Clinical trial NCT03284723
Conditions: Breast Neoplasms
Keywords: HER2 PF-06804103 ADC breast cancer neoplasms solid tumors human epidermal growth receptor 2
Sponsor: Pfizer
Start date: 2017-11-01; Completion date: 2021-08-31
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study will evaluate the safety, pharmacokinetics and pharmacodynamics of increasing doses of PF-06804103 in patients with HER2 positive and negative breast and gastric cancer (HER2 positive only and gastric were studied in Part 1A only). The study will expand to look at selected doses in patients with HER2 positive and negative breast cancer.

Detailed description:

Arms: arm 1: Study Treatment arm 2: Study Treatment
Interventions: intervention 1: PF-06804103 intervention 2: PF-06804103 + Palbociclib +Letrozole
Intervention descriptions: intervention 1: Dose Escalation Part - 1A Dose Expansion Part - 2A intervention 2: Dose Escalation - Part 1B Dose Expansion - Part 2B

Protocol documents:
Prot_000.pdf: 
PF-06804103
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Final Protocol Amendment 4, 24 January 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06804103 IN PATIENTS WITH HUMAN EPIDERMAL 
GROWTH FACTOR RECEPTOR 2 (HER2) POSITIVE AND NEGATIVE SOLID 
TUMORS
Investigational Product Number:
PF-06804103
Investigational Product Name:
Not applicable
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2017-002538-22
Protocol Number:
C0541001
Phase:
Phase 1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Protocol 
Amendment 4
24 January 2020
The changes in Amendment 4 include:
Introduction, Background, and Rationale:
•
Numerous changes were made to the 
headings and content of these sections to
streamline previous text, and to revise or 
add new information relevant to the study 
design changes.
Protocol Summary
•
Revised as appropriate for consistency 
with the body of the document.
Schedule of Activities
•
Main and PK tables were divided to more 
clearly reflect monotherapy dosing and 
sample collection activities and 
combination therapy dosing and sample
collection activities.
•
Individual changes were made to each 
table to remove or add activities required 
for each study part.
o
Footnotes were updated as 
appropriate to reflect the design 
changes.
 
Study Objectives and Endpoints
•
clarified and revised to reflect the changes 
to the study design .
Study Design and Schematic
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
Schematic revised to reflect new study 
design.

Updated or added language for each study 
part to reflect the changes to the study 
populations, the dose levels to be 
explored, the number of patients to be 
evaluated, the criteria for dose escalation, 
and the dose expansion plan for 
monotherapy and combination therapy.
Dose Limiting Toxicity

Revised to include DLT information for 
newly defined treatment arms.
Inclusion/Exclusion Criteria

Headings for General Inclusion and 
General Exclusion were added as well as 
subheadings for treatment arms with 
specific requirements.

Revised to remove the GC and NSCLC 
arms after Part 1A 

Updated to be more specific for each of 
the patient populations to be evaluated in 
the rest of the study including:
o
In Part 1B, postmenopausal
patients with HR-positive HER2
IHC 1+ or IHC 2+/ISH- BC
o
In Part 2A, HER2-positive BC 
patients in 3L 
o
In Part 2B, patients with HR-
positive HER2 IHC 1+ or IHC 
2+/ISH- BC in the 1L
Study Treatments

Revised to include a description of study 
treatments by study part and clarify that 
all study treatment are considered 


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investigational products

Remove “/kg” from Table 8 in reference 
to palbociclib dose
Allocation to Treatment Procedures:

updated to reflect the potential use of
IRT/and IWR
Patient Compliance

Updated to reflect compliance tracking
method for IP administration for each 
study part
Investigational Product Supplies (Form and 
Packaging)

Added dosing form and packaging 
information added for each IP
Administration of Investigational Products:

Added administration of IP details for 
each IP 

Updated premedication instructions and 
process information for handling infusion-
related reactions
Dose Delays

Section revised to clarify processes for 
Q2W and Q3W dosing schedules.
Dose Modifications

Dose modification information added for 
each IP to be administered as 
monotherapy and in combination therapy.

Dose modification tables for each IP 
added to appendices.
Re-Treatment Criteria


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
Section added to clarify retreatment
procedures.
Concomitant medications

Concomitant medication information 
added for palbociclib.
Patient Withdrawal

Updates to language to ensure proper 
documentation is recorded in the medical 
records and database
Diffusing Capacity of the Lungs for Carbon 
Dioxide

Revised acceptable ranges.
Tumor Biopsies

Section revised to differentiate Part 1 and 
Part 2 tumor collection requirements, 
optional biopsies, and biopsy samples 
collected for biomarker assessment.
o
Corresponding data added to 
footnotes of the SOA
Analysis Sets

Section revised for clarity and 
conciseness, major treatment deviation 
criteria removed and cross reference
added to appropriate section.
Statistical Methods and Properties

Section revised to remove redundant table 
and MTD information, and revise sample 
size language.

Sample Size Determination
Updated language to accommodate new 
design and new patient sample sizes


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Appendices:

Table describing HER2 IHC and/or ISH 
status descriptions added

Tables describing dose modification 
guidelines added
Table of Drugs known to predispose
patients the Torsade de Pointes added
Editorial, grammatical, and administrative changes were made throughout the 
document, including changes and additions to the List of Abbreviations.
Protocol 
Amendment 3
25 April 2019
The changes in Amendment 3 include:

Schedule of Activities: 

A notation was added that the visit 
window for a complete visit applies to 
all assessments on the study visit. 

Additional guidance on the timing of
diffusing capacity of the lungs for carbon 
monoxide (DLco) measurements for 
patients on study past 12 months is 
provided in footnote #10.

The tumor biopsy sampling (footnote 20) 
was re-written to split out and clarify 
biopsy collection based on each part and 
arm of the study and the patient 
population. These modifications are also 
reflected in Section 7.3.5. Tumor 
Biopsies.
Rationale: To add clarity for visits and visit 
windows, clarify DLco assessments after 
12 months on study and provide details for 
tumor biopsy collection requirements. 

Schedule of Pharmacokinetic, 
Immunogenicity, and 
Biomarker/Pharmacodynamic Assessments: 


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•
Flexibility for the 1-hour sample time 
point was added and details were 
provided for post-dose PK sampling
window periods.  
Rationale: To broaden the window period to 
reduce protocol deviations and add time points
for collection of blood samples for CTCs. 
 
 
 
 
 
 
•
The Study Overview section in the protocol
summary and “Section 3.1. Study 
Overview” was updated to differentiate each 
HER2 status required by Arm for Part 2. 
Rationale: The required HER2 expression levels
were added for each Part 2 Arm (patient 
population). 
•
The Overall Study Design figure (Figure 1) 
was updated. 
Rationale: To align with “Section 3.1 Study 
Overview” and the updates to Section 4.1 and 
4.2 Eligibility Criteria.
•
Table 1. for PF-06804103 Dose Escalation 
Levels was modified to reflect additional 
dose levels beyond 4.0 mg/kg based on the 
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footnote that higher doses may be explored. 
Changes were also reflected in Table 6. in 
Section 9.2. Statistical Methods and 
Properties.
Rationale – The study is enrolling at doses 
higher than 4 mg/kg and is supported by the 
footnote that higher doses may be explored.

Text was added to Section 3.4 Dose 
Expansion Phase (Part 2) to define the steps 
that will be taken once the MTD/RP2D has 
been determined in Part 1. 
Rationale: Direct the reader to the modified 
criteria in “Section 4.1. Inclusion Criteria” and 
Section 4.2. Exclusion Criteria” for Part 2. 

“Section 4.1. Inclusion Criteria”.

Part 1 and Part 2 were modified to define 
the specific criteria for each part of the 
study and each study population. 

Patients are required to have access to 
archival tumor sample.
Rationale: Part 1 was modified to provide 
additional clarity. Part 2 was modified to (1) 
define the biomarker driven population and (2) 
outline the specific lines of therapy for each 
patient population prior to study entry. In
addition, all patients will be required to have 
access to archival tissue sample to be 
retrospectively assessed for HER2 expression.
This was previously described in the Schedule 
of Activities footnote 20.

“Section 4.2. Exclusion Criteria”: #7 was 
removed. The criteria previously excluded 
patients in Part 2 that received prior TDM-1. 
Rationale: To study a patient population who 
received all prior monoclonal HER2 targeted 
therapies.


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
Korea specific language was added to the 
document as required by regulatory agency 
feedback.
Rationale: Previously addressed and agreed to in 
a protocol clarification letter.

“Section 5.4.3. Dose Reductions”: Table 3 
and Figure 2 were clarified for dose 
reduction criteria and algorithm for 
continuation and discontinuation of 
PF-06804103 based on LVEF assessments 
while on study.
Rationale: The text was contradictory and 
required modification.

“Section 6.4.1. Request to Continue 
Treatment” was added to allow the 
investigator and Sponsor to discuss the 
option for a patient to remain on study if 
deriving clinical benefit.

A timeframe was added to “Section 7.1.5. 
(12 Lead) Electrocardiogram” for the 
3 consecutive ECGs.
Rationale: To allow flexibility when performing 
the ECGs.

“Section 7.1.7. Diffusing Capacity of the
Lungs for Carbon Dioxide”: The units for on 
study measuring of DLco assessments were 
added. 
Rationale: In order to grade DLco assessments 
by CTCAE, the unit of measurement required an 
update. This grading is necessary for the 
determination of potential Dose 
Reductions/Discontinuations (Table 3).

“Section 9. The Data Analysis/Statistical
Methods” were updated to reflect the target 
patient population being studied. 
Rationale: To provide sufficient sample size to 


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be able to draw preliminary assessment on 
safety and clinical activity.
Protocol 
Amendment 2
11 January 2018
The changes in Amendment 2 include:

Exclusion of patients with a history of prior 
malignancy other than the diseases under 
study within the past 5 years – Section 4.2.
Rationale – Additional criteria included to
address feedback from regulatory agency.

Requirement for use of effective 
contraception extended from 28 days to 
90 days post the last dose of study treatment 
– Schedule of Activities and Sections 4.2, 
4.3 and 7.1.1.
Rationale – Requirement revised to address 
feedback from regulatory agency.

Requirement for a minimum 48-hour
interval between dosing of new patients 
during the dose escalation portion of the 
study – Section 3.1.1.
Rationale – Requirement added to address 
feedback from regulatory agency.

Administrative changes – Schedule of 
Activities, Sections 3.1, 4.1 and 9.3.
Rationale – Administrative changes and
corrections.
Protocol 
Amendment 1 
06 September
2017
The changes in Amendment 1 include:

Revisions to the dose limiting toxicity 
criteria definition – Section 3.2.
Rationale – Additional criteria included, and
existing criteria revised to address feedback 
from regulatory agency.

Modifications to inclusion criteria 1 and 2 to
further define the relevant patient 


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populations – Section 4.1.
Rationale – Addition of reference to the 
specific criteria to be used to address 
feedback from regulatory agency as well as 
simplification of the criteria for Part 2.

Inclusion of prior therapies required for 
non-small cell lung cancer patients added to 
inclusion criteria 3 – Section 4.1.
Rationale – Revised to address feedback 
from regulatory agency.

Revisions to timing for pregnancy tests prior 
to receipt of the first study treatment –
Schedule of Activities and Section 7.1.1.
Rationale – Revision to timing for second 
negative pregnancy test given the study will 
enroll patients requiring expedited treatment 
for their life-threatening condition.

Removal of blood sample for surfactant 
protein-A (SP-A) and SP-D test – Schedule 
of Activities and Section 7.1.7.
Rationale – High resolution imaging as well 
as diffusing capacity of the lungs for carbon 
monoxide determined to be sufficient
assessments for monitoring of potential 
pulmonary toxicity.

Inclusion of amylase and lipase as required 
blood chemistry assessment evaluations –
Schedule of Activities and Section 7.1.3.
Rationale – Analytes added to ensure 
appropriate monitoring for new dose limiting 
toxicity criteria.

Decrease in frequency of 
echocardiogram/multigated acquisition scan 
evaluation after one year of study treatment. 
– Schedule of Activities.
Rationale – Frequency of assessments 


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decreased to reduce the number of 
assessments after sufficient safety 
monitoring period has been completed.
 
•
Revision to definition for inclusion of 
patients in the DLT observation who 
discontinue study close to Day 21 –
Section 3.1.1.
Rationale – Editorial clarification.
•
Revision to exclusion criteria for carbon 
monoxide diffusing capacity – Section 4.2.
Rationale – Editorial clarification.
•
Administrative and editorial revisions –
Schedule of Activities, Section 3.1, 3.1.1, 
3.3, 4.2, 5.1, 5.4, 5.4.2, 7.1.4, 7.2.1, 7.3.3
and Table 3.
Original protocol
15 May 2017
Not applicable (N/A)
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...................................................................................................................19
LIST OF FIGURES .................................................................................................................19
APPENDICES .........................................................................................................................20
PROTOCOL SUMMARY.......................................................................................................21
SCHEDULE OF ACTIVITIES................................................................................................27
1. INTRODUCTION ...............................................................................................................40
1.1. Mechanism of Action and Indication......................................................................40
1.2. Background .............................................................................................................40
1.3. Study Rationale .......................................................................................................41
1.3.1. Arm C1: PF-06910403 in Combination with Palbociclib Plus 
Letrozole ..........................................................................................................41
1.4. Nonclinical Pharmacology and Safety....................................................................42
1.5. Starting Dose Rationale...........................................................................................44
1.5.1. Part 1A – Monotherapy Dose Escalation....................................................44
1.5.2. Part 1B – Combination Regimen Dose Escalation.....................................44
1.5.3. Part 2A – Monotherapy Dose Expansion ...................................................44
1.5.4. Part 2B – Combination Dose Regimen Expansion.....................................44
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................45
3. STUDY DESIGN.................................................................................................................47
3.1. Study Overview.......................................................................................................47
3.1.1. Criteria for Dose Escalation........................................................................49
3.1.1.1. Part 1A Monotherapy Dose Escalation .....................................49
3.1.1.2. Part 1B – Combination Regimen Dose Escalation....................51
3.1.1.3. Part 2A – Monotherapy Dose Expansion..................................52
3.1.1.4. Part 2B – Combination Regimen Dose Expansion ...................52
3.2. Dose Limiting Toxicity Definition..........................................................................53
3.3. Maximum Tolerated Dose Definition .....................................................................56
3.4. Recommended Phase 2 Dose Definition.................................................................56
4. PATIENT ELIGIBILITY CRITERIA.................................................................................56
4.1. Inclusion Criteria.....................................................................................................56
4.1.1. General Study Inclusion Criteria ................................................................56


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4.1.2. Inclusion Criteria for Part 1A – Monotherapy Dose Escalation.................57
4.1.2.1. Inclusion Criteria for Part 2A – Monotherapy Dose 
Expansion Arms M1 and M2 ............................................................58
4.1.2.2. Inclusion Criteria for Part 2A – Monotherapy Dose 
Expansion Arm  M3 ..........................................................................58
4.1.3. Inclusion Criteria for Part 1B and Part 2B - Combination Regimen 
Dose Escalation and Expansion:......................................................................59
4.2. Exclusion Criteria....................................................................................................59
4.2.1. General Study Exclusion Criteria...............................................................59
4.2.2. Exclusion Criteria Specific to Part 1B and 2B Combination Regimen 
Dose Escalation and Expansion – Arm C1......................................................62
4.3. Lifestyle Requirements ...........................................................................................62
4.4. Sponsor’s Qualified Medical Personnel..................................................................63
5. STUDY TREATMENTS.....................................................................................................64
5.1. Allocation to Treatment ..........................................................................................64
5.2. Patient Compliance .................................................................................................65
5.3. Investigational Product Supplies.............................................................................65
5.3.1. Dosage Form(s) and Packaging..................................................................65
5.3.2. Preparation and Dispensing........................................................................66
5.4. Administration of Investigational Products.............................................................66
5.4.1. Premedication for PF-06804103.................................................................66
5.4.2. Administration of PF-06804103.................................................................66
5.4.2.1. Infusion-Related Reactions – PF-06804103 .............................67
5.4.3. Palbociclib Administration.........................................................................67
5.4.4. Letrozole Administration............................................................................67
5.4.5. Dosing Delays.............................................................................................67
5.4.5.1. Re-Treatment Criteria................................................................68
5.4.6. Monotherapy PF-06804103 Dose Modifications .......................................68
5.4.7. Combination Therapy Dose Modifications ................................................69
5.4.8. Palbociclib Dose Modifications..................................................................69
5.4.9. Letrozole Dose Modifications ....................................................................69
5.5. Investigational Product Storage ..............................................................................70
5.6. Investigational Product Accountability...................................................................71


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5.6.1. Destruction of Investigational Product Supplies ........................................71
5.7. Concomitant Treatment(s).......................................................................................72
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................72
5.7.2. Supportive Care ..........................................................................................72
5.7.3. Hematopoietic Growth Factors...................................................................72
5.7.4. Anti-Diarrheal, Anti-Emetic Therapy.........................................................73
5.7.5. Anti-Inflammatory Therapy........................................................................73
5.7.6. Corticosteroids............................................................................................73
5.7.7. Surgery........................................................................................................73
6. STUDY PROCEDURES .....................................................................................................73
6.1. Screening.................................................................................................................73
6.2. Study Period ............................................................................................................73
6.3. Follow-up Period.....................................................................................................73
6.4. Patient Withdrawal..................................................................................................74
6.4.1. Request to Continue Treatment ..................................................................76
7. ASSESSMENTS..................................................................................................................76
7.1. Safety Assessments .................................................................................................77
7.1.1. Pregnancy Testing ......................................................................................77
7.1.2. Adverse Events ...........................................................................................77
7.1.3. Laboratory Safety Assessment ...................................................................77
7.1.4. Vital Signs and Physical Examination........................................................78
7.1.5. Twelve-Lead Electrocardiogram ................................................................79
7.1.6. Echocardiogram or Multigated Acquisition Scan.......................................80
7.1.7. Diffusing Capacity of the Lungs for Carbon Dioxide (DLco) ...................80
7.1.8. Ophthalmic Examination............................................................................80
7.2. Pharmacokinetics Assessments...............................................................................80
7.2.1. Serum Sample Collection for PK Analysis of PF-06804103 ADC, 
Total Antibody and Unconjugated Payload (PF-06380101) ...........................81
7.3. Immunogenicity Assessments.................................................................................81
7.4. Biomarker/Pharmacodynamic Assessments ...........................................................81
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7.4.5. Tumor Biopsies...........................................................................................83
7.4.5.1. Collection of Biopsy Samples – Part 1......................................83
7.4.5.2. Collection of Biopsy Samples -  Part 2 .....................................83
7.5. Tumor Response Assessments ................................................................................84
8. ADVERSE EVENT REPORTING......................................................................................86
8.1. Requirements...........................................................................................................86
8.1.1. Additional Details On Recording Adverse Events on the CRF..................88
8.1.2. Eliciting Adverse Event Information..........................................................88
8.1.3. Withdrawal From the Study Due to Adverse Events..................................88
8.1.4. Time Period for Collecting AE/SAE Information......................................88
8.1.4.1. SAE Reporting ..........................................................................88
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................89
8.1.5. Causality Assessment .................................................................................89
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................89
8.2. Definitions...............................................................................................................90
8.2.1. Adverse Events ...........................................................................................90
8.2.2. Abnormal Test Findings .............................................................................91
8.2.3. Serious Adverse Events..............................................................................91
8.2.4. Hospitalization............................................................................................92
8.3. Severity Assessment................................................................................................93
8.4. Special Situations ....................................................................................................93
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................93
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................95
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8.4.2.1. Exposure During Pregnancy......................................................95
8.4.2.2. Exposure During Breastfeeding ................................................96
8.4.2.3. Occupational Exposure .............................................................96
8.4.3. Medication Errors .......................................................................................97
8.4.3.1. Medication Errors......................................................................97
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................97
9.1. Analysis Sets ...........................................................................................................98
9.2. Statistical Methods and Properties ..........................................................................98
9.3. Sample Size Determination...................................................................................100
9.4. Efficacy Analysis ..................................................................................................101
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................101
9.5.1. Analysis of Pharmacokinetics...................................................................101
9.5.2. Pharmacokinetic/Pharmacodynamic Modeling........................................101
9.5.3. Analysis of Biomarkers ............................................................................101
9.5.4. Analysis of Immunogenicity Data............................................................102
9.6. Safety Analysis......................................................................................................102
9.6.1. Analysis of the Primary Endpoint.............................................................102
9.6.2. Analysis of Secondary Safety Endpoints..................................................102
9.6.3. Electrocardiogram.....................................................................................103
9.7. Data Monitoring Committee .................................................................................103
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................103
11. DATA HANDLING AND RECORD KEEPING ...........................................................105
11.1. Case Report Forms/Electronic Data Record .......................................................105
11.2. Record Retention.................................................................................................105
12. ETHICS............................................................................................................................106
12.1. Institutional Review Board/Ethics Committee....................................................106
12.2. Ethical Conduct of the Study ..............................................................................106
12.3. Patient Information and Consent.........................................................................106
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................107
13. DEFINITION OF END OF TRIAL.................................................................................107
13.1. End of Trial in a Member State...........................................................................107


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13.2. End of Trial in All Other Participating Countries...............................................107
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................107
15. PUBLICATION OF STUDY RESULTS........................................................................107
15.1. Communication of Results by Pfizer ..................................................................107
15.2. Publications by Investigators ..............................................................................108
16. REFERENCES ................................................................................................................110


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LIST OF TABLES
Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of 
Activities...................................................................................................27
Table 2.
Combination Regimen Escalation and Expansion – Schedule of 
Activities...................................................................................................32
Table 3.
Pharmacokinetic, Immunogenicity, and 
Biomarker/Pharmacodynamic Assessments – Monotherapy Dosing.......37
Table 4.
Pharmacokinetic, Immunogenicity, and 
Biomarker/Pharmacodynamic Assessments – Combination 
Regimen (PF 6804103 in combination with Palbociclib and 
Letrozole)..................................................................................................38
Table 5.
Part 1A  - PF 06804103 Dose Escalation Levels......................................49
Table 6.
Decision Rules – Part 1A and Part 1B......................................................50
Table 7.
Part 1B - PF 06804103 Dose Escalation Levels.......................................52
Table 8.
Planned Dose Levels for Part 2B..............................................................53
Table 9.
Safety Laboratory Tests............................................................................78
Table 10.
Pharmacodynamic Summary....................................................................82
Table 11.
Objective Response Status at Each Evaluation ......................................124
Table 12.
Objective Response Status at each Evaluation for Patients with Non  
Target Disease Only ...............................................................................125
Table 13.
PF 06804103 Recommend Dose Reductions .........................................129
Table 14.
Dose Modifications for Toxicities Considered Possibly Related to 
PF-06804103...........................................................................................129
Table 15.
Dose Modifications for Palbocicliba Related Toxicities.........................134
Table 16.
Recommended Dose Level Reductions for Palbociclib .........................135
Table 17.
Dose Levels Reductions for Letrozole ...................................................135
LIST OF FIGURES
Figure 1.
Overall Study Design................................................................................49
Figure 2.
Algorithm for Continuation and Discontinuation of PF-06804103 
Based on LVEF Assessments in Patients with LVEF ı40% or 
≤45%.......................................................................................................133


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APPENDICES
Appendix 1. Abbreviations....................................................................................................114
Appendix 2. ECOG Performance Status................................................................................118
Appendix 3. HER2/IHC Status Descriptions.........................................................................119
Appendix 4. RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1 
Guidelines...............................................................................................121
Appendix 5. Management of Infusion Related Reactions Including Allergic Reactions, 
Cytokine Release Syndrome or Anaphylaxis .........................................126
Appendix 6. Potent CYP3A Inhibitors and Inducers.............................................................128
Appendix 7. Dose Modification Guidelines ..........................................................................129
Appendix 8. List of Drugs Known to Predispose Patient to Torsade de Pointes...................136


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PROTOCOL SUMMARY
Background and Rationale
HER2 is a receptor tyrosine kinase that is involved in the regulation of various cellular 
functions.  Aberrant HER2 receptor activation has been implicated as a driving factor in the 
tumorigenesis and progression of a number of cancers.34,27,23
To date, 3 HER2-specific monoclonal antibodies have been approved by regulatory agencies
for treating HER2-positive metastatic breast cancer: trastuzumab, pertuzumab, and 
ado-trastuzumab emtansine (T-DM1).  Although these HER2-targeting therapies have 
transformed the clinical practice for HER2-positive breast cancer and have resulted in 
survival benefits, not all patients respond to the therapies. The vast majority of patients who 
initially respond to the treatment will eventually relapse.  This is thought to be due to the 
high degree of intratumoral heterogeneity of HER2 expression in breast cancer and lack of 
efficacy of current anti-HER2 therapeutics in tumor cells expressing relatively low levels of
HER2.  A great deal of effort has been put into developing better anti-HER2 agents that can 
kill cancer cell populations expressing a broad range of HER2.15,19  Given the lack of clinical 
success in developing therapies to treat tumors with relatively low levels of HER2, this 
remains an area of high unmet medical need.
The frequency of HER2 overexpression in GC ranges from 4.4% to 53.4%, with a mean of 
17.9%.3,25,33,8,11,6,16,4,7,14,20,30,2,13  Similar to breast cancer, HER2-positive status in gastric 
cancer was associated with decreased survival and clinicopathological features of tumor
progression, such as serosal invasion, metastases and higher disease stage.13 The results 
clearly set HER2 as a negative prognostic factor, suggesting that HER2 
overexpression/amplification is a molecular abnormality that might be associated with the
development of gastric cancer.16,13  To date, one HER2-specific monoclonal antibody has
been approved by regulatory agencies for treating HER2-positive gastric cancer: 
trastuzumab. However, that approval was for combination therapy with cisplatin and a 
fluoropyrimidine (chemotherapy) and there was only an increase in median survival of 2 
months over chemotherapy alone.
Although HER2 overexpression has been reported in 13% to 20% of NSCLC, 3+ expression 
is observed only in 2% to 6%.10,9,36 FISH assessed HER2 gene amplification is unusual, and 
it has been reported in 2% to 4% of NSCLCs, mainly of adenocarcinoma-type. Comparably
to breast cancer, in spite of the lack of large series, concordance between FISH and
immunohistochemistry (IHC) 3+ has been confirmed.9 In our internal IHC analysis of 
24 NSCLC specimens, 6 showed 2+/3+ HER2 expression. 
ADCs are a class of drugs that use antibodies specifically targeting tumor-associated antigens 
as vehicles to deliver covalently attached small-molecule toxins into cancer cells.24  
PF-06804103 is an anti-human epidermal growth factor receptor 2 (HER2) ADC that is 
currently being investigated in patients with HER2 positive solid tumors.
Significant tumor growth control has been observed in preclinical tumor models for various 
indications, including BC AND GC with HER2 IHC 1+ and IHC2+ levels of HER2 


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expression. This suggests that PF-06804103 may have the potential to provide therapeutic
benefit to patients currently ineligible for HER2 targeted therapy.
In an effort to identify patients with lower levels of HER2 protein who may respond to 
PF-06804103, patients with tumors expressing HER2 IHC 1+ and HER IHC 2+/ISH- will be 
included and patients with HER2 IHC 0 tumors will continue to be excluded from this study.
This study will be conducted in 2 parts, dose escalation and dose expansion. PF-06804103 
will be administered as monotherapy in escalating doses, and then as part of a combination 
regimen with palbociclib and letrozole. For part 2 combination therapy, patients with 
HR-positive, HER2 IHC 1+ or IHC 2+/ISH- BC will receive PF-6804103 (an anti
HER2-ADC consisting of an auristatin anti-microtubulin inhibitor payload site-specifically 
conjugated onto a Herceptin molecule using a cleavable linker), as combination therapy with 
an aromatase inhibitor (letrozole) and a CDK4/6 inhibitor (palbociclib) as 1L treatment.


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Study Objectives and Endpoints
Objective: 
Endpoint: 
Primary
To characterize the DLTs of escalating levels of 
PF-06804103
To assess the safety and tolerability of PF-06804103
To determine the RP2D for PF-06804103 as 
monotherapy
To determine the RP2D for PF-06804103 in 
combination with palbociclib and letrozole
First cycle (21 days) DLTs – Part 1A
First cycle (28 days) DLTs – Part 1B
All available safety data including: AEs, SAEs, and 
clinically meaningful abnormalities in laboratory values
and vital signs
Part 2:
To investigate preliminary antitumor activity
Part 2 y:
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP
Secondary
Objective
Endpoint
To characterize the single and multiple dose PK of
PF-06804103 ADC, total antibody and unconjugated 
payload (PF-06380101).
SD and MD PK parameters of PF-06804103 ADC, total 
antibody and unconjugated payload (PF-06380101).
To evaluate the immunogenicity of PF-06804103
Incidence and titers of ADA and NAbs against 
PF-06804103
To document antitumor activity
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP – Part 1
To explore preliminary antitumor activity in patients
that HER2 positive GC 
HER2 expression levels in pre-treatment tumor biopsies 
via IHC and ISH


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Study Design
This is a Phase 1, open-label, multicenter, multiple dose, safety, PK, and PD study of
PF-06804103 in adult patients with HER2-positive solid tumors (BC and GC [Part 1A only]) 
and in postmenopausal patients with HR-positive HER2 IHC 1 + or IHC 2+/ISH- BC. Part 
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1A and 1B will evaluate escalating doses of PF-06804103 as monotherapy and as part of a
combination regimen, respectively. Part 2A and Part 2B will evaluate selected doses of 
PF-06804103 in expansion cohorts as monotherapy and in a combination regimen, 
respectively.
Approximately 148 patients are expected to be enrolled in the study overall.  The actual 
number of patients enrolled will depend on the tolerability of PF-06804103 and the number 
of dose levels required to identify the MTD and select dose levels for Part 2 of the study.
Study Treatments
In Part 1A, PF-06804103 will be administered as an IV infusion every 21 days at a starting 
dose of 0.15 mg/kg, dose escalation is planned as described in Table 5. Treatment with 
investigational products will continue until either disease progression, patient refusal, or
unacceptable toxicity occurs, whichever occurs first, unless the investigator and medical 
monitor agree to treatment beyond progression based on individual benefit/risk assessments.
A modified toxicity probability interval (mTPI) method targeting a DLT rate of 
approximately 27.5% with an equivalence interval of (22.5%, 32.5%) will be utilized.  
In Part 1B, dose escalation in the combination regimen will also follow the mTPI design.
PF-06804103 will be administered as an IV infusion every 14 days in combination with SOC 
oral palbociclib and oral letrozole.  Dose escalation or de-escalation (Table 7) will be based 
on all available clinical, safety, PK, and/or PD data.
The combination regimen evaluated in Part 1B will be administered to patients with 1L BC
HR-positive/HER2 IHC 1 + or IHC 2+/ISH-.
The actual number of patients enrolled will depend on the tolerability of PF-06804103 at 
each of dose level when administered in combination with palbociclib and letrozole.
In Part 2A, PF-06804103 will be evaluated as monotherapy when administered as described
below:

Arm M1: ≥3L BC HER2-positive (HER2 IHC 3+ or ISH+) 3 mg/kg Q3W

Arm M2: ≥3L BC HER2-positive (HER2 IHC 3+ or ISH+) 4. mg/kg Q3W

Arm M3: ≥2L BC, HR-positive, HER2-negative (HER2 IHC 1+ or IHC 2+/ISH-)
4 mg/kg Q3W


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In Part 2B, the PF-06804103 dose level will be selected based on the dose level determined 
in Part 1B and all available clinical, safety, preliminary efficacy, PK, and PD data. 
PF-06804103 will be administered in combination with palbociclib and letrozole to the 
patients described below:

Arm C1: BC 1L, postmenopausal, HR-positive, HER2 IHC 1+ or IHC 2+/ISH-, 
PF-06804103 Q2W with SOC regimen for palbociclib and letrozole.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to Section 7 of the protocol for 
detailed information on each assessment required for compliance with the protocol. The investigator may schedule visits (unplanned 
visits) in addition to those listed in the schedule of activities table in order to conduct evaluations or assessments required to protect
the well-being of the patient.
Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of Activities
Q3W Dosing
Cycle 1
(Days 1-21)
Cycles 2 and 3
(Days 1-21)
Cycle 4 (Days 1 -21)
Cycles 5 and 
Subsequent Cycles 
(Days 1-21)
Post Treatment
Screen/Base
line
(28 days)
Day 
1
Day 
4
(Part 
1A 
only)
Day 
8
Part 
1A 
only)
Day 
15
Day 1
Day
8
(Part 
1A 
only)
Day 
15
Day 
1
Day 
4
(Part
1A 
only)
Day 
8
(Part 
1A 
only)
Day
15
Day 1
Day 
824
(Part 
1A 
only)
Day 
1524
EOT25
Follow
-Up26
Visit Window (days)*
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(2)
(2)
(2)
(2)
(+7)
(+7)
Protocol Activity
Informed consent1
X
Tumor history2
X
Medical history3
X
Complete PE
X
X4
X
Symptoms directed PE
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status6
X
X
X
X
X
X
X
12-Lead ECG7
X
X
X
X
X
X
X
X
X
X
ECHO or MUGA8
X
Day 1 of Cycle 3, Cycle 6 and then Day 1 every 3 cycles thereafter
X
DLco9
X
To be performed every 6 weeks starting at Cycle 3
Contraception check
X
X
X
X
X
X
X
Ophthalmic Examination10
X
Laboratory
Unique Screening Laboratory tests11
X
Hematology12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation14
X
X
X
X
X


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Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of Activities
Q3W Dosing
Cycle 1
(Days 1-21)
Cycles 2 and 3
(Days 1-21)
Cycle 4 (Days 1 -21)
Cycles 5 and 
Subsequent Cycles 
(Days 1-21)
Post Treatment
Screen/Base
line
(≤28 days)
Day 
1
Day 
4
(Part 
1A 
only)
Day 
8
Part 
1A 
only)
Day 
15
Day 1
Day
8
(Part 
1A 
only)
Day 
15
Day 
1
Day 
4
(Part
1A 
only)
Day 
8
(Part 
1A 
only)
Day
15
Day 1
Day 
824
(Part 
1A 
only)
Day 
1524
EOT25
Follow
-Up26
Visit Window (days)*
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(±2)
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(+7)
(+7)
Protocol Activity
Urinalysis15 (Part 1A only)
X
X
X
X
X
X
Pregnancy test16
X
X
X
X
X
X
X
Registration and Treatment 
Registration17
X
PF-0680410318
X
X
X
X
Tumor assessments
CT or MRI scan or equivalent19
X
To be obtained every 6 weeks starting at Cycle 3
X19
Other samplings
Tumor Tissue Samples20
X
X 
(Cycle
3 
only)
PK Blood Samples
Table 3. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Monotherapy Dosing
Blood sample for Immunogenicity 
Test
Table 3. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Monotherapy Dosing
Blood biomarker samples
Table 3. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Monotherapy Dosing
Other clinical assessments
AE and SAE monitoring22
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Concomitant treatment monitoring
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
*Unless otherwise stated below, the window period applies to all assessments on a given study visit.
1.
May be collected more than 28 days prior to study entry.
2.
Includes details of primary diagnosis and treatment history.
3.
Includes medical history of disease process other than the cancer under study (active or resolved) and significant concurrent illness. Includes prior 
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Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of Activities
Q3W Dosing
Cycle 1
(Days 1-21)
Cycles 2 and 3
(Days 1-21)
Cycle 4 (Days 1 -21)
Cycles 5 and 
Subsequent Cycles 
(Days 1-21)
Post Treatment
Screen/Base
line
(28 days)
Day 
1
Day 
4
(Part 
1A 
only)
Day 
8
Part 
1A 
only)
Day 
15
Day 1
Day
8
(Part 
1A 
only)
Day 
15
Day 
1
Day 
4
(Part
1A 
only)
Day 
8
(Part 
1A 
only)
Day
15
Day 1
Day 
824
(Part 
1A 
only)
Day 
1524
EOT25
Follow
-Up26
Visit Window (days)*
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(2)
(2)
(2)
(2)
(+7)
(+7)
Protocol Activity
treatments and any current medical treatment for any condition.
4.
No need to repeat on C1D1 if baseline assessment is performed within 3 days of dosing.
5.
Includes temperature, BP, and pulse rate (to be recorded in a supine or seated position), and pulse oximetry.  On Day 1 of each 21 day cycle, vital signs 
should be measured prior to infusion start (pre-dose) and BP and PR will be repeated 1 hour after the start of the infusion (ie, just prior to the end of the 
infusion).
6.
ECOG – see Appendix 2.
7.
Triplicate ECGs will be collected during Screening and at the End of Treatment.  Additional ECGs will be collected prior to dosing and at the end of 
infusion on dosing days as well as on Day 8.  When ECGs coincide with PK sampling, the ECG should be recorded before PK samples are drawn, so that 
the PK sample is collected at the nominal time. If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation.  Additional ECGs should be performed if clinically indicated (Section 7.1.5).
8.
To be conducted at screening, Cycle 3, Cycle 6 and then every 3 cycles thereafter through the first year of study treatment.  The frequency will change to 
every 6 months after one year of study treatment, unless clinically indicated.  If LVEF is reported as a range, the average should be reported.  ECHO or
MUGA scans should also be performed in the case of an adverse event which may be related to cardiac dysfunction in the opinion of the investigator.  The 
same modality used during screening should preferably be used for all subsequent timepoints.
9.
To be conducted at screening, Cycle 3 and then every other cycle at the same timepoints when imaging tumor assessments are performed. If the tumor 
assessment frequency is reduced to every 12 weeks after 6 months (±7 days) of study treatment (see footnote 19 below), the Dlco assessment should remain 
on a schedule of every 4th cycle. (Section 7.1.7).
10. An eye exam (performed by an ophthalmologist) will be performed at screening.  The eye exam includes BCVA, IOP preferably by Goldmann applanation, 
biomicroscopic examination to evaluate the lids/lashes/adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, lens, and dilated fundus exam to evaluate 
the optic nerve, vessels, macula, and the peripheral retina.  Further ophthalmic examinations should be guided by specific ocular signs and symptoms
should they occur during treatment and follow-up.
11. HBV, hepatitis B core antibody, HCV and HIV as well as FSH and estradiol for post-menopausal women who are amenorrhoeic for at least 12 consecutive 
months only.  Samples will be analyzed locally.
12. CBC to include hemoglobin, platelets, WBC, absolute neutrophils, lymphocytes, monocytes, eosinophils, and basophils. No need to repeat on C1D1 if 
baseline assessment performed within 3 days of dosing.  Samples will be analyzed locally.
13. Should include ALT, AST, ALP, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN or urea, creatinine, uric acid, glucose 


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Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of Activities
Q3W Dosing
Cycle 1
(Days 1-21)
Cycles 2 and 3
(Days 1-21)
Cycle 4 (Days 1 -21)
Cycles 5 and 
Subsequent Cycles 
(Days 1-21)
Post Treatment
Screen/Base
line
(≤28 days)
Day 
1
Day 
4
(Part 
1A 
only)
Day 
8
Part 
1A 
only)
Day 
15
Day 1
Day
8
(Part 
1A 
only)
Day 
15
Day 
1
Day 
4
(Part
1A 
only)
Day 
8
(Part 
1A 
only)
Day
15
Day 1
Day 
824
(Part 
1A 
only)
Day 
1524
EOT25
Follow
-Up26
Visit Window (days)*
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(±2)
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(+7)
(+7)
Protocol Activity
(non-fasted), bicarbonate or CO2, albumin, phosphorus or phosphate, amylase and lipase. No need to repeat on C1D1 if baseline assessment performed 
within 3 days of dosing. 
14. Should include INR or PT.
15. Dipstick is acceptable.  Microscopic analyses if dipstick abnormal. Abnormal test results will be  managed as indicated.
16. For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions
prior to starting study treatment – once at the start of screening and once immediately before the first investigational product administration.  Pregnancy 
tests will also be routinely repeated at every cycle (21 days) during the active treatment period, at the EOT and Follow-up visits and whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by the IRB or IECs or 
if required by local regulations.
17. Patient number and dose level allocation assigned by Pfizer Inc.  Registration should occur before any other Day 1 activities are performed.
18. Will be administered once every 21 days as an IV infusion over approximately 60 minutes (±15 minutes).
19. Tumor assessments will include all known or suspected disease sites and may include chest, abdomen and pelvis CT or MRI scans.  Brain scans and bone 
scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease.  At minimum, the chest CT must be a high-
resolution scan with a 1 mm slice thickness.  Baseline CNS MRI is not required with the exception of symptomatic patients to rule out CNS metastases (CT
is an option if MRI is not available or tolerated by the patient).  CT or MRI scans are to be done every 6 weeks (±7 days) from the start of study treatment 
until disease progression by RECIST (v1.1) or death, or until permanent discontinuation of study treatment.  The frequency will be reduced to every 
12 weeks after 6 months (±7 days) of study treatment.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  
Tumor assessments should be repeated at the EOT visit if more than 6 weeks have passed since the last evaluation.
20. Patient enrollment will be based on prior testing for HER2 positivity by an FDA approved, or locally validated, diagnostic test. Part 1A: Fresh pre-
treatment (screening) and Day 1 Cycle 3 (±5 days) biopsy collections are optional. Archival tissue from a prior biopsy will be collected from all patients
for central evaluation if available. If collected, the pre-treatment biopsy should be completed after all eligibility criteria have been verified and should be 
taken from the same lesion, not previously irradiated, if possible.  If the patient discontinues the study before Cycle 3, Day 1 the patient will be asked to 
provide a fresh biopsy at the EOT visit.  Bone biopsies, cytological specimens and fine-needle aspiration samples are excluded (Section 7.4.5). Part 2:  A 
mandatory fresh pre-treatment, diagnostic quality biopsy, representative of the diagnosed malignancy, will be collected at screening from all patients 
 
 to retrospectively confirm HER2 expression.  An archival sample collected prior to study start may be substituted for 
the mandatory pre-treatment biopsy if no prior anti-HER2 treatment between the collection of this tumor sample and study start had been administered.  In 
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Table 1.
Monotherapy Dose Escalation and Expansion – Schedule of Activities
Q3W Dosing
Cycle 1
(Days 1-21)
Cycles 2 and 3
(Days 1-21)
Cycle 4 (Days 1 -21)
Cycles 5 and 
Subsequent Cycles 
(Days 1-21)
Post Treatment
Screen/Base
line
(≤28 days)
Day 
1
Day 
4
(Part 
1A 
only)
Day 
8
Part 
1A 
only)
Day 
15
Day 1
Day
8
(Part 
1A 
only)
Day 
15
Day 
1
Day 
4
(Part
1A 
only)
Day 
8
(Part 
1A 
only)
Day
15
Day 1
Day 
824
(Part 
1A 
only)
Day 
1524
EOT25
Follow
-Up26
Visit Window (days)*
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(±2)
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(+7)
(+7)
Protocol Activity
additioan, for up to 10 patients in each arm, a mandatory fresh on-treatment diagnostic quality biopsy, representative of the diagnosed malignancy, will be 
collected at Day 1 Cycle 3 (±5 days). If the patient discontinues the study before the scheduled on-treatment biopsy, the patient will be asked to provide a 
fresh biopsy at the EOT visit. Bone biopsies, cytological specimens and fine-needle aspiration samples are excluded (Section 7.4.5).
22. AEs should be documented and recorded at each visit using the NCI CTCAE version 4.03. The time period for actively eliciting and collecting AEs and 
SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and including a minimum of 28 
calendar days after the last investigational product administration.  If the patient begins a new anticancer therapy, the period for recording non-serious AEs 
on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must still be reported to Pfizer 
Safety and recorded on the CRF, irrespective of any intervening treatment.
23. All concomitant medications and non-drug supportive interventions should be recorded on the CRF.
24. Beginning at Cycle 6, the Day 8 and Day 15 visits are no longer required.
25. Perform if not completed in the last week (last 6 weeks for tumor assessments).
26. At least 28 calendar days, and no more than 35 calendar days, after discontinuation of treatment, patients will return to undergo review of concomitant 
treatments, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the
investigator, that no further improvement is expected.
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Table 2.
Combination Regimen Escalation and Expansion – Schedule of Activities
Q2W Dosing
Cycle 1
(Days 1-28)
Cycles 2 and 3
(Days 1-28)
Cycle 4 (Days 1 -28)
Cycles 5 and 
Subsequent Cycles 
(Days 1-28)
Post Treatment
Screen/Base
line
(28 days)
Day 
1
Day
4
Day 
8
Day 
15
Day 1
Day 
8
Day 
15
Day 
1
Day 
4
Day 
8
Day
15
Day 1
Day 
825
Day 
15
EOT26
Follow
-Up27
Visit Window (days)*
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(2)
(2)
(2)
(2)
(+7)
(+7)
Protocol Activity
Informed consent1
X
Tumor history2
X
Medical history3
X
Complete PE
X
X4
X
Symptoms directed PE
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status6
X
X
X
X
X
X
X
12-Lead ECG7
X
X
X
X
X
X
X
X
X
X
ECHO or MUGA8
X
Day 1 of Cycle 3, Cycle 6, and then Day 1 every 3 cycles thereafter
X
Dlco9
X
To be performed every 8 weeks starting at Cycle 3
Contraception check
X
X
X
X
X
X
X
Ophthalmic Examination10
X
Laboratory
Unique screening laboratory tests11
X
Hematology12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation14
X
X
X
X
X
Pregnancy test15
X
X
X
X
X
X
X
Registration and Treatment 
Registration16
X
PF-0680410317
X
X
X
X
X
X
X
X
Palbociclib18
once daily on Days 1 through 21 of each cycle followed by a 7-day rest period
Letrozole19
once daily
Tumor assessments


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Table 2.
Combination Regimen Escalation and Expansion – Schedule of Activities
Q2W Dosing
Cycle 1
(Days 1-28)
Cycles 2 and 3
(Days 1-28)
Cycle 4 (Days 1 -28)
Cycles 5 and 
Subsequent Cycles 
(Days 1-28)
Post Treatment
Screen/Base
line
(≤28 days)
Day 
1
Day
4
Day 
8
Day 
15
Day 1
Day 
8
Day 
15
Day 
1
Day 
4
Day 
8
Day
15
Day 1
Day 
825
Day 
15
EOT26
Follow
-Up27
Visit Window (days)*
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(±2)
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(+7)
(+7)
Protocol Activity
CT or MRI scan or equivalent20
X
To be obtained every 8 weeks starting at Cycle 3
X19
Other samplings
Tumor Tissue Samples21
X
X
(Cycle
3 
only)
PK Blood Sampling
Table 4. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Combination Regimen (PF 6804103 in combination with Palbociclib and Letrozole)
Blood sample for Immunogenicity 
Test
Table 4. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Combination Regimen (PF 6804103 in combination with Palbociclib and Letrozole)
Blood biomarker samples
Table 4. Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments –
Combination Regimen (PF 6804103 in combination with Palbociclib and Letrozole)
Other clinical assessments
AE and SAE monitoring23
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Concomitant treatment(s)24
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
*Unless otherwise stated below, the window period applies to all assessments on a given study visit.
1.
May be collected more than 28 days prior to study entry. 
2.
Includes details of primary diagnosis and treatment history.
3.
Includes medical history of disease process other than the cancer under study (active or resolved) and significant concurrent illness.  Includes prior 
treatments and any current medical treatment for any condition.
4.
No need to repeat on C1D1 if baseline assessment is performed within 3 days of dosing. 
5.
Includes temperature, BP, and pulse rate to be recorded (in a supine or seated position) and pulse oximetry.  On Day 1 of each 28 day cycle, vital signs
should be measured prior to infusion start (pre-dose) and BP and PR will be repeated 1 hour after the start of the infusion (ie, just prior to the end of the
infusion).
6.
ECOG – see Appendix 2.
7.
Triplicate ECGs will be collected during Screening and at the End of Treatment. Additional ECGs will be collected prior to dosing and at the end of 
infusion on dosing days as well as on Day 8. When ECGs coincide with PK sampling, the ECG should be recorded before PK samples are drawn so that 
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Table 2.
Combination Regimen Escalation and Expansion – Schedule of Activities
Q2W Dosing
Cycle 1
(Days 1-28)
Cycles 2 and 3
(Days 1-28)
Cycle 4 (Days 1 -28)
Cycles 5 and 
Subsequent Cycles 
(Days 1-28)
Post Treatment
Screen/Base
line
(28 days)
Day 
1
Day
4
Day 
8
Day 
15
Day 1
Day 
8
Day 
15
Day 
1
Day 
4
Day 
8
Day
15
Day 1
Day 
825
Day 
15
EOT26
Follow
-Up27
Visit Window (days)*
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(2)
(2)
(2)
(2)
(+7)
(+7)
Protocol Activity
the PK sample is collected at the nominal time. If the mean QTcF is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation.  Additional ECGs should be performed if clinically indicated (Section 7.1.5).
8.
To be conducted at screening, Cycle 3, Cycle 6 and then every 3 cycles thereafter through the first year of study treatment.  The frequency will change to 
every 6 months after one year of study treatment, unless clinically indicated. If LVEF is reported as a range, the average should be reported.  ECHO or 
MUGA scans should also be performed in the case of an AE which may be related to cardiac dysfunction in the opinion of the investigator. The same 
modality used during screening should preferably be used for all subsequent timepoints.
9.
To be conducted at screening, Cycle 3 and then every other cycle at the same timepoints when imaging tumor assessments are performed. If the tumor 
assessment frequency is reduced to every 12 weeks after 6 months (±7 days) of study treatment (see footnote 20 below), the Dlco assessment should remain 
on a schedule of every 4th cycle. (Section 7.1.7).
10. An eye exam (performed by an ophthalmologist) will be performed at screening.  The eye exam includes BCVA, IOP preferably by Goldmann applanation, 
biomicroscopic examination to evaluate the lids/lashes/adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, lens, and dilated fundus exam to evaluate 
the optic nerve, vessels, macula, and the peripheral retina.  Further ophthalmic examinations should be guided by specific ocular signs and symptoms
should they occur during treatment and follow-up.
11. HBV, hepatitis B core antibody, HCV, and HIV as well as FSH and estradiol for post-menopausal women who are amenorrhoeic for at least 12 consecutive 
months only.  Samples will be analyzed locally.
12. CBC to include hemoglobin, platelets, WBC, absolute neutrophils, lymphocytes, monocytes, eosinophils, and basophils.  No need to repeat on C1D1 if 
baseline assessment performed within 3 days of dosing.  Samples will be analyzed locally.
13. Should include ALT, AST, ALP, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN or urea, creatinine, uric acid, glucose 
(non-fasted), bicarbonate or CO2, albumin, phosphorus or phosphate, amylase and lipase.  No need to repeat on C1D1 if baseline assessment performed 
within 3 days of dosing. 
14. Should include INR or PT.
15. For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions 
prior to starting study treatment – once at the start of screening and once immediately before the first investigational product administration.  Pregnancy 
tests will also be routinely repeated at every cycle during the active treatment period, at the EOT and Follow-up visits and whenever 1 menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by 
local regulations.
16. Patient number and dose level allocation assigned by Pfizer Inc.  Registration should occur before any other Day 1 activities are performed.
17. Will be administered once every 14 days as an IV infusion over approximately 60 minutes (15 minutes).


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Table 2.
Combination Regimen Escalation and Expansion – Schedule of Activities
Q2W Dosing
Cycle 1
(Days 1-28)
Cycles 2 and 3
(Days 1-28)
Cycle 4 (Days 1 -28)
Cycles 5 and 
Subsequent Cycles 
(Days 1-28)
Post Treatment
Screen/Base
line
(≤28 days)
Day 
1
Day
4
Day 
8
Day 
15
Day 1
Day 
8
Day 
15
Day 
1
Day 
4
Day 
8
Day
15
Day 1
Day 
825
Day 
15
EOT26
Follow
-Up27
Visit Window (days)*
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(±2)
(±1)
(±1)
(±2)
(±2)
(±2)
(±2)
(+7)
(+7)
Protocol Activity
18. Palbociclib: Patients will self-administer palbociclib (125 mg) PO QD (Day 1 through 21), followed by 1 week off, and repeat every 28 days. Patients will 
record each dose in their patient diary.
19. Letrozole: Patients will self-administer daily (2.5 mg) PO QD (Days 1 through 28). Patients will record each dose in their patient diary.
20. Tumor assessments will include all known or suspected disease sites and may include chest, abdomen and pelvis CT or MRI scans.  Brain scans and bone 
scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease.  At minimum, the chest CT must be a high-
resolution scan with a 1 mm slice thickness.  Baseline CNS MRI is not required with the exception of symptomatic patients to rule out CNS metastases.
(CT is an option if MRI is not available or tolerated by the patient). CT or MRI scans are to be done every 8 weeks (±7 days) from the start of study 
treatment until disease progression by RECIST (v1.1) or death, or until permanent discontinuation of study treatment.  The frequency will be reduced to 
every 12 weeks after 6 months (±7 days) of study treatment unless more frequent scans are clinically indicated.  Tumor assessments should be fixed 
according to the calendar, regardless of treatment delays.  Tumor assessments should be repeated at the EOT visit if more than 6 weeks have passed since 
the last evaluation.
21. Part 1B: Fresh pre-treatment (screening) and Day 1 Cycle 3 (±5 days) biopsy collections are optional. Archival tissue from a prior biopsy will be collected
from all patients for central evaluation if available. If collected, the pre-treatment biopsy should be completed after all eligibility criteria have been verified 
and should be taken from the same lesion, not previously irradiated, if possible.  If the patient discontinues the study before Cycle 3, Day 1 the patient will 
be asked to provide a fresh biopsy at the EOT visit.  Bone biopsies, cytological specimens and fine-needle aspiration samples are excluded (Section 7.4.5).  
Part 2:  A mandatory fresh pre-treatment, diagnostic quality biopsy, representative of the diagnosed malignancy, will be collected at screening from all 
patients 
 to retrospectively confirm HER2 expression.  An archival sample collected prior to study start may be 
substituted for the mandatory pre-treatment biopsy if no prior anti-HER2 treatment between the collection of this tumor sample and study start had been 
administered.  If the patient discontinues the study before the scheduled on-treatment optional biopsy, the patient will be asked to provide a fresh biopsy at
the EOT visit. The EOT optional biopsy will be requested of patients who discontinue prior to Cycle 3 Day 1. Bone biopsies, cytological specimens and 
fine-needle aspiration samples are excluded (Section 7.4.5).
 
23. AEs should be documented and recorded at each visit using the NCI CTCAE version 4.03.  The time period for actively eliciting and collecting AEs and 
SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and including a minimum of 28 
calendar days after the last investigational product administration.  If the patient begins a new anticancer therapy, the period for recording non-serious AEs 
on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must still be reported to Pfizer 
Safety and recorded on the CRF, irrespective of any intervening treatment.
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Table 2.
Combination Regimen Escalation and Expansion – Schedule of Activities
Q2W Dosing
Cycle 1
(Days 1-28)
Cycles 2 and 3
(Days 1-28)
Cycle 4 (Days 1 -28)
Cycles 5 and 
Subsequent Cycles 
(Days 1-28)
Post Treatment
Screen/Base
line
(28 days)
Day 
1
Day
4
Day 
8
Day 
15
Day 1
Day 
8
Day 
15
Day 
1
Day 
4
Day 
8
Day
15
Day 1
Day 
825
Day 
15
EOT26
Follow
-Up27
Visit Window (days)*
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(1)
(1)
(2)
(2)
(2)
(2)
(+7)
(+7)
Protocol Activity
24. All concomitant medications and non-drug supportive interventions should be recorded on the CRF.
25. Beginning at Cycle 6, Day 8 visits are no longer required.
26. Perform if not completed in the last week (last 6 weeks for tumor assessments).
27. At least 28 calendar days, and no more than 35 calendar days, after discontinuation of treatment, patients will return to undergo review of concomitant 
treatments, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at this point following
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the 
investigator, that no further improvement is expected.


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Table 3.
Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Assessments – Monotherapy Dosing
Q3W – Monotherapy
Treatment Period
Cycle 1 Only
(Days 1 to 21)
Cycle 2 and 3
(Days 1 to 21)
Cycle 4
(Days 1 to 21)
Every Cycle 
Thereafter
EOT
Day 1
Day 2
24
hr*
Part
1A 
only)
Day 4 
(Part 
1A 
only)
Day 8 
(Part 
1A 
only)
Day 
15
Day 1
Day 1
Day 2
24
hr*
(Part 1A 
only)
Day 4
(Part 
1A 
only)
Day 8 
(Part 
1A 
only)
Day 
15
Day 1
Pre-
dose*
1 hr* 4 hr*
Pre-
dose*
1 hr*
Pre-
dose*
1 hr*
4 hr*
Pre-
dose*
1 hr*
Visit Window (days)
(±1) (±1)
(±1)
(±2)
(±1)
(±1)
(±1)
(±2)
(+7)
Protocol Activity
PK Samples for PF-06804103 
and total antibody1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Samples for PF-063801012
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sample for PF-06804103
Immunogenicity3
X
X
X
X
X
X
 
 
 
* Sampling times are related to the start of infusion; 1 hr samples should be collected immediately at the end of infusion; all samples will be considered protocol compliant 
if collected ±10 minutes for the 1 hour sample, ±25 minutes for the 4 hour sample, ± 2 hours for the 24 hour sample, and ±2 days for the Day 15 sample. The exact time of 
the sample collection will be noted on the CRF.
1.
Blood samples (4 mL) will be collected for drug concentration measurement of PF-06804103 and total antibody.
2.
Blood samples (4 mL) will be collected for measurement of PF-06380101 concentrations.
3.
Blood samples (6 mL) will be collected for immunogenicity testing against PF-06804103.
 
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Table 4.
Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Assessments – Combination Regimen (PF 6804103 in 
combination with Palbociclib and Letrozole)
Q2W Combination
Treatment Period
Cycle 1 Only
(Days 1 to 28)
Cycle 2 and 3
(Days 1 to 28)
Cycle 4
(Days 1 to 28)
Every Cycle 
Thereafter
EOT
Day 1
Day 2
24
hr*
Day 
4
Day
8
Day 15
Day 1
Day 15
Day 1
Day 2
24
hr*
Day
4
Day
8
Day 15
Day 1
Pre-
dose*
1 hr*
4 hr*
Pre-
dose
1 hr* Pre-
dose*
1 hr
*
Pre-
dose*
1 hr*
Pre-
dose*
1 hr* 4 hr*
Pre-
dose
1 hr*
Pre-
dose*
1 hr*
Visit Window (days)
+1
(±1) (±1)
(±2)
(±2)
(±1)
(±1) (±1)
(±2)
(+7)
Protocol Activity
PK Samples for 
PF-06804103 and 
total antibody1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Samples for
PF-063801012
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sample for
PF-06804103 Immu
nogenicity3
X
X
X
X
X
X
 
 
* Sampling times are related to the start of infusion; 1 hr samples should be collected at the end of infusion; all samples will be considered protocol compliant if collected ±10 
minutes for the 1 hour sample, ±25 minutes for the 4 hour sample, ± 2 hours for the 24 hour sample, ±1 day for the Day 4, Day 8 samples, and ±2 days for the Day 15 sample. 
The exact time of the sample collection will be noted on the CRF.
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Table 4.
Pharmacokinetic, Immunogenicity, and Biomarker/Pharmacodynamic Assessments – Combination Regimen (PF 6804103 in 
combination with Palbociclib and Letrozole)
Q2W Combination
Treatment Period
Cycle 1 Only
(Days 1 to 28)
Cycle 2 and 3
(Days 1 to 28)
Cycle 4
(Days 1 to 28)
Every Cycle 
Thereafter
EOT
Day 1
Day 2
24
hr*
Day 
4
Day
8
Day 15
Day 1
Day 15
Day 1
Day 2
24
hr*
Day
4
Day
8
Day 15
Day 1
Pre-
dose*
1 hr*
4 hr*
Pre-
dose
1 hr* Pre-
dose*
1 hr
*
Pre-
dose*
1 hr*
Pre-
dose*
1 hr* 4 hr*
Pre-
dose
1 hr*
Pre-
dose*
1 hr*
1.
Blood samples (4 mL) will be collected for drug concentration measurement of PF-06804103 and total antibody. 
2.
Blood samples (4 mL) will be collected for measurement of PF-06380101 concentrations.
3.
Blood samples (6 mL) will be collected for immunogenicity testing against PF-06804103.
 
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1. INTRODUCTION
1.1. Mechanism of Action and Indication
PF-06804103 employs at least 2 different mechanisms of action.  The primary mechanism is 
the targeted delivery of the cytotoxic anti-microtubule auristatin payload to HER2 positive,
or HER2 low expressing cells.  An additional mechanism of action is inhibition of
HER2-mediated signaling in HER2 expressing cancer cells.
PF-06804103 is a HER2 ADC that is currently being investigated in patients with 
HER2-positive solid tumors or HER2 IHC 1+ or IHC 2+/ISH-BC.
1.2. Background
HER2 is a receptor tyrosine kinase that is involved in the regulation of various cellular 
functions.  Aberrant HER2 receptor activation has been implicated as a driving factor in the 
tumorigenesis and progression of a number of cancers.34,27,23  
In BC, overexpression and/or amplification of the HER2 gene, identified by IHC and FISH is 
observed in 20% to 25% of patients, and these patients are classified as HER2-positive in the
clinic.  Excessive expression of HER2 often leads to constitutive receptor activation and
therefore aggressive tumor growth.25 Inhibiting HER2 activity with monoclonal antibodies
has proven to be an effective therapy for treating HER2 positive metastatic BC.
The frequency of HER2 overexpression in GC ranges from 4.4% to 53.4%, with a mean of
17.9%.3,25,33,8,11,6,16,4,7,14,20,30,2,13 Similar to breast cancer, HER2-positive status in gastric
cancer was associated with decreased survival and clinicopathological features of tumor
progression, such as serosal invasion, metastases and higher disease stage.13 The results 
clearly set HER2 as a negative prognostic factor, suggesting that HER2 
overexpression/amplification is a molecular abnormality that might be associated with the 
development of gastric cancer.16,13 To date, one HER2-specific monoclonal antibody has
been approved by regulatory agencies for treating HER2-positive GC: trastuzumab.  
However, that approval was for combination therapy with cisplatin and a fluoropyrimidine
(chemotherapy) and there was only an increase in median survival of 2 months over 
chemotherapy alone.
Although HER2 overexpression has been reported in 13% to 20% of non-small cell lung 
cancer (NSCLC), 3+ expression is observed only in 2% to 6%.10,9,36 FISH assessed 
HER2 gene amplification is unusual, and it has been reported in 2% to 4% of NSCLCs, 
mainly of adenocarcinoma-type.  Comparably to breast cancer, in spite of the lack of large 
series, concordance between FISH and IHC 3+ has been confirmed.9 In our internal IHC 
analysis of 24 NSCLC specimens, 6 showed 2+/3+ HER2 expression. 
To date, 3 HER2-specific monoclonal antibodies have been approved by regulatory agencies
for treating HER2-positive metastatic breast cancer: trastuzumab, pertuzumab, and 
ado-trastuzumab emtansine (T-DM1).  Although these HER2-targeting therapies have 
transformed the clinical practice for HER2-positive breast cancer and have resulted in 
survival benefits, not all patients respond to the therapies. Moreover, the vast majority of 


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patients who initially respond to the treatment will eventually relapse. This is thought to be 
due to the high degree of intratumoral heterogeneity of HER2 expression in breast cancer and 
lack of efficacy of current anti-HER2 therapeutics in tumor cells expressing relatively low 
levels of HER2. A great deal of effort has been put into developing better anti-HER2 agents 
that can kill cancer cell populations expressing a broad range of HER2.15,19  Given the lack of 
clinical success in developing therapies to treat tumors with relatively low levels of HER2, 
this remains an area of high unmet medical need.
ADCs are a class of drugs that use antibodies specifically targeting tumor-associated antigens 
as vehicles to deliver covalently attached small-molecule toxins into cancer cells.24 T-DM1 
is built upon this principle and it consists of trastuzumab coupled with the microtubule 
poison maytansinoid emtansine (DM1) through a thioether linker.17,18 Approval of T-DM1 
by the FDA in February 2013 is mainly based on the key data derived from a phase III 
clinical trial investigating the efficacy and safety of T-DM1 in HER2-positive metastatic 
breast cancer patients.29 T-DM1 treatment prolonged overall survival by 5 to 6 months with 
an objective response rate of 44%.  While these results are encouraging, they also reveal the 
limitation of T-DM1 in efficacy.  Receptor tyrosine kinases are typically routed to lysosomes 
for degradation following ligand binding, which is a major, negative feedback mechanism 
regulating the intensity and duration of receptor activation.31 Unlike most receptor tyrosine 
kinases, HER2 has no natural ligand and it appears to be impaired in lysosomal 
trafficking.5,26,22 Instead, HER2 is largely recycled back to the plasma membrane following
spontaneous endocytosis.  Correspondingly, the majority of internalized T-DM1 passively
recycles with HER2 back to the cell surface and only a small fraction of T-DM1 is routed to
lysosomes for degradation.5 Since the amount of toxin released into the cytoplasm 
determines the cell killing potency of an ADC, this may explain the lack of activity with 
T-DM1 in tumors expressing low levels of HER2.  In this regard, it is likely that an 
improvement in ADC-mediated internalization and lysosomal trafficking would significantly
enhance the cytoplasmic delivery of toxins, which may result in the killing of cancer cell 
populations that express a broader range of HER2.
1.3. Study Rationale 
Significant tumor growth control has been observed in preclinical tumor models for various 
indications, including BC AND GC with HER2 IHC 1+ or IHC 2+/ISH- levels of HER2 
expression. This suggests that PF-06804103 may have the potential to provide therapeutic
benefit to patients currently ineligible for HER2 targeted therapy. In an effort to identify 
patients with lower levels of HER2 protein who may respond to PF-06804103, patients with 
tumors expressing HER2 IHC 1+ or IHC 2+/ISH-will be included and patients with HER2
IHC 0 tumors will continue to be excluded from this study.
1.3.1. Arm C1: PF-06910403 in Combination with Palbociclib Plus Letrozole
ER negatively regulates ERBB2 gene expression and thus HER2 protein production.37  As an
aromatase inhibitor, letrozole negatively regulates ER activation.  CDK 4/6 inhibition and
HER2 signaling pathways have recently been linked.  CDK4/6 inhibition may relieve
feedback inhibition on HER2 signaling networks to re-sensitize HER2-expressing tumors to 
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Endocrine treatment is one key component in the treatment of patients with HR-positive, 
metastatic BC. Combining endocrine therapy with CDKs has proven to enhance the efficacy 
of endocrine treatment. For example, CDK4/6 in combination with AIs as 1L treatment or 
fulvestrant as 2L has shown dramatic improvement in PFS.39 Clinical data has also 
documented a PFS advantage of adding trastuzumab or lapatinib to AI in postmenopausal
women with HR-positive metastatic breast cancer that is HER2-positive. In patients with 
HER2-positive BC SOC 1L regimen requires the use of HER-directed therapies (herceptin
+/- pertuzumab) plus chemotherapy (taxane).43
Targeting HER2 IHC 1+ or IHC 2+/ISH- BC with PF-06804103 is expanding the HER2 
targeted space to current HER2 IHC 1+ or IHC 2+/ISH- patient population. Furthermore, the 
recent data suggest combining a CDK 4/6 inhibitor (abemaciclib and HER directed therapy 
(trastuzumab) and hormonal receptor antagonist (fulvestrant) is superior to either abemaciclib
and trastuzumab or trastuzumab and SOC chemotherapy in HR+, HER2+ 3L BC.43 Taken
together, in this patient population, all 4 classes of drugs may be needed for maximum 
clinical benefit in 1L BC: 1) HER2-directed therapy, 2) chemotherapy (anti-microtubule 
agent), 3) CDK4/6 inhibitor, 4) endocrine therapy. Another, similar HER2 ADC platform 
using a cleavable linker along with a cytotoxic (topoisomerase inhibitor) payload has
demonstrated substantial clinical antitumor activity and an acceptable safety profile in 
heavily pretreated HER2 IHC 1+ or IHC 2+/ISH- BC.41 Therefore, adding a HER2 targeting
with a cytotoxic (chemotherapy) component to an antihormonal agent and a CDK4/6 
inhibitor in HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC patients is expected to enhance 
clinical efficacy and decrease the risk of developing resistance.
In this study, patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC will receive 
PF-06804103 (an anti HER2-ADC consisting of an auristatin anti-microtubulin inhibitor 
payload site-specifically conjugated onto a Herceptin molecule using a cleavable linker) as
combination therapy with an aromatase inhibitor (letrozole) and a CDK4/6 inhibitor 
(palbociclib) as 1L treatment.
More information about the known and expected benefits and risks and reasonably expected 
AEs of PF-06804103 may be found in the IB, which is the SRSD for this study.
More information about palbociclib may be found in the IB, which is the SRSD for this study
and information about letrozole may be found in the EU Summary of Product Characteristics,
which is the SRSD for this study.
1.4. Nonclinical Pharmacology and Safety
The nonclinical safety profile of PF-06804103 has been well characterized.  Studies
conducted with PF-06804103 were consistent with the ICH S6 (R1) and ICH S9 Guidelines 
and included a tissue cross-reactivity study in normal tissues of cynomolgus monkeys and
human tissues, and exploratory and/or pivotal toxicity studies in rats and/or monkeys.  In 
addition, repeat-dose toxicity studies were conducted in Wistar Han rats with the 
unconjugated auristatin payload (Aur0101; PF-06380101) as well as a hERG assay and
genotoxicity assays.


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The pivotal GLP study was conducted in the cynomolgus monkey, the most relevant species, 
and the proposed route of clinical administration, IV dosing.  The major findings in the 
repeat dose toxicity studies were observed in the bone marrow/hematopoietic system, lung, 
eye, and reproductive organs. After a 6-week recovery, findings in the lung and ovary did not
recover; findings in the eye and at the injection site partially recovered, and recovery of 
testicular findings could not be assessed as males were not included in the recovery phase 
due to unscheduled euthanasia.  The HNSTD in the pivotal monkey study was defined as 3 
mg/kg/dose.
There was no definitive evidence for HER2-dependent effects in the findings from 
exploratory and pivotal monkey toxicity studies and all effects were considered to be 
target-independent toxicity arising from payload released in circulation and/or nonspecific 
uptake of the ADC/payload.
The potential cross-reactivity of PF-06804103 (1 g/mL and 5 g/mL) with cryosections of 
human and cynomolgus monkey tissues was evaluated and showed generally comparable 
staining across human and monkey tissues. PF-06804103 was also generally consistent with
reported sites of HER2 expression,21 and no unexpected tissue cross reactivity was observed.  
For additional information about PF-06904103 refer to the IB. 


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1.5. Starting Dose Rationale
1.5.1. Part 1A – Monotherapy Dose Escalation
The selection of the monotherapy starting dose for Part 1A is based on the preclinical 
toxicology results in accordance with the ICH S9 Guidance entitled Nonclinical Evaluation
for Anticancer Pharmaceuticals.  The cynomolgus monkey was considered the most 
appropriate species for determining the proposed starting dose in patients. The HNSTD in the 
pivotal monkey study was 3 mg/kg/dose.
The proposed starting dose of 0.15 mg/kg given as an IV infusion Q3W represents 
approximately 1/6th of monkey HNSTD (based on human equivalent dose normalized to
body surface area). 
1.5.2. Part 1B – Combination Regimen Dose Escalation
The starting dose level of PF-06804103 is planned to be at the equivalent to monotherapy 
Part 2 dose minus 1 and was selected based on potential DDI, any overlapping toxicity 
considerations, and all available clinical, safety, PK, tolerability, and preliminary efficacy
data.  
Palbociclib is a weak time-dependent inhibitor of CYP3A and is expected to cause a low to 
moderate increase in exposure for unconjugated payload PF-06804103. Since the 
monotherapy Part 2 dose minus 1 is 3 mg/kg Q3W, the starting dose of PF-06804103 in Part
1B will be 2 mg/kg Q2W, to yield the same dosing intensity as 3 mg/kg Q3W in 
monotherapy dosing.  The expected maximum Part 1B dose will be 2.7 mg/kg Q2W, to yield 
the same dosing intensity as 4 mg/kg Q3W monotherapy dosing. Higher doses of 
PF-06804103 may be tolerated by patients previously untreated with systemic anticancer 
therapies. For those patients, the maximum Part 1B dose may exceed 2.7 mg/kg QW.
1.5.3. Part 2A – Monotherapy Dose Expansion
Dose levels of PF-06804103 to be administered will be selected following a review of all 
available safety, tolerability, preliminary efficacy, and PK data collected in Part 1A. The 
planned Part 2 monotherapy doses for PF-06804103 are 3.0 mg/kg/ and 4.0 mg/kg Q3W.
1.5.4. Part 2B – Combination Dose Regimen Expansion
The SOC administration of palbociclib is in 28-day cycles, the dose level selection of 
PF-06804103 Q2W will be based on all available clinical, safety, tolerability, preliminary 
efficacy, and PK data from Part 1B.  The anticipated Part 2 combination dose for 
PF-06804103 is 2.7 mg/kg Q2W.


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2. STUDY OBJECTIVES AND ENDPOINTS
Objective: 
Endpoint: 
Primary
To characterize the DLTs of escalating levels of
PF-06804103
To assess the safety and tolerability of PF-06804103
To determine the RP2D for PF-06804103 as 
monotherapy
To determine the RP2D for PF-06804103 in 
combination with palbociclib and letrozole
First cycle (21 days) DLTs – Part 1A
First cycle (28 days) DLTs – Part 1B
All available safety data including: AEs, SAEs, and 
clinically meaningful abnormalities in laboratory values
and vital signs
Part 2:
To investigate preliminary antitumor activity
Part 2 y:
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP
Secondary
Objective
Endpoint
To characterize the single and multiple dose PK of
PF-06804103 ADC, total antibody and unconjugated 
payload (PF-06380101).
SD and MD PK parameters of PF-06804103 ADC, total 
antibody and unconjugated payload (PF-06380101).
To evaluate the immunogenicity of PF-06804103
Incidence and titers of ADA and NAbs against 
PF-06804103
To document antitumor activity
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP – Part 1
To explore preliminary antitumor activity in patients
that HER2 positive GC 
HER2 expression levels in pre-treatment tumor biopsies 
via IHC and ISH


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CCI
CCI
CCI


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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label, multicenter, multiple dose, safety, PK, and PD study of
PF-06804103 in adult patients with HER2-positive solid tumors (BC and GC [Part 1A only]) 
and in postmenopausal patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC. Part 
1A and 1B will evaluate escalating doses of PF-06804103 as monotherapy and as part of a
combination regimen, respectively. Part 2A and Part 2B will evaluate selected doses of 
PF-06804103 in expansion cohorts as monotherapy and in a combination regimen, 
respectively.
In Part 1A, patients with HER2-positive BC or HER-positive GC will receive escalating
doses of PF-06804103 starting at 0.15 mg/kg, Q3W in a 21-day cycle to estimate the dose
level of PF-06804103 to be administered in Part 2A.
In Part 1B, postmenopausal patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC 
will receive escalating doses of PF-06804103 starting at the dose equivalent to the 
recommended monotherapy Q3W Part 2 dose minus 1 dose, Q2W in a 28-day cycle,
administered in combination with SOC doses of palbociclib and letrozole (as per local and 
regional guidelines). Data collected during Part 1B will inform the dose levels selected for
dose expansion in Part 2B.
In Part 2A, HER2-positive BC patients in 3L setting will be randomly assigned to receive 
3 mg/kg or 4 mg/kg doses of PF-06804103 administered as monotherapy Q3W to further 
evaluate safety, efficacy, and to evaluate the benefit/risk of 3 mg/kg and 4 mg/kg Q3W in a 
larger population to support optimal dose selection. Also in Part 2A, HR-positive HER2 IHC 
1+ or IHC 2+/ISH- BC patients in 2L setting will receive 4 mg/kg of PF-06804103
administered as monotherapy Q3W. A lower dose (eg., 3 mg/kg) may be tested if the 
observed toxicity of 4 mg/kg Q3W is determined to be too high.
In Part 2B, patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC in the 1L setting 
will receive the selected PF-06804103 dose administered Q2W (Part 1B) in a 28-day cycle in
combination with SOC doses of palbociclib and letrozole (as per local and regional 
guidelines).
Approximately 148 patients are expected to be enrolled in the study overall. The actual
number of patients enrolled will depend on the tolerability of PF-6804103 and the number of 
dose levels required to identify the MTD and select dose levels for Part 2 of the study.
Treatment with investigational products will continue until either disease progression, patient 
refusal, or unacceptable toxicity occurs, whichever occurs first, unless the investigator and 
medical monitor agree to treatment beyond progression based on individual benefit/risk 
assessments.
In both study parts, the proposed dose levels, schedules, and PK time points may be
reconsidered based on emerging safety and PK data. A dose level or treatment arm may be


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discontinued at any time depending on the totality of the data including, but not limited to the 
evaluation of all available clinical, safety, PK, PD, and preliminary efficacy results.


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Figure 1.
Overall Study Design
3.1.1. Criteria for Dose Escalation
3.1.1.1. Part 1A Monotherapy Dose Escalation
PF-06804103 will be administered as an IV infusion every 21 days at a starting dose of 
0.15 mg/kg, dose escalation is planned as described in Table 5. Additional dose levels, or
intermediate doses may be explored, if appropriate based on emerging clinical, safety, PK, or 
PD data.
A mTPI method targeting a DLT rate of approximately 27.5% with an equivalence interval 
of (22.5%, 32.5%) will be utilized in Part 1 of the study.  Patients will be enrolled in cohorts 
of 2 to 4 patients.  Intra-patient dose escalation is not permitted.
Table 5.
Part 1A  - PF 06804103 Dose Escalation Levels
Dose Level
PF-06804103 Dose (mg/kg)*
1 (Starting Dose)
0.15
2
0.5
3
1.2
4
2.0
5
3.0


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Table 5.
Part 1A  - PF 06804103 Dose Escalation Levels
Dose Level
PF-06804103 Dose (mg/kg)*
6
4.0
7
5.0
8
6.0
9**
n
*Intermediate doses may be evaluated.
**If needed, higher doses may be explored.
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in prior and current dose level to determine one of the following dose-finding
decisions: the subsequent dose should be escalated, maintained at the current dose, or
de-escalated in the next cohort, or the trial should be terminated (Table 6). 
Table 6.
Decision Rules – Part 1A and Part 1B
Number 
of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
n=13
n=14
n=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
Actions to be taken:
D=De-escalate the dose; E=Escalate the dose; S=Stay at the dose.
U=Unacceptable toxicity.
In principle, all patients must be evaluated for a minimum period of 21 days.  If a patient 
withdraws from the study before Day 21 for reasons other than drug-related toxicity, another 
patient may be enrolled to replace that patient in the current cohort.  However, if a patient 
discontinues close to Day 21 for reasons other than toxicity and due to an evident 


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non-drug-related event, the patient may be deemed evaluable for safety if the investigators 
and sponsor agree that the patient is evaluable for the DLT safety observation.
The dose escalation in Part 1A of the study will stop if any of the following criteria is met:

the maximum sample size in Part 1 has been achieved;

at least 9 patients have been accumulated on a dose that is predicted to be the MTD 
per the mTPI method;

all doses explored appear to be overly toxic, and the MTD cannot be determined.
There will be a minimum 48-hour interval between the first dose administered to each of the 
initial patients (ie, patients contributing to initial DLT evaluation) enrolled at a new dose 
level. Initially, up to 4 patients will be treated; occasionally, due to logistical/clinical 
reasons, more than 4, but, no more than 6, patients may be enrolled in each cohort for the 
initial DLT evaluation.  In addition, dose cohorts with an acceptable safety profile may be 
expanded up to n=15 to further assess safety, pharmacokinetics or pharmacodynamics.  
Decisions to enroll additional patients at dose levels already cleared for safety will be based 
on the clinical judgment of the investigators and the sponsor considering all evaluable safety, 
PK, dose discontinuations, dose reductions, and PD data.
3.1.1.2. Part 1B – Combination Regimen Dose Escalation
Dose escalation in the combination regimen will also follow the mTPI design. PF-06804103
will be administered as an IV infusion every 14 days in combination with SOC oral 
palbociclib and oral letrozole. Dose escalation up to 3.3 mg/kg Q2W or de-escalation
(Table 7) including higher, intermediate, or lower doses may be evaluated based on all 
available clinical, safety, PK, and/or PD data.  If further evaluation is needed, the number of 
dose levels may be expanded. Intra-patient dose escalation is not permitted
The combination regimen evaluated in Part 1B will be administered to patients with 1L BC
HR-positive HER2 IHC 1+ or IHC 2+/ISH-.   The actual number of patients enrolled will
depend on the tolerability of PF-06804103 at each of dose level when administered in 
combination with palbociclib and letrozole.
All patients will be evaluated for a minimum period of 28 days.  If a patient withdraws from 
the study before Day 28 for reasons other than drug related toxicity, the patient is not 
evaluable for the DLT observation period, and the patient will be replaced.  
Details on IP administration are provided in Section 5.4.2 (PF-06804103) Section 5.4.3
(palbociclib), and Section 5.4.4 (letrozole).


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Table 7.
Part 1B - PF 06804103 Dose Escalation Levels
Dose Level
PF-06804103 Dose (mg/kg) Q2W*
-1
1.3
1 (Starting Dose)
2.0
2
2.7
3
3.3
*Intermediate, higher or lower doses may be explored.
Dose escalation in Part 1 B will stop if any of the following criteria is met:

the maximum sample size has been achieved;

at least 6 (Part 1B) patients have been administered a dose that is predicted to be the 
MTD per mTPI;

all doses explored appear to be overly toxic, and the MTD cannot be determined.
3.1.1.3. Part 2A – Monotherapy Dose Expansion
PF-06804103 will be evaluated as monotherapy when administered as described below:

Arm M1: ≥3L BC HER2-positive (HER2 IHC 3+ or ISH+) 3 mg/kg Q3W

Arm M2: ≥3L BC HER2-positive (HER2 IHC 3+ or ISH+) 4 mg/kg Q3W

Arm M3: ≥2L BC HR-positive, HER2 IHC 1+ or IHC 2+/ISH- 4 mg/kg Q3W
3.1.1.4. Part 2B – Combination Regimen Dose Expansion
The dose level of PF-06804103 to be administered in Part 2B will be selected based on the 
dose level determined in Part 1B and all available clinical, safety, preliminary efficacy, PK, 
and PD data and will be administered with palbociclib and letrozole to the patients described 
below:

Arm C1: BC 1L, postmenopausal, HR-positive HER2 IHC 1+ or IHC 2+/ISH-,
PF-06804103 Q2W with SOC regiment for palbociclib and letrozole


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Table 8.
Planned Dose Levels for Part 2B
Arm
Regimen
PF-06804103
Palbociclib1
Letrozole
C1
Dose TBD mg/kg IV Q2W2
125 mg PO QD for 3 weeks1
repeat every 28 days
2.5 mg PO QD on Days 1 
through 28
1.
3 weeks on followed by 1 week off.
2.
PF-06804103 dose level to be administered in combination with palbociclib and letrozole to be established
from Part 1B.
Detailed sample size information is provided in Section 9.3.
3.2. Dose Limiting Toxicity Definition
Severity of AEs will be graded according to CTCAE version 4.03. For the purpose of dose 
escalation, any of the following AEs occurring in the first cycle of treatment will be 
classified as DLTs, unless there is a clear alternative explanation:
Part 1A
Hematologic:

Grade 4 neutropenia lasting >7 days;

Febrile neutropenia defined as ANC <1000/mm3 with a single temperature of 
>38.3C (101F) or a sustained temperature of 38C (100.4F) for more than 
1 hour);

Grade 3 neutropenic infection; 

Grade 3 thrombocytopenia with bleeding;

Thrombocytopenia defined as:

any <10,000/mm3 (or ≥100 x 109/L)

or 10,000 /mm3 or (≥100 x 109/L) to 25,000 mm3

(or ≥100 x 109/L for ) >5 days.


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Non-hematologic:

Grade 3 toxicities, that are considered clinically significant, except the following:

Grade 3 nausea, vomiting or diarrhea lasting <72 hours with adequate antiemetic 
or other supportive care;

Grade 3 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions;

Grade 3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.

Delay by more than 2 weeks in receiving the next scheduled cycle due to persisting 
treatment related toxicities.  Patients deriving clinical benefit from study treatment 
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.

Concurrent AST or ALT >3x ULN and total bilirubin >2x ULN (potential Hy’s law 
case, (Section 8.4.1).

Any Grade 5 event not clearly due to underlying disease or extraneous causes.
Part 1B
A DLT is defined as any of the following TEAEs occurring during the first cycle of treatment 
and considered possibly related to the combination of PF-06804103 plus palbociclib and
letrozole:
Hematologic:

A delay greater than 1 week in administration of the next scheduled dose of study
treatment due to persistent treatment-related toxicities (eg, platelet count and ANC of 
Grade >3 unless the criteria below are met during the DLT observation period):

Grade 4 neutropenia lasting >7 days;

Febrile neutropenia (defined as ANC <1000/mm3 with a single temperature of 
>38.3C (101F) or a sustained temperature of 38C (100.4F) for more than
1 hour);

Grade 3 neutropenic infection;

Grade 3 thrombocytopenia with bleeding;


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
thrombocytopenia (defined as):

any <10,000/mm3;

10,000 to 25,000/mm3 for >5 days.
Non-hematologic:

Grade 3 toxicities, that are considered clinically significant, except the following:
o
Grade 3 nausea, vomiting or diarrhea lasting <72 hours with adequate 
antiemetic or other supportive care;
o
Grade 3 electrolyte abnormality lasting <72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions;
o
Grade 3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.

Grade 3 QTc prolongation (QTc msec) despite correction of reversible causes:
o
In an asymptomatic patient, Grade 3 QTc prolongation (QTc >500 msec) first
required repeat testing, re-evaluation by a qualified person, and correction of
reversible causes such as electrolyte abnormalities or hypoxia for 
confirmation. 

Delay by >2 week in receiving the next scheduled dose of any study treatment due to 
persisting treatment-related toxicities.  Patients deriving clinical benefit from study
treatment 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.

Inability to administer at least 80% of the planned palbociclib or letrozole doses 
during Cycle 1 due to toxicity related to the study treatment.

Inability to administer 100% of the planned dose of PF 06804103 during Cycle 1 due 
to toxicity related to the study treatment.

Concurrent AST or ALT >3x ULN and total bilirubin >2x ULN (potential Hy’s law 
case (Section 8.4.1).

Any Grade 5 event not clearly due to underlying disease or extraneous causes.
In addition, clinically important or persistent toxicities that are not included in the above
criteria may be considered a DLT following review by the sponsor and the investigators. All 
DLTs need to represent a clinically significant shift from baseline.


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Grade 3 infusion reactions, allergic reactions, or anaphylaxis will not be considered DLTs,
as they are unlikely dose related, but may be a reason for study discontinuation and should be 
reviewed with the sponsor. If Grade 3 infusion reactions occur in 2 of the first 10 patients 
at any dose level, or if the occurrence is 5% thereafter, a mandatory pre-treatment regimen 
for all new patients will be implemented.  The incidence of Grade 1 and Grade 2 reactions 
will also be considered. If a total rate of >10% all-grade infusion or allergic reactions is 
observed, a mandatory pre-treatment regimen for all new patients will be implemented.
All AEs meeting DLT criteria are considered DLTs regardless of baseline .
3.3. Maximum Tolerated Dose Definition
The estimated MTD is the dose level associated with a target DLT rate of approximately 
27.5% with an equivalence interval of (22.5%, 32.5%).  Due to the discreteness of the dose 
levels and in the interest of the safety of patients, the estimated MTD is the highest tested 
dose level with DLT rate approximately 32.5%. Late onset toxicities which occur outside 
the DLT observation period may be used in determination of the MTD.
3.4. Recommended Phase 2 Dose Definition
The RP2D is the dose chosen for further investigation based on Phase 1 study results.  If the 
MTD proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D.  Further experience with the MTD may
result in a RP2D dose lower than the MTD.
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into
consideration when deciding whether a particular patient is suitable for this trial.
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the
study:
4.1.1. General Study Inclusion Criteria
1. ECOG Performance Status of 0 or 1 (Appendix 2)
2. Adequate bone marrow function including:

ANC ≥1,500/mm3 or ≥1.5 x 109/L;

Platelets ≥100,000/mm3 or ≥100 x 109/L;

Hemoglobin ≥9 g/dL.


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3. Adequate renal function, including:

Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution.
4. Adequate liver function, including:

Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease);

AST and ALT ≤2.5 x ULN; ≤5.0 x ULN if there is liver involvement by the 
tumor;

ALP ≤2.5 x ULN (≤5 x ULN in case of bone metastasis).
5. Resolution of acute effects of any prior therapy to baseline severity or to Grade ≤1
(NCI CTCAE, version 4.03), excluding AEs not constituting a safety risk as 
determined by the investigator.
6. Females of childbearing potential who have a negative serum or urine pregnancy test
at screening.
7. Females of nonchildbearing potential must meet at least 1 of the following criteria:

Postmenopausal, defined as follows: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause; 
have a serum FSH level confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure.
Note: All other female patients (including those with tubal ligations) are considered to be of 
childbearing potential.
8. Evidence of a signed and dated ICD indicating that the patient has been informed of 
all pertinent aspects of the study
9. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other procedures
4.1.2. Inclusion Criteria for Part 1A – Monotherapy Dose Escalation
1. Male or female patients age ≥18 years (or age ≥19 years where required by local 
regulations).
2. Advanced/unresectable or metastatic HER2-positive BC or metastatic HER2-positive
adenocarcinoma of the stomach or esophagogastric junction that is refractory to or 
intolerable with standard therapy or for which no standard therapy is available.


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3. Documented histologically or cytologically confirmed diagnosis of HER2 positive
BC or metastatic HER2-positive adenocarcinoma of the stomach or esophagogastric 
junction based on local laboratory results, defined according to the ASCO
Guidelines.32
4. Hemoglobin-adjusted DLco ≥60% predicted.
5. Documentation of HER2 IHC 3+ or ISH+ status as described in Appendix 3:
4.1.2.1. Inclusion Criteria for Part 2A – Monotherapy Dose Expansion Arms M1 and 
M2
1. Adult female patients age ≥18 years (or age ≥19 years where required by local 
regulations).
2. Advanced/unresectable or metastatic HER2-positive BC that is refractory to or 
intolerable with standard therapy or for which no standard therapy is available.
3. Documented HER2-positive BC histologically or cytologically defined as either 
HER2 IHC 3+ or ISH+ based on local laboratory results. Documentation of HER2
IHC and/or ISH status per Appendix 3 is required.
4. At least 1 measurable lesion, not previously irradiated, as defined by RECIST
version 1.1.
5. Available archival tumor biopsy sample, either FFPE tumor tissue block or unstained 
slides, for retrospective assessment for HER2 expression. A fresh biopsy sample must 
be provided (if clinically feasible) if archival material is not available. (See Table 2, 
Footnote 20, and Section 7.4.5. 
4.1.2.2. Inclusion Criteria for Part 2A – Monotherapy Dose Expansion Arm M3
1. Adult female patients age ≥18 years (or ≥19 years where required by local 
regulations).
2. Advanced/unresectable or metastatic HER2 IHC 1+ or IHC 2+/ISH- BC that has 
progressed on at least 1 prior line of systemic therapy including a hormonal based
regimen.
3. Documented HER2 IHC 1+ or IHC 2+/ISH- BC histologically or cytologically 
defined as either HER2 IHC 1+ or IHC 2+/ISH- based on local laboratory results. 
Documentation of HER2 IHC and/or ISH status per Appendix 3 is required.
4. At least 1 measurable lesion, not previously irradiated, as defined by RECIST v1.1.
5. Documentation of histologically or cytologically confirmed diagnosis of estrogen-
receptor positive or progesterone-receptor positive BC based on local laboratory 
results.


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6. Available archival tumor biopsy sample, either FFPE tumor tissue block or unstained 
slides, for retrospective assessment for HER2 expression. A fresh biopsy sample 
must be provided (if clinically feasible) if archival material is not available.
(Section 7.4.5).
4.1.3. Inclusion Criteria for Part 1B and Part 2B - Combination Regimen Dose 
Escalation and Expansion:
1. Adult female patients age ≥18 years (or age ≥19 years where required by local
regulations).
2. Postmenopausal women, defined as:

prior bilateral surgical oophorectomy, or

medically confirmed postmenopausal status defined as spontaneous 
cessation of regular menses for at least 12 consecutive months or FSH and 
estradiol blood levels in their respective postmenopausal ranges with no 
alternative pathological or physiological cause.
3. Advanced/unresectable or metastatic HER2 IHC 1+ or IHC 2+/ISH- BC previously
untreated with any systemic anti-cancer therapy. 
4. Documentation of histologically or cytologically confirmed diagnosis of HER2 IHC
1+ or IHC 2+/ISH- BC based on local laboratory results. Documentation of HER2 
IHC and/or ISH status as described in Appendix 3.
5. Documentation of histologically or cytologically confirmed diagnosis of estrogen-
receptor positive or progesterone-receptor positive BC based on local laboratory 
results.
6. A fresh biopsy sample must be provided (Section 7.4.5.2).
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
4.2.1. General Study Exclusion Criteria
1. Patients with HER2 IHC 0 as defined in Appendix 3.
2. Symptomatic brain metastases requiring steroid treatment.
Note: Patients with previously diagnosed brain metastases are eligible if they have completed 
treatment and recovered from the acute effects of radiation therapy or surgery prior to study entry, 
have not taken corticosteroids for at least 4 weeks and are neurologically stable.
3. History of prior malignancy other than the diseases under study within the past 
5 years (excluding successfully resected treated basal or squamous cell carcinoma of 
the skin, or any carcinoma in situ which has been adequately treated.)


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4. Major surgery within 4 weeks prior to registration.
5. Radiation therapy within 4 weeks prior to registration.
Note: Palliative radiotherapy to a limited field is allowed after consultation with Pfizer’s 
medical monitor.
6. Exposure to anthracyclines at the cumulative doses listed below:

Doxorubicin >500 mg/m2;

Liposomal doxorubicin >500 mg/m2;

Epirubicin >720 mg/m2;

Mitoxantrone >120 mg/m2;

Idarubicin >90 mg/m2.
If another anthracycline or more than 1 anthracycline has been used, the cumulative dose
must not exceed the equivalent of 500 mg/m2 doxorubicin.
7. Systemic anticancer therapy within 4 weeks prior to study entry; hormonal therapy 
7 days prior to registration; trastuzumab, trastuzumab emtansine, or pertuzumab
therapy and/or lapatinib 21 days prior to registration.
If systemic anticancer therapy was given within 4 weeks, patient may be included if 
5 times elimination half-life of drug has passed.
8. Patients with serious pulmonary illness including complications of advanced 
malignancy which may cause dyspnea at rest or requires supplementary oxygen 
therapy.
9. Grade 3 hypersensitivity reaction to prior receipt of any antibody therapy.
10. Previous high dose chemotherapy requiring stem cell rescue.
11. Prior irradiation to >25% of the bone marrow.
12. History or active interstitial lung disease, pulmonary fibrosis, or a history of other 
clinically significant lung diseases.
13. History of, or ongoing, corneal disorders.
14. Active and clinically significant bacterial, fungal, or viral infection, including HBV, 
HCV, known HIV or AIDS related illnesses.
15. Had had in the previous 6 months: myocardial infarction, severe/unstable angina, 
coronary/peripheral artery bypass graft, symptomatic congestive heart failure,


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cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism.
16. Has hypertension (>150/100 mmHg) that cannot be controlled by medications.
17. Has inadequate cardiopulmonary function defined as any of the following: LVEF 
<50% (by ECHO or MUGA), uncontrolled pleural effusion, pericardial effusion, or 
ascites requiring recurrent drainage procedures, clinical history of active hemoptysis; 
evidence of active pneumonitis during screening; or current unstable ventricular 
arrhythmia.
18. Has symptomatic hypercalcemia requiring use of bisphosphonate therapy within 
21 days prior to registration.

Patients who receive bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are 
eligible.
19. Has Grade >1 peripheral neuropathy per NCI CTCAE version 4.03 at the time of 
registration.
20. Is receiving chronic systemic corticosteroid treatment (topical applications, inhaled 
sprays, eye drops, local injections of corticosteroids and systemic steroids required
for acute medical interventions are allowed).
21. History of intolerance, including Grade 3 infusion reaction or hypersensitivity to
trastuzumab, murine proteins, or docetaxel/paclitaxel or known or suspected
hypersensitivity to recombinant human or murine proteins.
22. Patients treated within the 7 days prior to randomization with any of the following:

Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, 
atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, 
erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or 
grapefruit juice); The topical use of these mediations (if applicable), such as 2% 
ketoconazole cream, is allowed.

Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin,
and St. John’s wort).  
23. Participation in other studies involving investigational drugs within 30 days,
5 half-lives or twice the duration of the biological effect of the investigational drug
(whichever is longer) prior to study entry.


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24. Within the past year, any acute or chronic medical or psychiatric condition, including 
suicidal ideation, behavior, or a laboratory abnormality, that the investigator
determines may make the patient inappropriate for this study, increase the risks
associated with participation, investigational product administration, or that could
interfere with the interpretation of study results
25. Is a site staff member or family member of site staff directly involved in the conduct 
of the study, a site staff member otherwise supervised by the investigator, Pfizer 
employees or family members of a Pfizer employee directly involved in the conduct 
of the study.
26. Is pregnant or breastfeeding. Fertile male patients and female patients of childbearing 
potential who are unwilling or unable to use 2 highly effective methods of 
contraception as outlined in this protocol for the duration of the study and for at least 
90 days (or 180 days for patients enrolled in Korea) after the last dose of 
investigational product.
4.2.2. Exclusion Criteria Specific to Part 1B and 2B Combination Regimen Dose 
Escalation and Expansion – Arm C1
1. Prior treatment with any CDK4/6 inhibitor
2. Prior neoadjuvant or adjuvant treatment with a nonsteroidal aromatase inhibitor 
(ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of 
completing treatment.
3. Patients treated within the 7 days prior to randomization with drugs that are known to 
prolong the QT interval (refer to Appendix 6).
4. QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal 
history of long or short QT syndrome, Brugada syndrome, known history of QTc 
prolongation, or Torsade de Pointes (Appendix 8).
5. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
6. Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or any 
upper gastrointestinal surgery including gastric resection.
7. Known hypersensitivity to letrozole, or any of its excipients.
8. Known hypersensitivity to palbociclib, or any of its excipients.
4.3. Lifestyle Requirements
In this study, fertile male patients and female patients who are of childbearing potential will 
receive PF-06804103, a compound for which the teratogenic risk is currently unknown.  
Patients who are, in the opinion of the investigator, sexually active and at risk for pregnancy 


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with their partner(s) must agree to use 2 methods of highly effective contraception 
throughout the study and for at least 90 days (or 180 days for patients enrolled in Korea) after 
the last dose of investigational product.  The investigator or designee, in consultation with the 
patient, will confirm that the patient has selected 2 appropriate methods of contraception for 
the individual patient and his or her partner(s) from the list of permitted contraception
methods (see below) and will confirm that the patient has been instructed in their consistent 
and correct use.  At time points indicated in the Schedule of Activities, the investigator or 
designee will inform the patient of the need to use 2 highly effective methods of 
contraception consistently and correctly and document the conversation, and the patient’s
affirmation, in the patient’s chart.  In addition, the investigator or designee will instruct the 
patient to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the patient or partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing IUD.
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository). For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the post vasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the
patient’s participation in the study. The contact number can also be used by investigator staff 


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if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available. It is therefore intended to augment, but not replace, the
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per ICH guidelines, investigational product is defined as a 
pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference/comparator in a clinical trial, including a product with a marketing authorization 
when used or assembled (formulated or packaged) in a way different from the approved 
form, or when used for an unapproved indication, or when used to gain further information 
about an approved use (ICH E6 1.33).
In this study, the investigational products are all study treatments to be administered.
Study treatments in Part 1A included the following:

PF-06804103 administered IV at a starting dose of 0.15 mg/kg Q3W
Study treatments in Part 1B included the following:

PF-06804103 will be administered IV at a starting dose of 2 mg/kg Q2W + 
palbociclib (125 mg) + letrozole (2.5 mg) Q4W
Study treatments in Part 2A included the following: 

Arm M1: PF-06804103 will be administered IV at 3 mg/kg Q3W

Arm M2: PF-06804103 will be administered IV at 4 mg/kg Q3W

Arm M3: PF-06804103 will be administered IV at 4 mg/kg Q3W
Study treatments in Part 2B included the following:

Arm C1: PF-06804103 (TBD) Q2W will be administered IV + palbociclib (125 
mg) + letrozole (2.5 mg) Q4W
Details on dose administration and escalation can be found in Section 3.1.
5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will
email a completed Registration Form to the designated sponsor study team member or 


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designee.  The sponsor will assign a patient identification number documenting patient 
enrollment and will supply this number to the site.
In Parts 1B, 2A, and 2B allocation of patients to treatment groups may be performed through
an IRT/IWR system.  
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

confirmation of the patient’s enrollment;

specification of the dose level for that patient and;

permission to proceed with dosing the patient.
5.2. Patient Compliance
During dose escalation, all doses of investigational products will be administered by the 
appropriately designated study staff at the investigational site. During dose expansion, 
palbociclib and letrozole doses will be self-administered and each dose will be recorded in a 
patient diary.
The site will complete required dosage Preparation Record located in the IP manual.  The use 
of the Preparation Record is preferred but it does not preclude the use of an existing
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after
approval from the sponsor and/or designee.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
PF-06804103
PF-06804103 is supplied as a powder for reconstitution and IV administration.  Each vial 
contains 40 mg of PF-06804103, is sealed with a coated stopper and an overseal, and is 
labeled according to local regulatory requirements.
Palbociclib
Palbociclib is commercially available as 125 mg capsules in High Density Polyethylene 
(HDPE) bottles, labeled according to local regulatory requirements. The 100 mg, and 75 mg 
capsules will be available for dose reduction.
Letrozole
Letrozole is commercially available as a bottle of 2.5 mg tablets and is labeled according to 
local regulatory requirements.


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5.3.2. Preparation and Dispensing
See the IP manual, for instructions on how to prepare the investigational product for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as 
allowed by local, state, and institutional guidance.
Vials are for single-use, single-patient only.
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 chemotherapeutic agents.
5.4. Administration of Investigational Products
Every effort will be made to administer all study drugs on the planned dose schedule. All
PF-6804103 will be administered at the investigational site on an outpatient basis.  Patients 
will self-administer oral doses of palbociclib and letrozole at home.   
5.4.1. Premedication for PF-06804103
The decision to incorporate pre-medication in all patients will be made following discussions 
between the sponsor and the investigators.  Patients should be pre-treated with
acetaminophen and diphenhydramine (or other antihistamine) approximately 0.5 to 2 hours 
before each PF-06804103 administration.
Suggested starting doses are 650 mg to 1000 mg acetaminophen and 50 mg diphenhydramine 
(or equivalent of other antihistamine) IV or oral.  Two additional doses of acetaminophen
may be administered approximately every 4-6 hours after the initial pre-treatment or as
needed.
5.4.2. Administration of PF-06804103
In all study parts, PF-06804103 will be administered on Day 1 of each cycle, intravenously
over approximately 60 minutes (15 minutes), on an outpatient basis. A cycle is defined as 
the time from Day 1 dose to the next Day 1 dose.  If there are no treatment delays, a cycle 
will be 21 days for monotherapy dosing and 28 days for combination regimen dosing.
Dose levels for dose escalation are described in Section 3.1.1.1 and Section 3.1.1.2
(monotherapy and combination, respectively). Dose levels for dose expansion are described 
in Section 3.1.1.3 and Section 3.1.1.4 (monotherapy and combination, respectively). At the 
discretion of the sponsor, alternative dosing schedules may be explored.
Details for PF-06804103 infusion are provided in the IP manual.  The decision to recalculate
PF-06804103 dose based on the weight obtained at each cycle can be in accordance with 
institutional practice; however, if the patient experienced either a weight loss or gain 
>10% compared to the weight used to calculate the initial dose, the amount of PF-06804103


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required for preparation and administration for the current cycle must be recalculated using 
this most recent weight obtained.
Each patient may receive PF-06804103 until disease progression, unacceptable toxicity, 
withdrawal of consent, or study termination. 
Recommended dose reductions and dose modification guidelines are provided in Table 14.
5.4.2.1. Infusion-Related Reactions – PF-06804103
In the event of infusion related reactions, investigators should institute treatment measures 
according to best medical and nursing practice.  Monitoring and treatment guidelines are 
provided in Appendix 5.
In the case of infusion related reactions characterized by fever and chills, and less commonly
hypotension, the sponsor should be notified and pre-treatment medication should be 
administered prior to subsequent infusions (in the case that the patient is able to continue on 
treatment as per Appendix 5.
5.4.3. Palbociclib Administration
Palbociclib will be administered orally at 125 mg PO QD for 3 weeks followed by a 1-week
rest period.  
Patients should swallow capsules whole and not manipulate or chew them.  No capsule 
should be ingested if it is broken, cracked, or otherwise not intact.  Patients should take their 
dose at approximately the same time each day and record ingestion in the patient diary.
If a dose is missed, patients should skip that dose, record it as missed, and resume dosing the 
next day. If vomiting occurs following dosing, the dose should be recorded as missed. If an 
extra dose is taken in the same day, the next daily dose should be skipped. 
Recommended dose reductions and dose modification guidelines are provided in Table 15
and Table 16.
5.4.4. Letrozole Administration
Letrozole will be administered orally at 2.5 mg PO QD on Days 1 through 28. 
If a dose is missed, patients should skip that dose, record it as missed, and resume dosing the 
next day. If vomiting occurs following dosing, the dose should be recorded as missed. If an 
extra dose is taken in the same day, the next daily dose should be skipped. 
Recommended dose reductions and dose modification guidelines are provided in Table 17.
5.4.5. Dosing Delays
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care should have their treatment interrupted/delayed.  In 
addition, any occurrence of Grade 2 ejection fraction will require a treatment 


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interruption/delay.  Appropriate follow-up assessments should be done until adequate 
recovery occurs as assessed by the investigator. 
Specific guidelines for dose reduction for each IP are provided in Appendix 7.
5.4.5.1. Re-Treatment Criteria
If a treatment interruption continues beyond Day 21 (for monotherapy dosing) or beyond 
Day 28 (for combination regimen dosing) of the current cycle, then the day when treatment is 
restarted will be counted as Day 1 of the next cycle.  Re-treatment following treatment 
interruption for treatment related toxicity or at the start of any new cycle may not occur until 
all of the following parameters have been met:

ANC 1,000/mm3; 

Platelets count 75,000/mm3; 

Non hematologic toxicities have returned to baseline or Grade 1 severity (or, at the
investigator discretion, Grade 2 if not considered a safety risk for the patient).
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are not met, treatment must be delayed by 1 treatment cycle (3 or 4 weeks 
for monotherapy or combination treatment, respectively) unless otherwise specified in
Appendix 7. If, after a treatment cycle delay all toxicities have recovered within the limits
described above treatment with PF-06804103 can be resumed. 
Initiation of the next cycle can only be delayed by a maximum of 1 treatment cycle (3 or 
4 weeks for monotherapy or combination therapy, respectively) .  If a persisting toxicity does 
not allow resumption of PF-06804103 monotherapy within 42 days or resumption of 
combination therapy within 56 days of Day 1 of the previous cycle, the patient will be 
discontinued from treatment unless discussed and agreed with the sponsor. 
5.4.6. Monotherapy PF-06804103 Dose Modifications
In the event of significant toxicity during PF-06804103 monotherapy or combination therapy
dosing may be delayed and/or reduced as described in Appendix 7. 
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed.  Patients are to be instructed to notify investigators at the first occurrence of any 
adverse symptom.
Dose reduction, not dose delay, is the preferred management of Grade 2 or 3 peripheral 
neuropathy, myalgia, arthralgia, or skin toxicity PF-06804103-related AEs. To maintain 
sufficient drug exposure, dose reductions to dose levels lower than 2 mg/kg Q3W are not 
recommended. Dose delays during the first 6 cycles are also not recommended. Dose
modifications may occur in 1 of 3 ways:


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
within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;

between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

in the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
Recommended PF-06904103 dose level reductions are provided in Table 13, and are 
intended to be permanent (ie, if the patient’s dose is reduced to dose minus 1, it remains at 
the reduced dose level for the remainder of the study). Dose reductions below 2 mg/kg are
not allowed. Dose delays during the first 5 cycles as monotherapy are also not recommended.
Patients requiring more than 2 dose reductions will be discontinued from the treatment and
enter the follow-up period, unless otherwise agreed between the investigator and the sponsor.  
Intrapatient dose re-escalation is not allowed. 
5.4.7. Combination Therapy Dose Modifications
To maintain sufficient drug exposure, dose reductions below 1.3 mg/kg Q2W are not 
recommended. Dose delays during the first 5 cycles as combination therapy are also not 
recommended.
When combining with palbociclib and letrozole, the treatment schedule (cycle and day for 
treatment) for PF-06804103 should follow that of palbociclib. If palbociclib treatment is 
delayed and a new cycle is started for palbociclib, PF-06804103 treatment should also be 
delayed as well and restart on Day 1 of the new cycle. If PF-06804103 treatment needs to be 
delayed, the biweekly dose for PF-06804103 should be skipped, as needed, while
maintaining the original treatment schedule for palbociclib and letrozole.
5.4.8. Palbociclib Dose Modifications 
For AEs related to hematologic toxicities (neutropenia), palbociclib should be reduced to the 
lowest allowed dose per guidelines before initiating PF-06804103 dose modification.
Dose modifications for palbociclib, including dose interruption and dose reduction should be
based on the information provided in Table 15.  
In the event of a treatment interruption lasting >4 weeks for reasons other than 
treatment-related toxicity (eg, non-cancer related surgery), treatment may resume if the 
investigator and sponsor agree the patient is continuing to benefit from treatment.
Recommended dose reductions and dose modification guidelines are provided in Table 15
and Table 16.
5.4.9. Letrozole Dose Modifications 
Recommended dose reductions and dose modification guidelines are provided in Table 17.


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5.5. Investigational Product Storage
The investigator, or an approved representative (eg, pharmacist) will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
See the IP manual for storage conditions of the product once reconstituted and/or diluted.
Storage conditions for each IP stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 


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Site systems must be capable of measuring and documenting (for example, via a log), at a
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable,
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides permission to use the investigational product. It will not be 
considered a protocol deviation if the sponsor approves the use of the investigational product
after the temperature excursion. Use of the investigational product prior to the sponsor
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. All investigational products will be 
accounted for using a drug accountability form/record.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by
Pfizer, and all destruction must be adequately documented.


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5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician. All concomitant treatments, blood products, as well as 
nondrug interventions received by patients from screening until the end of study visit will be 
recorded on the CRF.
Since the payload Aur0101/ PF-06380101 is primarily metabolized by CYP3A4, there is a 
potential that its metabolism may be altered in the presence of potent inhibitors or inducers of 
CYP3A4. Since Aur0101/ PF-06380101 is a substrate for the P-gp efflux transporter, there is 
a potential that its metabolism may be altered in the presence of potent inhibitors or inducers 
of P-gp.  As a result, co-administration of PF-06804103 and potent CYP3A/P-gp inhibitors 
and/or inducers, as listed in Appendix 6, is not recommended. Selection of an alternate 
concomitant medication with no or minimal enzyme/transporter inhibition and/or induction 
potential is recommended.
Palbociclib is primarily metabolized by CYP3A and sulfotransferase enzyme SULT2A1
(Section 4.2.1). Co-administration of palbociclib and potent CYP3A inhibitors and /or 
inducers as listed in Appendix 6 is not recommended. See palbociclib prescribing
information (http://labeling.pfizer.com/ShowLabeling.aspx?id=2191#section-7) or refer to 
palbociclib IB.
Any questions regarding administration of concomitant medications, including alternate 
concomitant medications, should be directed to the sponsor.
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not
permitted.
Palliative radiotherapy on study is permitted for the treatment of painful bone lesions 
provided the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In 
view of the current lack of data about the interaction of PF-06804103 with radiotherapy, 
PF-06804103 treatment should be interrupted during palliative radiotherapy, stopping 7 days 
before and resuming treatment after recovery to baseline.
5.7.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available ASCO Guidelines. 
5.7.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
Cycle 1, but they may be used to treat treatment emergent neutropenia as indicated by the 
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Erythropoietin may be used at the investigator’s discretion for the supportive treatment of
anemia. 
5.7.4. Anti-Diarrheal, Anti-Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is not permitted in the first cycle.
Primary prophylaxis in subsequent cycles is at the investigator’s discretion. The choice of 
the prophylactic drug as well as the duration of treatment is up to the investigator with 
sponsor approval assuming there is no known or expected drug-drug interaction and 
assuming the drug is not contraindicated (Section 5.7).
5.7.5. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not contraindicated
(Section 5.7).
5.7.6. Corticosteroids 
Chronic systemic corticosteroid use for palliative or supportive purposes is not permitted.
Acute emergency administration, topical applications, inhaled sprays, eye drops, or local 
injections of corticosteroids are allowed.
5.7.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and PF-06804103 as monotherapy or 
combination therapy required to minimize the risk of impaired wound healing and bleeding 
has not been determined.  Stopping PF-06804103 as monotherapy or combination therapy is 
recommended at least 7 days prior to surgery. Postoperatively, the decision to reinitiate 
PF-06804103 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES
6.1. Screening
For screening procedures refer to Table 1 and Table 2 (monotherapy and combination 
therapy, respectively) and Section 7.
6.2. Study Period
For treatment period procedures, refer to Table 1 and Table 2 (monotherapy and combination 
therapy, respectively) and Section 7.
6.3. Follow-up Period
Refer to Table 1 and Table 2 (monotherapy and combination therapy, respectively) and 
Section 7.


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6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety 
(Section 8.1.3) or behavioral reasons, or the inability of the patient to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site. 


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Reasons for withdrawal of study treatment may include:

objective disease progression; 

global deterioration of health status requiring discontinuation;

unacceptable toxicity;

pregnancy;

significant protocol violation;

lost to follow-up;

patient refused further treatment;

study terminated by sponsor;

death.
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.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record. In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal and document the reason provided in the patient’s medical
record, request that the patient return for a final visit, if applicable, and follow-up with the 
patient regarding any unresolved AEs (if applicable).
If the patient refuses further visits, no further study-specific evaluations should be performed 
and no additional data should be collected.  The investigator should inquire about the reason 
and document the date and method in which the site was notified in the patient’s medical 
record and in the clinical database. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.


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Withdrawal of consent:
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information. 
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from
further receipt of investigational product or also from study procedures and/or post treatment
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter. All attempts should be documented in the patient’s medical records. If it is
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain
updated contact information. If, after all attempts, the patient remains lost to follow-up, then
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
6.4.1. Request to Continue Treatment
If the investigator feels the patient is still deriving benefit from treatment, then in discussion 
with the sponsor may elect treatment for the patient at the same dose or one dose lower until
such benefit no longer exists.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 


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he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment
instructions and contact information will be provided to the investigator site prior to initiation
of the study.
7.1. Safety Assessments
Safety assessments will include collection of, AEs, SAEs, vital signs and PE, 12-lead ECG, 
ophthalmic examinations, ECHO/MUGA, DLco evaluation, and laboratory assessments
(including pregnancy tests and verification of concomitant treatments).
7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  For female patients of 
childbearing potential, 2 negative pregnancy tests are required before receiving PF-06804103
(1 negative pregnancy test at screening and 1 at the baseline visit immediately before 
PF-06804103 administration).  Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced, and a second negative pregnancy test result 
will then be required at the baseline visit before the patient may receive the study treatment.  
Pregnancy tests will also be repeated at every treatment cycle during the active treatment
period, at the end of study treatment period and follow-up visit to confirm that the patient has 
not become pregnant during the study.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period and when potential pregnancy 
is otherwise suspected, and may be repeated if requested by IRBs) or EC or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the administration of IP will 
be discontinued.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
version 4.03) timing, seriousness, and relatedness.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry samples will be drawn at the time points described in 
Table 1 (Monotherapy Dose Escalation and Expansion) and Table 2 (Combination Regimen 
Dose Escalation and Expansion) and analyzed at local laboratories.


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Table 9.
Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy 
Test
Unique 
Screening 
Labs
Hemoglobin
ALT
PT or INR
Urine dipstick for 
urine protein: If 
positive collect 
24-hr and 
microscopic 
(Reflex Testing)
For female 
patients of
childbearing 
potential,
serum or urine 
Hepatitis B
surface
antigen
Platelets
AST
WBC
Alk Phos
Absolute 
Neutrophils
Sodium
Hepatitis B core 
antibody
Absolute 
Lymphocytes
Potassium
Hepatitis C
antibody
Absolute Monocytes
Magnesium
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic 
(Reflex Testing)
HIV
Absolute 
Eosinophils
Chloride
FSH – for
post-menopausal
women
Absolute Basophils
Total calcium
Total bilirubin***
BUN or Urea
Estradiol – for 
postmenopausal 
women
Creatinine
Uric Acid
Glucose 
(nonfasted)
Bicarbonate or CO2
Albumin
Phosphorus or 
Phosphate
Amylase
Lipase
*** For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, 
prothrombin time (PT)/INR, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein 
adduct levels.
7.1.4. Vital Signs and Physical Examination
Patients will have a PE to include weight, vital signs, assessment of ECOG performance 
status and height; height will be measured at screening only.
A complete PE will be performed at Screening and at the EOT visit for each patient and will 
include an assessment of all body systems (including neurological examination, 
genitourinary examination is optional).  Findings of all PEs 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 AE in the CRF.
Abbreviated PEs should be performed as described in Table 1 (Monotherapy Dose Escalation 
and Expansion) and Table 2 (Combination Regimen Dose Escalation and Expansion), and on
an as needed basis for assessment of AEs.  Abbreviated exams should be targeted to specific 
symptoms or complaints and be consistent with local standard of care.
Vital signs will include measurements of temperature, blood pressure (BP) and pulse rate to 
be recorded in the supine or seated position and pulse oximetry. On dosing days, BP and PR 
should be measured prior to administration of the investigational product (pre-dose) and 


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approximately 1 hour after the start of the infusion (ie, just prior to the end of the infusion).  
For BP assessment, the same arm (preferably the dominant arm) should preferably be used 
throughout the trial.  A blood pressure cuff, which has been properly sized and calibrated, 
should be used to measure BP. The use of automated devices for measuring BP is 
acceptable.
Pulse oximetry should preferably be collected prior to the collection of BP and PR.  Oxygen 
levels should be evaluated on the finger in accordance with the sites standard procedures. A 
single reading should be collected. 
7.1.5. Twelve-Lead Electrocardiogram
Triplicate 12-lead ECGs (with a 10-second rhythm strip) tracing will be recorded for all 
patients at each time point described in Table 1 (Monotherapy Dose Escalation and 
Expansion) and Table 2 (Combination Regimen Dose Escalation and Expansion).  It is
preferable that the machine used has a capacity to calculate the standard intervals
automatically. Three consecutive ECGs will be performed at approximately 2 minutes apart 
to determine the mean QTcF interval (all 3 consecutive ECGs should be performed within a 
10-minute timeframe).  If the mean QTcF is prolonged (>500 msec, ie, CTCAE Grade 3), 
then the ECGs should be re-evaluated by a qualified person at the institution for confirmation 
as soon as the finding is made, including verification that the machine reading is accurate. If 
manual reading verifies a QTcF of >500 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the
potential to prolong the QTcF interval) should be performed.  In addition, repeat ECGs 
should be immediately performed hourly for at least 3 hours until the QTcF interval falls
below 500 msec.  If QTcF interval reverts to less than 500 msec, and in the judgment of the 
investigator(s) and sponsor is determined to be due to cause(s) other than investigational 
product, treatment may be continued with regular ECG monitoring.  If in that timeframe the 
QTcF intervals rise above 500 msec the investigational product will be held until the QTcF 
interval decreases to 500 msec.  Patients will then restart the investigational product at the 
next lowest dose level. If the QTcF interval has still not decreased to 500 msec after 
3 weeks, or if at any time a patient has a QTcF interval >515 msec or becomes symptomatic, 
the patient will be removed from the study.  Additional triplicate ECGs may be performed as
clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte
disturbance) and possible evaluation by specialist.
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event.
When ECGs coincide with PK sampling, the ECG should be recorded before PK samples are 
obtained to allow for collection of the PK at the nominal time. 


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7.1.6. Echocardiogram or Multigated Acquisition Scan
ECHO or MUGA scans to measure cardiac function will be completed at the times specified 
in Table 1 (Monotherapy Dose Escalation and Expansion) and Table 2 (Combination
Regimen Dose Escalation and Expansion).  The same modality used at screening should 
preferably be used for all subsequent timepoints.
7.1.7. Diffusing Capacity of the Lungs for Carbon Dioxide (DLco)
DLco evaluation will be completed as part of screening procedures using a DLco simulator 
device and following the site’s standard procedures.  The DLco percent of predicted value 
obtained at screening will be assessed for eligibility (patients with a decrease of more than 
25% compared to the normal DLco range of 75% to 125% are excluded – Part 1A only). In 
addition, while the patient is on study, measurement in units of mL/min/mm Hg is required in 
order to grade toxicity by CTCAE version 4.03 which is necessary for potential dose 
modifications for toxicity per Appendix 7.
Results should be used in conjunction with the chest CT scans for evaluation of potential 
pulmonary toxicity.
7.1.8. Ophthalmic Examination
An eye exam, to be performed by an ophthalmologist, will be required at screening.  The eye 
exam is to include Best Corrected Visual Activity (BCVA), Intraocular Pressure (IOP) 
preferably by Goldmann applanation, Biomicroscopic exam (also called slit lamp exam) to 
evaluate the Lids/Lashes/Adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, lens, 
and Dilate fundus exam to evaluate the optic nerve, the vessels, the macula, and the 
peripheral retina.  Further ophthalmic examinations should be guided by specific ocular signs 
and symptoms should they occur during treatment and follow-up.
7.2. Pharmacokinetics Assessments
Blood samples will be collected from patients for analysis as described in Table 3
(Monotherapy) and Table 4 (Combination Regimen).  All efforts should be made to obtain
the PK samples at the scheduled nominal time. However, samples obtained within the
protocol specified time window will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).  If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample time may be re-scheduled with agreement of clinical investigators, patient and 
sponsor.  PK samples will be assayed using validated analytical methods in compliance with
Pfizer standard operating procedures.  Details regarding the collection, processing, storage, 
and shipping of the blood samples will be provided in the Study Manual.
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 


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integrity has been compromised.  Any deviation from the specified sample handling
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
metabolite scouting/identification and/or evaluation of the bioanalytical method, 
 
  These data will not be included in the CSR.
7.2.1. Serum Sample Collection for PK Analysis of PF-06804103 ADC, Total Antibody
and Unconjugated Payload (PF-06380101)
Blood samples (approximately 4 mL) for measurement of serum PF-06380101
concentrations and blood samples (approximately 4 mL) for determination of PF-06804103 
ADC and total antibody concentrations will be collected from patients in appropriately
labeled tubes as described in Table 3 (Monotherapy) and Table 4 (Combination Regimen). 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs and the date and time of 
blood sample collection and of last dosing prior to PK collection should be documented on
the CRF.
7.3. Immunogenicity Assessments
Blood samples (6 mL) to provide approximately 3 mL of serum to detect ADA and 
neutralizing antibody (Nab) against PF-06804103 will be collected into appropriately labeled 
tubes as described in Table 3 (Monotherapy) and Table 4 (Combination Regimen).  Details 
regarding the collection, processing, storage and shipping of the blood samples will be 
provided in the Study Manual.
Samples will be assayed using validated analytical methods in compliance with Pfizer 
standard operating procedures.  The ADA sample analysis will follow a tiered approach of 
screening, confirming and titer determination.  Samples tested positive for ADA may also be 
characterized for Nab.
7.4. Biomarker/Pharmacodynamic Assessments
One of the key elements of this study is the possibility to evaluate potential molecular targets 
that could be modified in vivo by the drug used in this study.  The biomarker studies will be 
used to confirm the MOA, elucidate the PD effects that could support the RP2D, and provide 
a rationale for combination therapies.  The studies may help in the future development of 
PF-06804103 as monotherapy, or in combination with other compounds.
Table 10 summarizes representative assays to be used and the source of the samples.  
Samples will be collected as described in Table 3 (Monotherapy) and Table 4 (Combination 
Regimen). Refer to the Study Manual for details about sample preparation.
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Table 10.
Pharmacodynamic Summary
Assay
Source
 
 
Assessment of HER2 expression 
 
 by IHC and ISH
tumor tissue
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.4.5. Tumor Biopsies
7.4.5.1. Collection of Biopsy Samples – Part 1
Patient enrollment will be based on prior testing for HER2 positivity by an FDA approved, or 
locally validated, diagnostic test.  Fresh pre-treatment (screening) and Day 1 Cycle 3 
(±5 days) biopsy collections are optional. Archival tissue from a prior biopsy will be 
collected for central evaluation if available.
If collected, the pre-treatment biopsy should be completed after all eligibility criteria have 
been verified and should be taken from the same lesion, not previously irradiated,
Bone biopsies, cytological specimens and fine-needle aspiration samples are excluded.  
 
7.4.5.2. Collection of Biopsy Samples -  Part 2
A mandatory fresh pre-treatment, diagnostic quality biopsy, representative of the diagnosed 
malignancy, will be collected at screening for all patients 
 
 to retrospectively confirm HER2 expression.  
 
 
 
  
 
 
An archival sample collected prior to study start may be substituted for the mandatory 
pre-treatment biopsy if no prior anti-HER2 treatment between the collection of this tumor
sample and study start had been administered. If performed, the pre-treatment biopsy should
be obtained after all the eligibility criteria have been verified.  The mandatory pre-treatment 
 should preferably be taken from the same lesion, which 
has not been previously irradiated
Bone biopsies, cytological specimens and fine-needle aspiration samples are excluded. 
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7.5. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites. Imaging may include 
chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan for patients with known 
or suspected brain metastases; bone scan and/or bone X-rays for patients with known or 
suspected bone metastases.  At a minimum, the chest CT scan must be a high-resolution scan 
with 1 mm slice thickness.
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 described in Table 3 (Monotherapy) and Table 4 (Combination 
Regimen), 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 (Appendix 4).
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All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial SAE Report Form to Pfizer Safety.  These
requirements are delineated for 3 types of events: (1) SAEs; (2) non-serious AEs; and (3) 
exposure to the investigational product under study during pregnancy or breastfeeding, and
occupational exposure. 
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Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether
associated with an AE), 
except occupational 
exposure
Exposure during
pregnancy, exposure via
breastfeeding, 
occupational exposure 
(regardless of whether
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the Clinical Trial 
SAE Report Form within 24 hours of awareness of the event by the investigator are to be 
reported regardless of whether the event is determined by the investigator to be related 
to an investigational product under study. In particular, if the SAE is fatal or 
life-threatening, notification to Pfizer Safety must be made immediately, irrespective of the 
extent of available event information.  This time frame also applies to additional new 
(follow-up) information on previously forwarded reports.  In the rare situation that the
investigator does not become immediately aware of the occurrence of an event, the 
investigator must report the event within 24 hours after learning of it and document the time
of his/her first awareness of the event.
For each event, the investigator must pursue and obtain adequate information both to
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(Section 8.2.3).  In addition, the investigator may be requested by Pfizer Safety to obtain 
specific follow-up information in an expedited fashion. This information is more detailed 
than that recorded on the CRF.  In general, this will include a description of the event in 
sufficient detail to allow for a complete medical assessment of the case and independent
determination of possible causality.  Any information relevant to the event, such as
concomitant medications and illnesses, must be provided.  In the case of a patient death, a
summary of available autopsy findings must be submitted as soon as possible to Pfizer 
Safety.  Any pertinent additional information must be reported on the Clinical Trial SAE
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to
be sent to Pfizer Safety ONLY upon request.


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF. It
should be noted that the Clinical Trial SAE Report Form for reporting of SAE information is 
not the same as the AE page of the CRF.  When the same data are collected, the forms must 
be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient/legally acceptable representative.  In addition, each study
patient/ legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes,
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with
Section 8.1.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a
minimum of 28 calendar days; except as indicated below after the last administration of the
investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. SAE Reporting
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the Clinical Trial SAE Report Form.


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SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable
possibility that the investigational product caused or contributed to an AE; generally the facts
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures,
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the Clinical Trial SAE Report Form and 
in accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions will be carried out in 
accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to:

abnormal test findings;

clinically significant signs and symptoms;

changes in physical examination findings;

hypersensitivity;

drug abuse;

drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

drug overdose;

drug withdrawal;

drug misuse; 

drug interactions;

extravasation;

exposure during pregnancy;

exposure via breastfeeding;

medication error;

occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.


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8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

test result is associated with accompanying symptoms; and/or

test result requires additional diagnostic testing or medical/surgical intervention;
and/or

test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

results in death;

is life-threatening (immediate risk of death);

requires inpatient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

results in congenital anomaly/birth defect.
Or that is considered to be:

an important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection
period. Hospitalization due to signs and symptoms of disease progression should not be
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with CTCAE Grade 5 (Section 8.3).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

rehabilitation facilities;

hospice facilities;

respite care (eg, caregiver relief);

skilled nursing facilities;

nursing homes;

same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

social admission (eg, patient has no place to sleep);

administrative admission (eg, for yearly physical examination);

protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

hospitalization for observation without a medical AE;


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
preplanned treatments or surgical procedures.  These should be noted in the baseline
documentation for the entire protocol and/or for the individual patient;

admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was
performed should be reported if it meets the definition of an SAE. For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD AE
2
MODERATE AE
3
SEVERE AE
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED to AE
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed tolerators, while those who show transient liver injury, but adapt 
are termed adaptors.  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are susceptible to
progressive and serious liver injury, commonly referred to as DILI.  Patients who experience 
a transaminase elevation above 3 × ULN should be monitored more frequently to determine
if they are an adaptor or are susceptible.
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin 
elevations (>2 × ULN) by several days or weeks. The increase in total bilirubin typically
occurs while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and total bilirubin 
values will be elevated within the same lab sample). In rare instances, by the time total 
bilirubin elevations are detected, AST/ALT values might have decreased.  This occurrence is 


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still regarded as a potential DILI.  Therefore, abnormal elevations in either AST OR ALT in 
addition to total bilirubin that meet the criteria outlined below are considered potential DILI 
(assessed per Hy’s law criteria) cases and should always be considered important medical 
events, even before all other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and total bilirubin baseline values within the normal range
who subsequently present with AST OR ALT values >3 × ULN AND a total bilirubin 
value >2 × ULN with no evidence of hemolysis and an ALP value <2 × ULN or not 
available;

For patients with baseline AST OR ALT OR total bilirubin values above the ULN, 
the following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

Preexisting values of total bilirubin above the normal range: total bilirubin 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 total bilirubin separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and total bilirubin, laboratory tests
should include albumin, CK, direct and indirect bilirubin, GGT, PT/ INR, total bile acids, 
alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  Consideration
should also be given to drawing a separate tube of clotted blood and an anticoagulated tube 
of blood for further testing, as needed, for further contemporaneous analyses at the time of 
the recognized initial abnormalities to determine etiology.  A detailed history, including
relevant information, such as review of ethanol, acetaminophen (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  


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Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and
total bilirubin elevation defined above should be considered potential DILI (Hy’s law) cases 
if no other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s 
law) cases are to be reported as SAEs, irrespective of availability of all the results of the
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure. The 
information submitted should include the anticipated date of delivery (see below for 
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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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
Clinical Trial SAE Report Form.  An exposure during breastfeeding report is not created 
when a Pfizer drug specifically approved for use in breastfeeding women (eg, vitamins) is 
administered in accord with authorized use.  However, if the infant experiences an SAE 
associated with such a drug’s administration, the SAE is reported together with the exposure 
during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
medication errors 
all (regardless of whether 
associated with an AE)
only if associated with an 
SAE
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Clinical Trial
SAE Report Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 


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maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Analysis Sets 
•
The safety analysis set includes all enrolled patients who receive at least one dose of 
study treatment.
•
The full analysis set includes all enrolled patients.
•
The PP Analysis Set (evaluable for MTD) includes all enrolled patients who receive at 
least 1 dose of study treatment and have no major treatment deviations 
(Section 3.2)during the DLT observation period (eg, first cycle).  
•
The mITT is the analysis population that will follow the ITT principle and includes all
patients who receive 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.
•
The Response Evaluable Population includes all participants who received at least 1 dose 
of study treatment and had a baseline disease assessment and at least one post baseline 
disease assessment.
•
The PK Parameter Analysis Population is defined as patients who receive at least 1 dose 
of study treatment, have at least 1 of the PK parameters of interest and who have no
major protocol deviations influencing the PK assessment.
•
The Immunogenicity Analysis Set includes all patients who receive at least 1 dose of 
study treatment and have at least 1 ADA sample collected.
 
 
9.2. Statistical Methods and Properties
This study has been designed to establish the MTD defined as the dose that yields 
approximately 27.5% probability of DLT and considers equivalent doses that yield
probability of DLT in the interval (equivalence interval) 22.5% to 32.5%.  The 27.5% target 
was chosen based on safety considerations and is considered appropriate based on 
simulations and expert input. The prior distribution of DLT is set as a beta (0.5,0.5) and the
threshold probability for early termination and dose exclusion is set to 0.95 as suggested in 
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the original mTPI method (Ji et al., 2010).12  Similarly, doses with an incidence of 
DLT>32.5% (eg, 4 out of 10) cannot be selected as MTD.
The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of three dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target rate (pT = 0.275).  If the 
toxicity rate of the currently used dose level is far smaller than pT, the mTPI will recommend 
escalating the dose level; if it is close to pT, the mTPI will recommend continuing at the
current dose; if it is far greater than pT, the mTPI will recommend de-escalating the dose 
level.  These rules are conceptually similar to those used by the 3+3 design, except the
decisions of an mTPI design are based on posterior probabilities calculated under a coherent 
probability model.  Being a model-based design, mTPI automatically and appropriately 
tailors dose-escalation and de-escalation decisions for different trials with different toxicity 
parameters.  More importantly, all the dose-escalation decisions for a given trial can be 
pre-calculated under the mTPI design and presented in a two-way table.  The decision rules 
to dose escalate (E), no change in dose (S), dose de-escalate (D) or dose de-escalate, 
unacceptable toxicity (U).
Patients could receive doses already tested but a dose that is associated with decision “Dose 
de-escalate, unacceptable toxicity” cannot be revisited and no additional patients should be
treated at this dose or higher doses for the remainder of the trial.
The maximum sample size for Part 1 will depend on the underlying dose toxicity profile and 
variability in actual data realization as described in Section 9.3.
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the true Probability (DLT) is fairly low.  This could result in the 
estimated posterior DLT rate to exceed the targeted 27.5% very early in the trial, triggering 
an early stop when very few patients (2-4) have been treated. 
The following table shows the probability of escalating to the next dose level for a range of 
underlying true DLT rates.  For example, for a cohort size of n=3 and for a DLT that occurs 
in 10% of patients, there is a greater than 90% probability of escalating.  Conversely, for a 
DLT that occurs with a rate of 70%, the probability of escalating is 3%.  It is assumed that
dose escalation occurs with either 0/3 or 1/6 patients with DLTs.


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Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
9.3. Sample Size Determination
This first in patient study is divided in to 2 parts (Section 3.1). Approximately 148 patients 
are anticipated to be enrolled overall.
Part 1
Patients in Part 1A will participate in dose escalation to determine the Part 2A monotherapy
dose level of PF-06804103.  
Patients in Part 1B will participate in escalating doses of PF-06804103 administered Q2W in 
combination with palbociclib and letrozole to determine the Part 2B combination dose level.
The actual number of patients enrolled in Part 1 B will depend upon tolerability and the 
number of dose levels required to identify the MTD of PF-06804103 administered as part of 
the combination regimen.
 
 
 
 
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9.4. Efficacy Analysis
Tumor response will be presented in the form of patient data listings that include, but are not
limited to, tumor type, starting dose, tumor response at each visit, and best overall response.  
In addition, 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 Appendix 4.
9.5. Analysis of Pharmacokinetics and Pharmacodynamics
9.5.1. Analysis of Pharmacokinetics
Drug concentrations of PF-06804103 ADC, total antibody and unconjugated payload 
(PF-06380101) will be measured using validated methods. PK parameters will be 
determined from the respective concentration-time data using standard non-compartmental 
methods.  Actual sample collection times will be used for the parameter calculations.  For 
PF-06804103 ADC and total antibody, PK parameters including Cmax, Tmax, AUClast, AUCτ , 
and if data permit or if considered appropriate, AUCinf, t½, CL, Vss, and Rac will be estimated.  
For unconjugated payload (PF-06380101), PK parameters including Cmax, Tmax, AUClast, 
AUCτ, AUCinf, t½, and Rac will be calculated as appropriate.
Drug concentrations of PF-06804103 ADC, total antibody and unconjugated payload 
(PF-06380101) will be summarized graphically and with descriptive statistics by dose, cycle, 
and the nominal PK sampling time.  Non-compartmental PK parameters will be summarized 
descriptively by dose and cycle. 
9.5.2. Pharmacokinetic
 Modeling
PK, efficacy, biomarker, and safety data from both Part 1 and Part 2 may be pooled for 
PK/
analyses using appropriate modeling to explore any association between 
PF-06804103, total antibody and/or payload exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
9.5.3. Analysis of Biomarkers
For biopsy samples, summary statistics (eg, the mean and standard deviation, median, and 
minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.
 
 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
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approach will examine correlations of biomarker results with PK parameters and measures of 
anti-tumor efficacy.
The percentage change from baseline for biomarkers over the period of the study will be 
tabulated by individual.  The mean change from baseline values over time per cohort will 
also be tabulated.  Data will be presented in tabular and/or graphical format and summarized 
descriptively. 
 
 
 
9.5.4. Analysis of Immunogenicity Data
For the immunogenicity data, the percentage of patients with positive ADA and Nab each 
will be summarized by dose level or by treatment.  For patients with positive ADA or Nab, 
the magnitude (titer), time of onset, and duration of ADA or Nab response will also be 
described, if data permit.
Potential impact of immunogenicity on PK, clinical responses, and safety/tolerability may be 
explored, if data warranted.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
9.6.1. Analysis of the Primary Endpoint
DLT is the primary endpoint of the dose escalation component of the study.  The occurrence 
of DLTs observed in the dosing cohorts is used to estimate the MTD as described in 
Section 3.  AEs constituting DLTs will be listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the MedDRA.  The focus of AE summaries will be on treatment-emergent AEs, those 
with initial onset or increasing in severity after the first dose of study treatment. The number 
and percentage of patients who experienced any AE, SAE, treatment related AE, and 
treatment related SAE will be summarized according to worst toxicity grades.  The 
summaries will present AEs both on the entire study period and by cycle (Cycle 1 and Cycles 
beyond 1). 
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
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analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the distribution of 
laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
9.6.3. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline, 
defined as the assessment at either Cycle 1 Day 1 or screening, whichever is closer to the first 
dose, and on-treatment ECG data.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates. Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Frederica’s).  Data will be summarized and listed for QT, heart rate , RR interval, PR
interval, QRS, QTcF, and by dose.  Individual QT (all evaluated corrections) intervals will be 
listed by time and dose.  The most appropriate correction factor will be selected and used for 
the following analyses of central tendency and outliers and used for the study conclusions.  
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment by dose and time point.  For each patient and by treatment, the maximum 
change from baseline will be calculated as well as the maximum post-baseline interval across 
time-points.  Categorical analysis will be conducted for the maximum change from baseline 
in corrected QT and the maximum post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may
be pooled with other study results and/or explored further with PK
 models.
9.7. Data Monitoring Committee 
Not applicable.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that
the protocol and GCP are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
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allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician's chart.  In these cases,
data collected on the CRFs must match the data in those charts.
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients. The investigator
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed. The investigator 
will retain the original of each patient's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the EU is defined as the time at which it is deemed that a 
sufficient number of patients have been recruited and completed the study as stated in the
regulatory application (ie, CTA) and ethics application in the Member State.  Poor 
recruitment (recruiting less than the anticipated number in the CTA) by a Member State is 
not a reason for premature termination but is considered a normal conclusion to the study in
that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. In addition, Pfizer retains the right to discontinue development of 
PF-06804103 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within a time period set by Pfizer.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 


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


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


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MonarcHER PhII (ESMO 2019 Congress), available upon request


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Appendix 1. Abbreviations
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
1L
first-line
2L
second-line
3L
third-line
ADA
anti-drug antibodies
ADC
antibody-drug conjugate 
AE
adverse event
AI
aromatase inhibitors
AIDS
Acquired Immune Deficiency Syndrome
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphotase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the concentration-time curve from time 0 
extrapolated to infinity time
AUClast
area under the concentration-time curve from time 0 to the last 
measurable concentration
AUCτ
area under the concentration-time curve during the dosing 
interval
BC
Breast cancer
BCVA
Best Corrected Visual Acuity
BP
blood pressure
BUN
blood urea nitrogen
C
Cycle
C1D1
cycle 1 day 1
Cav
Steady state
CBC
Complete blood count
CD
Cluster of differentiation
CDK
cyclin-dependent kinase
CEP17
Chromosome enumeration probe 17
CHF
congestive heart failure
CISH
Chromogenic in situ hybridization
CLIA
Clinical Laboratory Improvement Amendments
CK
creatine kinase
CCI
CCI


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CL
clearance
Cmax
maximum concentration
CNS
central nervous sytem
Cmax
maximum concentration
CNS
central nervous system
CRF
case report form
CSA
Clinical supply agreement
CSR
Clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
Cytochrome P450 3A4
DDI
drug-drug-interaction
DILI
Drug induced liver injury
DISH
Dual in situ hybridization
DLco
diffusing capacity of the lungs for carbon monoxide
DLT
dose-limiting toxicity
DM1
maytansinoid emtansine
DR
duration of response
DS
Daiichi Sankyo
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
eg
for example
EGFR
Epidermal growth factor receptor
EOT
end of treatment
ER
estrogen receptor
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FFPE
formalin-fixed paraffin-embedded
FISH
Fluorescence in situ hybridization
FSH
follicle-stimulating hormone
FU
fluorouracil
GC
gastric and gastoeosphageal cancer
GCP
Good Clinical Practice
GCLP
Good Clinical Laboratory Practices
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBV
Hepatitis B virus
CCI
CCI


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HCV
hepatitis C virus
hERG
human ether-a-go-go related gene
HER2
Human Epidermal Growth Factor Receptor 2
HNSTD
highest non-severely toxic dose
HR
hormone receptor
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
Identification code
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IOP
intraocular pressure
IP manual
Investigational Product manual
IRB
Institutional Review Board
ISH
in-situ hybridization
ITT
Intent-To-Ttreat
IUD
intrauterine device
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
mTPI
modified toxicity probability interval
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mITT
Modified Intent-To-Treat
MOA
mechanism of action
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NA
not applicable
Nab
Neutralizing antibody
NCI 
National Cancer Institute 
NSCLC
non-small cell lung cancer
NGS
Next-Generation sequencing
OR
Objective Response
ORR
Overall Response Rate
PCD
primary completion date
PD-1
programmed cell death-protein 1
PD-L1
programmed death-ligand 1
CCI
CCI


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PE
physical exam
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic
PO
per oral
PR
Partial Response
PR
pulse rate
pT
target probability
PT
prothrombin time
QD
daily
QW
once weekly
Q3W
Once every three weeks
QT
time between the start of the Q wave and the end of the T wave
Rac
accumulation ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
SD
single dose
SOA
schedule of activities
SOC
standard of care
SRSD
single reference safety document
t1/2
terminal elimination half-life
Tbili
total bilirubin
T-DMI
Ado-trastuzumab emtansine
TKI
Tyrosine kinase inhibitor
Tmax
time to maximum concentration
TTP
Time to progression
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady state
WBC
white blood cell 
CCI
CCI


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Appendix 2. ECOG Performance Status
Grade
ECOG Performance Status
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.


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Appendix 3. HER2/IHC Status Descriptions
HER2 IHC 3+ defined 
as:

BC: circumferential membrane staining that is complete,
intense and in 10% of tumor cells.

GC (Part 1A only): surgical specimen: strong, 
complete/basolateral or lateral membranous reactivity in 10% 
of cells.

GC (Part 1A only): biopsy specimen: tumor cell cluster (5 
tumor cells) with strong, complete basolateral or lateral 
membranous activity irrespective of percentage of tumor cells 
stained.
HER2 IHC 2+ defined 
as:

BC: weak to moderate complete membrane staining observed 
in 10% of tumor cells.

GC (Part 1A only): surgical specimen: weak to moderate
complete basolateral or lateral membranous reactivity in 10% 
of cells.

GC (Part 1A only): biopsy specimen: tumor cell cluster with 
weak to moderate, complete basolateral or lateral membranous 
activity irrespective of percentage of tumor cells stained.
HER2 IHC 1+ defined
as:

BC: incomplete membrane staining that is faint/barely 
perceptible and in >10% of tumor cells.

GC (Part 1A only): surgical specimen: faint/barely perceptible 
membranous reactivity in ≥10% of tumor cells; cells reactive 
only in part of their membrane

GC (Part 1A only): biopsy specimen: tumor cell cluster with 
faint or barely membranous reactivity irrespective of tumor
cells stained
HER2 IHC 0 defined as: 
BC: no staining is observed OR membrane staining that is 
incomplete and is faint/barely perceptible in ≤10% of tumor 
cells.

GC (Part 1A only): surgical specimen – no reactivity to 
membranous reactivity in ≤10% of tumor cells.

GC (Part 1A only): biopsy specimen – no reactivity in any 
tumor cells.


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Gene amplification by 
ISH defined as:

single probe: average HER2 copy number 6.0 signals/cell; OR

single probe: average HER2 copy number 4.0 and <6.0 
signals/cell and concurrent IHC 3-positive and/or concurrent 
dual-probe ISH Group 1.  

dual probe: HER2/chromosome enumeration probe 17 (CEP17) 
with a ratio 2.0 with an average HER2 copy number >4.0 
signals/cell (Group 1).  

<4.0 signals/cell (Group 2) and IHC 3-positive.

dual probe HER2/CEP17 ratio <2.0.  

average HER2 copy number >6.0 signals/cell (Group 3) 
requires additional work-up (IHC 3-positive, or IHC2-positive
and recount of ISH with observer blinded to previous results, 
counting at least 20 cells, shows a HER2/CEP17 Ratio <2.0 and 
an average HER2 signals/cell >6.0).

average HER2 copy number 4.0 and <6.0 signals/cell (Group 4) 
and IHC 3-positive.


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Appendix 4. RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1 
Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
Categorizing Lesions at Baseline
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable Disease 
Non-measurable disease includes lesions too small to be considered measurable (including
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion patientive to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal Sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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


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Target Disease

Complete Response (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 Progressive Disease (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. 

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. 


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
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed, or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 11.
Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New
Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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Table 12.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Appendix 5. Management of Infusion Related Reactions Including Allergic Reactions, 
Cytokine Release Syndrome or Anaphylaxis
In the event of infusion related reactions, investigators should institute treatment measures 
according to best medical and nursing practice.
The following treatment guidelines should be employed:
If chills and fever occur, the infusion should be interrupted.  Patients may be treated 
symptomatically and the infusion should be restarted at 50% of the original rate.
NCI-CTCAE Grade 1 allergic reaction or cytokine release syndrome

Monitor for worsening condition. If the reaction worsens, stop the infusion.  Institute
premedication for subsequent infusions as per Section 5.4. 
NCI-CTCAE Grade 2 allergic reaction or cytokine release syndrome

Stop PF-06804103 infusion.

Administer bronchodilators, oxygen, acetaminophen, and others as medically 
indicated.

Resume infusion at 50% of previous rate once reaction has decreased to Grade 1 in 
severity.  Monitor closely for any worsening including respiratory status. If the 
reaction recurs, stop infusion.  Institute premedication for subsequent infusions as per 
Section 5.4.
NCI-CTCAE Grade 3 or Grade 4 allergic reaction or cytokine release syndrome or 
anaphylaxis

A Grade 3 anaphylaxis (hypersensitivity reaction) consists of symptomatic 
bronchospasm requiring parenteral medications with or without urticaria, 
allergy-related edema/angioedema, or hypotension.

A Grade 4 anaphylaxis (hypersensitivity reaction) is a life-threatening event requiring 
urgent intervention.
Treatment of Grade 3 or Grade 4 allergic reaction, cytokine release syndrome or 
anaphylaxis

Stop the PF-06804103 infusion immediately and disconnect infusion tubing from the 
patient.

Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, and others as medically indicated.


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
Monitor closely respiratory and cardiovascular status, be prepared for potential need 
for intubation.

Telephone sponsor or designated representative to report an SAE as per Section 7.1.2.

For an NCI-CTCAE Grade 3 or 4 hypersensitivity reaction, study treatment will be 
discontinued.
Re-treatment following Grade 1 or Grade 2 allergic reactions or cytokine release 
syndrome

Once the PF-06804103 infusion rate has been decreased due to an allergic reaction or 
cytokine release syndrome, it will remain decreased for all subsequent infusions.

If the patient has a second reaction at the lower infusion rate, the infusion should be 
stopped and the patient should receive no further PF-06804103.

If the patient experiences a Grade 3 or 4 allergic reaction, cytokine release syndrome, 
or anaphylaxis at any time, the patient should receive no further PF-06804103.

If there are questions concerning whether an observed reaction is consistent with an 
allergic reaction, cytokine release syndrome, or anaphylaxis, the medical monitor 
should be contacted immediately to assist with grading the reaction.

PK, PD and ADA sampling should continue as long as the sampling does not
interfere with the medical treatment of the patient.


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Appendix 6. Potent CYP3A Inhibitors and Inducers
Potent CYP3A Inhibitors
P-gp Inhibitor
Non-P-gp Inhibitor
elvitegravir/ritonavir (RIT)
indinavir or indinavir/RIT
lopinavir/RIT
nelfinavir
ritonavir
saquinavir or saquinavir/RIT
tipranavir/RIT
danoprevir/RIT
telaprevir
itraconazole
ketoconazole
clarithromycin
mibefradil
conivaptan
voriconazole
nefazodone
cobicistat
boceprevir
posaconazole
telithromycin
troleandomycin
List of medications from fda.gov and University of Washington Drug Interaction Database.  
Potent CYP3A inhibitors are defined as those drugs that increase the AUC of oral 
midazolam or other CYP3A substrates 5-fold.
Potent CYP3A Inducers
St. John’s Wort
avasimibe
carbamazepine 
phenytoin
rifampin
List of medications from fda.gov. Potent CYP3A inducers are defined as those drugs that 
decrease the AUC of CYP3A substrates 80%.
As the list of CYP and/or P-gp inducers and inhibitors is a dynamic list continually changing 
when new information becomes available, use the following FDA website when deciding if a 
concomitant medication is considered a strong CYP3A/P-gp inhibitor and/or inducer: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm080499.htm.
Selection of an alternate concomitant medication with no or minimal enzyme inhibition 
and/or induction potential is recommended.


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Appendix 7. Dose Modification Guidelines
Table 13.
PF 06804103 Recommend Dose Reductions
PF-06804103 – Monotherapy
mg/kg, Q3W
PF-06804103 – Combination Regimen
mg/kg, Q2W
4
2.7
3
2.0
2
1.3
Table 14.
Dose Modifications for Toxicities Considered Possibly Related to 
PF-06804103
Toxicity
Action
Grade 3 non-hematologic (including 
persistent nausea, vomiting, diarrhea 
despite optimal medical therapy).

Hold PF-06804103 infusion until recovery to Grade
0-1 or baseline and reduce by 1 dose level.

Discontinue PF-06804103 if a dose delay of greater than 
1 cycle (3 or 4 weeks for monotherapy or combination
therapy, respectively)is required.

If toxicity reoccurs despite reduction, patient may be dose 
reduced again by another dose level upon recovery to 
Grade 0 to 1 or baseline unless the patient is in the first 
dose group. 

Prompt palliative measures are strongly encouraged 
(eg, anti-emetics). 
Grade 4 non-hematologic toxicity, 
including ejection fraction decrease or
persistent nausea, vomiting, diarrhea
despite optimal medical therapy.

Patients who experience Grade 4 non-hematologic 
toxicities despite intervention should be discontinued 
from treatment.
Grade 2/3 peripheral neuropathy,
myalgia/arthralgia and skin toxicity

Begin management with dose reduction (not dose 
delay)

Reduce by 1 dose level. 

If Grade 2/3 toxicities persist or reoccur despite 
reduction, patient may be sequentially dose reduced 
to the next lower dose level (see Table 5) unless 
current dose level is ≤ 2 mg/kg Q3W or ≤1.3 mg/kg 
Q2W.

Maximal allowed dose reductions should be followed 
before initiating dose delay. Dose delays during the 
first 6 (monotherapy) or 5 (combination regimen) 


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Table 14.
Dose Modifications for Toxicities Considered Possibly Related to 
PF-06804103
cycles are not recommended.

Discontinue PF-06804103 if a dose delay of greater than 
1 cycle (3 or 4 weeks for monotherapy or combination
therapy, respectively ) is required. Retreatment can be 
considered after discussion with the Sponsor if potential 
benefit outweighs risk
Grade 4 peripheral sensory neuropathy

Discontinue PF-06804103
Grade ≥3 peripheral motor neuropathy

Discontinue PF-06804103
Decrease in LVEF of 10% points from 
baseline for patients with LVEF from 
40% to 45%.

Hold PF-06804103 and repeat ECHO/MUGA in 14 or 21 
days (Q2W or Q3W, respectively) if absolute decline 
from baseline is 10% until recovery to Grade 2 or 
baseline.

At the discretion of the investigator, the dose may be 
resumed at the same dose level or reduced by 1 dose 
level.

If absolute decline from baseline is <10%, continue 
PF-06804103 and re-evaluate LVEF at the next cycle.

If toxicity recurs, clinically significant cardiac 
dysfunction or cardiac failure develops or persists, or if 
significant medical management is required to maintain
ejection fraction, discontinue PF-06804103.
Grade 3 left ventricular systolic 
dysfunction or drop of LVEF to below
40%.

Hold PF-06804103 and repeat ECHO/MUGA in 14 or
21 days (Q2W or Q3W, respectively) to confirm.

If confirmed, discontinue PF-06804103.  

If not confirmed, resume at the current dose or 
reduce by 1 dose level (at the discretion of the 
investigator) once recovered to Grade 2 or baseline.

Treat and monitor according to standard medical practice.
Grade 2 carbon monoxide diffusing 
capacity decreased.

Hold PF-06804103 until recovery to Grade 0 to 1 or 
baseline and reduce by 1 dose level.

Discontinue PF-06804103 if a dose delay greater than 1 
cycle (3 or 4 weeks for monotherapy or combination
therapy, respectively ) is required.

If toxicity reoccurs, discontinue PF-06804103.


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Table 14.
Dose Modifications for Toxicities Considered Possibly Related to 
PF-06804103
Grade 3 carbon monoxide diffusing 
capacity decreased.

Discontinue PF-06804103.
Grade 3 hepatic toxicity (including 
serum bilirubin, ALT, AST, alkaline 
phosphatase).

Hold PF-06804103 infusion until recovery to Grade 0 to 
1 or baseline and reduce by 1 dose level.

Discontinue PF-06804103 if a dose delay greater than 1 
cycle (3 or 4 weeks for monotherapy or combination
therapy, respectively ) is required. If toxicity reoccurs, the
dose may be reduced further by another dose level upon
recovery to grade 0 to 1 or baseline unless the patient is in
the first dose group.
ALT or AST 3.0 x ULN concurrent 
with elevation in bilirubin 2.0 x ULN.

Discontinue PF-06804103.
Hematologic toxicities:
Uncomplicated Grade 3 neutropenia 
(ANC<1000/mm3

If Grade 3 neutropenia is reported, a CBC should be 
repeated 1 week later. 

Palbociclib should be reduced to the lowest allowed dose
(i.e., 75 mg/day) per guidelines (Table 5) before initiating 
PF 06804103 dose modification.

Dose adjustments to PF-06804103 will only be initiated
upon fulfillment of palbociclib dose reduction as 
described above. 

Administration of PF-06804103 should be withheld and 
initiation of the next cycle delayed until recovery to 
Grade ≤2 (≥1000/mm3). 

No dose reductions to PF-06804103 are required for first
incidence. 

Recommended PF-06804103 dose level reductions are 
provided in Table 12. If toxicity reoccurs despite 
reduction, the patient may be dose reduced again by 
another dose level (Table 13) upon recovery to Grade 0 to 
1 or baseline unless the current dose is ≤2 mg/kg Q3W or 
1.3 mg Q2W).
Hematologic toxicities:

Grade 4 neutropenia, ie, ANC 
500/mm3
(0.5 x 109/L) for more than 
7 days. 

Febrile neutropenia, ie, fever 
with a single temp >38.3C or 
sustained temp 38C for more 

A CBC should be repeated no less than 1 week later.

Palbociclib should be reduced to the lowest allowed dose 
(i.e., 75 mg/day) per guidelines (Table 5) before 
initiating PF 06804103 dose modification .

Dose adjustments to PF-06804103 will only be initiated 
upon fulfillment of palbociclib dose reduction as 
described above.


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PFIZER CONFIDENTIAL
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Table 14.
Dose Modifications for Toxicities Considered Possibly Related to 
PF-06804103
than 1 hour with ANC 
<1000/mm3. 

Grade 4 Anemia.

Grade 3 Thrombocytopenia 
with bleeding. 
Grade 4 Thrombocytopenia, ie, platelets
25,000 mm3 (25.0 x 109/L).

Hold PF-06804103 until recovery of ANC to 1.0 x 109/L 
(1,000 cells/mm3), platelets 75 x 109/L 
(75,000 platelets/mm3) and hemoglobin to baseline.

Discontinue PF-06804103 if a dose delay of greater than 
1 cycle (3 or 4 weeks for monotherapy or combination
treatment, respectively) is needed.

If toxicity reoccurs despite dose reduction, dosing may be 
withheld until recovery and then continued at the same 
dose, or a further dose reduction by another dose level 
unless the current dose is <2 mg/kg Q3W or <1.3 mg/kg
Q2W.
Other grade 4 hematologic toxicity.

Hold PF-06804103 until recovery to Grade 0 to 1 or 
baseline and reduce PF-06804103 dose by 1 dose level.

Discontinue PF-06804103 if a dose delay of greater than 
1 cycle (3 or 4 weeks for monotherapy or combination
treatment, respectively) is needed.

If toxicity reoccurs despite dose reduction, dosing may be 
withheld until recovery and then continued at the same 
dose unless the current dose is <2 mg/kg Q3W or <1.3 
mg/kg Q2W.
No recovery of toxicities within 1 cycle 
(3 or 4 weeks for monotherapy or 
combination treatment, respectively) of 
scheduled PF-06804103 infusion.

Discontinue PF-06804103.


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Figure 2.
Algorithm for Continuation and Discontinuation of PF-06804103 Based on 
LVEF Assessments in Patients with LVEF ≥40% or 45%


6PF-06804103
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Page 134
Table 15.
Dose Modifications for Palbocicliba Related Toxicities
Hematologic Toxicitya
Grade 1 or Grade 2
Continue at same dose level.
Grade 3
Day 1 of cycle:
Consider repeating complete blood count monitoring 1 week later. 
Withhold palbociclib and initiate next cycle when recovery to Grade ≤2
(≥1000/mm3). No dose adjustment to palbociclib is required.
Day 15 of cycle:
If Grade 3, continue palbociclib at current dose to complete cycle and 
repeat CBC on Day 22.
Consider dose reduction in cases of prolonged (>1 week) recovery from 
Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of 
subsequent cycles.
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. 
Grade 3 ANC (<1000 to 
500/mm3) + Fever ≥38.5ºC 
and/or infection
Withhold palbociclib and initiate next cycle when recovery to Grade ≤2 
(≥1000/mm3). Resume at next lower dose.
Grade 4
Withhold palbociclib and initiate next cycle when recovery to Grade ≤2. 
Resume at next lower dose.
Non hematologic Toxicityb
Grade 1 or Grade 2
Continue at same dose level.
Grade 3 non-hematologic 
toxicityc
Withhold dose until toxicity is Grade 2, then resume treatment at next 
lower dose.
If the toxicity recurs with Grade 3 severity, withhold dose until toxicity 
is Grade 2 then resume treatment at the next lower dose of the 
combination or discontinue treatment (at the discretion of the 
investigator).
Grade 4 non-hematologic 
toxicityc
Discontinue Treatment.
Dose Modifications for Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh 
classes A and B).
The recommended dose of for patients with severe hepatic impairment (Child-Pugh class C), is 75 mg once 
daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.
Grading according to NCI CTCAE v. 5.0:

Grade 1: ANC < LLN - 1500/mm3; 

Grade 2: ANC 1000 - <1500/mm3; 

Grade 3: ANC 500 - <1000/mm3; 

Grade 4: ANC <500/mm3.
a.
Monitor CBC before the start of palbociclib therapy and at the beginning of each cycle, as well as on Day 14 of the 
first 2 cycles, and as clinically indicated.
b.
Table 5 applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, eg, 
opportunistic infections).


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Page 135
Table 15.
Dose Modifications for Palbocicliba Related Toxicities
c.
Including, nausea, vomiting, diarrhea, and hypertension (only if persisting despite optimal medical treatment).
Table 16.
Recommended Dose Level Reductions for Palbociclib
Available Dose of
Palbociclib (mg/day)
Recommended
starting dose
125
First dose reduction
100
Second dose reduction
75*
* If further dose reduction below 75 mg/day is required, discontinue the treatment.
Table 17.
Dose Levels Reductions for Letrozole 
Criteria
Available Dose of
Letrozole (mg)
Dose
Recommended
starting dose
2.5
First dose reduction
2.5*
* In patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose 
for such patients is 2.5 mg administered every other day (see prescribing information).


6PF-06804103
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Page 136
Appendix 8. List of Drugs Known to Predispose Patient to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone®, Pacerone®
Arsenic trioxide
Trisenox®
Astemizole
Hismanal®
Azithromycin
Zithromax®
Bepridil
Vascor®
Chloroquine
Aralen®
Chlorpromazine
Thorazine®
Cisapride
Propulsid®
Citalopram
Celexa®
Clarithromycin
Biaxin®
Disopyramide
Norpace®
Dofetilide
Tikosyn®
Domperidone
Motilium®
Droperidol
Inapsine®
Erythromycin
Erythrocin®, E.E.S. ®
Flecainide
Tambocor®
Halofantrine
Halfan®
Haloperidol
Haldol®
Ibutilide
Corvert®
Levomethadyl
Orlaam®
Mesoridazine
Serentil®
Methadone
Dolophine®, Methadose®
Moxifloxacin
Avelox®
Ondansetron*
Zofran®
Pentamidine
Pentam®, NebuPent®
Pimozide
Orap®
Probucol
Lorelco®
Procainamide
Pronestyl®, Procan®
Quinidine
Cardioquin®, Quinaglute®
Sotalol
Betapace®
Sparfloxacin
Zagam®
Terfenadine
Seldane®
Thioridazine
Mellaril®
Vandetanib
Caprelsa®
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on 
Therapeutics: "Torsades List: Drugs with a Risk of Torsades de Pointes," drugs that are 
generally accepted by the QTdrugs.org Advisory Board to carry a risk of Torsades de Pointes 


6PF-06804103
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PFIZER CONFIDENTIAL
Page 137
on the University of Arizona CERT website: http://www.crediblemeds.org/. This list is not 
meant to be considered all inclusive. See website for current list.

SAP_001.pdf: 
Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 1
Protocol C0541001
PF-06804103
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06804103 IN PATIENTS WITH HUMAN EPIDERMAL 
GROWTH FACTOR RECEPTOR 2 (HER2) POSITIVE SOLID TUMORS
Statistical Analysis Plan
(SAP)  
Version: Amendment 1
Author: 
 (Early Clinical Development,
 USA)
Date:     23-August-2021
PPD
PPD


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.1.1. MTD Determination (Part 1) ........................................................................6
2.1.2. Dose Expansion Phase (Part 2).....................................................................8
2.2. Study Objectives  and Endpoints ..............................................................................9
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................11
4. HYPOTHESES AND DECISION RULES.........................................................................11
4.1. Statistical Hypotheses .............................................................................................11
4.2. Statistical Decision Rules........................................................................................11
4.2.1. Part 1...........................................................................................................11
4.2.2. Part 2...........................................................................................................12
5. SAMPLE SIZE DETERMINATION ..................................................................................12
6. ANALYSIS SETS ...............................................................................................................13
6.1. Full Analysis Set .....................................................................................................13
6.2. ‘PER PROTOCOL’ Analysis Set (evaluable for MTD) .........................................13
6.3. Safety Analysis Set..................................................................................................13
6.4. Modified Intent to Treat (mITT) Population...........................................................13
6.5. PK Analysis Set.......................................................................................................14
6.6. Biomarker Analysis Set...........................................................................................14
6.7. Other Analysis Sets .................................................................................................14
6.7.1. Immunogenicity analysis set.......................................................................14
6.7.2. Soluble HER2 analysis set..........................................................................14
6.8. Treatment Misallocations........................................................................................14
6.9. Protocol Deviations.................................................................................................14
7. ENDPOINTS AND COVARIATES ...................................................................................14
7.1. Efficacy Endpoint(s) ...............................................................................................14
7.2. Safety Endpoints .....................................................................................................16
7.2.1. DLT Definitions..........................................................................................16
7.2.2. MTD Definition..........................................................................................18
7.2.3. Recommended Phase 2 Dose (RP2D) Definition.......................................18


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 3
7.2.4. Vital Signs ..................................................................................................18
7.2.5. Laboratory Data..........................................................................................18
7.2.6. Adverse Events...........................................................................................19
7.2.7. ECG and QTc Interval................................................................................19
7.2.8. Immunogenicity Endpoints.........................................................................20
7.3. PK Endpoints...........................................................................................................20
7.4. Biomarker Endpoints...............................................................................................21
7.5. Covariates................................................................................................................22
8. HANDLING OF MISSING VALUES ................................................................................23
8.1. Missing Dates..........................................................................................................23
8.2. Efficacy Analysis ....................................................................................................23
8.3. Pharmacokinetics ....................................................................................................23
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................24
9.1. Statistical Methods ..................................................................................................24
9.2. Statistical Analyses .................................................................................................24
9.2.1. Safety Analyses ..........................................................................................24
9.2.2. Efficacy Analysis........................................................................................25
9.2.3. Pharmacokinetics Analyses ........................................................................26
9.2.4. Biomarker Analyses....................................................................................28
9.2.5. Standard Analyses ......................................................................................28
10. REFERENCES ..................................................................................................................31
11. APPENDICES ...................................................................................................................32
11.1. APPENDIX 1: RECIST 1.1 TUMOR ASSESSMENT CRITERIA.....................32
11.2. APPENDIX 2: CATEGORICAL CLASSES FOR ECG AND VITAL 
SIGNS........................................................................................................................38
11.3. APPENDIX 3: CENSORING DETAILS .............................................................39
11.4. APPENDIX 4: LIST OF ABBREVIATIONS ......................................................41


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 4
LIST OF TABLES
Table 1A.
Part 1A  - PF 06804103 Dose Escalation Levels....................................................6
Table 1B.
Part 1B - PF 06804103 Dose Escalation Levels.....................................................7
Table 2.
Decision Rules........................................................................................................7


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 5
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Amendment 1
Section
Update
All 
Texts taken directly from the protocol are made 
italicized
Updated per protocol amendment 4
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol C0541001. This
analysis plan is meant to supplement the study protocol. In this document, any text taken
directly from the protocol is italicized. Any deviations from this analysis plan will be
described in the Clinical Study Report (CSR).
2.1. Study Design
This is a Phase 1, open-label, multicenter, multiple dose, safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) study of PF-06804103 in adult patients with HER2-positive solid 
tumors (breast cancer (BC) and gastric cancer (GC) [Part 1A only]) and in postmenopausal 
patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC. Part 1A and 1B will evaluate 
escalating doses of PF-06804103 as monotherapy and as part of a combination regimen,
respectively. Part 2A and Part 2B will evaluate selected doses of PF-06804103 in expansion 
cohorts as monotherapy and in a combination regimen, respectively.
In Part 1A, patients with HER2-positive BC or HER-positive GC will receive escalating
doses of PF-06804103 starting at 0.15 mg/kg, Q3W in a 21-day cycle to estimate the dose
level of PF-06804103 to be administered in Part 2A.
In Part 1B, postmenopausal patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC
will receive escalating doses of PF-06804103 starting at the dose equivalent to the
recommended monotherapy Q3W Part 2 dose minus 1 dose, Q2W in a 28-day cycle,
administered in combination with SOC doses of palbociclib and letrozole (as per local and
regional guidelines). Data collected during Part 1B will inform the dose levels selected for
dose expansion in Part 2B.
In Part 2A, HER2-positive BC patients in 3L setting will be randomly assigned to receive 3 
mg/kg or 4 mg/kg doses of PF-06804103 administered as monotherapy Q3W to further
evaluate safety, efficacy, and to evaluate the benefit/risk of 3 mg/kg and 4 mg/kg Q3W in a
larger population to support optimal dose selection. Also in Part 2A, HR-positive HER2 IHC
1+ or IHC 2+/ISH- BC patients in 2L setting will receive 4 mg/kg of PF-06804103
administered as monotherapy Q3W. A lower dose (eg., 3 mg/kg) may be tested if the
observed toxicity of 4 mg/kg Q3W is determined to be too high.
In Part 2B, patients with HR-positive HER2 IHC 1+ or IHC 2+/ISH- BC in the 1L setting
will receive the selected PF-06804103 dose administered Q2W (Part 1B) in a 28-day cycle in


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 6
combination with SOC doses of palbociclib and letrozole (as per local and regional
guidelines).
Approximately 148 patients are expected to be enrolled in the study overall. The actual
number of patients enrolled will depend on the tolerability of PF-6804103 and the number of
dose levels required to identify the MTD and select dose levels for Part 2 of the study.
2.1.1. MTD Determination (Part 1)
The estimated MTD is the dose level associated with a target dose limiting toxity (DLT) rate 
of approximately 27.5% with an equivalence interval of (22.5%, 32.5%).  Due to the 
discreteness of the dose levels and in the interest of the safety of patients, the estimated MTD 
is the highest tested dose level with DLT rate ≤ approximately 32.5%.  Late onset toxicities 
which occur outside the DLT observation period will be used in determination of the MTD.
A modified toxicity probability interval (mTPI) method will be utilized in Part 1 of the study.  
Patients will be enrolled in cohorts of 2 to 4 patients.  Intra patient dose escalation is not 
permitted. 
The planned dose levels in Part 1A monotherapy escalation and Part 1B combination 
regimen escalation are described in Tables 1A and 1B. Additional dose levels, or 
intermediate doses may be explored, if appropriate based on emerging clinical, safety, PK, 
or PD data.
Table 1A. Part 1A  - PF 06804103 Dose Escalation Levels
Dose Level
PF-06804103 Dose (mg/kg)*
1 (Starting Dose)
0.15
2
0.5
3
1.2
4
2.0
5
3.0
6
4.0
7
5.0
8
6.0
9**
n
*Intermediate doses may be evaluated.
**If needed, higher doses may be explored.


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 7
Table 1B. Part 1B - PF 06804103 Dose Escalation Levels
Dose Level
PF-06804103 Dose (mg/kg) Q2W*
-1
1.3
1 (Starting Dose)
2.0
2
2.7
3
3.3
*Intermediate, higher or lower doses may be explored.
The modified toxicity probability interval (mTPI) design uses a Bayesian decision-theoretic 
framework and a beta/binomial hierarchical model to tailor dose-escalation and de-escalation 
decisions. These rules are conceptually similar to those used by the 3+3 design and all the 
dose-escalation decisions for a given trial can be pre-calculated under the mTPI design and 
presented in a two-way table.
The decision rules to “dose escalate” (E), “no change in dose” (S), “dose de-escalate” (D) or 
“dose de-escalate, unacceptable toxicity” (U) are described below:
Table 2.
Decision Rules
Number 
of 
Patients 
having 
DLT
Number of Patients Treated at a Dose Level
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
n=13
n=14
n=15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
E
E
E
3
U
U
D
D
S
S
S
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
S
S
S
5
U
U
U
U
U
D
D
D
D
D
S
6
U
U
U
U
U
U
U
D
D
D
7
U
U
U
U
U
U
U
U
U
Actions to be taken:
D = De-escalate the dose; E: Escalate the dose; S: Stay at the dose.
U = Unacceptable toxicity.


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 8
For Part 1A, in principle, all patients must be evaluated for a minimum period of 21 days.  If 
a patient withdraws from the study before Day 21 for reasons other than drug related 
toxicity, another patient may be enrolled to replace that patient in the current cohort.  
However, if a patient discontinues close to Day 21 for reasons other than toxicity and due to 
an evident non drug related event, the patient may be deemed evaluable for safety if the 
investigators and sponsor agree that the patient is evaluable for the DLT safety observation.
The dose escalation in Part 1A of the study will stop if any of the following criteria is met:
•
the maximum sample size in Part 1 has been achieved;
•
at least 9 patients have been accumulated on a dose that is predicted to be the MTD
per the mTPI method;
•
all doses explored appear to be overly toxic, and the MTD cannot be determined.
There will be a minimum 48 hour interval between the first dose administered to each of the 
initial patients (ie, patients contributing to initial DLT evaluation) enrolled at a new dose 
level.  Initially, up to 4 patients will be treated; occasionally, due to logistical/clinical 
reasons, more than 4, but, no more than 6, patients may be enrolled in each cohort for the 
initial DLT evaluation.  In addition, dose cohorts with an acceptable safety profile may be 
expanded up to n=15 to further assess safety, pharmacokinetics or pharmacodynamics.  
Decisions to enroll additional patients at dose levels already cleared for safety will be based 
on the clinical judgment of the investigators and the sponsor considering all evaluable safety, 
PK, dose discontinuations, dose reductions, and PD data.
Dose escalation in the combination regimen will also follow the mTPI design. PF 06804103 
will be administered as an IV infusion every 14 days in combination with SOC oral 
palbociclib and oral letrozole.     
Dose escalation in Part 1B will stop if any of the following criteria is met:
•
the maximum sample size has been achieved;
•
at least 6 (Part 1B) patients have been administered a dose that is predicted to be the 
MTD per mTPI;
•
all doses explored appear to be overly toxic, and the MTD cannot be determined.
2.1.2. Dose Expansion Phase (Part 2)
In Part 2A, PF-06804103 will be evaluated as monotherapy when administered as described 
below: 

Arm M1: ≥3L BC HER2-positive (HER2 IHC 3+ or  ISH+) 3 mg/kg Q3W

Arm M2: ≥3L BC HER2-positive (HER2 IHC 3+ or ISH+) 4 mg/kg Q3W

Arm M3: ≥2L BC  HR-positive, HER2 IHC 1+ or IHC 2+/ISH- 4 mg/kg Q3W


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 9
The dose level of PF 06804103 to be administered in Part 2B will be selected based on the 
dose level determined in Part 1B and all available clinical, safety, preliminary efficacy, PK, 
and PD data and will be administered with palbociclib and letrozole to the patients described 
below:
•  Arm C1: BC 1L, postmenopausal, HR-positive HER2 IHC 1+ or IHC 2+/ISH-, 
PF-06804103 Q2W with SOC regiment for palbociclib and letrozole
2.2. Study Objectives and Endpoints
Objective: 
Endpoint: 
Primary
To characterize the DLTs of escalating levels of 
PF-06804103
To assess the safety and tolerability of 
PF-06804103 
To determine the RP2D for PF-06804103 as 
monotherapy 
To determine the RP2D for PF-06804103 in 
combination with palbociclib and letrozole
First cycle (21 days) DLTs – Part 1A
First cycle (28 days) DLTs – Part 1B
All available safety data including: AEs, SAEs, and 
clinically meaningful abnormalities in laboratory 
values and vital signs
Part 2:
To investigate preliminary antitumor activity
Part 2 y:
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP
Secondary
Objective 
Endpoint 
To characterize the single and multiple dose PK of 
PF-06804103 ADC, total antibody and 
unconjugated payload (PF-06380101).
SD and MD PK parameters of PF-06804103 ADC, 
total antibody and unconjugated payload 
(PF-06380101).
To evaluate the immunogenicity of PF-06804103
Incidence and titers of ADA and NAbs against 
PF-06804103
To document antitumor activity
OR, as assessed using RECIST version 1.1. 
Time-to-event endpoints: DR, PFS, TTP – Part 1
To explore preliminary antitumor activity in 
patients that HER2 positive GC 
HER2 expression levels in pre-treatment tumor 
biopsies via IHC and ISH


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 10
 
 
 
 
 
 
 
 
 
 
β
 
β
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
CCI
CCI


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
Page 11
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No interim analysis or blinding is planned for this study. The final analysis will be 
conducted after the last subject last visit (LSLV).
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses. The emphasis of the final analyses will be on estimation 
of key summary statistics.
4.2. Statistical Decision Rules
4.2.1. Part 1
Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT-e1, pT+ e2), where e1 and e2 are small fractions. For a target 
DLT rate of 0.25, the target equivalence interval is (0.225, 0.325).  The three dosing intervals 
are associated with three different dose-escalation decisions (Table 2). The under-dosing 
interval corresponds to a dose escalation (E), over-dosing corresponds to a dose de-escalation 
(D), and proper-dosing corresponds to remaining at the current dose (S). Given a dosing 
interval and a probability distribution, the unit probability mass (UPM) is defined as the ratio 
of the probability of the interval to the length of the interval.  Once the safety assessment is 
complete for Cycle 1 (ie, 21 days after the first dose), the focus will be on allocation of new 
subjects to the dose most likely to be an MTD. 
The study continues accruing until one of the three stopping conditions below is triggered.  
The algorithm will stop if any of the following criteria is met:

The maximum sample size has been achieved.

MTD has been identified with sufficient accuracy: at least 9 patients have been 
accumulated on a dose that is currently estimated to be the MTD, or

All doses explored appear to be overly toxic and the MTD cannot be determined. 
Specifically the mTPI approach formalizes stopping rules as follow:
Rule 1 (early termination): if the first dose is too toxic 
Rule 2 (dose exclusion), if dose= i is too toxic 
then exclude doses ≥i
975
.0
;
)
/
Pr( 1





data
p
p
T
75
9.0
;
)
/
Pr(



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data
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4.2.2. Part 2
Part 2 of this study is intended to confirm the safety and tolerability of the dose selected in 
Part 1 while assessing the antitumor activity of PF-06804103 in patients with solid tumors.  
Analyses may be performed on data from both Part 1 and Part 2 to explore the relationships 
between PK parameters, safety endpoints, and efficacy endpoints.
5. SAMPLE SIZE DETERMINATION
This first in patient study is divided in to 2 parts (Section 3.1). Approximately 148 patients 
are anticipated to be enrolled overall.
Part 1
Patients in Part 1A will participate in dose escalation to determine the Part 2A monotherapy 
dose level of PF 06804103.  
Patients in Part 1B will participate in escalating doses of PF 06804103 administered Q2W in 
combination with palbociclib and letrozole to determine the Part 2B combination dose level. 
The actual number of patients enrolled in Part 1 B will depend upon tolerability and the 
number of dose levels required to identify the MTD of PF 06804103 administered as part of 
the combination regimen. 
Part 2
Patients in Part 2 will participate in monotherapy dose expansion (Part 2A) and in 
combination regimen expansion (Part 2B]).  
Part 2A
Arm M1 and Arm M2 (≥3L BC HER2-positive) and Arm M3 (≥2L BC  HR-positive HER2 
IHC 1+ or IHC 2+/ISH-: assuming a non informative prior (ie, Jeffrey’s prior) if 10 out of 
20 participants have tumor response, this would predict a posterior probability (Beta 
Binomial) equal to 0.82 that the true response is not inferior to the target response rate of 
40%.
Part 2B 
Arm C1 1L BC HR-positive HER2 IHC 1 + or IHC 2+/ISH-, assuming a noninformative 
prior (ie, Jeffrey’s prior) if 13 out of 20 participants have tumor response, this would predict 
a posterior probability (Beta Binomial) equal to 0.82 that the true response is not inferior to 
the target response rate of 55%.
It is anticipated that approximately 60 patients will be enrolled in Part 2A, and 20 patients
will be enrolled in Part 2B.  The sample size may be modified (up to 40 patients per arm) 
depending on the totality of the data including but not limited to the evaluation of clinical, 
safety, PK, PD, and preliminary efficacy.


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6. ANALYSIS SETS
Several analysis sets are defined and will be considered for this study.
6.1. Full Analysis Set
The full analysis set includes all enrolled patients.  This is equivalent to the ITT (intent-to-
treat) population.
6.2. ‘PER PROTOCOL’ Analysis Set (evaluable for MTD)
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study treatment and who do not have major treatment deviations during the DLT observation 
period (e.g., first cycle).  Patients with major treatment deviations during the DLT 
observation period are not evaluable for the MTD assessment and will be replaced as needed 
to permit MTD estimation.  Major treatment deviations include but are not limited to:
•
Failure to satisfy major entry criteria (eg, confirmation of the target disease, signed 
informed consent).
•
Administration of less than 80% of the planned dose of PF-06804103, palbociclib or 
letrozole (provided that the reduction is not due to toxicity attributable to PF-06804103)
in Cycle 1.
•
Use of other anticancer treatments during the active treatment and disease follow-up 
phases other than as defined/allowed in this protocol.
6.3. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
treatment.
6.4. Modified Intent to Treat (mITT) Population
The modified intent to treat (mITT) is the analysis population that will follow the ITT 
principle and include patients receiving at least 1 dose of investigational product with 
adequate baseline assessment and at least 1 determinate post baseline assessment (for SD or 
Non-CR/Non-PD, at least five weeks after treatment start date), disease progression, or death 
before the first tumor assessment.
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 31 days prior to and including the date of 
first dose of study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at 
baseline for non-target lesions).  
The mITT population will be used for analyses and to support conference presentations when 
the study is still ongoing.


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6.5. PK Analysis Set
The PK parameter analysis set is defined as patients who receive at least 1 dose of study 
treatment and have at least 1 of the PK parameters of interest. If specified clearly, the 
patients who have major protocol deviations influencing the PK assessment will be excluded.
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for PF-06804103, palbociclib or letrozole.
6.6. Biomarker Analysis Set
The biomarker analysis population is defined as all enrolled patients with at least 1 of the 
biomarkers evaluated at pre- and/or post-dose.
6.7. Other Analysis Sets
6.7.1. Immunogenicity analysis set
The immunogenicity analysis set includes all patients who receive at least 1 dose of study 
treatment and have at least 1 ADA sample collected.
6.7.2. Soluble HER2 analysis set
The soluble HER2 concentration analysis set is a subset of the biomarker analysis set 
including patients who have at least 1 soluble HER2 concentration above the lower limit of 
quantification.
6.8. Treatment Misallocations
Patients who receive the wrong initial dose for whatever reason will be analyzed according to 
the initial dose actually received.  Patients who receive the wrong dose after the initial dose 
will be analyzed according to the initial dose received.
6.9. Protocol Deviations
All deviations will be listed in the clinical study report (CSR). Major treatment deviations 
requiring a patient to be excluded from the MTD evaluaton are listed above in Section 6.2.
7. ENDPOINTS AND COVARIATES
7.1. Efficacy Endpoint(s)
In this first in patient study, anti-tumor activity will include evaluation of objective tumor 
response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) 
version 1.1 by calculating the Overall Response Rate (ORR).  Time to event endpoints, 
including Duration of Response (DR), Progression Free Survival (PFS), and Time to 
Progression (TPP) will also be evaluated.
The above efficacy endpoints are derived based on the disease response per investigator 
evaluation on the CRF pages, which is the primary method of documentation of disease. 


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
Overall Response (OR) – or Response Rate (RR) is defined as complete response (CR) 
or partial response (PR) according to RECIST 1.1 (Appendix 1). Overall response is the 
best response recorded from first dose until disease progression/recurrence.

  Progression Free Survival (PFS) - is defined as the time from Cycle 1 Day 1 (C1D1) 
to first documentation of disease progression or death due to any cause, whichever occurs 
first. Patients last known to be 1) alive 2) on treatment or within the post-treatment 
follow-up period and 3) progression-free, are censored at the date of the last disease 
assessment that verified lack of disease progression.  Patients who start new anti-cancer 
treatment (drug and non-drug therapy) prior to the end of post-treatment follow-up period 
and have adequate baseline and on-treatment objective disease assessments without 
evidence of progressive disease are censored at the date of the last objective disease 
assessment.  Patients with inadequate baseline or no on-study disease assessments are 
censored at C1D1 unless death occurred prior to the first planned assessment (in which 
case the death is an event).  Patients with documentation of progression or death after an 
unacceptably long interval (>16 weeks) since the previous disease assessment will be 
censored at the time of the previous assessment.

      PFS (months) = [progression/death date – C1D1 + 1]/30.3475.

Duration of Response: Time from the date of first documentation of CR or PR to the 
date of first documentation of objective progression or death due to any cause.

Time to progression: Time from Cycle 1 Day 1 (C1D1) to disease progression
More details of censoring are provided in Appendix 2.


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7.2. Safety Endpoints
7.2.1. DLT Definitions
Severity of AEs will be graded according to CTCAE version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring in the first cycle of treatment  will be 
classified as DLTs, unless there is a clear alternative explanation:
Part 1A
Hematologic:
•
Grade 4 neutropenia lasting >7 days;
•
Febrile neutropenia defined as ANC <1000/mm3 with a single temperature of 
>38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour);
•
Grade ≥3 neutropenic infection; 
•
Grade ≥3 thrombocytopenia with bleeding; 
•
Thrombocytopenia defined as:
•
  any <10,000/mm3 (or ≥100 x 109/L)
•
or  10,000 /mm3 or (≥100 x 109/L)  to 25,000 mm3
•
(or ≥100 x 109/L for ) >5 days.
Non hematologic:
•
Grade 3 toxicities, that are considered clinically significant, except the following:
•
Grade 3 nausea, vomiting or diarrhea lasting <72 hours with adequate antiemetic or 
other supportive care;
•
Grade ≥3 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions;
•
Grade ≥3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.
•
Delay by more than 2 weeks in receiving the next scheduled cycle due to persisting 
treatment related toxicities.  Patients deriving clinical benefit from study treatment 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.
•
Concurrent AST or ALT >3x  ULN and total bilirubin >2x ULN (potential Hy’s law 
case, (Section 8.4.1).
•
Any Grade 5 event not clearly due to underlying disease or extraneous causes.
Part 1B


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A DLT is defined as any of the following TEAEs occurring during the first cycle of treatment 
and considered possibly related to the combination of PF-06804103 plus palbociclib and 
letrozole:
Hematologic:
•
A delay greater than 1 week in administration of the next scheduled dose of study 
treatment due to persistent treatment-related toxicities (eg, platelet count and ANC of Grade 
>3 unless the criteria below are met during the DLT observation period):
•
Grade 4 neutropenia lasting >7 days;
•
Febrile neutropenia (defined as ANC <1000/mm3 with a single temperature of 
>38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour);
•
Grade ≥3 neutropenic infection;
•
Grade ≥3 thrombocytopenia with bleeding;
•
thrombocytopenia (defined as):
•
any <10,000/mm3;
•
10,000 to 25,000/mm3 for >5 days.
Non hematologic:
•
Grade ≥3 toxicities, that are considered clinically significant, except the following:
o
Grade 3 nausea, vomiting or diarrhea lasting <72 hours with adequate antiemetic or 
other supportive care;
o
Grade ≥3 electrolyte abnormality lasting <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical interventions;
o
Grade ≥3 amylase or lipase that is not associated with symptoms or clinical 
manifestations or pancreatitis.
•
Grade 3 QTc prolongation (QTc msec) despite correction of reversible causes:
o
In an asymptomatic patient, Grade 3 QTc prolongation (QTc >500 msec) first 
required repeat testing, re-evaluation by a qualified person, and correction of reversible 
causes such as electrolyte abnormalities or hypoxia for confirmation. 
•
Delay by >2 week in receiving the next scheduled dose of any study treatment due to 
persisting treatment-related toxicities.  Patients deriving clinical benefit from study treatment 
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.
•
Inability to administer at least 80% of the planned palbociclib or letrozole doses 
during Cycle 1 due to toxicity related to the study treatment.


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•
Inability to administer 100% of the planned dose of PF 06804103 during Cycle 1 due 
to toxicity related to the study treatment.
•
Concurrent AST or ALT >3x  ULN and total bilirubin >2x ULN (potential Hy’s law 
case (Section 8.4.1).
•
Any Grade 5 event not clearly due to underlying disease or extraneous causes.
In addition, clinically important or persistent toxicities that are not included in the above 
criteria may be considered a DLT following review by the sponsor and the investigators.  All 
DLTs need to represent a clinically significant shift from baseline. 
Grade ≥3 infusion reactions, allergic reactions, or anaphylaxis will not be considered DLTs, 
as they are unlikely dose related, but may be a reason for study discontinuation and should 
be reviewed with the sponsor.  If Grade ≥3 infusion reactions occur in ≥2 of the first 10 
patients at any dose level, or if the occurrence is ≥5% thereafter, a mandatory pre treatment 
regimen for all new patients will be implemented.  The incidence of Grade 1 and Grade 2 
reactions will also be considered.  If a total rate of >10% all grade infusion or allergic 
reactions is observed, a mandatory pre treatment regimen for all new patients will be 
implemented.
All AEs meeting DLT criteria are considered DLTs regardless of baseline .
7.2.2. MTD Definition
The estimated MTD is the dose level associated with a target DLT rate of approximately 
27.5% with an equivalence interval of (22.5%, 32.5%).  Due to the discreteness of the dose 
levels and in the interest of the safety of patients, the estimated MTD is the highest tested 
dose level with DLT rate ≤ approximately 32.5%.  Late onset toxicities which occur outside 
the DLT observation period may be used in determination of the MTD.
7.2.3. Recommended Phase 2 Dose (RP2D) Definition
The Recommended Phase 2 Dose (RP2D) is the dose chosen for further study based on 
Phase 1 results.  If the MTD proves to be clinically feasible for long term administration in a 
reasonable number of patients, such dose usually becomes the RP2D.  Further experience 
with the MTD may result in a RP2D dose lower than the MTD.
7.2.4. Vital Signs  
Vital signs will include measurements of temperature, blood pressure (BP) and pulse rate to 
be recorded in the supine or seated position and pulse oximetry. See Schedule of Activities 
in the protocol for details.
7.2.5. Laboratory Data
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade. For 
labs for which an NCI CTCAE v4.03 scale does not exist, the frequency of patients with 


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values below, within, and above the normal ranges will be summarized by dose. Baseline 
evaluations for laboratory data are those collected:

Within 28 days prior to Cycle 1/Day 1.

Closest but prior to Cycle 1/Day 1 if there is more than one baseline evaluation.
7.2.6. Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE 
version 4.03 and coded using the MedDRA.  The focus of AE summaries will be on 
Treatment Emergent Adverse Events, those with the onset dates occurring during the on-
treatment period.  The on-treatment period is defined as the time from the first dose of study 
treatment through minimum (30 days + last dose of study treatment, start day of new anti-
cancer drug therapy – 1 day). The number and percentage of patients who experienced any 
AE, serious AE (SAE), treatment related AE, and treatment related SAE will be summarized 
according to worst toxicity grades.  The summaries will present AEs both on the entire study 
period and by cycle (Cycle 1 and Cycles beyond 1).  The Safety Analysis Set will be used.  
Part 1 and Part 2 data will be summarized separately and may also be pooled together for 
analysis. Pfizer standard on safety data reporting will be followed.
7.2.7. ECG and QTc Interval
The analysis of ECG results will be based on patients in the safety analysis set with baseline, 
defined as the assessment at either Cycle 1 Day 1 or screening, whichever is closer to the 
first dose, and on treatment ECG data. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Frederica’s).  Data will be summarized and listed for QT, heart rate , RR interval, PR 
interval, QRS, QTcF, and by dose.  Individual QT (all evaluated corrections) intervals will 
be listed by time and dose.  The most appropriate correction factor will be selected and used 
for the following analyses of central tendency and outliers and used for the study 
conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, and 
maximum) will be used to summarize the absolute corrected QT interval and changes from 
baseline in corrected QT after treatment by dose and time point.  For each patient and by 
treatment, the maximum change from baseline will be calculated as well as the maximum 
post-baseline interval across time-points.  Categorical analysis will be conducted for the 
maximum change from baseline in corrected QT and the maximum post-baseline QT interval. 
The analysis will be conducted and summarized as follows:

The number of patients with maximum change from baseline in QTc (<30, 30-60, and 
≥60 ms).


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
The number of patients with maximum post-dose (post-baseline) QTc (≤450, 450-
≤480, 480-≤500, and >500 ms).
In addition, the number of patients with corrected and uncorrected QT values ≥500 msec will 
be summarized.
Shift tables will be provided for baseline vs. worst on study QTc (one or more correction 
method will be used) using absolute value. Shift tables will also be provided for ECG 
abnormality at baseline vs. on treatment (yes, no, not done: (n, %)).  Patients experiencing 
clinically relevant morphological ECG changes will be summarized (including frequency and 
percentage).
If more than one ECG is collected at a nominal time post dose (for example, triplicate 
ECGs), the mean of the replicate measurements will be used to represent a single observation 
at that time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, 
but the mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing 
will be described in a safety section of the study report in order to place the ≥500 msec value 
in appropriate clinical context. However, values from individual tracings within triplicate 
measurements that are ≥500 msec will not be included in the categorical analysis unless the 
average from those triplicate measurements is also ≥500 msec. Changes from baseline will be 
defined as the change between QTc post dose from Day 0, or the pre-dose values on Day 1.
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
7.2.8. Immunogenicity Endpoints
For the immunogenicity data, the percentage of patients with positive ADA and Nab each 
will be summarized by dose level or by treatment.  For patients with positive ADA or Nab, 
the magnitude (titer), time of onset, and duration of ADA or Nab response will also be 
described, if data permit.
Potential impact of immunogenicity on PK, clinical responses, and safety/tolerability may be 
explored, if data warranted.
7.3. PK Endpoints 
Blood samples for PK analysis of PF-06804103 (ADC), total antibody, and unconjugated 
payload will be taken according to the Schedule of Activities given in the protocol. Drug 
concentrations of ADC (PF-06804103), total antibody, and unconjugated payload will be 
measured using validated methods.  PK parameters will be determined from the respective 
concentration time data using standard noncompartmental methods.  Actual sample 
collection times will be used for the parameter calculations.  For ADC and total antibody, 
PK parameters including maximum concentration (Cmax), time to maximum concentration 
(Tmax), area under the concentration time curve over 1 dosing interval (AUCτ), area under 
the concentration time curve from time 0 to the last measurable concentration (AUClast), and 
if data permit or if considered appropriate, area under the concentration-time curve from 


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time 0 extrapolated to infinity time (AUCinf), terminal elimination half-life (t½), clearance 
(CL), volume of distribution at steady state (Vss), and accumulation ratio (Rac) will be 
calculated.  For unconjugated payload, PK parameters including Cmax, Tmax, AUClast, AUCinf, 
AUCτ, t½, , and Rac will be calculated as appropriate.  
PK parameters will be derived from the concentration-time data as follows:
Parameter
Definition
Method of Determination
AUClast
Area under the concentration-time 
profile from time zero to the time of 
the last quantifiable concentration
Linear/Log trapezoidal method
AUCτ
Area under the concentration-time 
profile from time zero to the time τ,
the dosing interval
Linear/Log trapezoidal method
AUCinf
Area under the concentration-time 
profile from time zero extrapolated to 
infinite time
AUC(0-t[last]) + (Clast*/kel),
where Clast* is the predicted serum concentration at 
the last quantifiable time point estimated from the 
log-linear regression analysis.
AUCτ (dn)
Dose-normalized AUCτ
AUC τ /Dose
AUCinf (dn)
Dose-normalized AUCinf
AUCinf /Dose
Cmax
Maximum observed concentration
Observed directly from data
Cmax (dn)
Dose-normalized Cmax
Cmax/Dose
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the log-linear 
concentration-time curve.  Only those data points 
judged to describe the terminal log-linear decline will 
be used in the regression.
CL
Clearance
Dose/ AUCinf for cycle 1; Dose/ AUCτ for cycle 4
Vss
Volume of distribution at steady state
CL×MRT
Vz
Volume of distribution based on the 
terminal phase
CL/λz
Rac
Observed accumulation ratio
AUC cycle 4, τ/ AUCcycle 1, τ
7.4. Biomarker Endpoints 
For biopsy samples, summary statistics (eg, the mean and standard deviation, median, and 
minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.
Soluble HER2 data will be summarized with descriptive statistics.  
 
CCI


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Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with PK parameters and measures 
of anti tumor efficacy.
The percentage change from baseline for biomarkers over the period of the study will be 
tabulated by individual.  The mean change from baseline values over time per cohort will 
also be tabulated.  Data will be presented in tabular and/or graphical format and 
summarized descriptively. 
 
 
 
7.5. Covariates
Not applicable. 
CCI


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8. HANDLING OF MISSING VALUES
8.1. 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.
8.2. Efficacy Analysis
Censoring rules for time-to-event endpoints are detailed in Section 11.2 Appendix 2.
8.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.).
Deviations, missing concentrations and anomalous values
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC.  For statistical analyses, PK parameters coded as NC will also 
be set to missing.


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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 drug is 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.
QTc
For the QTc analyses, no values will be imputed for missing data.  
Pharmacodynamic parameters
Missing data for the pharmacodynamic parameters will be treated as such and no imputed 
values will be derived.
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
9.1. Statistical Methods
No formal hypothesis testing will be performed in this exploratory study.
Analyses of Time-to-Event Endpoints 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence intervals for 
each time-to-event endpoint (Brookmeyer and Crowley, 1982) will be provided.   
Analyses of Binary Endpoint
The rates of binary endpoints will be provided along with the corresponding 2-sided 95% 
confidence intervals using an exact method. 
Analyses of Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median,
minimum, and maximum values, will be provided for continuous endpoints. 
9.2. Statistical Analyses
9.2.1. Safety Analyses
Dose Limiting Toxicity
Dose Limiting Toxicity (DLT) is the primary endpoint in Part 1 of the study, which will be 
summarized by dose level using the Per Protocol Analysis Set for patients in the dose 
escalation portion of the study.  A listing of the DLTs will also be provided.
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE version 
4.03 and coded using the MedDRA. The focus of AE summaries will be on Treatment 
Emergent Adverse Events. The number and percentage of patients who experienced any AE, 
serious AE (SAE), treatment related AE, and treatment related SAE will be summarized 


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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).  The Safety Analysis Set will be used.
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be
summarized according to worst toxicity grade observed for each laboratory test. The
analyses will summarize laboratory tests both in the entire study period and by cycle (Cycle 1 
and Cycles beyond 1). Shift tables will be provided to examine the distribution of laboratory 
abnormalities. The Safety Analysis Set will be used.
For laboratory tests without CTC grade definitions, results will be categorized as normal,
abnormal high/low or not done.
Vital Signs
Vital signs data will be presented as summaries for change from baseline and as categorical 
summaries for absolute value, decrease and increase from baseline.  Absolute values will also 
be summarized by cycle/day and dose combinations.
9.2.2. Efficacy Analysis
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response.  
In addition, progression date, death date, date of first response and last tumor assessment 
date, and date of last contact will be listed.
Summary tables of best Overall Response Rate will be provided by tumor type (GC and BC)
and dose for Part 1A, and will be provided by patient population and dose (3 mg and 4 mg)
for Part 2. Time to event endpoints such as PFS, TTP and DR will also be summarized, but 
the cohorts could be combined to ensure sufficient sample size with meaningful 
interpretation.
Efficacy listings will be provided that include best response, first CR/PR date, last date with 
CR or PR, most recent date without progression, progression date, death date, date of first 
response and last tumor assessment date, etc.
The following table provides an overview of the efficacy analysis.


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Endpoint
Analysis Set
Statistical Method
Model/Covariates/Stra
ta
Missing Data
Overall response
mITT
Exact CI
See aforementioned 
summary descriptions 
on data pooling
across dose and tumor 
type
Observed case
Progression Free 
Survival (PFS)
Full Analysis 
Set
Kaplan-Meier
See aforementioned 
summary descriptions 
on data pooling across 
dose and tumor type
Censored per 
Appendix 3
Time to 
Progression (TTP) 
Full Analysis 
Set
Kaplan-Meier
See aforementioned 
summary descriptions 
on data pooling
across dose and tumor 
type
Censored per 
Appendix 3
Duration of 
Response (DOR)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling
across dose and tumor 
type
Censored per 
Appendix 3
9.2.3. Pharmacokinetics Analyses 
Pharmacokinetic Parameters
To assess the pharmacokinetics of PF-06804103 (ADC), total antibody and unconjugated 
payload, the PK parameters detailed in Section 7.3 will be listed and summarized for subjects 
in the PK analysis set (as defined in Section 6.5).  Missing values will be handled as detailed 
in Section 8.  Each PK parameter will be summarized by dose and cycle and will include the
set of summary statistics as specified in the table below: 
Parameter
Summary statistics
AUClast, AUCinf
AUCinf(dn)
AUC,
AUC(dn)Cmax
Cmax(dn)
CL, 
VZ, 
Vss,
Rac
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean
T1/2
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum
Tmax
N, median, minimum, maximum


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There will be 1 summary table presenting all PK parameters.  This will include data from all 
cohorts and will be summarized by dose group and cycle.  
To assess the relationship between the PK parameters and dose, dose normalized AUC inf, 
AUClast, AUC, and Cmax will be plotted against dose (using a logarithmic scale), and will 
include individual subject values and the geometric means for each dose.  Geometric means 
will have a different symbol than the individual values.  The values will be dose normalized 
(to a 1 mg/kg dose) by dividing the individual values and raw geometric means by dose.  A 
footnote will be added to the plots to indicate that geometric means are presented are 
presented on the plot. 
Pharmacokinetic Concentrations
To assess the PK profile of PF-06804103 (ADC), total antibody and unconjugated payload, 
PK concentrations will be listed, summarized and plotted for subjects in the PK analysis set 
(as defined in Section 6.5), where missing and BLQ values will be handled as detailed in 
Section 8.3.
Presentations for PF-06804103 (ADC), total antibody and unconjugated payload will
include:

a listing of all concentrations sorted by dose, subject id, day and nominal time post dose.  
The listing of concentrations will include the actual times.  Deviations from the nominal 
time will be given in a separate listing.

a summary of concentrations by dose, day and nominal time post dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv) 
and the number of concentrations above the lower limit of quantification.

a plot of mean concentrations against nominal time postdose by dose (based on the 
summary of concentrations by dose and time postdose), preferably with all doses also on 
the same graph.

a plot of median concentrations against nominal time postdose by dose (based on the 
summary of concentrations by dose and time postdose), preferably with all doses also on 
the same graph.

a log-linear plot of mean concentrations against nominal time postdose by dose (on the 
same plot), preferably with all doses also on the same graph.

a log-linear plot of median concentrations against nominal time postdose by dose (on the 
same plot), preferably with all doses also on the same graph.

plots (linear and log scale) of individual concentrations against actual time postdose.
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PK concentration is quantifiable in the matrix.
In addition to the above, a median plot (linear and log scale) of the predose concentrations at 
each cycle against day will be provided for each dose, on the same plot, in order to assess the 
attainment of steady-state.  Individual subject profiles will also be plotted.


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For summary statistics and mean/median plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
Population Pharmacokinetic Analysis or PK/PD Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
compartmental or mixed-effect modeling approaches and may also be pooled with other 
study results.  PK/PD modeling may be attempted to investigate any causal relationship 
between PF-06804103 exposure and biomarkers or significant safety endpoints.  The results 
of these analyses, if performed, may be reported separately.
9.2.4. Biomarker Analyses 
For biomarker biopsy samples and blood samples, appropriate summary statistics at 
screening and post-treatment will be provided; these may include the mean and standard 
deviation, median, and minimum/maximum levels of biomarker measures or frequency 
statistics, as appropriate. All summaries will be provided separately for each dosing cohort.  
For the expansion cohort, summaries will be provided overall and by eachcohort.  Summaries 
will be provided separately for each biomarker type.  Graphical methods may be displayed, 
as appropriate.  The appropriate Biomarker Analysis Set will be used.
Other Variables: Immunogenicity Analysis
For the immunogenicity data, a listing, sorted by subject and study day, of the result of ADA 
screening (positive/negative [<1:negative]), the specificity, and titer will be listed. The 
percentage of patients with positive ADA and NAb each will be summarized by dose level 
(Part 1) or by treatment arms (Part 2).  For patients with positive ADA or NAb, the 
magnitude (titer), time of onset, and duration of ADA or NAb response will also be 
described, if data permit.  Potential impact of immunogenicity on PK and clinical response 
including PD markers, safety/tolerability and efficacy of PF-06804103 will be explored, if 
data is warranted.
9.2.5. Standard Analyses
Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.
Patient discontinuation from treatment and study will be tabulated and listed separately with 
their reason for discontinuation.  The Safety Analysis Set will be used.
Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, HER2 status, and primary diagnosis will be tabulated and listed. For 


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ECOG performance status a shift table (worst post-baseline vs baseline may be produced).
The Safety Analysis Set will be used.
Treatment Administration/Compliance
Listings and tables by dose level will be provided. Cycle length is 21 days for monotherapy 
and 28 days for combination therapy. Day 1 of a cycle is the first date of dose within that 
cycle.  The safety analysis set will be used.
Dose modifications may occur in the following ways:

Cycle delay—Day 1 of current cycle starts later than 21(+4) days for monotherapy and 28 
(+4) days for combination therapy from Day 1 of the previous cycle (only applies to 
cycle 2 and above); 

Cycle skip (dose delay of greater than 1 cycle)—Day 1 of current cycle starts later than 
42 days for monotherapy and 56 days for combination therapy from Day 1 of the 
previous cycle (only applies to cycle 2 and above). For example, After cycle 1 ended for 
a patient in Part 1A, a new cycle didn’t start until 42 days after cycle 1 day 1, the newly 
started cycle will be considered as cycle 3, and cycle 2 is considered skipped for this 
patient.

Dose reduction—A decrease in the administered total daily dose (non-zero) compared to 
the planned total daily dose upon enrollment. If in the CRF the prescribed dose unit is 
mg/kg, but the actual dose is in mg the actual dose mg/kg should be calculated 
considering the body weight of the patient at that visit if the patient experiences more 
than 10% change in body weight.  To account for the measurement error in IV dosing, 
only more than 10% above dose reduction from the planned dose for the actual dose will
be considered. Occasionally, if sites recalculate doses as per their local standard 
procedures, such changes will also be documented and used in this analysis.
Intra-patient dose escalation is not allowed in this study.  The following will be summarized 
for each dose level in Part 1 and Part 2, respectively: 

Number of subjects per dose level 

Median and range of number of cycles started per subject

Number (%) of subjects with cycle delays and cycle skips


Number (%) of subjects with dose reductions

Number (%) of each reason (AE vs. Other) for cycle delays, cycle skip and dose 
reductions

Duration of treatment (median, range)

Number of cycles before 1st delay (median, range)

Number of cycles before 1st dose reduction (median, range)

Number of cycles before 1st dose interruption (median, range)


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Listings by patient (ordered by dose level): start date and stop date of each dosing period 
within each cycle (including records with 0mg), administered total daily dose for each 
period, any missed doses with unknown dates (yes/no), number of missed doses with 
unknown dates, reason for any dosing changes will be provided.
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose, 
administered total dose, percentage of planned dose, dose delay (yes/no), dose reduction 
(yes/no), and dose interruption (yes/no) will be provided. 
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary.  Listings of prior, concomitant, and 
further therapies will be provided.


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10. REFERENCES 
Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  Biometrics 
1982; 38:29-41.
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
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc 1958; 53:457-481.
NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE).
http://evs.nci.nih.gov/ftp1/CTCAE/Documentation/CTCAE_Governance_2010-03-11.pdf
Verma, S., Miles, D., Gianni, L., Krop, I.E., Welslau, M., Baselga, J., Pegram, M., Oh,
D.Y., Diéras, V., Guardino, E. et al. Trastuzumab emtansine for HER2-positive
advanced breast cancer. N. Engl. J. Med. 2012; 367: 1783–1791.


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11. APPENDICES 
11.1. APPENDIX 1: 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. 
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. 


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


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


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If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.
Determination of Overall Response by the RECIST 1.1 Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in 
Table 11.1.1.
Table 11.1.1: Response Evaluation Criteria in Solid Tumors
Target 
lesions
Non-target 
lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-
CR/non-PD
No
PR
CR
Indeterminat
e or Missing
No
PR
PR
Non 
CR/Non-PD, 
Indeterminat
e or Missing
No
PR
SD
NON-
CR/Non-PD, 
Indeterminat
e, or Missing
No
SD
Indetermi
nate or 
missing
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 = Indeterminate


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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 in Table 11.1.2.
Table 11.1.2:  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 = indeterminate.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, the original 
CR should be changed to PR and the best response is PR.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as ‘Global 


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deterioration of health status’. 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. However, it must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.


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11.2. APPENDIX 2: CATEGORICAL CLASSES FOR ECG AND VITAL SIGNS 
Categories for QTc
QTcF (ms)
max. ≤450
450< max. ≤480
480< max.≤500
max. >500
QTcF (ms) increase 
from baseline
max. < 30
30≤ max. <60
max. ≥60
QTc Interval (ms)
max. ≤450
450< max. ≤480
480< max.≤500
max. >500
QTc Interval 
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
Measurements that fulfil these criteria are to be listed in the study report.


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11.3. APPENDIX 3: CENSORING DETAILS
Table 11.3.1:  Progression Free Survival and Duration of Response
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessment/’start date’
Event after missing or inadequate 
assessments a
4
No event and [withdrawal of consent date ≥ ‘start date’ 
OR End of study (EOS) = Patient refused further FU] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
EPOCH after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7
Discontinued Due to Adverse Event
Discontinued Due to Adverse 
Event
8
COMPLETED in Follow-up disposition page.
Completed without an event
9
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.
Table 11.3.2: TTP Outcome and Event Dates
Situation
Date of Progression/Censoring
Outcome
No adequate baseline assessment
‘start date’
Censored
PD 
- after at most 1 missing or inadequate post-
baseline tumor assessment, or 
- ≤ xx weeks after ‘start date’
Date of PD
Event
PD 
- after 2 or more missing or inadequate tumor 
assessmentsa
Date of last adequate tumor 
assessmenta documenting no PD 
prior to new anticancer therapy or 
missed tumor assessments.
Censored
No PD
New anticancer therapy given prior to PD
Death due to any cause
a.  If there are no adequate post-baseline assessments prior to the PD, then the time without adequate 
assessment should be measured from the ‘start date’; if the criteria were met, the censoring will be on the 
‘start date’.
Note: usually xx is 2 times the length of the tumor assessment interval. If no adequate tumor assessment 
within xx weeks after ‘start date’ then censor at ‘start date’.
TTP = time to progression; PD = progressive disease.


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Reasons for censoring should be summarized according to the categories in Table 11.3.3 
(could be modified as relevant for each trial) following the hierarchy shown.
Table 11.3.3
TTP Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessment/’start date’
Event after missing or inadequate 
assessments a
4
No event and [withdrawal of consent date ≥ ‘start date’ 
OR End of study (EOS) = Patient refused further FU] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
EPOCH after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7
Discontinued Due to Adverse Event
Discontinued Due to Adverse 
Event
8
COMPLETED in Follow-up disposition page.
Completed without an event
9
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a.  2 or more missing or inadequate post-baseline tumor assessments.
TTP = time to progression; PD = progressive disease; EOS = end of study; FU = follow-up.


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11.4. APPENDIX 4: LIST OF ABBREVIATIONS
The following is a list of abbreviations that may be used in the SAP.  
Abbreviation
Term
1L
first-line
2L
second-line
3L
third-line
ADA
anti-drug antibodies
ADC
antibody-drug conjugate 
AE
adverse event
AI
aromatase inhibitors
AIDS
Acquired Immune Deficiency Syndrome
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphotase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the concentration-time curve from time 0 
extrapolated to infinity time
AUClast
area under the concentration-time curve from time 0 to the 
last measurable concentration
AUCτ
area under the concentration-time curve during the dosing 
interval
BC
Breast cancer
BCVA
Best Corrected Visual Acuity
BP
blood pressure
BUN
blood urea nitrogen
C
Cycle
C1D1
cycle 1 day 1
Cav
Steady state
CBC
Complete blood count
CD
Cluster of differentiation
CDK
cyclin-dependent kinase
CEP17
Chromosome enumeration probe 17
CHF
congestive heart failure
CISH
Chromogenic in situ hybridization
CLIA
Clinical Laboratory Improvement Amendments
CK
creatine kinase
CL
clearance
CCI
CCI


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Abbreviation
Term
Cmax
maximum concentration
CNS
central nervous sytem
Cmax
maximum concentration
CNS
central nervous system
CRF
case report form
CSA
Clinical supply agreement
CSR
Clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
Cytochrome P450 3A4
DDI
drug-drug-interaction
DILI
Drug induced liver injury
DISH
Dual in situ hybridization
DLco
diffusing capacity of the lungs for carbon monoxide
DLT
dose-limiting toxicity
DM1
maytansinoid emtansine
DMC
data monitoring committee
DR
duration of response
DS
Daiichi Sankyo
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
eg
for example
EGFR
Epidermal growth factor receptor
EOT
end of treatment
ERBB2
ER
estrogen receptor
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FFPE
formalin-fixed paraffin-embedded
FISH
Fluorescence in situ hybridization
FSH
follicle-stimulating hormone
FU
fluorouracil
GC
gastric and gastoeosphageal cancer
GCP
Good Clinical Practice
GCLP
Good Clinical Laboratory Practices
GGT
gamma-glutamyl transferase
CCI
CCI


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
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Abbreviation
Term
GLP
Good Laboratory Practice
HBV
Hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-a-go-go related gene
HER2
Human Epidermal Growth Factor Receptor 2
HNSTD
highest non-severely toxic dose
HR
hormone receptor
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
Identification code
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IOP
intraocular pressure
IP manual
Investigational Product manual
IRB
Institutional Review Board
ISH
in-situ hybridization
ITT
Intent-To-Ttreat
IUD
intrauterine device
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
LSLV
last subject last visit
LVEF
left ventricular ejection fraction
mTPI
modified toxicity probability interval
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mITT
Modified Intent-ToTtreat
MOA
mechanism of action
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NA
not applicable
Nab
Neutralizing antibody
NCI 
National Cancer Institute 
NSCLC
non-small cell lung cancer
NGS
Next-Generation sequencing
OR
Objective Response 
ORR
Overall Response Rate
PCD
primary completion date
CCI


Protocol C0541001 (PF-06804103) 
Statistical Analysis Plan Amendment 1
PFIZER CONFIDENTIAL
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Abbreviation
Term
PD
pharmacodynamics
PD-1
programmed cell death-protein 1
PD-L1
programmed death-ligand 1
PE
physical exam
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic
PO
per oral
PR
Partial Response
PR
pulse rate
pT
target probability
PT
prothrombin time
QW
once weekly
Q3W
Once every three weeks
QT
time between the start of the Q wave and the end of the T 
wave
Rac
accumulation ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
SD
single dose
SOA
schedule of activities
SOC
standard of care
SRSD
single reference safety document
t1/2
terminal elimination half-life
Tbili
total bilirubin
TCR/ TCRβ
T cell receptoire/T cell receptor
T-DMI
Ado-trastuzumab emtansine
TKI
Tyrosine kinase inhibitor
Tmax
time to maximum concentration
TTP
Time to progression
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady state
WBC
white blood cell 
CCI