Conditions: Neoplasms Breast Cancer
Keywords: solid tumors triple negative breast cancer PF-06650808 Phase 1
Enrollment: 40
Healthy volunteers: no

Brief summary:
To assess the safety and tolerability at increasing dose levels of PF-06650808 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: PF-06650808 intervention 2: PF-06650808
Intervention descriptions: intervention 1: Dose Escalation Phase \[Part 1\] - PF-06650808 will be administered at doses starting at 0.2 mg/kg. Increases in dose will continue until MTD is determined. intervention 2: Dose Expansion Phase \[Part 2\] - Patients will be treated at the MTD or Recommended Phase 2 dose selected in Part 1.

Protocol document:
Prot_000.pdf: 
PF-06650808
B7501001
Final Protocol Amendment 1, 07May 2014
Page 1
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND 
TOLERABILITY OF PF-06650808 IN PATIENTS WITH ADVANCED SOLID 
TUMORS
Compound:
PF-06650808
Compound Name:
Not applicable
US IND Number:
120498
European Clinical Trial Database 
(EudraCT) Number:
Not applicable
Protocol Number:
B7501001
Phase:
1


PF-06650808
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Document History
Document
Version Date
Summary of Changes
Original protocol
19 March 2014
N/A
Amendment 1
07 May 2014
Section 1.4.1 Clarification 
that PF-06380101 is a P-
glycoprotein substrate.
Section 5.4
Recommendation to avoid 
co-administration of potent 
CYP3A/P-gp inhibitors 
and/or inducers and addition 
of Appendix 6: CYP3A and 
P-Glycoprotein Inducers 
and Inhibitors.
Section 5.2.3 (Medication 
Error text), Section 8
(Adverse Event Reporting) 
and Section 15 (Publication 
of Study Results) updated to 
align with updated Protocol 
Template.


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PROTOCOL SUMMARY
Background and Rationale:
Antibody-drug conjugates (ADCs) are being developed to improve the therapeutic index of 
cytotoxic anti-cancer agents.  The strategy makes use of an immunoconjugate in which a 
cytotoxic agent is chemically linked to an antibody that selectively binds to an internalizing 
tumor-associated antigen.  This strategy allows the delivery of the cytotoxic agent to the 
tumor site while minimizing the exposure to normal tissues.
PF-06650808 is an anti-Notch3 ADC for the treatment of patients with cancer.  PF-06650808 
is comprised of a humanized anti-Notch3 antibody linked to an auristatin-based cytotoxic 
agent with a peptide cleavable maleimidocapronic-valine-citruline-
p-aminobenzyloxycarbonyl (vc) linker.  The auristatin-based payload is a highly potent, 
cell-permeable, anti-mitotic agent that blocks tubulin polymerization resulting in cell cycle 
arrest, induction of apoptosis and inhibition of tumor growth in preclinical models. 
The Notch3 receptor is a highly conserved transmembrane protein that undergoes 
ligand-dependent and independent internalization, and traffics to the lysosome for 
degradation (Jia, et al. 2009).11  Notch3 is over-expressed or amplified in certain human 
tumors and regulates cell proliferation, differentiation, and survival (Bellavia et al., 2008; 
Park et al, 2006; Cancer Genome Atlas Research Network, 2011).4,6,16  Constitutive 
activation of Notch3 signaling is oncogenic in many contexts and induces tumors in mouse 
models.  Immunohistochemical studies showed the presence of Notch3 on a variety of human 
carcinomas, including breast, lung and ovary (Hirose et al., 2010; Haruki et al, 2005; Jung et 
al., 2010).8,9,12  Further, in ovarian cancer, high levels of Notch3 messenger ribonucleic acid 
(mRNA) expression are associated with poorer survival.  In lung cancer, Notch3 signaling 
has been linked with a tumor-initiating cell (cancer stem cell) phenotype (Zheng et al, 
2013).17  
 
 
Triple negative breast cancer (TNBC) is a heterogenous 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 (Andre et al., 2012).1  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 (Liedtke et al., 2008).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 (Pal et al., 2011).15  Thus, novel therapeutic options are urgently needed.
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Study Objectives and Endpoints:
Dose Escalation (Part 1) Objectives
Primary Objective:

To assess safety and tolerability at increasing dose levels of PF-06650808 in patients
with advanced solid tumors unresponsive to currently available therapies, or for
whom no standard therapy is available in order to determine 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 of ADC
(PF-06650808), total antibody (PF-06460005) and unconjugated payload
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.

To document any preliminary evidence of anti-tumor activity.
:

Dose Expansion (Part 2) Objectives
Primary Objective:

To confirm safety and tolerability and explore preliminary evidence of anti-tumor
activity of PF-06650808 at the RP2D in patients with TNBC.
Secondary Objectives:

To evaluate the overall safety profile at the R2PD.

To characterize the single and multiple dose pharmacokinetics of ADC
(PF-06650808), total antibody (PF-06460005) and unconjugated payload
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.
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:

.
Primary Endpoints
Primary Endpoint (Part 1):

First cycle Dose Limiting Toxicities (DLTs) in order to determine the MTD and
RP2D.
Primary Endpoint (Part 2):

Response rate (RR) as determined by the Response Evaluation Criteria in Solid
Tumor (RECIST) version 1.1 criteria.
Study Design:
This is a Phase 1, open label, multi-center, single arm, non randomized, multiple dose, safety, 
pharmacokinetic (PK) and pharmacodynamic (PD) study of single agent PF-06650808 in 
sequential cohorts of adult patients with advanced solid tumors for whom no standard 
therapy is available.  Successive cohorts of patients will receive escalating doses of 
PF-06650808 intravenously every 21 days starting at a dose of 0.2 mg/kg. 
Approximately 55 patients are expected to be enrolled in the study at approximately 3-4 sites.  
The actual number of patients enrolled will depend upon tolerability of PF-06650808 and the 
number of dose levels required to identify the MTD.
The study will include two parts, a dose escalation phase (Part 1) followed by a dose 
expansion phase (Part 2).  Part 1 will estimate the MTD in dose escalation cohorts in patients 
with advanced solid tumors for whom no standard therapy is available in order to establish 
the RP2D.  Part 2 will include approximately 20 patients with TNBC enrolled at the MTD in 
order to explore benefit from treatment as suggested by preclinical findings, and will better 
define the safety profile at the RP2D.  Additional safety information gathered in Part 2 may 
be used to modify the dose recommended for future Phase 2 studies.
The study is expected to be completed in approximately 24 months.  The end of the study is 
the last visit of the last patient.
Study Treatment:
A modified continual reassessment method (mCRM) targeting a DLT rate of 25% will be 
utilized for Part 1 (dose escalation phase).  Patients will be enrolled in cohorts of 2 to 4, 
starting with 0.2 mg/kg for the first cohort.  The possible doses explored will be from a fine 
grid of doses ranging from 0.2 mg/kg to 6.4 mg/kg.  If a high DLT rate is observed at the 
starting dose of 0.2 mg/kg, a lower dose such as 0.14 mg/kg or lower will be considered.  The 
study may be stopped if the drug is deemed not tolerable at the lowest reduced dose.  
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Part 2 will include patients enrolled at the MTD in order to explore benefit from treatment 
and will better define the safety profile at the RP2D.
Patients will continue with study treatment every 21 days until disease progression, 
withdrawal of consent, unacceptable toxicity occurs, or the study is terminated.  Patients 
experiencing a DLT may be managed with dose modification or discontinuation.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments section of the 
protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the patient.
Protocol Activity
Screen/ 
Baseline1
(28 days)
Treatment Period
Post Treatment
Cycle 1 Only (Days 1 -21)
Cycle 2 and Subsequent Cycles 
(Days 1-21)
End of 
Treatment22
Follow-Up23
Day 1 Day 2 Day 4 Day 8 Day 15
Day 1
Day 8
Day 15
Visit Window (Days)
1
1
2
2
2
2
Informed consent2
X
Tumor history3
X
Medical history4
X
Complete Physical Examination
including skin examination5
X
X
X
Abbreviated Physical Examination
including skin examination
X
X
X
X
X
Baseline signs and symptoms6
X
Height
X
Weight
X
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
ECOG Performance status8
X
X
X
X
X
12-Lead ECG9
X
X
X
X
X
X
Laboratory
Hematology10
X
X
X
X
X
X
X
X
X
X
Blood Chemistry11
X
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
Urinalysis13
X
X
X
X
Pregnancy test14
X
X
X
X
Registration15
X
Study treatment16
X
X
CT or MRI scan or equivalent17
X
X (every 
6 weeks)
X


PF-06650808
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Page 8
Protocol Activity
Screen/ 
Baseline1
(28 days)
Treatment Period
Post Treatment
Cycle 1 Only (Days 1 -21)
Cycle 2 and Subsequent Cycles 
(Days 1-21)
End of 
Treatment22
Follow-Up23
Day 1 Day 2 Day 4 Day 8 Day 15
Day 1
Day 8
Day 15
Visit Window (Days)
1
1
2
2
2
2
 
Blood Samples for PK
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below
Blood Sample for 
Anti-PF-06650808 Antibody19
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below
Adverse Events20
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and non drug 
supportive interventions21
X
X
X
X
X
X
X
X
X
X
X
1.
Screening: To be conducted within 28 days prior to treatment start.
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.
3.
Tumor History: Will be collected within 28 days prior to treatment start.  Includes history of disease under study including details of primary diagnosis and treatment 
history.
4.
Medical History: Includes history of disease process other than the cancer under study (active or resolved) and concurrent illness.  Includes prior treatments and any 
current medical treatments for any condition.
5.
Complete Physical Examination: No need to repeat on C1D1 if baseline assessment performed within 72 hours of dosing.
6.
Baseline Signs & Symptoms: On Day 1 prior to the start of study treatment, patients will be asked about any signs and symptoms experienced within the past 14 days.  
Baseline signs and symptoms will be recorded on the AE CRF page.
7.
Vital Signs: Includes temperature, blood pressure (BP), and pulse rate (PR) to be recorded in the sitting position after approximately 5 minutes of rest.  On Day 1 of each 
cycle, vital signs should be measured prior to infusion start (pre-dose) and 1 hour after the start of infusion (ie, just prior to the end of the infusion).
8.
Performance Status: per ECOG scale (see Appendix 3).
9.
12 Lead ECG: ECGs will be collected during Screening and at the End of Treatment visit.  Additional ECGs will be collected prior to dosing, at end of infusion and at 
Day 8 following administration of each dose of study treatment.  If the mean QTc is prolonged (value of >500 msec), the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation.  Additional ECGs should be performed if clinically indicated.
10. Hematology: Complete blood count (CBC) to include hemoglobin, platelets, WBC, absolute neutrophils, lymphocytes, monocytes, eosinophils, and basophils.  No need to 
repeat on C1D1 if baseline assessment performed within 72 hour prior to dosing.  Hematology to be collected weekly through Cycle 6.  Beginning at Cycle 7, hematology 
will be collected on Day 1 of the cycle only.
11. Blood Chemistry: Should include sodium, potassium, chloride, bicarbonate or carbon dioxide, BUN (or urea), uric acid, creatinine, glucose, calcium, magnesium, 
phosphorus, albumin, total protein, AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, and lactate dehydrogenase (LDH).  No need to repeat on C1D1 if 
baseline assessment performed within 72 hours prior to dosing.  Chemistry to be collected weekly through Cycle 6.  Beginning at Cycle 7, chemistry will be collected on 
Day 1 of the cycle only.
12. Coagulation: Should include Prothrombin Time (PT) or International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT).
13. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  If 2+ protein on urine dipstick, then collect spot urine sample to calculate urine protein to 
creatinine ratio (UPCR).
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14. Pregnancy Test (serum or urine): 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 therapy - once at the start of screening and once on Day 1 of Cycle 1 before investigational product administration.  Pregnancy tests 
will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local regulations.
15. Registration: Patient number and dose level allocation will be provided by Pfizer Inc.  Treatment should begin no longer than 3 days from registration.
16. Study Treatment: PF-06650808 will be administered once every 21 days as an infusion over approximately 60 minutes.
17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites and may include chest, abdomen and pelvis CT or MRI scans.  Brain scans and 
bone scans should be performed at baseline if disease is suspected and on-study as appropriate to follow disease.  Baseline CNS imaging is not required with the exception 
of symptomatic patients to rule out CNS metastases. CT or MRI scans are to be done every 6 weeks (5 days) for the first two assessments (Week 6 and Week 12) and will 
then be collected every 12 weeks thereafter until disease progression by RECIST (v1.1) or death, or until permanent discontinuation of study treatment.  Tumor assessments 
should be fixed according to the calendar, regardless of treatment delays.  For patients enrolled in Part 2, responses of CR or PR must be confirmed by repeat assessment no 
more than 4 weeks after the criteria for response are first met.  Tumor assessments should be repeated at the End of Treatment visit if more than 6 weeks have passed since 
the last evaluation.
 
 
 
.
19. Anti PF-06650808 Antibodies: Collection of serum to detect the presence of antibodies to PF-06650808 is to be obtained prior to the start of study drug infusion.  Patients 
having an unresolved adverse event that is possibly related to anti-PF-06650808 antibodies at their last assessment will be asked to return to the clinic for ADA and drug 
concentration blood sampling at up to 3 month intervals until the adverse event or its sequelae resolve or stabilize at a level acceptable to the investigator and sponsor.
20. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTC AE version 4.03.  Patients must be followed for AEs 
for 28 days after the last 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 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.  Serious adverse events 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 serious adverse events that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.
21. Concomitant Medications and Non Drug Supportive Interventions: All concomitant medications and non drug supportive interventions should be recorded in the CRF.
22. End of Treatment Visit: 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 undergo review of concomitant medications, performance 
status, vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation of 
treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further improvement is 
expected.
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PHARMACOKINETIC, ANTI-DRUG ANTIBODY AND PHARMACODYNAMIC SAMPLING SCHEDULE
Protocol Activity
Screen
(28 day
s)
Treatment Period
Post 
Treatment
Cycle 1 Only
(Days 1 to 21)
Cycles
2 and 3
Cycle 4
Every Cycle 
Thereafter
EOT (+7)
Day 1
Day 2 Day 4
(1)
Day 8
(1)
Day 15
(2)
Day 1
Day 1
Day 2 Day 4
(1)
Day 8
(1)
Day 15
(2)
Day 1
Pre-dose
*
1 hr* 4 hr*
24
hr*
Pre-dose
*
1 hr* Pre-dose
*
1 hr*
4 hr*
24
hr*
Pre-dos
e*
1 hr*
Blood PK sample 
for PF-063801011
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood PK sample 
for 
PF-06650808 and 
PF-064600052
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Sample for 
Anti-PF-0665080
8 Antibody 3
X
X
X
X
X
X
 
* Sampling times are related to the start of the infusion; 1 hr samples should be collected immediately before the infusion ends
1.
Blood PK sample for PF-06380101: 4 mL of whole blood will be collected for PK analysis of unconjugated payload (PF-06380101).
2.
Blood PK sample for PF-06650808 and PF-06460005: Approximately 6 mL of whole blood will be collected for PK analysis of ADC (PF-06650808) and total antibody 
(PF-06460005).
3.
Anti PF-06650808 Antibodies: Collection of serum to detect the presence of antibodies to PF-06650808 is to be obtained prior to the start of treatment.  Patients having an 
unresolved adverse event that is possibly related to anti-PF-06650808 antibodies at their last assessment will be asked to return to the clinic for ADA and drug concentration 
blood sampling at approximately 3 month intervals until the adverse event or its sequelae resolve or stabilize at a level acceptable to the investigator and sponsor.
 
 
C
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TABLE OF CONTENTS
LIST OF FIGURES .................................................................................................................15
APPENDICES .........................................................................................................................15
1. INTRODUCTION ...............................................................................................................16
1.1. Indication.................................................................................................................16
1.2. Background and Rationale ......................................................................................16
1.3. PF-06650808 ...........................................................................................................17
1.3.1. Efficacy.......................................................................................................17
1.5. Starting Dose Rationale...........................................................................................21
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................21
2.1. Objectives................................................................................................................21
2.1.1. Dose Escalation (Part 1) Objectives ...........................................................21
2.1.2. Dose Expansion (Part 2) Objectives...........................................................22
2.2. Endpoints.................................................................................................................22
3. STUDY DESIGN.................................................................................................................24
3.1. Study Overview.......................................................................................................24
3.2. Dose Escalation Phase (Part 1)................................................................................24
3.3. DLT Definition........................................................................................................26
3.4. Recommended Phase 2 Dose (RP2D) Definition ...................................................26
4. PATIENT SELECTION......................................................................................................27
4.1. Inclusion Criteria.....................................................................................................27
4.2. Exclusion Criteria....................................................................................................28
4.3. Life Style Guidelines...............................................................................................29
4.4. Sponsor Qualified Medical Personnel.....................................................................30
5. STUDY TREATMENTS.....................................................................................................30
5.1. Allocation to Treatment ..........................................................................................30
5.2. Drug Supplies..........................................................................................................31
5.2.1. Formulation and Packaging........................................................................31
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5.2.2. Preparation and Dispensing........................................................................31
5.2.3. Administration............................................................................................31
5.2.4. Recommended Dose Modifications............................................................32
5.2.5. Dose Interruptions/Delay............................................................................33
5.2.6. Dose Reductions.........................................................................................33
5.2.7. Compliance.................................................................................................35
5.3. Drug Storage and Drug Accountability...................................................................35
5.4. Concomitant Medication(s).....................................................................................36
5.4.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................36
5.4.2. Supportive care ...........................................................................................36
5.4.3. Hematopoietic Growth Factors...................................................................36
5.4.4. Anti Diarrhea, Anti Emetic Therapy ..........................................................37
5.4.5. Corticosteroids............................................................................................37
5.4.6. Surgery........................................................................................................37
6. STUDY PROCEDURES .....................................................................................................37
6.1. Screening.................................................................................................................37
6.2. Treatment Period.....................................................................................................37
6.3. Follow-up Visit .......................................................................................................37
6.4. Patient Withdrawal..................................................................................................38
7. ASSESSMENTS..................................................................................................................39
7.1. Safety Assessment...................................................................................................39
7.1.1. Pregnancy Testing ......................................................................................39
7.1.2. Adverse Events...........................................................................................40
7.1.3. Laboratory Safety Assessment ...................................................................40
7.1.4. Vital Signs and Physical Examination........................................................40
7.1.5. (12-Lead) ECG ...........................................................................................41
7.2. Pharmacokinetics Assessments...............................................................................42
7.2.1. Blood for PK analysis of PF-06650808, Total Antibody 
(PF-06460005); and Unconjugated Payload (PF-06380101) ..........................42
7.4. Tumor Response Assessments ................................................................................43
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7.6. Immunogenicity Evaluations...................................................................................43
7.7. Banked Biospecimens .............................................................................................44
7.7.1. Markers of Drug Response.........................................................................44
7.8. Other Assessments ..................................................................................................45
7.8.1. Tumor and Medical History........................................................................45
7.8.2. Baseline Signs and Symptoms....................................................................46
8. ADVERSE EVENT REPORTING......................................................................................46
8.1. Adverse Events........................................................................................................46
8.2. Reporting Period .....................................................................................................46
8.3. Definition of an Adverse Event...............................................................................47
8.4. Abnormal Test Findings..........................................................................................47
8.5. Serious Adverse Events...........................................................................................48
8.5.1. Protocol-Specified Serious Adverse Events...............................................49
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................49
8.6. Hospitalization ........................................................................................................50
8.7. Severity Assessment................................................................................................51
8.8. Causality Assessment..............................................................................................51
8.9. Exposure During Pregnancy....................................................................................52
8.10. Occupational Exposure .........................................................................................53
8.11. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal) ........53
8.12. Eliciting Adverse Event Information ....................................................................53
8.13. Reporting Requirements........................................................................................53
8.13.1. Serious Adverse Event Reporting Requirements .....................................54
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................54
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................54
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................54
9.1. Analysis sets............................................................................................................54
9.2. Statistical Methods and Properties ..........................................................................55
9.2.1. Part 1...........................................................................................................55
9.2.2. Part 2...........................................................................................................57
9.3. Sample Size Determination.....................................................................................57
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9.4. Efficacy Analysis ....................................................................................................57
9.4.1. Analysis of Overall Response.....................................................................58
9.5. Analysis of Other Endpoints ...................................................................................58
9.5.1. Analysis of Pharmacokinetics.....................................................................58
9.5.2. Pharmacokinetic/Pharmacodynamic Analysis............................................59
9.5.3. Immunogenicity..........................................................................................59
9.6. Safety Analysis........................................................................................................59
9.6.1. Analysis of Primary Endpoint ....................................................................60
9.6.2. Analysis of Secondary Safety Endpoints....................................................60
9.6.2.1. Adverse Events..........................................................................60
9.6.2.2. Laboratory tests abnormalities ..................................................60
9.6.3. ECG ............................................................................................................60
9.7. Data Safety Monitoring Committee ........................................................................61
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................61
11. DATA HANDLING AND RECORD KEEPING .............................................................62
11.1. Case Report Forms/Electronic Data Record .........................................................62
11.2. Record Retention...................................................................................................62
12. ETHICS..............................................................................................................................63
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............63
12.2. Ethical Conduct of the Study ................................................................................63
12.3. Patient Information and Consent...........................................................................63
12.4. Patient Recruitment...............................................................................................64
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................64
13. DEFINITION OF END OF TRIAL...................................................................................64
13.1. End of Trial ...........................................................................................................64
14. SPONSOR DISCONTINUATION CRITERIA ................................................................64
15. PUBLICATION OF STUDY RESULTS..........................................................................64
15.1. Communication of Results by Pfizer ....................................................................64
15.2. Publications by Investigators ................................................................................66
16. REFERENCES ..................................................................................................................67


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LIST OF FIGURES
Figure 1.
Effect of PF-06650808 on the Growth of 37622A1 NSCLC PDX ......................18
Figure 2.
Effect of PF-06650808 on the Growth of TNBC CLX Model.............................18
Figure 3.
Effect of PF-06650808 on the Growth of OVCAR-3 CLX Model ......................19
APPENDICES
Appendix 1. Abbreviations......................................................................................................69
Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines.............................................................................................................71
Appendix 3. ECOG Performance Status..................................................................................76
Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ....................................................................................77
Appendix 5. Management of Infusion Related Reactions Including Allergic Reactions, 
Cytokine Release Syndrome or Anaphylaxis .......................................................78
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1. INTRODUCTION
1.1. Indication
PF-06650808 is intended to be used 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
Antibody-drug conjugates (ADCs) are being developed to improve the therapeutic index of 
cytotoxic anti-cancer agents.  The strategy makes use of an immunoconjugate in which a 
cytotoxic agent is chemically linked to an antibody that selectively binds to an internalizing 
tumor-associated antigen.  This strategy allows the delivery of the cytotoxic agent to the 
tumor site while minimizing the exposure to normal tissues.
PF-06650808 is an anti-Notch3 ADC for the treatment of patients with cancer.  The 
Notch3 receptor is a highly conserved, 244 kDa, type I transmembrane glyoprotein that is 
over-expressed or amplified in certain human tumors and regulates cell proliferation, 
differentiation, and survival (Bellavia et al., 2008; Park et al, 2006; Cancer Genome Atlas 
Research Network, 2011).4,6,16 Constitutive activation of Notch3 signaling is oncogenic in 
many contexts and induces tumors in mouse models.  The Notch3 receptor undergoes 
ligand-dependent and independent internalization, and traffics to the lysosome for 
degradation (Jia, et al. 2009).11 Immunohistochemical studies demonstrated the presence of 
Notch3 on a variety of human carcinomas, including breast, lung and ovary (Hirose et al., 
2010; Haruki et al, 2005; Jung et al., 2010).8,9,12
In ovarian cancer, high levels of Notch3 mRNA expression are associated with poorer 
survival.  In lung cancer, Notch3 signaling has been linked with a tumor-initiating cell 
(cancer stem cell) phenotype (Zheng et al, 2013).17
 
 
  In non-tumor tissues, Notch3 is 
expressed primarily in vascular smooth muscle cells (vSMC), various thymocyte 
subpopulations and the developing nervous system (Bellavia, 2008).4 Consistent with its 
restricted normal tissue distribution, targeted deletion of murine Notch3 does not lead to 
embryonic lethality.  Instead, Notch3-null mice are viable, but have defects in the maturation 
and differentiation of vSMCs (Domenga et al, 2004).5
Triple negative breast cancer (TNBC) is a heterogenous 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 (Andre et al, 2012).1 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 (Liedtke et al., 2008).13 The majority of patients receive anthracyclines and 
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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 (Pal et al., 2011).15 Thus, novel therapeutic options are urgently needed.
 
 
  
 
1.3. PF-06650808
PF-06650808 is comprised of the hu28 humanized IgG1 antibody linked to an 
auristatin-based cytotoxic agent with a peptide cleavable 
maleimidocapronic-valine-citruline-p-aminobenzyloxycarbonyl (vc) linker.  Hu28 is a 
non-inhibitory antibody that binds to Notch3 but does not neutralize Notch3 signaling.  The 
auristatin-based payload is a highly potent, cell-permeable, anti-mitotic agent that blocks 
tubulin polymerization resulting in cell cycle arrest, induction of apoptosis and inhibition of 
tumor growth in preclinical xenograft studies.  
 
 
 
 
 
.
1.3.1. Efficacy
Efficacy studies were carried out in immune-compromised mice harboring subcutaneously 
(lung, ovarian) or orthotopically (breast) implanted human tumor cells.  The panel of tumor 
models represented a broad range of tumor types and included both PDX and cell line 
xenografts (CLX).  High levels of target expression were assessed in tumor extracts by 
immunoblot and immunohistochemistry on formalin-fixed paraffin embedded xenografts.
PF-06650808 treatment resulted in long-term tumor regressions and/or tumor-free mice at a 
dose of 3 mg/kg when given every four days for a total of four treatments (q4dx4).
37622A1 is a PDX model of human non-small cell lung cancer (NSCLC) (Squamous Cell 
Carcinoma).  PF-06650808 completely suppressed tumor growth up to Day 60 at which time 
5 out of the 9 treated tumors slowly began to regrow (4 of the 9 animals remained tumor-free 
by Day 84).  The non-targeted control-ADC did not inhibit tumor growth in any meaningful 
manner.  Further, 37622A1 xenografts failed to respond to cisplatin administered at 5 mg/kg 
when dosed q4dx4, thus PF-06650808 outperformed standard-of-care and inhibited the 
growth of cisplatin-resistant tumors Figure 1.
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Figure 1.
Effect of PF-06650808 on the Growth of 37622A1 NSCLC PDX
MDA-MB-468 is an orthotopic CLX model of TNBC.  The 3 mg/kg dose of 
PF-06650808 completely regressed tumors and all 8 animals remained tumor-free through 
study end on Day 125.  At the 1 mg/kg dose of PF-06650808, tumor growth was inhibited by 
66%. No activity was observed at the 0.3 mg/kg dose of PF-06650808. The non-targeted 
control-ADC did not inhibit tumor growth in any meaningful manner Figure 2.
Figure 2.
Effect of PF-06650808 on the Growth of TNBC CLX Model
OVCAR-3 is a CLX model of ovarian cancer.  Mice bearing OVCAR-3 ovarian cancer 
xenografts were dosed q4Dx4 with PF-06650808, control ADC or vehicle.  
PF-06650808 inhibited tumor growth in a dose-dependent manner.  At the 6 mg/kg dose of 
PF-06650808, tumors regressed and did not regrow larger than mean staging volume by 
122 days (relative to the first dose) or study end.  At the 3 mg/kg dose of PF-06650808, 
tumors regressed and then slowly regrew (slightly larger than mean staging volume) after 
102 days (relative to the first dose).  At the 1 mg/kg dose of PF-06650808, tumor growth was 
inhibited by 57%.  No significant tumor growth inhibition was observed at the 0.3 mg/kg 


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dose of PF-06650808.  At the 6 mg/kg, 3 mg/kg and 1 mg/kg dose of control ADC, tumor 
growth was non-specifically inhibited by 91%, 46% and 30%, respectively, by Day 49.  
Tumors from control ADC treated groups quickly regrew into large tumors that were similar 
in volume to vehicle treated group by study end.  At the maximum tolerated dose of 
Paclitaxel (60 mg/kg) dosed q7Dx4, tumors regressed and did not regrow for at least 
122 days, which was the end of the study. Further, OVCAR-3 tumors failed to respond to 
carboplatin administered at 20 mg/kg when dosed q7dx8, thus PF-06650808 outperformed a 
standard-of-care chemotherapy and inhibited the growth of carboplatin-resistant tumors
Figure 3.
Figure 3.
Effect of PF-06650808 on the Growth of OVCAR-3 CLX Model
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
1.5. Starting Dose Rationale
The selection of the starting dose for the human Phase 1 trial was based on the preclinical 
safety study results following ICH S9 Guidance entitled “Nonclinical Evaluation for 
Anticancer Pharmaceuticals”.  Cynomolgus monkey was considered to be the most 
appropriate species for determining the proposed starting dose in patients.  
 
  The proposed starting dose of 
0.2 mg/kg given as an IV infusion every three weeks (Q3W) represents approximately 1/6 of 
monkey HNSTD (based on human equivalent dose normalized to body surface area).  In 
addition, given the projected human PK parameters based on allometric scaling from 
cynomolgus monkey PK, the projected human Cavg for PF-06650808 at the proposed starting 
dose of 0.2 mg/kg is expected to be approximately 1/20th of the observed monkey Cavg at 
HNSTD.
 
 
 
 
Complete information for this compound may be found in the Single Reference Safety
Document (SRSD), which for this study is the Investigator Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Dose Escalation (Part 1) Objectives
Primary Objective

To assess safety and tolerability at increasing dose levels of PF-06650808 in patients 
with advanced solid tumors unresponsive to currently available therapies, or for 
whom no standard therapy is available in order to determine the Maximum Tolerated 
Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
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Secondary Objectives

To evaluate the overall safety profile.

To characterize the single and multiple dose pharmacokinetics of ADC 
(PF-06650808), total antibody (PF-06460005) and unconjugated payload 
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.

To document any preliminary evidence of anti-tumor activity.

 
2.1.2. Dose Expansion (Part 2) Objectives
Primary Objectives

To confirm safety and tolerability and explore preliminary evidence of anti-tumor 
activity of PF-06650808 at the RP2D in patients with triple negative breast cancer.
Secondary Objectives

To evaluate the overall safety profile at the R2PD.

To characterize the single and multiple dose pharmacokinetics of ADC 
(PF-06650808), total antibody (PF-06460005) and unconjugated payload 
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.

.
2.2. Endpoints
Primary Endpoint (Part 1)

First cycle Dose Limiting Toxicities (DLTs) in order to determine the MTD and 
RP2D.
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Primary Endpoint (Part 2)

Response rate (RR) as determined by the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 criteria.
Secondary Endpoints

Adverse Events (AEs) as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study treatment.

Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.

Vital Signs. 

Systemic pharmacokinetic (PK) exposure of ADC (PF-06650808), total antibody 
(PF-06460005) and unconjugated payload (PF-06380101) will be determined with 
validated methods.  Standard noncompartmental PK parameters will be determined 
from the respective concentration-time data.

Immunogenicity of ADC (PF-06650808); Human serum ADA 
(anti-PF-06650808 antibody) samples will be analyzed for the presence or absence of 
anti-PF-06650808 antibodies, following a tiered approach using screening, 
confirmation and titer/quantitation.

Objective tumor response, as assessed using the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 by calculating the Overall Response Rate (ORR),
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, single arm, non randomized, multiple dose, safety, 
PK and PD study of single agent PF-06650808 in sequential cohorts of adult patients with 
advanced solid tumors for whom no standard therapy is available. Successive cohorts of 
patients will receive escalating doses of PF-06650808 intravenously every 21 days starting at 
a dose of 0.2 mg/kg. 
The proposed doses, schedule(s) and PK timepoints may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
Approximately 55 patients are expected to be enrolled in the study at approximately 3-4 sites.  
The actual number of patients enrolled will depend upon tolerability of PF-06650808 and the 
number of dose levels required to identify the MTD.
Patients will participate in the study for approximately 6 months.  This includes a 28 days 
screening period and approximately 4 month treatment period and a 28 day post dose 
follow-up period.  Treatment with study drug will continue until: disease progression, patient 
refusal or unacceptable toxicity occurs.  Patients who demonstrate clinical benefit with 
manageable toxicity and are willing to continue receiving the study treatment will be given 
the opportunity to continue treatment upon agreement between investigator and sponsor. 
Therefore, participation may be longer than 6 months for some patients. 
The study will include two parts, a dose escalation phase (Part 1) followed by a dose 
expansion phase (Part 2).  Part 1 will estimate the MTD in dose escalation cohorts in patients 
with advanced solid tumors for whom no standard therapy is available in order to establish 
the RP2D.  Part 2 will include approximately 20 patients with TNBC enrolled at the MTD in 
order to explore benefit from treatment as suggested by preclinical findings by providing an 
estimate of the likely response rate in this patient population and will better define the safety 
profile at the RP2D.  Additional safety information gathered in Part 2 may be used to modify 
the dose recommended for future Phase 2 studies.
The study is expected to be completed in approximately 24 months.  The end of the study is 
the last visit of the last patient.
3.2. Dose Escalation Phase (Part 1)
A modified continual reassessment method (mCRM) targeting a DLT rate of 25% will be 
utilized for Part 1 (dose escalation phase) (Goodman et al, 1995; O’Quigley et al, 1990).7,14
Patients will be enrolled in cohorts of 2 to 4, starting with 0.2 mg/kg for the first cohort.  The 
possible doses explored will be from a fine grid of doses ranging from 0.2 mg/kg to 
6.4 mg/kg.  If a high DLT rate is observed at the starting dose of 0.2 mg/kg, a lower dose 
such as 0.14 mg/kg (a 30% reduction from starting dose) or lower will be considered.  The 
study may be stopped if the drug is deemed not tolerable at the lowest reduced dose.  The 
mCRM model will determine the next dose level based on the DLT rate using a 30%, 69% 
and 100% dose increment for 0, 1 or 2 dose skips respectively. 


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Starting with the second cohort, patients will be assigned to a dose that is closest to the 
current MTD prediction based on a model that mCRM utilized to learn about overall 
dose-toxicity relationship.  This model is updated after DLT assessment of each cohort.  At 
any given point in this phase, doses can be escalated, deescalated, unchanged or revisited, but 
always aiming towards the target MTD.  To prevent overly aggressive dose-escalation, the 
maximum allowed dose increase will be limited to 2 increments at a time (ie, no more than 
100% dose increase at a time).  In addition, if two clinically significant Grade 2 toxicities of 
the same type are seen in a cohort, dose escalation will be limited to no greater than 69% for 
the next cohort.  If there is one additional case of the same Grade 2 toxicity or two other 
cases of clinically significant Grade 2 toxicities of the same type, dose escalation will again 
be limited to no greater than 69% for the next cohort; otherwise dose escalation following the 
mCRM algorithm will resume.  Grade 2 toxicities will not be considered clinically significant 
if a corresponding Grade 3 toxicity exists (by NCI CTCAE v 4.03); Grade 2 toxicities 
without a corresponding Grade 3 toxicity will be considered clinically significant 
(eg, Grade 2 alopecia, dry skin, libido decrease).  In addition, Grade 2 nausea, vomiting, and 
diarrhea will not be considered clinically significant unless it has been optimally medically 
managed.
The combination of a fine dose grid and the ability to skip doses allows rapid dose escalation 
if no DLTs are observed and small dose changes with exploration of adjacent doses once the 
observed DLT rate becomes noticeable.  The algorithm will stop if any of the following 
criteria is met:
1. The maximum sample size has been achieved (approximately 35 patients total).
2. At least 6 patients have been accumulated on a dose that is predicted to be the MTD, 
or
3. All doses explored appear to be overly toxic and the MTD cannot be determined.
Although dose levels are capped at 6.4 mg/kg, this mCRM will continue to operate subject to 
the constraints detailed above while allowing for doses higher than specified.  Doses may 
continue to be skipped, visited more than once, or not visited at all.  In addition, if necessary, 
doses beyond 6.4 mg/kg may be allowed in 30% increments.
All significant AEs and serious adverse events (SAEs) will be reviewed by the sponsor and 
investigators to determine if the dose allocation schedule requires modification.  The cohort 
steering committee, comprised of the sponsor clinical team and the investigators, can 
override the dose escalation increment determined by the algorithm if a more conservative 
approach is mandated.
Patients will continue with study treatment every 21 days until disease progression, patient 
refusal or unacceptable toxicity occurs.  Patients experiencing a DLT may be managed with 
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Subsequent dose levels may not be opened until all patients entered at the current dose level 
have been treated and observed for at least one complete cycle (through Day 21) and the 
number of DLTs among those patients in their first cycle has been determined.
3.3. DLT Definition
Severity of AEs will be graded according to CTCAE version 4.03.  For the purpose of dose 
escalation, any of the following adverse events which are not considered related to disease 
progression occurring in the first cycle of treatment (21 days) will be classified as DLTs:
Hematologic:

Grade 4 neutropenia lasting >7 days.

Febrile neutropenia (defined as neutropenia Grade 3 and a single body 
temperature >38.3C or a sustained temperature of 38C for more than one hour).

Grade 3 neutropenia with infection. 

Any grade thrombocytopenia associated with clinically significant or life-threatening 
bleeding.

Grade 4 thrombocytopenia 72 hours or platelets 10,000/mm3 regardless of 
duration.
Non-hematologic:

Grade 3 toxicities, except those that have not been maximally treated (eg, nausea, 
vomiting, diarrhea).

Delay by more than 2 weeks in receiving the next scheduled cycle due to persisting 
toxicities not attributable to disease progression.
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 cytokine release syndrome, 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. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study based on Phase 1 results.  If the MTD proves 
to be clinically feasible for long term administration in a reasonable number of patients, such 
dose usually becomes the RP2D.  Further experience with the MTD may result in a RP2D 
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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 protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified 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 the dose escalation phase: Histological or cytological diagnosis of 
advanced/metastatic solid tumor that is resistant to standard therapy or for which no 
standard therapy is available. 
2. For the dose expansion phase:  Previously treated metastatic triple negative breast 
cancer that expresses Notch3 with at least one measurable lesion.
3. For the dose expansion phase: Archival core needle biopsy or prospectively collected 
core needle biopsy available for exploratory biomarker and Notch3 expression 
analysis.
4. Age 18 years.
5. ECOG Performance Status (PS) of 0 or 1.
6. Life expectancy 12 weeks.
7. Adequate Bone Marrow Function as defined by:
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
Platelets 100,000/mm3 or 100 x 109/L;
Hemoglobin 9 g/dL.
8. Adequate Renal Function as defined by:
a.
Serum creatinine 1.5 x upper limit of normal (ULN); or 
b. Estimated creatinine clearance 60 ml/min as calculated using the method 
standard for the institution.
9. Adequate Liver Function as defined by:


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a.
Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome;
b. Aspartate and Alanine Aminotransferase (AST & 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).
10. Recovery from all prior surgical or adjuvant treatment-related toxicities, to Baseline 
status, or a CTCAE Grade of 0 or 1, except for toxicities not considered a safety risk, 
such as alopecia.  Post-surgical pain will not be considered a basis for exclusion.
11. Negative serum/urine pregnancy test (for females of childbearing potential).
12. Male and female patients of childbearing potential must agree to use a highly 
effective method of contraception throughout the study and for at least 28 days after 
the last dose of assigned treatment.  A patient is of childbearing potential if, in the 
opinion of the investigator, he/she is biologically capable of having children and is 
sexually active.
13. Evidence of a signed and dated informed consent document indicating that the patient 
has been informed of all pertinent aspects of the study.
14. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Patients with known symptomatic brain metastases requiring steroids Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery 
prior to the start of study medication, have discontinued corticosteroid treatment for 
these metastases for at least 4 weeks and are neurologically stable.
2. Major surgery, radiation therapy or systemic anti-cancer therapy within 4 weeks of 
starting study treatment (6 weeks for mitomycin C or nitrosoureas).
3. Prior treatment with a compound of the same mechanism.
4. Presence of Grade 2 peripheral neuropathy.
5. Significant prior allergic reaction to recombinant human or murine proteins.
6. Active and clinically significant bacterial, fungal or viral infection.  Known infections 
with hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus 
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7. Pregnant or breastfeeding; males and females of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 28 days after last dose of 
investigational product.
8. Currently active treatment in another clinical study.
9. Any of the following in the previous 12 months or currently: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident, transient ischemic attack or 
symptomatic pulmonary embolism, as well as ongoing cardiac dysrhythmias of NCI 
CTCAE Grade 2, atrial fibrillation of any grade, or QTc interval >470 msec at 
screening.
10. Known or suspected hypersensitivity to recombinant human or murine proteins.
11. 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.
12. Patients who are investigational site staff members directly involved in the conduct of 
the trial 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 trial.
4.3. Life Style Guidelines
In this study, patients of childbearing potential will received PF-06650808, a compound for 
which a 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 investigational product.  The investigator, in consultation with the patient, will 
select two appropriate methods of contraception for the individual patient from the permitted 
list of contraception methods, and instruct the patient in their consistent and correct use.  The 
investigator, at each study visit, will discuss with the patient the need to use highly effective 
contraception consistently and correctly and document such conversation in the patient chart.  
In addition, the investigator will instruct the patient to call immediately if a selected birth 
control method is discontinued or if pregnancy is known or suspected. 
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:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
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2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial 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 number, 
contact information for the investigational site and contact details for a help desk 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 patients 
participation in the study. The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used 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 the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study. The help desk 
number is not intended for use by the patient directly and if a patient calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Eligible patients will be enrolled to receive PF-06650808 in an open-labeled, unblinded 
manner.  Patients will be successively assigned to the next available treatment slot at a dose 
level decided on after the previous cohort’s safety evaluation and ongoing observations of 
earlier enrolled patients.  Treatment should begin no longer than 3 days from registration of 
the patient.
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, which will be used on all Case Report 
Form (CRF) pages and other trial-related documentation or correspondence referencing that 
patient.


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No patient shall receive study drug until the investigator or designee has received the 
following information in writing from the Sponsor:

Confirmation of the patient’s enrollment;

Specification of the dose level for that patient and;

Permission to proceed with dosing the patient.
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Drug Supplies
PF-06650808 will be supplied for the study by Pfizer.
Study centers will receive a supply of clinical trial material upon site activation with 
instructions on how to confirm drug receipt.  Resupplies will be made during the course of 
the study based on need.  The details on drug supply will be provided in the Study Manual.  
The study monitor should be contacted for any issues related to drug supplies.
5.2.1. Formulation and Packaging
PF-06650808 for injection, 60 mg extractable per vial, is presented as a sterile lyophilized 
product, white to off white cake, packaged in a 6 mL type 1 tubing glass vial with a 13 mm 
rubber stopper and a 13 mm aluminum overseal.  Each vial of PF-06650808 for injection is
reconstituted with 2.2 mL of water for injection (WFI).  The volume of the solution in the 
vial after reconstitution is 2.4 mL to ensure that the extractable volume (2 mL) can be 
withdrawn by syringe.  The vial is designed for single use.
The packages will be properly labeled according to local regulatory requirements.
5.2.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.  All preparations should take place under asceptic conditions.
The starting dose level will be 0.2 mg/kg.  The patient’s actual body weight will be used to
calculate the mg/kg dose, and the calculated dose will be rounded off to the first decimal 
point.  Specific preparation and dispensing instructions are provided in the Dosage 
Administration Instruction (DAI) located in the Study Manual. 
5.2.3. Administration
PF-06650808 will be administered on Day 1 of each 21-day cycle per the DAI as an IV 
infusion over approximately 60 minutes.  A cycle is defined as the time from Day 1 dose to 
the next Day 1 dose.  If there are no treatment delays, a cycle will be 21 days.  Each patient 
may receive PF-06650808 until disease progression, unacceptable toxicity, withdrawal of 
consent, or study termination. 


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In the case of infusion related reactions, characterized by fever and chills, and less commonly 
hypotension, the sponsor should be notified and pre-treatment medication should be 
administered prior to subsequent infusions (in the case that the patient is able to continue on 
treatment as per Appendix 5). The decision to incorporate pre-medication in all patients will 
be made following discussions between the sponsor and the investigators. Patients should be 
pre-treated with acetaminophen and diphenhydramine (or other antihistamine) approximately 
0.5 to 2 hours before each PF-06650808 administration.  The pre-treatment medications 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 (2) additional doses of acetaminophen 
may be administered approximately every 4 hours after the initial pre-treatment or as needed.
PF-06650808 will be administered as a 60-minute (5 minutes) IV infusion.  The use of an 
infusion pump is the preferred method of administration to ensure accurate delivery of the 
investigational product, but gravity drips are allowed.  Please refer to the DAI for infusion 
rate and duration.
Medication errors may result, in this study, from the administration of the wrong drug, 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 case report form 
(CRF) which is a specific version of the AE page of the CRFs 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 should be captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated adverse event(s) is captured on an 
adverse event (AE) CRF page.
5.2.4. Recommended Dose Modifications
Every effort should be made to administer study treatment 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.


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Dose modifications may occur in 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 toxicity in the 
previous cycle;

In the next cycle: dose reduction based on worst toxicity in the previous cycle. 
5.2.5. Dose Interruptions/Delay
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care should have their treatment interrupted/delayed.  
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. 
If a treatment interruption continues beyond Day 21 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle.  A treatment delay or 
interruption of more than 14 days due to lack of recovery will result in discontinuation of the 
patient from the treatment. 
A new cycle of treatment may begin only if:

ANC 1,000/mm3. 

Platelets count 75,000/mm3. 

Non-hematologic toxicities have returned to baseline or Grade 1 severity (or, at the 
investigator discretion, Grade 2 if not considered a safety risk for the patient).
If these conditions are not met, treatment must be delayed by 1 week.  If, after a 1-week 
delay, all toxicities have recovered within the limits described above treatment with 
PF-06650808 can be resumed.  If the patient has not recovered after 1 week of delay, 
treatment may be delayed by 1 more week.  However, initiation of the next cycle can only be 
delayed by a maximum of 2 weeks.  Therefore, if persisting toxicity does not allow 
PF-06650808 treatment resumption within 35 days of Day 1 of previous cycle, treatment 
with PF-06650808 will be permanently discontinued.
5.2.6. Dose Reductions
Dose reductions or delays in the administration of PF-06650808 are permitted as described 
below for PF-006650808 related toxicity.  The sponsor should be notified when dose 
reductions are planned and consulted for any dose reduction related questions.
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. The reduced dose 
will be considered the maximum dose for all subsequent cycles for that patient.  Doses 
should be reduced to the next lowest cohort dose level.  Dose re-escalation is not allowed.
Patients enrolled in the first cohort should be discontinued from the study if more than 1 dose 
reduction is required.  Patients enrolled in subsequent cohorts should be discontinued from 
the study if more than 2 dose reductions are required.  For patients experiencing an adverse 


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event related to PF-06650808 that fails to recover to CTCAE Grade 1 (or within 1 grade of 
starting values for pre-existing laboratory abnormalities) leading to treatment delay of 
>2 weeks should be discontinued unless discussed with the sponsor.
The following table summarizes the actions following the toxicities observed during the 
study period.
Event
Action
Grade 3 or 4 nonhematologic toxicity considered at 
least possibly related to PF-06650808 per 
investigator judgment (including persistent nausea, 
vomiting, diarrhea despite optimal medical 
therapy)

Hold PF-06650808 infusion until recovery to 
Grade 0-1 or baseline and reduce by 1 dose level.

Discontinue PF-06650808 if dose delay is more 
than 2 weeks.

If toxicity reoccurs despite reduction, patient may 
be dose reduced again by another dose level upon 
recovery to grade 0-1 or baseline unless the patient 
is in the first dose group, then only 1 dose 
reduction is allowed. 

Prompt palliative measures are strongly 
encouraged (eg, anti-emetics). 

Patients who experience Grade 4 non hematologic 
toxicities despite intervention should be 
discontinued from the study.
Hematologic toxicity considered at least possibly 
related to PF-06650808 per investigator judgment

Grade 4 neutropenia, ie, ANC 500/mm3
(1.0 x 109/L) for more than 7 days. 
or

Febrile neutropenia, ie, fever with a single temp 
>38.3C or sustained temp 38C for more than 
1 hour with ANC <1000/mm3. 
or

Grade 4 Thrombocytopenia, ie, PLTS 
25,000 mm3 (25.0 x 109/L). 
or

Any grade Thrombocytopenia with bleeding.

Hold PF-06650808 until recovery of ANC to 
1.0 x 109/L (1,000 cells/mm3) and platelets 75 x 
109/L (75,000 platelets/mm3).

Reduce PF-06650808 by 1 dose level.

If toxicity reoccurs despite dose reduction, patient 
may either be held until recovery and continuation 
at same dose, or undergo further dose reduction by 
another dose level unless the patient is in the first 
dose group, then only 1 dose reduction is allowed.
Other grade 4 hematologic toxicity considered at 
least possibly related to PF-06650808 per 
investigator judgment

Hold PF-06650808 until recovery to Grade 0-1 or 
baseline and reduce PF-06650808 dose by 1 dose 
level.

If toxicity reoccurs despite dose reduction, patient 
may either be held until recovery and continuation 
at same dose, or undergo further dose reduction by
another dose level unless the patient is in the first 
dose group, then only 1 dose reduction is allowed.
No recovery of toxicities within 2 weeks of 
scheduled PF-06650808 infusion

Discontinue treatment


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5.2.7. Compliance
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 monitor. 
At each study visit, the Investigator, or designee, will assess the patient’s compliance with 
the study requirements.  The assessment will include checks of protocol compliance and 
concomitant medication use.
5.3. Drug Storage and Drug Accountability 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
PF-06650808 is stored in a secure area, under recommended storage conditions and in 
accordance with applicable regulatory requirements.  PF-06650808 should be stored at 2-8C 
(36-46F) and protected from light until ready to use.  PF-06650808 should not be frozen.  
Specific instructions on storage and handling are provided in the DAI located in the Study 
Manual.  To ensure adequate records, all PF-06650808 will be accounted for in the CRF and 
drug accountability inventory forms as instructed by the sponsor.  Unless otherwise 
authorized by the sponsor, at the end of the clinical trial all drug supplies unallocated or 
unused must be returned to Pfizer or its appointed agent (eg, a contract research organization 
[CRO]).  If the sponsor authorizes destruction at the trial site, the investigator must ensure 
that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by the sponsor.  Destruction must 
be adequately documented.
Storage conditions stated in the Investigator Brochure may be superseded by the label 
storage.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products.  Any temperature 
excursions should be reported immediately to the sponsor.  The investigational product(s) 
must be stored as indicated.  Deviations from the storage requirements, including any actions 
taken must be documented and reported to the sponsor.  Once a deviation is identified, the
investigational product must be quarantined and not used until the sponsor provides 
documentation to use the investigational product.
Under no circumstances should the investigator or other site personnel supply study drug to 
other investigators, patients, or clinics, or allow supplies to be used other than directed by 
this protocol without prior authorization from the sponsor.


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5.4. Concomitant Medication(s)
Concomitant treatment considered necessary for the patient’s well being may be given at 
discretion of the treating physician.
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. (Anonymous, 2006).2
 
 
 
 
 
 
 
 
 
All concomitant medications, blood products, as well as non drug interventions (eg, analgesic 
use or paracentesis) received by patients within 28 days prior to the first dose of study 
treatment until the Follow-Up Visit will be recorded on the CRF. 
5.4.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor therapy including chemotherapy, hormonal therapy, radiotherapy, 
or experimental anticancer medications will be permitted while patients are receiving study 
therapy. Additionally, the concurrent use of herbal supplements for an anticancer treatment
is not permitted.
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing 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. 
5.4.2. 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. 
5.4.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first cycle but they may be used to treat treatment emergent neutropenia as indicated by 
the current American Society of Clinical Oncology (ASCO) guidelines. 
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
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5.4.4. Anti Diarrhea, Anti Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is permitted in this study at the 
investigator’s discretion. The choice of the prophylactic drug is up to the investigator with 
sponsor approval and assuming there is no known or expected drug-drug interaction.  If so it 
must be approved by the sponsor.
5.4.5. Corticosteroids
Chronic, systemic corticosteroid use (prednisone 12.5 mg/day or dexamethasone 
2 mg/day) for palliative or supportive purpose is not permitted. Acute emergency 
administration, topical applications, inhaled sprays, eye drops or local injections of 
corticosteroids are allowed.
5.4.6. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and PF-06650808 required to minimize the risk 
of impaired wound healing and bleeding has not been determined. Stopping PF-06650808 is 
recommended at least 7 days prior to surgery. Postoperatively, the decision to reinitiate 
PF-06650808 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
6. STUDY PROCEDURES 
6.1. Screening
All patients being considered for the study and eligible for screening must provide evidence 
of informed consent for the study before completing any study-specific procedures.  A 
patient identification number will be assigned.  The investigator (or appropriate delegate at 
the site) will obtain informed consent from each patient in accordance with the procedures 
described in the Schedule of Activities and Section Patient Information and Consent. 
Patients will be screened within 28 days prior to administration of the study treatment to 
confirm that they meet the patient selection criteria for the study. 
For screening procedures see Schedule of Activities and Assessments section.  Following 
completion of the screening assessments and confirmation of eligibility, patients may be 
enrolled. 
6.2. Treatment 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.  Patients will 
return to the clinic at least 28 days, and no more than 35 days, after discontinuation of 
treatment to undergo review of concomitant medications, performance status, vital signs, and 
assessment for resolution of any treatment related toxicity.  Patients continuing to experience 


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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.
In the event a patient is unable to return to the clinic for the follow-up visit, telephone contact 
with the patient to assess adverse events and concomitant medications and treatment is 
expected.  If laboratory assessments are needed to follow-up unresolved adverse events, 
retrieval of assessments performed at an institution local to the patient is acceptable.
6.4. Patient Withdrawal
The reason for a patient’s discontinuation from treatment will be documented in the end of 
study/withdrawal CRF.  Patients will be followed for at least 28 days after the last dose of 
study drug for adverse events. 
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 according to RECIST 1.1;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Adverse Event;

Medication error without associated adverse event;

Significant protocol violation;

Lost to follow-up;

Patient no longer willing to participate in study;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;


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
Lost to follow-up;

Patient refusal for further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, , request the patient to return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved adverse events (AEs).
If the patient refuses further visits, the patient withdraws consent for disclosure of future 
information or for further contact, 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, which 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 
which he/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 AEs, SAEs, vital signs and physical 
examination, electrocardiogram (ECG) (12-lead), laboratory assessments, including 
pregnancy tests and verification of concurrent medications.
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, will be performed on two occasions prior to starting study 
therapy – once at the start of screening and once on Day 1 of Cycle 1 before investigator 
product administration.  Following a negative pregnancy result at screening, appropriate 
contraception must be commenced.  Pregnancy tests will also be routinely repeated at every 
cycle during the active treatment period, at the end of study therapy and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
In the case of a positive hCG test, the patient will be withdrawn from study medication but 
may remain in the study.  Pregnancy tests may also be repeated as per request of IRB/IECs 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 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the AE CRF page.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  On Day 1 of Cycle 1, the hematology and 
blood chemistry samples do not need to be repeated if the screening assessment is performed 
within 72 hours prior to dosing.  Hematology and blood chemistry will be collected on 
Day 1, Day 8 and Day 15 of each cycle through Cycle 6.  For subsequent cycles, hematology 
and blood chemistry will be collected on Day 1 of each cycle.
Investigators may have additional blood tests performed for the purpose of planning 
treatment administration, dose modification, or following AEs.
Hematology
Chemistry*
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT/SGPT
PT or INR
Urine dipstick 
For female patients 
Platelets
AST/SGOT
PTT
For urine protein: If
of childbearing
WBC
Alk Phos
2+ protein on urine
potential,  serum or
Absolute Neutrophils
Sodium
dipstick, then collect
urine
Absolute Lymphocytes Potassium
spot urine sample to
Absolute Monocytes
Magnesium
calculate urine
Absolute Eosinophils
Chloride
protein to creatinine
Absolute Basophils
Calcium
ratio (UPCR)
Total Bilirubin*
Total protein
Microscopic analysis 
BUN or Urea
if dipstick abnormal
Creatinine
Uric Acid
Glucose (non-fasted)
Albumin
Phosphorous
Bicarbonate or carbon 
dioxide
LDH
* For Hy's law potential 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, and alkaline phosphatase.
7.1.4. Vital Signs and Physical Examination
Patients will have a physical exam to include weight, vital signs, assessment of ECOG status 
and height; height will be measured at screening only.


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A complete physical examination (PE) will be performed at Screening, Day 1 of Cycle 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 
measurement of body weight, vital signs and assessment of ECOG performance status.  The 
complete PE on Day 1 of Cycle 1 is not required if the screening complete PE is performed 
within 72 hours of dosing.  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 adverse event in the CRF.
Abbreviated PEs, including skin assessment, should be performed as appropriate at each visit 
where complete physical exams are not required, and on an as needed basis for assessment of 
adverse events.  Abbreviated exams should be targeted to specific symptoms or complaints 
and be consistent with local standard of care. 
Weight and body surface area (BSA) do not need to be performed at each visit; however 
patients should be monitored throughout the study for significant weight change.  If, in the 
Investigator’s opinion, clinically significant weight change occurs, BSA should be 
recalculated to determine appropriate dose. 
Vital signs will include measurements of blood pressure, pulse rate and temperature (oral, 
tympanic or axillary).  On Day 1 of each cycle, vital signs should be measured prior to 
infusion start (pre-dose) and 1 hour after the start of the infusion.  Sitting blood pressure (BP) 
will be measured with the patient’s arm supported at the level of the heart and recorded to the 
nearest mmHg sufficient.  The same arm (preferably the dominant arm) should preferably be 
used throughout the trial.  The 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 and pulse rate is acceptable.  When the timing of the measurements coincides 
with a blood collection, blood pressure and pulse rate should be obtained prior to the nominal 
time of the blood collection.
7.1.5. (12-Lead) ECG
12-lead ECG will be collected as per the Schedule of Activities and should be performed 
after the patient has rested quietly for at least 10 minutes.  ECGs will be compared to the 
patient’s screening ECG and any clinically significant changes will be recorded as adverse 
events and evaluated further, as clinically warranted. If the mean QTc is prolonged (value of 
>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation.  Additional ECGs should be performed if clinically indicated.
If 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 should preferably be carried out before or after 
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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7.2. Pharmacokinetics Assessments
7.2.1. Blood for PK analysis of PF-06650808, Total Antibody (PF-06460005); and 
Unconjugated Payload (PF-06380101)
Blood samples (4 mL of whole blood for PK analysis of unconjugated payload 
(PF-06380101) analysis and 6 mL of whole blood for PK analysis of ADC (PF-06650808) 
and total antibody (PF-06460005) will be collected in appropriately labeled tubes at times 
specified 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 
documented in the CRF.
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) will be considered protocol compliant, and the exact time of the sample 
collection noted on the CRF. If a scheduled blood sample collection cannot be completed for 
any reason, the missed sample time may be re-scheduled with agreement of clinical 
investigators, patient and Sponsor.
 
 
 
 
.  Samples collected for this purpose will be retained in accordance to local 
regulations and if not consumed during the course of these experiments, will be discarded.
 
 
 
 
 
 
 
 
 
 
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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 computed tomography (CT) or magnetic resonance imaging 
(MRI) scans; brain CT or MRI scan for patients with known or suspected brain metastases; 
bone scan and/or bone X-rays for patients with known or suspected bone metastases.  
Baseline CNS imaging is not required with the exception of symptomatic patients to rule out 
central nervous system (CNS) metastases. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the subsequent tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Activity, 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 2).  Changes in 
tumor size will be categorized as complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD), the latter incorporating the appearance of new 
lesions.  For patients in Part 2, responses of CR or PR must be confirmed by repeat 
assessment no more 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. 
 
 
  
 
  
7.6. Immunogenicity Evaluations
Assays to assess for anti-drug (anti-PF-06650808) antibodies (ADA) will be performed.  All 
samples that are positive in a screening assay will be further characterized in terms of 
antibody specificity.  Confirmed ADA responses may also be characterized for neutralizing 
antibodies (Nab). Patients found to have anti-PF-06650808 antibodies at their final study 
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visit and an ongoing AE possibly related to ADA will be asked to return to the clinic for 
ADA assessment 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 5 mL of serum for ADA and Nab analysis 
will be collected into appropriately labeled tubes at 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 a validated analytical method in compliance with Pfizer 
standard operating procedures.
 
 
 
.  Samples collected for this purpose will be retained in 
accordance to local regulations and if not used within this timeframe, will be destroyed.
7.7. Banked Biospecimens
7.7.1. Markers of Drug Response
Variation in genetic markers and other biomarkers may help to explain some of the 
variability in response seen with some drugs among different individuals.  This is referred to 
as pharmacogenomic/biomarker research.  Comparing the DNA, RNA, protein, and 
metabolite variation patterns of patients who respond well and those who respond poorly to 
treatment may help to better define the most appropriate group of patients in which to target a 
given treatment.  Collecting biospecimens for exploratory pharmacogenomic/biomarker 
analyses and retaining them in the Pfizer BioBank makes it possible to better understand the 
drug’s mechanism of action and to seek explanations for differences in, for example, 
exposure, efficacy, tolerability, or safety not anticipated prior to the beginning of the study.  
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited as such by local regulations or ethics committee decision. 
 
 
 
 
 
 
 
 
 
 
 
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A 4 mL blood sample 
 
 will be collected at the Baseline visit to be retained for potential
pharmacogenomic/biomarker analyses related to drug response unless prohibited by local 
regulations or ethics committee decision.  For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to 
the mechanism of drug action may be examined. 
The Banked Biospecimens will be collected from all patients unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
 
 
 
 
 
 
 
 
7.8. Other Assessments
7.8.1. Tumor and Medical History
History of the patient’s disease under study including details of the primary diagnosis and 
treatment history will be collected within 28 before the start of treatment.  In addition, a 
history of disease process other than the cancer under study (active or resolved) and 
concurrent illnesses will be collected.  This will also include prior treatments and any current 
medical treatments for any condition.
CCI
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7.8.2. Baseline Signs and Symptoms
On Day 1 prior to the start of treatment, patients will be asked about any signs and symptoms 
experienced within the past 14 days.  Baseline signs and symptoms will be recorded on the 
AE CRF.
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 adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as a 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.  Serious adverse events 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 serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug 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 one dose of study treatment through last patient 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.


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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;

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. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 


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
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 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 
reporting as an AE.
8.5. Serious Adverse Events
An SAE 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 Common Terminology Criteria (CTC)
Grade 5 (see 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.


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8.5.1. 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 Section Serious Adverse Event Reporting Requirements). 
8.5.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (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 
important medical events. 
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 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X UNL with no evidence of hemolysis 
and an alkaline phosphatase 2 X ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range, AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN
(whichever is smaller);

Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least by 1 X ULN or if 
the value reaches 3 X 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 


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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.
8.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute an 
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 
work-up of persistent pre-treatment lab 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);


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
Hospitalization for observation without a medical AE;

Pre-planned 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 non-invasive 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.
8.7. 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 CTC 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 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.8. 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 serious adverse 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 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. 


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In addition, if the investigator determines 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.
8.9. Exposure During Pregnancy
For investigational 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 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male patient 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 a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (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 pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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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 investigational product.
Additional information regarding the exposure during pregnancy 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 EDP Pregnant Partner 
Release of Information Form to deliver to his partner.  The investigator must document in the 
source documents that the patient was given the Pregnant Partner Release of Information 
Form to provide to his partner.
8.10. 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 adverse event.
An occupational exposure is reported to safety within 24 hours of 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 study
master file.
8.11. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal)
Withdrawal due to AE 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 a SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. 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.
8.13. 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.


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8.13.1. 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 timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, 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/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes 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 
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.
8.13.2. 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.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event 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).  This 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 analyses will be performed on the following analysis population.


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1. Safety analysis set.

The safety analysis set includes all enrolled patients who receive at least one dose 
of study medication.
2. Full analysis set.

The full analysis set includes all enrolled patients.  This is equivalent to the 
intent-to-treat (ITT) population.
3. 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 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. Per protocol analysis set (evaluable for MTD).

The per protocol analysis set includes all enrolled patients who receive at least 
one dose of study medication at the dose level of RP2D and who do not have 
major treatment deviations during first cycle.  Patients with major treatment 
deviations in cycle 1 are not evaluable for the RP2D assessment.  Major 
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.  A baseline disease assessment and at least one 
post-baseline disease assessment are appropriate to allow efficacy analysis.
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.
6. PD/Biomarker analysis sets.

The PD/Biomarker analysis population is defined as all enrolled patients with at 
least 1 of the PD/Biomarker evaluated at pre- and/or post-dose.
9.2. Statistical Methods and Properties
9.2.1. Part 1
Part 1 of this study employs a modified continual reassessment method (mCRM) targeting a 
DLT rate of 25% to estimate the MTD.  The mCRM algorithm utilizes Bayesian 


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methodology to consistently learn about dose-toxicity relationship after each cohort’s DLT 
response becomes available.  The underlying model assumption is that DLT rate at each dose 
can be expressed as Pr (DLT| x)=f(x, ), where x is a quantity associated with a dose, f is a 
monotonically increasing function, and is an unknown parameter with prior distribution 
placed on it at the beginning of the trial.  The first cohort of (2-4) patients will be assigned to 
0.2 mg/kg.  After the first cohort’s response becomes available (all patients through Day 21), 
the prior distribution of is updated based on their DLT responses and becomes a posterior 
distribution.  The current estimate of MTD is as the dose corresponding to x= f--1 (0.25, ), 
given posterior information about (ie, DLT data + modeling ), and the next cohort’s dose 
assignment is chosen as the dose closest to this estimated MTD but not exceeding it.  This 
process is continued until 1 of the stopping rules below is triggered. 
1. Maximum sample size of 35 patients has been reached. 
2. MTD has been identified with sufficient accuracy: at least 6 patients have been 
accumulated on a dose that is currently estimated to be the MTD and there are at least 
12 patients overall enrolled in the trial. 
3. All doses appear to be overly toxic and the MTD cannot be determined in the current 
trial setting.
Starting from the second cohort and until the end of trial, the above described mCRM 
algorithm constantly incorporates additional information about dose-DLT relationship 
learned from the data via modeling and that is reflected on the projected MTD.  By design, 
such dose allocation procedure will eventually cluster dose assignments around the dose 
yielding an approximately 25% DLT rate.  Because CRM derives MTD estimate from all the 
data accumulated at a given time and not just the last cohort’s response, the procedure is 
capable of incorporating DLT information occurring late in the trial, ie, after the minimum 
required DLT follow-up of 21 days. 
Like all Bayesian methods, mCRM may be sensitive to prior information placed on the 
model parameter at the beginning of the trial.  However, as the trial progresses and DLT 
data accumulates, it eventually overrules the prior information and the latter becomes less 
important.  Furthermore, a non-informative prior distribution is used for in this study.  
Although simulation was performed assuming a maximum dose of 6.4 mg/kg, actual doses 
may be limited at this or a lower dose level until additional information is obtained to support 
a higher dose exposure.
Due to binomial data variability in small samples, DLTs may be observed in a first cohort at 
0.2 mg/kg simply by chance even when the true Pr(DLT at 0.2 mg/kg) is fairly low.  This 
could result in the estimated posterior DLT rate at 0.2 mg/kg (and all higher doses) to exceed 
the targeted 25% very early in the trial, triggering an early stop when very few patients (2-4) 
have been treated.  To prevent stopping the trial prematurely for futility in such cases, a 
step-down option with dose 0.14 mg/kg (a 30% reduction from starting dose) is added to the 
dose grid.  This dose will be explored only if a high DLT rate occurs in the first cohort 
assigned to 0.2 mg/kg, ie, it will not be used as a starting dose.


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9.2.2. Part 2
Part 2 of this study is intended to confirm the safety and tolerability of the dose selected in 
Part 1 while assessing the antitumor activity of PF-06650808 in patients with TNBC.  The 
DLT rate and its 95% confidence interval at the selected dose may be estimated.
Analyses may be performed on data from both Part 1 and Part 2 to explore the relationships 
between PK parameters, safety endpoints, and efficacy endpoints.
9.3. Sample Size Determination
Approximately 55 patients are expected to be enrolled in this study.
The exact sample size of the mCRM design in Part 1 cannot be pre-specified in advance 
because it is a dynamic feature of the design.  The minimum and maximum sample sizes 
after which the Part 1 can be stopped and MTD declared are approximately 12 and 
35 patients, respectively.  Also, a minimum of 6 patients on MTD dose at Part 1 is required 
to establish such dose as RP2D.  The actual sample size of Part 1 will depend on the 
underlying dose toxicity profile and variability in actual data realization. 
As for the number of patients treated at each dose, it is expected that the typical number will 
be 2 to 4 patients for the doses actually studied.  For the dose declared as MTD at the end of 
Part 1, this number will be 6 or more patients.  However, since not every dose listed will be 
studied and variable cohort size is allowed, the actual number of patients treated at each dose 
will vary. 
The sample size in Part 2 is based on clinical consideration, rather than statistical 
justification.  Upon identification of the MTD by the mCRM method, approximately 
20 patients with triple negative breast cancer will be enrolled in Part 2 to further evaluate 
safety and preliminary efficacy parameters. 
 
 
 
 
 
 
9.4. Efficacy Analysis
Anti tumor activity will be presented in the form of patient data listings that include, but will 
not be limited to, tumor type, starting dose, tumor measurements, tumor response at each 
visit, and best overall response. 
Objective tumor response rate, progression-free survival, overall survival and clinical benefit 
response rate will be summarized and presented if data permits.
CCI


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9.4.1. Analysis of Overall Response
For patients to be considered evaluable for efficacy they must have received at least one dose 
of study medication and have a baseline tumor assessment.  Patients must also present with 
measureable disease.
The best overall response is the best response recorded from first dose until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since 
screening).  In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  All measurements (or “too 
small to measure”) must be provided for every target lesion to document SD or PR.
The main goal of confirmation of objective response is to avoid an incorrect estimation of the 
response rate observed.  In cases where confirmation of response is not feasible, it should be 
made clear when reporting the outcome of such studies that the responses are not confirmed.
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met.  Clinical benefit response (CBR) is defined as a CR, PR or SD 
6 cycles.
9.5. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance,
  
Data will also be displayed graphically, where appropriate.  Additional details of the analyses 
are outlined in the SAP.
9.5.1. Analysis of Pharmacokinetics
Drug concentrations of ADC (PF-06650808), total antibody (PF-06460005) and 
unconjugated payload (PF-06380101) will be measured using validated methods.  PK 
parameters will be determined from the respective concentration-time data using standard 
noncompartmental methods.  Actual sample collection times will be used for the parameter 
calculations.  For ADC (PF-06650808) and total antibody (PF-06460005), PK parameters 
including maximum concentration (Cmax), time to maximum concentration (Tmax), area under 
the concentration-time curve (AUCinf, and AUCτ), clearance (CL), volume of distribution 
(Vss), terminal elimination half-life (t1/2), and accumulation ratio (Rac) will be calculated.  
For unconjugated payload (PF-06380101), PK parameters including maximum concentration 
(Cmax), time to maximum concentration (Tmax), area under the concentration-time curve 
(AUCinf, and AUCτ), terminal elimination half-life (t1/2), and accumulation ratio (Rac) will be 
calculated. 
Drug concentrations of ADC (PF-06650808), total antibody (PF-06460005) and 
unconjugated payload (PF-06380101) will be summarized graphically and with descriptive 
statistics by dose, cycle, and the nominal PK sampling time.  Noncompartmental PK 
parameters will be summarized descriptively by dose and cycle.
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9.5.2. Pharmacokinetic/Pharmacodynamic Analysis
Safety (eg, DLT, platelet count) and efficacy (ORR) data from both Part 1 and Part 2 will be 
pooled.  PK/PD analyses will be conducted to explore the exposure-response relationship 
using appropriate model-based methods to assist MTD estimation.
 
9.5.3. Immunogenicity
The development of anti-PF-06650808 antibodies will be measured using validated assays.  
Listings and summary tabulations of the anti-PF-06650808 antibody data at baseline and post 
randomization will be generated.
Potential impact of immunogenicity on PK and clinical responses including PD markers, 
safety/tolerability and efficacy of PF-06650808 will be explored, if data is warranted.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
AEs will be presented with and without regard to causality based on the investigator’s 
judgment.  The frequency of overall toxicity, categorized by toxicity Grades 1 through 5, will 
be described.  Additional summaries will be provided for AEs that are observed with higher 
frequency.
Adverse events, ECGs, blood pressure, pulse rate, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
patients.  Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical 
concern will be described.  Safety data will be presented in tabular and/or graphical format 
and summarized descriptively, where appropriate.
Medical history and physical exam information collected during the course of the study will 
not be captured for inclusion into the study database, unless otherwise noted.  However, any 
untoward findings identified on physical and/or neurologic exams conducted after the 
administration of the first dose of study medication will be captured as an adverse event, if 
those findings meet the definition of an adverse event.  Data collected at Screening that is 
used for inclusion/exclusion criteria, such as laboratory data, ECGs and vital signs will be 
considered source data, and will not be captured for inclusion into the study database, unless 
otherwise noted.  Demographic data collected at Screening will be included in the study 
database.
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9.6.1. Analysis of Primary Endpoint
DLT is the primary endpoint of the dose escalation phase of the study.  The occurrence of 
DLTs observed in the dosing cohorts is used to estimate the MTD as described in 
Section Dose Escalation Phase (Part 1).  AEs constituting DLTs will be listed per dose level.  
Because the intent is to find a desirable dose that meets the tolerability criteria based on DLT 
rate while demonstrating clinical activity based on response rate, descriptive statistics 
(n, frequency and percentage) will be reported.  Corresponding listings of data will be 
generated.
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Adverse Events
AEs will be graded by the investigator according to the 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 medication.  The number and percentage of 
patients who experienced any AE, SAE, treatment related AE, and treatment related SAE 
will be summarized according to worst toxicity grades.  The summaries will present AEs 
both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). 
9.6.2.2. 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 assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1). 
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done.
9.6.3. ECG
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval and QRS interval will be summarized by treatment and time.  QT intervals will be 
corrected for heart rate (QTc) using Fridericia’s correction factors (QTcF).
The number (%) of patients with maximum post dose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTcF
Borderline (msec)
Prolonged (msec)
Absolute Value
450 - <480
480
Absolute Change
30-<60
60
In addition, the number of patients with corrected and uncorrected QT values 500 msec will 
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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 QTcF value 500 msec, 
but the mean of the triplicates is not 500 msec, the data from the patient’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 that triplicate measurements is also 500 msec.  Changes from baseline will be 
defined as the change between QTcF post dose and the pre-dose value on Day 1.
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 SAEs according to regulatory guidelines;

Discussions between the investigators and the sponsor of AEs and laboratory tests 
alterations seen at each dose level 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
During study conduct, Pfizer or its agent will conduct periodic monitoring visits 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 is 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.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), 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.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, 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 investigator’s 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, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
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.


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12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
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/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
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 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient.
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each patient's signed 
consent document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
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 which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial
End of Trial is defined as Last Patient Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-06650808 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 reasonable period of time.  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), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations. 
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Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.
The timing of the posting depends on whether the Pfizer product is approved for marketing in 
any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, Food and Drug 
Administration (FDA)-approved products, Pfizer posts results within one year of the 
primary completion date (PCD). For studies involving products approved in any 
country, but not FDA approved, Pfizer posts results one year from last patient, last 
visit (LPLV);

For studies involving products that are not yet approved in any country, Pfizer posts
the results of already-completed studies within 30 days of US regulatory approval or 
one year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for outlicensing or within two years if outlicensing plans have not 
completed).
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 pre-specified protocol or was 
terminated.
www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an FDA-approved Pfizer product 
with a LSLV on or after 27-Sep-2007 for which Basic Results were posted on 
www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01-May-2004, regardless of the marketing status 
of the compound.


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15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) 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, Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, investigator agrees that the first publication is to 
be a joint publication covering all centers. 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, investigator is free to publish separately, subject to the other requirements 
of this Section.
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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
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.
2.
Anonymous.  Update of Recommendations for the Use of White Blood Cell Growth 
Factors: An Evidence-Based Clinical Practice Guideline. JCO Jul 1, 2006:3187-3205
3.
Bellavia D, Campese AF, Alesse E, et al. Constitutive activation of NF-kappaB and 
T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J 2000; 19(13):3337-48.
4.
Bellavia D, Checquolo S, Campese AF, et al.  Notch3: from subtle structural differences 
to functional diversity.  Oncogene 2008; 27(38):5092-8.
5.
Domenga V, Fardoux P, Lacombe P, et al.  Notch3 is required for arterial identity and 
maturation of vascular smooth muscle cells.  Genes Dev 2004; 18(22):2730-5.
6.
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian 
carcinoma. Nature 2011; 474:609-15.
7.
Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the 
Continual Reassessment Method for Phase 1 Studies. Stat Med. 1995;4:1149-1161.
8.
Haruki N, Kawaguchi KS, Eichenberger S, et al. Dominant-negative Notch3 receptor 
inhibits mitogen-activated protein kinase pathway and the growth of human lung 
cancers. Cancer Res 2005; 65(9):3555-61.
9.
Hirose H, Ishii H, Mimori K, et al. Notch pathway as candidate therapeutic target in 
Her2/Neu/ErbB2 receptor-negative breast tumors. Oncol Rep. 2010; 23(1):35-43.
10.
Hu C, Dievart A, Lupien M, et al. Overexpression of activated murine Notch1 and 
Notch3 in transgenic mice blocks mammary gland development and induces mammary 
tumors.  Am J Pathol 2006; 168(3):973-90.
11.
Jia L, Yu G, Zhang Y, Wang MM. Lysosome-dependent degradation of Notch3. Int J 
Biochem Cell Biol. 2009; 41(12):2594-8.
12.
Jung SG, Kwon YD, Song JA, et al. Prognostic significance of Notch 3 gene expression 
in ovarian serous carcinoma. Cancer Sci. 2010; 101(9):1977-83.
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.
14.
O’Quigley J, Pepe M, Fisher L. Continual Reassessment Method. A practical design for 
phase 1 clinical trials in cancer. Biometrics. 1990;46:33-48.


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15.
Pal SK, Childs BH, and  Pegram M.  Triple negative breast cancer: unmet medical 
needs.  Breast Cancer Res Treat 2011; 125:627-636.
16.
Park JT, Li M, Nakayama K, et al. Notch3 gene amplification in ovarian cancer. Cancer 
Res 2006; 66(12):6312-8.
17.
Zheng Y, de la Cruz CC, Sayles LC, et al. A rare population of 
CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires 
Notch3 for self-renewal. Cancer Cell 2013; 24(1):59-74.


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Appendix 1. Abbreviations
Abbreviation
Term
ADA
Anti-drug Antibody
ADC
Anti-Drug Congugate
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BP
Blood Pressure
C1D1
Cycle 1 Day 1
CBC
Complete Blood Count
CLX
Cell Line Xenograft
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report Form
CT
Computed Tomography
CTC
Circulating Tumor Cells
CTCAE
Common Terminology Criteria for Adverse Events
DAI
Dosage Administration Instruction
DFS
Disease Free Survival
DLT
Dose Limiting Toxicities
ECG
Electrocardiograms
ECOG
Eastern Cooperative Oncology Group
HNSTD
Highest Non-Severely Toxic Dose
ICH
International Conference on Harmonisation
IHC
Immunohistochemistry
IND
Investigational New Drug
ITT
Intent-to-Treat
IV
Intravenous
mg/kg
Milligram/kilogram
mITT
Modified Intent-to-Treat
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTPI
Modified Toxicity Probability Interval
N/A
Not Applicable
NCI
National Cancer Institute
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PDX
Patient Derived Xenograft
PK
Pharmacokinetic
PFS
Progression Free Survival
PR
Partial Response


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PR
Pulse Rate
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
TNBC
Triple Negative Breast Cancer
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell


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Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion patiented to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

one or more target measurable lesions have not been assessed; 

or assessment methods used were inconsistent with those used at baseline;

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);

or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Patientive 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. 


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Table 1. Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
NewLesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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


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Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (Version 4.03 dated 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 5. Management of Infusion Related Reactions Including Allergic Reactions, 
Cytokine Release Syndrome or Anaphylaxis
In the event of infusion related reactions, Investigators should institute treatment measures 
according to best medical and nursing practice.
The following treatment guidelines should be employed:
If chills and fever occur, the infusion should be interrupted.  Patients may be treated 
symptomatically and the infusion should be restarted at 50% of the original rate.
NCI-CTCAE Grade 1 allergic reaction or cytokine release syndrome

Monitor for worsening condition.  If the reaction worsens, stop the infusion.  Institute 
premedication for subsequent infusions as per Section Administration. 
NCI-CTCAE Grade 2 allergic reaction or cytokine release syndrome

Stop PF-06647263 infusion.

Administer bronchodilators, oxygen, acetaminophen, and others as medically 
indicated.

Resume infusion at 50% of previous rate once reaction has decreased to Grade 1 in 
severity.  Monitor closely for any worsening including respiratory status.  If the 
reaction recurs, stop infusion.  Institute premedication for subsequent infusions as per 
Section Administration.
NCI-CTCAE Grade 3 or Grade 4 allergic reaction or cytokine release syndrome or 
anaphylaxis

A Grade 3 anaphylaxis (hypersensitivity reaction) consists of symptomatic 
bronchospasm requiring parenteral medications with or without urticaria, 
allergy-related edema/angioedema, or hypotension.

A Grade 4 anaphylaxis (hypersensitivity reaction) is a life-threatening event requiring 
urgent intervention.
Treatment of Grade 3 or Grade 4 allergic reaction, cytokine release syndrome or 
anaphylaxis

Stop the PF-06647263 infusion immediately and disconnect infusion tubing from the 
patient.

Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, and others as medically indicated.


PF-06650808
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
Monitor closely respiratory and cardiovascular status, be prepared for potential need 
for intubation.

Telephone Sponsor or designated representative to report an SAE as per Section
Adverse Event Reporting.

For a NCI-CTCAE Grade 3 or 4 hypersensitivity reaction, study treatment will be 
discontinued.
Re-treatment following Grade 1 or Grade 2 allergic reactions or cytokine release 
syndrome

Once the PF-06647263 infusion rate has been decreased due to an allergic reaction or 
cytokine release syndrome, it will remain decreased for all subsequent infusions.

If the patient has a second reaction at the lower infusion rate, the infusion should be 
stopped and the patient should receive no further PF-06647263.

If the patient experiences a Grade 3 or 4 allergic reaction, cytokine release syndrome, 
or anaphylaxis at any time, the patient should receive no further PF-06647263.

If there are questions concerning whether an observed reaction is consistent with an 
allergic reaction, cytokine release syndrome, or anaphylaxis, the medical monitor 
should be contacted immediately to assist with grading the reaction.

PK, PD and ADA sampling should continue as long as the sampling does not 
interfere with the medical treatment of the patient.


PF-06650808
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SAP_001.pdf: 
Page 1 of 31
 
Protocol B7501001
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE 
SAFETY AND TOLERABILITY OF PF-06650808 IN PATIENTS 
WITH ADVANCED SOLID TUMORS
Statistical Analysis Plan
(SAP)
Version: 1.0
Author:
 (Statistics, WRD-BCD, La Jolla, CA, USA)
   
(Statistics, WRD-BCD, La Jolla, CA, USA)
Date:     17-November-2014
PPD
PPD


Protocol B7501001 (PF-06650808)
Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Design .............................................................................................................4
2.2. Study Treatment ........................................................................................................4
2.3. Study Objectives .......................................................................................................5
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
4.2.1. Part 1.............................................................................................................6
4.2.2. Part 2.............................................................................................................7
5. SAMPLE SIZE DETERMINATION ....................................................................................7
6. ANALYSIS SETS .................................................................................................................8
6.1. Full Analysis Set .......................................................................................................8
6.2. ‘PER PROTOCOL’ Analysis Set..............................................................................8
6.3. Safety Analysis Set....................................................................................................8
6.4. PK Analysis Set.........................................................................................................8
6.4.1. PK Concentration Set ...................................................................................8
6.4.2. PK Parameter Set..........................................................................................9
6.6. Other Analysis Sets ...................................................................................................9
6.6.1. Modified Intent-to-Treat Set.........................................................................9
6.7. Treatment Misallocations..........................................................................................9
6.8. Protocol Deviations...................................................................................................9
7. ENDPOINTS AND COVARIATES .....................................................................................9
7.1. Efficacy Endpoint(s) .................................................................................................9
7.2. Safety Endpoints .....................................................................................................10
7.2.1. DLT Definition...........................................................................................10
7.2.2. Vitals...........................................................................................................11
7.2.3. Laboratory Data..........................................................................................11
7.2.4. Adverse Events...........................................................................................11
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Protocol B7501001 (PF-06650808)
Statistical Analysis Plan
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7.2.5. ECG and QTc Interval................................................................................12
7.2.6. Immunogenicity..........................................................................................13
7.3. PK Endpoints...........................................................................................................13
7.5. Covariates................................................................................................................14
8. HANDLING OF MISSING VALUES ................................................................................14
8.1. Missing Dates..........................................................................................................14
8.2. Efficacy Analysis ....................................................................................................14
8.3. Pharmacokinetics ....................................................................................................14
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................15
9.1. Statistical Methods ..................................................................................................15
9.2. Statistical Analyses .................................................................................................16
9.2.1. Primary Analysis ........................................................................................16
9.2.2. Secondary Analyses....................................................................................16
9.2.2.1. Efficacy Analysis ......................................................................16
9.2.2.2. Pharmacokinetics Analyses.......................................................17
9.2.3. Safety Analyses ..........................................................................................19
9.2.4. Standard Analyses ......................................................................................20
9.2.5. Additional Analysis ....................................................................................21
10. REFERENCES ..................................................................................................................22
11. APPENDICES ...................................................................................................................23
11.1. APPENDIX 1: CATEGORICAL CLASSES FOR ECG AND VITAL 
SIGNS........................................................................................................................23
11.2. APPENDIX 2: RECIST 1.1 TUMOR ASSESSMENT CRITERIA.....................24
11.3. APPENDIX 3: CENSORING DETAILS .............................................................31
LIST OF TABLES
Table 1.
Response Evaluation Criteria in Solid Tumors ....................................................28
Table 2.
Best Overall Response when Confirmation of CR and PR Required...................29
Table 3.
Progression Free Survival and Duration of Response..........................................31
Table 4.
Time to Progression..............................................................................................31
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Protocol B7501001 (PF-06650808)
Statistical Analysis Plan
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Not applicable.
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol B7501001.  This
analysis plan is meant to supplement the study protocol.  In this document, any text taken
directly from the protocol is italicized.  Any deviations from this analysis plan will be
described in the Clinical Study Report (CSR).
2.1. Study Design
This is a Phase 1, open label, multi-center, single arm, non randomized, multiple dose, 
safety, pharmacokinetic (PK) and pharmacodynamic (PD) study of single agent 
PF-06650808 in sequential cohorts of adult patients with advanced solid tumors for whom 
no standard therapy is available.  Successive cohorts of patients will receive escalating doses 
of PF-06650808 intravenously every 21 days starting at a dose of 0.2 mg/kg.
Approximately 55 patients are expected to be enrolled in the study at approximately 3-4 sites.  
The actual number of patients enrolled will depend upon tolerability of PF-06650808 and the
number of dose levels required to identify the MTD.
The study will include two parts, a dose escalation phase (Part 1) followed by a dose
expansion phase (Part 2).  Part 1 will estimate the MTD in dose escalation cohorts in 
patients with advanced solid tumors for whom no standard therapy is available in order to 
establish the RP2D.  Part 2 will include approximately 20 patients with TNBC enrolled at the 
MTD in order to explore benefit from treatment as suggested by preclinical findings, and will 
better define the safety profile at the RP2D.  Additional safety information gathered in Part 2 
may be used to modify the dose recommended for future Phase 2 studies.
The study is expected to be completed in approximately 24 months.  The end of the study is
the last visit of the last patient.
2.2. Study Treatment
A modified continual reassessment method (mCRM) targeting a DLT rate of 25% will be
utilized for Part 1 (dose escalation phase).  Patients will be enrolled in cohorts of 2 to 4,
starting with 0.2 mg/kg for the first cohort.  The possible doses explored will be from a fine
grid of doses ranging from 0.2 mg/kg to 6.4 mg/kg.  If a high DLT rate is observed at the
starting dose of 0.2 mg/kg, a lower dose such as 0.14 mg/kg or lower will be considered.  The
study may be stopped if the drug is deemed not tolerable at the lowest reduced dose.
Patients will continue with study treatment every 21 days until disease progression,
withdrawal of consent, unacceptable toxicity occurs, or the study is terminated.  Patients
experiencing a DLT may be managed with dose modification or discontinuation.
Part 2 will include patients enrolled at the MTD in order to explore benefit from treatment
and will better define the safety profile at the RP2D.


Protocol B7501001 (PF-06650808)
Statistical Analysis Plan
Page 5
2.3. Study Objectives 
Dose Escalation (Part 1) Objectives
Primary Objective:

To assess safety and tolerability at increasing dose levels of PF-06650808 in patients 
with advanced solid tumors unresponsive to currently available therapies, or for 
whom no standard therapy is available in order to determine 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 of ADC 
(PF-06650808), total antibody (PF-06460005) and unconjugated payload 
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.

To document any preliminary evidence of anti-tumor activity.
:

 
Dose Expansion (Part 2) Objectives
Primary Objective:

To confirm safety and tolerability and explore preliminary evidence of 
anti-tumoractivity of PF-06650808 at the RP2D in patients with TNBC.
Secondary Objectives:

To evaluate the overall safety profile at the R2PD.

To characterize the single and multiple dose pharmacokinetics of ADC 
(PF-06650808), total antibody (PF-06460005) and unconjugated payload 
(PF-06380101).

To evaluate the immunogenicity of PF-06650808.
:

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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No interim analysis or blinding is planned for this study.  The final analysis will be 
conducted after the last subject last visit (LSLV).
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses.  The emphasis of the final analyses will be on estimation 
of key summary statistics.
4.2. Statistical Decision Rules
4.2.1. Part 1
A modified continual reassessment method (mCRM) targeting a DLT rate of 25% will be
utilized for Part 1 (dose escalation phase) (Goodman et al, 1995; O’Quigley et al, 1990).3,7  
Patients will be enrolled in cohorts of 2 to 4, starting with 0.2 mg/kg for the first cohort.  The
possible doses explored will be from a fine grid of doses ranging from 0.2 mg/kg to
6.4 mg/kg.  If a high DLT rate is observed at the starting dose of 0.2 mg/kg, a lower dose
such as 0.14 mg/kg (a 30% reduction from starting dose) or lower will be considered.  The
study may be stopped if the drug is deemed not tolerable at the lowest reduced dose.  The
mCRM model will determine the next dose level based on the DLT rate using a 30%, 69%
and 100% dose increment for 0, 1 or 2 dose skips respectively.
Starting with the second cohort, patients will be assigned to a dose that is closest to the 
current MTD prediction based on a model that mCRM utilized to learn about overall 
dose-toxicity relationship.  This model is updated after DLT assessment of each cohort.  At 
any given point in this phase, doses can be escalated, deescalated, unchanged or revisited, 
but always aiming towards the target MTD.  To prevent overly aggressive dose-escalation, 
the maximum allowed dose increase will be limited to 2 increments at a time (ie, no more 
than 100% dose increase at a time).  In addition, if two clinically significant Grade 2 
toxicities of the same type are seen in a cohort, dose escalation will be limited to no greater 
than 69% for the next cohort.  If there is one additional case of the same Grade 2 toxicity or 
two other cases of clinically significant Grade 2 toxicities of the same type, dose escalation 
will again be limited to no greater than 69% for the next cohort; otherwise dose escalation 
following the mCRM algorithm will resume.  Grade 2 toxicities will not be considered 
clinically significant if a corresponding Grade 3 toxicity exists (by NCI CTCAE v 4.03);6
Grade 2 toxicities without a corresponding Grade 3 toxicity will be considered clinically 
significant (eg, Grade 2 alopecia, dry skin, libido decrease).  In addition, Grade 2 nausea, 
vomiting, and diarrhea will not be considered clinically significant unless it has been 
optimally medically managed.
The combination of a fine dose grid and the ability to skip doses allows rapid dose escalation 
if no DLTs are observed and small dose changes with exploration of adjacent doses once the 
observed DLT rate becomes noticeable.  The algorithm will stop if any of the following 
criteria is met:
1. The maximum sample size has been achieved (approximately 35 patients total).


Protocol B7501001 (PF-06650808)
Statistical Analysis Plan
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2. At least 6 patients have been accumulated on a dose that is predicted to be the MTD and 
there are at least 12 patients overall enrolled in the trial, or
3. All doses explored appear to be overly toxic and the MTD cannot be determined in the 
current trial setting.
Although dose levels are capped at 6.4 mg/kg, this mCRM will continue to operate subject to 
the constraints detailed above while allowing for doses higher than specified.  Doses may 
continue to be skipped, visited more than once, or not visited at all.  In addition, if necessary, 
doses beyond 6.4 mg/kg may be allowed in 30% increments.
All significant AEs and serious adverse events (SAEs) will be reviewed by the sponsor and 
investigators to determine if the dose allocation schedule requires modification.  The cohort 
steering committee, comprised of the sponsor clinical team and the investigators, can 
override the dose escalation increment determined by the algorithm if a more conservative 
approach is mandated.
Patients will continue with study treatment every 21 days until disease progression, patient 
refusal or unacceptable toxicity occurs.  Patients experiencing a DLT may be managed with 
dose modification or discontinuation.
Subsequent dose levels may not be opened until all patients entered at the current dose level 
have been treated and observed for at least one complete cycle (through Day 21) and the 
number of DLTs among those patients in their first cycle has been determined.
4.2.2. Part 2
Part 2 of this study is intended to confirm the safety and tolerability of the dose selected in 
Part 1 while assessing the antitumor activity of ADC (PF-06650808) in TNBC patients.  
Patients in the expansion cohort will be pre-selected according to their target tumor 
expression using archival tumor tissues.  Only patients with relatively high target expression 
will be selected.  The DLT rate and its 95% confidence interval at the selected dose may be 
estimated.
Analyses may be performed on data from both Part 1 and Part 2 to explore the relationships 
between PK parameters, safety endpoints, and efficacy endpoints.
5. SAMPLE SIZE DETERMINATION
Approximately 55 patients are expected to be enrolled in this study. 
Similar to the conventional 3+3 design, the exact sample size of the CRM design in Part 1 
cannot be pre-specified in advance due to the dynamic feature of the design.  The minimum 
and maximum sample sizes after which the Part 1 can be stopped and MTD declared are 
approximately 12 and approximately 35 patients, respectively.  Also, a minimum of 6 patients 
treated at the MTD dose in Part 1 is required to establish such dose as the RP2D.  The actual 
sample size of Part 1 will depend on the underlying dose toxicity profile and variability in 
actual data realization. 


Protocol B7501001 (PF-06650808)
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As for the number of patients treated at each dose, it is expected that the typical number will 
be 2 to 4 patients for the doses actually studied.  For the dose declared as MTD at the end of 
Part 1, this number will be 6 or more patients.  However, since not every dose listed will be 
studied and variable cohort size is allowed, the actual number of patients treated at each 
dose will vary. 
The sample size in Part 2 is based on clinical consideration, rather than statistical
justification.  Upon identification of the MTD by the mCRM method, approximately
20 patients with triple negative breast cancer will be enrolled in Part 2 to further evaluate
safety and preliminary efficacy parameters.
 
6. ANALYSIS SETS
Several analysis sets are defined and will be considered for this study.
6.1. Full Analysis Set
The full analysis set includes all enrolled patients.  This is equivalent to the ITT 
(intent-to-treat) population.
6.2. ‘PER PROTOCOL’ Analysis Set 
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study medication at the dose level of RP2D and who do not have major treatment deviations 
during first cycle.  Patients with major treatment deviations in Cycle 1 are not evaluable for 
the RP2D assessment.  Major 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.  A baseline disease assessment and at least one 
post-baseline disease assessment are appropriate to allow efficacy analysis.
6.3. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
medication.
6.4. PK Analysis Set
6.4.1. PK Concentration Set
The PK concentration population is defined as all treated patients who have at least 
1 concentration measured.
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6.4.2. PK Parameter 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.
 
6.6. Other Analysis Sets
6.6.1. Modified Intent-to-Treat Set
The modified intent-to-treat (mITT) is the analysis population that will follow the ITT 
principle and include subjects receiving at least 1 dose of study medication with baseline 
assessment and at least 1 post baseline assessment or disease progression or death before 
the first tumor assessment.  The mITT population may be used for occasions such as 
conference presentation when the study is still ongoing.
6.7. Treatment Misallocations 
Subjects who receive the wrong initial dose for whatever reason will be analyzed according 
to the initial dose actually received.  Subjects who receive the wrong dose after the initial 
dose will be analyzed according to the initial dose received.
6.8. Protocol Deviations
All deviations will be listed in the CSR.  Major treatment deviations include, but are not 
limited to, less than 80% of the planned Cycle 1 PF-06650808 dose provided the 
reduction/omission is not due to treatment-related toxicity.  Subjects with major Cycle 1 
treatment deviations are not evaluable for MTD.
7. ENDPOINTS AND COVARIATES
7.1. Efficacy Endpoint(s)
Objective tumor response, as assessed using the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1 by calculating the Overall Response Rate (ORR), Progression 
Free Survival (PFS), and Overall Survival (OS).
All efficacy endpoints are secondary in this study, which include objective tumor response, 
progression-free survival (PFS), and overall survival (OS) in the expansion cohort.  The 
above efficacy endpoints are derived based on the disease response per investigator 
evaluation on the CRF pages, which is the primary method of documentation of disease. 

Overall Response (OR) – is defined as confirmed complete response (CR) or confirmed 
partial response (PR) according to RECIST 1.1 (Appendix 2).  Confirmed responses are 
those that persist on repeat imaging study at least 4 weeks after the initial documentation 
of response.  Patients who do not have on-study radiographic tumor re-evaluation, who 
receive anti-tumor treatment other than the study medication prior to reaching a CR or 
PR, or who die, progress, or drop out for any reason prior to reaching a CR or PR will not 
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Protocol B7501001 (PF-06650808)
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be counted as responders in the assessment of OR.  Clinical benefit response (CBR) is 
defined as a CR, PR or SD >=6 cycles.

Progression Free Survival (PFS) - is defined as the time from Cycle 1 Day 1 (C1D1) to 
first documentation of disease progression or to death due to any cause, whichever occurs 
first.  Subjects last known to be 1) alive 2) on treatment or within the post-treatment 
follow-up period and 3) progression-free, are censored at the date of the last disease 
assessment that verified lack of disease progression.  Subjects who start new anti-cancer 
treatment prior to the end of post-treatment follow-up period and have adequate baseline 
and on-treatment objective disease assessments without evidence of progressive disease 
are censored at the date of the last objective disease assessment.  Subjects with 
inadequate baseline or no on-study disease assessments are censored at C1D1 unless 
death occurred prior to the first planned assessment (in which case the death is an event).  
Subjects with at least one on-study disease assessment who discontinue treatment without 
disease progression and without death within 28 days of discontinuation are censored at 
the date of the last objective disease assessment that verified lack of disease progression 
(if progression or death is within 28 days of discontinuation the progression or death is an 
event).  Subjects with documentation of progression or death after an unacceptably long 
interval (>16 weeks) since the previous disease assessment will be censored at the time of 
the previous assessment.
PFS (days) = [progression/death date – C1D1 + 1].

Overall survival (OS) is defined as the time from initial dose until death from any cause, 
and is measured in the intent-to-treat population.
More details of censoring are provided in Appendix 3.
7.2. Safety Endpoints
7.2.1. DLT Definition
Dose limiting toxicity (DLT) is the primary endpoint of this study.  Severity of adverse 
events will be graded according to CTCAE version 4.03.  For the purpose of dose escalation, 
any of the following adverse events which are not considered related to disease progression 
occurring in the first cycle of treatment (21 days) will be classified as DLTs:

Hematologic:

Grade 4 neutropenia lasting >7 days.

Febrile neutropenia (defined as neutropenia Grade 3 and a single body 
temperature >38.3C or a sustained temperature of 38C for more than one hour).

Grade 3 neutropenia with infection. 

Thrombocytopenia (of any grade) associated with clinically significant or 
life-threatening bleeding.


Protocol B7501001 (PF-06650808)
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
Grade 4 thrombocytopenia 72 hours or platelets 10,000/mm3 regardless of 
duration.

Non-hematologic:

Grade 3 toxicities, except those that have not been maximally treated (eg, nausea, 
vomiting, diarrhea).

Delay by more than 2 weeks in receiving the next scheduled cycle due to persisting 
toxicities not attributable to disease progression.
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 cytokine release syndrome, infusion reaction, and allergic reaction will not be 
considered as DLTs but may be a reason for study discontinuation and should be reviewed 
with the sponsor.
7.2.2. Vitals 
See Schedule of Activities in the protocol for details.
7.2.3. Laboratory Data
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade.  For 
labs for which an NCI CTCAE v4.03 scale does not exist, the frequency of subjects with 
values below, within, and above the normal ranges will be summarized by dose.  Baseline 
evaluations for laboratory data are those collected:

Within 28 days prior to Cycle 1/Day 1.

Closest but prior to Cycle 1/Day 1 if there is more than one baseline evaluation.
7.2.4. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
version 4.03) timing, seriousness, and relatedness.
All AEs will be coded by system organ class (SOC) and preferred term using Medical 
Dictionary for Regualtory Activities (MedDRA).  The severity of all AEs will be graded by 
the investigator using NCI CTCAE version 4.03 whenever possible.  For other AEs without 
specific CTC definitions, results are identified according to CTCAE “other” categories.  
Adverse events will be assigned to the appropriate cycle based on Day 1 of each cycle. 
Treatment Emergent Adverse Events

All deaths from start of treatment until 28 days after the final dose.


Protocol B7501001 (PF-06650808)
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
All treatment related SAEs.

All unrelated SAEs from treatment start until 28 days after final dose of treatment.

All non-fatal AEs occurring after treatment start up until 28 days after final dose of 
treatment or until start of new anti-cancer treatment, whichever is first.

Disease progression is not considered a treatment emergent adverse event unless the 
subject dies of disease prior to 28 days after discontinuation of treatment.

Events that are continuations of baseline abnormalities are considered treatment emergent 
adverse events only if there is an increase in grade over baseline.
Treatment Related Adverse Events
Treatment Related Adverse Events are treatment emergent adverse events with cause 
categorized by the investigator as related to study treatment.  Events that are continuations of 
baseline abnormalities (signs and symptoms) are not considered treatment emergent, and 
hence are not considered treatment related, unless there is an increase in grade over baseline.
7.2.5. ECG and QTc Interval
ECG data will be collected.  See Schedule of Activities in the protocol for details.  12 lead 
ECGs will be summarized.  The baseline evaluation for ECGs is the pre-dose value on
Cycle 1/Day 1.  If the pre-dose value is not collected, the ECG closest but prior to 
Cycle 1/Day 1 will be used.  If the closest ECGs are triplicate ECGs (or only 2), they will be 
averaged.  If the closest ECG is a single, that will be used as baseline.
QT intervals will be corrected for heart rate (QTc) using Fridericia’s correction factors 
(QTcF).  The adequacy of the correction method will be assessed graphically (plots of QT 
and QTcF versus RR) and supplementary transformations may be considered, as 
appropriate.  Data will be summarized and listed for QT, HR, RR, PR, QRS and QTcF by 
treatment and dose.  Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the absolute QTcF value and changes from 
baseline in QTcF after treatment by compound, dose and by time point.  For each patient and 
by treatment, the maximum change from baseline will be calculated as well as the maximum 
post-baseline value across time-points.  Outlier analysis of the QTcF data will be conducted 
and summarized as follows:

The number of patients with maximum change from baseline in QTcF (<30, 30-60, 
and 60 ms).

The number of patients with maximum post-dose (post-baseline) QTcF (<450, 
450-<480, and >=480 ms).
In addition, the number of patients with corrected and uncorrected QT values 500 msec will 
be summarized.


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Shift tables will be provided for baseline vs. worst on study QTcF using Maximum CTCAE 
Grade.  As well as tables of ECG abnormality at baseline (yes, no, not done: (n, %)).  
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).
If more than one ECG is collected at a nominal time post dose (for example, triplicate 
ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point.  If any of the three individual ECG tracings has a QTc value 
500 msec, but the mean of the triplicates is not 500 msec, the data from the subject’s 
individual tracing will be described in a safety section of the study report in order to place 
the 500 msec value in appropriate clinical context.  However, values from individual 
tracings within triplicate measurements that are 500 msec will not be included in the 
categorical analysis unless the average from those triplicate measurements is also 
500 msec.  Changes from baseline will be defined as the change between QTcF post dose 
and the pre-dose values on Day 1.
The effect of drug concentrations on QTcF change from baseline will be explored 
graphically.  Additional concentration-QTcF analyses may be performed.  Data may be 
pooled with other study results and/or explored further with PK/PD models.
7.2.6. Immunogenicity
Anti-PF-06650808 antibody data will be collected at baseline and post-randomization according 
to the protocol.
7.3. PK Endpoints 
Blood samples for PK analysis of PF-06650808 (ADC), PF-06460005 (total antibody), and 
PF-06380101 (unconjugated payload) will be taken according to the Schedule of Activities 
given in the protocol. 

Pharmacokinetic parameters of PF-06650808 (ADC):
Cycle 1 - Cmax, Tmax, AUClast, AUCinf, AUC,t1/2, CL, and Vss as data permit. 
Cycle 4 - Cmax, Tmax, AUClast, AUC, t1/2, and Rac as data permit.

Pharmacokinetic parameters of PF-06460005 (total antibody) and PF-06380101 
(unconjugated payload):
Cycle 1 - Cmax, Tmax, AUClast, AUCinf, AUC, and t1/2 as data permit. 
Cycle 4 - Cmax, Tmax, AUClast, AUC, t1/2, and Rac as data permit. 
PK parameters will be derived from the concentration-time data as follows:


Protocol B7501001 (PF-06650808)
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Parameter
Definition
Method of Determination
AUClast
Area under the concentration-time 
profile from time zero to the time of 
the last quantifiable concentration
Linear/Log trapezoidal method
AUC
Area under the concentration-time 
profile from time zero to the time , 
the dosing interval
Linear/Log trapezoidal method
AUCinf
Area under the concentration-time 
profile from time zero extrapolated to 
infinite time
AUC(0-t[last]) + (Clast*/kel),
where Clast* is the predicted serum concentration at the 
last quantifiable time point estimated from the log-linear 
regression analysis.
Cmax
Maximum cobserved oncentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first occurrence
T½
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate constant calculated 
by a linear regression of the log-linear concentration-time 
curve.  Only those data points judged to describe the 
terminal log-linear decline will be used in the regression.
CL
Clearance
Dose/ AUCinf for cycle 1; Dose/ AUCfor cycle 4
Vss
Volume of distribution at steady state
CLMRT
Rac
Observed accumulation ratio
AUC cycle 4, / AUCcycle 1, 
 
 
7.5. Covariates
Not applicable. 
8. HANDLING OF MISSING VALUES
8.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of onset cannot be prior to day one 
date).  In this case, the date resulting in 0 time duration will be used.  Pfizer standards are 
also used if both month and day are missing (Jan 1 unless negative time duration). This 
excludes the pharmacokinetic, ECG, and pharmacodynamic analyses, which will only use the 
actual date collected or if date not available deem the data missing.
8.2. Efficacy Analysis
Censoring rules for time-to-event endpoints are detailed in Section 11.3 Appendix 3.
8.3. Pharmacokinetics
Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
CCI


Protocol B7501001 (PF-06650808)
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Deviations, missing concentrations and anomalous values
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
Pharmacokinetic parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC.  For statistical analyses, PK parameters coded as NC will also 
be set to missing.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the drug is absorbed in the body), this will 
be footnoted in summary tables and will not be included in the calculation of summary 
statistics or statistical analyses.
QTc
For the QTc analyses, no values will be imputed for missing data.
 
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
9.1. Statistical Methods
No formal hypothesis testing will be performed in this exploratory study.
Analyses of Time-to-Event Endpoints 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence intervals for 
each time-to-event endpoint (Brookmeyer and Crowley, 1982)1 will be provided. 
CCI


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Analyses of Binary Endpoint
The rates of binary endpoints will be provided along with the corresponding 2-sided 95% 
confidence intervals using an exact method. 
Analyses of Continuous Data
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values, will be provided for continuous endpoints. 
9.2. Statistical Analyses
9.2.1. Primary Analysis
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 Safety Analysis Set for patients 
in the dose escalation portion of the study.  A listing of the DLTs will also be provided.
If necessary, a summary and listing of the DLT may be provided using the Per Protocol 
Analysis Set for patients in the MTD expansion portion of the study.
9.2.2. Secondary Analyses
9.2.2.1. Efficacy Analysis
In this Phase 1 study efficacy is a secondary objective. Note that the efficacy analysis is to 
be conducted for patients in the MTD expansion cohorts who are in the Safety Analysis Set
and have baseline disease assessment and at least one post-baseline disease assessment.  In 
the event that a large number of patients in the escalation portion of the study have the same 
malignancy, the efficacy analysis may be conducted.
Summary tables of best Overall Response Rate, Progression Free Survival, and Overall 
Survival will be provided overall and by malignancy if necessary.  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.
A response rate overall for Part 1 dose escalation and response rates by low, medium, and 
high dose groups may be presented. 
The following table provides an overview of the efficacy analysis.


Protocol B7501001 (PF-06650808)
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Endpoint
Analysis Set
Statistical 
Method 
Model/ 
Covariates/ 
Strata*
Missing 
Data
Interpretation
Overall 
response
Per Protocol, 
expansion 
cohorts, etc.
Exact CI
By dose 
range/ 
malignancy
Censored 
per Section 
11.3
Secondary 
Analysis
Progression 
Free Survival 
(PFS)
Per Protocol, 
expansion 
cohorts
Kaplan-Meier
By 
malignancy
Censored 
per Section 
11.3
Secondary 
Analysis
Time to 
Progression 
(TTP)
Per Protocol, 
expansion 
cohorts
Kaplan-Meier
By 
malignancy
Censored 
per Section 
11.3
Secondary 
Analysis
Duration of 
Response 
(DR)
Per Prtocol, 
expansion 
cohorts
Kaplan-Meier
By 
malignancy
Censored 
per Section 
11.3
Secondary 
Analysis
* If patients in dose escalation phase are included.
9.2.2.2. Pharmacokinetics Analyses 
Pharmacokinetic Parameters
To assess the pharmacokinetics of PF-06650808 (ADC), PF-06460005 (total antibody) and 
PF-06380101 (unconjugated payload), the PK parameters detailed in Section 7.3 will be 
listed and summarized for subjects in the PK analysis set (as defined in Section 6.4).  Missing 
values will be handled as detailed in Section 8.  Each PK parameter will be summarized by 
dose and cycle and will include the set of summary statistics as specified in the table below: 
Parameter
Summary statistics
AUClast, 
AUCinf, 
AUC, Cmax,
CL, Vss, 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
N, median, minimum, maximum
There will be 1 summary table presenting all PK parameters.  This will include data from all 
cohorts and will be summarized by dose group and cycle. 
To assess the relationship between the PK parameters and dose, dose normalized AUCinf,
AUClast, AUC, and Cmax will be plotted against dose (using a logarithmic scale), and will 
include individual subject values and the geometric means for each dose.  Geometric means 
will have a different symbol than the individual values.  The values will be dose normalized 
(to a 1 mg/kg dose) by dividing the individual values and raw geometric means by dose.  A 
footnote will be added to the plots to indicate that geometric means are presented are 
presented on the plot. 


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Pharmacokinetic Concentrations
To assess the PK profile of PF-06650808 (ADC), PF-06460005 (total antibody) and 
PF-06380101 (unconjugated payload), PK concentrations will be listed, summarized and 
plotted for subjects in the PK analysis set (as defined in Section 6.4), where missing and 
BLQ values will be handled as detailed in Section 8.3.
Presentations for PF-06650808 (ADC), PF-06460005 (total antibody) and PF-06380101 
(unconjugated payload) will include:

a listing of all concentrations sorted by dose, subject id, day and nominal time post dose.  
The listing of concentrations will include the actual times.  Deviations from the nominal 
time will be given in a separate listing.

a summary of concentrations by dose, day and nominal time post dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv) 
and the number of concentrations above the lower limit of quantification.

a plot of mean concentrations against nominal time postdose by dose (based on the 
summary of concentrations by dose and time postdose), preferably with all doses also on 
the same graph.

a plot of median concentrations against nominal time postdose by dose (based on the 
summary of concentrations by dose and time postdose), preferably with all doses also on 
the same graph.

a log-linear plot of mean concentrations against nominal time postdose by dose (on the 
same plot), preferably with all doses also on the same graph.

a log-linear plot of median concentrations against nominal time postdose by dose (on the 
same plot), preferably with all doses also on the same graph.

plots of individual concentrations against actual time postdose.
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long PK concentration is quantifiable in the matrix.
In addition to the above, a median plot of the predose concentrations at each cycle against 
day will be provided for each dose, on the same plot, in order to assess the attainment of 
steady-state.  Individual subject profiles will also be plotted.
For summary statistics and mean/median plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.


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Population Pharmacokinetic Analysis or PK/PD Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
compartmental or mixed-effect modeling approaches and may also be pooled with other 
study results.  PK/PD modeling may be attempted to investigate any causal relationship 
between PF-06650808 exposure and biomarkers or significant safety endpoints.  The results 
of these analyses, if performed, may be reported separately.
 
 
  
 
9.2.3. Safety Analyses
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the CTCAE 
version 4.03 and coded using the MedDRA.  The focus of AE summaries will be on
Treatment Emergent Adverse Events, those with 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).  The Safety Analysis Set 
will be used.
Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be
summarized according to worst toxicity grade observed for each laboratory test. The
analyses will summarize laboratory tests both in the entire study period and by cycle (Cycle 1 
and Cycles beyond 1). The Safety Analysis Set will be used.
For laboratory tests without CTC grade definitions, results will be categorized as normal,
abnormal or not done.
Other Variables: Anti-PF-06650808 antibody
For anti-PF-06650808 antibody, a listing, sorted by subject and study day, of the result of 
anti-PF-06650808 antibody screening (positive/negative [<1:negative]), the specificity, and 
titer will be listed.  Summary counts of the patients, who are positive for the anti-
PF-06650808, will be derived by study treatment and visit for the safety population.  No
summary statistics other than those cited above, will be generated.
CCI


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9.2.4. 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.  The Safety Analysis 
Set will be used.
Treatment Administration/Compliance
Listings and tables by dose level will be provided. Cycle length is 21 days.  Day 1 of a cycle 
is the first date of dose within that cycle.  The safety analysis set will be used.
Dose modifications may occur in the following ways:

Cycle delay—Day 1 of current cycle starts later than 21 days from Day 1 of the 
previous cycle (only applies to cycle 2 and above); 

Dose reduction—A decrease in the administered total daily dose (non-zero) compared 
to the planned total daily dose upon enrollment.
Intra-patient dose escalation is not allowed in this study.  The following will be summarized 
by subject for each dose level: 

Number of subjects per dose level.

Median and range of number of cycles started per subject.

Number (%) of subjects starting a cycle (1, 2, 3…).

Number (%) of subjects with cycle delays.

Number (%) of dose interruptions (include both known and unknown dates).

Number (%) of subjects with dose reductions.

Number (%) of each reason (AE vs. Other) for cycle delays, dose interruptions and 
dose reductions.

Time on treatment (median, range).


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The following will be summarized by cycle received for each dose level:

Total number of cycles started.

Number of cycles started per subject (median, range).

Number of cycles before 1st delay (median, range).

Number of cycles before 1st reduction (median, range).

Number of cycles before 1st interruption (median, range).
The following will be summarized for cumulative dose by dose level and cycle: 

Summary statistics (mean, median, standard deviation and range) of cumulative dose 
and percent of starting dose (compared to Day 1 dose of each cycle).
Listings by subject (ordered by dose level): start date and stop date of each dosing period 
within each cycle (including records with 0mg), administered total daily dose for each 
period, any missed doses with unknown dates (Y/N), number of missed doses with unknown 
dates, reason for any dosing changes.
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose, 
administered total dose, percentage of planned dose, dose delay (yes/no), dose reduction 
(yes/no), and dose interruption (yes/no). 
Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary.  Listings of prior, concomitant, and 
further therapies will be provided separately.
9.2.5. Additional Analysis 
Not applicable


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10. REFERENCES 
1.
Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  
Biometrics 1982; 38:29-41.
2.
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.
3.
Goodman SN, Zahurak ML, Piantadosi S. Some Practical Improvements in the
Continual Reassessment Method for Phase 1 Studies. STAT MED. 1995;4:1149-1161.
4.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
5.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am 
Stat Assoc 1958; 53:457-481.
6.
NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE).
http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
7.
O’Quigley J, Pepe M, Fisher L. Continual Reassessment Method. A practical design for
phase 1 clinical trials in cancer. Biometrics. 1990;46:33-48.


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11. APPENDICES 
11.1. APPENDIX 1: 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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11.2. APPENDIX 2: RECIST 1.1 TUMOR ASSESSMENT CRITERIA
Adapted from E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. 
Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.2
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below:
Measurable Lesions
Lesions that can be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice 
thickness no greater than 5 mm).

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot 
be accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
Non-measurable Lesions
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a 10 but <15 mm short axis) as well as truly non-measurable lesions.  
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam and not measurable by reproducible imaging techniques.
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
Special Considerations Regarding Specific Lesions 
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

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 


Protocol B7501001 (PF-06650808)
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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.

Blastic bone lesions are non-measurable. 
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Solitary lesions:
If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment. Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion. The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. 
One exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of 15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller 
of these measures is the short axis. 


Protocol B7501001 (PF-06650808)
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
Definition of Tumor Response 
Target Lesions
Response in target lesions is defined as follows:

Complete Response (CR): disappearance of all target lesions. 

Partial Response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. The appearance of one 
or more new lesions is also considered a sign of progression.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 


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Response in non-target lesions is defined as follows:

Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors). When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or stable disease and progressive 
disease.
For patients having effusions or ascites, only cases having cytological proof of malignancy 
should be recorded on the CRF. Effusions that have not been evaluated using cytology or 
were found to be non-malignant should not be recorded on the CRF. 
New Lesions 
The appearance of new malignant lesions indicates PD. New lesion should be unequivocal
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor). If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease. If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
The use of FDG-PET is sometimes reasonable to complement a CT scan assessment of a PD 
(particularly for possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can 
be identified according to the following algorithm: 

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up.

No FDG-PET at baseline and a positive FDG-PET at follow- up: if the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).


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If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not PD.
Determination of Overall Response by the RECIST 1.1 Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately. The overall assessment of response will involve all parameters as depicted in 
Table 1.
Table 1.
Response Evaluation Criteria in Solid Tumors
Target 
lesions
Non-target 
lesions
New
Lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/no
n-PD
No
PR
CR
Not 
evaluated
No
PR
PR
Non-PD or
not all 
evaluated
No
PR
SD
Non-PD or
not all 
evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or 
No
PD
Any
PD
Yes or 
No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Best overall response
The best overall response is defined according to the tumor response along the study.  
Complete or partial responses may be claimed only if the criteria for each are met at a 
following time point as specified in the protocol (generally 4 weeks later).  In this 
circumstance, the best overall response can be interpreted as in Table 2.


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Table 2.
Best Overall Response when Confirmation of CR and PR Required
Overall 
response 
First time 
point 
Overall 
response 
Subsequent 
time point
BEST overall response
CR 
CR 
CR
CR 
PR 
SD, PD or PRa
CR 
SD
SD provided minimum criteria 
for SD duration met, otherwise, 
PD
CR 
PD
SD provided minimum criteria 
for SD duration met, otherwise, 
PD
CR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise 
NE
PR 
CR 
PR
PR 
PR 
PR
PR 
SD 
SD
PR 
PD
SD provided minimum criteria 
for SD duration met, otherwise, 
PD
PR 
NE
SD provided minimum criteria 
for SD duration met, otherwise 
NE
NE 
NE
NE
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent 
time point, even disease meeting PR criteria relative to baseline, makes the 
disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest 
small lesions were likely still present and in fact the patient had PR, not CR at 
the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions.


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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease specific medical literature for the 
indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.


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11.3. APPENDIX 3: CENSORING DETAILS
Table 3.
Progression Free Survival and Duration of Response
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment 
Start date (C1D1)
Censored
No on-study assessments
Start date (C1D1)
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor assessment
Censored
Progression Documented on or 
between scheduled tumor assessments 
prior to  treatment discontinuation2
Date of first objective tumor assessment 
showing objective progression
Progressed (Event)
Treatment discontinuation for 
undocumented progression
Date of last objective tumor assessment 
prior to discontinuation2
Censored
Treatment discontinuation due to 
toxicity or other reason
Date of last objective tumor assessment 
prior to discontinuation2
Censored
Death prior to first planned tumor 
assessment 
Date of death
Death (Event)  
Death without objective progression 
prior to treatment discontinuation2
Date of death
Death (Event) 
Death or progression after 2 or more 
missed tumor assessments
Date of last objective tumor assessment 
prior to the event
Censored
1: For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
2: or within 28 days of discontinuation of treatment. 
Table 4.
Time to Progression
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment 
Start date (C1D1)
Censored
No on-study assessments
Start date (C1D1)
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.