
NOAEL
no-observed-adverse-effect level
NPC
neural stem/progenitor cells
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PCWG3
Prostate Cancer Working Group 3
PCD
primary completion date
PD
pharmacodynamics(s)
PD-1
programmed cell death protein-1
PD-L1
programmed death-ligand 1 
PFS
progression-free Survival
PGIS
patient global impression of severity 
PK
pharmacokinetic(s)
PMAR
Population Modeling and Analysis Report 
PMT
protein methyltransferase
PR
partial response
PRMT5
protein arginine methyltransferase 5
PRO
patient reported outcome
PS
performance status
PT
prothrombin time
PVC
premature ventricular complex
QD
once daily
QTc
corrected QT
QTcB
corrected QT (Bazett method)
QTcF
corrected QT (Fridericia method)
Rac
accumulation ratio
RARS
refractory anemia with ring sideroblasts
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Part 2 Dose
RR
the interval between successive heartbeats
SAE
serious adverse event
CCI
CCI


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Abbreviation
Term
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome 
SD
single dose
SD
standard deviation
SFRF2
splicing factor, arginine/serine-rich 2 protein
snRMP
small nuclear ribonucleoprotein
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life
TBili
total bilirubin
TCGA
The Cancer Genome Atlas
TEAE
treatment-emergent adverse event
TGI
tumor growth inhibition
Tmax
time to maximum concentration
TTP
time to progression 
TME
tumor microenvironment
Tmax,ss
maximum steady state concentration
U2AF1
U2 small nuclear RNA auxiliary factor 1
ULN
upper limit of normal
US
United States
USPI
United States product insert
UVB
ultraviolet B
Vd/F
volume of distribution 
Vss/F 
apparent volume of distribution steady state
WBC
white blood cell
WOCBP
woman of childbearing potential
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11. REFERENCES
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Tighiouart M and Rogatko A. Dose finding with escalation with overdose control 
(EWOC) in cancer clinical trials. Statistical Science 2010; 25(2): 217–226.
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Stopa N, Krebs JE, Shechter D. The PRMT5 arginine methyltransferase: many roles in 
development, cancer and beyond. Cell Mol Life Sci 2015; 72(11):2041-59.
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Climente-Gonzalez H, Porta-Pardo E, Godzik A, et al. The functional impact of 
alternative splicing in cancer. Cell Rep 2017; 20(9):2215-26.
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Gonsalvez GB, Tian L, Ospina JK, et al. Two distinct arginine methyltransferases are 
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Bezzi M, Teo SX, Muller J, et al. Regulation of constitutive and alternative splicing by 
PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal 
machinery. Gene Dev 2013; 27(17):1903-16.
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Koh CM, Bezzi M, Low DH, et al. MYC regulates the core pre-mRNA splicing 
machinery as an essential step in lymphomagenesis. Nature 2015; 523(7558):96-100.
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Braun CJ, Stanciu M, Boutz PL, et al. Coordinated splicing of regulatory detained 
introns within oncogenic transcripts creates an exploitable vulnerability in malignant 
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Neuenkirchen N, Chari A, Fischer U. Deciphering the assembly pathway of Sm-class U 
snRNPs. FEBS Lett 2008; 582(14):1997-2003.
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Chan-Penebre E, Kuplast KG, Majer CR, et al. A selective inhibitor of PRMT5 with in 
vivo and in vitro potency in MCL models. Nat Chem Biol 2015; 11(6):432-7.
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Gerhart SV, Kellner WA, Thompson C, et al. Activation of the p53-MDM4 regulatory 
axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating 
cellular splicing. Sci Rep 2018; 8(1):9711.
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Gu Z, Gao S, Zhang F, et al. Protein arginine methyltransferase 5 is essential for growth 
of lung cancer cells. Biochem J 2012; 446(2):235-41.
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Kahles A, Lehmann KV, Toussaint NC, et al. Comprehensive analysis of alternative 
splicing across tumors from 8,705 patients. Cancer Cell 2018; 34(2):211-224.e6.
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Darman RB, Seiler M, Agrawal AA, et al. Cancer-associated SF3B1 hotspot mutations 
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14.
Obeng EA, Chappell RJ, Seiler M, et al. Physiologic expression of Sf3b1(K700E) 
impaired erythropoiesis, aberrant splicing, and sensitivity to therapeutic spliceosome 
modulation. Cancer Cell 2016; 30(3):404-17.
15.
Fong JY, Pignata L, Goy PA, et al. Therapeutic targeting of RNA splicing catalysis 
through inhibition of protein arginine methylation. Cancer Cell. 2019;36(2):194‐209.
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Yoda S, Dagogo-Jack I, Hata AN. Targeting oncogenic drivers in lung cancer: recent 
progress, current challenges and future opportunities. Pharmacol Ther 2019;193:20‐30.
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Taxotere® (docetaxel) Prescribing information. Sanofi-aventis U.S. LLC. June 2019.
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Seiler M, Peng S, Agrawal AA, et al. Somatic mutational landscape of splicing factor 
genes and their functional consequences across 33 cancer types. Cell Rep 2018; 
23(1):282-296.e4.
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Zhao J, Sun Y, Huang Y, et al. Functional analysis reveals that RBM10 mutations 
contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci Rep 2017; 
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Economopoulou P, Perisanidis C, Giotakis EI, et al. The emerging role of 
immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor 
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Suresh T, Burtness B. The emerging role of immunotherapy in head and neck squamous 
cell cancer. Am J Hematol Oncol 2017; 13(6):20-7.
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About Non-Small Cell Lung Cancer.  American Cancer Society.  Cancer Facts & 
Figures 2017. Atlanta: American Cancer Society; 2017.
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immunotherapies in non-small-cell lung cancer: a systematic review and meta-analysis. 
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Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab 
for non-small-cell lung cancer. New Engl J Med 2006; 355:2542-50.
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cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010; 
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Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 
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Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-
small-cell lung cancer to gefitinib. N Engl J Med 2005; 352(8):786-92.
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Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance 
in ALK-rearranged lung cancers. Sci Transl Med 2012; 4(120):120ra17.
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factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N 
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Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373(2):123-35.
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lung cancer. N Engl J Med 2015; 372(21):2018-28.
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Zatloukal PHD, Park K, Kang J, et al. Randomized phase II clinical trial comparing 
tremelimumab (CP-675,206) with best supportive care following first line platinum-
based therapy in patients with advanced non-small cell lung cancer. J Clin Oncol 2009; 
27(Suppl):Abstr 8071.
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pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol 
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Herszenyi L, Tulassay Z. Epidemiology of gastrointestinal and liver tumors. Eur Rev 
Med Pharmacol Sci 2010; 14(4):249-58.
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381(9864):400-12.
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Borcoman E, Le Tourneau C. Pembrolizumab in cervical cancer: latest evidence and 
clinical usefulness. Ther Adv Med Oncol 2017; 9(6):431-9.
41.
Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet 2009; 374(9685):239-
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Rouanne M, Roumiguie M, Houede N, et al. Development of immunotherapy in bladder 
cancer: present and future on targeting PD(L)1 and CTLA-4 pathways. World J Urol 
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Roupret M. Immunotherapy for bladder cancer: the fight is on. World J Urol 2018; 
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Emrich IE, Zawada AM, Martens-Lobenhoffer J, et al. 
 
 outperforms asymmetric dimethylarginine (ADMA) and other methylarginines 
as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease. 
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dimethylated H3R2 using liquid chromatography-tandem mass spectrometry-based 
targeted proteomics. Anal Chem 2016; 88(17):8441-9.
CCI

SAP_001.pdf: 
Protocol C3851001 (PF-06939999) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C3851001
A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS,
AND PHARMACODYNAMICS OF ESCALATING DOSES OF PF-06939999 (PRMT5
INHIBITOR) IN PARTICIPANTS WITH ADVANCED OR METASTATIC
NON-SMALL CELL LUNG CANCER, HEAD AND NECK SQUAMOUS CELL
CARCINOMA, ESOPHAGEAL CANCER, ENDOMETRIAL CANCER, CERVICAL
CANCER AND BLADDER CANCER
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
14 Mar 2019


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Objectives .......................................................................................5
2.1.2. Secondary Objectives ...................................................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint(s) ..................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................9
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events...........................................................................................10
3.5.2. Laboratory Data..........................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.2. General Methods .....................................................................................................11
5.2.1. Analyses for Continuous Data....................................................................11
5.2.2. Analyses for Categorical Data....................................................................11
5.2.3. Analyses for Binary endpoints....................................................................11
5.2.4. Analyses for time-to-event data..................................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
5.3.1. Missing Dates .............................................................................................12
5.3.2. Efficacy Analysis........................................................................................12
5.3.3. Pharmacokinetics........................................................................................12
5.3.3.1. Concentrations Below the Limit of Quantification...................12
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5.3.3.2. Deviations, Missing Concentrations and Anomalous 
Values................................................................................................12
5.3.4. Pharmacokinetic Parameters.......................................................................13
5.3.5. QTc .............................................................................................................13
6. ANALYSES AND SUMMARIES ......................................................................................13
6.1. Primary Endpoint(s) ................................................................................................13
6.1.1. Dose Limiting Toxicities (DLTs)...............................................................13
6.1.2. Adverse Events...........................................................................................14
6.1.3. Laboratory abnormalities............................................................................14
6.2. Secondary Endpoint(s) ............................................................................................15
6.2.1. Pharmacokinetic Analysis ..........................................................................15
6.2.2. Tumor Response.........................................................................................16
6.3. Baseline and Other Summaries and Analyses.........................................................16
6.3.1. Baseline Summaries....................................................................................16
6.3.2. Study Conduct and Participant Disposition................................................16
6.3.3. Study Treatment Exposure .........................................................................16
6.3.4. Concomitant Medications and Nondrug Treatments..................................17
6.4. Safety Summaries and Analyses .............................................................................18
6.4.1. Adverse Events...........................................................................................18
6.4.2. Laboratory Data..........................................................................................18
6.4.3. Vital Signs ..................................................................................................19
7. ELECTROCARDIOGRAMS..............................................................................................19
7.1. Physical Examination..............................................................................................20
8. INTERIM ANALYSES.......................................................................................................20
9. REFERENCES ....................................................................................................................20
10. APPENDICES ...................................................................................................................21
LIST OF TABLES
Table 1:
Analysis Sets.............................................................................................10
Table 2:
Safety QTc Assessment ............................................................................20
Table 3.
Progression Free Survival and Duration of Response..............................22
Table 4.
Time to Progression..................................................................................23
Table 5.
Response Evaluation Criteria in Solid Tumors by RECIST 1.1...............29


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Table 6.
Best Overall Response When Confirmation of CR and PR Required......30
LIST OF FIGURES
Figure 1.
Part 1 Dose Escalation (BLRM design)......................................................7
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................21
Appendix 2. Time to Event Data Analysis Censoring Rules...................................................22
Appendix 3. Categorical Classes for ECG and Vital Signs.....................................................24
Appendix 4. RECIST 1.1 Tumor Assessment Criteria............................................................25


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1. VERSION HISTORY
This is the first version.
2. INTRODUCTION
PF-06939999 is an orally available small molecule inhibitor of protein arginine 
methyltransferase 5 (PRMT5) that is investigated in participants with advanced or metastatic 
HNSCC, NSCLC, esophageal, endometrial, cervical and bladder cancer.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3851001.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
2.1.1. Primary Objectives
To assess safety and tolerability at increasing dose levels of PF-06939999 in successive 
cohorts of participants with selected advanced or metastatic solid tumors in order to estimate 
the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the 
Recommended Phase 2 Dose (RP2D)/schedule.
2.1.2. Secondary Objectives
•
To characterize the single and multiple dose pharmacokinetics (PK) of PF-06939999 
following oral administration.
•
To evaluate preliminary anti-tumor activity.
 
 
 
2.2. Study Design
The study is divided into 2 parts, dose escalation (Part 1) followed by dose expansion (Part 
2). The Part 2 dose expansion protocol specifics will be covered in a subsequent amendment 
once the maximum tolerated dose (MTD) is reached in Part 1. 
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Part 1 (dose escalation) is estimated to enroll approximately 40 participants. Bayesian 
Logistic Regression Model (BLRM) will be used to determine the MTD. Participants will 
receive escalating doses of PF-06939999 starting from 0.5 mg once daily (QD) which is one 
sixth the human equivalent dose of the highest non-severely toxic dose (HNSTD)/no-
observed-adverse-effect level (NOAEL) based on body surface area scaling of the dose. Dose 
limiting toxicities (DLT) will be assessed during Cycle 1 (the first 28 days) to inform dose 
escalation and determine the MTD. Cohort size will be approximately 3 participants, with at 
least 1 DLT-evaluable participant per cohort in the first three cohorts and at least 2 DLT 
evaluable participants per cohort in the remaining cohorts.
PF-06939999 will be administered as a single agent, orally QD for the first cohort then BID 
in 28 day cycles for all subsequent cohorts on a continuous basis until disease progression, 
participant refusal or unacceptable toxicity. The estimated length of treatment is 
approximately 2 years. Any additional treatment with PF-06939999 beyond 2 years shall be 
discussed and approved by the Sponsor.
Number of Participants: According to stopping criteria for dose escalation, approximately 
15–50 participants will be enrolled in the Part 1 dose escalation portion of the study, 
however the total number of participants will depend on the number of dose levels needed to 
determine the MTD and number of participants evaluable for DLT at each dose level.  It is 
envisioned that overall sample size for Part 1 will be approximately 40 participants. 
Intervention Groups and Duration: Part 1 is estimated to enroll approximately 40 
participants. On average the total duration of study participation for each participant is 
anticipated to be approximately 2 years, with 28 days of screening, length of treatment of 
approximately 22 months and a follow-up period of 28 days after the last dose. Participants 
will receive PF-06939999 at the dose level of their enrollment cohort QD for the first cohort 
then BID for all subsequent cohorts on a continuous basis. Other dosing regimen, eg, once 
daily or intermittent dosing, may also be considered in the study if supported by emerging 
clinical data.
Data Monitoring Committee: No.
Study Schema


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Figure 1.
Part 1 Dose Escalation (BLRM design)
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

Dose Limiting Toxicities (DLTs).
Participants who discontinue treatment before completing Cycle 1 or receive less than 
75% of the planed doses for reasons other than treatment-related toxicity (eg, missed 
appointments, misplaced investigational product supplies, development of coexisting medical 
condition rendering the participant unable to swallow medication, development of rapidly 
progressing disease) might be replaced. 
For the purpose of dose escalation, the DLT observation period will be first cycle of 
treatment (within 28 days of first dose) in each participant including day 29 labs. Significant 
adverse events considered to be related to the investigational product or treatment under 
investigation that occur after the DLT observation period will be reviewed in context of all 
safety data available. That review may result in re-evaluation of the dosing level or regimen. 
Hematologic Dose-Limiting Toxicities:
Any Grade 4 hematologic AE is a DLT with the following clarifications:


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1. Grade 4 neutropenia regardless of intervention is a DLT.
2. Febrile neutropenia (defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.5°C [101.3°F] or a temperature of ≥38°C [100.4°F] sustained 
for more than 1 hour) is a DLT.
3. Grade 3 neutropenia with infection is a DLT.
4. Grade 3 thrombocytopenia with ≥Grade 2 clinically significant bleeding (defined as 
hospitalization or urgent medical intervention for atypical bleeding sites) is a DLT.
5. Grade 3 anemia requiring blood transfusion is a DLT.
Non Hematologic Dose-Limiting Toxicities:
Any Grade ≥3 non-hematologic adverse events (AEs) is a DLTs with the following 
clarifications:
1. Grade 3 nausea/vomiting or diarrhea lasting ≥4 days after treatment with adequate 
antiemetics or other supportive care is a DLT.
2. Confirmed drug induced liver injury (DILI) meeting Hy's law criteria is a DLT. 
3. For participants with Grade 2 hepatic transaminase or alkaline phosphatase levels at 
baseline as a result of liver metastasis or bone metastasis, a hepatic transaminase or 
alkaline phosphatase level >10 times the upper limit of normal will be considered a 
DLT.
4. Clinically important or persistent toxicities that are not included in the above criteria 
may be considered a DLT following review by Pfizer and the investigators. All DLTs 
need to represent a clinically significant shift from baseline.
Any toxicity causing greater than 2 weeks of dose delay is a DLT. Note: Participants 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 1 or baseline, only after discussion 
between the Investigator and Sponsor.
Any dose reduction due to an adverse event (per protocol) during the first cycle will be 
qualified as participant experiencing DLT.
The following AEs will not be adjudicated as DLTs:

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.


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•
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. Detailed 
description is available in Section 3.5.1.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE version 5.0), and timing.
3.2. Secondary Endpoint(s)
•
Pharmacokinetic parameters of PF-06939999: Single Dose (SD) - Cmax, Tmax, 
AUClast, and as data permit, t1/2, AUCinf, CL/F, and Vz/F.
•
Pharmacokinetic parameters of PF-06939999: Multiple Dose (MD) - Css,max, 
Tss,max, AUCss,τ , and as data permit, CL/F, Vss/F, and Rac (AUCss,τ,/AUCsd,τ,).
•
Tumor response: Objective response rate (ORR) and duration of response (DoR), as 
assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 
Appendix 4) version 1.1.
 
 
 
3.4. Baseline Variables
Baseline characteristics will be collected according to Schedule of Activities as specified in 
the protocol. No baseline variable will be used for stratification or as covariates in the 
statistical analysis. 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. 
Laboratory baseline will be the last predose measurement of before the first dose of any 
component of the study treatment.
Baseline for ECG is defined as Cycle 1 Day 1 predose. ECG measurements (an average of 
the triplicate measurements) will be used for the statistical analysis and all data 
presentations. 
CCI


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3.5. Safety Endpoints
3.5.1. Adverse Events
Severity of adverse events (AEs) will be graded according to CTCAE version 5.0.
The definitions of an AE and an SAE can be found in Appendix 3 of the protocol.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and
recording events that meet the definition of an AE or SAE and remain responsible to pursue
and obtain adequate information both to determine the outcome and to assess whether it
meets the criteria for classification as an SAE or that caused the participant to discontinue
PF-06939999 (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow up
information in an expedited fashion.
3.5.2. Laboratory Data
Oral temperature, pulse rate, and blood pressure (BP) will be assessed.
Further details of the laboratory tests can be found in Appendix 2 of the protocol.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior releasing the database and classifications will be 
documented per standard operating procedures.
Table 1:
Analysis Sets
Population
Description
Full analysis set
The full analysis set includes all enrolled participants.
Per protocol analysis set
(Evaluable for MTD)
The per protocol analysis set includes all enrolled participants 
who had at least one dose of study treatment and either 
experienced DLT or do not have major treatment deviations 
during the DLT observation period. 
Safety set
The safety analysis set includes all enrolled participants who 
receive at least one dose of study treatment
Modified Intent to Treat 
(mITT)
The modified intent to treat (mITT) is the analysis population 
that will follow the ITT principle and include participants 
receiving at least 1 dose of study medication with baseline 
assessment and at least 1 post baseline assessment, disease 
progression, or death before the first tumor assessment. The 
mITT population may be used for interim analysis and 


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Population
Description
conference presentations when the study is still ongoing.
PK analysis
The PK parameter analysis population is defined as all enrolled 
participants treated who do not have protocol deviations 
influencing PK assessment, and have sufficient information to 
estimate at least 1 of the PK parameters of interest.
The PK concentration population is defined as all enrolled 
participants who are treated and have at least 1 analyte 
concentration.
Response Evaluable
The response evaluable population will include all participants 
who received at least one dose of study treatment and had 
baseline disease assessment or measurable disease at baseline, 
if applicable and at least one post baseline disease assessment.
/Biomarker
The 
/Biomarker analysis population is defined as all enrolled 
participants with at least 1 of the PD/Biomarkers evaluated at 
pre and/or post dose.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There will be no hypothesis testing in this study.
5.2. General Methods
The data are summarized by cohort defined by the initial dose of the study drug. DLT rates 
at the study dose levels will be presented via mean and medians and a Bayesian credible 
interval based on the posterior density from the full probability model and will be used for 
the dose escalation decision meetings. 
5.2.1. Analyses for Continuous Data
Continuous data will be summarized with the mean, median, minimum, maximum,
coefficient of variation and standard deviation. Missing values will be excluded from the 
analysis.
5.2.2. Analyses for Categorical Data 
Categorical data will be summarized by number of unique patient incidence. Missing data 
will be excluded from the analysis. 
5.2.3. Analyses for Binary endpoints
Binary data will be summarized using number of unique patient incidence, and Wilson’s 
confidence interval for binomial proportions will be presented if warranted.
CCI
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Binary endpoints in this study include ORR, complete response (CR), partial response (PR)
based on RECIST 1.1. Descriptive statistics along with the corresponding 2-sided 
95% confidence intervals using an exact method will be provided for these endpoints if the 
sample size per cohort permits.
5.2.4. Analyses for time-to-event data
The time-to-event data will be presented for individual patient and by cohort when 
applicable. 
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.1. 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, and pharmacodynamic analyses, which will only use the 
actual date collected or if date not available deem the data missing.
5.3.2. 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 Appendix 2.
5.3.3. Pharmacokinetics 
5.3.3.1. 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 
will be replaced with the value for the lower limit of quantification.)
5.3.3.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged 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.


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5.3.4. 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 be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
5.3.5. QTc
For the QTc analyses, no values will be imputed for missing data.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Dose Limiting Toxicities (DLTs)

Analysis set: Per protocol analysis set. Dose limiting toxicities (DLT) will be 
assessed during Cycle 1 (the first 28 days) to inform dose escalation and determine 
the MTD.  

Analysis methodology: 
Statistical Methods: 
Bayesian adaptive approach: The dose escalation in the Part 1 of the study will be guided by 
a Bayesian analysis of Cycle 1 dose limiting toxicity (DLT) data for PF-06939999. Toxicity 
is modelled using two-parameter logistic regression for the probability of a participant 
experiencing a DLT at the given dose.
Assessment of participant risk: After each cohort of participants, the posterior distribution 
for the risk of DLT for new participants at different doses of interest for PF-06939999 will be 
evaluated. The posterior distributions will be summarized to provide the posterior 
probability that the risk of DLT lies within the following intervals:
Under-dosing:
[0, 0.16]
Targeted dosing:
[0.16, 0.33]
Overdosing:
[0.33, 1]


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The escalation with overdose control (EWOC) principle: Dosing decisions are guided by the 
escalation with overdose control principal (Rogatko 2007). A dose may only be used for 
newly enrolled participants if the risk of over-dosing at that dose is less than 25%. 
Prior distributions: Weakly informative prior distributions based on pre-clinical/expert 
opinion information will be chosen for the logistic parameters.
Stopping criteria:
The maximum number of participants in dose escalation part of the trial was set to 50. The
trial will be stopped when the following criteria are met:

At least 6 participants have been treated at the recommended MTD/RP2D.

The dose d ̃ satisfies one of the following conditions:

The probability of target toxicity at dose d ̃ exceeds 50%, 
ie, Pr(0.16 ≤πd ̃ <0.33)≥50%. 

A minimum of 15 participants have been treated in the trial.
In case of change of the dosing regimen, DLT data accumulated during the dose escalation
with the original regimen might be used to form a prior for further BLRM analysis. Details
about derivation of this prior using Meta-Analytic-Predictive (MAP) approach can be found
in Technical supplement to Appendix 9 of the protocol.

Intercurrent events and missing data: Each cohort will have at least one DLT-
evaluable patient for first 3 dose levels and and at least two DLT-evaluable patient for 
all other dose levels. Missing values will not be imputed.
6.1.2. Adverse Events

Analysis set: Safety analysis set.   

Analysis methodology:  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. Further 
description is given in Section 6.4.1. The treatment emergent adverse events will be 
defined according to Pfizer’s standard definition. 

Intercurrent events and missing data: intermediate missing values will not be imputed.
6.1.3. Laboratory abnormalities

Analysis set: safety analysis set.  


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
Analysis methodology: Presented as tables and characterized by type, frequency, 
severity (as graded by NCI CTCAE version 5.0), and timing. The number and 
percentage of participants 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). For laboratory tests without CTCAE grade 
definitions, results will be categorized as normal, abnormal, or not done. Shift tables 
or figures may be created for select laboratory abnormalities. Results meeting the 
Hy’s Law as defined in the protocol may also be presented as tables or listings.

Intercurrent events and missing data: intermediate missing values will not be imputed.
6.2. Secondary Endpoint(s)
6.2.1. Pharmacokinetic Analysis
Plasma concentrations of PF-06939999 will be summarized descriptively (n, mean, standard 
deviation, coefficient of variation, median, minimum, maximum, geometric mean and its 
associated coefficient of variation) by dose, cycle, day and nominal time. 
Individual participant plasma concentration-time data within a dose interval after Cycle 1 
Day 1 and Cycle 1 Day 15 will be analyzed using noncompartmental methods to determine 
single- and multiple- dose PK parameters. 
Single-dose PK parameters to be estimated will include the maximum plasma concentration 
(Cmax), time to maximum plasma concentration (Tmax), and area under the plasma 
concentration versus time curve (AUC) from time 0 to the last sampling time point within the 
dose inveral (AUClast), and if data permit, AUC from time 0 extrapolated to infinity 
(AUCinf), terminal elimination half life (t1/2), apparent oral plasma clearance (CL/F), and 
apparent volume of distribution (Vz/F). 
Multiple-dose PK parameters to be estimated will include steady state Cmax (Cmax,ss), 
Tmax, AUC within one dose interval (AUCtau,ss), minimum plasma concentration (Cmin,ss), 
steady-state CL/F (CLss/F), and if data permit, apparent volume of distribution (Vss/F), t1/2, 
and accumulation ratio (Rac). 
The single dose and steady state (ie, multiple dose) PK parameters will be summarized 
descriptively (n, mean, standard deviation, coefficient of variation, median, minimum, 
maximum, geometric mean and its associated coefficient of variation) by dose level, cycle 
and day. 
Dose normalized AUCinf (AUCtau at steady state), AUClast and Cmax will be plotted 
against dose (using a logarithmic scale) by cycle and day. These plots will include 
individual participant values and the geometric means for each dose.


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Pharmacokinetic/Pharmacodynamic (PK/PD) Correlation
PK and PD data from this study may be analyzed using modeling approaches and may also
be pooled with data from other studies to investigate any association between PF-0639999 
exposure and biomarkers or significant safety endpoints. The results of these analyses, if
performed, may be reported separately.
6.2.2. Tumor Response

Overall Response Rate (ORR).

ORR as assessed using RECIST version 1.1. ORR is defined as the proportion of 
patients who achieved completed response (CR) or partial response (PR) per RECIST 
1.1.

Duration of Response (DOR).

Duration of response is defined as the time from start date (which is the date of first 
documentation of PR or CR) to date of first documentation of objective progression 
or death. DOR is only applicable to those patients with an objective response.

Analysis set: Response Evaluable. 

Intercurrent events and missing data: Data after study drug discontinuation and rescue 
will be excluded; intermediate missing values will not be imputed.
6.3. Baseline and Other Summaries and Analyses
6.3.1. Baseline Summaries
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, and primary diagnosis will be tabulated and listed. For ECOG 
performance status a shift table (worst post-baseline vs baseline) may be produced. The 
Safety Analysis Set will be used.
6.3.2. Study Conduct and Participant 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.
6.3.3. Study Treatment Exposure
The safety analysis set will be used.
Dose modifications are described in the protocol.  The following will be summarized by 
subject for overall and each dose level:

Number of subjects per dose level; 


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
Median and range of number of cycles started per subject; 

Number (%) of subjects starting a cycle (1, 2, 3…); 

Number (%) of dose interruptions (include both known and unknown dates); 

Number (%) of subjects with dose reductions; 

Number (%) of each reason (drug related AE vs AE vs. Other) dose interruptions and 
dose reductions; 

Time on treatment (median, range).
The following will be summarized by cycle received for overall and each dose level: 

Total number of cycles started; 

Number of cycles started per subject (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 cumulative percent of administered dose (compared to planned dose) by cycle 
and overall.
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 reduction (yes/no), and dose 
interruption (yes/no).
6.3.4. Concomitant Medications and Nondrug Treatments
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.


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6.4. Safety Summaries and Analyses
All safety analyses will be performed on the safety population.
Summaries and analyses of safety parameters will include all participants in the safety
analysis set.
AEs, ECGs, BP, PR, continuous cardiac monitoring, and safety laboratory data will be
reviewed and summarized on an ongoing basis during the study to evaluate the safety of
participants. Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical
concern will be described. Safety data will be presented in tabular and/or graphical format
and summarized descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the
course of the study will be considered source data and will not be required to be reported,
unless otherwise noted. However, any untoward findings identified on physical examinations 
conducted during the active collection period will be captured as AEs, if those findings meet 
the definition of an AE. Data collected at screening that are used for inclusion/exclusion 
criteria, such as laboratory data, ECGs, and vital signs, will be considered source data, and 
will not be required to be reported, unless otherwise noted. Demographic data collected at 
screening will be reported.
6.4.1. Adverse Events
AEs will graded by the investigator according to the CTCAE version 5.0 and coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Adverse event data will be
reported in tables and listings. Summaries of adverse event by mapped terms, appropriate
thesaurus level, toxicity grade, and seriousness and relationship to study treatment will be
presented, as well as summaries of adverse events leading to death and premature 
withdrawal from study treatment. The number and percentage of participants who 
experienced any AE, SAE, treatment related AE, treatment related SAE, and AEs leading to 
treatment discontinuation, dose interruption and dose reduction 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). Listings of DLTs and deaths will be 
provided.
6.4.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards. The assessment will take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
The data will be summarized with respect to demographic and baseline characteristics,
efficacy observations and measurements, safety observations and measurements,
pharmacokinetic and biomarker measurements.


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6.4.3. Vital Signs
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse
rate and 3 blood pressure measurements (3 consecutive blood pressure readings will be
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings will
be recorded on the CRF.
7. ELECTROCARDIOGRAMS
The analysis of ECG results will be based on participants 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. 
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.
QT intervals will be corrected for heart rate (HR) (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, HR, RR interval, PR interval (PR), 
QRS, QTcF (and other correction factors, eg, QTcB as appropriate), and dose. Individual 
QT (all evaluated corrections) intervals will be listed by time and dose. The most 
appropriate correction factor depending on HR (default QTcF) 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 dose and time point. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum absolute QTc results. Shift tables will also 
be provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %).
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.  The mean of the replicate measurements (eg, triplicate ECGs obtained) will be 
used to represent a single observation at that time point. If any of the 3 individual ECG 
tracings has a QTc value >500 msec, but the mean of the triplicates is not >500 msec, the 
data from the participant’s individual tracing will be described in a safety section of the 
clinical study report (CSR) 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 the postdose QTc value and the average of the predose triplicate values on 
Day 1.


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Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR
interval, and QRS complex will be summarized by treatment and time.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment:
Table 2:
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
Patients experiencing clinically-relevant morphological ECG changes will be summarized
(including frequency and percentage).
Categorical data analysis will follow Appendix 3. 
7.1. Physical Examination
Participants will have a physical examination to include weight, vital signs, assessment of 
ECOG performance status and height; height will be measured at screening only.
Findings should be recorded in the source documents, and any change from baseline 
considered by the investigation to be clinically significant should be recorded as an adverse 
event in the CRF.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD
modeling, and/or supporting clinical development.
9. REFERENCES


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10. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules 
for Handling Intercurrent 
Events and Missing Data 
Analysis 
Model
Tumor response: 
Objective response 
rate (ORR) and 
duration of response 
(DoR), as assessed 
using the Response 
Evaluation Criteria 
in Solid Tumors 
(RECIST 
Appendix 4) version 
1.1
Summary
Response 
Evaluable
Separately for 
observed data.
N/A


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Appendix 2. Time to Event Data Analysis Censoring Rules
Table 3.
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.  


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Table 4.
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
Treatment discontinuation due 
to toxicity or other reason
Date of last objective tumor 
assessment prior to discontinuation
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.
DOSD and DOR
Censoring rules for DOSD and DOR will be the same as for PFS. 


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Appendix 3. Categorical Classes for ECG and Vital Signs
Categories for QTcB and QTcF
QTcB/QTcF 
(ms)
max. ≤450
450<max. 
≤480
480<max.≤50
0
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) 
increase from 
baseline
Baseline 
>100 and 
max. ≥25% 
increase
Baseline ≤100 
and max. 
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease 
≥30
max. increase 
≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease 
≥20
max. increase 
≥20
Supine pulse rate (bpm)
min. <40
max. >120


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Measurements that fulfil these criteria are to be listed in the study report.
Appendix 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.
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. 
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.


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
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). 
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 


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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.
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. 


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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. 
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).


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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.
Table 5.
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/no
n-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. 
Table 6.
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.


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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 
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.