Conditions: Neoplasms
Keywords: P-cadherin PF-06671008 solid tumors lung cancer breast cancer colorectal cancer NSCLC TNBC CRC neoplasms Triple negative breast cancer Non-small cell lung cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
The study will evaluate the safety, pharmacokinetics and pharmacodynamics of increasing doses of PF-06671008 in patients with advanced solid tumors with the potential to have P-cadherin expression. The study will then expand to look at the selected dose in patients with P-cadherin expressing TNBC, CRC or NSCLC.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: PF-06671008 intervention 2: PF-06671008
Intervention descriptions: intervention 1: Dose Escalation Phase - Part 1 intervention 2: Dose Expansion Phase - Part 2

Protocol document:
Prot_000.pdf: 
PF-06671008
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A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06671008 IN PATIENTS WITH ADVANCED SOLID 
TUMORS
Compound:
PF-06671008
Compound Name:
Not applicable 
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not applicable
Protocol Number:
B7831001
Phase:
Phase 1
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................17
APPENDICES .........................................................................................................................17
1. INTRODUCTION ...............................................................................................................36
1.1. Mechanism of Action/Indication.............................................................................36
1.2. Background and Rationale ......................................................................................36
1.3. PF-06671008 ...........................................................................................................38
1.3.1. Efficacy.......................................................................................................38
1.5.1. Intravenous Administration ........................................................................44
1.5.2. Subcutaneous Administration.....................................................................45
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................46
2.1. Objectives................................................................................................................46
2.1.1. Dose Escalation (Part 1) Objectives ...........................................................46
2.1.2. Dose Expansion (Part 2) Objectives...........................................................47
2.2. Endpoints.................................................................................................................48
3. STUDY DESIGN.................................................................................................................49
3.1. Study Overview.......................................................................................................49
3.2. Dose Escalation Phase (Part 1)................................................................................51
3.2.1. Evaluation of a Priming Dose.....................................................................52
3.2.2. Criteria for Dose Escalation........................................................................54
3.3. DLT Definition........................................................................................................55
3.4. MTD Definition.......................................................................................................56
3.5. Dose Expansion Phase (Part 2) ...............................................................................56
3.6. Recommended Phase 2 Dose (RP2D) Definition ...................................................56
4. PATIENT SELECTION......................................................................................................57
4.1. Inclusion Criteria.....................................................................................................57
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4.2. Exclusion Criteria....................................................................................................59
4.3. Lifestyle Guidelines ................................................................................................60
4.4. Sponsor’s Qualified Medical Personnel..................................................................61
5. STUDY TREATMENTS.....................................................................................................62
5.1. Allocation to Treatment ..........................................................................................62
5.2. Patient Compliance .................................................................................................62
5.3. Investigational Product Supplies.............................................................................63
5.3.1. Dosage Form(s) and Packaging..................................................................63
5.3.2. Preparation and Dispensing........................................................................63
5.4. Administration.........................................................................................................63
5.4.2. Infusion Reactions ......................................................................................65
5.4.3. Hypersensitivity Types 1 and 3 ..................................................................65
5.4.4. Extravasation ..............................................................................................65
5.4.5. Recommended Dose Modifications............................................................66
5.4.6. Dosing Interruptions...................................................................................66
5.4.7. Dose Delays................................................................................................67
5.4.8. Dose Reductions .........................................................................................67
5.5. Investigational Product Storage ..............................................................................69
5.6. Investigational Product Accountability...................................................................69
5.6.1. Destruction of Investigational Product Supplies ........................................70
5.7. Concomitant Treatment(s).......................................................................................70
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................70
5.7.2. Supportive Care ..........................................................................................70
5.7.3. Hematopoietic Growth Factors...................................................................70
5.7.4. Anti-Diarrheal, Anti Emetic Therapy.........................................................71
5.7.5. Anti-inflammatory Therapy........................................................................71
5.7.6. Corticosteroids............................................................................................71
5.7.7. Surgery........................................................................................................71
6. STUDY PROCEDURES .....................................................................................................71
6.1. Screening.................................................................................................................71
6.2. Study Period ............................................................................................................71
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6.3. Follow-up Visit .......................................................................................................71
6.4. Patient Withdrawal..................................................................................................72
7. ASSESSMENTS..................................................................................................................73
7.1. Safety Assessment...................................................................................................73
7.1.1. Pregnancy Testing ......................................................................................73
7.1.2. Adverse Events...........................................................................................74
7.1.3. Laboratory Safety Assessment ...................................................................74
7.1.4. Vital Signs and Physical Examination........................................................75
7.1.5. Ophthalmic Examination............................................................................75
7.1.6. (12-Lead) Electrocardiogram......................................................................76
7.1.8. Injection Site Tolerability Assessment (SC Only)......................................77
7.2. Pharmacokinetics Assessments...............................................................................77
7.2.1. Blood for Assessment of PF-06671008 Pharmacokinetics ........................77
7.5. Immunogenicity Evaluations...................................................................................81
7.6. Banked Biospecimens .............................................................................................81
7.6.1. Markers of Drug Response.........................................................................81
7.6.2. Additional Research....................................................................................83
8. ADVERSE EVENT REPORTING......................................................................................83
8.1. Adverse Events........................................................................................................83
8.2. Reporting Period .....................................................................................................83
8.3. Definition of an Adverse Event...............................................................................84
8.4. Medication Errors....................................................................................................85
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8.5. Abnormal Test Findings..........................................................................................85
8.6. Serious Adverse Events...........................................................................................86
8.6.1. Protocol-Specified Serious Adverse Events...............................................86
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.7. Hospitalization ........................................................................................................87
8.8. Severity Assessment................................................................................................89
8.9. Causality Assessment..............................................................................................89
8.10. Exposure During Pregnancy..................................................................................89
8.11. Occupational Exposure .........................................................................................91
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient 
Withdrawal)...............................................................................................................91
8.13. Eliciting Adverse Event Information ....................................................................91
8.14. Reporting Requirements........................................................................................91
8.14.1. Serious Adverse Event Reporting Requirements .....................................91
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................92
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................92
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Analysis Sets ...........................................................................................................92
9.2. Statistical Methods and Properties ..........................................................................93
9.3. Sample Size Determination.....................................................................................95
9.4. Efficacy Analysis ....................................................................................................96
9.5. Analysis of Pharmacokinetics 
..........................................96
9.5.1. Analysis of Pharmacokinetics.....................................................................96
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/
 (PK
 Modeling ................................97
9.5.4. Immunogenicity..........................................................................................98
9.6. Safety Analysis........................................................................................................98
9.6.1. Analysis of the Primary Endpoint...............................................................98
9.6.2. Analysis of Secondary Safety Endpoints....................................................98
9.6.3. Electrocardiogram.......................................................................................99
9.7. Data Safety Monitoring Committee ........................................................................99
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10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................100
11. DATA HANDLING AND RECORD KEEPING ...........................................................100
11.1. Case Report Forms/Electronic Data Record .......................................................100
11.2. Record Retention.................................................................................................101
12. ETHICS............................................................................................................................101
12.1. Institutional Review Board /Ethics Committee...................................................101
12.2. Ethical Conduct of the Study ..............................................................................102
12.3. Patient Information and Consent.........................................................................102
12.4. Patient Recruitment.............................................................................................102
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................102
13. DEFINITION OF END OF TRIAL.................................................................................103
13.1. End of Trial in a Member State...........................................................................103
13.2. End of Trial in All Other Participating Countries...............................................103
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................103
15. PUBLICATION OF STUDY RESULTS........................................................................103
15.1. Communication of Results by Pfizer ..................................................................103
15.2. Publications by Investigators ..............................................................................104
16. REFERENCES ................................................................................................................106
LIST OF TABLES
Table 1.
Dose Escalation Levels for IV Administration.....................................................54
Table 2.
Decision Rules......................................................................................................55
Table 3.
Dose Reductions...................................................................................................68
Table 4.
Laboratory Tests ...................................................................................................74
Table 6.
Dose Escalation Levels for IV Administration.....................................................94
Table 7.
Objective Response Status at Each Evaluation ..................................................116
Table 8.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................117
Table 9.
Overall Response Derived from Changes in Index, Non-index and New 
Lesions................................................................................................................119
Table 10.
Simulation Parameters Selected for the Final Design ........................................125
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Table 11.
Dose-toxicity Scenarios used in Simulations and Their Respective Target 
Dose Ranges .......................................................................................................126
Table 12.
Operating Characteristics of the mTPI Design (n at MTF=9) versus 
Conventional 3+3 Design ...................................................................................129
Table 13.
Operating Characteristics of the mTPI Design by Minimum Number of 
Patients on MTD.................................................................................................130
LIST OF FIGURES
Figure 1.
PF-06671008 Activity in SUM149.......................................................................39
Figure 2.
PF-06671008 Activity in HCT116 .......................................................................40
Figure 3.
Overall Study Design............................................................................................51
Figure 4.
Study Schematic Should Dose Prime Be Explored ..............................................53
Figure 5.
Dose-toxicity Scenarios used in Simulations .....................................................127
APPENDICES
Appendix 1. Abbreviations....................................................................................................108
Appendix 2. Tumor Types with Potential for P-cadherin Expression Eligible in Dose 
Escalation (Part 1)...............................................................................................111
Appendix 3. EGOG Performance Status ...............................................................................112
Appendix 4. RECIST (Response Evaluation Criteria In Solid Tumors) Version 1.1 
Guidelines...........................................................................................................113
Appendix 5. Immune-Related Response Criteria Derived from RECIST 1.1 
(irRECIST) .........................................................................................................118
Appendix 6. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................121
Appendix 7. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design.................122
Appendix 8. Suggested Cytokine Release Syndrome Management Algorithm and 
Revised CRS Grading System............................................................................131


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PROTOCOL SUMMARY
Background and Rationale:
Bispecific redirected T-cell-engaging therapies have demonstrated proof of concept (POC) in 
hematological malignancies with the recent US FDA (United States Food and Drug 
Administration) approval of the bispecific agent blinatumomab4 for the treatment of acute 
lymphoblastic leukemia (ALL). This modality has also shown promise for the treatment of 
solid tumors with several bispecific agents targeting solid tumors in early clinical studies.
Bispecific redirected T cell molecules are typically recombinant bispecific antibody 
fragments with one binding domain targeting a specific tumor antigen of choice and the other 
binding domain targeting the T cell receptor complex, most often the cluster of 
differentiation 3 epsilon (CD3ε) molecule. Similar to a standard synapse formation, once a 
threshold of bispecific mediated-immune synapses have formed, CD3ε signals the T cell to 
initiate a cytotoxic response toward the adjacent tumor cell expressing the specific antigen. 
The most clinically advanced bispecific platforms that have been reported are typically 
smaller protein molecules, around 50 kilodalton (kD), with short circulating half-lives
(t1/2 ~1 hour) that require constant infusion through the use of a pump to achieve a stable 
exposure to the therapeutic molecule.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Study Objectives and Endpoints:
Dose Escalation (Part 1) Objectives
Primary Objective
•
To assess safety and tolerability of increasing dose levels of PF-06671008 
administered in patients with advanced solid tumors for whom no standard therapy is 
available in order to estimate the Maximum Tolerated Dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 
Secondary Objectives
•
To evaluate the overall safety profile; 
•
To characterize the single and multiple dose pharmacokinetics (PK) of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To document any anti-tumor activity.
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Dose Expansion (Part 2 Objectives)
Primary Objective
•
To confirm safety and tolerability and explore preliminary evidence of anti-tumor 
activity of PF-06671008 at the RP2D in patients with P-cadherin expressing advanced 
CRC, TNBC or NSCLC.
Secondary Objectives
•
To evaluate the overall safety profile at the RP2D;
•
To characterize the single and multiple dose PK of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To evaluate preliminary anti-tumor activity through time to event endpoints.
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Primary Endpoints
Primary Endpoint (Part 1)
•
First cycle Dose-Limiting Toxicities (DLTs).
Primary Endpoint (Part 2)
•
Objective response (OR) as determined by the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 (Appendix 4) criteria.
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v.4.03), (Appendix 6) timing, seriousness, and relationship to study therapy;
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing;
•
Vital sign abnormalities;
•
Pharmacokinetic parameters of PF-06671008 Single Dose (SD) - Cmax, Tmax, AUC sd,τ, 
t1/2, AUCinf, and CL for intravenous (IV) administration or apparent clearance (CL/F) 
for subcutaneous (SC) administration as data permit.  Multiple Dose (MD) (assuming 
steady state is achieved) - Css,max, Tss,max,  AUCss,τ, t1/2, Css,min, CL for IV or CL/F for 
SC, volume of distribution (Vss) for IV or volume of distribution at steady state (Vss/F)
for SC, and Rac (AUCss,τ,/AUC sd,τ) as data permit;
•
Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies against
PF-06671008;
•
Objective response, as assessed using the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 – Part 1 only;
•
Progression Free Survival (PFS) and Overall Survival (OS) – Part 2 only.
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Study Design
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK
study of 
single-agent PF-06671008.  This study contains two parts, dose escalation (Part 1) followed 
by dose expansion (Part 2).  Sequential cohorts of patients with tumor types with the 
potential to have P-cadherin expression (see Appendix 2), and that are not candidates for 
regimens known to provide clinical benefit, will receive escalating doses of PF-06671008, in 
Part 1 of the study.  In addition, at clinically relevant dose levels with the IV or SC route of 
administration of 100 ng/kg or higher (ie, doses where the exposure is near the target 
effective exposure) where the safety is confirmed in the first 2-4 patients dosed, 
approximately up to 5 additional patients with colorectal, triple negative breast, non-small 
cell lung cancer or squamous cell carcinoma of the head and neck may be enrolled.  Pfizer 
internal data shows high level of P-cadherin is frequently found in these tumors.  Paired 
biopsies will be required for these additional patients. Part 2 will evaluate the dose selected 
from Part 1 in patients with P-cadherin expressing TNBC, CRC or NSCLC. 
Up to approximately 152 patients are expected to be enrolled in the study overall.  The actual 
number of patients enrolled will depend on the tolerability of PF-06671008 and the number 
of dose levels required to identify the MTD.
PF-06671008 will be administered as a weekly intravenous (IV) infusion in 21-day cycles 
with a starting dose of 1.5 ng/kg.  There will be a minimum 72-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 due to the unknown time course of possible 
infusion-related reaction or cytokine release. All patients will be observed in-patient for at 
least 24 hours after the first dose on Cycle 1 Day 1 (C1D1).  At doses of 100 ng/kg or higher, 
especially when the total dose exceeds 10,000 ng, additional in-patient overnight observation 
for subsequent doses beyond C1D1 may be considered based on the investigator’s discretion 
and should be discussed with Pfizer.
In addition, PF-06671008 will be administered in cohorts as a weekly subcutaneous (SC) 
injection in 21-day cycles with a starting dose equal to the dose level selected as the IV Dose 
Prime (See Section Evaluation of a Priming Dose).  Dose escalation cohorts with
PF-06671008 SC administration will be evaluated in parallel with dose escalation cohorts 
evaluating PF-06671008 IV administration (See Section Criteria for Dose Escalation).  For 
cohorts where a SC route of administration will be evaluated, there will also be a minimum 
72-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 due to the unknown time 
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course of possible cytokine release.  All patients who will be dosed subcutaneously will be 
observed in-patient for at least 48 hours after the first dose on Cycle 1 Day 1 (C1D1).  
Additional in-patient observation for subsequent cycles beyond C1D1 may be considered 
based on the investigator’s discretion and should be discussed with Pfizer.
Evaluation of either the IV or SC route of administration may be discontinued based on 
emerging clinical and safety data.
Study Treatment
Increasing dose levels of PF-06671008 administered weekly will be evaluated using a 
modified toxicity probability interval (mTPI) method that targets a MTD associated with a 
27.5% probability of DLT.  Part 1 will follow a mTPI method initially with cohorts of 
1-2 patients each and a primary DLT observation period of 21 days following the first dose 
(C1D1). 
Based on the toxicity study results, the evaluation of a priming dose to allow subsequent 
higher level dose administration may be instituted in this study.  The initial priming dose will 
be defined to facilitate subsequent dose escalation towards establishing the MTD of a dosing 
regimen that includes a priming dose.  The study aims to determine a MTD for an IV dose 
regimen that does not include a priming dose, and an independent MTD for an IV dose 
regimen that includes a priming dose.  In addition, the study aims to similarly determine a 
MTD for PF-06671008 administered subcutaneously that may or may not include a priming 
dose. 
If a dose level induces symptoms consistent with cytokine release syndrome (CRS) of 
Grade 3 lasting >24 hours considered not to be due to an infusion related reaction (IRR), 
allergic reaction, anaphylaxis or other causes in a cohort of 2-4 patients after the initial 
infusion, an additional 1-4 patients (up to approximately 6 patients overall) will be enrolled 
at that dose to confirm implementation of a priming dose (Dose Prime) for subsequent 
cohorts.  If an additional confirmed CRS of Grade 3 lasting >24 hours is observed at that 
dose, then a lower dose, which has been evaluated in at least 2-4 patients will be chosen as a 
priming dose (Dose Prime) for subsequent cohorts.  If a dose level induces confirmed CRS of 
Grade 4 in a cohort of 2-4 patients, then a lower dose, which has been evaluated in at least 
2-4 patients, will be chosen as a priming dose (Dose Prime) for subsequent cohorts. If a 
Dose Prime is selected, dose escalation will continue to determine the MTD of a dose 
regimen that includes a priming dose.  The evaluation of a Dose Prime may be implemented 
for both the IV and/or SC routes of administration.
After confirmation of the safety of Dose Prime, the treatment schedule will implement the 
inclusion of the fixed priming dose as the first dose (C1D1) followed by a second dose 
(C1D8) that will continue to be escalated in subsequent cohorts following an mTPI method in 
cohorts of 2-4 patients.  The primary DLT observation period for cohorts that include Dose 
Prime will be 21 days following the first dose (C1D1). 


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SCHEDULE OF ACTIVITIES FOR INTRAVENOUS ADMINISTRATION
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Treatment Period
Post Treatment
Cycle 1
(1 cycle = 21 days)
Cycles ≥2
Visit Identifier
Screen1
(28 days 
prior to 
registration)
Day 1
Day 4
Day 8
Day 
15
Day 1
Day 8
Day 15
End of 
Treatment21
Follow-up22
Visit Window (days)
(1)
(1)
(1)
(2)
(2)
Informed consent2
X
Tumor history
X
Medical history
X
Complete physical 
examination
X
X3
X
Abbreviated physical 
examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
Performance status5
X
X
X
X
X
Contraception check
X
X
X
X
Laboratory
Unique screening 
laboratory tests6
X
Hematology7
X
X
X
X
X
X
X
X
X
X
Blood Chemistry8
X
X
X
X
X
X
X
X
X
X
Coagulation9
X
X
X
X
X
X
X
Urinalysis10
X
X
X
X
X
X
X
Pregnancy test11
X
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Treatment Period
Post Treatment
Cycle 1
(1 cycle = 21 days)
Cycles ≥2
Visit Identifier
Screen1
(≤28 days 
prior to 
registration)
Day 1
Day 4
Day 8
Day 
15
Day 1
Day 8
Day 15
End of 
Treatment21
Follow-up22
Visit Window (days)
(±1)
(±1)
(±1)
(±2)
(±2)
(12 lead) ECG12
X
X
X
X
X
X
(Cycle 
2 only)
X (Cycle 2 
only)
X
Registration and 
Treatment 
Registration13
X
Study treatment14
X
X
X
X
X
X
Inpatient Monitoring15
X
X15
Tumor assessments
CT or MRI scan or 
equivalent16
X
X (every 6 weeks beginning at 
Cycle 3 and then every 12 weeks 
beginning at Cycle 8)
X16
Other samplings
Refer to Schedule of Pharmacokinetic,
 Assessments for Intravenous 
Administration
Blood samples for 
PF-06671008
Blood sample for 
Anti-PF-06671008 
Antibody
Other clinical assessments
Adverse events18
X
X
X
X
X
X
X
X
X
Concomitant Treatments19
X
X
X
X
X
X
X
X
X
X
Ophthalmic Examination20
X
* Visit windows are calculated off the first day of each cycle.  See Dose Delays section for calculation of visit windows for Cycle 1.
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Abbreviations: CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging
1.
Screening: to be obtained within 28 days prior to registration.
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures.  May be obtained more than 28 days prior to registration.
3.
Complete Physical Examination: No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment is performed within 3 days of dosing.
4.
Vital Signs: Includes temperature (oral, tympanic, temporal or axillary), blood pressure (BP) and pulse rate to be recorded in a supine or seated position.  On each dosing day, 
vitals should be measured prior to infusion start (pre-dose) and at the end of the PF-06671008 infusion.  In addition, pulse oximetry is to be collected on dosing days prior to 
infusion start (pre-dose) and at the end of the PF-06671008 infusion as part of the vital sign evaluation.
5.
Performance Status: Use Eastern Cooperative Oncology Group (ECOG).  – see Appendix 3.
6.
Unique Screening Laboratory Tests: Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and human immunodeficiency virus (HIV) as well as 
follicle stimulating hormone (FSH) for post-menopausal women who are amenorrheic for at least 12 consecutive months only.  Samples will be analyzed locally.
7.
Hematology: Complete blood count (CBC) to include hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils and basophils.  No 
need to repeat on C1D1 if baseline assessment performed within 3 days of dosing.  Assessments performed at all subsequent dosing visits should be performed within 48 
hours prior to dosing.  Samples will be analyzed locally.
8.
Blood Chemistry: Should include sodium, potassium, chloride, BUN (or urea), uric acid, creatinine, glucose, calcium, magnesium, phosphorus, albumin, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), and C-reactive protein (CRP).  
Measurement of CRP not required after C2D1 if within normal range or similar to baseline levels; however, CRP should be measured anytime cytokine release syndrome is 
suspected and not already scheduled to be measured (eg, Cycle 2).  No need to repeat on C1D1 if baseline assessment performed within 3 days prior to dosing.  Assessments 
performed at all subsequent dosing visits should be performed within 48 hours prior to dosing.  Samples will be analyzed locally.
9.
Coagulation: Prothrombin Time (PT) or International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT).  No need to repeat on C1D1 if baseline assessment 
performed within 3 days of dosing.  Samples will be analyzed locally.
10. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if baseline assessment performed within 3 days of dosing.  
Samples will be analyzed locally.
11. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will be performed on two occasions 
prior to starting study treatment – once at the start of screening and once on C1D1 immediately before investigational product administration.  Pregnancy tests will also be 
routinely repeated at every cycle during the active treatment period, at the end of study treatment and additional whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board (IRB) or if required by local regulations.
12. Triplicate 12-Lead ECG: Triplicate ECGs to be collected before dosing and at the end of the PF-06671008 infusion on dosing days as outlined above.  At each time point, 
three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF interval.  When coinciding with blood sample draws for 
pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If the mean QTcF 
is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed as 
clinically indicated.
13. Registration: Patient enrollment number and dose level allocation provided by Pfizer Inc.  Registration should occur before any other Day 1 activities are performed.
14. Study Treatment: PF-06671008 will be administered once every 7 days as an intravenous (IV) infusion.  For Cohort 1 only, the infusion will be given over 60 minutes 
(±5 minutes).  For Cohort 2 and beyond, the infusion will be given over 120 minutes (±15 minutes).
15. Inpatient Monitoring: Patients receiving PF-06671008 intravenously will be admitted for inpatient monitoring for at least 24 hours following the first administration of study 
treatment (C1D1).  For patients enrolled in cohorts where Dose Prime will be given on C1D1 followed by a higher dose on C1D8, patients will also be admitted for inpatient 
monitoring for at least 24 hours (for cohorts evaluating IV route of administration) following the second dose (C1D8).  Patients may be released only after the investigator has 
confirmed the patient has not exhibited signs of a cytokine reaction.  Patients should complete the required study specific laboratory assessments as detailed in the Schedule of 
Pharmacokinetic, 
 Assessment table and should be monitored per local standard practice for inpatient monitoring.  At doses of 
100 ng/kg or higher, especially when the total dose exceeds 10,000 ng, additional in-patient overnight observation for subsequent doses beyond C1D1 may be considered 
based on the investigator’s discretion and should be discussed with Pfizer.
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16. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans or equivalent.  
The same modality should be completed, if possible throughout the study.  Bone scans will be performed at baseline if disease is suspected and on study as appropriate to 
follow disease.  Baseline central nervous system (CNS) imaging is not required with the exception of symptomatic patients to rule out CNS metastases; patient ineligible if 
positive for CNS metastases.  CT or MRI scans to be done every 6 weeks (7 days) from the start of study treatment until disease progression by irRECIST or death, or until 
permanent discontinuation of study treatment.  The frequency will change to every 12 weeks (7 days) beginning at Cycle 8. Response (complete response (CR)/partial 
response (PR)) and disease progression will be confirmed with two consecutive timepoints at least 4 weeks apart (in the absence of rapid clinical deterioration for 
progression).  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  Tumor assessments should be repeated at the End of Treatment 
visit if more than 6 weeks have passed since the last evaluation. 
17. Tumor Tissue Samples: Patients enrolled in Part 1 and Part 2 will provide archival formalin-fixed paraffin embedded material containing tumor that is of diagnostic quality 
and representative of their diagnosed malignancy or fresh pre-treatment biopsy if the archival tumor is not available (tissue blocks are preferable, but freshly-cut paraffin 
sections are acceptable and must comprise 10 paraffin section, 4-microns in thickness, cut within 1 week of submission, and place individually on unstained, unbaked charged 
glass microscope slides) for evaluation of P-cadherin expression level. The mandated archival tumor sample will be assayed for P-cadherin expression levels retrospectively 
in Part 1 and prospectively for eligibility for Part 2.  Additionally, fresh pre-treatment biopsy (ie, collected during screening) and on-treatment biopsy samples on Cycle 3 
Day 1 (5 days) are optional for the initial 2-4 patients enrolled in each cohort in Part 1.  Fresh pre- treatment biopsy (ie, collected during screening) and on-treatment biopsy 
samples on Cycle 3 Day 1 (5 days) will be mandatory for patients enrolled in Part 1 in cohorts with clinically relevant dose levels of 100 ng/kg or higher where the safety has 
been confirmed in the initial 2-4 patients and a decision is made to expand a dose for further evaluation and for patients enrolled in Part 2.  Additional unscheduled 
on-treatment biopsies may be collected, if indicated, and agreed upon by the sponsor and investigator and agreed to by the patient.  The screening biopsy should preferably be 
completed after all eligibility criteria have been verified.  Fresh pre-treatment and on-treatment biopsies should be taken from the same lesion, not previously irradiated, if 
possible. An archival biopsy collected 6 months prior to study start may be substituted for the pre-treatment biopsy if the patient received no treatment between the 
collection of this tumor biopsy and study start. If the patient discontinues the study before the scheduled on treatment biopsy (C3D1), the patient will be asked to provide a 
fresh biopsy at the End of Treatment visit.
18. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03.  Patients must be followed for AEs for 28 days after the last study treatment administration or until all drug-related toxicities 
have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the meantime.  For serious adverse events (SAEs), the 
active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 28 calendar days after the last 
study treatment administration.  SAEs occurring to a patient after the active reporting period has ended should be reported to the sponsor 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 are to be reported to the sponsor.
19. Concomitant Treatments: All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the 
drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
20. Ophthalmic Examination: An eye exam (performed by an ophthalmologist) will be performed at screening. The eye exam includes Best Corrected Visual Acuity (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.
21. End of Treatment Visit (EOT): Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
22. Follow-Up: At least 28 days, and no more than 35 days, after discontinuation of treatment, patients will return to obtain these assessments as well as an evaluate the
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. Subsequent to the Follow-Up visit, 
patients should be contacted by telephone every 8 weeks (7 days) to obtain information on subsequent anti-cancer treatment and overall survival for up to two years from the 
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Schedule of Pharmacokinetic, 
 Assessments for Intravenous Administration –
Cohort 1 Only
Visit Identifier 
Screen
Cycle 1
Cycle 2
Subsequent Cycles
EOT
Study Day
1
2
4
8
9
11
15
1
2
4
8
15
1
8
15
Hours Pre-/Post-Dose*
0
1
2
4
8
24
72
0
1
2
4
8
24
72
0
1
0
1
4
24
72
0
1
0
1
0
1
0
1
0
1
Blood samples for PF-06671008
X
X
X
X
X
X X
X
X
X
X X X X X
X
X
X X X
X
X
X
X
X X X
X
Blood samples for Anti-PF-06671008 
Antibody
X
X
X
X
X
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Schedule of Pharmacokinetic, 
 Assessments for Intravenous Administration – Part 1 
Cohort 2 and Beyond and Part 2
Visit Identifier 
Screen
Cycle 1
Cycle 2
Subsequent Cycles
EOT
Study Day
1
2
4
8
9
11
15
1
2
4
8
15
1
8
15
Hours Pre-/Post-Dose*
0
2◊
4
8
24
72
0
2◊
4
8
24
72
0
2◊
0
2◊
4
24
72
0
2◊
0
2◊
0
2◊
0
2◊
0
2◊
Blood samples for PF-06671008 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
Anti-PF-06671008 Antibody3
X
X
X
X
X
CCI
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SCHEDULE OF ACTIVITIES FOR SUBCUTANEOUS ADMINISTRATION
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Treatment Period
Post Treatment
Cycle 1
(1 cycle = 21 days)
Cycles 2
Visit Identifier
Screen1
(28 days 
prior to 
registration)
Day 
1
Day 2 Day 3 Day 5 Day 8
Day 
15
Day 1
Day 2
Day 8
Day 15
End of 
Treatment22
Follow-up23
Visit Window (days)
(1)
(1)
(1)
(2)
(2)
Informed consent2
X
Tumor history
X
Medical history
X
Complete physical 
examination
X
X3
X
Abbreviated physical 
examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
Performance status5
X
X
X
X
X
Contraception check
X
X
X
X
Laboratory
Unique screening 
laboratory tests6
X
Hematology7
X
X
X
X
X
X
X
X
X
X
Blood Chemistry8
X
X
X
X
X
X
X
X
X
X
Coagulation9
X
X
X
X
X
X
X
Urinalysis10
X
X
X
X
X
X
X
Pregnancy test11
X
X
X
X


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Treatment Period
Post Treatment
Cycle 1
(1 cycle = 21 days)
Cycles ≥2
Visit Identifier
Screen1
(≤28 days 
prior to 
registration)
Day 
1
Day 2 Day 3 Day 5 Day 8
Day 
15
Day 1
Day 2
Day 8
Day 15
End of 
Treatment22
Follow-up23
Visit Window (days)
(±1)
(±1)
(±1)
(±2)
(±2)
(12 lead) ECG12
X
X
X
X (Cycle 
2 only)
X 
(Cycle 
2 only)
X
Registration and 
Treatment 
Registration13
X
Study treatment14
X
X
X
X
X
X
Injection Site 
Tolerability 
Assessment15
X
X
X
X
As clinically indicated
Inpatient Monitoring16
→
X16
Tumor assessments
CT or MRI scan or 
equivalent17
X
X (every 6 weeks beginning at Cycle 3 
and then every 12 weeks beginning at 
Cycle 8)
X17
Other samplings
Refer to Schedule of Pharmacokinetic, 
 Assessments for Subcutaneous Administration
Blood samples for 
PF-06671008
Blood sample for 
Anti-PF-06671008 
Antibody
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Treatment Period
Post Treatment
Cycle 1
(1 cycle = 21 days)
Cycles 2
Visit Identifier
Screen1
(28 days 
prior to 
registration)
Day 
1
Day 2 Day 3 Day 5 Day 8
Day 
15
Day 1
Day 2
Day 8
Day 15
End of 
Treatment22
Follow-up23
Visit Window (days)
(1)
(1)
(1)
(2)
(2)
Other clinical 
assessments
Adverse events19
X
X
X
X
X
X
X
X
X
X
Concomitant 
Treatments20
X
X
X
X
X
X
X
X
X
X
X
Ophthalmic 
Examination21
X
* Visit windows are calculated off the first day of each cycle.  See Dose Delays section for calculation of visit windows for Cycle 1.
Abbreviations: CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging
1.
Screening: to be obtained within 28 days prior to registration.
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures.  May be obtained more than 28 days prior to registration.
3.
Complete Physical Examination: No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment is performed within 3 days of dosing.
4.
Vital Signs: Includes temperature (oral, tympanic, temporal or axillary), blood pressure (BP) and pulse rate to be recorded in a supine or seated position.  On each dosing day, 
vitals should be measured prior to the PF-06671008 injection.  In addition, pulse oximetry is to be collected on dosing days prior to the PF-06671008 injection as part of the 
vital sign evaluation.
5.
Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendix 3.
6.
Unique Screening Laboratory Tests: Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and human immunodeficiency virus (HIV) as well as 
follicle stimulating hormone (FSH) for post-menopausal women who are amenorrheic for at least 12 consecutive months only.  Samples will be analyzed locally.
7.
Hematology: Complete blood count (CBC) to include hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils and basophils.  No 
need to repeat on C1D1 if baseline assessment performed within 3 days of dosing.  Assessments performed at all subsequent dosing visits should be performed within 
48 hours prior to dosing.  Samples will be analyzed locally.
8.
Blood Chemistry: Should include sodium, potassium, chloride, BUN (or urea), uric acid, creatinine, glucose, calcium, magnesium, phosphorus, albumin, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), and C-reactive protein (CRP).  
Measurement of CRP not required after C2D1 if within normal range or similar to baseline levels; however, CRP should be measured anytime cytokine release syndrome is 
suspected and not already scheduled to be measured (eg, Cycle 2).  No need to repeat on C1D1 if baseline assessment performed within 3 days prior to dosing.  Assessments 
performed at all subsequent dosing visits should be performed within 48 hours prior to dosing.  Samples will be analyzed locally.
9.
Coagulation: Prothrombin Time (PT) or International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT).  No need to repeat on C1D1 if baseline assessment 
performed within 3 days of dosing.  Samples will be analyzed locally.


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10. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 if baseline assessment performed within 3 days of dosing.  
Samples will be analyzed locally.
11. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will be performed on two occasions 
prior to starting study treatment – once at the start of screening and once on C1D1 immediately before investigational product administration.  Pregnancy tests will also be 
routinely repeated at every cycle during the active treatment period, at the end of study treatment and additional whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board (IRB) or if required by local regulations.
12. Triplicate 12-Lead ECG: Triplicate ECGs to be collected before dosing and at 24 hours post the Cycle 1 Day 1 and Cycle 2 Day 1 PF-06671008 injections.  At each time 
point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF interval.  When coinciding with blood sample draws for 
pharmacokinetics (PK), ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If the mean QTcF 
is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Additional triplicate ECGs may be performed as 
clinically indicated.
13. Registration: Patient enrollment number and dose level allocation provided by Pfizer Inc.  Registration should occur before any other Day 1 activities are performed.
14. Study Treatment: PF-06671008 will be administered once every 7 days as a subcutaneous injection.  
15. Injection Site Tolerability Assessment: Assessment of each injection should be conducted for at least 1 hour following each treatment administration in Cycle 1.  In 
addition, an assessment should be performed 24 hours (±1 hour) after the Cycle 1 Day 1 dose.  Injection site tolerability assessments should continue after each dosing visit in 
Cycle 2 and beyond, only if injection site pain or injection site reaction (ISR) characteristics continue to persist.  The assessments should continue at regularly scheduled visits 
until the symptoms resolve.
16. Inpatient Monitoring: Patients receiving PF-06671008 subcutaneously will be admitted for inpatient monitoring for at least 48 hours following the first administration of 
study treatment (C1D1).  For patients enrolled in cohorts where Dose Prime will be given on C1D1 followed by a higher dose on C1D8, patients will also be admitted for 
inpatient monitoring for at least 48 hours (for cohorts evaluating SC route of administration) following the second dose (C1D8).  Patients may be released only after the 
investigator has confirmed the patient has not exhibited signs of a cytokine reaction.  Patients should complete the required study specific laboratory assessments as detailed in 
the Schedule of Pharmacokinetic, 
 for Cohorts Where PF-06671008 Will Be Administered Subcutaneously table and 
should be monitored per local standard practice for inpatient monitoring.  At doses of 100 ng/kg or higher, especially when the total dose exceeds 10,000 ng, additional 
in-patient overnight observation for subsequent doses beyond C1D1 may be considered based on the investigator’s discretion and should be discussed with Pfizer.
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans or equivalent.  
The same modality should be completed, if possible throughout the study.  Bone scans will be performed at baseline if disease is suspected and on study as appropriate to 
follow disease.  Baseline central nervous system (CNS) imaging is not required with the exception of symptomatic patients to rule out CNS metastases; patient ineligible if 
positive for CNS metastases.  CT or MRI scans to be done every 6 weeks (±7 days) from the start of study treatment until disease progression by irRECIST or death, or until 
permanent discontinuation of study treatment.  The frequency will change to every 12 weeks (±7 days) beginning at Cycle 8. Response (complete response (CR)/partial 
response (PR)) and disease progression will be confirmed with two consecutive timepoints at least 4 weeks apart (in the absence of rapid clinical deterioration for 
progression).  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  Tumor assessments should be repeated at the End of Treatment 
visit if more than 6 weeks have passed since the last evaluation. 
18. Tumor Tissue Samples: Patients enrolled in Part 1 and Part 2 will provide archival formalin-fixed paraffin embedded material containing tumor that is of diagnostic quality 
and representative of their diagnosed malignancy or fresh pre-treatment biopsy if the archival tumor is not available (tissue blocks are preferable, but freshly-cut paraffin 
sections are acceptable and must comprise 10 paraffin section, 4-microns in thickness, cut within 1 week of submission, and place individually on unstained, unbaked charged 
glass microscope slides) for evaluation of P-cadherin expression level.  The mandated archival tumor sample will be assayed for P-cadherin expression levels retrospectively 
in Part 1 and prospectively for eligibility for Part 2.  Additionally, fresh pre-treatment biopsy (ie, collected during screening) and on-treatment biopsy samples on Cycle 3 
Day 1 (±5 days) are optional for the initial 2-4 patients enrolled in each cohort in Part 1.  Fresh pre- treatment biopsy (ie, collected during screening) and on-treatment biopsy 
samples on Cycle 3 Day 1 (±5 days) will be mandatory for patients enrolled in Part 1 in cohorts with clinically relevant dose levels of 100 ng/kg or higher where the safety has 
been confirmed in the initial 2-4 patients and a decision is made to expand a dose for further evaluation and for patients enrolled in Part 2.  Additional unscheduled 
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on-treatment biopsies may be collected, if indicated, and agreed upon by the sponsor and investigator and agreed to by the patient.  The screening biopsy should preferably be 
completed after all eligibility criteria have been verified.  Fresh pre-treatment and on-treatment biopsies should be taken from the same lesion, not previously irradiated, if 
possible.  An archival biopsy collected 6 months prior to study start may be substituted for the pre-treatment biopsy if the patient received no treatment between the 
collection of this tumor biopsy and study start.  If the patient discontinues the study before the scheduled on treatment biopsy (C3D1), the patient will be asked to provide a 
fresh biopsy at the End of Treatment visit.
19. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03.  Patients must be followed for AEs for 28 days after the last study treatment administration or until all drug-related toxicities 
have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the meantime.  For serious adverse events (SAEs), the 
active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 28 calendar days after the last 
study treatment administration.  SAEs occurring to a patient after the active reporting period has ended should be reported to the sponsor 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 are to be reported to the sponsor.
20. Concomitant Treatments: All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the 
drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
21. Ophthalmic Examination: An eye exam (performed by an ophthalmologist) will be performed at screening.  The eye exam includes Best Corrected Visual Acuity (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.
22. End of Treatment Visit (EOT): Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
23. Follow-Up: At least 28 days, and no more than 35 days, after discontinuation of treatment, patients will return to obtain these assessments as well as an evaluate the 
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.  Subsequent to the Follow-Up visit, 
patients should be contacted by telephone every 8 weeks (7 days) to obtain information on subsequent anti-cancer treatment and overall survival for up to two years from the 
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Schedule of Pharmacokinetic, 
 Assessments for Subcutaneous Administration
Visit Identifier 
Screen
Cycle 1
Cycle 2
Subsequent Cycles EOT
Study Day
1
2
3
5
8
9
10
15
1
2
3
8
15
1
8
15
Hours Pre-/Post-Dose*
0+
4
8
24
48
96
0
4
8
24
48
0
0
4
8
24
48
0
0
0
0
0
Blood samples for 
PF-06671008 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
Anti-PF-06671008 Antibody3
X
X
X
X
X
CCI
CCI
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06671008 is a bi-specific T-cell-engaging therapy being developed for the treatment of 
adult patients with advanced solid tumors unresponsive to currently available therapies or for 
whom no standard therapy is available.
1.2. Background and Rationale
Bispecific redirected T-cell-engaging therapies have demonstrated proof of concept (POC) in 
hematological malignancies with the recent United States Food and Drug Administration 
(US FDA) approval of the bispecific agent blinatumomab4 for the treatment of acute 
lymphoblastic leukemia (ALL). This modality has also shown promise for the treatment of 
solid tumors with several bispecific agents targeting solid tumors in early clinical studies.
Bispecific redirected T cell molecules are typically recombinant bispecific antibody 
fragments with one binding domain targeting a specific tumor antigen of choice and the other 
binding domain targeting the T cell receptor complex, most often the cluster of 
differentiation 3 epsilon (CD3ε) molecule. Similar to a standard synapse formation, once a 
threshold of bispecific mediated-immune synapses have formed, CD3ε signals the T cell to 
initiate a cytotoxic response toward the adjacent tumor cell expressing the specific antigen. 
The most clinically advanced bispecific platforms that have been reported are typically 
smaller protein molecules, around 50 kD, with short circulating half-lives (t1/2 ~1 hour) that 
require constant infusion through the use of a pump to achieve a stable exposure to the 
therapeutic molecule.
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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The cadherin superfamily includes classical cadherins, protocadherins, and desmosomal 
cadherins. Classical cadherins constitute a family of molecules that mediate 
calcium-dependent cell-cell adhesion and are localized at the adherens junctions.  Their 
intracellular domains directly interact with cytoplasmic catenins that link to the actin 
cytoskeletal network, providing the molecular basis for stable cell interactions.  The 
cadherin/catenin complex, as well as the signaling pathways controlled by this structure, 
represent a major regulatory mechanism that guide cell fate decisions, through its influence 
on cell growth, differentiation, motility, and survival.  Classical cadherins include the 
E-cadherin (CDH1), N cadherin (CDH2) and P-cadherin (CDH3).  P-cadherin expression has 
been reported to correlate with increased tumor cell motility and invasiveness when 
overexpressed.  Elevated expression of P-cadherin has been reported in various tumors, 
including breast, gastric, endometrial, colorectal, lung and pancreatic cancers, and is 
correlated with poor survival of breast cancer patients.7,10,16,19,20,22  In contrast, significantly 
lower levels of the P-cadherin gene expression have been detected in normal tissues.10  
 
 
TNBC is a heterogeneous disease constituting approximately 15-20% of breast cancers and is 
characterized by the lack of expression of estrogen receptor (ER), progesterone receptor 
(PgR), and the absence of human epidermal growth factor receptor 2 (HER2) overexpression 
and/or amplification.  It occurs more frequently in women less than 50 years old and 
generally behaves more aggressively than other breast cancer subtypes.3  Although TNBC 
patients experience higher rates of pathological complete responses (pCR), when treated with 
neoadjuvant chemotherapy, they experience shorter duration-free survival (DFS) and overall 
survival (OS) relative to patients with non-TNBC.13  The majority of patients receive 
anthracyclines and taxanes in the neoadjuvant or adjuvant settings.  A variety of single 
agent and combination regimens are active in metastatic TNBC, although rapid 
progression is observed in most patients.15  Thus, novel therapeutic options are urgently 
needed.
NSCLC is the most commonly fatal malignancy in the US accounting for nearly 30% of all
cancer related deaths, and a frequent cause of mortality throughout the world. In the US in 
2013, there were over 200,000 new cases. Approximately 80% of lung cancer is
histologically defined as non-small cell and the remaining 20% as small cell.  The majority of 
patients with NSCLC present with inoperable locally advanced (Stage IIIB) or metastatic
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(Stage IV) disease for which no curative treatment is available. Platinum-based doublet
combination chemotherapy regimens have become the clinical and regulatory standard of 
care for these patients. Patients with disease progression on or after first-line treatment 
may be candidates for second-line treatment. Second-line treatment options are limited and 
are of limited benefit.8 NSCLC continues to be an area of high unmet medical need.
CRC also continues to be an area of unmet medical need despite advances in cytotoxic 
chemotherapies and newer targeted agents.  In the US, nearly 150,000 new cases are 
diagnosed each year, and it results in the death of nearly 50,000 people annually.1  Currently, 
treatment options include combinations of a fluoropyrimidine with either oxaliplatin or 
irinotecan as a backbone.  Targeted agents have shown added benefit when added to these 
regimens, including monoclonal antibodies directed against the Epidermal Growth Factor 
Receptor (EGFR; cetuximab and panitumumab) and vascular endothelial growth factor 
(VEGF; bevacizumab, aflibercept).9,18,5 Recently, the first oral multikinase inhibitor 
regorafenib has been approved for the treatment of refractory CRC.6  However, despite 
advances in the treatment of CRC, the metastatic disease will ultimately progress and patients 
will die due to the advanced CRC.
1.2.1. P-cadherin Expression in Human Cancers
Bioinformatics, expression profiling and immunohistochemistry (IHC) data indicated that 
P-cadherin is over-expressed in triple negative breast, non-small cell lung and colorectal
cancers. These findings have been confirmed using preclinical cell line and patient-derived 
xenograft models representing these three indications. PF-06671008 mediated activity in 
vivo has been observed in all three indications.
1.3. PF-06671008
PF-06671008 is a heterodimeric diabody Fc fusion protein comprised of two recombinant 
scFv domains, one against P-cadherin (human) and the other against the CD3ε chain
(humanized), fused to the human Fc domain of IgG1.  PF-06671008 allows the T cell to 
circumvent the need for the interaction of the TCR and MHC class I in complex with antigen, 
and instead redirects T cells to target cells through direct co-engagement of CD3ε expressed 
on the T cell and P-cadherin expressed on the tumor. The subsequent CD3ε signaling 
cascade directs T cell mediated killing of cells expressing P-cadherin through the release and 
transfer of granzyme B and perforin from the T cell to the target cell.
1.3.1. Efficacy
 
 
 
 
 
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1.5. Starting Dose Rationale
1.5.1. Intravenous Administration
The selection of the starting dose for this first-in-patient (FIP) study was based on the 
MABEL in accordance with the International Conference on Harmonization (ICH) S9 
Guidance, given that PF-06671008 is a bi-specific T cell-engaging agent with immune 
agonistic properties.  
 
 
 
 
 
 
 
 
 
 
 
Based on this MABEL approach, the clinical starting dose selected for the study is 1.5 ng/kg
given as a 1-hour intravenous infusion weekly.  
 
 
 
 
 
 
Prediction of clinical efficacious dose was based on efficacious concentration (Ceff) estimated 
from mouse PK
studies and predicted human PK.  
 
 
 
 
 
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Body weight-based dosing approach (mg/kg) will be applied for the FIP study of 
PF-06671008 with the goal to reduce inter-individual variations in PK exposure.  Pfizer 
intends to conduct population PK analysis of PF-06671008 after sufficient data have been 
collected to inform optimal dosing approach for future studies.
1.5.2. Subcutaneous Administration
Based on emerging safety, tolerability, and PK data from the initial IV administration 
cohorts, the study will be expanded to evaluate the safety and tolerability of PF-06671008 
with SC administration.
 
The SC administration dose escalation cohorts are planned to commence after 
the IV priming dose level is declared and the SC cohort will proceed in parallel with the 
IV dose escalation cohorts (See Section Criteria for Dose Escalation).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Once the IV Dose Prime (according to the criteria specified in Section Evaluation of a 
Priming Dose) is declared, the SC administration cohort will be started at the IV priming 
dose level. The SC starting dose selection takes into consideration the clinical safety, 
tolerability and PK data from the initial IV administration cohorts, and the expected drug 
exposure with SC administration.
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A SC starting dose at the IV priming dose level is projected to result in lower systemic 
exposure of study drug relative to IV priming dose. 
 
 
 
 
Safety measures for monitoring potential toxicities following SC drug administration are 
planned, including AE and CRS evalatuion along with serial assessment of the injection site
(See Section 7.1). In the SC cohorts in Part 1, there will be a minimum 72-hour separation of 
the first dose administered to each of the initial patients (ie, patients contributing to initial 
DLT evaluation.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Dose Escalation (Part 1) Objectives
Primary Objective
•
To assess safety and tolerability of increasing dose levels of PF-06671008 
administered in patients with advanced solid tumors for whom no standard therapy is 
available in order to estimate the Maximum Tolerated Dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 
Secondary Objectives
•
To evaluate the overall safety profile; 
•
To characterize the single and multiple dose PK of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To document any anti-tumor activity.
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2.1.2. Dose Expansion (Part 2) Objectives
Primary Objective
•
To confirm safety and tolerability and explore preliminary evidence of anti-tumor 
activity of PF-06671008 at the RP2D in patients with P-cadherin expressing advanced 
CRC, TNBC or NSCLC.
Secondary Objectives
•
To evaluate the overall safety profile at the RP2D;
•
To characterize the single and multiple dose PK of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To evaluate preliminary anti-tumor activity through time to event endpoints.
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2.2. Endpoints
Primary Endpoint (Part 1)
•
First cycle Dose-Limiting Toxicities (DLTs).
Primary Endpoint (Part 2)
•
Objective response (OR) as determined by the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 criteria (Appendix 4).
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v.4.03) (Appendix 6), timing, seriousness, and relationship to study therapy;
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing;
•
Vital sign abnormalities;
•
Pharmacokinetic parameters of PF-06671008 Single Dose (SD) - Cmax, Tmax, AUC sd,τ, 
t1/2, AUCinf, and CL for IV administration or CL/F for SC administration as data 
permit.  Multiple Dose (MD) (assuming steady state is achieved) - Css,max, Tss,max, 
AUCss,τ, t1/2, Css,min, CL for IV or CL/F for SC, Vss for IV or Vss/F for SC, and Rac
(AUCss,τ/AUCsd,τ) as data permit;
•
Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies against 
PF-06671008;
•
Objective response, as assessed using the RECIST version 1.1 – Part 1 only;
•
Progression Free Survival (PFS) and Overall Survival (OS) – Part 2 only.
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK 
 study of 
single-agent PF-06671008.  This study contains two parts, dose escalation (Part 1) followed 
by dose expansion (Part 2).  Sequential cohorts of patients with tumor types with the 
potential to have P-cadherin expression (see Appendix 2), that are resistant to standard 
therapy or for whom no standard therapy is available, will receive escalating doses of 
PF-06671008 in Part 1 of the study.  In addition, at clinically relevant dose levels of 
100 ng/kg or higher (ie, doses where the exposure is near the target effective exposure) where 
the safety is confirmed in the initial 2-4 patients dosed, approximately up to 5 additional 
patients with CRC, TNBC, NSCLC or squamous cell carcinoma of the head and neck 
(SCCHN) may be enrolled.  
 
 
Up to approximately 152 patients are expected to be enrolled in the study overall. The actual 
number of patients enrolled will depend on the tolerability of PF-06671008 and the number 
of dose levels required to identify the MTD.
PF-06671008 will be administered as a weekly IV infusion in 21-day cycles with a starting
dose of 1.5 ng/kg. There will be a minimum 72-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 due to the unknown time course of possible infusion-related 
reaction or cytokine release. All patients will be observed in-patient for at least 24 hours 
after the first dose on C1D1.  At doses of 100 ng/kg or higher, especially when the total dose 
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exceeds 10,000 ng, additional in-patient overnight observation for subsequent doses beyond 
C1D1 may be considered based on the investigator’s discretion and should be discussed with 
Pfizer.
In addition, PF-06671008 will also be administered in cohorts as a weekly SC injection in 
21-day cycles with a starting dose equal to the dose level selected as the IV Dose Prime (See 
Section Evaluation of a Priming Dose).  Dose escalation cohorts with PF-06671008 
SC administration will be evaluated independently in parallel with dose escalation cohorts 
evaluating PF-06671008 IV administration (See Section Criteria for Dose Escalation).  For 
cohorts where a SC route of administration will be evaluated, there will also be a minimum 
72-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 due to the unknown time 
course of possible cytokine release.  All patients who will be dosed subcutaneously will be 
observed in-patient for at least 48 hours after the first dose on Cycle 1 Day 1 (C1D1).  
Additional in-patient observation for subsequent cycles beyond C1D1 may be considered 
based on the investigator’s discretion and should be discussed with Pfizer.  Evaluation of 
either the IV or SC route of administration may be discontinued based on emerging clinical 
and safety data.
In the event study treatment administration is delayed due to toxicities during Cycle 1, the 
day when the patient receives their 4th dose of study drug will be counted as Day 1 of 
Cycle 2. 
Treatment with investigational product will continue until either disease progression, patient 
refusal, or unacceptable toxicity occurs, whichever is earliest, unless the investigator and 
medical monitor agree to treatment beyond disease progression based on individual 
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Figure 3.
Overall Study Design
The proposed doses, schedule(s), and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
3.2. Dose Escalation Phase (Part 1)
Increasing dose levels of PF-06671008 administered weekly will be evaluated using a 
modified toxicity probability interval (mTPI) method that targets a MTD associated with a 
27.5% probability of DLT.  Part 1 will follow a mTPI method initially with cohorts of 
1-2 patients each and a primary DLT observation period of 21 days following the first dose 
(C1D1). 
If a DLT or other toxicities occur (ie, those that have the potential to be DLTs if more severe) 
during Cycle 1 but prior to the observation of Grade 3 cytokine release syndrome 
(as described below in Evaluation of a Priming Dose), dose escalation will continue to follow 
a mTPI design but with cohorts of 2-4 patients each. The primary DLT observation period 
will continue to be 21 days following the first dose (C1D1).


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Additional patients may be entered at any dose level in the IV and/or SC routes of 
administration at or below the MTD, after discussion with and permission by the sponsor, to 
obtain additional safety, PK
and anti-tumor activity data. 
 
  These additional patients will require paired biopsies.  Because these 
additional patients will receive a dose lower than the concurrent dose escalation cohort or 
will be enrolled at dose following the DLT evaluation period in the first 2-4 patients enrolled, 
their potential DLT observations may not be strictly used in the mTPI algorithm for the 
ongoing dose finding.  However, the safety profile from these additional patients will be used 
to establish the MTD or recommended Phase 2 dose (RP2D).
3.2.1. Evaluation of a Priming Dose
Based on toxicity study results, the evaluation of a priming dose to allow subsequent higher 
level dose administration may be instituted in this study. In addition, blinatumomab, an 
approved bispecific agent for the treatment of ALL, has been able to overcome symptoms of 
cytokine release syndrome (CRS) with the implementation of a priming dose (Topp et al, 
2014).21  Therefore, this study may implement the evaluation of a priming dose during the 
escalation phase.
The initial priming dose will be defined to facilitate subsequent dose escalation towards
establishing the MTD of a dosing regimen that includes a priming dose.  The study aims to 
determine a MTD for an IV dose regimen that does not include a priming dose, and an 
independent MTD for an IV dose regimen that includes a priming dose. In addition, the 
study aims to similarly determine a MTD for PF-06671008 administered subcutaneously that 
may or may not include a priming dose.
The decision to evaluate a regimen that includes a priming dose may be made by the 
investigators and sponsor prior to reaching a MTD using the following criteria as guidance:
If a dose level induces symptoms consistent with Grade 3 CRS as defined in Appendix 8
lasting for >24 hours considered not to be due to an infusion related reaction (IRR), allergic 
reaction, anaphylaxis or other causes in a cohort of 2-4 patients after the initial infusion, an 
additional 1-4 patients (up to approximately 6 patients overall) will be enrolled at that dose to 
confirm implementation of a priming dose (Dose Prime) for subsequent cohorts.  If an 
additional confirmed CRS of Grade 3 lasting for >24 hours is observed at that dose, then a 
lower dose, which has been evaluated in at least 2-4 patients, will be chosen as a priming 
dose (Dose Prime) for subsequent cohorts.  If a Dose Prime is selected, dose escalation will 
continue to determine the MTD of a dose regimen that includes a priming dose.  The 
evaluation of a Dose Prime may be implemented for both the IV and/or SC routes of 
administration.
If a dose level induces confirmed CRS of Grade 4 considered not to be due to an IRR, 
allergic reaction, anaphylaxis or other causes, then a lower dose, which has been evaluated in 
at least 2-4 patients, will be chosen as a priming dose (Dose Prime) for subsequent cohorts.
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In addition, observation of a confirmed CRS event that meets the above qualifications 
following later infusions (ie, after Cycle 1 Day 1) or CRS events that are approaching the 
limit of tolerablity may prompt the investigators and sponsor to include evaluation of a Dose 
Prime for subsequent cohorts.
After confirmation of the safety of Dose Prime, the treatment schedule will implement the 
inclusion of the fixed priming dose as the first dose (C1D1) followed by a second dose 
(C1D8) that will continue to be escalated in subsequent cohorts following an mTPI method in 
cohorts of 2-4 patients.  After the MTD has been established, the priming dose may 
potentially be further verified in connection to the established MTD/RP2D, including 
consideration of more than one priming step, if indicated, using information from all patients 
who were included in the initial priming dose determination as well as those enrolled in 
subsequent dosing cohorts.
The primary DLT observation period for cohorts that include Dose Prime will be 21 days 
following the first dose (C1D1).  The dose escalation should a Dose Prime be instituted is 
depicted in Figure 4.
For cohorts instituting a Dose Prime, there will be a 72 hour observation period between the 
first dose administered to each of the initial patients enrolled (ie, patients contributing to 
initial DLT evaluation) at a new dose level.  In addition to in-patient observation following 
the C1D1 dose, patients enrolled in cohorts instituting a Dose Prime must also undergo 
in-patient observation for at least 24 hours (for cohorts where PF-06671008 will be 
administered IV) or 48 hours (for cohorts where PF-06671008 will be administered SC)
following the C1D8 dose.
Figure 4.
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3.2.2. Criteria for Dose Escalation
The 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%.
Typically patients will be enrolled in cohorts of 2 to 4, but patients could be initially enrolled 
in cohorts of 1-2 for the lower doses (see section Dose Escalation Phase (Part 1)).  The initial 
2-4 patients to be included in a cohort will be open to any of the tumor types outlined in 
Appendix 2.  When required to expand a cohort for further evaluation of the MTD, 
enrollment of patients may be limited to those with NSCLC, SCCHN, CRC or TNBC.
For IV administration cohorts, initial dose levels are provided in Table 1 and will be followed 
if no DLTs are observed; intermediate doses may be evaluated based on clinical findings. 
Subsequent maximum dose increases will be a maximum of 2-fold (100%) if no DLTs are 
observed.  For SC administration cohorts, during the initial dose escalation levels, maximum 
dose increases will be up to 3-fold if no DLTs or safety events that are approaching the limit 
of tolerability are observed.  The initial dose to be evaluated for SC administration will be 
equal to the dose level selected as the IV Dose Prime. The evaluation of the IV and 
SC routes of administration will proceed through dose escalation independently according to 
the mTPI method. Once the first DLT is observed, the maximum increase would follow a 
modified Fibonacci series in case of dose escalation (ie, 67%, 50%, 33%, etc.).  Patients will 
be assigned to a dose that is closest to the current MTD prediction based on the mTPI 
method.  The mTPI method relies upon a statistical probability algorithm, calculated using all 
patients treated in prior and current cohorts at the same dose level to determine (Decision 
Rules) where future cohorts should involve dose escalation, no change in dose, or dose
de-escalation as presented in Table 2 (see also Section Statistical Methods and Properties).
Table 1.
Dose Escalation Levels for 
IV Administration
Dose Level
Dose
(ng/kg)
1 (Starting Dose)
1.5
2
7.5
3
20
4
50
5
100
6
200
7
300
8
400
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Table 2.
Decision Rules
Number of Patient Treated at a Dose Level
Number of 
Patients 
Having 
DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
3
U
U
D
D
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
5
U
U
U
U
U
D
D
D
6
U
U
U
U
U
U
U
7
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; U: Unacceptable toxicity
Note: If one patient has a DLT event observed in a dose cohort with 1 patient enrolled, additional patients 
(eg, 1 or 2) may be enrolled for dose escalation assessment.
Dose escalation will stop under any of the following conditions:

The maximum sample size has been achieved;

6-12 patients have been enrolled at a dose that is predicted to be the MTD;

All doses explored appear to be overly toxic and the MTD cannot be determined.
Intrapatient dose escalation, other than the potential inclusion of priming doses, will not be 
permitted in this study.
3.3. DLT Definition
Severity of adverse events will be graded according to CTCAE version 4.03 (Appendix 6). 
For the purpose of dose escalation, any of the following adverse events occurring in the first
cycle of treatment (21 days after the first dose) will be classified as DLTs, unless there is a 
clear alternative explanation (eg, related to underlying disease/progression):
Hematologic:

Grade 4 neutropenia lasting 5 days;

Febrile neutropenia defined as an absolute neutrophil count (ANC) <1.0 x 109/L with 
a single temperature of >38.3C, or 101oF, or a sustained temperature of 38C, or 
100.4F, for more than one hour;

Grade 3 neutropenia with infection;

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
Grade 4 thrombocytopenia.
Non-hematologic:

Grade 4 toxicities (not attributed to CRS) that are considered clinically significant;

Grade 3 toxicities (not attributed to CRS) that are considered clinically significant
despite maximal supportive care (eg, nausea, vomiting, diarrhea, easily corrected 
electrolyte abnormalities) that last >72 hours;

Grade 3 CRS considered not to be due to an IRR, allergic reaction or anaphylaxis, 
except those i) not maximally treated or ii) events that are maximally treated, 
(eg, including the use of tocilizumab and/or vasopressors), and resolve to Grade 2 
within 72 hours;

Delay by more than 2 weeks in receiving the next scheduled dose due to persisting 
treatment related toxicities.
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.
Grade 3 infusion reaction, allergic reaction or anaphylaxis will not be considered as DLTs
but may be a reason for study discontinuation and should be reviewed with the sponsor.
3.4. MTD Definition
The estimated MTD is the dose level associated with approximately 27.5% of DLT-evaluable 
patients experiencing a DLT. The target interval for the DLT rate is (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 0.325 in at least 6-12 evaluable patients
for DLT.  The study aims to determine a MTD for a dose regimen that does not include a 
priming dose administered IV, and an independent MTD for an IV dose regimen that 
includes a priming dose. In addition, the study aims to determine a MTD for PF-06671008 
administered SC and may also determine an independent MTD for a SC dose regimen that 
includes a priming dose.
3.5. Dose Expansion Phase (Part 2)
The maximum sample size for each tumor indication (ie, TNBC, CRC and NSCLC) will be 
in the range n=10 to n=20. Enrollment of patients in one indication may be discontinued if 
minimal or no anti-tumor activity (eg, 0 or 1 response) is observed in the first 10 evaluable 
patients for that indication (see section Sample Size Determination). 
3.6. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study based on Phase 1 study results.  If the MTD 
proves to be clinically feasible for long-term administration in a reasonable number of 
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result in a RP2D dose lower than the MTD (eg, if in the expansion part >25% of patients 
require a dose reduction due to toxicity, then the sponsor may convene a safety committee to 
determine if a lower RP2D needs to be determined).
4. PATIENT SELECTION
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 non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. For dose escalation (Part 1): Histological or cytological diagnosis of a tumor type 
with the potential to have P-cadherin expression (see Appendix 2). Patients with 
tumor types other than those listed in Appendix 2 may be allowed to enroll based on 
emerging data and with the agreement of the sponsor. Patients must be refractory to, 
intolerant of established therapy known to provide clinical benefit for their condition, 
ie, patients must not be candidates for regimens known to provide clinical benefit.
2. For dose escalation (Part 1): Must have tumor tissue available for submission to the 
sponsor.  Patients enrolled in Part 1 should have access to their archival 
formalin-fixed paraffin embedded material containing tumor that is of diagnostic 
quality and representative of their diagnosed malignancy or consent to undergo a 
biopsy during screening.
3. For dose expansion (Part 2): Histological or cytological diagnosis of previously 
treated CRC, TNBC or NSCLC with at least one measurable lesion, not previously 
irradiated, as defined by RECIST version 1.1 (Appendix 4).  Patients must be 
refractory to, intolerant of established therapy known to provide clinical benefit for 
their condition, ie, patients must not be candidates for regimens known to provide 
clinical benefit.
4. For dose expansion (Part 2): Must have tumor tissue available for P-cadherin 
expression evaluation and must meet minimum required P-cadherin expression level
(to be determined prior to activation of Part 2).  Patients enrolled in Part 2 should 
have access to their archival formalin-fixed paraffin embedded material containing 
tumor that is of diagnostic quality and representative of their diagnosed malignancy. 
5. For dose expansion (Part 2): Must have at least one tumor lesion, not previously
irradiated, that is amenable to biopsy and must agree to undergo biopsies required per 
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6. Age 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be
0 or 1. 
8. Total body weight 70 kg (154 lbs) for IV starting dose level only.
9. Adequate bone marrow function, including:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 10 g/dL.
10. Adequate renal function, including:
a.
Estimated creatinine clearance 60 mL/min as calculated using the method 
standard for the institution. 
11. Adequate liver function, including:
a.
Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome;
b. Aspartate and Alanine transaminase (AST and ALT) 2.5 x ULN; 5.0 x ULN if 
there is liver involvement secondary to tumor; 
c.
Alkaline phosphatase 2.5 x ULN; (5 x ULN in case of bone metastasis). 
12. Resolved acute effects of any prior therapy to baseline severity or CTCAE 
Grade 1 except for adverse events (AEs) not constituting a safety risk by 
investigator judgment.
13. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
14. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use two highly effective method(s) of 
contraception throughout the study and for at least 28 days after the last dose of study
treatment.
Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 


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
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range 
for postmenopausal women. 
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. 
16. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory, tests and other procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients with known CNS disease including, but not limited to, metastases. 
2. Current or history of seizure disorder.
3. History of or active autoimmune disorders (including but not limited to: Crohn’s 
Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave’s 
disease) and other conditions that compromise or impair the immune system.
4. Active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C 
(HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness.
5. Bleeding esophageal or gastric varices within 2 months prior to registration.
6. History of or current requirement for chronic blood product support.
7. Grade 2 peripheral neuropathy.
8. Pregnant female patients; breastfeeding female patients.
9. Major surgery within 4 weeks prior to registration.
10. Radiation therapy within 4 weeks prior to registration.  Palliative radiotherapy to a 
limited field is allowed after consultation with the sponsor’s medical monitor unless it 
is clearly indicative of disease progression.
11. Systemic anti-cancer therapy within 4 weeks of registration (6 weeks for mitomycin 
C or nitrosoureas).  If systemic anti-cancer therapy was given within 4 weeks, patient 
may be included if 5 times elimination half-life of drug has passed.
12. Previous high-dose chemotherapy requiring stem cell rescue.
13. Requirement for systemic immune suppressive medication [eg, 10 mg of prednisone 
or equivalent (1.5 mg of dexamethasone)].


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14. History of CTCAE Grade 3 immune-mediated adverse event (including AST/ALT 
elevations that where considered drug related and cytokine release syndrome) that 
was considered related to prior immune-modulatory therapy (eg, checkpoint 
inhibitors, co-stimulatory agents, etc.) or any-grade immune-related AEs that required 
immunosuppressive therapy.
15. Prior treatment with a compound of the same mechanism.
16. Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism. 
17. Participation in other studies involving investigational drug(s) within 28 days prior to 
registration.
18. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
19. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
4.3. Lifestyle Guidelines
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive PF-06671008, a compound for which the teratogenic risk 
is currently unknown.  Two (2) methods of highly effective contraception must be used 
throughout the study and continued for at least 28 days after the last dose of study treatment.  
The investigator or his or her designee, in consultation with the patient, will confirm the 
patient has selected two appropriate methods of contraception for the individual patient and 
his/her partner from the list of permitted contraception methods (see below) and will confirm 
the patient has been instructed in their consistent and correct use.  Patients need to affirm that 
they meet the criteria for correct use of at least 2 of the selected methods of contraception.  
The investigator or his or her designee will discuss with the patient the need to use highly 
effective contraception consistently and correctly according to the Schedule of Activities and
document such conversation in the patient’s chart.  In addition, the investigator or his or her 
designee will instruct the patient to call immediately if a selected contraception method is 
discontinued or if pregnancy is known or suspected in the patient or the patient’s 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:


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1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (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 or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range 
for postmenopausal women.
All sexually active male patients must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
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 study manual.
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 compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational 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 investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 


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the established communication pathways between the investigational 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 investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference of Harmonisation (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference 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).
5.1. Allocation to Treatment
Patient enrollment number and 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 complete Registration Form to the designated 
sponsor study team member.  The sponsor will assign a patient identification number
documenting patient enrollment.  IV and SC routes of administration will be enrolled in 
parallel.  Patients will be allocated to a dose escalation cohort and route of administration
based on the sequential available slots.
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 and route of administration for that patient and;

permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Patient Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigational site.
The site will complete required dosage Preparation Record located in the study 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 Pfizer monitor. 


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5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
PF-06671008 solution for injection, 1 mg/mL is presented as a sterile solution for IV or SC 
administration.  Each vial contains 1 mg of PF-06671008 in 1 mL of aqueous buffered 
solution, is sealed with a coated stopper and an overseal, and is labeled according to local 
regulatory requirements.
5.3.2. Preparation and Dispensing
See the Investigational Product (IP) Manual for instructions on how to prepare the 
investigational product for administration and how to handle the investigational product once 
it is prepared 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, practitioner, pharmacist, or medical assistant) as allowed by 
local, state, and institutional guidance.
Vials are for single-use, single-patient only.
5.4. Administration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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5.4.1. Cytokine Release Syndrome
Symptoms associated with CRS vary greatly and may be difficult to distinguish from other 
conditions. The more common symptoms include fever, nausea, headache, tachycardia, 
hypotension, rash and shortness of breath. The severity of symptoms can be mild to life 
threatening and thus, there should be a high suspicion for CRS if these symptoms occur.  
Grade 1 CRS does not require any intervention but patients should be monitored closely. 
Grade ≥2 CRS requires PF-06671008 infusion interruption and prompt symptomatic 
treatment per local standard of care. For CRS not rapidly responsive to supportive care or 
CRS of Grade ≥3, treatment with corticosteroids and/or tocilizumab,2 an anti-human IL-6R 
mAb, should be considered.12 A suggested treatment algorithm for the management and 
grading of CRS based on a revised CRS grading system by Lee et al. is provided in 
Appendix 8.
The decision to incorporate pre-medication (ie, corticosteroids) for CRS prophylaxis in all 
patients will be made following discussions between the sponsor and the investigators. The 
pre-treatment medication will not be supplied by Pfizer.
CCI


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5.4.2. Infusion Reactions
In the case of infusion related reactions, characterized by fever and chills, and less commonly 
hypotension, the sponsor should be notified and adjustment of infusion rate may be 
considered, which could include interrupting the infusion or slowing the infusion rate to a 
previously acceptable rate by increasing duration of the infusion.  When the infusion rate is 
adjusted to a previously acceptable rate for 2 or more patients at the current cohort, the 
sponsor should be notified and the infusion rates for current and subsequent cohorts should 
be maintained at the previously acceptable rate.
In addition, pre-treatment medication should be administered prior to subsequent infusions 
(in the case that the patient is able to continue on treatment).  The decision to incorporate 
pre-medication for infusion related reaction prophylaxis 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-06671008 administration.  The pre-treatment medication will 
not be supplied by Pfizer.
Suggested starting doses are 650 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 hours after the initial pre-treatment or as needed.
5.4.3. Hypersensitivity Types 1 and 3
Type 1 hypersensitivity or allergic (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) reactions are theoretically possible in response to any injected protein.  Immune 
complex mediated Type 3 hypersensitivity reactions are similar to the adverse events (AEs) 
of Type 1 reactions but are likely to be delayed from the time of infusion and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
All patients should be closely observed while receiving investigational product and 
monitoring for clinical signs of a systemic reaction will continue thereafter for clinical signs 
of allergic reactions/hypersensitivity. 
In the case of a hypersensitivity reaction, the patient will be treated symptomatically with 
supportive care, further monitoring, and treatment with anti-histamines and/or 
corticosteroids.  Study administration may be stopped and the patient will be followed until 
the end of the study.
5.4.4. Extravasation
In the event of extravasation, infusion should be stopped immediately and the investigator 
needs to be consulted immediately.  Treatment of extravasation should follow local standard 
of care.


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5.4.5. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule.
In the event of significant toxicity dosing may be delayed and/or reduced as described below.  
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 modifications may occur in one of three ways:

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. 
5.4.6. Dosing Interruptions
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care should have their treatment interrupted. 
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
the Dose Delays section.
Doses may be held as needed until toxicity resolution.  Depending on when the AE resolved, 
a treatment interruption may lead to the patient missing all subsequent planned doses within 
that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in the Dose Reductions section, unless expressly agreed 
otherwise following discussion between the investigator and the sponsor. 
In the event of a treatment interruption for reasons other than treatment-related toxicity
(eg, elective surgery) lasting >2 weeks, treatment resumption will be decided in consultation 
with the sponsor.


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5.4.7. Dose Delays
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 50,000/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 met within 14 days of treatment interruption or cycle delay, 
PF-06671008 may be resumed.  Refer to Section Dose Reductions for AEs requiring dose 
reduction at the time of treatment resumption.
If treatment interruption due to toxicity exceeds 14 days, treatment with this agent should be 
permanently discontinued.
The day when the patient receives their 4th dose of study drug will be counted as Day 1 of the 
next cycle. Subsequent cycles will be 21 days in length regardless of treatment delays.
5.4.8. Dose Reductions
Following dosing interruption or cycle delay due to toxicity, the PF-06671008 dose may need 
to be reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Dose reduction of PF-06671008 by 1 and, if needed, 2 dose levels will be allowed depending 
on the type and severity of toxicity encountered.  Patients enrolled in the first cohort should 
be discontinued from the study if more than 1 dose reduction is required.  Patients requiring 
more than 2 (or 1 for the first cohort) dose reductions will be discontinued from the treatment 
and entered into the follow-up phase, unless otherwise agreed between the investigator and 
the sponsor.  All dose modifications/adjustments must be clearly documented in the patient's 
source notes and CRF. 
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is not allowed.
Patients experiencing a DLT may resume dosing at the next lower dose level (if applicable) 
once adequate recovery is achieved. 


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Recommended dose reductions are described in Table 3.
Table 3.
Dose Reductions
Event
Action
Grade 3 or 4 non-hematologic toxicity (except CRS)
considered related to PF-06671008 per investigator 
judgment (including persistent nausea, vomiting, diarrhea 
despite optimal medical therapy), excluding clinically 
manageable electrolyte abnormalities.

Hold PF-06671008  until recovery to Grade 0-1 or 
baseline and reduce by 1 dose level.

If toxicity (Grade 3-4) reoccurs despite reduction, 
patient may be dose reduced again by 1 more dose level 
(except for the first cohort) upon recovery to Grade 0-1 
or baseline. 

Prompt palliative and supportive measures mandated 
per local standard of care (eg, antiemetic). 

Patients who experience Grade 4 non hematologic 
toxicities despite intervention should be discontinued 
from study treatment, unless restarting treatment at 
reduced dose level is in the patient’s best interest per 
investigator judgment and after consultation with 
Pfizer’s medical monitor (eg, clear clinical benefit and 
no alternative treatment options).
Cytokine Release Syndrome

Grade 2: Hold PF-06671008 until resolved and resume 
at same dose level.  If Grade 2 CRS reoccurs, hold 
PF-06671008 until resolved and consider reduction by 
1 dose level based on the investigator’s discretion.

Grade 3: Hold PF-06671008 until resolved and 
consider reduction by 1 dose level based on the 
investigator’s discretion.  If Grade 3 CRS recurs 
despite reduction, permanently discontinue 
PF-06671008.

Grade 4: Permanently discontinue PF-06671008.
Hematologic toxicity considered related to PF-06671008 
per investigator judgment

Grade 4 neutropenia, ie, ANC 500 mm3
(1.0 x 109/L) for more than 5 days 
or

Febrile neutropenia, ie, fever >38.3C (101F)or 
a sustained temperature of 38C (100.4F) 
with ANC <1000/mm3
or

Grade 3 neutropenic infection
or

Grade 4 Thrombocytopenia, ie, PLTS 
25,000 mm3 (25.0 x 109/L) 
or

Grade 3 Thrombocytopenia, ie, PLTS 
50,000 mm3 (50.0 x 109/L) with bleeding.

Hold PF-06671008 until recovery of ANC to 1.0 x 
109/L (1,000 cells/mm3) and platelets 75 x 109/L 
(75,000 cells/mm3). 

Reduce PF-06671008 by 1 dose level.

If toxicity reoccurs (grades as described on the left 
side) despite dose reduction, patients may either be 
held until recovery and continuation at same dose, or 
undergo further dose reduction by 1 more dose level
(except for the first cohort).
Other grade 4 hematologic toxicity considered related to 
PF-06671008 per investigator judgment

Hold PF-06671008 until recovery to Grade 0-1 or 
baseline and reduce PF-06671008 dose by 1 dose level.

If toxicity reoccurs (Grade 4) despite dose reduction, 
patient may either be held until recovery and 
continuation at same dose, or undergo further dose 
reduction by 1 more dose level.
No recovery of toxicities within 4 weeks of scheduled 
PF-06671008 infusion

Discontinue treatment, unless restarting treatment at 
reduced dose level is in the patient’s best interest per 
investigator judgment and after consultation with 
Pfizer’s medical monitor (eg, clear clinical benefit and 
no alternative treatment options).


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5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational product is stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  See the investigational product label for storage conditions of the product.
Storage conditions stated in the SRSD (ie, IB) will be superseded by the storage conditions 
stated in the labeling. 
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 daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of 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 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 product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.  More specific details will be provided to the sites separately.
Refer to the investigational product manual for any additional guidance on storage conditions 
and actions to be taken when conditions are outside of the specified range. 
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.


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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 study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.
All concomitant treatments, including supportive care drugs (eg, anti-emetic treatment and 
prophylaxis), drugs used to treat AEs or chronic disease, blood products, as well as non-drug 
interventions (eg, transfusions) received by patients from screening until the Follow-up visit 
will be recorded on the CRF. 
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 bony 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-06671008 with radiotherapy, 
PF-06671008 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 American Society of Clinical 
Oncology (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 
current ASCO guidelines. 
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 


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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 is up to the investigator with sponsor approval and assuming the drug 
is not included in the Concomitant Treatment(s) section, as well as the duration of treatment,
assuming there is no known or expected drug-drug interaction.  If so, then it must be 
approved by the sponsor.
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 included in the 
Concomitant Treatment(s) section. 
5.7.6. Corticosteroids
Chronic, systemic corticosteroid use for palliative or supportive purposes is not permitted in 
cases other than those discussed in the Cytokine Release Syndrome section.  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-06671008 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-06671008 is 
recommended at least 7 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-06671008 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES
6.1. Screening
For screening procedures see Schedule of Activities and Assessments section.  Screening to 
be obtained within 28 days prior to registration.  The informed consent document must be 
obtained prior to undergoing any study specific procedures.  Informed consent may be 
obtained more than 28 days prior to registration.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and Assessments section.
6.3. Follow-up Visit
For follow-up procedures see Schedule of Activities and Assessments section.  The EOT 
assessments are to be obtained if they are not completed in the last week (last 6 weeks for 
tumor assessments).  The Follow-Up visit should be conducted at least 28 days, and no more 
than 35 days, after discontinuation of treatment.  Patient will return to undergo assessments 
per the Schedule of Activities and will be evaluated for the resolution of any 


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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.  Subsequent to the Follow-Up visit, patients should be contacted 
by telephone every 8 weeks (7 days) to obtain information on subsequent anti-cancer 
treatment and overall survival for up to two years after randomization.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression by irRECIST (see Appendix 5). Disease progression 
will be confirmed with two consecutive timepoints at least 4 weeks apart in the 
absence of rapid clinical deterioration;  

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.


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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of adverse events (AEs), serious adverse events 
(SAEs), vital signs (including pulse oximetry) and physical examination, electrocardiogram 
(ECG [12-lead]), laboratory assessments, including pregnancy tests and verification of 
concomitant treatments.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatment-once at the start of screening and once at C1D1,
immediately before investigational product administration. Following a negative pregnancy 
result at screening, appropriate contraception must be commenced and a further negative 
pregnancy result will then be required at the baseline visit within 5 days after the first day of 
the menstrual period counting the first day as Day 1 before the patient may receive the 
investigational product. Pregnancy tests will also be routinely repeated at every cycle during 
the active treatment period, at the end of study treatment, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case 
of a positive human chorionic gonadotropin (hCG) test, the patient will be withdrawn from 
treatment and will be withdrawn from the study. Additional pregnancy tests may also be 
undertaken if requested by IRB/ECs or if required by local regulations.


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7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study will be recorded on the adverse events CRF page.
7.1.3. Laboratory Safety Assessment
Hematology, blood chemistry, coagulation and urinalysis will be evaulated at the time points 
described in the Schedule of Activities and analyzed at local laboratories.  There is no need 
to repeat the C1D1 laboratory assessments if the baseline assessment is performed within 
3 days prior to dosing.  Assessments performed at all subsequent dosing visits should be 
performed within 48 hours prior to dosing.  Additional local laboratory assessments outside 
of the timepoints outlined in the Schedule of Activities, (eg, additional local cytokine 
samples), may be obtained for patient safety evaluation at the discretion of the investigator.
Table 4.
Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy 
Test
Unique 
Screening Labs
Hemoglobin
ALT/SGPT
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/SGOT
PTT
Hepatitis B core 
antibody
WBC
Alk Phos
Hepatitis C 
antibody
Absolute 
Neutrophils
Sodium
HIV
Absolute 
Lymphocytes
Potassium
Absolute 
Monocytes
Magnesium
Urine dipstick 
for urine blood: 
If positive collect 
a microscopic 
(Reflex Testing)
Absolute 
Eosinophils
Chloride
Absolute 
Basophils
Calcium
Total Bilirubin1
BUN or Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous or 
Phosphate
LDH
CRP2


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* All samples will be analyzed locally.
1.
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. 
2.
Measurement of CRP is not required after C2D1 if within normal range or similar to baseline levels; however, CRP should be 
measured anytime CRS is suspected and not already scheduled to be measured (eg, Cycle 2).  
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination (PE) to include vital signs, assessment of ECOG 
performance status and height; height will be measured at screening only.  Weight will be 
measured at screening, the beginning of each cycle and the end of treatment.  Weight does
not need to be performed at each visit; however patients should be monitored throughout the 
study for significant weight change.
A complete PE will be performed at Screening, on Cycle 1 Day 1 and at the End of 
Treatment visit for each patient and will include an assessment of all body systems (including 
neurological examination, genitourinary examination is optional).  The Cycle 1 Day 1 PE 
does not need to be repeated if the screening assessment is performed within 3 days of the 
visit.  Findings of all physical examinations 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 appropriate per the Schedule of Activities (SOA), 
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 measurement of temperature (oral, tympanic, temporal or axillary), 
blood pressure (BP) and pulse rate to be recorded in a seated or supine position.  On dosing 
days, vital signs should be measured prior to administration of investigational product
(pre-dose) and at the end of the PF-06671008 infusion (for cohorts where PF-06671008 is 
administered IV).  For BP assessment, the same arm (preferably the dominant arm) should be 
used throughout the trial.  A blood pressure cuff, which has been properly sized and 
calibrated, should be used to measure blood pressure.  The use of automated devices for 
measuring BP is acceptable.
On dosing days, pulse oximetry should be measured prior to administration of investigational 
product (pre-dose) and at the end of the PF-06671008 infusion (for cohorts where 
PF-06671008 is administered IV) as part of the vital sign evaluation.  Pulse oximetry should 
be collected prior to the collection of BP and pulse rate.  Oxygen levels should be evaluated 
on the finger in accordance with the sites standard procedures.  A single reading should be 
collected.
7.1.5. Ophthalmic Examination
An eye exam, to be performed by an ophthalmologist, will be performed 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, 


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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.
7.1.6. (12-Lead) Electrocardiogram
Electrocardiogram (ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing will be 
used for all ECGs.  It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically.  At each time point (see the Schedule of Activities), 
3 consecutive ECGs will be performed at approximately 2 minutes apart to determine the 
mean QTcF interval.  If the mean QTcF is prolonged (>500 msec, ie, CTCAE Grade ≥3), 
then the ECGs should be re-evaluated by a qualified person at the site for confirmation as 
soon as the finding is made, including verification that the machine reading is accurate.  If 
manual reading verifies a QTcF of >500 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 
potential to prolong the QTcF interval) should be performed.  In addition, repeat ECGs 
should be immediately performed hourly for at least 3 hours until the QTcF interval falls 
below 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 
2-weeks, or if at any time a patient has a QTcF interval >515 msec or becomes symptomatic, 
the patient will be removed from the study.  Additional triplicate ECGs may be performed as 
clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If the 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 matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
 
 
 
 
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7.1.8. Injection Site Tolerability Assessment (SC Only)
Assessments of the injection sites in the abdominal fat fold to monitor local tolerability to 
PF-06671008 SC injections will be performed for at least 1 hour following study drug 
administration in Cycle 1, as per the Schedule of Activities.  An assessment should also be 
performed 24 hours (1 hour) after the Cycle 1 Day 1 dose.  Injection site tolerability 
assessments for at least one hour post the PF-06671008 injection should continue after each 
dosing day visit in Cycle 2 and beyond, only if injection site pain or injection site reaction 
(ISR) characteristics continue to persist.  The assessments should continue at regularly 
scheduled visits until the symptoms resolve.  The injection sites will be assessed for 
erythema, induration, ecchymosis, injection site pain, injection site pruritus, or other 
observed characteristics after PF-06671008 administration.  The diameter of the affected area 
will be measured, and the condition of the injection site will be recorded on the CRF.  Any 
observed abnormality at the injection site will be judged by the investigator to determine if 
the event should also be reported as an adverse event.  ISRs should be immediately 
photographed in color, with scaled ruler placed by the reaction, and these photographs should 
be included in the patient’s source documentation.  When appropriate, at the discretion of the 
investigator, a patient with an ISR may be referred for a dermatological consultation and skin 
biopsy may be obtained for future examination of the ISR.  
7.2. Pharmacokinetics Assessments
7.2.1. Blood for Assessment of PF-06671008 Pharmacokinetics
Blood samples (approximately 2 mL whole blood) will be collected for measurement of 
PF-06671008 PK as outlined in the Schedule of Activities.  PK sampling schedule may be 
modified based on emerging PK data. 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time of
blood sample collection and of last dosing prior to PK collection documented in the CRF.
Where noted in the Schedule of Activities, blood samples for PF-06671008 concentrations 
will be collected at approximately the same time as other assessments such as PD samples,
ECGs etc., wherever possible. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing 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 CRF.  The actual 
times may change but the number of samples will remain the same. 
If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of the clinical investigator, patient, and 
sponsor.  PF-06671008 PK samples will be assayed using a validated analytical method 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.


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7.4. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or MRI scans or equivalent; 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. The same modality should be completed, if possible, 
throughout the study.  Bone scans will be performed at baseline if disease is suspected and on 
study as appropriate to follow disease.  Baseline central nervous system (CNS) imaging is 
not required with the exception of symptomatic patients to rule out CNS metastases; patient 
ineligible if positive for CNS metastases.  CT or MRI scans to be done every 6 weeks 
(±7 days) from the start of study treatment until disease progression by irRECIST or death, or 
until permanent discontinuation of study treatment.  The frequency will change to every 
12 weeks (±7 days) beginning at Cycle 8.
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
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Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
treatment (if not done in the previous 6 weeks).
Assessment of response will be made using RECIST version 1.1 (Appendix 4) and irRECIST 
(Appendix 5). Disease progression will be confirmed with two consecutive timepoints at 
least 4 weeks apart in the absence of rapid clinical deterioration.  Responses of CR or PR 
must be confirmed by repeat assessment no less than 4 weeks after the criteria for response 
are first met.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
7.5. Immunogenicity Evaluations
Assays to assess for anti-drug (anti-PF-06671008) antibodies (ADA) will be performed.  All 
samples that are positive in a screening assay will be further characterized in terms of 
antibody specificity.  Samples tested positive for ADA may also be characterized for
neutralized antibodies (Nab).  Patients with an unresolved AE possibly related to ADA will 
be asked to return to the clinic for ADA and drug concentration assessments at approximately 
3 month intervals until the AE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and sponsor. 
Blood samples (6 mL) to provide approximately 3 mL of serum for ADA and Nab analysis 
will be collected into appropriately labeled tubes at the times specified in the Schedule of 
Activities.  Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the study manual.
Samples will be analyzed using validated analytical methods in compliance with Pfizer 
standard operating procedures.
As part of understanding the immunogenicity of the study drug, samples may be used for 
additional characterization of an observed immunogenicity response and/or evaluation of the 
bioanalytical method.  These data will be used for internal exploratory purposes and will not
be included in the clinical report.  Samples collected for this purpose will be retained in 
accordance to local regulations and if not used within this timeframe, will be destroyed.
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  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.
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.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
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reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.

If a patient begins a new anticancer therapy, the AE reporting period for non-serious
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation 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 symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;


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
Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength. 
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

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.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

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 the protocol-stipulated 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 
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8.6. 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;

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 
safety reporting 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 safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE) grade 5 (see the section on 
Severity Assessment).
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.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase(AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above;

For patients with preexisting AST or ALT baseline values above the normal range,
AST or ALT value 2 times the baseline values and 3 × ULN, or 8 × ULN
(whichever is smaller).
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug,
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected. Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time, should be 
considered potential Hy’s law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs. Such potential Hy’s 
law cases should be reported as SAEs.
8.7. 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 


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tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be 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 persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.8. 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 adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example 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.
8.9. 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 in the CRF, as appropriate, 
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 (see the section on Reporting Requirements).  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, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. 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 
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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).
2. 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 study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an 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) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer 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
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported 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 investigator.  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 study 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 
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8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 


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on the AE CRF.  In general, this will include a description of the AE in sufficient detail to
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or 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 or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. 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.
9. DATA ANALYSIS/STATISTICAL METHODS
Additional details of the analyses will be provided in the statistical analysis plan (SAP) and 
the clinical study report (CSR), which will be maintained by Pfizer.  This document may 
modify the plans outlined in the protocol; however, any major modifications of the 
preliminary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment. 
The information may include details of missing and, if applicable, unused and spurious data.  
Deviations from the statistical plan will be reported in the clinical study report.
9.1. Analysis Sets 
Data analysis will be performed on the following analysis populations:
1. Safety analysis set.

The safety analysis set includes all enrolled patients who receive at least one dose 
of study treatment.
2. Full analysis set.

The full analysis set includes all enrolled patients.


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3. Per-protocol analysis set (evaluable for MTD).
•
The per protocol analysis set includes all enrolled patients who receive at least 
one dose of study treatment and who do not have major treatment deviations 
during first cycle.  Patients with major treatment deviations during the first cycle 
of treatment are not evaluable for the MTD assessment and will be replaced as 
needed to permit MTD estimation.  Major treatment deviations include failure to 
satisfy major entry criteria (eg, confirmation of the target disease; signed 
informed consent) or use of other anticancer treatments during the active 
treatment and disease follow-up phases other than as defined/allowed in this 
protocol.
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 study medication
with baseline assessment and at least 1 post baseline assessment, disease 
progression, or death before the first tumor assessment. The mITT population 
may be used for interim analysis and conference presentations when the study is
still ongoing.
5. PK analysis sets.
•
The PK parameter analysis population is defined as all enrolled patients treated 
who have sufficient information to estimate at least 1 of the PK parameters of 
interest and who have no major protocol deviations influencing the PK 
assessment.
6.
7. Immunogenicity analysis sets.
•
The immunogenicity analysis set is defined as patients who receive at least 1 dose 
of study treatment and have at least 1 ADA sample analyzed.
9.2. Statistical Methods and Properties
This study has been designed to establish the Maximum Tolerated Dose (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 
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in the original mTPI method.11  Similarly, doses with an incidence of DLT>32.5% (eg, 4 out 
of 10) cannot be selected as MTD although is allowed by the mTPI method. 
The modified toxicity probability interval (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) (See Appendix 7). 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) are described in Table 2.
Table 6.
Dose Escalation Levels
for IV Administration
Dose Level
Dose (ng/kg)
1 (Starting Dose)
1.5
2
7.5
3
20
4
50
5
100
6
200
7
300
8
400
* Intermediate doses may be evaluated based on clinical findings (eg, a dose between 20 and 50 ng/kg).
Cohorts of patients could receive doses already tested but a dose that is associated with 
decision “Dose de-escalate, unacceptable toxicity” cannot be revisited and no more patients 
should be treated at this dose or higher doses for the remainder of the trial.
The maximum sample size for Part 1 would be N=92 but actual sample size will depend on 
the underlying dose toxicity profile and variability in actual data realization. 
The study will continue accruing until one of the three stopping conditions below is 
triggered. 
The algorithm will stop if any of the following criteria is met:
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2. MTD has been identified with sufficient accuracy: 6 to 12 patients have been 
accumulated on a dose that is currently estimated to be the MTD; or
3. All doses explored appear to be overly toxic and the MTD cannot be determined. 
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the true Probability (DLT) is fairly low. This could result in the 
estimated posterior DLT rate to exceed the targeted 27.5% very early in the trial, triggering 
an early stop when very few patients (2-4) have been treated. To prevent stopping the trial 
prematurely in such cases, a step-down option with a lower dose of 1.0 ng/kg is added to the 
dose grid. This dose will be explored only if a high DLT rate occurs in the first cohort 
assigned to 1.5 ng/kg, ie, it will not be used as a starting dose and the algorithm will always 
assign the first cohort of patients to 1.5 ng/kg.
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.
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 two parts.  Up to approximately 152 patients are 
expected to be enrolled in the study overall.
In Part 1, patients will participate in a dose escalation phase aimed at estimating the MTD.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.  It is anticipated that the maximum sample size of approximately 92 patients are 
expected to be enrolled in Part 1 of the study at approximately 6 sites. The actual number of 
patients enrolled will depend upon tolerability and the number of dose levels required to 
identify the MTD. 
The minimum and maximum sample sizes after which Part 1 can be stopped and MTD 
declared are approximately 6-12 and approximately 92 patients, respectively. As for the 
number of patients treated at each dose, it is expected that the typical number will be 1 to 
4 patients for the doses actually studied. However, since variable cohort size is allowed, the 
actual number of patients treated at each dose will vary from 1 to 12.
In Part 2 the maximum sample sizes for each tumor indication (ie, TNBC, CRC and 
NSCLC) will be in the range n=10 to n=20. Enrollment of patients in one indication may be 
discontinued if minimal or no anti-tumor activity (eg 0 or 1 response) is observed in the first 
10 evaluable patients for that indication. Assuming a non-informative prior (ie, Jeffrey’s 
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(Beta-Binomial) equal to 0.93 that the true response is inferior to 30%. On the other hand, if 
7 out of 20 patients have tumor response, this would predict a posterior probability equal to 
0.70 that the true response is not inferior to 30% and a posterior probability equal to 
0.05 (5%) that the true response is inferior to 20%. In addition, posterior probabilities may 
be calculated by using informative priors based on the antitumor activity that may be 
observed during Part 1 (eg 2 out of 3 TNBC patients experience tumor response in Part 1). 
These posterior probabilities will be assessed for each indication during Part 2 when at least 
the first 10 Pts are enrolled in that indication. Posterior Probabilities >0.75 of an 
ORR<20% (eg, 0,1 out of 10; 0,1,2 out of 16) may provide evidence of no substantial 
anti-tumor activity for that indication.
Assuming a Kappa statistic equal to 0.7, N=20 would determine a 90% CI lower bound equal 
to 0.44 if Kappa is calculated as a measure of concordance between positive/negative 
P-cadherin results in different samples when the proportion of P-cadherin positive is 80%.
9.4. Efficacy Analysis
In this First In Patient study anti-tumor activity is a primary objective for Part 2 of the study.
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 (RECIST v1.1) 
 
9.5. Analysis of Pharmacokinetics
 
9.5.1. Analysis of Pharmacokinetics
PK parameters for single dose including the maximum concentration (Cmax), time to 
maximum concentration (Tmax), and area under the concentration versus time curve (AUClast, 
AUCsd,τ) will be estimated using non-compartmental analysis.  PK parameters for multiple 
dose (assuming steady state is achieved) including the maximum concentration (Css,max), time 
to maximum concentration (Tss,max), and area under the concentration versus time curve 
(AUCss,τ) will be estimated using non-compartmental analysis. If data permit or if considered 
appropriate, area under the concentration versus time curve to infinity (AUCinf), terminal 
elimination half-life (t1/2), clearance (CL) for IV administration or apparent clearance (CL/F) 
for SC administration, volume of distribution at steady state (Vss) for IV administration or 
apparent volume of distribution at steady state (Vss/F) for SC administration, and
accumulation ratio (Rac = AUCss,τ,/AUC sd,τ) will be also estimated. Actual sample collection 
times will be used for the parameter calculations. The PK parameters will be summarized 
descriptively by dose, cycle, dosing day and route of administration.
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PF-06671008 concentrations will be summarized descriptively (n, mean, SD, coefficient of 
variation(CV), median, minimum, maximum, geometric mean and its associated CV) by 
dose, cycle, day and nominal time.  Median profiles of the concentration-time data will be 
plotted by dose, cycle and day (single dose and steady state) using nominal times, for dosing 
intervals with full PK profile.  Median profiles will be presented on both linear-linear and 
log-linear scales.
Dose normalized AUCinf (AUCτ at steady state), AUClast and Cmax will be plotted against 
dose (using a logarithmic scale) by cycle and dosing day.  These plots will include individual 
patient values and the geometric means for each dose level.  These plots will be used to help 
understand the relationship between the PK parameters and dose.
The observed accumulation ratio and the linearity ratio will be summarized descriptively.  
Each will be analyzed after natural log transformation using a one-way analysis of variance 
with a single term for dose.  The means and 90% confidence intervals (CIs) obtained from 
the model will be back-transformed to provide means and 90% CIs for the accumulation and 
linearity ratios for each dose.
Trough concentrations will be plotted for the first 2 cycles using a box-whisker plot by cycle 
and day within cycle in order to assess the attainment of steady state.
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic
 
(PK
) Modeling
PK, efficacy, 
, 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-06671008 exposure 
 or significant safety endpoints.  The results of these 
analyses, if performed, may be reported separately.
 
 
 
 
 
 
 
 
 
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9.5.4. Immunogenicity
The development of anti-PF-06671008 antibodies will be measured using validated assays.  
Listings and summary tabulations of the anti-PF-06671008 antibody data at baseline and 
post-treatment will be generated.
Potential impact of immunogenicity on PK, clinical responses, and safety/tolerability will 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
Dose-Limiting Toxicity (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 the STUDY DESIGN section.  Adverse Events constituting DLTs will 
be listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of study treatment.  The number and percentage of patients who 
experienced any AE, 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). 
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the distribution of 
laboratory toxicities.
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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 
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 (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF (and other correction factors, eg, QTcB as appropriate), and by study arm and dose.  
Individual QT (all evaluated corrections) intervals will be listed by study arm time and dose.  
The most appropriate correction factor will be selected and used for the following analyses of 
central tendency and outliers and used for the study conclusions.  Descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum) will be used to summarize the 
absolute corrected QT interval and changes from baseline in corrected QT after treatment by 
study arm, dose and time point.  For each patient and by treatment, the maximum change 
from baseline will be calculated as well as the maximum post-baseline interval across
time-points.  Categorical analysis will be conducted for the maximum change from baseline 
in corrected QT and the maximum post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction method 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 Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases. Procedures include:
Surveillance for serious adverse events (SAEs) according to regulatory guidelines.
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Discussions between the investigators and the sponsor of AEs and laboratory test alterations 
seen at each dose level will be conducted in an on-going manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if further 
enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (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 study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator 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 


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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's or the physician's patient chart. In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board /Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
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 a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. The study 
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 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 must be 
reviewed and approved by the sponsor, 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. 
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. 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 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study 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 European Union (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, clinical trial application (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 the 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-06671008 at any time.
If a study is prematurely terminated or discontinued, 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. 
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 for studies in 


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adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report 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 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, 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 they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator 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.


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For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Ahmedin, J., et al., Cancer Statistics. CA A Cancer Journal for Clinicians, 2009. 59(4): 
p. 225-249.
2.
Actemra(tocilizumab) United States Package Insert. South San Francisco, CA: 
Genentech; 2014. https://www.gene.com/download/pdf/actemra_prescribing.pdf. 
Accessed Oct 11, 2016.
3.
Andre F, and Zielinski CC.  Optimal strategies for the treatment of metastatic triple 
negative breast cancer with currently approved agents. Ann Oncol 2012;23;vi46 vi51.
4.
Blincyto™ (blinatumomab) United States Package Insert. Thousand Oaks, CA: Amgen; 
2016. http://pi.amgen.com/united_states/blincyto/blincyto_pi_hcp_english.pdf. 
Accessed Oct 11, 2016.
5.
Chau, I. and D. Cunningham, Treatment in advanced colorectal cancer: what, when and 
how [quest]. Br J Cancer, 2009. 100(11): p. 1704-1719.
6.
Grothey A, et al., Regorafenib monotherapy for previously treated metastatic colorectal 
cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, 
phase 3 trial. The Lancet, 2013. Volume 381, Issue 9863, Pages 303 - 312.
7.
Hardy RG, Tselepis C, Hoyland J, et al. Aberrant P-cadherin expression is an early 
event in hyperplastic and dysplastic transformation in the colon. Gut 2002; 50(4):513-9.
8.
http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofession
al/page12. Accessed 11 May 2015.
9.
Hurwitz, H.I., et al., The Clinical Benefit of Bevacizumab in Metastatic Colorectal 
Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of 
Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal 
Cancer. Oncologist, 2009. 14(1): p. 22-28.
10.
Imai K, Hirata S, Irie A, et al. Identification of a novel tumor-associated antigen, 
cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, 
and colorectal cancers. Clin Cancer Res 2008; 14(20):6487-95.
11.
Ji Y, Wang SJ; Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials.  J Clin Oncol 2013; 
Vol. 31 no 14 1785-1791.
12.
Lee D.W., et al., Current concepts in the diagnosis and management of cytokine release 
syndrome. Blood 2014; 124:188-195.
13.
Liedtke C, Mazouni C, Hess KR, et. al.  Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer.  J Clin Oncol 2008; 
26:1275-1281.


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14.
Nishino M et al. Developing a common language for tumor response to immunotherapy:
immune-related response criteria using unidimensional measurements. Clin Cancer Res. 
2013 Jul 15;19(14):3936-43.
15.
Pal SK, Childs BH, and  Pegram M.  Triple negative breast cancer: unmet medical 
needs.  Breast Cancer Res Treat 2011; 125:627-636.
16.
Paredes J, Albergaria A, Oliveira JT, et al. P-cadherin overexpression is an indicator of 
clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter 
hypomethylation. Clin Cancer Res 2005; 11(16):5869-77.
17.
http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofession
al/page12 accessed 11 May 2015.
18.
Saltz, L.B., et al., Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy 
As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. 
J Clin Oncol, 2008. 26(12): p. 2013-2019.
19.
Stefansson IM, Salvesen HB, Akslen LA. Prognostic impact of alterations in P-cadherin 
expression and related cell adhesion markers in endometrial cancer. J Clin Oncol 2004; 
22(7):1242-52.
20.
Taniuchi K, Nakagawa H, Hosokawa M, et al. Overexpressed P-cadherin/CDH3 
promotes motility of pancreatic cancer cells by interacting with p120ctn and activating 
rho-family GTPa6. Cancer Res 2005; 65(8):3092-9.
21.
Topp MS, Gokbuget N, Zugmaier G, et al. A phase II trial of the anti-CD19 BiTE 
blinatumomab shows hematologic and molecular remissions in patients with relapsed or 
refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 2014; published 
online Nov 10. DOI:10.1200/JCO.2014.56.3247.
22.
Turashvili G, McKinney SE, Goktepe O, et al. P-cadherin expression as a prognostic 
biomarker in a 3992 case tissue microarray series of breast cancer. Mod Pathol. 2011; 
24(1):64-81 ses.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
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
BP
Blood pressure
BUN
Blood urea nitrogen
C
Cycle
C1D1
Cycle 1 Day 1
Cave
Average concentration
CBC
Complete blood count
CD3ε
Cluster of differentiation 3 epsilon
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance
CLIA
Clinical laboratory improvement amendments
Cmax
Maximum concentration
CNS
Central nervous system
CR
Complete response
CRC
Colorectal cancer
CRF
Case report form
CRP
C-reactive protein
CRS
Cytokine release syndrome
CSR
Clinical study report
CT
Computed tomography
CTC
Circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
D
Day
DART
Dual affinity re-targeting
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure during pregnancy
ELISA
Enzyme-linked immunosorbent assay
EOT
End of treatment


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F
Absolute bioavailability
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United 
States)
FFPE
Formalin-fixed paraffin-embedded 
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
IND
Investigational new drug 
INR
International normalized ratio
IP
Investigational product
IRB
Institutional review board
irPFS
Immune-related progression free survival
IRR
Infusion Related Reaction
irRECIST
Immune-related response criteria in solid tumor
IV
Intravenous
K2EDTA
Dipotassium ethylene diamine tetraacetic acid
kD
Kilodalton 
kg
Kilogram
LDH
Lactate dehydrogenase
LFT
Liver function test
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
MABEL
Minimally anticipated biologic effect level
MHC
Major histocompatibility class
mTPI
Modified toxicity probability interval
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
Milliliter
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
Nab
Neutralizing antibody
NCI 
National Cancer Institute 
ng
Nanogram


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NSCLC
Non-small cell lung cancer
OR
Overall response
OS
Overall survival
PBMC
Peripheral blood mononuclear cells
PE
Physical examination
PD
Progressive disease
PFS
Progression-Free Survival
PK
Pharmacokinetics
PLTS
Platelets
PR
Partial response
PS
Performance status
PT
Prothrombin time
PTT
Partial thromboplastin time
QT
Time between the start of the Q wave and the end of the T wave
RECIST
Response Evaluation Criteria in Solid Tumors
RO
Receptor occupancy
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SCCHN
Squamous cell carcinoma of the head and neck
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOA
Schedule of activities
SRSD
Single reference safety document
T
Time
T1/2
Terminal elimination half-life
TCR
T cell repertoire
TK
Toxicokinetic
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor
TSC
Tumor static concentration
ULN
Upper limit of normal
US
United States
USPI
United States Package Insert
Vss
Volume of distribution
Vss/F
Volume of distribution at steady state
WBC
White blood cell count
CCI
CCI


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Appendix 2. Tumor Types with Potential for P-cadherin Expression Eligible in Dose 
Escalation (Part 1)
Bladder urothelial carcinoma
Breast carcinoma
Colorectal adenocarcinoma
Head and neck squamous cell carcinoma
Non-small cell lung cancer
Ovarian (epithelial) carcinoma 
Pancreatic adenocarcinoma
Prostate Adenocarcinoma


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Appendix 3. EGOG 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 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. 
a. Categorizing Lesions at Baseline
1. Measurable Lesions
Lesions that can be accurately measured in at least one dimension.
1. 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).
2. Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
3. Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.
4. 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. 
2. Non-measurable Disease 
1. 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.
2. 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.
3. 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.
3. Normal Sites
1. 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 
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2. 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.
4. 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. 
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
5. 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. 
1. 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.
2. 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.
6. Non-target Disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).


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b. 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. 
7. Target Disease
1. 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.
2. 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. 
3. 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. 
4. Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 
5. 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. 
8. Non-target Disease
1. 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).
2. Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 


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3. 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. 
4. 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.
9. 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.
10. Supplemental Investigations
1. 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.
2. 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. 
11. 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 7.
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 8.
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. Immune-Related Response Criteria Derived from RECIST 1.1 (irRECIST)
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and 
anti-PD-1/anti-PD-L1 antibodies which exert the antitumor activity by augmenting activation 
and proliferation of T cells, thus leading to tumor infiltration by T cells and tumor regression 
rather than direct cytotoxic effects (Hoos et al, 2010; Hodi et al, 2008).1,2  Clinical 
observations of patients with advanced melanoma treated with ipilimumab, for example, 
suggested that conventional response assessment criteria such as Response Evaluation 
Criteria in Solid Tumors (RECIST) and WHO criteria are not sufficient to fully characterize 
patterns of tumor response to immunotherapy because tumors treated with 
immunotherapeutic agents may show additional response patterns that are not described in 
these conventional criteria (Wolchok et al, 2009; Nishino et al, 2012).3,4
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have 
been reported as not capturing the existence of a subset of patients who have an OS similar to 
those who have experienced CR or PR but were flagged as PD by WHO criteria.(Wolchok et 
al, 2009; Nishino et al, 2012).3,4
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST v1.1 (irRECIST). (Nishino et al, 2014).5
For irRECIST, only target and measurable lesions are taken into account.  In contrast to 
RECIST v1.1, irRECIST: 
1. Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented, and 
2. Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm longest diameter per 
non-nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by 
20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial. 
irRECIST is defined as follows: 
1. Overall immune-related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions.  All measurable lymph nodes 
also must have a reduction in short axis to <10 mm. 


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2. Overall immune-related partial response (irPR): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
decreases 30%. 
3. Overall immune-related stable disease (irSD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions is 
neither irCR, irPR, (compared to baseline) or immune-related progressive disease 
(irPD, compared to nadir). 
4. Overall immune-related progressive disease (irPD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
increases 20% (compared to nadir), confirmed by a repeat, consecutive observation 
at least 4 weeks from the date first documented. 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements).  A lymph node has to be 15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum.  Up to 2 new lesions per organ and up 
to 5 new lesions in total can be added to the measurements. 
New non-measurable lesions: Do not define progression but preclude irCR.
Overall responses derived from changes in index, non-index, and new lesions are outlines in 
Table 9.
Table 9.
Overall Response Derived from Changes in Index, Non-index and New 
Lesions
Measurable response
Non-measurable Response
Overall response using 
irRECISTb
Index and New 
Measurable Lesions 
(Tumor Burden)a
Non-Index Lesions
Measurable Lesions
Decrease 100%
Absent
Absent
irCR
Decrease 100%
Stable
Any
irPR
Decrease 100%
Unequivocal progression
Any
irPR
Decrease 30%
Absent/stable
Any
irPR
Decrease 30%
Unequivocal progression
Any
irPR
Decrease <30% and 
increase <20%
Absent/stable
Any
irSD
Decrease <30% and 
increase <20%
Unequivocal progression
Any
irSD
Increase 20%
Any
Any
irPD
a.
Decrease assessed relative to baseline.
b.
Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive 
assessment at least 4 weeks apart.


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References:
1.
Hoos A, Egermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy 
trials.  J Natl Cancer Inst  2010;102(18):1388-1397.
2.
Hodi FS, Bulter M, Oble DA, Seiden MV, haluska FG, Kruse A, et al. Immnologic and 
clinical effects of antibody blockade of cytotoic T lymphocyte-associated antigen 4 in 
previously vaccinated cancer patients.  Proc Natl Acad Sci U S A 2008;105:3005-3010.
3.
Wolchok JD, et al.: Guidelines for the Evaluation of Immune Therapy Activity in Solid 
Tumors: Immune-Related Response Criteria.  Clin Cancer Res 2009;15(23):7412-7420.
4.
Nishino M, Jagannathan JP, Krajewski KM, O'Regan K, Hatabu H, Shapiro G, Ramaiya 
NH.  Personalized tumor response assessment in the era of molecular medicine: 
cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST.  
AJR Am J Roentgenol 2012;198(4):737–745.
5.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS.  Optimizing immune-related 
tumor response assessment: does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab?  J Immunother Cancer 
2014;2:17.


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Appendix 6. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (Version 4.03 date June 14, 2010) has been placed in the Study Manual for 
this protocol.  Alternatively, the NCI CTCAE may be reviewed on-line at the following NCI 
website: 
http://ctep.cancer.gov/reporting/ctc.html


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Appendix 7. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design
Escalation/De-escalation algorithms for total number of patients treated at the current 
dose level (current and previous cohorts)

With 1 patient treated at current dose level

0 DLT -> escalate

1 DLT or other toxicities occur (ie, those that have the potential to be DLTs if more 
severe) -> may add additional patients to asses safety on a cohort size of n=2-4

With 2 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose 

2 DLTs -> de-escalate and consider current dose as intolerable

With 3 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> de-escalate 

3 DLTs -> de-escalate and consider current dose as intolerable

With 4 patients treated at current dose level

0 DLT -> escalate

1-2 DLTs -> remain at the same dose

3-4 DLTs -> de-escalate and consider current dose as intolerable

With 5 patients treated at current dose level

0 DLT -> escalate

1 DLT -> remain at the same dose

2 DLTs -> remain at the same dose (mTPI suggests “escalate”)

3 DLTs -> de-escalate


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
4-5 DLTs -> de-escalate and consider current dose as intolerable

With 6 patients treated at current dose level

0-1 DLT -> escalate

2 DLTs -> remain at the same dose

3 DLTs -> de-escalate

4-6 DLTs -> de-escalate and consider current dose as intolerable

With 7 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4-7 DLTs -> de-escalate and consider current dose as intolerable

With 8 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4 DLTs -> de-escalate

5-8 DLTs -> de-escalate and consider current dose as intolerable

With 9 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4 DLTs -> de-escalate (mTPI suggests “remain at the same dose”)

5-9 DLTs -> de-escalate and consider current dose as intolerable


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
With 10 patients treated at current dose level

0-1 DLT -> escalate

2-3 DLTs -> remain at the same dose

4 DLTs -> de-escalate (mTPI suggests “remain at the same dose”)

5 DLTs -> de-escalate

6-10 DLTs -> de-escalate and consider current dose as intolerable

With 11 patients treated at current dose level

0-2 DLT -> escalate

3-4 DLTs -> remain at the same dose

5 DLTs -> de-escalate (mTPI suggests “remain at the same dose”)

6-11 DLTs -> de-escalate and consider current dose as intolerable

With 12 patients treated at current dose level

0-2 DLTs -> escalate

3-4 DLTs -> remain at the same dose

5 DLTs -> de-escalate (mTPI suggest “remain at the same dose”)

6-12 DLTs -> de-escalate and consider current dose as intolerable
mTPI Operating Characteristics
This is a dose-escalation study primarily driven by safety.  While efficacy endpoints will also 
be assessed, they will play only a supportive role. The primary safety endpoint will be 
presence or absence of DLT The simulation focuses on a follow-up period for DLT 
assessment and ignores non DLTs toxicities or DLTs occurring outside of this time frame.
This simulation refer to the escalation phase after the selection of the priming dose as that 
will be based on non DLTs lower grade cytokine release (eg < Grade 2; see Evaluation of a 
Priming Dose).
This study has been designed to establish the Maximum Tolerated Dose (MTD) defined as 
the dose that yields approximately 27.5% probability of DLT and considers equivalent doses
that yield probability of DLTs 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.  Since mTPI algorithms are known to assign more patients 


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above the target dose compared to 3+3 designs, the target was chosen slightly below the 
maximum acceptable DLT rate of 33.3% (in order to protect study patients from exposure to 
doses with DLT rate higher than 33%). Doses with an incidence of DLT>33% cannot be 
selected as MTD in the current protocol therefore the decision rules implemented in the 
actual study are more conservative of the ones used in this simulation, therefore results of 
these simulations represent more aggressive scenario.  In addition, in the study patients will 
be enrolled in cohorts of size 2-4 but constant size of 3 was assumed for all simulations. 
Table 10.
Simulation Parameters Selected for the Final Design
Final Design Value 
Control Parameters
Cohort size
3 patients
Max doses levels 
5 levels 
Minimum number of patients on MTD to stop for success
6,9,12 patients
Other parameters
Max sample size for one regimen of part 1
50 patients
DLT target rate at MTD  
pT= 0.275
Equivalence Interval for DLT target rate at MTD  
EI: 0.225-0.325  
Prior distribution of DLT
Beta(0.5,0.5)
Threshold probability for early termination and dose exclusion
ξ = 0.95
Simulation Scenarios
Simulations are created to summarize the operating characteristics of the proposed model 
based design under multiple scenarios. In order to simulate the design, assumptions have to 
be made about how the data are generated.  These assumptions do not affect the design or the 
analysis, but they are necessary to simulate patient results. The simulations assume patients
are accrued in cohorts of 3 and all patients within a cohort are enrolled at the same time.  The 
next cohort of patients is available for enrollment immediately after the previous cohort’s 
DLT responses are obtained. 
For the two competing designs (ie, 3+3 and mTPI), the following operating characteristics 
were assessed, by scenario, to further quantify the trade-off between precision of MTD 
estimation and design cost: 

Probability to select MTD:

Correctly (dose with 22.5%-32.5% DLT rate);

Underestimate (dose with <22.5% DLT rate);

Overestimate (dose with >32.5% DLT rate);

N/A (all doses declared too toxic).


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
Design cost:

Average Number of Treated Patients;

Average Number of DLTs;

Average proportion of DLTs.
The scenarios used in simulations are summarized in Table 11:
Table 11.
Dose-toxicity Scenarios used in Simulations and Their Respective Target 
Dose Ranges
Probability of DLT as a function of dose
Dose Level
Sc. 1
MTD:
level 5
Sc. 2
MTD:
level 5
Sc. 3
MTD:
level 4
Sc. 4
MTD:
level 2
Sc. 5
MTD:
level 1
1
0.01
0.05
0.05
0.125
0.32
2
0.02
0.1
0.1
0.275
0.45
3
0.05
0.15
0.175
0.425
0.575
4
0.08
0.2
0.275
0.6
0.7
5
0.12
0.25
0.425
0.8
0.85


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Figure 5.
Dose-toxicity Scenarios used in Simulations
Figure 5 provides graphical summary of the same scenarios. These scenarios cover situations 
where the true MTD lies to the left, middle and to the right of the studied dose range and 
different levels of increased toxicity for each escalation step. 
Operating characteristics are summarized in Table 12 and Table 13.  Based on 10000 trials 
simulated, on average, this particular mTPI design provides more accurate estimates of MTD 
versus the 3+3 design, with comparable overall proportion of toxicities. In certain 
dose-toxicity scenarios (eg, when DLT can be observed early in the trial), mTPI may require 
slightly larger sample size and, consequently, duration of the study. The magnitude of 
trade-off between quality of MTD information obtained and design costs (such as sample 
size, duration and observed toxicities) varies depending on the underlying dose-toxicity 
relationship.  A specific variant of mTPI design (cohort size 3 and stopping rule with 
9 patients on MTD) was chosen among several variants examined for comparison with the 
3+3 design. 
Scenarios #1-3 have a relatively flat dose-toxicity profile. Scenarios #4-5 assume a more 
aggressive dose-toxicity profile.  Both groups of scenarios cover situations where the true 
MTD lies to the left, middle and to the right of the studied dose range.  In case of 
Scenarios #2 and #3, there are small increases of DLT rate from dose-to-dose.  As a result, 
there are several doses that could trigger a stopping rule and be selected as MTD for these 
scenarios.  Such DLT profiles may present a challenge for the algorithms to find the right 
dose given a generally acceptable sample size, as there will be several “competing” MTD 
doses.  On the other hand, Scenario 4 has noticeable changes in toxicity around the true MTD 
dose resulting in only 1 dose adequate to be selected as MTD).  Even though the sample size 
required to find MTD in such cases may be smaller (compared to Scenarios 2 & 3), the 
consequences of missing the true MTD dose are more severe because all the neighboring 
doses have toxicities well below or above the acceptable range of 22.5%-32.5%.  
Scenarios #1-2 describe two situations where all tested doses are below the target toxicity.


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Design Operating Characteristics
In this section, selected operating characteristics of the mTPI design are presented.  In each 
scenario, 10000 simulated trials were conducted and the key operating characteristics that 
influenced the design selection are summarized in 3.  We also report similar operating 
characteristics for the traditional 3+3 design at the same dose levels for comparison.  Since
both methods operate on the same dose space, these methods are 100% comparable and 
providing operating characteristics of the 3+3 design (under the same dose-toxicity 
scenarios) serves as a useful “benchmark” of performance. 
The simulations in this report were performed using the R software. 
The first column in 3 contains scenario name, labeled by location of the “true” MTD under 
such scenario.  Second column is for “Design” mTPI (n at MTD=9) or 3+3. Four columns 
under “MTD dose selection decision” header summarize the proportion of times (out of 
10000 trials) that MTD was identified correctly, underestimated, over-estimated or not 
identified at all, respectively.  The following definition was used to specify the above four 
categories: 

Correct MTD:
selected dose produces 22.5%-32.5% true DLT rate 

Underestimated MTD:
selected dose produces <22.5% true DLT rate

Overestimated MTD:
selected dose produces >32.5% true DLT rate

N/A:
trial stopped early 
The last three columns of 3 summarize the operating characteristics associated with trial 
“cost”: average sample size, average number and proportion of patients experiencing DLTs.  
These operating characteristics played an important role in design selection process by 
quantifying the trade-off between precision of MTD selection and exposing more patients to 
doses with higher toxicity levels.  The studied scenarios cover situations where the true MTD 
lies to the left, middle and to the right of the studied dose range. 
As expected, those Scenarios in which there are small increases of DLT rate from 
dose-to-dose present a challenge for the algorithms to find the right dose in terms of sample 
size, as there will be many “competing” MTD doses.  For example in Scenarios #1 and #2 
mTPI selects the correct MTD 90% and 44% of the times respectively.  Specifically in 
Scenario #1, mTPI selected the correct MTD 90% of the times compared to 79% by 3+3 but 
required approximately 5 more patients.  Similarly, in Scenario #2, mTPI estimated the 
correct MTD more often than 3+3 with slight increase in sample size. Also the absolute and 
relative numbers of toxicity events were comparable. Scenario #5 represents a situation 
where the DLT curve is very steep and only one dose is within the EI.  mTPI selected the 
correct MTD 66% of the times compared to 31% by 3+3 and required approximately 
5 patients more.  In all scenarios #1-2-3-4-5 the performance of the mTPI method was always 
superior to 3+3, selecting the correct MTD at least 13% more often (35% in Scenario #5) and 
requiring approximately 4 more patients on average. 


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Stopping rules with 6, 9 and 12 patients on MTD were considered for the mTPI design and 
compared via simulations.  These results are summarized in Table 13.  The stopping rule 
with 9 patients on MTD performed adequately for MTD estimation and required a study 
sample size comparable to that of 3+3 design (Table 13).  A stopping rule with 12 patients
had greater chance of identifying MTD correctly (scenarios 1,2,3,4).  However this added 
benefit came at a price of additional patients.  In cases of early toxicity (eg, Scenario 5), 
where the first tested dose is within the EI, there were no noticeable improvements in quality
of correct MTD estimation if 12 patients were required on MTD to stop, rather than 6 or 9. 
In summary, since there was no a priori knowledge about the likelihood of a particular 
toxicity scenario, performance of the mTPI design under all scenarios was taken into 
consideration in the choice of the final design.  Across all scenarios examined, a design 
employing the mTPI algorithm with at least n=6 at MTD (up to n=12) will have a better 
chance to estimate MTD correctly compared to a traditional 3+3 design, while the overall 
proportion of toxicities observed within a study remains acceptable and similar between 
mTPI and 3+3.  mTPI design may result in a longer trial duration compared to the duration of 
3+3 design, however, this increase is off-set by a better performance of mTPI in all simulated 
scenarios. Among many design parameters examined, the stopping rule (number of patients
on MTD) had the most impact on the design’s performance.  As expected, increasing the 
minimum number of patients treated on MTD prior to stopping leads to a more precise MTD 
estimation; however this requirement would also lead to larger overall sample size, longer 
trial duration and greater overall number of toxicities (but not necessarily the proportion of 
toxicities). 
Table 12.
Operating Characteristics of the mTPI Design (n at MTF=9) versus 
Conventional 3+3 Design
MTD dose selection decision 
(proportion)
DLT Scenario 
Design CORRECT
UNDER
OVER
NA
Av 
Size
Num
Tox
Prop 
tox
1: 
3+3
0.79
0.20
-
0.01
17.1
1.0
0.06
mTPI
0.90
0.10
-
0.00
21.9
1.6
0.07
2: 
3+3
0.31
0.66
-
0.03
17.3
2.4
0.14
mTPI
0.44
0.56
-
0.00
21.1
3.2
0.15
3: 
3+3
0.23
0.71
0.03
0.03
17.2
2.9
0.17
mTPI
0.38
0.45
0.17
0.00
20.9
4.1
0.20
4: 
3+3
0.37
0.43
0.09
0.15
12.2
3.1
0.26
mTPI
0.50
0.26
0.23
0.005
16.2
4.5
0.27
5:
3+3
0.31
-
0.07
0.62
7.7
2.8
0.38
mTPI
0.66
-
0.18
0.17
11.5
4.3
0.38


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Table 13.
Operating Characteristics of the mTPI Design by Minimum Number of 
Patients on MTD
mTPI: Dose selection decision (%) by Minimum number of patients on MTD
(ie, n=6,9,12)
scenario N at MTD
%
CORRECT
%
UNDER
%
OVER
%
NA
Av Size
Num. 
Tox
Prop Tox
1
6
0.893
0.108
0.000
0.000
18.837
1.214
0.064
1
9
0.900
0.101
0.000
0.000
21.943
1.564
0.071
1
12
0.956
0.044
0.000
0.000
25.802
2.012
0.078
2
6
0.437
0.563
0.000
0.000
17.600
2.562
0.146
2
9
0.437
0.563
0.000
0.000
21.051
3.233
0.154
2
12
0.544
0.456
0.000
0.000
26.637
4.364
0.164
3
6
0.374
0.434
0.192
0.000
17.277
3.154
0.183
3
9
0.378
0.448
0.174
0.000
20.919
4.109
0.196
3
12
0.460
0.342
0.198
0.000
26.728
5.700
0.213
4
6
0.470
0.266
0.260
0.004
12.333
3.334
0.270
4
9
0.504
0.263
0.228
0.005
16.235
4.469
0.275
4
12
0.560
0.189
0.245
0.006
21.146
6.033
0.285
5
6
0.676
0.000
0.221
0.103
8.496
3.193
0.376
5
9
0.656
0.000
0.178
0.166
11.459
4.322
0.377
5
12
0.616
0.000
0.176
0.208
14.765
5.531
0.375


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Appendix 8. Suggested Cytokine Release Syndrome Management Algorithm and 
Revised CRS Grading System
Adapted from D.W.Lee, et al: Current Concepts in the Diagnosis and Management of 
Cytokine Release Syndrome.  Blood 124 (2014) 188-195.
Suggested tocilizumab administration: 4 mg/kg over 1 hour; consider a second dose if no clinical improvement 
within 24 to 48 hours.


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CRS Revised Grading System
Grade
Toxicity
1
Symptoms are not life threatening and require symptomatic treatment only, 
eg, fever, nausea, fatigue, headache, myalgias, malaise
2
Grade 2 hypoxia* [decreased oxygen saturation with activity (eg, pulse oximeter 
<88%); intermittent supplemental oxygen] or
Hypotension responsive to fluids or low dose of one vasopressor or 
Grade 2 organ toxicity
3
Grade 3 hypoxia* [decreased oxygen saturation at rest (eg, pulse oximeter 
<88% or partial pressure of oxygen (PaO2) <=55 mm Hg)] or
Hypotension requiring high dose or multiple vasopressors or
Grade 3 organ toxicity or grade 4 transaminitis 
4
Life-threatening symptoms
Grade 4 hypoxia*  [life-threatening airway compromise; urgent intervention 
indicated (eg, tracheotomy or intubation)]
Grade 4 organ toxicity (excluding transaminitis)
5
Death
*Modification to the Lee et al CRS Revised Grading System according to the CTCAE 
v4.03.  Transient decreases in oxygen levels below 88% will not be considered to have met 
the criteria.

SAP_001.pdf: 
Protocol B7831001 (PF-06671008) Statistical Analysis Plan
Page 1
Protocol B7831001
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06671008 IN PATIENTS WITH ADVANCED SOLID 
TUMORS
Statistical Analysis Plan 
(SAP)
Version:
2.0
Author: 
(Early Oncology Development and Clinical Research
Statistics, San Diego, CA, USA)
Date:
17-July-2018
PPD


Protocol B7831001 (PF-06671008)
Statistical Analysis Plan V2.0
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................7
2.2.1. Dose Escalation Phase (Part 1).....................................................................7
2.2.2. Evaluation of a Priming Dose.......................................................................8
2.2.3. Criteria for Dose Escalation........................................................................10
2.2.4. MTD Definition..........................................................................................11
2.3. Dose Expansion Phase (Part 2) ...............................................................................11
2.3.1. Recommended Phase 2 Dose (RP2D) Definition.......................................12
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS .................12
3.1. Primary Endpoint(s) ................................................................................................12
3.2. Secondary Endpoint (s) ...........................................................................................12
3.4. Covariates................................................................................................................13
4. ANALYSIS SETS ...............................................................................................................13
4.1. Full Analysis Set .....................................................................................................13
4.2. Safety Analysis Set..................................................................................................13
4.3. ‘PER PROTOCOL’ Analysis Set (Part 1)...............................................................13
4.4. PK Analysis Set.......................................................................................................14
4.6. Modified Intent-to-Treat Set ...................................................................................14
4.7. Immunogenicity Analysis Set .................................................................................14
4.8. Protocol Deviations.................................................................................................14
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Statistical Hypotheses .............................................................................................14
5.2. Statistical Decision Rules........................................................................................14
5.2.1. Part 1 (MTD Finding).................................................................................14
5.2.2. Part 2 (Dose Expansion).............................................................................15
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5.2.3. Sample Size Determination ........................................................................15
5.3. General Methods .....................................................................................................15
5.3.1. Analyses for Time to Event Data................................................................16
5.3.2. Analyses for Binary Data............................................................................16
5.3.3. Analyses for Continuous Data....................................................................16
5.3.4. Analyses for Pharmacokinetic Data............................................................16
5.3.5. Analyses for Immunogenicity Data............................................................17
5.4. Methods...................................................................................................................17
5.4.1. Missing Data...............................................................................................17
5.4.2. Efficacy Analysis........................................................................................17
5.4.3. Pharmacokinetics........................................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................19
6.1. Standard Analyses...................................................................................................19
6.2. Analysis of Primary Endpoint.................................................................................21
6.2.1. DLT(Part 1) ................................................................................................21
6.2.2. Safety Endpoints (Part 1 and Part 2)...........................................................21
6.3. Analysis for Secondary Endpoints ..........................................................................22
6.3.1. Efficacy Endpoints Analysis.......................................................................22
6.3.2. Pharmacokinetics Analyses ........................................................................23
6.3.3. Immunogenicity Assessment......................................................................25
6.5. Population PK and PK
 Modeling......................................................................25
6.6. ECG Analysis..........................................................................................................25
7. INTERIM ANALYSES.......................................................................................................27
8. REFERENCES ....................................................................................................................28
9. APPENDICES .....................................................................................................................29
LIST OF TABLES
Table 1.
Dose Escalation Levels.........................................................................................10
Table 2.
Decision Rules......................................................................................................11
Table 3.
Progression Free Survival and Duration of Response..........................................29
Table 4.
Time to Progression..............................................................................................30
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APPENDICES
Appendix 1. Time to Event Data Analysis Censoring Rules...................................................29
Appendix 2. Categorical Classes for ECG and Vital Signs.....................................................31
Appendix 3. RECIST 1.1 Tumor Assessment Criteria............................................................32
Appendix 4. Immune-related RECIST (irRECIST) Tumor Assessment Criteria....................38


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1. VERSION HISTORY
This is the second version of the statistical analysis plan, based on the protocol dated 
Jan 12, 2018.1
Texts taken directly from the protocol are made Italicized.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7831001.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Part 1 (Dose-Escalation) Primary Objective
•
To assess safety and tolerability of increasing dose levels of PF-06671008 
administered in patients with advanced solid tumors for whom no standard therapy is 
available in order to estimate the Maximum Tolerated Dose (MTD) and select the 
Recommended Phase 2 Dose (RP2D). 
Part 1 (Dose-Escalation) Secondary Objectives
•
To evaluate the overall safety profile; 
•
To characterize the single and multiple dose pharmacokinetics (PK) of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To document any anti-tumor activity.
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Part 2 (Dose-Expansion) Primary Objective
•
To confirm safety and tolerability and explore preliminary evidence of anti-tumor 
activity of PF-06671008 at the RP2D in patients with P-cadherin expressing 
advanced CRC, TNBC or NSCLC.
Part 2 (Dose-Expansion) Secondary Objectives
•
To evaluate the overall safety profile at the RP2D;
•
To characterize the single and multiple dose PK of PF-06671008;
•
To evaluate the immunogenicity of PF-06671008;
•
To evaluate preliminary anti-tumor activity through time to event endpoints.
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2.2. Study Design
This is a Phase 1, open-label, multi-center, multiple-dose, safety, PK 
 study of 
single-agent PF-06671008.  This study contains two parts, dose escalation (Part 1) followed 
by dose expansion (Part 2).  Sequential cohorts of patients with tumor types with the 
potential to have P-cadherin expression, that is resistant to standard therapy or for whom no
standard therapy is available will receive escalating doses of PF-06671008, in Part 1 of the 
study.  Part 2 will evaluate the dose selected from Part 1 in patients with P-cadherin 
expressing TNBC, CRC or NSCLC. The overall study design is depicted in Figure 1 below. 
Figure 1. Overall Study Design
Upto approximately 152 patients are expected to be enrolled in the study overall.  The actual 
number of patients enrolled will depend on the tolerability of PF-06671008 and the number 
of dose levels required to identify the MTD.
[Reference Source: Protocol Section 3.1]
2.2.1. Dose Escalation Phase (Part 1)
Increasing dose levels of PF-06671008 administered weekly will be evaluated using a 
modified toxicity probability interval (mTPI) method that targets a MTD associated with a 
27.5% probability of DLT.  Part 1 will follow a mTPI method initially with cohorts of 
1-2 patients each and a primary DLT observation period of 21 days following the first dose 
(C1D1).  
If a DLT or other toxicities occur (ie, those that have the potential to be DLTs if more severe) 
during Cycle 1 but prior to the observation of CTCAE Grade ≥2 cytokine release syndrome 
(as described below in Evaluation of a Priming Dose), dose escalation will continue to 
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follow a mTPI design but with cohorts of 2-4 patients each.  The primary DLT observation 
period will continue to be 21 days following the first dose (C1D1).
Additional patients may be entered at any dose level in the IV and/or SC routes of 
administration at or below the MTD, after discussion with and permission by the sponsor, to 
obtain additional safety, PK
 and anti-tumor activity data. 
 
 
 
These additional patients will require paired biopsies. Because these 
additional patients will receive a dose lower than the concurrent dose escalation cohort or 
will be enrolled at dose following the DLT evaluation period in the first 2-4 patients enrolled, 
their potential DLT observations may not be strictly used in the mTPI algorithm for the 
ongoing dose finding. However, the safety profile from these additional patients will be used 
to establish the MTD or recommended Phase 2 dose (RP2D).
2.2.2. Evaluation of a Priming Dose
Based on toxicity study results, the evaluation of a priming dose to allow subsequent higher 
level dose administration may be instituted in this study. In addition, blinatumomab, an 
approved bispecific agent for the treatment of ALL, has been able to overcome symptoms of 
cytokine release syndrome (CRS) with the implementation of a priming dose (Topp et al,
2014).9 Therefore, this study may implement the evaluation of a priming dose during the
escalation phase. 
The initial priming dose will be defined to facilitate subsequent dose escalation towards 
establishing the MTD of a dosing regimen that includes a priming dose. The study aims to 
determine a MTD for an IV dose regimen that does not include a priming dose, and an 
independent MTD for an IV dose regimen that includes a priming dose. In addition, the 
study aims to similarly determine a MTD for PF-06671008 administered subcutaneously that 
may or may not include a priming dose.
The decision to evaluate a regimen that includes a priming dose may be made by the 
investigators and sponsor prior to reaching a MTD using the following criteria as guidance: 
If a dose level induces symptoms consistent with Grade 3 CRS as defined in the protocol 
lasting for >24 hours considered not to be due to an infusion related reaction (IRR), allergic 
reaction, anaphylaxis or other causes in a cohort of 2-4 patients after the initial infusion, an 
additional 1-4 patients (up to approximately 6 patients overall) will be enrolled at that dose 
to confirm implementation of a priming dose (Dose Prime) for subsequent cohorts. If an 
additional confirmed CRS of Grade 3 lasting for >24 hours is observed at that dose, then a 
lower dose, which has been evaluated in at least 2-4 patients, will be chosen as a priming 
dose (Dose Prime) for subsequent cohorts. If a Dose Prime is selected, dose escalation will 
continue to determine the MTD of a dose regimen that includes a priming dose. The 
evaluation of a Dose Prime may be implemented for both the IV and/or SC routes of 
administration.
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If a dose level induces confirmed CRS of Grade 4 considered not to be due to an IRR, 
allergic reaction, anaphylaxis or other causes, then a lower dose, which has been evaluated 
in at least 2-4 patients, will be chosen as a priming dose (Dose Prime) for subsequent 
cohorts. 
In addition, observation of a confirmed CRS event that meets the above qualifications 
following later infusions (ie, after Cycle 1 Day 1) or CRS events that are approaching the 
limit of tolerablity may prompt the investigators and sponsor to include evaluation of a Dose 
Prime for subsequent cohorts.
After confirmation of the safety of Dose Prime, the treatment schedule will implement the 
inclusion of the fixed priming dose as the first dose (C1D1) followed by a second dose 
(C1D8) that will continue to be escalated in subsequent cohorts following an mTPI method in 
cohorts of 2-4 patients.  After the MTD has been established, the priming dose may 
potentially be further verified in connection to the established MTD/RP2D, including 
consideration of more than one priming step, if indicated, using information from all patients 
who were included in the initial priming dose determination as well as those enrolled in 
subsequent dosing cohorts.
The primary DLT observation period for cohorts that include Dose Prime will be 21 days 
following the first dose (C1D1). The dose escalation should a Dose Prime be instituted is 
depicted in Figure 2.  
Figure 2 Study Schematic Should Dose Prime Be Explored
For cohorts instituting a Dose Prime, there will be a 72 hour observation period between the 
first dose administered to each of the initial patients enrolled (ie, patients contributing to 
initial DLT evaluation) at a new dose level. In addition to in-patient observation following 
the C1D1 dose, patients enrolled in cohorts instituting a Dose Prime must also undergo in-
patient observation for at least 24 hours (for cohorts where PF-06671008 will be 
administered IV) or 48 hours (for cohorts where PF-06671008 will be administered SC) 
following the C1D8 dose.


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2.2.3. Criteria for Dose Escalation
The 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%.
Typically patients will be enrolled in cohorts of 2 to 4, but patients could be initially enrolled 
in cohorts of 1-2 for the lower doses (see section Dose Escalation Phase (Part 1)). The 
initial 2-4 patients to be included in a cohort will be open to any of the tumor types outlined 
in the protocol. When required to expand a cohort for further evaluation of the MTD, 
enrollment of patients may be limited to those with NSCLC, SCCHN, CRC or TNBC.
For IV administration cohorts, initial dose levels are provided in Table 1 and will be 
followed if no DLTs are observed; intermediate doses may be evaluated based on clinical 
findings. Subsequent maximum dose increases will be a maximum of 2-fold (100%) if no 
DLTs are observed. For SC administration cohorts, during the initial dose escalation levels, 
maximum dose increases will be up to 3-fold if no DLTs or safety events that are 
approaching the limit of tolerability are observed. The initial dose to be evaluated for SC 
administration will be equal to the dose level selected as the IV Dose Prime. The evaluation 
of the IV and SC routes of administration will proceed through dose escalation independently 
according to the mTPI method.  Once the first DLT is observed, the maximum increase would 
follow a modified Fibonacci series in case of dose escalation (ie, 67%, 50%, 33%, etc.). 
Patients will be assigned to a dose that is closest to the current MTD prediction based on the 
mTPI method. The mTPI method relies upon a statistical probability algorithm, calculated 
using all patients treated in prior and current cohorts at the same dose level to determine 
(Decision Rules) where future cohorts should involve dose escalation, no change in dose, or 
dose de-escalation as presented in Table 2.
Table 1.
Dose Escalation Levels
Dose Level
Dose
(ng/kg)
1 (Starting Dose)
1.5
2
7.5
3
20
4
50
5
100
6
200
7
300
8
400


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Table 2.
Decision Rules
Number of Patient Treated at a Dose Level
Number of 
Patients 
Having 
DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
E
E
E
E
E
E
E
2
U
D
S
S
S
S
S
S
S
E
E
3
U
U
D
D
S
S
S
S
S
S
4
U
U
U
U
D
D
D
S
S
5
U
U
U
U
U
D
D
D
6
U
U
U
U
U
U
U
7
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; U: Unacceptable toxicity
Note: If one patient has a DLT event observed in a dose cohort with 1 patient enrolled, additional patients
(eg, 1 or 2) may be enrolled for dose escalation assessment.
Dose escalation will stop under any of the following conditions:

The maximum sample size has been achieved;

6-12 patients have been enrolled at a dose that is predicted to be the MTD;

All doses explored appear to be overly toxic and the MTD cannot be determined.
Intrapatient dose escalation, other than the potential inclusion of a priming dose, will not be 
permitted in this study.
2.2.4. MTD Definition
The estimated MTD is the dose level associated with approximately 27.5% of DLT-evaluable 
patients experiencing a DLT.  The target interval for the DLT rate is (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 0.325 in at least 6-12 DLT evaluable 
patients for DLT. The study aims to determine a MTD for a dose regimen that does not 
include a priming dose administered IV, and an independent MTD for an IV dose regimen 
that includes a priming dose. In addition, the study aims to determine a MTD for 
PF-06671008 administered SC and may also determine an independent MTD for a SC dose 
regimen that includes a priming dose.
2.3. Dose Expansion Phase (Part 2)
The maximum sample size for each tumor indication (ie, TNBC, CRC and NSCLC) will be in 
the range of n=10 to 20 evaluable  patients.  Enrollment of patients in one indication may be 
discontinued if minimal or no anti-tumor activity (eg, 0 or 1 response) is observed in the first 
10 evaluable patients for that indication.  


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2.3.1. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study 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 (eg, if in the expansion part >25% of patients 
require a dose reduction due to toxicity, then the sponsor and investigator determine if a 
lower RP2D needs to be determined).
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoint(s)
Primary Endpoint (Part 1)

First cycle Dose-Limiting Toxicities (DLTs).
Primary Endpoint (Part 2)

Objective response (OR) as determined by the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 criteria (Appendix 3).
3.2. Secondary Endpoint (s)

Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v.4.03) timing, seriousness, and relationship to study therapy;

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03) and timing;

Vital sign abnormalities; 

Pharmacokinetic parameters of PF-06671008 Single Dose (SD) - Cmax, Tmax, AUCsd,τ, 
t1/2, AUCinf, and CL for intravenous (IV) administration or apparent clearance (CL/F) 
for subcutaneous (SC) administration as data permit. Multiple Dose (MD) (assuming 
steady state is achieved) - Cmax,ss, Tmax,ss, AUCss,τ, t1/2, Cmin,ss, CL for IV or CL/F for 
SC, volume of distribution (Vss) for IV or apparent volume of distribution at steady
state (Vss/F) for SC, and Rac (AUCss,τ/AUCsd,τ) as data permit;

Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies against 
PF-06671008;

Objective response, as assessed using the RECIST version 1.1 – Part 1 only;

Progression Free Survival (PFS) and Overall Survival (OS) – Part 2 only.


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Covariates may also be considered when exploring QTc and PK relationship.
4. ANALYSIS SETS
Several analysis sets are defined and will be considered for this study.
4.1. Full Analysis Set
The full analysis set includes all enrolled patients.  This is equivalent to the ITT 
(intent-to-treat) population.
4.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
medication.
4.3. ‘PER PROTOCOL’ Analysis Set (Part 1)
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study treatment and who do not have major treatment deviations during the first cycle.  
Patients with major treatment deviations during the first cycle of treatment are not evaluable 
for the MTD assessment and will be replaced as needed to permit MTD estimation.  Major 
treatment deviations include failure to satisfy major entry criteria (eg, confirmation of the 
target disease; signed informed consent) or use of other anticancer treatments during the 
active treatment and disease follow-up phases other than as defined/allowed in this protocol.
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4.4. PK Analysis Set
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest and who have no 
major protocol deviations influencing the PK assessment.
 
.
4.6. Modified Intent-to-Treat Set
The modified intent-to-treat (mITT) population is defined as all the randomized subjects who 
have received at least 1 dose of study medication, have measurable disease baseline 
assessment (within 28 days prior to study entry) and at least 1 post baseline assessment or 
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. 
4.7. Immunogenicity Analysis Set
The immunogenicity analysis set is defined as patients who receive at least 1 dose of study 
treatment and have at least 1 ADA sample analyzed.
4.8. Protocol Deviations
The determination of protocol deviations (PDs) and important protocol deviations (IPDs) will
follow Pfizer standard operating procedures. A full list of PDs, IPDs, and IPDs that exclude 
a patient from the Per-protocol analysis will be determined prior to the database release and 
be included in the CSR. 
5. GENERAL METHODOLOGY AND CONVENTIONS
This is an open-label dose escalation study and no interim analysis or blinding is planned for 
this study.  The final analysis will be conducted after the last subject last visit (LSLV).
5.1. Statistical Hypotheses
There are no statistical hypotheses.  The emphasis of the final analyses will be on estimation 
of study endpoints.
5.2. Statistical Decision Rules
5.2.1. Part 1 (MTD Finding)
In Part 1, patients will participate in a dose escalation phase aimed at estimating the MTD.  
The sample size for this component of the study will vary depending on the number of DLTs 
observed.  It is anticipated that the maximum sample size of approximately upto 92 patients 
are expected to be enrolled in Part 1 of the study at 3 - 6 sites.  The actual number of patients 
enrolled will depend upon tolerability and the number of dose levels required to identify the 
MTD.  
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The minimum and maximum sample sizes after which Part 1 can be stopped and MTD 
declared are approximately 6-12 and approximately 92 patients, respectively. As for the 
number of patients treated at each dose, it is expected that the typical number will be 1 to 
4 patients for the doses actually studied.  However, since variable cohort size is allowed, the 
actual number of patients treated at each dose will vary from 1 to 12. 
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.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating
d
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009 0.001
5.2.2. Part 2 (Dose Expansion)
In Part 2 the maximum sample sizes for each tumor indication (ie, TNBC, CRC and 
NSCLC) will be of n=10 to 20 evaluable patients.  Enrollment of patients in one indication 
may be discontinued if minimal or no anti-tumor activity (eg 0 or 1 response) is observed in 
the first 10 evaluable patients for that indication.  
5.2.3. Sample Size Determination
The exact sample size for the dose escalation design in Part 1 cannot be specified in advance
due to the dynamic features of mTPI.
Assuming a non-informative prior (ie, Jeffrey’s prior) if 1 out of 10 patients have tumor 
response, this would predict a posterior probability (Beta-Binomial) equal to 0.93 that the 
true response is inferior to 30%.  On the other hand, if 7 out of 20 patients have tumor 
response, this would predict a posterior probability equal to 0.70 that the true response is 
not inferior to 30% and a posterior probability equal to 0.05 (5%) that the true response is 
inferior to 20%.  In addition, posterior probabilities may be calculated by using informative 
priors based on the antitumor activity that may be observed during Part 1 (eg 2 out of 
3 TNBC patients experience tumor response in Part 1).  These posterior probabilities will be 
assessed for each indication during Part 2 when at least the first 10 Pts are enrolled in that 
indication.  Posterior Probabilities >0.75 of an ORR <20% (eg, 0,1 out of 10; 0,1,2 out of 
16) may provide evidence of no substantial anti-tumor activity for that indication. 
[Reference Source: Protocol Section 9.3]
 
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Unless otherwise specified, the baseline value is defined as the value collected at the time
closest to, but prior to, the start of study drug administration in the first cycle (in general 
C1D1). All data will be categorized based on the scheduled visit at which it was collected.
These visit designators are predefined values that appear as part of the visit tab in the eCRF.
5.3.1. Analyses for Time to Event Data
Time-to-event endpoints will be summarized using the Kaplan-Meier method2 and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence intervals for 
each time-to-event endpoint (Brookmeyer and Crowley, 19823) will be provided.   
5.3.2. Analyses for Binary Data
The rates of binary endpoints will be provided along with the corresponding 2-sided 
95% confidence intervals using an exact method. 
5.3.3. Analyses for Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values, will be provided for continuous endpoints. 
5.3.4. Analyses for Pharmacokinetic Data
Blood samples for PK analysis of PF-06671008 will be taken according to the Schedule of 
Activities given in the protocol.  PK parameters listed in Section 3.2 will be derived from the 
concentration-time data using non compartmental analysis as follows: 


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Parameter
Definition
Method of Determination
AUCsd,τ
Area under the concentration-time 
profile from time zero to the time τ, 
the dosing interval
Linear/Log trapezoidal method
AUCss,τ
Area under the concentration-time 
profile during one dosing interval, τ, 
at steady state
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.
Cmax
Maximum observed oncentration
Observed directly from data
Cmax,ss
Maximum observed oncentration at 
steady state
Observed directly from data
Cmin,ss
Minimum observed oncentration at 
steady state
Observed directly from data
Tmax
Time for Cmax
Observed directly from data 
Tmax,ss
Time for Cmax at steady state
Observed directly from data 
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 for IV administration
Dose/ AUCinf for dose 1; Dose/ AUCτ for dose 4
CL/F
Apparent clearance for SC 
administration
Dose/ AUCinf for dose 1; Dose/ AUCτ for dose 4
Vss
Volume of distribution at steady state
for IV administration
CL×MRT
Vss/F
Apparent volume of distribution at 
steady state for SC administration
CL/F×MRT
Rac
Observed accumulation ratio
AUC dose 4, τ/ AUCdose 1, τ
5.3.5. Analyses for Immunogenicity Data
Anti-PF-06671008 antibody data will be collected at baseline and post treatment according to 
the protocol.
5.4. Methods
5.4.1. Missing Data
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, 
 which will only use the 
actual date collected or if date not available deem the data missing.
5.4.2. Efficacy Analysis
In this First In Patient study anti-tumor activity is a primary objective for Part 2 of the study.
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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 3 (RECIST v1.1) 
 
For the time-to-event endpoints, the missing data handling method will be censoring. 
Censoring rules for time-to-event endpoints are detailed in Appendix 1.
5.4.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, missing concentrations and anomalous values
Patients who experience events that may affect their PK (eg, incomplete dosing) may be 
excluded from the PK analysis. 
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
subjects. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters. In the event that 
the actual sampling time is not available, the nominal time may be used if there is no 
evidence that the actual sampling time deviates substantially from the nominal time.
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If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC.  For statistical analyses, PK parameters coded as NC will also 
be set to missing.
If an individual subject has a known biased estimate of a PK parameter (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.
6. ANALYSES AND SUMMARIES
6.1. Standard Analyses
Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.
Subject discontinuation from treatment and study will be tabulated and listed separately with 
their reason for discontinuation.  The Safety Analysis Set will be used.
Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, and primary diagnosis will be tabulated and listed. For ECOG 
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. The safety analysis set will be used.
Dose modifications may occur in the following ways:

Cycle delay;

Dose delay within a Cycle;

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 ng the actual dose ng/kg should be calculated 
considering the body weight of the patient at that visit. 


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The following will be summarized by patient for overall and each dose level: 

Number of subjects per dose level (Prime and non-Prime);

Median and range of number of cycles started per subject;

Number (%) of subjects starting a cycle (1, 2, 3…);

Number (%) of patients with cycle delays;

Number (%) of dose interruptions (include both known and unknown dates);

Number (%) of patients with dose reductions;

Number (%) of each reason (drug related AE vs AE vs. Other) for cycle delays, dose 
interruptions and dose reductions;

Time on treatment (median, range).
The following will be summarized by cycle:

For ongoing subjects, the last cycle end date is the cycle start date + number of days 
per cycle - 1 day;

For completers and discontinued subjects, if the Systemic Therapy dataset exists , the 
end date would be the earliest date of the start date of the new anticancer treatment or 
last active treatment + 27 days. If the Systemic Therapy SCRF data does not exist 
then the last cycle end date will be set to last active treatment + 20 days;

Total number of cycles started;

Total number of doses;

Number of cycles and doses started per patient (median, range);

Number of cycles and doses before 1st delay (median, range);

Number of cycles and doses before 1st reduction (median, range);

Number of cycles and doses before 1st interruption (median, range).
The following will be summarized for cumulative dose by dose level and cycle: 

Summary statistics (mean, median, standard deviation and range) of cumulative dose 
and percent of starting dose (compared to Day 1 dose of each cycle).


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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 0 ng), administered total daily dose for each period, 
any missed doses, number of missed doses, reason for any dosing changes. 
Listings by patient 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), dose interruption (yes/no), and infusion rate and reason for infusion rate changes. 
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary.  Listings of prior, concomitant, and 
further therapies will be provided separately.
6.2. Analysis of Primary Endpoint
6.2.1. DLT(Part 1)
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study, which will be summarized by dose level using the Per Protocol Analysis Set for 
patients in the dose escalation portion of the study.  A listing of the DLTs will also be 
provided. If necessary, a summary and listing of AEs meeting the criteria for DLT by 
malignancy may be provided using the Per Protocol Analysis Set for patients in the MTD 
expansion portion of the study.
6.2.2. Safety Endpoints (Part 1 and Part 2)
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE version 
4.03 and coded using the MedDRA.4  The focus of AE summaries will be on Treatment 
Emergent Adverse Events, those with initial onset or increasing in severity after the first dose 
of study medication.  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) for overall and each dose.  The Safety 
Analysis Set will be used. Part 1 and Part 2 data will be summarized separately and will also 
be pooled together for analysis. Pfizer standard on safety data reporting will be followed. 
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory test for overall 
and each dose.  The analyses will summarize laboratory tests both in the entire study period 
and by cycle (Cycle 1 and Cycles beyond 1).  Shift tables will be provided to examine the 
distribution of laboratory abnormalities. The Safety Analysis Set will be used.
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal high/low or not done.


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Vital signs
The number and percentage of patients who experienced vital signs abnormalities will be 
summarized (See Schedule of Activities in the protocol for details and Appendix 2).
6.3. Analysis for Secondary Endpoints
6.3.1. Efficacy Endpoints Analysis
In this Phase 1 study efficacy is a secondary objective for Part 1.  The efficacy analysis will 
be performed in the mITT population. Part 1 and Part 2 data will be summarized separately 
and will also be pooled together for analysis. Efficacy will be analyzed separately from those 
assessed by RECIST 
 criteria for solid tumor.
Efficacy data in Part 1, Part 2 and across the two Parts may be summarized in the following 
groups: 
•
Overall summary for all doses and all tumor types assessed by RECIST 
 criteria;
•
Same tumor type regardless of dose;
•
Same dose regardless of tumor type;
•
Same dose and same tumor type if data permit.
Summary tables of best Overall Response Rate, Progression Free Survival, and Overall 
Survival (for Part 2), duration of stable disease (DOSD), and duration of response (DOR)
will be provided by the groups aforementioned.  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. Swimmer plot for individual clinical response and time on treatment, waterfall plot 
for individual tumor size percent change from baseline, and spider plot for individual tumor 
size percent change from baseline over time will be presented.
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The following table provides an overview of the efficacy analysis.
Endpoint
Analysis Set
Statistical 
Method 
Model/ Covariates/ 
Strata
Missing 
Data
Overall 
response
mITT
Exact CI
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Observed 
case
Overall 
Survival
ITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Censored at 
last visit
Progression 
Free Survival 
(PFS)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Censored per 
Appendix 1
Time to 
Progression 
(TTP)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Censored per
Appendix 1
Duration of 
Response 
(DOR)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Censored per 
Appendix 1
Duration of 
Stable Disease 
(DOSD)
mITT
Kaplan-Meier
See aformentioned 
summary descriptions 
on data pooling 
across dose and 
tumor type 
Censored per 
Appendix 1
6.3.2. Pharmacokinetics Analyses 
Pharmacokinetic Concentrations
The concentration-time data will be summarized by descriptive statistics (n, mean, standard 
deviation, coefficient of variation (CV), median, minimum, maximum, geometric mean and 
its associated CV) by treatment/dose, cycle, day and nominal time. In addition, the 
concentration-time data from Part 2 may also be summarized by descriptive statistics 
according to tumor type if data permit.  


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The concentration-time data will be presented as below:

A listing of all concentrations by treatment/dose, subject ID, cycle, day, and nominal 
time post dose. The concentration listing will also include the actual times. 
Deviations from the nominal time will be given in a separate listing.

A summary of concentrations by treatment/dose, cycle, day, and nominal time post 
dose, where the set of statistics will include n, mean, standard deviation, median, 
coefficient of variation (CV), minimum, maximum and the number of concentrations 
above the lower limit of quantification.

Median concentration-time plots (on both linear and semi-log scales) against nominal 
time postdose by cohort (all cohorts on the same plot per scale, based on the summary 
of concentrations by cohort and time postdose).

Mean concentration-time plots (on both linear and semi-log scales) against nominal 
time postdose by cohort (all cohorts on the same plot per scale, based on the summary 
of concentrations by cohort and time postdose).

Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each subject per scale].
For drug concentration summary statistics, median and mean plots by sampling time, the 
nominal PK sampling time will be used; for individual subject plots by time, the actual PK 
sampling time will be used.
In addition to the above, predose concentrations will be plotted for each dose using a 
box-whisker plot by cycle and day within cycle in order to assess the attainment of steady 
state.
Pharmacokinetic Parameters
To assess the pharmacokinetics of PF-06671008, the PK parameters detailed in Section 3.2
will be listed and summarized for subjects in the PK analysis set (as defined in Section 4.4).  
Missing values will be handled as detailed in Section 5.4.3.  Each PK parameter will be 
summarized by dose, cycle, and day and will include the set of summary statistics as 
specified in the table below:
Parameter
Summary statistics
Cmax, AUCinf, AUCsd,, CL (for 
IV), CL/F (for SC), Cmax,ss, Cmin,ss, 
AUCss,τ, Vss (for IV), Vss/F (for 
SC) and Rac
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean
t1/2
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum
Tmax, Tmax,ss
N, median, minimum, maximum


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For Part 1, dose normalized AUCinf (AUCτ at steady state), and Cmax will be plotted against 
dose (using a logarithmic scale) by cycle and day.  These plots will include individual patient 
values and the geometric means for each dose.  These plots will be used to help understand 
the relationship between the PK parameters and dose.
6.3.3. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADAs and neutralizing 
antibodies will be summarized by overall, by treatment/dose and by tumor type, as data 
permit.  For patients with positive ADAs, titer, time of onset, and duration of ADA response 
will also be described, if data permit.  In addition, efforts will be made if data permit, as 
appropriate, to examine possible correlations of the ADA response with clinical data on the 
PK, safety and/or efficacy. 
 
 
 
 
 
6.5. Population PK and PK
 Modeling 
Pharmacokinetic 
 data from this study may be analyzed using modeling approaches 
and may also be pooled with data from other studies to investigate any association between 
PF-06671008 exposure 
 or significant safety endpoints. The results of these 
analyses, if performed, may be reported separately.
6.6. ECG Analysis
The analysis of ECG results will be based on patients in the Safety Analysis Set with baseline
and on-treatment ECG data, and will follow the ICH E14 guidance on the clinical evaluation 
of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.5
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.
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QT intervals will be corrected for HR (QTc) using standard correction factors [ie, Fridericia’s 
(default correction), , and possibly a study specific factor, as appropriate]. QTcF interval will 
be calculated using the Friderica formula, as follows:
3 RR
QT
QTcF =
Data will be summarized and listed for QT, HR, RR, PR, QRS, QTcF (and/or QTcB if 
deemed appropriate by overall, and dose.  Individual QT (all evaluated corrections) intervals 
will be listed by cohort, time and dose.  The most appropriate correction factor will be 
selected and used for the following analyses of central tendency and outliers and used for the 
study conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the absolute corrected QT interval and changes 
from baseline in corrected QT after treatment by study arm dose and time point. For each
patient and by treatment, the maximum change from baseline will be calculated as well as the 
maximum post-baseline interval across time points. Categorical analysis will be conducted
for the maximum change from baseline in corrected QT and the maximum post-baseline QT
interval.
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE version 4.03 Grade. Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: 
(n, %).
Patients experiencing clinically-relevant morphological ECG changes will be summarized
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline 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.
Changes from baseline for the ECG parameters QT interval, heart rate (HR), QTc interval,
PR interval and QRS interval will be summarized by treatment and visit. Categorical data 
analysis will follow Appendix 2. 
If more than one ECG is collected at a nominal time post dose (for example, triplicate ECGs), 
the mean of the replicate measurements will be used to represent a single observation at that 
time point.  If any of the three individual ECG tracings has a QTc value ≥500 msec, but the 
mean of the triplicates is not ≥500 msec, the data from the subject’s individual tracing will be 
described in a safety section of the study report in order to place the ≥500 msec value in 
appropriate clinical context.  However, values from individual tracings within triplicate 
measurements that are ≥500 msec will not be included in the categorical analysis unless the
average from the triplicate measurements is also ≥500 msec. Changes from baseline will be
defined as the change between QTc post dose from the time-matched average of the pre-dose
triplicate values on Day 1.
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In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK
modeling approach, if data 
warranted. If a PK
relationship is found, the impact of subject factors (covariates) on 
the relationship will be examined.
7. INTERIM ANALYSES
No formal interim analysis is planned in this study. However, since this is an pen-label 
study, safety data 
 data will be monitored. 
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8. REFERENCES 
1.
B783 Protocol Amendment 5, Jan. 12, 2018.  
2.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am 
Stat Assoc 1958; 53:457-481.
3.
Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  
Biometrics 1982; 38:29-41.
4.
NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.
pdf.
5.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
6.
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.
7.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related
tumor response assessment: does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab?  J Immunother Cancer
2014;2:17.
8.
Guha M:The new era of immune checkpoint inhibitors; Pharm J Volume 293, 18 NOV 
2014, No 7837/8 online URL 200671127.
9.
Topp MS, Gokbuget N, Zugmaier G, et al. A phase II trial of the anti-CD19 BiTE 
blinatumomab shows hematologic and molecular remissions in patients with relapsed or 
refractory B-precursor acute lymphoblactic leukemia. J Clin Onco 2014; published 
online Nov 10. DOI:10.1200/JCO.2014.56.3247.


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9. APPENDICES 
Appendix 1. Time to Event Data Analysis Censoring Rules
Table 3.
Progression Free Survival and Duration of Response
Situation
Date 
of 
Progression/Censoring1
Outcome
Inadequate baseline assessment 
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor 
assessment
Censored
Progression Documented on or 
between scheduled tumor 
assessments prior to treatment 
discontinuation2
Date of first objective tumor 
assessment showing objective 
progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor 
assessment prior to 
discontinuation2
Censored
Treatment discontinuation due to 
toxicity or other reason
Date of last objective tumor 
assessment prior to 
discontinuation2
Censored
Death prior to first planned 
tumor assessment 
Date of death
Death (Event)
Death without objective 
progression prior to treatment 
discontinuation2
Date of death
Death (Event)
Death or progression after 2 or 
more missed tumor assessments
Date of last objective tumor 
assessment prior to the event
Censored
1: For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
2: or within 28 days of discontinuation of treatment.  


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Table 4.
Time to Progression
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline 
assessment 
First dosing date in Cycle 1
Censored
No on-study assessments
First dosing date in Cycle 1
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor 
assessment
Censored
Progression Documented on or 
between scheduled tumor 
assessments prior to treatment 
discontinuation2
Date of first objective tumor 
assessment showing objective 
progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor 
assessment prior to 
discontinuation2
Censored
Treatment discontinuation due 
to toxicity or other reason
Date of last objective tumor 
assessment prior to 
discontinuation2
Censored
New anticancer treatment 
<28 days after discontinuation 
of treatment without 
progression
Date of last objective tumor 
assessment prior to new anticancer 
treatment
Censored
Death prior to first planned 
tumor assessment 
Start date (C1D1)
Censored
Death without objective 
progression prior to treatment 
discontinuation2
Date of last objective tumor 
assessment prior to death
Censored
Progression after 2 or more 
missed tumor assessments
Date of last objective tumor 
assessment prior to the event
Censored
1: For censoring date, if a tumor assessment takes place over a number of days (eg, superficial lesions one day, 
scans another), the last date is used as the assessment date.
2: or within 28 days of discontinuation of treatment.
DOSD and DOR
Censoring rules for DOSD and DOR will be the same as for PFS.


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Appendix 2. Categorical Classes for ECG and Vital Signs
Categories for QTcB and QTcF
QTcB/QTcF 
(ms)
max. 450
450< max. 480
480< max.500
max. >500
QTcB/QTcF 
(ms) increase 
from baseline
max. <30
30max. <60
max. 60
Categories for PR and QRS
PR (ms)
max 300
PR (ms) increase 
from baseline
Baseline >200 and 
max. 25% increase
Baseline 200 and max. 
50% increase
QRS (ms)
max 200
QRS (ms) 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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Appendix 3. RECIST 1.1 Tumor Assessment Criteria
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. 
a. Categorizing Lesions at Baseline
1. Measurable Lesions
Lesions that can be accurately measured in at least one dimension.
1. 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).
2. Lesions with longest diameter at least 20 mm when assessed by chest X-ray. 
3. Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.
4. 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. 
2. Non-measurable Disease 
1. 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.
2. 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.
3. 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.
3. Normal Sites
1. 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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2. Bone lesions: Bone scan, PET scan or plain films are not considered adequate 
imaging techniques to measure bone lesions.  However, these techniques can be used 
to confirm the presence or disappearance of bone lesions. Lytic bone lesions or mixed 
lytic blastic lesions, with identifiable soft tissue components, that can be evaluated by 
cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above. Blastic bone lesions are non measurable. 
3. 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.
4. Lesions with prior local treatment: Tumor lesions situated in a previously irradiated 
area, or in an area subjected to other loco regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.
5. Solitary lesions: If a measurable disease is restricted to a solitary lesion, its neoplastic 
nature should be confirmed by cytology/histology. 
4. 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. 
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
5. 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. 
1. 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.
2. 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.


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NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
6. 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’).
b. 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. 
7. Target Disease
1. 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.
2. 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. 
3. Stable Disease (SD): 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. 
4. Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 
5. 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);


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
or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
8. Non-target Disease
1. Complete Response (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).
2. Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
3. Progressive Disease (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. 
4. 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.
5. Cytology, histology.
6. 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.
7. 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.
9. 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: 


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
Negative FDG PET at baseline, with a positive FDG PET at follow up 

No FDG PET at baseline and a positive FDG PET at follow  up: if the positive FDG 
PET at follow up corresponds to a new site of disease confirmed by CT, this is PD.
If the positive FDG PET at follow up is not confirmed as a new site of disease on CT, 
additional follow up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG PET scan).
If the positive FDG PET at follow up corresponds to a pre existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.
10. Supplemental Investigations
1. 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.
2. 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. 
11. 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 5.
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 6.
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 4. Immune-related RECIST (irRECIST) Tumor Assessment Criteria
Increasing clinical experience indicates that traditional response criteria may not be sufficient
to fully characterize activity in this new era of targeted therapies and/or biologics.
This is particularly true for immunotherapeutic agents such as anti-cytotoxic T
lymphocyte-associated protein 4 (CTLA4) and anti PD-1/anti-PD-L1 antibodies which exert
the antitumor activity by augmenting activation and proliferation of T cells, thus leading to
tumor infiltration by T cells and tumor regression rather than direct cytotoxic effects. Clinical
observations of patients with advanced melanoma treated with ipilimumab, for example, 
suggested that conventional response assessment criteria such as Response Evaluation 
Criteria in Solid Tumors (RECIST) and WHO criteria are not sufficient to fully characterize 
patterns of tumor response to immunotherapy because tumors treated with
immunotherapeutic agents may show additional response patterns that are not described in 
these conventional criteria.
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have
been reported as not capturing the existence of a subset of patients who have an OS similar to 
those who have experienced CR or PR but were flagged as PD by WHO criteria.
On these grounds, a tumor assessment system has been developed that incorporates these
delayed or flare type responses into the RECIST v1.1 (irRECIST) [7].
For irRECIST, only target and measurable lesions are taken into account. In contrast to
RECIST v1.1, irRECIST:

Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented, and

Does not necessarily score the appearance of new lesions as progressive disease if the
sum of lesion diameters of target lesions (minimum of 10 mm longest diameter per
non-nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 target
lesions, maximum of 2 per organ) and measurable new lesions does not increase
by 20%.
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial.
irRECIST is defined as follows:

Overall immune related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions. All measurable lymph nodes 
also must have a reduction in short axis to <10 mm.


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
Overall immune-related partial response (irPR): Sum of the diameters (longest for
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions
decreases 30%.  Overall immune related stable disease (irSD): Sum of the diameters 
(longest for non-nodal lesions, shortest for nodal lesions) of target and new 
measurable lesions is neither irCR, irPR, (compared to baseline) or immune related
progressive disease (irPD, compared to nadir).

Overall immune related progressive disease (irPD): Sum of the diameters (longest for
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions
increases 20% (compared to nadir), confirmed by a repeat, consecutive observation 
at least 4 weeks from the date first documented.
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion
measurements). A lymph node has to be 15 mm in short axis to be a measurable new lesion
and its short axis measurement is included in the sum.  Up to 2 new lesions per organ and up
to 5 new lesions in total can be added to the measurements.
New non measurable lesions: Do not define progression but preclude irCR.