A PHASE 1, OPEN-LABEL, DOSE ESCALATION STUDY OF PF-04518600 AS A SINGLE AGENT AND IN COMBINATION WITH PF-05082566 IN PATIENTS WITH SELECTED LOCALLY ADVANCED OR METASTATIC CANCERS
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Pfizer

PF-04518600 and PF-05082566
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PFIZER CONFIDENTIAL
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A PHASE 1, OPEN-LABEL, DOSE ESCALATION STUDY OF PF-04518600 AS A 
SINGLE AGENT AND IN COMBINATION WITH PF-05082566 IN PATIENTS 
WITH SELECTED LOCALLY ADVANCED OR METASTATIC CANCERS
Compounds:
PF-04518600 and PF-05082566
Compound Name:
Not Applicable (N/A) for PF-04518600
Utomilumab for PF-05082566
United States (US) Investigational New 
Drug Application (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2014-004107-75
Protocol Number:
B0601002
Phase:
1
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Document History
Document
Version Date
Summary of Changes and Rationale
Final Protocol 
Amendment 6
02 May 2018
Major changes to the protocol include the following:

Section 4.1.1 Part A2 Monotherapy.
Change: Incorporated previous protocol 
administrative changes.
Rationale: Nivolumab has been approved for 
the treatment of HCC by the FDA. 
Change: Revised Part A2 inclusion: Patients 
with histological or cytological diagnosis of 
advanced/metastatic HCC who are treatment 
naïve and have declined standard of care, or 
have had at least 1 prior line of systemic 
therapy.  Prior anti-programmed death-ligand 
1 / anti-programmed cell death 
protein-1 (anti-PD-L1/PD-1) therapy is allowed.
Rationale: Clarification provided, as previous 
language allowed for 0 to 2 prior lines of 
therapy, and now includes prior 
anti-PD-L1/PD-1 for HCC as well.
Change: Provided specific ANC inclusion value 
≥1,000/mm3 or 1.0 x 10 9L for HCC patients 
only.
Rationale:  Lowering the entry criteria from 
1,500/mm3 to 1,000/mm3 for the HCC 
monotherapy cohort (A2) is not considered a 
significant safety risk based on previous cohort 
data.  One out of 52 patients treated in the 
A1 monotherapy cohort experienced a 
treatment-related Grade 2 decrease in 
neutrophils. .  The ANC threshold was lowered 
for just HCC, as HCC patients often have lower 
baseline ANC due to cirrhosis and portal 
hypertension.
Change: Removed inclusion criteria 9 –Amylase 
and lipase <1.5 ULN for HCC only patients. 

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Rationale:  There is no safety concern for the 
removal of this criteria based on the previous 
cohort data.  Asymptomatic elevations of 
amylase and lipase have been noted on the study 
without clinical consequences, and amylase and 
lipase are not reflective of liver function.

Section 3, Section 5, and the Study Design 
Section of the Protocol Summary.
Change: Incorporated previous protocol 
administrative changes.
Rationale: Selected dose for PF-04518600 in 
the B2 combination therapy dose expansion 
cohorts is 30 mg (a flat dose equivalent to 
0.3 mg/kg) intravenously (IV) Q2W in 
combination with PF-05082566 20 mg IV every 
28 days.

Section 3.1.2.2 Part B2 Dose Expansion Section 
4.1 Inclusion Criteria, Sub-section 4.1.2 Part B 
Combination Therapy – Part B2 Arm 1 only (a).
Change: (a) Ocular melanoma patients with 
advanced/metastatic disease.
Rationale: Provided clarification to the inclusion 
criteria for the ocular melanoma patient 
population to now include all 
advanced/metastatic disease regardless of prior 
therapy.

Section 3.1.2.2 Part B2 Dose Expansion Section 
4.1 Inclusion Criteria, Sub-section 4.1.2 Part B 
Combination Therapy – Part B2 Arm 1 only (b).
Change:
(b) Cutaneous/acral melanoma patients with 
advanced/metastatic disease who have received 
checkpoint inhibitor (anti-PD-L1, anti-PD-1, or 
anti-cytotoxic T-lymphocyte antigen 
4 (anti-CTLA4)) based treatment on which 
disease progressed. [Note: Checkpoint inhibitor 
may have been part of a combination therapy, as 
long as the combination did not contain 

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OX40 or 4-1BB agonist.]  Any questions on 
prior treatment may be discussed with the 
Sponsor.
Rationale: (1) The specification anti-PD-L1, 
anti-PD-1, or anti-CTLA4 “given as most recent 
line of therapy” was removed, as well as the text 
regarding specific prior systemic therapy for 
advanced/metastatic disease therapies for BRAF 
and MEK inhibitors.
Change: (2) Removed conditional statement “as 
long as progression did not occur in the first 
3 months of receiving checkpoint inhibitor 
treatment.”
Rationale: Stability on checkpoint inhibitors 
may not necessarily correlate with response to 
study treatment.  As long as the cutaneous/acral 
melanoma patient has received checkpoint 
inhibitor based treatment and progressed, the 
patient qualifies for study entry.

Section 3.1.2.2 Part B2 Dose Expansion

Section 4.1 Inclusion Criteria, Sub-section 
4.1.2 Part B Combination Therapy – Part 
B2 Arm 2
Change – Part B2 Arm 2: Histological or 
cytological diagnosis of NSCLC with 
advanced/metastatic disease.  Patients must have 
previously received prior anti-PD-L1 or 
anti-PD-1 mAb on which disease progressed. 
[Note: Previous anti-PD-L1 or anti-PD-1 mAb 
may have been part of a combination therapy, 
eg, in combination with chemotherapy, as long 
as the combination did not contain OX40 or 
4-1BB agonist.]
Rationale: Checkpoint inhibitors are 
increasingly being used in combinations both as 
approved therapies such as with chemotherapy 
and experimental combinations.  As a result, this 
amendment clarified combination therapy as an 
acceptable previous line of therapy.
Change: The specification that previous 

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anti-PD-L1 or anti-PD-1“given as most recent 
line of therapy” was removed for Part B2, Arm 
2, as well as the conditional statement that 
NSCLC patients did not have progressive 
disease as best overall response on recent 
PD-L1/PD-1 therapy (ie, stable disease 
≥3 months, PR, or CR).
Rationale: Patients may have received treatment 
following a checkpoint inhibitor prior to 
enrollment.  Stability on checkpoint inhibitors 
may not necessarily correlate with response to 
study treatment. Patient will now be eligible for 
enrollment regardless of prior best overall 
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Final Protocol 
Amendment 5
16 August 2017
Major changes to the protocol include the following:

The administrative changes described in past 
Protocol Administrative Change Letters (PACL) 
have been incorporated into the amendment.

Time ranges/windows of 2 days have been 
added for follow-up phone calls to collect 
additional late immune related adverse event 
information.

Part B2 Arm 1 has been changed from head and 
neck squamous cell carcinoma (HNSCC) 
patients to melanoma patients (including both 
ocular and cutaneous melanoma).  Rationale for 
melanoma as tumor type: 1) 2 confirmed 
partial responses (PR) in the melanoma patients 
enrolled to date: 1 in an ocular melanoma 
patient and 1 in a cutaneous melanoma patient; 
2) no PRs observed in the HNSCC patients 
enrolled to date.

Part A2 hepatocellular carcinoma (HCC) 
patients are now allowed to have up to 2 prior 
lines of approved therapy.  Rationale:
Regorafenib has been approved for HCC.

Part A HCC patients with the following 
subtypes are exclusionary: fibrolamellar HCC, 
sarcomatoid HCC, and mixed 
cholangiocarcinoma.  Rationale: It is important 
to exclude rare HCC subtypes, as these may 
introduce heterogeneity into the patient 
population and make it more difficult to choose 
a recommended phase two dose (RP2D). 

Part A2 HCC patients: patients with chronic 
hepatitis C virus (HCV) infection are allowed; 
however, patients with hepatitis B virus (HBV)
infection must be receiving effective antiviral 
therapy (viral load <100 IU/ml).  Patients with 
active coinfection with HBV and HCV, active 
coinfection with HBV and hepatitis D virus are 
excluded.  Rationale: The updated hepatitis 
requirements are more in-line with standard of 
care practices and with the patient population 

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enrolled in the Checkmate 040 trial. 

Part A2 HCC patients who are positive for 
HBsAg, HBcAb or HCV Ab at screening, must
be retested every 3 months and at the EOT visit.  
Rationale: Enable the monitoring of viral load 
for patients with hepatitis.

Part A2 HCC patients with detectable viral load 
for hepatitis B at screening must also be tested 
for hepatitis D antibody (HDV Ab).  Rationale: 
Enable the monitoring of the new HCC 
exclusion criteria of active coinfection with 
HBV and hepatitis D virus.

Allowed anticoagulation now includes factor Xa 
inhibitors, as well as heparin.  Rationale: 
Factor Xa inhibitors are being increasingly used 
in the treatment of thromboembolism and to date 
there have not been major bleeding events 
related to study drug.

The Background sections have been updated 
with the most up to date information (1.2).

Melanoma tumor type rationale Section (1.2.5.1)
has been updated with information on ocular 
melanoma.  Rationale: Part B2 Arm 1 has been 
changed from HNSCC patients to melanoma 
patients (including both ocular and cutaneous 
melanoma).  And there is no proven standard of 
care for ocular melanoma.

HCC tumor type rationale Section (1.2.5.3) has 
been updated with information on regorafenib.  
Rationale: Regorafenib has been approved for 
HCC.

Summary of benefit risk assessment has been 
added (Section 1.2.5.10).  Rationale:  Studies 
conducted in Europe and Canada should include 
a Summary of Benefit Risk Assessment.  This 
study has sites in France and the Netherlands, so 
this section was added to be in compliance.

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
In addition to palliative radiotherapy, 
consideration may be given for optional 
radiotherapy administered at palliative doses to 
a tumor between time of first progression by 
RECIST and when the patient has confirmed 
disease progression by irRECIST
(Section 5.7.9). Rationale:  There has been 
tumor regression observed in a non-irradiated 
tumor following palliative radiotherapy in a 
melanoma patient treated with 10 mg/kg of 
PF-04518600 who had initially met criteria for 
progression by RECIST.  It is possible that 
radiation may have benefited the anti-tumor 
immune response from PF-04518600 similar to 
what has been reported in a preclinical study 
evaluating the anti-tumor activity of 
OX40 agonist and radiation.  Therefore, this 
section has been added to allow for optional 
radiotherapy, at the discretion of the 
Investigator.

For Parts A1 and B1 the interval of radiographic 
assessments has an option for scans to be moved 
to every 12 weeks after 24 weeks.  Rationale:
Reducing scan interval to every 12 weeks will 
be more in alignment with standard of care.

For Parts A2 and B2 the interval of radiographic 
assessments was changed from every 8 weeks 
up to 48 weeks and then every 12 weeks to 
every 8 weeks up to 24 weeks and then every 
12 weeks.  Rationale: 48 weeks may be too 
long to perform more frequent scans.  Reducing 
scan interval to every 12 weeks will be more in 
alignment with standard of care.

Table 6’s rows for Other non hematologic 
toxicities and laboratory abnormalities
Grade 4 has the following added: Amylase or 
lipase abnormality that is not associated with 
symptoms or clinical manifestations of 
pancreatitis.  Rationale: A patient on this study 
had transient, asymptomatic, Grade 4 lipase 
elevations but was able to remain on study 
treatment with clinical benefit and no clinical 

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manifestations of pancreatitis. 

Figure 4. Study Schematic has been updated 
with the above information.

In the Analysis Sets, the immunogenicity 
assessment set has been defined.  Rationale:  
Wording added to define the immunogenicity 
assessment population, which will be part of the 
statistical analysis.

Appendix 6 has been updated with definitions of 
new measurable lesions for clarification 
purposes.

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Final Protocol 
Amendment 4
08 February 2017
Major changes to the protocol include the following: 

“PF-05082566” replaced with the proposed 
International Nonproprietary Name (INN), 
“utomilumab”, throughout the protocol.

PF-04518600 and utomilumab clinical 
experience data (safety, efficacy,
Pharmacokinetics [PK], and immunogenicity) 
updated in the Introduction section.

Tumor type rationales have been updated with 
recent publication findings.

Dosing rationales have been updated, including 
the addition of a rationale for flat dosing in 
Parts A2 and B2 (Section 1.4).

The administrative changes described in past 
Protocol Administrative Change Letters (PACL)
have been incorporated into the amendment.

Part A1 Monotherapy was updated to reflect that 
the study is enrolling patients into the optional 
10 mg/kg cohort, as the Maximum Tolerated 
Dose (MTD) has not been met.

Part A2 Monotherapy was updated to reflect that 
only hepatocellular carcinoma (HCC) patients 
will be enrolled into the 2 arms at a high and 
low flat dose of PF-04518600 (randomized 1:1)
instead of an arm of HCC and an arm of 
melanoma patients at the same weight-based 
dose.  Rationale for HCC as tumor type: 
1) Tumor regressions seen in 5 of 19 patients 
with HCC, 1 confirmed partial response (PR)
which is ongoing for >6 months; 2) 
Anti-programmed cell death protein-1 (PD-1)
and anti-programmed death-ligand 1 (PD-L1)
are not standard therapy in HCC yet, so would 
be able to enroll immuno-oncology (IO) naïve 
patients.  Rationale to explore 2 dose levels of 
PF-04518600 (30 mg and 250 mg) at flat 
doses: 1) 0.3 mg/kg appears to be the lowest 
dose at which full receptor occupancy (RO)
occurred for all patients and had the most 
favorable safety, efficacy, PK, and 
pharmacodynamics (PD) data (30 mg 

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equivalent). 2) Although no responses were 
observed in the 3 mg/kg cohort, increases in 
peripheral blood central memory CD4 T cell 
proliferation and activation were also observed 
at 3 mg/kg (250 mg equivalent).  3) Patients 
enrolled in 3 mg/kg were a distinctly different 
population from those enrolled in lower dose 
cohorts, which could have accounted for 
differences in clinical outcome.  4) Evaluating 
30 mg and 250 mg in randomized arms with a 
single tumor type 
 
 
•
Part A2 inclusion criteria has been changed to 
HCC patients who 1) have had 0 to 1 prior 
line(s) of systemic therapy (ie, progressed or 
intolerant to sorafenib or have declined standard 
therapy) and 2) who have not received prior 
anti-PD-L1/PD-1 therapy.  Treatment of HCC is 
most effective in the early stages and limiting 
prior therapies may help to identify early stage 
patients.
•
Parts A2 and B2 on treatment biopsies were 
modified from 1 mandatory on-treatment biopsy 
at Cycle 4 Day 1(C4D1) to 2 to 3 mandatory 
on-treatment biopsies.  The added mandatory 
on-treatment biopsy will be at time of initial 
progression or initial response. However, if the 
Investigator judges the risk of certain 
on-treatment biopsies unacceptable for the 
patient the medical monitor must be consulted. 
Rationale: Will provide an additional 
opportunity to obtain biomarker data at the point 
when treatment resistance (PD) or anti-tumor 
activity (PR) is occurring.
•
 
 
 
 
 
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•
The secondary endpoints of time to event 
endpoints have been re-categorized as 
“Anti-tumor activity assessments” to better 
reflect the endpoints as they are not all time to 
event endpoints in nature and this is more in 
alignment with the Food and Drug 
Administration (FDA) guidance for endpoints 
for cancer drugs.  Time to Progression has also 
been added to this endpoint.
•
The Schedule of Events and Pharmacokinetic 
and Pharmacodynamic Sampling Schedules for 
Parts A2 and B2 have been broken out from 
Parts A1 and B1 and aligned to differentiate the 
dose escalation and dose expansion parts of the 
study.
•
For Parts A2 and B2 the interval of radiographic 
assessments was changed from every 6 weeks to 
every 8 weeks up to 48 weeks and then every 
12 weeks. Rationale: 6 weeks may be too early 
to look for response and too frequent over the 
long term.  Reducing scan interval will be more 
in alignment with standard of care.
•
The Pharmacokinetic and Pharmacodynamic 
Sampling Schedules have been modified to 
allow for less total blood volume from patients.
•
Flexible language has been added to allow for 
the evaluation of the 10 mg/kg A1 dose in 
Japanese patients to support potential future 
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development at this dose in Japan.

Flexible language has been included for 
Part B1 to allow for an optional cohort of 
10 mg/kg PF-04518600 in combination with 
100 mg of utomilumab to be evaluated based on 
emerging data in the 10 mg/kg Part A1 cohort.

Part B Combination Therapy Exclusion #2 For 
Part B2, head and neck squamous cell 
carcinoma (HNSCC) patients will need to have 
either never been treated with anti-PD-L1 or 
anti-PD-1 mAb or those who 1) previously 
received prior anti-PD-L1 or anti-PD-1 mAb as 
most recent therapy, and 2) did not have 
progressive disease as best overall response on 
recent PD-L1/PD-1 therapy (ie, stable disease 
3 months, PR, or complete response [CR]), and 
3) who subsequently progressed, or are 
intolerant to PD-L1/PD-1 therapy.  
Pembrolizumab is now approved for HNSCC. 

The following Part B inclusion criteria has been 
removed: Sum of the longest diameter(s) of 
metastatic liver lesion(s) should be <5 cm. No 
liver toxicity has been seen with either 
PF-04518600 or utomilumab that would warrant 
this criterion. 

The following exclusion criteria has been 
modified and added to Part A and Part B, 
respectively: Patients who have undergone solid 
organ or hematopoietic transplant.  
Rationale: Avoid any graft versus host disease 
or graft rejection in all transplant patients.

Dosage Administration Instructions (DAI) has 
been replaced with Investigational Product (IP) 
Manual throughout the protocol.

Administration sections for Part A2 and B2 have 
been broken out from Part A1 and B1 to reflect 
the change to flat dosing from weight-based 
dosing mentioned above.

Table 4 Management of Immune-Related 

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Adverse Events has been updated to align with 
similar protocols so there is a uniform approach 
to studies involving the same or similar
compounds.
•
Redundant information has been minimized 
throughout the protocol to help minimize 
discrepancies between sections.
•
The reporting period for adverse events (AEs) 
and serious adverse events (SAEs) has been 
aligned between the Schedule of Activities and 
Section 8.2 so it is clear.
•
The maximum approximate sample size has 
been updated to better reflect the current 
estimates.
•
Section 9.3.1 Part A Monotherapy has additional 
information on the confidence interval of 
objective response rate (ORR) as it pertains to 
sample size.
•
It was clarified that there are no planned formal 
interim analyses.
•
The end of study was defined in Section 6.3, as 
it had been absent.
•
The term subject has been replaced with patient 
throughout the protocol for consistency.
Final Protocol 
Amendment 3
29 February 2016
1. Protocol Summary, Pharmacokinetic and 
Pharmacodynamic Sampling Schedule for Part B 
Combination Therapy, Section 1.5 Biomarker 
Rationale, Section 2.1.2 Objectives for Part B 
Combination Therapy, Section 2.2.2 Endpoints 
for Part B Combination Therapy, and Section 
 
have been revised to clarified that 4-1BB 
receptor assay will not be completed due to lack 
of an appropriate Ab reagent.  Therefore target 
engagement (TE) of PF-05082566 will not be 
evaluated
 
2. Schedule of activities: Part A monotherapy, 
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Schedule of activities: Part B combination 
therapy, and Section 7.1.3 Laboratory Safety 
Assessments.  Protocol has been revised to 
include monitoring of cardiac enzymes troponin
I and prohormone brain natriuretic peptide 
(NT-proBNP) for patients who have a history of 
adriamycin (doxorubicin) treatment. Adriamycin 
is a known cardiac toxic agent and innate 
immunity activation may contribute to its 
toxicity.
3. Schedule of activities: Part A monotherapy, 
Schedule of activities: Part B combination 
therapy, and Section 7.1.6 Echocardiogram or 
Multigated Acquisition (MUGA) Scan.  Protocol 
has been revised to include echocardiogram or 
MUGA assessments for patients who have a 
history of adriamycin treatment.  Adriamycin is a 
known cardiac toxic agent and innate immunity 
activation may contribute to its toxicity.
4. Pharmacokinetic and Pharmacodynamic 
Sampling Schedule for Part B Combination 
Therapy
 
 
 
5. Section 3.1 Study Overview and Section 
5.4 Administration.  A cycle has been revised to 
be defined as 2 weeks in duration rather than 
14 days to take into account the +/- 2 day 
window allowed for Cycle 2 and beyond per 
Schedule of Assessment tables.
6. Section 3.1.1 Part A Monotherapy: Participation 
of Japan in Part A1 has been clarified such that 
Japanese enrollment into 3 mg/kg dose level will 
only occur after safety of that dose level has been 
established in patients enrolled in non-Japanese 
sites.
7. Section 3.1.2 Part B Combination Therapy.  
Protocol has been clarified such that Japan will 
only participate in Part B after safety of 
PF-04518600 as a single agent has been
evaluated in Japanese patients.
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8. Section 3.1.5.2 Criteria for Dose Escalation for 
Part B Combination Therapy.  Administrative 
edits has been completed to align this section 
with statistical methods outlined in Section 
9.2.1.2.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. Section 3.3 Maximum Tolerated Dose (MTD).  
Definition has been clarified that the option to 
terminate the study will be considered for late 
immune related DLTs that are consistently
observed in all dose levels.
13. Section 3.4 Maximum Administered Dose 
(MAD).  Definition has been clarified to state 
that the MAD will be the highest dose actually 
administered instead of “not planned to be 
administered”.
14. Section 4.1.1 Inclusion Criteria for Part A 
Monotherapy.  Administrative edits to state that 
only clear cell renal cell carcinoma (RCC) 
patients will be enrolled, which aligns with 
protocol synopsis and Section 3 Study Design.
15. Section 4.2.1 and 4.2.2 Exclusion Criteria.  
Added “patients with a previous history of 
adriamycin treatment and are at risk of cardiac 
failure (New York Heart Association [NYHA]
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Class II or above)” since adriamycin is a known 
cardiac toxic agent and innate immunity 
activation may contribute to its toxicity.
 
 
17. Section 7.1.3 Laboratory Safety Assessments.  
Hematocrit assessment has been added to table to 
align with the hematology tests outlined in 
footnotes for Schedule of Activities.
Final Protocol 
Amendment 2
04 December 
2015
1. Title: Administrative edits based on tumor types 
to be evaluated
2. Throughout protocol: Objective tumor response 
will be evaluated by Response Evaluation 
Criteria in Solid Tumor (RECIST) version 
1.1 and irRECIST, instead of RECIST version 
1.1 and irRC. 
3. Throughout protocol: the term “study drug” has 
been replaced with “investigational product”.
4. Schedule of Activities: Tables have been 
updated and now includes a table for 
monotherapy (Part A), and combination therapy 
with 4-1BB (Part B).  Administrative edits have 
been completed for Schedule of Activities for 
Part A to align schedules with footnotes. 
5. Schedule of Activities: For Japan, a follow up 
consent is required prior to initiation of 
Cycle 3 in Parts A1 and B1.
6. Schedule of Activities and Section 7.1.3.  
Thyroid stimulating hormone (TSH) and 
gamma-glutamyltransferase (GGT) tests have 
been added to the blood chemistry panel, and an 
alpha fetoprotein test has been added for 
hepatocellular carcinoma (HCC) patients.  For 
TSH, should abnormalities be observed, a 
T4 thyroxine test will be performed. 
7. Schedule of Activities and Section 8.2.  To align 
with monitoring period for late immune 
toxicities, serious adverse events (SAEs) will be 
reported through 98 calendar days from first 
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administration of the investigational product, or 
up to 60 days after last administration of 
investigational product, whichever is later.
8. Schedule of Activities, and Sections 3.1 and 5.4.  
A window of 5 minutes has been incorporated 
for investigational product administration.
9. Pharmacokinetic and pharmacodynamics sample 
schedule: Tables have been updated and now 
includes a table for monotherapy (Part A), and 
combination therapy with 4-1BB (Part B).  
Administrative edits have been completed for 
Schedule of Activities for Part A to include the 
wording “other” for procedures that are to be 
completed every other cycle.  Sampling window 
for 1 hr samples have been clarified.  A banked 
specimen sample for C4D1 pre-dose has been 
added for Parts A and B.
10. Section 1.2.1 Background and Study Rationale 
for OX40 has been updated to include 
nonclinical pharmacokinetics data.
11. Section 1.2.2 Background and Study Rationale: 
4-1BB, and OX40/4-1BB background and study 
rationale have been included.
12. Section 1.2.4 Tumor Type Rationale: Rationale 
for selection of bladder cancer, cervical cancer, 
non-small cell lung cancer (NSCLC) and gastric 
cancer have been included.  Information 
regarding selection of tumor types based on the 
cancer genome atlas (TCGA) analysis has been 
included.
13. Section 1.3.2 Combination starting dose 
rationale: rationale for starting doses for 
PF-04518600/PF-05082566 combination study 
has been included. 
14. Section 1.4 Rationale for pre-treatment and 
on-treatment biopsies:  information for 4-1BB 
and combination study has been added.
15. Section 1.5 Rationale for biomarker assessments 
has been included.
16. Section 2.1 Objectives.  Administrative edits to 
objectives for Part A monotherapy include 
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dose expansion into 1 section based on 
similarities between the objectives.  Objectives 
for Part B combination therapy have been 
included. 
 
 
 
 
 
 
18. Section 2.2 Endpoints.  Administrative edits to 
objectives for Part A monotherapy include 
combining endpoints for dose escalation and 
dose expansion into 1 section based on 
similarities between the objectives.  Endpoints 
for Part B combination therapy have been 
included.  Anti-drug antibody (ADA) endpoint 
for Part A Monotherapy is now a secondary 
endpoint in alignment with pharmacokinetics 
(PK) secondary objective.
 
 
 
 
 
 
20. Section 3.1 and Protocol Synopsis: Study design 
has been revised, and the study is now divided 
into a Part A monotherapy phase and a Part B 
combination therapy phase.  Japan only 
information has been included.  A study 
schematic, information regarding Part B 
combination therapy, an enrollment 
prioritization section (Section 3.1.4) has been 
added.
21. Section 3.1.5 Starting dose: Starting dose 
information for Part B combination therapy 
phase has been added.
22. Section 3.1.6 Criteria for dose escalation: 
Criteria for dose escalation in Part B 
combination therapy phase have been added.
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23. Section 4.1 Inclusion Criteria.  Inclusion criteria 
for Part B combination phase have been added. 
24. Sections 4.1 Inclusion Criteria and 4.3 Lifestyle 
guides.  All patients must agree to use two 
highly effective method(s) of contraception for
at least 90 days after the last dose of assigned 
treatment.
25. Section 4.2 Exclusion Criteria.  Inclusion criteria 
for Part B combination phase have been added.
26. Section 4.3 Lifestyle guides: or transdermal 
hormonal methods of contraception has been 
added as an example and criteria for female 
partner who meets the criteria for 
non-childbearing potential has been 
incorporated.
27. Section 4.4 Sponsor’s Qualified Medical 
Personnel: administrative edits have been 
incorporated to definition.
28. Section 5: Definition of investigational product 
has been included.
29. Section 5.3.1 Dosage forms and packaging: 
information for PF-05082566 has been added.
30. Section 5.4 Administration.  Administration 
information for 
PF-04518600/PF-05082566 combination therapy 
has been added.  Administrative edits have been 
incorporated to include information on 
PF-05082566 and 4-1BB.
31. Section 5.4.3.4 Immune-related adverse events 
(irAEs).  Information regarding the management 
and follow up of immune related adverse events 
have been added for different types of irAEs.
32. Section 5.4.3.6 Dose reductions, interruptions 
and discontinuation criteria.  Information 
regarding dose reductions and treatment 
modifications for Part B combination has been 
added.
33. Section 5.4.4 Treatment after initial evidence of 
radiological disease progression section has been 
added.
34. Section 5.5 Drug Storage.  Use of investigational 

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product after temperature excursion will now be 
considered a deviation.
35. Section 5.6 Drug accountability.  Information for 
destruction of investigational product has been 
added.
36. Section 7.1.3 Laboratory safety assessments: In 
alignment with schedule of activities tables, 
hematology, chemistry and urinalysis tests must 
be reviewed by a physician prior to dosing. 
37. Section 7.1.5 12 Lead Electrocardiogram.  In 
alignment with schedule of activities tables, a 
single electrocardiogram (ECG) will be 
completed at screening.
38. Section 7.2.1 Pharmacokinetic assessments.  
Information for 
PF-04518600/PF-05082566 combination therapy 
has been added.
39. Section 7.3.1 Tumor Biopsy Markers.  In 
alignment with Section 3, fresh pre-treatment 
and on-treatment biopsies for the first 
2-4 patients in Parts A1 and B1 will not be 
required.
  
 
41. Section 7.5.1 Markers of drug response.  
Specific information for the Netherlands has 
been added.
42. Section 10 Quality control and quality 
assurance.  Investigator will notify Pfizer of any 
regulatory inspections, and Pfizer or 
representative will be present during inspections 
if feasible.
43. Section 10.1.  New section regarding good 
clinical practice (GCP) training has been added.
44. Section 12.4 Patient recruitment.  Pfizer will 
review any recruitment materials before use.
45. Section 15 Publication of study results.  
Administrative edits have been incorporated, 
including revised language on posting of basic 
results, and referencing of primary publications 
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by investigators.
46. Appendix 4: Management of infusion reactions 
has been updated to include PF-05082566.
47. Appendix 6: irRECIST information has been 
added.
Final Protocol 
Amendment 1
08 January 2015
1. Schedule of activities has been updated to 
include adverse event and concomitant 
medication assessments on Cycle 
7 Day 1 (C7D1).
2. Schedule of activities and footnote 26, and 
Section 6.3.1 have been updated to include a 
follow up visit on 14 (for patients who withdraw 
after 6 cycles), 42 (for patients who withdraw 
after 4 cycles), 56 (for patients who withdraw 
after 3 cycles), 70 (for patients who withdraw 
after 2 cycles), or 84 (for patients who withdraw 
after 1 cycles) days after end of treatment to 
enable the collection of late immune related 
adverse events.
3. Section 3.1.1 study overview part 1 has been 
revised to include a statement that includes late 
immune related Dose Limiting Toxicities 
(DLTs) in the determination of Maximum 
Tolerated Dose (MTD).
4. Section 3.1.4 criteria for dose escalation has 
been revised to include 3-fold, or one- half a log 
changes to a dose if a DLT related to 
PF-04518600 or a grade 2 cytokine release 
syndrome, infusion reaction, or allergic reaction 
is observed.
5. Section 3.2 DLT definition has been revised to 
include Grade 3 cytokine release syndrome, 
infusion reactions and allergic reactions as 
DLTs, except those that have not been 
maximally treated. 
6. Section 3.2 DLT definition has been revised to 
include a statement regarding collection of 
safety and tolerability assessment for the first 
98 days for estimation of MTD, even though 
dose escalation is based on 28 days.
7. Section 3.2.1 Late immune related DLTs section 

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has been added.  This includes a definition of a 
late immune related DLT, and stopping rules 
should these events be observed within 98 days 
of starting treatment (C1D1).  Also includes the 
need to re-consent a patient if treatment at a dose 
subsequently found to be above MTD is to be 
continued.
8. Section 3.3 MTD definition has been revised to 
include MTD dose considerations if a grade 3 or 
4 cytokine release syndrome, infusion reaction, 
or allergic reaction arises.
9. Section 3.3 MTD definition has been revised to 
include MTD dose considerations that take into 
account cumulative incidence of all late immune 
related DLTs.
10. Section 5.4.3 Dose reduction section has been 
revised to include the possibility of dose 
reductions if a late immune related DLT occurs.
11. Section 9.2.2 statistical method for estimating 
the MTD has been modified to include 
assumptions if grade 4 or 3 cytokine release 
syndrome, infusion reaction or allergic reaction 
is observed.
Original 
Protocol
18 November 
2014
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.

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ABBREVIATIONS
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
4-1BBL
4-1BB ligand
Ab
Antibody
ADA
anti-drug antibody
ADL
activities of daily living
AE
adverse event
AEs
adverse events
AIDS
acquired immunodeficiency syndrome
ALK
Anaplastic lymphoma kinase
Alk Phos
alkaline phosphatase
ALT
alanine aminotransferase
ANC 
absolute neutrophil count
ANOVA
analysis of variance
APCs
antigen presenting cells
ARCTIC
A Global Study to Assess the Effects of MEDI4736, Given as 
Monotherapy or in Combination With Tremelimumab Determined by 
PD-L1 Expression Versus Standard of Care in Patients With Locally 
Advanced or Metastatic Non Small Cell Lung Cancer
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC
area under the concentration versus time curve
AUCinf
area under the concentration versus time curve from time zero to infinity
AUCss
area-under-the-curve at steady state
AUCsdo
area-under-the-curve at single dose
BCG
bacillus Calmette-Guérin
BCL
B-cell lymphoma
BP
blood pressure
BRAF or 
BRAFV600
B-Raf proto-oncogene
BUN
blood urea nitrogen
C
Cycle
C1D1
Cycle 1 Day 1
C2D1
Cycle 2 Day 1
Cav
average concentration
Cmax
maximum concentration
Cmin
minimum concentration
C_D_
cycle _ day _
CBA
cytometric bead array
CBC
complete blood count
CD38
cluster of differentiation 38

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CD4 TCM
central memory CD4 T cells
CDS
core data sheet
CHF
congestive heart failure
CI
confidence interval
CL
Clearance
coBRIM
Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant 
melanoma
CNS
central nervous system
CRF
case report form
CR 
complete response
CRO
a contract research organization
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTC
common terminology criteria
CTCs
circulating tumor cells
CTCAE
common terminology criteria for adverse events
CTLA-4
cytotoxic T-lymphocyte antigen 4
CV
coefficient of variation
CYT
cytotoxic
D
Day
DAI
dosage and administration instructions
DC
dendritic cells
DeCOG
German Dermatologic Cooperative Oncology Group
DLI
donor lymphocyte infusion
DLT
dose limiting toxicities
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
duration of response
EBV
Epstein–Barr virus
EC
ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
eastern cooperative oncology group
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EDV
end diastolic volume
EFS
event free survival
EOT
end of treatment
EGFR
epidermal growth factor receptor
Erk
extracellular signal-regulated kinases
ESV
end systolic volume
EudraCT
European clinical trials database

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Factor Xa
trypsin-like serine protease
FcγRs
Fc-gamma receptors
FDA
food and drug administration (United States)
FDAAA
food and drug administration amendments act (United States)
FFPE
formalin-fixed paraffin-embedded 
FIP
first in patient
FoxP3
forkhead box P3
FSH
follicle-stimulating hormone
GBM
Glioma
GCP
good clinical practice
GGT
gamma-glutamyltransferase
GITR
glucocorticoid-induced tumor necrosis factor receptor
GLP
good laboratory practice
G-CSF
granulocyte-colony stimulating factors
Gp100
glycoprotein 100
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus 
HDV Ab
hepatitis D by antibody
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HNSCC
head and neck squamous cell carcinoma
HPV
human papilloma virus
HR
heart rate
huPBL
human peripheral blood lymphocytes
IB
investigator’s brochure
IARC
international association of research in cancer
ICD
informed consent document
ICH
international conference on harmonization
ICOS
inducible t-cell co-stimulator
IEC
institutional ethics committee
ID
Identification
IFN-γ
interferon gamma
IgG
immunoglobulin g
IHC
immunohistochemistry
IL-
Interleukin
IM
Immunomodulatory
IND
investigational new drug application
INN
International Nonproprietary Name
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INR
international normalized ratio
IO
Immuno-Oncology
IP Manual
Investigational Product Manual
irAEs
immune related adverse events
IRB
institutional review board
irRC
immune-related response criteria
irRECIST
immune-related response criteria derived from RECIST v1.1
irSD
Stable disease per Immune-related Response Criteria Derived from 
RECIST
IUD
intrauterine device
IV
intravenous
JAK2
Janus kinase 2
JAK3
Janus kinase 3
JAVELIN 
LUNG 200
Avelumab in Non-Small Cell Lung Cancer
Jnk
c-Jun N-terminal kinases
KLH
keyhole limpet hemocyanin
KRAS
Kirsten rat sarcoma proto-oncogene
LAG3
lymphocyte-activation gene 3
LFT
liver function test
LLN
lower limit of normal
LPD
local product document
LPLV
last patient last visit
LVEF
left ventricular ejection fraction
mTPI
modified toxicity probability interval
mAb
monoclonal antibody
MAD
maximum administered dose
MAP kinase
mitogen-activated protein kinases
MCC
merkel cell carcinoma 
MCL
Mantle Cell Lymphoma
MCP-1
monocyte chemoattractant protein-1
MD
multiple dose
MedDRA
medical dictionary for regulatory activities
MEK
MAPK/ERK kinase
MIP-1
macrophage inflammatory protein-1 alpha
MIP-1
macrophage inflammatory protein-1 beta
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
MUGA
multigated acquisition
MYSTIC
Phase III Open Label First Line Therapy Study of MEDI 
4736 (Durvalumab) With or Without Tremelimumab Versus SOC in Non 
Small-Cell Lung Cancer (NSCLC)
N/A
not applicable

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NAb
neutralization assays
NCI 
National Cancer Institute 
NCT
National Clinical Trial
NEPTUNE
Study of 1st Line Therapy Study of Durvalumab With Tremelimumab 
Versus SoC in Non Small-Cell Lung Cancer (NSCLC)
NF-κB
nuclear factor kappa-light-chain-enhancer of activated B cells
NHL
non-Hodgkin’s lymphoma
NK
natural killer
NKT
natural killer T cells
NMIBC
non- muscle invasive bladder cancer
NSAIDs
nonsteroidal anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
NT-proBNP
N-terminal of the prohormone brain natriuretic peptide
NYHA
New York Heart Association
OBD
optimal biological dose
ORR
objective response rate
OS
overall survival
PACL
Protocol Administrative Change Letters
pT
target probability
PBMCs
peripheral blood mononuclear cells
PCD
primary completion date
PCR
Polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein-1
PD-L1
programmed death-ligand 1
PE
physical exam
PET
positron emission tomography
PFS
progression free survival
PIK3CA
Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha
PK
Pharmacokinetics
PLTS
Platelets
PMDA
pharmaceuticals and medical devices agency
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
Every 3 weeks
Q4W
every 4-weeks
QD
every day
QT
time between the start of the Q wave and the end of the T wave
R
Ratio
RCC
renal cell carcinoma
RD
response/remission duration 
RECIST
response evaluation criteria in solid tumor

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RFS
relapse free survival
RNA
ribonucleic acid
RO
receptor occupancy
ROS1
ROS proto-oncogene 1
RP2D
recommended phase 2 dose
RR
response rate
s4-1BB
soluble 4-1BB
sOX40
soluble OX40
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCCHN
Squamous Cell Carcinoma of the Head and Neck
SCID
severe combined immune deficiency
SCLC
small cell lung cancer
SD
stable disease
SDo
single Dose
SOC
System Organ Class
SPC
summary of product characteristics
SRSD
single reference safety document
T
Time
T1/2
terminal elimination half-life
T4
thyroxine 
TBNK assay
T, B, NK lymphocyte assay
TCGA
the cancer genome atlas
TCR
T-cell receptor
TE
target engagement
TEAEs
treatment-emergent adverse events
Th
T-helper
TILs
tumor infiltrating lymphocytes
TME
tumor microenvironment
TNFRSF
tumor necrosis factor receptor superfamily
TNF
tumor-necrosis factor
TNF-
tumor-necrosis factor alpha
TNF-
tumor-necrosis factor beta
TNFR
tumor-necrosis factor receptor
TP53
tumor protein p53 gene
TRAF
TNFR-associated factor
TNFSF4
tumor necrosis factor (ligand) superfamily, member 4
Tregs
T regulatory cells
TSH
thyroid-stimulating hormone
TTL
target toxicity level
TTP
time to progression
ULN
upper limit of normal
UPM
unit probability mass

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US
United States
USPI
United States package insert
VEGF
vascular endothelial growth factor
Vss
volume of distribution at steady state
WBC
white blood cell count

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PROTOCOL SUMMARY
Background and Rationale:
Immunotherapy offers the opportunity to not only stop tumor growth, but also decrease the 
rate of tumor recurrence.1 By activating and expanding tumor-associated antigen T cells, it 
may be possible to enhance tumor immunity.  However, T cell activation is not mediated by 
antigen stimulation alone.  Instead, co-stimulatory receptors are required.  OX40 (CD134) 
and 4-1BB (CD137) are co-stimulatory receptors that act on antigen stimulated T cells but 
not native T cells.2,3 OX40 plays a key role in T cell survival, proliferation, and activation.  
Upon OX40 ligand (also known as OX40L, CD252 or TNFSF4 [tumor necrosis factor 
(ligand) superfamily, member 4]) binding, OX40 signaling upregulates anti-apoptotic 
molecules including B-cell lymphoma-2 (Bcl-2), Bcl-xL, and survivin,4 and increases 
interleukin-2 (IL-2), IL-4, IL-5, and interferon gamma (IFN-) cytokine secretion.  Similarly, 
activation of 4-1BB signaling leads to an upregulation of pro-survival factors Bfl-1 and 
Bcl-xL, down-regulation of pro-apoptotic protein Bim, increased T cell proliferation and 
differentiation into T memory cells.5
PF-04518600 is a fully human Immunoglobulin G2 (IgG2) agonistic monoclonal antibody 
(mAb) specific for human OX40 (CD134).  By binding to OX40 on activated tumor 
infiltrating T cells, PF-04518600 may reverse T cells’ anergic state, and enhance tumor 
immunity. 
Utomilumab (PF-05082566) is a fully human IgG2 agonist monoclonal antibody specific for 
human 4-1BB.  The safety and tolerability of utomilumab is currently being evaluated in a 
First-in-Patient Phase 1 study as a single agent and in combination with rituximab (Study 
B1641001, IND 109,154).6 Utomilumab has been well tolerated (thus far up to 10 mg/kg) 
when administered as a single agent every 4 weeks (Q4W). The safety profile of utomilumab
either as single agent or in combination with rituximab was manageable without occurrence 
of treatment related life threatening (>Grade 4) adverse events (AEs). 
In this clinical study, PF-04518600 as a monotherapy (Part A), and PF-04518600 in 
combination with utomilumab (Part B) will be evaluated for the treatment of adult patients 
with select locally advanced or metastatic cancers who are unresponsive to current available 
therapies, or for whom no standard therapy is available.
Study Design:
This is a Phase 1, open label, multi-center, multiple dose, dose escalation, safety, 
pharmacokinetic, and pharmacodynamic study of PF-04518600 monotherapy in Part A, and 
PF-04518600 in combination with utomilumab in Part B.  Each part includes a dose 
escalation phase, and a dose expansion phase.  A maximum of approximately 210 patients 
are expected to be enrolled into the study. 

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All patients will complete up to 4 weeks of screening.  Following the initial dose(s), 
treatment with investigational product will continue until disease progression by 
immune-related response evaluation criteria in solid tumors (irRECIST), patient refusal,
unacceptable toxicity occurs, or the end of the study, whichever occurs first.  Patients will be 
allowed to stay on study, if the treating physician feels that it is in the patient’s best interest 
in the case of radiological progression, and the absence of clear clinical progression (see
Section 5.4.6 Treatment after Initial Evidence of Radiological Disease Progression).  A 
follow-up visit approximately 4 weeks after the last dose for adverse event (AE) and serious 
AE (SAE) collection will be conducted.  Late immune related responses will be evaluated up 
to 98 days after the first dose(s) of Cycle 1. Because atypical tumor responses after growth 
of pre-existing lesions or appearance of new lesions have been observed with immune 
checkpoint inhibitors, study B0601002 will assess tumor response based on both response 
evaluation criteria in solid tumor (RECIST) and Immune-related Response Criteria Derived 
From RECIST v1.1 (irRECIST).  Survival data will also be collected (see Section 
5.4.6 Treatment after Initial Evidence of Radiological Progression, Section 6.3 Follow-up 
Visit, Section 7.4 Tumor Response Assessments, and Appendix 6).  The time on study can 
vary depending on the observed toxicity and potential benefit an individual patient derives.  
It’s estimated that patients will remain on treatment for approximately 12-18 weeks, making 
total study duration approximately 20-26 weeks (exclusive of 2 year survival follow-up).  
Actual duration can be longer, if a patient derives benefit from study treatment.
Part A Monotherapy:
Part A1 Monotherapy Dose Escalation.
Part A1 monotherapy dose escalation phase will enroll approximately 58 adult patients with 
locally advanced or metastatic cancers hepatocellular carcinoma (HCC), melanoma, clear cell 
renal cell carcinoma (RCC) or head and neck squamous cell carcinoma (HNSCC).  The 
actual number of patients enrolled will depend on the observed safety and tolerability profile 
of PF-04518600, the number of dose levels that will be tested and expanded to characterize 
the pharmacodynamic or immunomodulatory (IM) effects, and the number of dose levels 
required to identify the maximum tolerated dose (MTD) or optimal biological dose (OBD).  
Six dose levels are proposed: 0.01, 0.1, 0.3, 1.5, 3 and 10 mg/kg. Each cohort will include an 
initial cohort of 2-4 patients that may be expanded to approximately 10 patients.  
Approximately 3 patients enrolled in Japan will be included for at least 2 dose levels (see 
Section 3.1.1.3 Japan Participation in Part A Monotherapy).
A staggered start will be employed at all dose levels.  A single patient will be dosed and 
observed for 48 hours.  If no safety concerns arise during this 48 hr period, a second patient 
will be enrolled into the same dose level cohort.  A modified toxicity probability interval 
(mTPI) method, targeting a dose limiting toxicities (DLT) rate of 25% and an acceptable 
DLT interval (20%-30%),7 will be utilized for dose escalation (see Section 3.1.5 Criteria for 
Dose Escalation).  If peripheral blood samples indicate preliminary signs of immune 
modulation in the first 2-4 patients, the dose level will be expanded for pharmacodynamic
evaluation; these additional patients will undergo mandatory pre-treatment and on treatment 
biopsies. If the Investigator judges the risk of certain on-treatment biopsies unacceptable for 

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the patient (eg, based on site of tumor, potential for complications during/after procedure, 
etc.) the medical monitor must be consulted (see Section 1.4 Rationale for Pretreatment and 
On-treatment Biopsies).  Depending on observed safety data and pharmacodynamic data, 
additional cohorts (lower, intermediate or higher dose levels, up to maximum of 20 mg/kg, 
see Section 3.1.5 Criteria for Dose Escalation) may also be tested. 
Part A2 Monotherapy Dose Expansion.
Part A2 monotherapy dose expansion phase will randomize HCC patients 1:1 to flat dose 
levels of either 30 mg (Arm 1) or 250 mg (Arm 2) of PF-04518600 given every 2 weeks. 
Both doses were chosen based on data from Part A1. Each arm in Part A2 will include 
approximately 20 HCC patients. 
Based on emerging data from the 10 mg/kg cohort of Part A1, an additional flat dose level of 
800 mg PF-04518600 (approximately equivalent to 10 mg/kg), may be added after initiation 
of enrollment into Arms 1 and 2. 
Patients will undergo mandatory pre-treatment and on treatment biopsies as specified in the 
Schedule of Activities. If the Investigator judges the risk of certain on-treatment biopsies 
unacceptable for the patient (eg, based on site of tumor, potential for complications 
during/after procedure, etc.) the medical monitor must be consulted (see 
Section 1.4 Rationale for Pretreatment and On-treatment Biopsies).
Part B Combination Therapy:
Part B1 Combination Therapy Dose Escalation.
Part B1, the combination therapy dose escalation phase, will enroll approximately 55 patients. 
At least 6 patients must have been evaluated for the 28 day DLT observation period at the 
0.3 mg/kg dose level in Part A1 PF-04518600 (OX40 agonist) monotherapy before 
Part B1 can be initiated.  Part B1 will study sequential dose levels of PF-04518600 (0.1, 0.3, 
1.0 and 3 mg/kg with an option of 10 mg/kg pending data from Part A1) combined with 
either 20 mg or 100 mg of utomilumab (4-1BB agonist) in adult patients with non-small cell 
lung cancer (NSCLC), HNSCC, melanoma, bladder, gastric or cervical cancer who are 
unresponsive to currently available therapies or for whom no standard therapy is available.  
The starting dose level will be 0.1 mg/kg of PF-04518600 and 20 mg of utomilumab, given 
no sooner than 30 minutes apart (for dosing schedule, please see 
Section 5.4.3 Administration Part B Combination Therapy). Based on emerging data in the 
10 mg/kg Part A1 cohort, an optional cohort of 10 mg/kg PF-04518600 in combination with 
100 mg of utomilumab may be evaluated.
A mTPI method, targeting a DLT rate of 25% and an acceptable DLT interval 
(20%-30%),7 will be utilized for dose escalation (see Section 3.1.5 Criteria for Dose 
Escalation). If peripheral blood samples indicate preliminary signs of immune modulation in 
the first 2-4 patients, the dose level will be expanded for pharmacodynamic evaluation; these 
additional patients will undergo mandatory pre-treatment and on treatment biopsies. In case 
of intolerable toxicity at the starting dose level, the dose combination will be reduced to 

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0.1 mg/kg of PF-04518600 and 10 mg of utomilumab. Subsequent to the starting dose level, 
if dose de-escalation is recommended after evaluation, intermediate dose levels between the 
previous dose combination and current dose combination may be studied.  Intrapatient dose 
reductions are not permitted during the combination therapy with PF-04518600 and 
utomilumab unless, in discussion with the sponsor, a dose combination level is deemed 
beyond the determined MTD for the combination. Each dose combination level will include 
an initial cohort of 2-4 patients that may be expanded up to approximately 10 patients based 
on peripheral pharmacodynamic assessments (see Section 7.3 Biomarker and 
Pharmacodynamic Assessments).  To allow for better characterization of pharmacodynamic 
effects, these additional patients will undergo mandatory pre-treatment and on treatment 
biopsies.  If the Investigator judges the risk of certain on-treatment biopsies unacceptable for 
the patient (eg, based on site of tumor, potential for complications during/after procedure, 
etc.) the medical monitor must be consulted (see Section 1.4 Rationale for Pretreatment and 
On-treatment Biopsies).  The safety of the first patient at each dose combination level will be 
observed for 48 hours prior to enrolling subsequent patients. 
Part B2 Combination Therapy Dose Expansion.
Part B2 combination therapy dose expansion phase will further evaluate safety and 
anti-tumor activity of PF-04518600/utomilumab combination with a dosing regimen selected 
based on results of Part B1 with flat dose equivalents of PF-04518600. 
From the results of Part B1, the selected dose for PF-04518600 in the B2 combination 
therapy dose expansion cohorts is 30 mg (a flat dose equivalent to 0.3 mg/kg) intravenously 
(IV) every 2 weeks (Q2W) in combination with PF-05082566 20 mg IV every 28 days. 
Part B2 will be divided into 2 arms: 
Arm 1 will enroll melanoma patients who have either:
a.
Ocular melanoma patients with advanced/metastatic disease, or
b. Cutaneous/acral melanoma patients with advanced metasatic disease who have 
received checkpoint inhibitor (anti-PD-L1, anti-PD-1, or anti-cytotoxic 
T-lymphocyte antigen 4(anti-CTLA4)) based treatment on which disease 
progressed. [Note: Checkpoint inhibitor may have been part of a combination 
therapy, as long as the combination did not contain OX40 or 4-1BB agonist].  
Any questions on prior treatment may be discussed with the Sponsor.
Arm 2 will enroll patients with histological or cytological diagnosis of NSCLC with 
advanced/metastatic disease.  Patients must have previously received prior 
anti-PD-L1 or anti-PD-1 mAb on which disease progressed.  [Note: Previous 
anti-PD-L1 or anti-PD-1 mAb may have been part of a combination therapy, eg, in 
combination with chemotherapy, as long as the combination did not contain OX40 or 
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Part B2 will enroll up to 20 patients in each arm (including approximately 5 ocular 
melanoma patients in Arm 1), and all patients will undergo mandatory pre- and 
on-treatment tumor biopsies. If the Investigator judges the risk of certain on-treatment 
biopsies unacceptable for the patient (eg, based on site of tumor, potential for 
complications during/after procedure, etc.) the medical monitor must be consulted (see
Section 1.4 Rationale for Pretreatment and On-treatment Biopsies). 
Study Objectives:
Objectives for Part A1 Monotherapy Dose Escalation:
Primary Objective:
•
To assess safety, and tolerability at increasing dose levels of PF-04518600 in patients 
with selected advanced or metastatic solid tumors in order to establish the MTD.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity induced by PF-04518600 in patients 
with selected advanced or metastatic solid tumors solid tumors. 
•
To characterize the single dose and multiple dose pharmacokinetics (PK) of 
PF-04518600 following intravenous (IV) administration.
•
To evaluate the immunogenicity of PF-04518600 following IV administration.
•
To characterize the degree of target engagement (TE) by PF-04518600 at multiple 
doses by measuring unbound (free) cell surface OX40 in peripheral blood.
 
 
 
 
 
 
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Objectives for Part A2 Monotherapy Dose Expansion:
Primary Objectives:
•
To establish the recommended phase 2 dose (RP2D) of PF-04518600 in patients with
selected advanced or metastatic HCC.
•
To further characterize the safety and tolerability of PF-04518600 in patients with 
selected advanced or metastatic HCC.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in patients with 
selected advanced or metastatic HCC. 
•
To characterize the single dose and multiple dose PK of PF-04518600 following 
IV administration.
•
To evaluate the immunogenicity of PF-04518600 following IV administration.
 
 
 
 
 
 
 
 
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Objectives for Part B1 Combination Therapy Dose Escalation:
Primary Objective:
•
To assess safety and tolerability at increasing dose levels of PF-04518600 in 
combination with utomilumab in patients with selected advanced or metastatic solid 
tumors and to estimate MTD of the combination.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in combination 
with utomilumab. 
•
To characterize single and multiple dose pharmacokinetics of PF-04518600 and 
utomilumab when given in combination.
•
To evaluate immunogenicity of PF-04518600 and utomilumab when given in 
combination.
 
 
 
 
 
 
 
 
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Objectives for Part B2 Combination Therapy Dose Expansion:
Primary Objective:
•
To further assess safety and tolerability of PF-04518600 in combination with 
utomilumab in patients with melanoma or NSCLC in order to establish RP2D for the 
combination.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in combination 
with utomilumab. 
•
To characterize single and multiple dose pharmacokinetics of PF-04518600 and 
utomilumab when given in combination.
•
To evaluate immunogenicity of PF-04518600 and utomilumab when given in 
combination.
 
 
 
 
 
 
 
 
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Endpoints:
Endpoints for Part A1 Monotherapy Dose Escalation:
Primary Endpoints:
•
Dose limiting toxicities (DLTs) observed in each patient during the first 98 days in 
order to determine the MTD.
•
Adverse Events (AEs) as characterized by type, frequency, severity (as graded by 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v 4.03, timing, seriousness and relationship to study therapy PF-04518600.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: progression free survival (PFS), Time to 
Progression (TTP), duration of stable disease (SD), duration of response (DR) by 
RECIST version 1.1 and irRECIST and overall survival (OS).
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600:
Single Dose (SDo) - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  Multiple Dose (MD) 
(assuming steady-state is achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, 
and Rac (AUCss,τ/AUCsdo,τ) as data permit.
•
Incidence of anti-drug antibody (ADA) and neutralizaing antibody (NAb) against
PF-04518600.
•
Levels of free OX40 receptor expressed on T cells in peripheral blood.
 
 
 
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Endpoints for Part A2 Monotherapy Dose Expansion:
Primary Endpoints:
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to study therapy PF-04518600.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA and NAb against PF-04518600.
 
 
 
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Endpoints for Part B1 Combination Therapy Dose Escalation:
Primary Endpoints:
•
DLTs observed in each patient during the first 98 days in order to determine the 
MTD.
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to PF-04518600/utomilumab combination.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600 and utomilumab:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA and NAb against PF-04518600 and utomilumab.
 
 
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Endpoints for Part B2 Combination Therapy Dose Expansion:
Primary Endpoints:
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to PF-04518600/utomilumab combination.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600 and utomilumab:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA and NAb against PF-04518600 and utomilumab.
 
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SCHEDULE OF ACTIVITIES: Part A1 Monotherapy
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS Section 7 of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Part A1 Monotherapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit IdentifierScreen1
(28
days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
1
1
2
2
2
2
2
2
2
Informed 
Consent2
X
Tumor History3
X
Medical History4
X
Complete 
Physical 
Examination
X
X
X
X
Abbreviated 
Physical
Examination5
X
X
X
X
X
X
X
X
X
Baseline Signs 
and Symptoms6
X
Height
X
Weight7
X
X
X
X
X
X
X
X
X
Vital signs 
(BP/PR/Temp)8
X
X
X
X
X
X
X
X
X
X
X
X
X

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Part A1 Monotherapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit IdentifierScreen1
(28
days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
1
1
2
2
2
2
2
2
2
Eastern 
cooperative 
oncology group 
(ECOG) 
Performance 
Status9
X
X
X
X
X
X
X
X
X
Triplicate 
12 Lead ECG10
X 
(single 
ECG 
only)
X
X
X
X
X
X
X
X
X
X
X
Laboratory
Hematology11
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry 
12
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation13
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis14
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test15
X
X
X
X
X
X
X
X
Hepatitis B, C 
and HIV tests16
X
Cardiac enzymes 
17
X
X
X
X (Cycle 
5 only)
X
X (Cycle 
9 and every 
other cycle)
X
Alpha 
Fetoprotein for 
HCC patients 
only
X
Every 6 weeks

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Part A1 Monotherapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit IdentifierScreen1
(≤28
days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
±1
±1
±2
±2
±2
±2
±2
±2
±2
Registration 
and Treatment
Registration18
X
PF-04518600 Tr
eatment19
X
X
X
X
X
X
Tumor 
Assessments
CT or MRI scan 
or equivalent20
X
Every 6 weeks until confirmed progressive disease. Scans may be moved to every 
12 weeks after 24 weeks until confirmed progressive disease.
Other 
samplings
 
 
 
.
Blood Samples 
for PK23
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
Blood Sample 
for
Anti-PF-045186
00 Antibodies24
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
 
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Part A1 Monotherapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit IdentifierScreen1
(28
days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
1
1
2
2
2
2
2
2
2
Other clinical 
assessments
Adverse Events26
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication and 
non-drug 
supportive 
interventions27
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram
or MUGA28
X
Every 3 months
X
Except for safety assessments, all other activities performed during Cycle 1 can be performed 1 day, and for Cycle 2 onwards 2 days. Safety assessments must 
be performed prior to dosing (see footnotes for details). 
Footnotes 
1.
Screening: to be obtained within 28 days prior to treatment start.
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures. For Japan Part A1 only: after completion of 2 treatment cycles and 
prior to initiation of Cycle 3, a follow up consent must be obtained to confirm patient’s willingness to continue on study.  All Japanese patients in
Part A1 should be hospitalized until 2nd dosing.
3.
Tumor History: will be collected within 28 days during screening 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.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete physical exams are not required.  
Refer to Section 7.1 Assessments for further details.

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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.  During the study, any new or worsened conditions since baseline will be recorded on the Adverse Events (AE) case report form (CRF) page.
7.
Weight: Patient’s body weight will be measured prior to the preparation of investigational product (PF-04518600) and patient’s dose of PF-04518600 for 
that cycle will be based on the patient’s body weight (see Administration Section 5.4). 
8.
Vital signs: includes temperature (oral, tympanic, temporal or axillary), blood pressure (BP), and pulse rate to be recorded in the sitting position after 
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 the infusion. 
9.
Performance status: use Eastern Cooperative Oncology Group (ECOG) scale in Appendix 1.
10. Triplicate 12-leads electrocardiogram (ECG): Triplicate ECGs will be collected at times specified in the Schedule of Activities.  At each time point, at least a 
10 second strip, three consecutive 12-lead ECGs will be performed 1-5 minutes apart to determine mean QTcF interval.  The Screening ECG will be a 
single, 12 lead ECG.  ECGs on Day 1 of each Cycle will be collected prior to dosing, and at the end of infusion (approximately 1 hour) following 
administration of each dose of PF-04518600.  Additional ECGs will be collected on Cycle 1 Day 2 (C1D2), Cycle 1 Day 8 (C1D8), Cycle 2 Day 8 (C2D8), 
and Cycle 3 Day 8 (C3D8) and EOT.  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be 
performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  All ECGs will be reviewed by a centralized ECG 
vendor.  If the mean QTcF is prolonged (value of >500 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation.  
Additional triplicate ECGs may be performed as clinically indicated.  Refer to Section 7.1.5 (12-Lead) ECG for further details.
11. Hematology: complete blood count (CBC) to include hematocrit, hemoglobin, platelets, white blood cells (WBC), absolute neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed within 48 hours prior to dosing.  If screening
assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments performed on 
Cycle 2 Day 1 (C2D1) and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments Section 7.1.3 for 
Laboratory Tests list.
12. Blood Chemistry: Tests for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk Phos), 
gamma-glutamyltransferase (GGT), sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, 
uric acid, glucose (non-fasted), albumin, phosphorous or phosphate, amylase, lipase and thyroid stimulating hormone (TSH) will be performed. 
Assessments conducted on C1D1 must be completed within 48 hours prior to dosing.  If screening assessments are performed within 72 hours prior to C1D1, 
there is no need to repeat assessments on C1D1.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours 
prior to dosing.  If abnormalities are observed in TSH values, a T4 thyroxine test will be performed.  See Assessments Section 7.1.3 for laboratory tests list.
13. Coagulation Assays: prothrombin time (PT) and partial thromboplastin time (PTT).  Assessments conducted on C1D1 must be completed within 48 hours
prior to dosing.  If screening assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments 
performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments Section 7.1.3 for laboratory 
tests list.
14. Urinalysis: Dipstick is acceptable. Microscopic analyses required if dipstick abnormal.  If 2+ protein on urine dipstick, then collect 24 hr urine.  
Assessments conducted on C1D1 must be completed within 48 hours prior to dosing.  No need to repeat on C1D1 if screening assessment performed within 
7 days prior to that date.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing. See 
Assessments Section 7.1.3 for Laboratory Tests list.
15. Pregnancy Test (Serum/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 at C1D1, before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle prior to dosing during the active treatment period, at the end of study therapy and additionally 

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whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Results will be obtained prior to initiating therapy at all times.  
Additional pregnancy tests may also be undertaken if requested by institutional review board (IRB)/institutional ethics committee (IEC)s or if required by 
local regulations.
16. Hepatitis B, C and HIV Tests: Conduct tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCV Ab) 
and human immunodeficiency virus (HIV) serology. 
17. Cardiac enzymes: Troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) and N-terminal of the prohormone brain 
natriuretic peptide (NT-proBNP) will be evaluated in patients with previous history of anthracycline treatment.  Assessments must be performed prior to 
dosing.  No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 72 hours prior to that date.  Assessments performed on 
Cycle 3 Day 1 (C3D1) and Day 1 of each subsequent odd number cycles should be performed within 48 hours prior to dosing.  Assessments should also be 
performed when clinically indicated.  See Assessments Section 7.1.3 for Laboratory Tests list.
18. Registration: Patient number and dose level allocation provided by Pfizer Inc.  Treatment should begin no longer than four days from registration.
19. PF-04518600 Treatment: PF-04518600 will be administered once every 2 weeks as an IV infusion over 60 minutes (-5 to +15 minutes) and should include 
the time needed to flush the infusion line.  Day 1 safety labs (blood chemistry, hematology, and urinalysis) need to be reviewed by a physician prior to 
dosing at the beginning of each cycle. Treatment with investigational product will continue until disease progression by irRECIST, patient refusal, 
unacceptable toxicity occurs, or the end of the study, whichever occurs first.
 
 
 
 
 
 
 
  
 
23. PK Sampling: Specific timing for collection of pharmacokinetic samples can be found in the pharmacokinetic and pharmacodynamic sampling schedule
table below. 
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24. Anti PF-04518600 Antibodies: Specific timing for collection of anti-PF-04518600 antibody samples can be found in the Pharmacokinetic and 
Pharmacodynamic Sampling Schedule table below. 
 
26. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.03.  Patients must be followed for adverse events (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.  However, late immune-related DLTs that are not SAEs need to be collected consistent with Section 3.2.1.  For serious 
adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, 
which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure and/or receiving investigational product, 
through 98 calendar days from first administration of the investigational product, or up to 60 days after last administration of investigational product, 
whichever is later.  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 investigational product are to be reported to the sponsor.
27. Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care 
drugs (eg, Anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions).
28. Echocardiogram or multigated acquisition (MUGA) scan: echocardiogram or MUGA will be evaluated in patients with previous history of anthracycline
treatment.  For these patients, an echocardiogram or MUGA will be performed at screening and every 3 months whilst on treatment and when clinically 
indicated.  An echocardiogram or MUGA will be performed at the end of treatment (EOT) visit if not performed within 3 months of discontinuation.
29. End of treatment visit (EOT visit): Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments). 
30. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Late immune related adverse event information will be collected during the 28 to 
35 day follow up visit. 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.  Independent to time of 
disease progression, all patients (unless patients are lost to follow up, consent is withdrawn, or study is discontinued by the sponsor) will be followed for 
survival for at least 2 years from the time of their first dose of investigational product. After the completion of end of treatment visits, Patients will be 
contacted every 2 months for survival status. To collect additional late immune related adverse event information, any patient who discontinue from 
treatment after 1 to 4 or 6 cycles of treatment will also be contacted by phone during the follow up period.  For patients who discontinues after receiving 
5 cycles of treatment, late immune information will be collected during the 28 to 35 day follow up visit.  If the patient discontinues after receiving 6 cycles 
of treatment, they will be contacted by phone 14 days (±2 days) after EOT.  If the patient discontinues after receiving 4 cycles of treatment, they will be 
contacted by phone 42 days (±2 days) after EOT.  If the patient discontinues after receiving 3 cycles of treatment, they will be contacted by phone 56 days 
(±2 days) after EOT. If the patient discontinues after receiving 2 cycles of treatment, they will be contacted by phone 70 days (±2 days) after EOT. If the 
patient discontinues after receiving 1 cycle of treatment, they will be contacted by phone 84 days (±2 days) after EOT. If any concern arises, patient will be 
called in for an inpatient follow up visit within 5 calendar days of initial phone call (assessments will be the same as the assessments performed 28-35 days 
after end of treatment follow up visit).
31. Subsequent cycles: Day 8 is not required after Cycle 3. 
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SCHEDULE OF ACTIVITIES: Part B1 Combination Therapy 
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments Section 7 of the 
protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Part B1 Combination Therapy
Treatment Period
Post Treatment
Cycle 
1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 
1 to 14)
Cycles 4
to 6
(Days 
1 to 14) 
Cycle 7
(Days 1 to 
14)
Subsequent 
Cycles
(Days 1 to 
14)32
End of 
Treatment 
(EOT)30
Follow Up 
(Days after EOT visit)31
Visit Identifier
Screen1
(28 days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14 days 28 to 
35 days
42 days56 days70 days 84 days 
Visit Window in Days
1
1 2 2 2 2
2
2
2
Informed Consent2
X
Tumor History3
X
Medical History4
X
Complete Physical 
Examination
X
X
X
X
Abbreviated Physical 
Examination5
X
X
X
X
X
X
X
X
X
Baseline Signs and 
Symptoms6
X
Height
X
Weight7
X
X
X
X
X
X
X
X
X
Vital signs 
(BP/PR/Temp)8
X
X
X
X
X
X
X
X
X
X
X
X
X
Eastern cooperative 
oncology group (ECOG) 
Performance Status9
X
X (Cycle 
4 only)
X
X
Triplicate 12 Lead ECG10
X (single 
ECG only)
X
X
X
X
X
X
X
X
X
X
X

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Part B1 Combination Therapy
Treatment Period
Post Treatment
Cycle 
1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 
1 to 14)
Cycles 4
to 6
(Days 
1 to 14) 
Cycle 7
(Days 1 to 
14)
Subsequent 
Cycles
(Days 1 to 
14)32
End of 
Treatment 
(EOT)30
Follow Up 
(Days after EOT visit)31
Visit Identifier
Screen1
(≤28 days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14 days 28 to 
35 days
42 days56 days70 days 84 days 
Visit Window in Days
±1
±1 ±2 ±2 ±2 ±2
±2
±2
±2
Laboratory
Hematology11
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry12
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation13
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis14
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test15
X
X
X
X
X
X
X
X
Hepatitis B, C and HIV 
tests16
X
Cardiac enzymes17
X
X
X
X (Cycle 
5 only)
X
X (Cycle 
9 and every 
other cycle)
X
Registration and 
Treatment
Registration18
X
Utomilumab Treatment19
X
X
X (Cycle 
5 only)
X
Cycle 9 and 
every other 
cycle
PF-04518600 Treatment20
X
X
X
X
X
X
Tumor Assessments
CT or MRI scan or 
equivalent21
X
Every 6 weeks until confirmed progressive disease. Scans may be moved to every 
12 weeks after 24 weeks until confirmed progressive disease. 
Other samplings
 
 
 
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Part B1 Combination Therapy
Treatment Period
Post Treatment
Cycle 
1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 
1 to 14)
Cycles 4
to 6
(Days 
1 to 14) 
Cycle 7
(Days 1 to 
14)
Subsequent 
Cycles
(Days 1 to 
14)32
End of 
Treatment 
(EOT)30
Follow Up 
(Days after EOT visit)31
Visit Identifier
Screen1
(≤28 days)
Day 
1
Day 
2
Day 
8
Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14 days 28 to 
35 days
42 days56 days70 days 84 days 
Visit Window in Days
±1
±1 ±2 ±2 ±2 ±2
±2
±2
±2
Blood Samples for PK24
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
Blood Sample for 
Anti-Drug antibodies25
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
 
Other clinical 
assessments
Adverse Events27
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
and non-drug supportive 
interventions28
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA29
X
Every 3 months
X
Except for safety assessments, all other activities performed during Cycle 1 can be performed ±1 day, and for Cycle 2 onwards ±2 days. Safety assessments must 
be performed prior to dosing (see footnotes for details).  All cycles are relative to PF-04518600 administration.
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Footnotes 
1.
Screening: to be obtained within 28 days prior to treatment start.
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures. For Japan Part B1 only: after completion of 2 treatment cycles and 
prior to initiation of Cycle 3, a follow up consent must be obtained to confirm patient’s willingness to continue on study.
3.
Tumor History: will be collected within 28 days during screening 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.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete physical exams are not required.  
Refer to Section 7.1 Assessments for further details.
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.  During the study, any new or worsened conditions since baseline will be recorded on the Adverse Events (AE) case report form (CRF) page.
7.
Weight: Patient’s body weight will be measured prior to the preparation of investigational product (PF-04518600) and patient’s dose of PF-04518600 for 
that cycle will be based on the patient’s body weight (see Administration Section 5.4). 
8.
Vital signs: includes temperature (oral, tympanic, temporal or axillary), blood pressure (BP), and pulse rate to be recorded in the sitting position after 
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 the infusion. 
9.
Performance status: use Eastern Cooperative Oncology Group (ECOG) scale in Appendix 1.
10. Triplicate 12-leads electrocardiogram (ECG): Triplicate ECGs will be collected at times specified in the Schedule of Activities.  At each time point, at least a 
10 second strip, three consecutive 12-lead ECGs will be performed 1-5 minutes apart to determine mean QTcF interval.  The Screening ECG will be a 
single, 12-lead ECG.  ECGs on Day 1 of each Cycle will be collected prior to dosing, and at the end of infusion (approximately 1 hour) following 
administration of each dose of PF-04518600.  Additional ECGs will be collected on Cycle 1 Day 2 (C1D2), Cycle 1 Day 8 (C1D8), Cycle 2 Day 8 (C2D8), 
and Cycle 3 Day 8 (C3D8).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to 
blood sample collection, such that the blood sample is collected at the nominal time.  All ECGs will be reviewed by a centralized ECG vendor.  If the mean 
QTcF is prolonged (value of >500 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation.  Additional triplicate 
ECGs may be performed as clinically indicated.  Refer to Section 7.1.5 (12-Lead) ECG for further details. 
11. Hematology: complete blood count (CBC) to include hematocrit, hemoglobin, platelets, white blood cells (WBC), absolute neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed within 48 hours prior to dosing.  If screening 
assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments performed on 
Cycle 2 Day 1 (C2D1) and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments Section 7.1.3 for 
Laboratory Tests list.
12. Blood Chemistry: Tests for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk Phos), 
gamma-glutamyltransferase (GGT), sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, 
uric acid, glucose (non-fasted), albumin, phosphorous or phosphate, amylase, lipase and thyroid stimulating hormone (TSH) will be performed.  
Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed within 48 hours prior to dosing.  If screening assessments are performed within 
72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be 
performed within 48 hours prior to dosing.  If abnormalities are observed in TSH values, a T4 Thyroxine test will be performed.

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13. Coagulation Assays: prothrombin time (PT) and partial thromboplastin time (PTT).  Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed 
within 48 hours prior to dosing.  If screening assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  
Assessments performed on C1D2 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments 
Section 7.1.3 for laboratory tests list.
14. Urinalysis: Dipstick is acceptable.  Microscopic analyses required if dipstick abnormal.  If 2+ protein on urine dipstick, then collect 24 hr urine.  
Assessments conducted on C1D1 must be completed within 48 hours prior to dosing.  No need to repeat on C1D1 if screening assessment performed within 
7 days prior to that date.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See 
Assessments Section 7.1.3 for Laboratory Tests list.
15. Pregnancy Test (Serum/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 at C1D1, before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle prior to dosing 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.  Results will be obtained prior to initiating therapy at all times.  
Additional pregnancy tests may also be undertaken if requested by institutional review board (IRB)/institutional ethics committee (IEC)s or if required by 
local regulations.
16. Hepatitis B, C and HIV Tests: Conduct tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCV Ab) 
and human immunodeficiency virus (HIV) serology. History of human papilloma virus (HPV) will be recorded for HNSCC patients.
17. Cardiac enzymes: Troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) and N-terminal of the prohormone brain 
natriuretic peptide (NT-proBNP) will be evaluated in patients with previous history of anthracycline treatment.  Assessments must be performed prior to 
dosing.  No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 72 hours prior to that date.  Assessments performed on 
Cycle 3 Day 1 (C3D1) and Day 1 of each subsequent odd number cycles should be performed within 48 hours prior to dosing.  Assessments should also be 
performed when clinically indicated.  See Assessments Section 7.1.3 for Laboratory Tests list.
18. Registration: Patient number and dose level allocation provided by Pfizer Inc.  Treatment should begin no longer than four days from registration.
19. Utomilumab Treatment: utomilumab will be administered once every 28 days as an IV infusion over 60 minutes (-5 to +15 minutes) and should include the 
time needed to flush the infusion line.  Day 1 safety labs (blood chemistry, hematology, coagulation, and urinalysis) need to be reviewed by a physician prior 
to dosing at the beginning of each cycle. On cycles whereby both PF-04518600 and utomilumab are to be administered on the same day, PF-04518600 will 
be administered no sooner than 30 minutes after completion of the utomilumab infusion and after post- utomilumab and pre- PF-04518600 pharmacokinetic 
blood draws.  Furthermore, separate infusion bags and filters must be used for each investigational product.  Treatment with investigational product will 
continue until disease progression by irRECIST, patient refusal, unacceptable toxicity occurs, or the end of the study, whichever occurs first.
20. PF-04518600 Treatment: PF-04518600 will be administered once every 2 weeks as an IV infusion over 60 minutes (-5 to +15 minutes) and should include 
the time needed to flush the infusion line. Utomilumab will be administered first, and PF-04518600 will be administered no sooner than 30 minutes after
completion of utomilumab infusion and after post- utomilumab and pre- PF-04518600 pharmacokinetic blood draws. Day 1 safety labs (blood chemistry, 
hematology and urinalysis) need to be reviewed by a physician prior to dosing at the beginning of each cycle.  Treatment with investigational product will 
continue until disease progression by irRECIST, patient refusal, unacceptable toxicity occurs, or the end of the study, whichever occurs first.

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21. Tumor 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 scans and bone scans will be performed at baseline and on-study if disease is 
suspected or has been previously documented as appropriate to follow disease.  Baseline central nervous system (CNS) imaging is not required with the 
exception of symptomatic patients to rule out CNS metastases.  CT or MRI scans to be done every 6 weeks (±5 days) from the start of study treatment until 
confirmed disease progression by RECIST (1.1), irRECIST or death, or patient begins a different anti-cancer therapy. Scans may be moved to every 
12 weeks after 24 weeks until confirmed progressive disease.  Tumor assessments should be fixed according to the calendar, regardless of treatment delays.  
Confirmation of response (complete response (CR)/partial response (PR)) is not required.  CT or MRI scans should be completed before tumor biopsy 
samples are collected.
 
 
 
 
 
 
24. PK Sampling: Specific timing for collection of pharmacokinetic samples can be found in the pharmacokinetic and pharmacodynamic sampling schedule
table below. 
25. Anti-drug antibodies: Specific timing for collection of anti-PF-04518600 and anti-utomilumab antibody samples can be found in the Pharmacokinetic and 
Pharmacodynamic Sampling Schedule table below. 
 
27. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.03.  Patients must be followed for adverse events (AEs) for 60 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.  However, late immune-related DLTs that are not SAEs need to be collected consistent with Section 3.2.1.  For serious 
adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, 
which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure and/or receiving investigational product, 
through 98 calendar days from first administration of the investigational product, or up to 60 days after last administration of investigational product, 
whichever is later. 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 investigational product are to be reported to the sponsor.
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28. Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care 
drugs (eg, Anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions).
29. Echocardiogram or multigated acquisition (MUGA) scan: echocardiogram or MUGA will be evaluated in patients with previous history of anthracycline
treatment. For these patients, an echocardiogram or MUGA will be performed at screening and every 3 months whilst on treatment and when clinically 
indicated.  An echocardiogram or MUGA will be performed at the end of treatment (EOT) visit if not performed within 3 months of discontinuation.
30. End of treatment visit (EOT visit): Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments). 
31. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Late immune related adverse event information will be collected during the 28 to 
35 day follow up visit. 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. Independent to time of 
disease progression, all patients (unless patients are lost to follow up, consent is withdrawn, or study is discontinued by the sponsor) will be followed for 
survival for at least 2 years from the time of their first dose of investigational products. After the completion of end of treatment visits, Patients will be 
contacted every 2 months for survival status. To collect additional late immune related adverse event information, any patient who discontinue from 
treatment after 1 to 4 or 6 cycles of treatment will also be contacted by phone during the follow up period.  For patients who discontinues after receiving 
5 cycles of treatment, late immune information will be collected during the 28 to 35 day follow up visit.  If the patient discontinues after receiving 6 cycles 
of treatment, they will be contacted by phone 14 days (2 days) after EOT.  If the patient discontinues after receiving 4 cycles of treatment, they will be 
contacted by phone 42 days (2 days) after EOT.  If the patient discontinues after receiving 3 cycles of treatment, they will be contacted by phone 56 days 
(2 days) after EOT. If the patient discontinues after receiving 2 cycles of treatment, they will be contacted by phone 70 days (2 days) after EOT. If the 
patient discontinues after receiving 1 cycle of treatment, they will be contacted by phone 84 days (2 days) after EOT. If any concern arises, patient will be 
called in for an inpatient follow up visit within 5 calendar days of initial phone call (assessments will be the same as the assessments performed 28-35 days 
after end of treatment follow up visit).
32. Subsequent cycles: Day 8 is not required after Cycle 3. 

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SCHEDULE OF ACTIVITIES: Part A2 Monotherapy and B2 Combination Therapy
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS Section 7 of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Part A2 Monotherapy 
& B2 Combination 
Therapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit 
Identifier
Screen1
(28
days)
Day 1 Day 8 Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
1
2
2
2
2
2
2
2
Informed 
Consent2
X
Tumor History3
X
Medical History4
X
Complete 
Physical 
Examination
X
X
X
X
Abbreviated 
Physical 
Examination5
X
X
X
X
X
X
X
X
Baseline Signs 
and Symptoms6
X
Height
X
Weight7
X
X
X
X
Vital signs 
(BP/PR/Temp)8
X
X
X
X
X
X
X
X
X
X
X
X

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Part A2 Monotherapy 
& B2 Combination 
Therapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit 
Identifier
Screen1
(28
days)
Day 1 Day 8 Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
1
2
2
2
2
2
2
2
Eastern 
cooperative 
oncology group 
(ECOG) 
Performance 
Status9
X
X
X
X
X
X
X
X
X
Triplicate 
12 Lead ECG10
X (single 
ECG 
only)
X
X
X
X
X
X
X
X
X
X
Laboratory
Hematology11
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry 
12
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation13
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis14
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test15
X
X
X
X
X
X
X
X
Hepatitis B, C, 
D and HIV 
tests16
X
Hepatitis B or C 
viral load tests 
(Part A2 HCV/ 
HBV+ only)16
X
X
X (every 
3 months)
X
Cardiac enzymes 
17
X
X
X
X (Cycle 
5 only)
X
X (Cycle 
9 and every 
other cycle)
X

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Part A2 Monotherapy 
& B2 Combination 
Therapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit 
Identifier
Screen1
(≤28
days)
Day 1 Day 8 Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
±1
±2
±2
±2
±2
±2
±2
±2
Alpha 
Fetoprotein 
(A2 only)
X
Every 8 weeks for 48 weeks and then every 12 weeks, until 
confirmed progressive disease
Registration 
and Treatment
Registration18
X
PF-04518600 Tr
eatment19
X
X
X
X
X
X
Utomilumab 
Treatment 
(B2 Only)20
X
X
X (Cycle 
5 only)
X
Cycle 9 and 
every other 
cycle
Tumor 
Assessments
CT or MRI scan 
or equivalent21
X
Every 8 weeks for 24 weeks and then every 12 weeks, until confirmed progressive 
disease
Other 
samplings
 
 
 
Blood Samples 
for PK23
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
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Part A2 Monotherapy 
& B2 Combination 
Therapy
Treatment Period
Post Treatment
Cycle 1 Only
(Days 1 to 
14)
Cycle 2
(Days 
1 to 14)
Cycle 3
(Days 1 to 
14)
Cycles 4
to 6
(Days 1 to 
14) 
Cycle 7
(Days 
1 to 14)
Subsequent 
Cycles
(Days 1 to 
14)31
End of 
Treatment 
(EOT)29
Follow Up 
(Days after EOT visit)30
Visit 
Identifier
Screen1
(≤28
days)
Day 1 Day 8 Day 
1
Day 
8
Day 
1
Day 
8
Day 1
Day 1
Day 1
14
days
28 to 
35
days
42
days
56
days
70
days 
84 days 
Visit Window 
in Days
±1
±2
±2
±2
±2
±2
±2
±2
Blood Sample 
for Anti-drug 
Antibodies24
See Pharmacokinetic and Pharmacodynamic Sampling Schedule Table below.
 
Other clinical 
assessments
Adverse 
Events26
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medication and 
non-drug 
supportive 
interventions27
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
or MUGA28
X
Every 3 months
X
Except for safety assessments, all other activities performed during Cycle 1 can be performed ±1 day, and for Cycle 2 onwards ±2 days. Safety assessments must 
be performed prior to dosing (see footnotes for details). 
Footnotes 
1.
Screening: to be obtained 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 during screening prior to treatment start.  Includes history of disease under study including details of 
primary diagnosis and treatment history. 
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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.
Abbreviated Physical Examination (PE): Abbreviated PEs should be performed as appropriate at each visit where complete physical exams are not required.  
Refer to Section 7.1 Assessments for further details.
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.  During the study, any new or worsened conditions since baseline will be recorded on the Adverse Events (AE) case report form (CRF) page.
7.
Weight. Patient’s body weight is not needed prior to the preparation of investigational product.
8.
Vital signs: includes temperature (oral, tympanic, temporal or axillary), blood pressure (BP), and pulse rate to be recorded in the sitting position after 
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 the infusion. 
9.
Performance status: use Eastern Cooperative Oncology Group (ECOG) scale in Appendix 1.
10. Triplicate 12-leads electrocardiogram (ECG): Triplicate ECGs will be collected at times specified in the Schedule of Activities.  At each time point, at least a 
10 second strip, three consecutive 12-lead ECGs will be performed 1 to 5 minutes apart to determine mean QTcF interval.  The Screening ECG will be a 
single, 12 lead ECG.  ECGs on Day 1 of each Cycle will be collected prior to dosing, and at the end of infusion (approximately 1 hour) following 
administration of each dose of PF-04518600.  Additional ECGs will be collected on Cycle 1 Day 8 (C1D8), Cycle 2 Day 8 (C2D8), and 
Cycle 3 Day 8 (C3D8).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should preferably be performed prior to 
blood sample collection, such that the blood sample is collected at the nominal time.  All ECGs will be reviewed by a centralized ECG vendor.  If the mean 
QTcF is prolonged (value of >500 msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation.  Additional triplicate 
ECGs may be performed as clinically indicated.  Refer to Section 7.1.5 (12-Lead) ECG for further details.
11. Hematology: complete blood count (CBC) to include hematocrit, hemoglobin, platelets, white blood cells (WBC), absolute neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils. Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed within 48 hours prior to dosing.  If screening 
assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments performed on 
Cycle 2 Day 1 (C2D1) and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments Section 7.1.3 for 
Laboratory Tests list.
12. Blood Chemistry: Tests for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk Phos), 
gamma-glutamyltransferase (GGT), sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, 
uric acid, glucose (non-fasted), albumin, phosphorous or phosphate, amylase, lipase and thyroid stimulating hormone (TSH) will be performed. 
Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed within 48 hours prior to dosing.  If screening assessments are performed within 
72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be 
performed within 48 hours prior to dosing.  If abnormalities are observed in TSH values, a T4 thyroxine test will be performed.  See Assessments 
Section 7.1.3 for laboratory tests list.
13. Coagulation Assays: prothrombin time (PT) and partial thromboplastin time (PTT).  Assessments conducted on Cycle 1 Day 1 (C1D1) must be completed 
within 48 hours prior to dosing.  If screening assessments are performed within 72 hours prior to C1D1, there is no need to repeat assessments on C1D1.  
Assessments performed on C1D2 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See Assessments 
Section 7.1.3 for laboratory tests list.
14. Urinalysis: Dipstick is acceptable. Microscopic analyses required if dipstick abnormal.  If 2+ protein on urine dipstick, then collect 24 hr urine.  
Assessments conducted on C1D1 must be completed within 48 hours prior to dosing.  No need to repeat on C1D1 if screening assessment performed within 
7 days prior to that date.  Assessments performed on C2D1 and Day 1 of each subsequent cycle should be performed within 48 hours prior to dosing.  See 
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15. Pregnancy Test (Serum/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 at C1D1, before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle prior to dosing 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.  Results will be obtained prior to initiating therapy at all times.  
Additional pregnancy tests may also be undertaken if requested by institutional review board (IRB)/institutional ethics committee (IEC)s or if required by 
local regulations.
16. Hepatitis B, C and HIV Tests: Conduct tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCV Ab) 
and human immunodeficiency virus (HIV) serology at screening. All Part A2 HCC patients with detectable viral load for hepatitis B at screening must also 
be tested for hepatitis D by antibody (HDV Ab) or polymerase chain reaction (PCR).  All Part A2 HCC patients with detectable viral load for HCV or HBV
at screening, must be retested every 3 months (ie, Cycle 7 Day 1, Cycle 13 Day 1, Cycle 19 Day 1, etc) and at the EOT visit.
17. Cardiac enzymes: Troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) and N-terminal of the prohormone brain 
natriuretic peptide (NT-proBNP) will be evaluated in patients with previous history of anthracycline treatment.  Assessments must be performed prior to 
dosing.  No need to repeat on Cycle 1 Day 1 (C1D1) if screening assessment performed within 72 hours prior to that date.  Assessments performed on 
Cycle 3 Day 1 (C3D1) and Day 1 of each subsequent odd number cycles should be performed within 48 hours prior to dosing.  Assessments should also be 
performed when clinically indicated.  See Assessments Section 7.1.3 for Laboratory Tests list.
18. Registration: Patient number and dose level allocation provided by Pfizer Inc.  Treatment should begin no longer than four days from registration.
19. PF-04518600 Treatment: PF-04518600 will be administered once every 2 weeks as an IV infusion over 60 minutes (-5 to +15 minutes) and should include 
the time needed to flush the infusion line.  Day 1 safety labs (blood chemistry, hematology, and urinalysis) need to be reviewed by a physician prior to 
dosing at the beginning of each cycle. Treatment with investigational product will continue until disease progression by irRECIST, patient refusal, 
unacceptable toxicity occurs, or the end of the study, whichever occurs first.
20. Utomilumab Treatment: utomilumab will be administered once every 28 days as an IV infusion over 60 minutes (-5 to +15 minutes) and should include the 
time needed to flush the infusion line.  Day 1 safety labs (blood chemistry, hematology, coagulation, and urinalysis) need to be reviewed by a physician prior 
to dosing at the beginning of each cycle.  On cycles whereby both PF-04518600 and utomilumab are to be administered on the same day, PF-04518600 will 
be administered no sooner than 30 minutes after completion of the utomilumab infusion and after post-utomilumab and pre- PF-04518600 pharmacokinetic 
blood draws.  Furthermore, separate infusion bags and filters must be used for each investigational product.  Treatment with investigational product will 
continue until disease progression by irRECIST, patient refusal, unacceptable toxicity occurs, the or end of the study, whichever occurs first.
 
 
 
 
  
 
 
 
 
 
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23. PK Sampling: Specific timing for collection of pharmacokinetic samples can be found in the pharmacokinetic and pharmacodynamic sampling schedule
table below. 
24. Anti-drug Antibodies: Specific timing for collection of anti-drug antibody samples can be found in the Pharmacokinetic and Pharmacodynamic Sampling 
Schedule table below. 
 
26. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTC AE) version 4.03.  Patients must be followed for adverse events (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.  However, late immune-related DLTs that are not SAEs need to be collected consistent with Section 3.2.1.  For serious 
adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, 
which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure and/or receiving investigational product, 
through 98 calendar days from first administration of the investigational product, or up to 60 days after last administration of investigational product, 
whichever is later.  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 investigational product are to be reported to the sponsor.
27. Concomitant Medications and Non Drug Supportive Interventions: all concomitant medications should be recorded in the CRF including supportive care 
drugs (eg, Anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions).
28. Echocardiogram or multigated acquisition (MUGA) scan: echocardiogram or MUGA will be evaluated in patients with previous history of anthracycline
treatment.  For these patients, an echocardiogram or MUGA will be performed at screening and every 3 months whilst on treatment and when clinically 
indicated.  An echocardiogram or MUGA will be performed at the end of treatment (EOT) visit if not performed within 3 months of discontinuation.
29. End of treatment visit (EOT visit): Obtain these assessments if not completed in the last week (last 8 weeks for tumor assessments). 
30. 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, 
vital signs, and assessment for resolution of any treatment related toxicity.  Late immune related adverse event information will be collected during the 28 to 
35 day follow up visit. 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.  Independent to time of 
disease progression, all patients (unless patients are lost to follow up, consent is withdrawn, or study is discontinued by the sponsor) will be followed for 
survival for at least 2 years from the time of their first dose of investigational product.  After the completion of end of treatment visits, Patients will be 
contacted every 2 months for survival status and subsequent anti-cancer treatment.  Subsequent anti-cancer therapy will be documented and recorded for 
patients who discontinue investigational products and continue in follow up, and during survival follow up.  To collect additional late immune related 
adverse event information, any patient who discontinues from treatment after 1 to 4 or 6 cycles of treatment will also be contacted by phone during the 
follow up period.  For patients who discontinues after receiving 5 cycles of treatment, late immune information will be collected during the 28 to 35 day 
follow up visit.  If the patient discontinues after receiving 6 cycles of treatment, they will be contacted by phone 14 days (±2 days) after EOT.  If the patient 
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discontinues after receiving 4 cycles of treatment, they will be contacted by phone 42 days (2 days) after EOT.  If the patient discontinues after receiving 
3 cycles of treatment, they will be contacted by phone 56 days (2 days) after EOT. If the patient discontinues after receiving 2 cycles of treatment, they 
will be contacted by phone 70 days (2 days) after EOT. If the patient discontinues after receiving 1 cycle of treatment, they will be contacted by phone 
84 days (2 days) after EOT. If any concern arises, patient will be called in for an inpatient follow up visit within 5 calendar days of initial phone call 
(assessments will be the same as the assessments performed 28-35 days after end of treatment follow up visit).
31. Subsequent cycles: Day 8 is not required after Cycle 3. 

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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part A1 Monotherapy
Part A1 Monotherapy
Cycle 1
(Days 1 to 14)
Cycle 2 and 3
(Days 1 to 14)
Cycle 4
(Days 1 to 
14)
Cycles 5 and 
6
(Days 1 to 
14)
Cycle 7
(Days 1 to 
14)
Every Other 
Cycle  
Thereafter
End of 
Treatment
Visit Identifier
Day 1
Day 8
Day 1
Day 8
Day 1
Day 1
Day 1
Day 1
Pre-
dose* 1 hr* 4 hr* 24 hr*
Pre-
dose* 1 hr* 4 hr*
Pre-
dose* 1 hr*
Pre-
dose
1 hr
Pre-dose
Pre-dose*
Visit Window in Days
±1
±2
±2
±2
±2
±2
±2
Blood PK sample for 
PF-04518600
X
X
X
X
X
X
X
X 
(Cycle 
3 only)
X
X
X
X
X
X
X3
X3
Blood sample for 
anti-PF-04518600-
antibodies1
X
X
X
X
(Cycle 
5 only)
X
X
X
 
 
 
 
 
 
 
 
*Sampling times are related to the start of infusion; 1 hr samples should be collected immediately before the infusion ends.  All sample time windows, 
except 1 hr samples will be ±10% of nominal time.  Therefore, a 4 hr sample will have a ±24 minutes collection window.  Similarly, a Day 4 sample will 
have a ±9.6 hrs collection window.
1.
Blood sample for anti-PF-04518600-antibodies and NAb: Samples for anti-PF-04518600-antibodies and NAb will be collected pre-dose on Day 1 of 
Cycle 1 to 5, 7 and every other cycle after ie, Cycle 9, 11, 13, 15 etc. and again at end of treatment visit.  Patients having an unresolved adverse event that is 
possibly related to ADA formation will be asked to return 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 concurs with that the investigator’s assessment, up to 
6 months from the EOT or the day of early withdrawal (see Section 3.1 Study Overview).
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3.
Companion blood sample for the determination of drug concentration will be collected in conjunction with the ADA sample collection to facilitate ADA 
assessment.
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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part B1 Combination Therapy
Part 
B1 Combination 
Therapy
Cycle 1
(Days 1 to 14)
Cycle 2
(Days 1 to 14)
Cycle 3
(Days 1 to 14)
Cycle 4
(Days 1 to 
14)
Cycle 5
(Days 1 to 
14)
Cycle 6
(Days 1 to 
14)
Cycle 7
(Days 
1 to 14)
Every 
Other 
Cycle  
There-af
ter
EOT
Visit Identifier
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 1
Day 1
Day 1
Day 1
Pre-
dose*
1 hr* 4 hr* 24 (±4) 
hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*
1 hr*
Pre-dose*
Pre-dose*
Visit Window in 
Days
±1
±2
±2
±2
±2
±2
±2
±2
±2
±2
Blood PK sample for 
PF-04518600
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
X3
Blood sample for 
anti-PF-04518600-
antibodies1
X
X
X
X
X
X
X
X
Blood PK sample for 
utomilumab
X
X
X
X
X
X4
X
X
X
X4
X
X
X
X3
X3
Blood sample for 
anti-utomilumab
antibodies2
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
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*Sampling times are related to the start of infusion of the corresponding investigational product; 1 hr samples should be collected immediately before 
the infusion of the corresponding investigational product ends. Each cycle is 2 weeks and is relative to PF-04518600 dosing.
1.
Blood sample for anti-PF-04518600-antibodies and NAb: Samples for anti-PF-04518600-antibodies and NAb will be collected pre-dose on Day 1 of 
Cycle 1 to 5, 7 and every other cycle after ie, Cycle 9, 11, 13, 15 etc. and again at end of treatment visit.  Patients having an unresolved adverse event that is 
possibly related to ADA formation will be asked to return 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 concurs with that the investigator’s assessment, up to 
6 months from the EOT or the day of early withdrawal (see Section 3.1 Study Overview).
2.
Blood sample for anti-utomilumab-antibodies and NAb: Samples for anti-utomilumab-antibodies and NAb will be collected pre-dose on Day 1 of Cycle 1, 3,
5, 7 and every other cycle after ie, Cycle 9, 11, 13, 15 etc. and again at end of treatment visit.  Patients having an unresolved adverse event that is possibly 
related to ADA formation will be asked to return 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 concurs with that the investigator’s assessment, up to 6 months from 
the EOT or the day of early withdrawal (see Section 3.1 Study Overview).
3.
Companion blood sample for the determination of drug concentration will be collected in conjunction with the ADA sample collection to facilitate ADA 
assessment.
 
 
 
 
 
 
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Pharmacokinetic and Pharmacodynamic Sampling Schedule for Part A2 and B2 Combination Therapy
Part 
A2 Monotherapy & 
B2 Combination 
Therapy
Cycle 1
(Days 1 to 14)
Cycle 2
(Days 1 to 14)
Cycle 3
(Days 1 to 14)
Cycle 4
(Days 1 to 
14)
Cycle 5
(Days 1 to 
14)
Cycle 6
(Days 1 to 
14)
Cycle 7
(Days 
1 to 14)
Every 
Other 
Cycle 
There-af
ter
EOT
Visit Identifier
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 1
Day 1
Day 1
Day 1
Pre-
dose*
1 hr*
4 hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*
1 hr*
Pre-dose*
Pre-dose*
Visit Window in 
Days
±1
±2
±2
±2
±2
±2
±2
±2
±2
±2
Assessments for Both A2 and B2
Blood PK sample for 
PF-04518600
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X5
X5
Blood sample for 
anti-PF-04518600-
antibodies1
X
X
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
Assessments for Part B2 only
Blood PK sample for 
utomilumab
X
X
X
X
X6
X
X
X
X6
X
X
X
X5
X5
Blood sample for 
anti-utomilumab 
antibodies2
X
X
X
X
X
X
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Part 
A2 Monotherapy & 
B2 Combination 
Therapy
Cycle 1
(Days 1 to 14)
Cycle 2
(Days 1 to 14)
Cycle 3
(Days 1 to 14)
Cycle 4
(Days 1 to 
14)
Cycle 5
(Days 1 to 
14)
Cycle 6
(Days 1 to 
14)
Cycle 7
(Days 
1 to 14)
Every 
Other 
Cycle 
There-af
ter
EOT
Visit Identifier
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 1
Day 1
Day 1
Day 1
Pre-
dose*
1 hr*
4 hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*,3
1 hr*, 
Pre-
dose*
1 hr*
Pre-
dose*
1 hr*
Pre-dose*
Pre-dose*
Visit Window in 
Days
±1
±2
±2
±2
±2
±2
±2
±2
±2
±2
Serum sample for 
soluble 4-1BB 
(s4-1BB)8
X
X
X
X
X
X
X
X
X
X
*Sampling times are related to the start of infusion of the corresponding investigational product; 1 hr samples should be collected immediately before 
the infusion of the corresponding investigational product ends.  Each cycle is 2 weeks and is relative to PF-04518600 dosing.
1.
Blood sample for anti-PF-04518600-antibodies and NAb: Samples for anti-PF-04518600-antibodies and NAb will be collected pre-dose on Day 1 of 
Cycle 1 to 5, 7 and every other cycle after ie, Cycle 9, 11, 13, 15 etc. and again at end of treatment visit.  Patients having an unresolved adverse event that is 
possibly related to ADA formation will be asked to return 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 concurs with that the investigator’s assessment, up to 
6 months from the EOT or the day of early withdrawal (see Section 3.1 Study Overview).
2.
Blood sample for anti-utomilumab-antibodies and NAb (Part-B2 only): Samples for anti-utomilumab-antibodies and NAb will be collected pre-dose on 
Day 1 of Cycle 1, 3, 5, 7 and every other cycle after ie, Cycle 9, 11, 13, 15 etc. and again at termination visit.  Patients having an unresolved adverse event 
that is possibly related to ADA formation will be asked to return 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 concurs with that the investigator’s assessment, up 
to 6 months from the EOT or the day of early withdrawal (see Section 3.1 Study Overview).
 
 
 
6.
During Cycles 2 and 4 when utomilumab will not be infused, PK and pharmacodynamic samples for utomilumab/4-1BB will be collected within 1 hour 
before start of PF-04518600 infusion (Part B2 only). 
 
 
8.
Sampling of sOX40 and s4-1BB (Part B2 only) will be relative to the infusion of PF-04518600 on cycles whereby PF-04518600 is administered alone, or to 
utomilumab on cycles whereby PF-04518600 is administered in combination with utomilumab.
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TABLE OF CONTENTS
PROTOCOL SUMMARY.......................................................................................................31
LIST OF TABLES...................................................................................................................78
LIST OF FIGURES .................................................................................................................79
APPENDICES .........................................................................................................................79
1. INTRODUCTION ...............................................................................................................80
1.1. Mechanism of Action/Indication.............................................................................80
1.2. Background and Study Rationale............................................................................80
1.2.1. OX40 (CD134) ...........................................................................................80
1.2.1.3. PF-04518600 Clinical Safety ....................................................85
1.2.1.4. PF-04518600 Clinical Efficacy.................................................85
1.2.1.6. PF-04518600 Clinical Anti-Drug Antibodies ...........................86
1.2.1.7. PF-04518600 Clinical Pharmacodynamics ...............................86
1.2.2. 4-1BB (CD137) ..........................................................................................87
1.2.2.1. Utomilumab Clinical Efficacy ..................................................88
1.2.2.2. Utomilumab Clinical Safety......................................................89
1.2.2.4. Utomilumab Immunogenicity ...................................................91
1.2.4. Clinical Combination of PF 04518600 and Utomilumab...........................94
1.2.5. Tumor Type Rationale................................................................................95
1.2.5.1. Melanoma..................................................................................96
1.2.5.2. Head and Neck Squamous Cell Carcinoma (HNSCC) .............97
1.2.5.3. Hepatocellular Carcinoma (HCC).............................................97
1.2.5.4. Renal Cell Carcinoma (RCC)....................................................98
1.2.5.5. Bladder Cancer..........................................................................98
1.2.5.6. Cervical Cancer.........................................................................99
1.2.5.7. Gastric Adenocarcinoma...........................................................99
1.2.5.8. Non-Small Cell Lung Cancer (NSCLC) .................................100
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1.2.5.9. Selection of Tumor Types for Combination Studies Using 
The Cancer Genome Atlas (TCGA)................................................101
1.2.5.10. Summary of Benefit Risk Assessment..................................102
1.3. Starting Dose Rationale.........................................................................................102
1.3.1. Monotherapy Starting Dose Rationale......................................................102
1.3.2. Combination Starting Dose Rationale ......................................................103
1.3.2.1. PF-04518600...........................................................................103
1.3.2.2. Utomilumab.............................................................................103
1.4. Rationale for Flat Dosing in Part A2 and Part B2.................................................103
1.5. Rationale for Pre-Treatment and On-Treatment Biopsies.....................................104
1.6. Biomarker Rationale .............................................................................................105
2. STUDY OBJECTIVES AND ENDPOINTS.....................................................................106
2.1. Objectives..............................................................................................................106
2.1.1. Objectives for Part A Monotherapy..........................................................106
2.1.1.1. Objectives for Part A1 Monotherapy Dose Escalation ...........106
2.1.1.2. Objectives for Part A2 Monotherapy Dose Expansion ...........107
2.1.2. Objectives for Part B Combination Therapy ............................................108
2.1.2.1. Objectives for Part B1 Combination Therapy Dose 
Escalation ........................................................................................108
2.1.2.2. Objectives for Part B2 Combination Therapy Dose 
Expansion ........................................................................................109
2.2. Endpoints...............................................................................................................110
2.2.1. Endpoints for Part A Monotherapy...........................................................110
2.2.1.1. Endpoints for Part A1 Monotherapy Dose Escalation ............110
2.2.1.2. Endpoints for Part A2 Monotherapy Dose Expansion............111
2.2.2. Endpoints for Part B Combination Therapy.............................................112
2.2.2.1. Endpoints for Part B1 Combination Therapy Dose 
Escalation ........................................................................................112
2.2.2.2. Endpoints for Part B2 Combination Therapy Dose 
Expansion ........................................................................................113
3. STUDY DESIGN...............................................................................................................114
3.1. Study Overview.....................................................................................................114
3.1.1. Part A Monotherapy .................................................................................115
3.1.1.1. Part A1 Dose Escalation..........................................................115

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3.1.1.2. Part A2 Dose Expansion .........................................................117
117
3.1.2. Part B Combination Therapy....................................................................118
3.1.2.1. Part B1 Dose Escalation..........................................................118
3.1.2.2. Part B2 Dose Expansion..........................................................120
3.1.2.3. Japan participation in Part B Combination Therapy ...............121
3.1.3. Enrollment Prioritization ..........................................................................121
3.1.3.1. Dose Escalation Phase.............................................................121
3.1.4. Starting Dose ............................................................................................122
3.1.5. Criteria for Dose Escalation......................................................................122
3.1.5.1. Part A Monotherapy................................................................122
3.1.5.2. Part B Combination Therapy...................................................124
3.2. DLT Definition......................................................................................................124
3.2.1. Late Immune Related DLTs .....................................................................125
3.3. Maximum Tolerated Dose (MTD) Definition.......................................................126
3.4. Optimal Biological Dose (OBD) Definitions........................................................126
3.5. Maximum Administered Dose (MAD) .................................................................126
3.6. Recommended Phase 2 Dose (RP2D) Definition .................................................127
4. PATIENT SELECTION....................................................................................................127
4.1. Inclusion Criteria...................................................................................................127
4.1.1. Part A Monotherapy .................................................................................127
4.1.2. Part B Combination Therapy....................................................................129
4.2. Exclusion Criteria..................................................................................................131
4.2.1. Part A Monotherapy .................................................................................131
4.2.2. Part B Combination Therapy....................................................................133
4.3. Lifestyle Guidelines ..............................................................................................135
4.4. Sponsor’s Qualified Medical Personnel................................................................136
5. STUDY TREATMENTS...................................................................................................137
5.1. Allocation to Treatment ........................................................................................137
5.2. Patient Compliance ...............................................................................................138
5.3. Investigational Product Supplies...........................................................................138
5.3.1. Dosage Forms and Packaging...................................................................138
5.3.1.1. PF-04518600...........................................................................138
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5.3.1.2. Utomilumab.............................................................................138
5.3.2. Preparation and Dispensing......................................................................138
5.4. Administration.......................................................................................................139
5.4.1. Part A1 Monotherapy ...............................................................................139
5.4.2. Part A2 Monotherapy ...............................................................................139
5.4.3. Part B1 Combination Therapy..................................................................140
5.4.4. Part B2 Combination Therapy..................................................................140
5.4.5. Recommended Dose Modifications..........................................................141
5.4.5.1. Infusion Reactions...................................................................141
5.4.5.2. Hypersensitivity Types 1 and 3...............................................142
5.4.5.3. Extravasation...........................................................................142
5.4.5.4. Immune-Related Adverse Events (irAEs)...............................142
5.4.5.5. Dose Delay ..............................................................................146
5.4.5.6. Dose Reductions, Interruptions and Discontinuation 
Criteria.............................................................................................147
5.4.6. Treatment after Initial Evidence of Radiological Disease Progression....151
5.5. Drug Storage .........................................................................................................152
5.6. Drug Accountability..............................................................................................152
5.6.1. Destruction of Investigational Product Supplies ......................................153
5.7. Concomitant Treatment(s).....................................................................................153
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs.............................153
5.7.2. Supportive Care ........................................................................................153
5.7.3. Hematopoietic Growth Factors.................................................................153
5.7.4. Anti Diarrhea, Anti Emetic Therapy ........................................................154
5.7.5. Anti-inflammatory Therapy......................................................................154
5.7.6. Corticosteroids..........................................................................................154
5.7.7. Surgery......................................................................................................154
5.7.8. Anticoagulation.........................................................................................154
5.7.9. Radiotherapy.............................................................................................154
6. STUDY PROCEDURES ...................................................................................................155
6.1. Screening...............................................................................................................155
6.2. Study Period ..........................................................................................................155
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6.3.1. Follow-Up for Late Immune-Related Events ...........................................156
6.4. Patient Withdrawal................................................................................................156
7. ASSESSMENTS................................................................................................................158
7.1. Safety Assessment.................................................................................................158
7.1.1. Pregnancy Testing ....................................................................................158
7.1.2. Adverse Events.........................................................................................158
7.1.3. Laboratory Safety Assessment .................................................................158
7.1.4. Vital Signs and Physical Examination......................................................160
7.1.5. (12-Lead) Electrocardiogram....................................................................160
7.1.6. Echocardiogram or Multigated Acquisition (MUGA) Scan.....................161
7.2. Pharmacokinetics Assessments.............................................................................162
7.2.1. Blood for PK Analysis of PF-04518600 and Utomilumab.......................162
7.4. Tumor Response Assessments ..............................................................................164
7.6. Immunogenicity Evaluations.................................................................................166
8. ADVERSE EVENT REPORTING....................................................................................167
8.1. Adverse Events......................................................................................................167
8.2. Reporting Period ...................................................................................................167
8.3. Definition of an Adverse Event.............................................................................168
8.4. Medication Errors..................................................................................................169
8.5. Abnormal Test Findings........................................................................................169
8.6. Serious Adverse Events.........................................................................................170
8.6.1. Protocol Specified Serious Adverse Events .............................................170
8.6.2. Potential Cases of Drug Induced Liver Injury..........................................170
8.7. Hospitalization ......................................................................................................171
8.8. Severity Assessment..............................................................................................173
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8.9. Causality Assessment............................................................................................173
8.10. Exposure During Pregnancy................................................................................173
8.11. Occupational Exposure .......................................................................................175
8.12. Withdrawal Due to Adverse Events (See also Section 6.4 Patient 
Withdrawal).............................................................................................................175
8.13. Eliciting Adverse Event Information ..................................................................175
8.14. Reporting Requirements......................................................................................175
8.14.1. Serious Adverse Event Reporting Requirements ...................................175
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................176
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities .................176
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................176
9.1. Analysis Sets .........................................................................................................176
9.2. Statistical Methods and Properties ........................................................................177
9.2.1. Statistical Methods for Dose Escalation/De-Escalation ...........................177
9.2.1.1. Part A Monotherapy................................................................177
9.2.1.2. Part B Combination Therapy...................................................178
9.2.2. Statistical Method for Estimating the MTD .............................................178
9.2.2.1. Part A Monotherapy................................................................178
9.2.2.2. Part B Combination Therapy...................................................178
9.3. Sample Size Determination...................................................................................178
9.3.1. Part A Monotherapy .................................................................................178
9.3.2. Part B Combination Therapy....................................................................179
9.4. Efficacy Analysis ..................................................................................................180
9.5. Analysis of Pharmacokinetics ...............................................................................180
9.5.1. PF-04518600 and Utomilumab PK Analysis ...........................................180
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetics 
(PK)/Pharmacodynamic Modeling ................................................................180
9.5.3. Immunogenicity........................................................................................181
9.5.4. Statistical Analysis of Biomarker Endpoint .............................................181
9.6. Safety Analysis......................................................................................................181
9.6.1. Analysis of Primary Endpoint ..................................................................181
9.6.2. Analysis of Secondary Endpoints.............................................................182
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9.6.2.2. Laboratory Tests Abnormalities..............................................182
9.6.3. ECG ..........................................................................................................182
9.7. Analysis of Anti-drug Antibody (ADA) for PF-04518600 and Utomilumab.......183
9.9. Interim Analysis ....................................................................................................183
9.10. Data Safety Monitoring Committee....................................................................183
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................184
10.1. GCP Training ......................................................................................................184
11. DATA HANDLING AND RECORD KEEPING ...........................................................184
11.1. Case Report Forms/Electronic Data Record .......................................................184
11.2. Record Retention.................................................................................................185
12. ETHICS............................................................................................................................185
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................185
12.2. Ethical Conduct of the Study ..............................................................................186
12.3. Patient Information and Consent.........................................................................186
12.4. Patient Recruitment.............................................................................................186
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................187
13. DEFINITION OF END OF TRIAL.................................................................................187
13.1. End of Trial in a Member State...........................................................................187
13.2. End of Trial in All Other Participating Countries...............................................187
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................187
15. PUBLICATION OF STUDY RESULTS........................................................................187
15.1. Communication of Results by Pfizer ..................................................................187
15.2. Publications by Investigators ..............................................................................188
16. REFERENCES ................................................................................................................190
LIST OF TABLES
 
Table 2.
Table of Potential Dose Levels...........................................................................122
Table 3.
Decision Rules....................................................................................................123
Table 4.
Management of Immune-Related Adverse Events (irAEs)................................143
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Table 5.
Dose Modification for Drug Related Toxicity at Start of Subsequent Cycle 
in Part A..............................................................................................................148
Table 6.
Treatment Interruptions/ Discontinuations for Drug Related Toxicity at 
Start of Subsequent Cycle...................................................................................149
Table 7.
90% Confidence Intervals of Overall Response Rate.........................................179
Table 8.
Objective Response Status at Each Evaluation ..................................................209
Table 9.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................210
Table 10.
Overall Responses derived from Changes in Index, Non-index, and New 
Lesions................................................................................................................212
LIST OF FIGURES
 
 
 
 
Figure 4.
Study Schematic .................................................................................................114
Figure 5.
Dose Escalation Scheme based on the Proposed Doses for PF-04518600 
and Utomilumab .................................................................................................119
APPENDICES
Appendix 1. ECOG Performance Status................................................................................201
Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................202
Appendix 3. Child-Pugh Score ..............................................................................................203
Appendix 4. Management of Infusion Related Reactions Including Allergic Reactions, 
Cytokine Release Syndrome or Anaphylaxis .....................................................204
Appendix 5. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines.....................................................................................................206
Appendix 6. Immune-related Response Criteria Derived From RECIST 
v1.1 (irRECIST) .................................................................................................211
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-04518600 is a fully human IgG2 monoclonal antibody (mAb) specific for human 
OX40 (CD134).  OX40 is a member of the tumor-necrosis factor receptor (TNFR) 
superfamily that is expressed primarily on activated T cells.2,3 By acting as a co-stimulatory 
receptor, OX40 plays a key role in the regulation of antigen-specific T-cell expansion, 
differentiation and function.  Mechanistically, PF-04518600 has been shown to costimulate 
OX40, thereby inducing a T cell mediated anti-tumor response in vivo.  In this clinical study, 
PF-04518600 as a monotherapy (Part A), and PF-04518600 in combination with utomilumab
(Part B) will be evaluated for the treatment of adult patients with select locally advanced or 
metastatic cancers who are unresponsive to current available therapies, or for whom no 
standard therapy is available.
1.2. Background and Study Rationale
Additional pre-clinical and clinical information for PF-04518600 may be found in the single 
reference safety document (SRSD), which for this study is the Investigator’s Brochure for 
PF-04518600.
1.2.1. OX40 (CD134) 
The ability to escape immune recognition is a hallmark of cancer progression.  By 
manipulating the immune system and restoring immune surveillance, immunotherapy offers 
the opportunity to not only eradicate or stop tumor growth, but also the opportunity to 
decrease the rate of recurrence.1 One strategy for increasing tumor immunity would be to 
activate and expand tumor-associated antigen T cells.  It has long been recognized that T cell 
activation is not mediated by antigen stimulation alone.  Indeed, tumor antigens may induce 
T-cell anergy, rendering T cells unable to proliferate in response to antigen, and 
hypo-responsive to further antigen encounter.8 Instead, co-stimulatory receptors are required 
to complete the process of T cell activation and expansion.  Thus, co-stimulatory receptors 
may have the potential to prevent tumor-induced immune tolerance.9,10
OX40 (CD134) is a co-stimulatory receptor that acts on antigen stimulated T cells but not 
native T cells.1,3 OX40 expression is transient, and peaks 48 to 72 hours following T cell 
receptor (TCR) stimulation.  High numbers of OX40 positive infiltrating T cells have been 
found within tumor biopsies, and lymph nodes of primary melanoma, breast, colon and head 
and neck cancer patients.11-14 OX40 plays a key role in T cell survival, proliferation, and 
activation.  Upon binding to OX40 ligand (also known as OX40L, CD252 or TNFSF4), 
OX40 signaling activates both the canonical and noncanonical NF-κB (nuclear factor 
kappa-light-chain-enhancer of activated B cells) survival pathways, leading to an 
upregulation of anti-apoptotic molecules including Bcl-2, Bcl-xL, and 
surviving.4 Furthermore, OX40 engagement may enhance IL-2, IL-4, IL-5, IFN-cytokine 
secretion by activated CD4 T cells.  It is interesting to note that OX40 activation has been 
shown to not require co-stimulation from other co-stimulatory receptors.15 OX40L is usually 
expressed on activated B cells and dendritic cells, but due to the immunosuppressive 
environment within a tumor, OX40L was not detected in the tumor mass of several syngeneic 
mouse models.16 Mechanistically, it is therefore possible that an agonistic mAb to 

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OX40 may reverse T cell’s anergic state, and enhance tumor immunity. Indeed, eradication 
of tumor growth has been observed by using agonistic OX40 mAbs and OX40 agonists in 
preclinical models of melanoma, sarcoma, and glioma, and colon, breast, prostate and renal 
cancers.3,12,17,18 Given the potential for OX40 agonistic mAbs to enhance anti-tumor T cell 
responses, and induce tumor regression, a Phase 1 clinical trial with a murine 
anti-OX40 antibody has been completed.19 In this study, tumor regression was observed in 
12 of 30 advance cancer patients, as well as an acceptable toxicity profile. To date, two 
additional combination Phase 1/2 studies with cyclophosphamide and radiation have been 
initiated.21 Pfizer has generated a fully human IgG2 monoclonal antibody specific for the 
human OX40 (PF-04518600).  PF-04518600 has been demonstrated to be an agonistic 
antibody against OX40.  Furthermore, PF-04518600 can selectively and reversibly bind to 
human OX40 with a high affinity, and in conjunction with TCR signals, is able to 
functionally co-stimulate T cells as measured by IL-2, IL-6, tumor necrosis factor (TNF) and 
IFNγ release in vitro.  In a syngeneic mouse model, a murine surrogate anti-OX40 agonistic 
antibody (OX86) demonstrated growth inhibition of colon tumors (see 
Section 1.2.1.1 Nonclinical Efficacy).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.1.3. PF-04518600 Clinical Safety
PF-04518600 as monotherapy has been well-tolerated in doses from 0.01 to 10 mg/kg. As of 
a data cut-off date of 24 May 2017, 52 patients (43 male and 9 female, mean ages of 
60.0 years) were treated with PF-04518600 across 6 dose levels (0.01, 0.1, 0.3, 1.5, 3 and 
10 mg/kg) in B0601002 Part A1.
The most frequent treatment-emergent adverse events (TEAEs) regardless of causality that 
occurred in ≥10% of patients were: fatigue (46.2%), nausea (28.8%), decreased appetite 
(23.1%), pruritus (23.1%), anemia (21.2%), aspartate aminotransferase increase (21.2%),
abdominal pain (19.2%), constipation (19.2%), dyspnea (19.2%), headache (17.3%), alanine
aminotransferase increase (15.4%), chills (15.4%), cough (15.4%), diarrhea (15.4%), pyrexia 
(15.4%),  vomiting (15.4%), back pain (13.5%), blood bilirubin increase (11.5%), and 
insomnia (11.5%).
A total of 30 (57.7%) patients out of 52 experienced treatment-related AEs. The most 
frequent treatment-related AE experienced by ≥10% of patients was fatigue (25.0%). Most
treatment-related events reported were Grade 2 or below.  There was 
1 Grade 3 treatment-related event of gamma-glutamyltransferase increased reported. There 
did not appear to be a dose-dependent increase in any treatment-related AEs. No 
dose-limiting toxicities (DLTs) were observed.
The only treatment-related Serious Adverse Event (SAE) reported to date was 
Grade 2 congestive heart failure (CHF) in an HCC patient receiving the 0.1 mg/kg dose. 
This patient had a prior history of anthracycline exposure. There were no treatment-related 
deaths in study B0601002. 
As B0601002 is an ongoing study, the available data are preliminary in nature and are subject 
to further review and quality control and may therefore change. 
1.2.1.4. PF-04518600 Clinical Efficacy
As of data cutoff date of 24 May 2017, 2 confirmed partial responses (PRs) were reported in 
Study B0601002 Part A1; 1 PR was reported in a cutaneous melanoma patient treated at 
0.1 mg/kg dose level who had a duration of response of 10.3 weeks, and a second PR was 
reported in a hepatocellular carcinoma (HCC) patient treated at 0.3 mg/kg dose level who 
had a duration of response of 44.1+ weeks and is still on study drug. A total of 27 (51.9%)
patients, of the 49 evaluable patients treated in Part A1, experienced a best overall response 
of stable disease (SD). 
As B0601002 is an ongoing study, the available data are preliminary in nature and are subject 
to further review and quality control and may therefore change. 
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1.2.1.6. PF-04518600 Clinical Anti-Drug Antibodies
As of 17 November 2016, preliminary data were available for 46 patients who had the 
baseline and at least one ADA sample after treatment initiation analyzed from Part A1 of 
B0601002.  A total of 3 patients (6.5%) tested positive for ADA at baseline. A total of 
16 patients (35%) were ADA positive at a minimum of one time point post treatment 
initiation. The majority of ADA responses were transient with no noticeable effect on the PK 
of PF-04518600, except for 3 patients at the 0.1 mg/kg dose level; these 3 patients had the 
highest titers in that group and the Ctrough of PF-04518600 appeared to be lower compared to 
the expected profiles.
As B0601002 is an ongoing study, the available data are preliminary in nature and are subject 
to further review and quality control and may therefore change. 
1.2.1.7. PF-04518600 Clinical Pharmacodynamics
As of 30 January 2017, preliminary data were available for ~52 patients at the 0.01, 0.1, 0.3, 
1.5, 3, or 10 mg/kg dose levels in the ongoing B0601002 study. 
 
 
 
 
 
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As B0601002 is an ongoing study, the available data are preliminary in nature and are subject 
to further review and quality control and may therefore change. 
1.2.2. 4-1BB (CD137)
4-1BB (CD137, tumor necrosis factor receptor superfamily 9 [TNFRSF9]), first identified as 
an inducible costimulatory receptor expressed on activated T cells, is a membrane spanning 
glycoprotein of the tumor necrosis factor receptor superfamily (TNFRSF).  Current 
understanding of 4-1BB indicates that expression is generally activation dependent and 
encompasses a broad subset of immune cells including activated natural killer (NK and 
natural killer T (NKT) cells; regulatory T cells; dendritic cells (DC) including follicular DC; 
stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, eosinophils and 
activated B cells.22,23 The ligand that stimulates 4-1BB (4-1BB Ligand [4-1BBL]) is 
expressed on activated antigen-presenting cells (APCs), myeloid progenitor cells and 
hematopoietic stem cells.
4-1BB is undetectable on the surface of T cells but expression increases upon activation.  
Based on homology to other members of the TNFRSF, ligand binding is expected to induce 
receptor trimerization resulting in activation.24 Some members of the TNFRSF can cleave 
the extracellular domain from the cell surface and exist in a soluble form.  Soluble 4-1BB 
and soluble 4-1BBL have been demonstrated in the serum of some patients with autoimmune 
diseases and cancers.25-27
Upon 4-1BB activation, TNFR-associated factor (TRAF) 1 and TRAF 2, pro-survival 
members of the TNFR-associated factor (TRAF) family are recruited to the 4-1BB 
cytoplasmic tail resulting in downstream activation of nuclear factor 
kappa-light-chain-enhancer of activated B cells (NF-kB) and the Mitogen Activated Protein 
(MAP) Kinase cascade including extracellular signal-regulated kinases (Erk), c-Jun 
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N-terminal kinases (Jnk), and p38 MAP kinases.  NFkB activation leads to up regulation of 
Bfl-1 and Bcl-XL, pro-survival members of the Bcl-2 family.  The pro-apoptotic protein Bim 
is downregulated in a TRAF1 and Erk dependent manner.5
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production.28 Reports have shown that 4-1BB 
agonist mAbs increase costimulatory molecule expression, and markedly enhance cytolytic 
T lymphocyte responses, resulting in anti-tumor efficacy in various models.  4-1BB agonist 
mAbs have demonstrated efficacy in prophylactic and therapeutic settings and both 
monotherapy and combination therapy tumor models and have established durable anti-tumor 
protective T cell memory responses.29 4-1BB agonists also inhibit autoimmune reactions in a 
variety of autoimmunity models.30 This dual activity of 4-1BB offers the potential to provide 
anti-tumor activity while dampening autoimmune side effects that can be associated with 
immunotherapy approaches that break immune tolerance.
1.2.2.1. Utomilumab Clinical Efficacy
As of the data cut-off date of 06 June 2016, the safety and efficacy of utomilumab are being 
evaluated in 3 ongoing studies either as a single agent (B1641001 Portion A) or in 
combination with other anti-cancer treatments (B1641001 Portion B, B1641003, and 
B1641004).
For these ongoing studies, the available data are preliminary in nature and are subject to 
change.
Study B1641001
For B1641001, safety and efficacy data were recorded for 86 patients in Portion A treated 
with utomilumab in dose levels between 0.006 and 10 mg/kg and 47 patients in Portion B 
treated with utomilumab in dose levels between 0.03 and 10 mg/kg in combination with 
rituximab at 375 mg/m2.
As of the data cut-off date 06 June 2016, in Portion A, 1 confirmed complete response (CR)
and 1 confirmed PR in Merkel cell carcinoma (MCC) were reported in patients who were 
treated at 0.24 mg/kg and 0.6 mg/kg respectively. In addition, 1 patient with 
anti-PD-1 refractory melanoma treated at 0.24 mg/kg had a PR that was not yet confirmed at 
the time of data cut-off date; however, this response was confirmed at a subsequent 
assessment. In addition, 1 patient with anti-PD-1 refractory melanoma treated at 0.24 mg/kg 
had a greater than 30% reduction in the diameters of multiple target tumors but was 
considered to have stable disease (irSD) per Immune-related Response Criteria Derived from 
RECIST version 1.1.
In Portion B, 8 patients with follicular lymphoma (7 patients were refractory to prior 
rituximab-containing regimen) achieved an objective response: 4 patients achieved a CR 
(2 treated at 1.2 mg/kg, 1 at 0.12 mg/kg, and 1 at 0.03 mg/kg) and 4 patients achieved a PR 
(2 treated at treated at 0.18 mg/kg, 1 treated at 1.2 mg/kg, and 1 treated at 5.0 mg/kg). One 
(1) patient with CD20 + Hodgkin’s lymphoma treated at 1.2 mg/kg achieved a PR and 
1 patient with Mantle Cell Lymphoma (MCL) treated at 2.4 mg/kg achieved a PR.

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Study B1641003
For B1641003, safety and efficacy data were recorded for 23 patients treated with 
utomilumab in dose levels between 0.45 and 5.0 mg/kg in combination with 2 mg/kg of 
pembrolizumab.
Among the 23 patients treated, 6 had confirmed objective response providing an objective 
response rate (ORR) of 26.0%. Two (2) patients had a confirmed CR (1 patient with renal 
cell carcinoma (RCC) treated at 1.8 mg/kg and 1 patient with small cell lung cancer (SCLC)
treated at 5.0 mg/kg). Four (4) patients achieved a PR: 1 patient with RCC and 1 patient with 
non-small cell lung cancer (NSCLC) treated at 0.45 mg/kg; 1 patient with anaplastic thyroid 
disease treated at 3.6 mg/kg, and 1 patient with Squamous Cell Carcinoma of the Head and 
Neck (SCCHN) treated at 5 mg/kg.
Study B1641004
For B1641004, safety and efficacy data were recorded for 11 patients treated with 
utomilumab in dose levels between 1.2 and 5 mg/kg, in combination with 1 mg/kg of 
mogamulizumab.
Efficacy assessments are ongoing for Study B1641004. Out of 11 patients evaluated during 
the utomilumabdose escalation phase of the study, no RECIST-defined responses were 
observed. Four (4) patients achieved a best overall response of SD of 4 months duration. 
Response was not determined in 2 patients (2.4 mg/kg) and 5 patients had a best overall 
response of progressive disease (PD).
1.2.2.2. Utomilumab Clinical Safety
Based on a data cut-off date of 06 June 2016 for B1641001, B1641003 and B1641004, 
utomilumab has been administered to 167 patients, and the amount of safety data collected 
are beginning to create a picture of the overall safety profile up to the 10 mg/kg in both single 
agent and in combination with rituximab, and 5.0 mg/kg in combination with pembrolizumab 
and mogamulizumab.
There were no specific AEs of note in patients treated up to 10 mg/kg utomilumab.
Study B1641001
The most frequently reported TEAEs in Portion A (10% of patients, all grades) regardless 
of causality were fatigue (24.4%), nausea (18.6%), decreased appetite (16.3%), vomiting 
(16.3%) abdominal pain (15.1%), diarrhea (11.6%), dizziness (11.6%), constipation (10.5%), 
and pyrexia (10.5%).
The most frequently observed treatment-related TEAE in Portion A (10% of patients; all 
grades) was fatigue (11.6%).

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The most frequently reported TEAEs in Portion B (10% of patients; all grades) regardless 
of causality were fatigue (31.9%), infusion-related reaction (21.3%), upper respiratory tract 
infection (14.9%), diarrhoea (12.8%), pyrexia (12.8%), chills (10.6%), cough (10.6%), and 
headache (10.6%).
The most commonly reported treatment-related TEAEs in Portion B (10% of patients; all 
grades) that were considered treatment-related were fatigue (23.4%) and infusion-related 
reaction (21.3%).
One event each of enterocolitis, alanine aminotransferase (ALT)/ aspartate aminotransferase
(AST) increased, decreased appetite and pneumonitis were reported as treatment-related in 
3 patients. After the data cut-off date, the causality of the ALT and AST elevations were 
re-assessed by the Investigator as not related to utomilumab. One (1) SAE of 
infusion-related reaction was considered related to rituximab but not to utomilumab, per 
Investigator assessment. 
There were no DLTs reported in either Portion A or Portion B and no deaths were attributed 
to study treatment.
In summary, the observed safety profile, based on a data cut-off date of 06 June 2016 for 
B1641001, support the use of utomilumab both as a single agent and in combination with 
rituximab.
Study B1641003
The most frequently reported TEAEs (10% of patients; all grades) regardless of causality, 
were fatigue (43.5%), cough (34.8%), decreased appetite (30.4%), nausea (30.4%), 
constipation, pruritus, rash maculo-papular (26.1% each), pyrexia and vomiting 
(21.7% each), anaemia, dyspepsia, rash, and upper respiratory tract infection (17.4%, each), 
arthralgia, asthenia, back pain, dry mouth, dry skin, dyspnoea, fall, haemoptysis, 
hypokalaemia, hyponatraemia, muscle spasms, oedema peripheral, pleural effusion, 
pneumonia, sinusitis, and stomatitis (13.0% each).
The most frequently observed treatment-related TEAEs (10% of patients; all grades) were 
fatigue (34.8%), rash maculo-papular (26.1%), pruritus (21.7%), pyrexia (17.4%), nausea, 
decreased appetite, dry skin, and dry mouth (13.0% each).
No SAEs were considered related to utomilumab per Investigator assessment.
There were no DLTs reported and no deaths were attributed to study treatment.
In summary, the observed safety profile, based on a data cut-off date of 06 June 2016 for 
B1641003, supports utomilumab use in combination with pembrolizumab.
Study B1641004
The most frequently observed TEAEs (10% of patients; all grades) regardless of causality, 
were rash (36.4%), abnormal dreams, constipation, fatigue and nausea (27.3% each), 

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decreased appetite, diarrhoea, dyspnoea, infusion related reaction, pruritus, and rhinorrhoea 
(18.2% each).
The most frequently observed treatment-related TEAEs (≥10% of patients; all grades) were 
abnormal dreams, nausea, rash, (27.3% each), decreased appetite, diarrhoea, fatigue, 
infusion-related reaction and pruritus (18.2% each).
No SAEs were considered related to utomilumab per Investigator assessment.
There were no DLTs reported and no deaths were attributed to study treatment.
In summary, the observed safety profile, based on a data cut-off date of 06 June 2016 for 
B1641004, supports utomilumab in combination with mogamulizumab.
Please refer to the Investigator’s Brochure for utomilumab, Section 6.2.1 for the analysis of 
common adverse events for patients treated with utomilumab.6
 
 
 
 
 
 
 
1.2.2.4. Utomilumab Immunogenicity
Study B1641001
In Portion A (monotherapy), 9 out of 61 (14.8%) patients exhibited positive ADA prior to 
treatment with utomilumab. Thirty-five out of 61 patients (57.4%) were positive for ADA 
for at least one time point regardless of baseline ADA status.  Among 35 ADA-positive 
patients, 7 (20%) exhibited positive neutralizing antibody (NAb) against utomilumab.
In Portion B, 2 out of 41 (4.9%) patients exhibited positive ADA against utomilumab prior to 
treatment with utomilumab plus rituximab. Three out of 41 patients (7.3%) were positive for 
CCI

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ADA for at least 1 time point regardless of baseline ADA status when administered in 
combination with rituximab. Among 3 ADA-positive patients, 1 (33.3%) exhibited positive 
NAb against utomilumab. The impact of ADA on PK of utomilumab was characterized.  
ADA negative patients were defined as those with negative antibody status for all samples 
collected during the study including baseline (pre-treatment). ADA positive patients were 
defined as those with at least 1 positive ADA sample anytime during the study including 
baseline (pre-treatment). Utomilumab clearance (CL) was similar in ADA negative and 
ADA positive patients suggesting that ADA status had minimal impact on the PK of 
utomilumab.
Study B1641003
Two out of 23 (8.7%) patients exhibited positive ADA against utomilumab prior to treatment 
with utomilumab plus MK-3457. Seventeen out of 23 patients (73.9%) were positive for 
ADA for at least 1 time point regardless of baseline ADA status when administered in 
combination with MK-3457. Among 14 ADA-positive patients who were tested for NAb
analysis, 5 (35.7%) patients exhibited positive NAb against utomilumab.
Study B1641004
Among 10 patients tested for ADA analysis, none of them exhibited positive ADA against 
utomilumab prior to treatment with utomilumab plus mogamulizumab. Five out of 
10 patients (50%) were positive for ADA against utomilumab for at least 1 time point when 
administered in combination with mogamulizumab. 
Additional pre-clinical and clinical information for utomilumab, including PK data in 
patients, may be found in the SRSD, which for this study is the utomilumab IB.6
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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CCI

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1.2.4. Clinical Combination of PF 04518600 and Utomilumab
As of the data cut-off date of 24 May 2017, 42 patients (23 male and 19 female, mean ages of 
58.6 years) were treated with PF-04518600 across 5 dose levels of PF-04518600 (0.1, 0.3, 
1 or 3 mg/kg) in combination with 20 or 100 mg of utomilumab in Part B of B0601002.
CCI
CCI
CCI
CCI

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The most frequent all-causality TEAEs that occurred in 10% of patients include: decreased 
appetite (23.8%), nausea (21.4%), fatigue (19.0%), anemia (16.7%), pyrexia (16.7%), 
abdominal pain (14.3%), constipation (14.3%), diarrhea (14.3%), and pain (11.9%).
A total of 15 (32.1%) patients out of 42 experienced treatment-related TEAEs. The most 
frequent treatment-related TEAE experienced in 5% of patients include fatigue (9.5%) and 
nausea (7.1%). All treatment-related events reported were Grade 1 or 2, with the exception 
of a Grade 3 amylase and a Grade 4 lipase elevation in a single subject receiving 0.3 mg/kg 
PF-04518600 and 100 mg utomilumab. No DLTs have been reported.
The only treatment-related SAE, which occurred on 19 June 2017, was a Grade 3 infusion 
reaction in a 67 year old patient with bladder cancer who was receiving 1 mg/kg 
PF-04518600 and 100 mg utomilumab. 
Preliminary efficacy data as of 24 May 2017, indicated that there were 2 ongoing partial 
responses (PR) in the 10 melanoma patients enrolled: 1 confirmed in a cutaneous melanoma
patient at 0.3 mg/kg PF-04518600 and 20 mg utomilumab and 1 unconfirmed in an ocular
melanoma patient at 0.3 mg/kg PF-04518600 and 100 mg utomilumab.  Both patients are still 
ongoing in the study.  The cutaneous melanoma patient had received prior pembrolizumab 
plus ipilimumab and had a partial response (PR), then progressed on pembrolizumab
maintenance.  The ocular melanoma patient had progressed after prior radiotherapy. 
As B0601002 is an ongoing study, the available data are preliminary in nature and are subject 
to further review and quality control and may therefore change.
1.2.5. Tumor Type Rationale
Anti-tumor immune response is the ability for a tumor to elicit an adaptive immune response 
and prevent tumor growth.  It has long been understood that immunodepressed patients have 
a higher incidence of cancer,34 and immunodeficient murine models have increased levels of 
tumor growth.35 Central to the adaptive defense against tumor cells are the tumor infiltrating 
lymphocytes (TILs) that include CD8+ effector T cells, and CD4+ T helper (Th) cells.  For a 
number of tumor types, including melanoma, head and neck cancers, hepatocellular 
carcinoma (HCC), bladder urothelial cell carcinoma and colorectal cancer, a favorable 
prognosis has been associated with a high number of TILs.22,36-39 High numbers of 
OX40 positive infiltrating T cells have been found within tumor biopsies, and lymph nodes 
of primary melanoma, breast, colon and head and neck cancer patients.11-14 Thus, for these 
tumor types, the abundance of activated TILs has been suggested to be a surrogate marker for 
anti-tumor immune response.40 Indeed, it has been postulated that the host response to 
immunotherapeutics may be dependent on the anti-tumor immune response for a given 
tumor.40 Nonetheless, a combination of immunotherapeutics may elicit a robust immune 
response even in a poorly immunogenic tumor type.41 In the study by Chen et at (2015),41 a 
combination of anti-4-1BB/anti-PD-1 demonstrated that it was possible to elicit an effective 
antitumor response in a poorly immunogenic mouse model.  Furthermore, Lee et 
al31 demonstrated that a combination of OX40 and 4-1BB agonists induced tumor growth 
inhibition in an immunologically resistant fibrosarcoma model.

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This clinical protocol will be the first to study PF-04518600 as monotherapy, and in 
combination with utomilumab in patients with advanced or metastatic select tumor types who 
are unresponsive to existing therapies, or for whom no standard treatment is available.
1.2.5.1. Melanoma
Melanoma is considered to be one of the most immunogenic tumor types due to its ability to 
undergo spontaneous regression.  Worldwide, an estimated 232,000 new cases are diagnosed 
each year.42 It is a highly aggressive tumor; 5 year survival rate for patient with regional 
metastasis is expected to be 63%, whilst survival for a patient with distant metastasis is 
expected be 16%.43 Recent Food and Drug Administration (FDA) approval of immune 
checkpoint inhibitors ipilimumab (a fully human IgG1 anti- cytotoxic T-lymphocyte 
antigen 4 [CTLA-4] antibody), nivolumab and pembrolizumab (both humanized IgG4 an 
anti-PD-1 antibodies) provide compelling evidence that melanoma is amenable to 
immunotherapeutic approaches.  In clinical Phase 3 studies, metastatic melanoma patients 
treated with ipilimumab demonstrated median overall survival of 10.1 months, compared to 
6.4 months among patients receiving glycoprotein 100 (gp100) peptide vaccine 
alone.44 Notably, durable tumor control was observed, with overall survival (OS) noted for 
18% of patients at 5 years and 17% at 7 years, with no deaths reported after 
7 year.45 Historically, 3% Stage IV M1c, 6% Stage IV M1b and 16% of Stage IV M1a 
patients are expected to survive 10 years.46 For pembrolizumab, clinical studies showed 
tumor shrinkage in 24% of treated advance melanoma patients that lasts from 1.4 to 
8.5 months, overall median progression-free survival of longer than 7 months and an overall 
response rate of 26%.47 Responses were durable.48 With a median follow-up of 11 months, 
though the median duration of response had not been reached for all advance melanoma 
patients, the fast majority (88%) of responders were still on treatment at time of database 
lock.47 In patients refractory to ipilimumab treated with pembrolizumab, objective response 
rate (ORR) by RECIST was 28%, and again durable response was observed.48 Combining 
checkpoint inhibitors nivolumab and ipilimumab in previously untreated melanoma yields a 
greater response rate of 57.6% versus nivolumab alone (43.7%) or ipilimumab alone (19%). 
However, greater frequency of Grade 3 or 4 treatment-related adverse events are seen in 
patients treated with nivolumab and ipilimumab (55.0%) vs nivolumab (16.3%) or 
ipilimumab (27.3%).95 In 2015 the FDA approved two BRAF and MEK inhibitor 
combinations to treat patients with unresectable or metastatic BRAF-mutated melanoma: 
cobimetinib with vemurafenib and dabrafenib with trametinib. The Phase 3 Cobimetinib 
combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM) study
showed that vemurafenib with cobimetinib improved OS at 9 months of 81% vs 73% for 
vemurafenib with placebo, PFS 11.3 vs 6.0 months, ORR of 68% vs 45%.123 The 
Phase 3 COMBI-d study showed that dabrafenib with trametinib improved overall survival 
with a median survival of 25.1 months vs 18.7 months for dabrafenib alone, PFS 11.0 vs 
8.8 months, ORR of 69% vs 53%.124
The most common melanoma subtype is cutaneous, which arises from melanocytes located
in the basal layer of the epidermis, and was the subtype of melanoma primarily evaluated in 
the clinical trials described above.107 Ocular melanoma located anywhere in the uveal tract is 
the most common primary intraocular malignancy in adults, representing ~85% of 
cases.108 The remaining ocular melanomas arise from the conjunctiva (~5%) or other sites 

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(~10%).108 The molecular profile of ocular melanoma is different from those of cutaneous or 
mucosal melanomas and is composed of a number of chromosomal abnormalities and 
somatic gene alterations.  As a result of these differences, no effective adjuvant systemic 
therapy has been demonstrated to reduce the risk of metastasis of ocular melanoma, as 
recently reviewed by Triozzi and Singh.109 And for those patients with ocular melanoma
who do develop metastatic disease, there is no proven standard of care. Dacarbazine, a 
chemotherapeutic option for treatment of cutaneous melanoma, has been used for ocular
melanoma; however, activity has been limited.110,111,112 Other chemotherapeutic regimens 
including temozolomide, cisplatin, treosulfan, fotemustine and various combinations have 
been investigated in ocular melanoma with disappointing results to date.113,114,115 Immune 
checkpoint inhibitors evaluated in several small prospective and/or retrospective studies have 
rarely demonstrated responses and no overall survival benefit.125 Ipilimumab has shown 
response rates of ~5%–10% in metastatic ocular melanoma, but evidence of a median overall 
survival (OS) of 6.0–9.7 months in these trials suggests that responses could be delayed and 
durable in only a minority of patients.116,117,118,119 Additionally, ipilimumab demonstrated 
very limited clinical activity in treatment-naïve or pre-treated patients with metastatic ocular
melanoma in the Phase II German Dermatologic Cooperative Oncology Group (DeCOG)
trial; median progression-free survival (PFS) was 2.8 months and median OS was 
6.8 months.120 Initial assessment of pembrolizumab in seven patients with metastatic ocular
melanoma who had progressed on ipilimumab reported a median PFS of ~3 months.121
1.2.5.2. Head and Neck Squamous Cell Carcinoma (HNSCC)
Approximately 650,000 new cases of head and neck cancers are diagnosed globally each 
year, and head and neck squamous cell carcinoma (HNSCC) is the most common 
form.42,49,50 HNSCC is an aggressive tumor type with a 10.1 month overall survival rate for 
patients with recurrent and/or metastatic disease.51 HNSCC is considered to be an 
immunosuppressive tumor,52 circulating and tumor-infiltrating T cells of HNSCC patients 
have signaling defects,53 and immune effector cell anergy is well described.  This, together 
with TILs’ ability to act against HNSCC tumor antigens, makes HNSCC a good candidate 
for immunotherapy.  Cetuximab, an anti-EGFR (epidermal growth factor receptor) antibody
targets,  EGFR, which is expressed on >90% of all HNSCC tumors.  In Phase 3 studies, 
recurrent and metastatic HNSCC treated with cetuximab plus chemotherapy increased overall 
survival from 7.4 months to 10.1 months, when compared with HNSCC patients treated with 
chemotherapy alone.51 Pembrolizumab has received accelerated approval from the FDA for 
recurrent or metastatic SCCHN with disease progression on or after platinum-containing 
chemotherapy based on the results of KEYNOTE-012, with an ORR of 16% and CR rate of 
5%.97 The FDA approved nivolumab for HNSCC that has progressed during chemotherapy 
with a platinum-based drug or that has recurred or metastasized after platinum-based 
chemotherapy in 2016.  Nivolumab improved overall survival with a median survival of 
7.5 months vs 5.1 months for standard therapy, ORR of 13.3% vs 5.8%, PFS was 
approximately the same 2.0 vs 2.3 months.131
1.2.5.3. Hepatocellular Carcinoma (HCC)
An estimated 782,000 cases of HCC are diagnosed worldwide each year; it is the third 
leading cause of tumor deaths, with an expected 5-year survival rate of 5-6%.42,54 Sorafenib, 
a multikinase inhibitor, was the first approved systemic therapy for unresectable HCC with 

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overall survival of 10.7 vs 7.9 months, PFS 5.5 vs 2.8 months, ORR of 2% vs 1%, disease 
control rate of 43% vs 32% compared to placebo.96 Recently, regorafenib, another
multikinase inhibitor, was approved for HCC patients who have progressed during sorafenib
treatment. Regorafenib improved overall survival with a median survival of 10.6 months vs 
7.8 months for placebo, PFS 3.1 vs 1.5 months, ORR of 11% vs 4%, disease control rate of 
49% vs 23%.105 Additionally, a Phase II study evaluating lenvatinib, a multi-tyrosine kinase 
receptor inhibitor, for HCC treatment showed promising outcomes, with median survival of 
18.7 months, TTP of 7.4 months, an ORR of 37%, and a disease control rate of 
78%.106 There is evidence to suggest that HCC is amenable to immunotherapy.  Firstly, HCC 
tumor recurrence has been linked to immunosuppression.  Secondly, HCC patients treated 
with autologous lymphocytes activated in vitro with recombinant interleukin-2 and antibody 
to CD3 had significantly improved recurrence-free survival and disease-specific survival.  
Thirdly, CD4+ regulatory T cells and immunosuppressive T regulatory cells (Tregs) that may 
suppress T cell responses have been identified in tumors of HCC patients, and it has been 
demonstrated that engagement of another T cell co-stimulatory receptor GITR can reverse 
the suppressive effect of Tregs.55,56 It should however be noted that the liver has a unique 
intrinsic tolerogenic and intra-hepatic immunosuppressive environment, with mechanisms 
that preferentially inactivate T cells, as well as mechanisms that increase T cell tolerance, and 
apoptosis.57 As such, for the limited number of immunotherapeutic trials completed to date 
involving therapeutic vaccination and cell therapy strategies, only modest results have been 
observed.54 There are data that suggest that immune checkpoint inhibition with 
anti-PD1 may have anti-tumor efficacy in HCC. In the Checkmate 040 Phase 1/2 study, 
patients with advanced or metastatic HCC were treated with nivolumab. Objective responses 
occurred in 16% and CR in 1% of 214 patients, and responses were seen regardless of 
PD-L1 status, prior sorafenib treatment, or hepatitis C virus (HCV) or hepatitis B virus
(HBV) infection.98
1.2.5.4. Renal Cell Carcinoma (RCC)
Renal cell carcinoma (RCC) accounts for >90% of all kidney cancers, and approximately 
338,000 cases are diagnosed worldwide each year.42,58 In the US, for the last 30 years, the 
incidence of RCC has been raising by approximately 3% each year.59 Clear cell RCC is the 
most common form of renal adenocarcinomas, representing 70% of all RCC, and the 
expected 5-year survival rate for these patients are 55%.60,61 There is nonetheless other 
compelling evidence for an immunotherapeutic approach for this disease.64 Increased 
expression of immune checkpoint PD-1 receptor and PDL-1 ligand have been identified on 
TILs and tumor cells from RCC patients, and this correlated with patient survival.64 Lastly, 
results of a Phase 3 trial of nivolumab versus (vs) everolimus in metastatic RCC patients who 
failed prior (anti-VEGF [Vascular endothelial growth factor]) treatment found improved
ORR of 21.5 vs 5%, and median overall survival of 25.0 vs 19.6 months.104
1.2.5.5. Bladder Cancer
For bladder cancer, tumor infiltration of CD3+ and CD8+ T cells has been associated with 
better overall survival.22,65 Bladder cancer was the first indication with an FDA approved 
immunotherapy, and vaccination using weakened, live bacterium bacillus calmette-guérin 
(BCG) first took place in the 1970s.22,65 Worldwide, it is estimated that 386,000 new cases 
of bladder cancer will occur each year, with approximately 105,000 deaths.42 Approximately 

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75% of cases of bladder cancer are non- muscle invasive bladder cancer (NMIBC). While 
treatment with BCG has been shown to reduce the risk of tumor recurrence,67 approximately 
40% of patient with NMIBC will fail BCG therapy.68 Atezolizumab, an 
anti-PD-L1 antibody, has received accelerated approval from the FDA for locally advanced 
and metastatic urothelial carcinoma that has progressed following treatment with 
platinum-based chemotherapy following a single-arm multicenter trial with 310 patients that 
demonstrated an ORR of 14.8% in all patients (5.5% CR, 9.4% PR) and ORR of 
26% (12% CR, 14% PR) in patients with PD-L1 expression in 5% of immune cells.99,100
1.2.5.6. Cervical Cancer
According to published data by the International Association of Research in Cancer (IARC),
528,000 new cases of cervical cancer are diagnosed worldwide each year.42 It is understood 
that cervical cancer is caused by high risk human papilloma virus (HPV).  There are two 
main types of cervical cancer. The first one, which accounts for about 90% of diagnosed 
cervical cancers, is squamous cell carcinoma that covers the cervix.126 The second type of 
cervical cancer, located in the gland cells of the endocervix, is called cervical 
adenocarcinoma. There has been an increase in the incidence of cerival adenocarcinoma in 
many countries, mainly in women under the age of 40.127,128,129,130 Whilst vaccination against 
the HPV oncogenes E6 and E7 have been effective for premalignant lesions, there were no 
clinical effects on advance or recurrent tumor.71 Spontaneous regression of premalignant 
lesions has been associated with circulating HPV specific CD4+ and CD8+ T cells, and a 
higher ratio of effector T cells to Tregs.71 The ratio between CD8 T cells and Foxp3+ 
regulatory CD4 T cells (Tregs), and the number of tumor infiltrating M1 macrophages are 
also independent prognostic factors.
Currently, there are a number of immunotherapeutics in development for cervical cancer.  
They include T cell adoptive therapy,72 and therapies that target immune checkpoints.73,74 In 
a Phase 1 study of HPV infused TILs, out of 9 metastatic cervical cancer patients CR with 
long term durability (22 to 15 months) was observed in 2 patients, and PR was observed in 
1 patient.72 In a Phase 1/2 study of ipililumab in recurrent or metastatic cervical cancer 
patients, preliminary results revealed 3 PR (1 PR and 2 unconfirmed PR) and 8 SD in 
34 patients.73 In a Phase 1b study KEYNOTE-028 pembrolizumab had a 17% ORR in 
24 patients with PD-L1 positive advanced cervical cancer.74
1.2.5.7. Gastric Adenocarcinoma
Gastric cancer is the 5th most common cancer in the world, with 952,000 new cases reported 
in 2012.42 Approximately 50% these cases were reported in Eastern Asia.  It is also the third 
leading cause of cancer deaths, with 723,000 deaths recorded in 2012.  Except in countries 
like Japan and Korea, gastric cancer often presents with advanced disease upon diagnosis.  
The principle treatment method is still surgical resection; whilst 20-30% patients will have 
resectable disease, those with lymph node metastasis will be deemed inoperable.  Even for 
those patients treatable with surgical resection, the recurrence rate remains high and the 
five-year survival rate is 29%.43

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It is understood that gastric cancer is a histologically diverse disease, and the majority is 
associated with infectious agents such as helicobacter pylori and Epstein–Barr virus (EBV).  
Recently, the Cancer Genome Atlas (TCGA) Research Network analyzed the molecular 
characteristics of gastric adenocarcinoma (TCGA 2014) and identified 4 distinct subtypes: 
tumors positive for EBV, microsatellite unstable tumors, genomically stable tumors, and 
tumors with chromosomal instability. Each distinct subtype may therefore require a different 
therapeutic option.
Immunotherapy may offer an alternative treatment strategy for gastric cancer patients.  
Gastric cancer patients with increased numbers of CD3, CD8, and CD45RO positive TILs 
have improved survival rates compared to patients with lower numbers of TILs.75
A limited number of immunotherapy approaches are currently being evaluated in gastric 
cancer.  Checkpoint inhibitors, including CTLA-4, PD-L1 and PD-1 are currently being 
evaluated.  In the Phase 2 study with Tremelimumab (CTLA-1 mAb), a 5% response rate 
was observed in 18 gastric cancer patients.84 In the KEYNOTE-012 study, a multicenter 
open-label Phase 1b trial pembrolizumab for positive recurrent or metastatic adenocarcinoma 
of the stomach of gastro-esophageal junction, 36 patients evaluable for response 8 (22%) had 
overall response (all PR).101
1.2.5.8. Non-Small Cell Lung Cancer (NSCLC)
Lung cancer remains to be the most common cancer worldwide, with 1.8 million cases 
reported in 2012.42 In the US, non-small cell lung cancer (NSCLC) accounts for over 85% of 
these cases, and with a 17.1% 5-year survival rate.84 NSCLCs represent a heterogeneous set 
of diseases with diverse pathological, genetic and cellular features, with three NSCLC 
histological sub-types: adenocarcinoma (~50% of cases), squamous cell carcinoma (~40% of 
cases), and large cell carcinoma.132,133 There are differences in mutation burden between 
smokers and non-smokers: 1) smokers have significantly higher mutation frequencies; 
2) point mutations in smokers are predominantly C:G->A:T, but non-smokers are 
predominantly C:G->T:A; and 3) the distinctive sets of mutations identified in non-smokers 
are EGFR mutations and ROS proto-oncogene 1 (ROS1) and anaplastic lymphoma kinase 
(ALK) fusions, while smokers have Kirsten rat sarcoma proto-oncogene (KRAS), tumor 
protein p53 gene (TP53), BRAF, Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and 
mismatch repair gene mutations.133 For NSCLC with specific genetic alterations, including 
epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) 
translocations (2-8%), molecular targeted therapies with erlotinib and crizotinib, have 
improved median overall survival (OS).84 However, the majority of NSCLC patients do not 
harbor these genetic mutations, since only 15-18% of NSCLC has EGFR genetic alterations 
and 2-8% have ALK translocations.
In October 2015, nivolumab and pembrolizumab (PD-1 mAbs) were approved for the 
treatment of metastatic NSCLC.  In the pivotal studies for nivolumab,84 overall survival of 
12.2 months was observed for nivolumab treated patients, whilst overall survival for 
docetaxel treated patients was 9.4 months.  Furthermore, PR/CR was observed in 19% of 
nivolumab treated patients.  In the 495 patient study for pembrolizumab, an overall response 
rate of approximately 20% was observed for previously treated and treatment-naive advanced 
or metastatic NSCLC patients.84 Patients with high PD-L1-expressing NSCLC had an even 

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more impressive overall response rate of 45.2%.  Median overall survival for all patients 
treated with pembrolizumab was 12.0 months.  An open-label Phase 3 study randomizing 
305 patients with previously untreated advanced NSCLC with PD-L1 expression on at least 
50% of tumor cells to pembrolizumab versus investigator’s choice platinum-based 
chemotherapy demonstrated superior PFS (10.3 vs 6 months, hazard ratio 0.5), response rate 
(44.8 vs 27.8%), duration of response (1.9+ to 14.5+ vs 6.3 months), and overall survival at 
6 months (80.2% vs 72.4%, HR for death = 0.6) for pembrolizumab.102 In 2016, another 
checkpoint inhibitor targeting program death-ligand 1 (PD-L1), atezolizumab was approved 
for the same indication.134 Moreover, pembrolizumab also received approval in 2016 for 
first-line NSCLC treatment in patients with high PD-L1 expressing tumors (50% of tumor 
cells).135,136 More recently, in May 2017, FDA approved pembrolizumab as First-Line 
Combination Therapy with Pemetrexed and Carboplatin, irrespective of 
PD-L1 Expression.137 Other inhibitors of PD-1/PD-L1 pathway, such as avelumab 
(Avelumab in Non-Small Cell Lung Cancer/JAVELIN LUNG 200; ClinicalTrials.gov,
National Clinical Trial (NCT)02395172) and durvalumab (ClinicalTrials.gov, 
NCT02087423), are also being assessed in phase 3 trials.138,139,140
CTLA-4 inhibitors are being evaluated too. Ipilimumab appeared to show improved efficacy 
for squamous histology but not for non-squamous histology.141 A phase III trial 
(ClinicalTrials.gov, NCT01285609) is currently ongoing to compare the standard carboplatin 
and paclitaxel chemotherapy with concomitant administration of ipilimumab specifically in 
patients with squamous NSCLC. Ipilimumab is also being studied empirically in 
combination with targeted inhibitors (erlotinib or crizotinib) for EGFR and ALK 
translocation-positive NSCLC (ClinicalTrials.gov, NCT01998126), and PD-1 antibody. 
Tremelimumab did not demonstrate strong efficacy as single agent.142 The combination of 
durvalumab and tremelimumab is tested as well in third-line (A Global Study to Assess the 
Effects of MEDI4736, Given as Monotherapy or in Combination With Tremelimumab 
Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally 
Advanced or Metastatic Non Small Cell Lung Cancer (ARCTIC) ClinicalTrials.gov, 
NCT02352948) and in first-line (Phase III Open Label First Line Therapy Study of 
MEDI 4736 (Durvalumab) With or Without Tremelimumab Versus SOC in NSCLC
(MYSTIC) ClinicalTrials.gov, NCT02453282) and Study of 1st Line Therapy Study of 
Durvalumab With Tremelimumab Versus Standard of Care in NSCLC (NEPTUNE)
(ClinicalTrials.gov, NCT02542293).
1.2.5.9. Selection of Tumor Types for Combination Studies Using The Cancer Genome 
Atlas (TCGA) 
RNA-seq data generated by the cancer genome atlas (TCGA) research network 
(http://cancergenome.nih.gov/) across multiple tumor types was used as a guide for the 
selection of tumor types for Part B PF-04518600/utomilumab combination phase. Given that 
the RNA-seq data is generated from bulk tumor, spearman correlations of mRNA expression 
of target of interest (4-1BB or OX40) to mRNA expression of markers of specific immune 
cell subsets was completed. This correlation was used as a guide for the determination of 
OX40 or 4-1BB expression levels within different immune cells. For 4-1BB, since an 
anti-4-1BB agonist is expected to stimulate cytotoxic T-cells (see Section 1.2.2 4-1BB 
[CD137]), correlation of 4-1BB expression to expression of granzyme A and 

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perforin 1 (enzymes indicative of a cytotoxic [CYT] signature)75 was completed. For OX40, 
since anti-OX40 agonist is expected to stimulate CD4 cells, correlation of OX40 expression 
to CD4 expression was completed. 
Based on the results from this analysis, the combination of PF-04518600 and utomilumab 
will be conducted in patients with locally advanced or metastatic HNSCC, melanoma, 
urothelial bladder carcinoma, NSCLC, gastric cancer or squamous cell carcinoma of the 
uterine cervix that is either resistant to standard therapy or for which no standard therapy is 
available.
1.2.5.10. Summary of Benefit Risk Assessment
Overall, the nonclinical package and the preliminary clinical experience with 
PF-04518600 support the safety and design of Protocol B0601002 for both single agent 
treatment and in combination with utomilumab.
1.3. Starting Dose Rationale
1.3.1. Monotherapy Starting Dose Rationale
The objective for this first-in-patient (FIP) study is to assess safety, tolerability, 
pharmacokinetics, and pharmacodynamics (immune-modulatory or IM effects) of 
PF-04518600 in patients with advanced or metastatic HCC, melanoma, clear cell RCC or 
HNSCC. 
The selected starting dose for PF-04518600, 0.01 mg/kg, represents approximately 60% of a 
theoretical receptor occupancy calculated by the Duff equation.84
The starting dose and subsequent PF-04518600 doses of 0.01, 0.1, 0.3, 1.5, and 3 mg/kg were
proposed based on: 
1. Published clinical trial results of a similar agonist monoclonal antibody (9B12) 
against OX40, the same target as PF-04518600, which was studied in patients with 
advanced cancer at 3 dose levels, 0.1, 0.4, and 2 mg/kg.12,19
2. Differences between PF-04518600 and 9B12 in terms of co-stimulatory potency on 
T cell proliferation. 
3. Expected differences in PK properties. 
4. Preclinical toxicology data on PF-04518600. 
The proposed doses have been studied in an ascending order, please refer to 
Section 3.1.5 Criteria for Dose Escalation).  As MTD was not reached up to 3 mg/kg, and 
there was evidence for a pharmacodynamic response at 3 mg/kg, a 10 mg/kg additional 
cohort has been added (see Section 3.1.1 Part A1 Monotherapy).

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1.3.2. Combination Starting Dose Rationale
1.3.2.1. PF-04518600
The initial proposed PF-04518600 dose is 0.1 mg/kg based on safety information obtained in 
Part A monotherapy. Subsequently, the doses to be evaluated for combination are 0.3, 1.0, 
and 3 mg/kg. If preliminary data suggest that 10 mg/kg may be effective and safe, an 
additional 10 mg/kg dose may be studied in combination as well.  Except at 10 mg/kg, a
given dose of PF-04518600 will not be tested in combination with utomilumab until at least 
an one-half-log higher dose of PF-04518600 monotherapy has been deemed to be safe and 
well tolerated.  Please refer to Section 3.1.5.2 (Criteria for Dose Escalation Part B 
Combination Therapy) for dose combination level information.
1.3.2.2. Utomilumab
The proposed starting dose of utomilumab to be tested in Part B combination therapy is 
20 mg. The starting dose takes into account potential safety findings for OX40 monotherapy 
study (Part A) but also the possible overlap in safety profiles between utomilumab and 
PF-04518600. Subsequently the other dose to be evaluated for combination is 100 mg.
In the ongoing First-In-Human Phase 1 Study B1641001, utomilumab as single agent has 
been well tolerated up to the dose of 10 mg/kg (the highest planned dose level).  To date, no 
DLTs have been observed in Study B1641001, either for utomilumab as a monotherapy or 
utomilumab in combination with rituximab.  The safety profile of utomilumab either as 
single agent or in combination with rituximab was manageable without occurrence of 
treatment related life threatening (>Grade 4) adverse events (AEs).
Activities of utomilumab were observed at doses as low as 0.24 mg/kg (approximately 
20 mg) in MCC as a single agent. It is not clear if higher doses might be active as limited 
number of MCC patients (5 of 15 patients) were treated at higher doses. Responses were 
also observed with the combination of utomilumab and rituximab in R-refractory 
Non-Hodgkin's Lymphoma (NHL) as low as 0.03 mg/kg with highest active dose of 
2.4 mg/kg. These data suggest that the active dose range of utomilumab is quite broad, 
spanning an approximate 100-fold dose range. Flat utomilumab doses of 20 (approximately 
0.2 mg/kg), 100 (approximately 1.2 mg/kg), and 500 mg (approximately 6 mg/kg) are being 
tested in Study B9991004.
1.4. Rationale for Flat Dosing in Part A2 and Part B2
Based on the population PK/PD analysis using preliminary data from Part A1 (monotherapy 
dose escalation) of this study, the predicted median and 5th and 95th percentiles of 
PF-04518600 exposure parameters, particularly the trough concentrations of PF-04518600, 
over the weight range of the patient population are expected to be comparable between 
body-weight based and flat dosing. Therefore, PF-04518600 will be given as a flat dose in 
the dose expansion cohorts (Part A2 and Part B2) to simplify the dosage preparation 
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1.5. Rationale for Pre-Treatment and On-Treatment Biopsies 
PF-04518600 as a monotherapy and in combination with utomilumab is hypothesized to 
elicit its anti-tumor clinical activity by activating and enhancing anti-tumor T cell response.  
The effect on TILs in the tumor microenvironment will provide important data to estimate 
the optimal biological dose (OBD) of the PF-04518600 (see Section 3.4 Optimal Biological 
Dose).  It has been shown that OX40 has negligible expression on resting T cells in 
peripheral blood, but is much higher in TILs and in tumor draining lymph nodes in patients
with melanoma and head and neck cancer.11 Similarly, 4-1BB is expressed on activated 
immune cells including activated CD8 cells, activated NK and natural killer T (NKT) cells; 
regulatory T cells; dendritic cells (DC) including follicular DC; stimulated mast cells, 
differentiating myeloid cells, monocytes, neutrophils, eosinophils and activated 
B cells.5 This difference in receptor expression suggests potential differences between 
pharmacodynamic (immune modulatory) effects of OX40 and 4-1BB agonist in tumor verses 
peripheral blood.  All patients will be required to provide an archival biopsy sample, which 
will be shipped to the central lab after Cycle 1 Day 1 (C1D1).  Except for the first 
2-4 patients in the each dose level in Parts A1 and B1, all other patients in this study will be 
required to provide tumor biopsy samples before, and on Cycle 4 Day 1 (C4D1) after 
PF-04518600 or PF-04518600/utomilumab combination treatment.  Any CT or MRI scans 
for tumor assessments should be completed before tumor biopsy samples are collected. In 
Part A1, a second on treatment biopsy is mandatory on C7D1 for melanoma patients.  This 
second on treatment biopsy is optional for all other patients in Parts A1.  In Part A2 and B2, 
all patients will provide an archival biopsy sample.  Additionally, there will be 2 to 
3 mandatory biopsy collections: 1) fresh pre-treatment biopsy (ie, collected during 
screening), 2) on-treatment biopsy on Cycle 4 Day 1 (C4D1), 3) at time of initial response or 
initial progression (whichever occurs first), provided the biopsy is not within 4 weeks of the 
C4D1 biopsy. If a patient terminates study drug treatment before the scheduled on treatment 
biopsy at C4D1, the patient will be asked to provide a fresh biopsy at the termination visit. If 
tissue is collected from clinically indicated procedures at other time points, a portion may be 
submitted to the Sponsor.  If the Investigator judges the risk of certain on-treatment biopsies 
unacceptable for the patient (eg, based on site of tumor, potential for complications 
during/after procedure, etc.) the medical monitor must be consulted.  Part B1 patients will not 
be required to provide a second on treatment biopsy.
The number, type and location of TILs can present large heterogeneity among different 
tumor types and among patients.  Furthermore, it is hypothesized that pharmacodynamic 
effects may vary widely from patient to patient.  Therefore, each dose level in Part A1 will be 
expanded to approximately 10 patients following safety and peripheral pharmacodynamic 
assessments in the first 2-4 patients.  Patients who are part of the expansion of any dose level 
will undergo mandatory pre- and on-treatment biopsies.  To better estimate the OBD, tumor 
pharmacodynamic data from all patients will be evaluated at the end of Part A1.
While the decision to dose escalate will depend on the adjudication of the safety data from 
the initial data set of 2 to 4 patients, safety information provided by additional patients within 
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Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the PF-04518600 and PF-utomilumab IBs.6,20
1.6. Biomarker Rationale
The aim of biomarker collections and analyses is to provide evidence of target engagement 
(TE), pharmacodynamic activity and immune-modulatory (IM) activity for PF-04518600 and 
utomilumab. This will provide data to guide dose selection, and allow characterization of the 
relationship between PF-04518600/utomilumab TE, pharmacodynamic activity and any 
observed anti-tumor effects.  Furthermore, this may enable the identification of patients 
and/or tumor types most responsive to PF-04518600 alone or in combination with 
utomilumab. 
TE by PF-04518600 will be assessed by using a flow cytometry assay to measure unbound 
(free) OX40 receptor expressed on peripheral blood T cells.  The relationship between TE
and the pharmacokinetics of PF-04518600 will provide guidance for dose selection for 
PF-04518600. The measurement of TE by utomilumab has been shown to be problematic 
due to receptor down-modulation upon antibody binding and the lack of an appropriate 
antibody (Ab) reagent; therefore only total 4-1BB receptor expression on peripheral blood 
T cells will be assessed as a measure of target load.  Other pharmacodynamic measures will 
be used to inform utomilumab dose selection. The goal of this analysis will be to select 
doses that result in full TE and pharmacodynamic activity while exhibiting an acceptable 
safety profile, and potentially providing evidence of anti-tumor activity.
The pharmacodynamic effect of OX40 or OX40 plus 4-1BB agonism will be investigated in 
peripheral blood for all patients and in tumor tissues for patients enrolled into the expansion 
cohorts in Parts A1 and B1, and in expansion Phases A2 and B2. Potential effects of
PF-04518600 or PF-04518600 plus utomilumab on relative proportions and phenotypes of 
T cells (including memory and regulatory subsets) and on T cell activation status will be 
assessed by flow cytometry. In the tumor tissue samples, the phenotype, quantity and tissue 
localization of TILs will be assessed by immunohistochemistry (IHC). These evaluations of 
peripheral blood and tumor infiltrating T cell subsets will be undertaken in an effort to 
identify components of cell-based immunity responsive to dosing with PF-04518600 or 
PF-04518600 plus utomilumab, and potentially serve as a guide for tumor or patient 
selection.
 
 
 
 
 
 
 
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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Objectives for Part A Monotherapy
2.1.1.1. Objectives for Part A1 Monotherapy Dose Escalation
Primary Objective:
•
To assess safety, and tolerability at increasing dose levels of PF-04518600 in patients 
with selected advanced or metastatic solid tumors in order to establish the MTD.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in patients with 
selected advanced or metastatic solid tumors solid tumors. 
•
To characterize the single dose and multiple dose PK of PF-04518600 following 
IV administration.
•
To evaluate the immunogenicity of PF-04518600 following IV administration.
•
To characterize the degree of target engagement (TE) by PF-04518600 at multiple 
doses by measuring unbound (free) cell surface OX40 in peripheral blood. 
 
 
 
 
 
 
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2.1.1.2. Objectives for Part A2 Monotherapy Dose Expansion
Primary Objectives:
•
To establish the RP2D of PF-04518600 in patients with selected advanced or 
metastatic HCC.
•
To further characterize the safety and tolerability of PF-04518600 in patients with 
selected advanced or metastatic HCC.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in patients with 
selected advanced or metastatic HCC. 
•
To characterize the single dose and multiple dose PK of PF-04518600 following 
IV administration.
•
To evaluate the immunogenicity of PF-04518600 following IV administration.
 
 
 
 
 
 
 
 
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2.1.2. Objectives for Part B Combination Therapy
2.1.2.1. Objectives for Part B1 Combination Therapy Dose Escalation
Primary Objective:
•
To assess safety and tolerability at increasing dose levels of PF-04518600 in 
combination with utomilumab in patients with selected advanced or metastatic solid 
tumors and to estimate MTD of the combination.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in combination 
with utomilumab. 
•
To characterize single and multiple dose pharmacokinetics of PF-04518600 and 
utomilumab when given in combination.
•
To evaluate immunogenicity of PF-04518600 and utomilumab when given in 
combination.
 
 
 
 
 
 
 
 
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2.1.2.2. Objectives for Part B2 Combination Therapy Dose Expansion
Primary Objective:
•
To further assess safety and tolerability of PF-04518600 in combination with 
utomilumab in patients with melanoma or NSCLC in order to establish RP2D for the 
combination.
Secondary Objectives:
•
To assess preliminary anti-tumor clinical activity of PF-04518600 in combination 
with utomilumab. 
•
To characterize single and multiple dose pharmacokinetics of PF-04518600 and 
utomilumab when given in combination.
•
To evaluate immunogenicity of PF-04518600 and utomilumab when given in 
combination.
 
 
 
 
 
 
 
 
 
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2.2. Endpoints 
2.2.1. Endpoints for Part A Monotherapy
2.2.1.1. Endpoints for Part A1 Monotherapy Dose Escalation
Primary Endpoints:
•
Dose limiting toxicities (DLTs) observed in each patient during the first 98 days in 
order to determine the MTD.
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to study therapy PF-04518600.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ)
as data permit.
•
Incidence of ADA and NAb against PF-04518600.
•
Levels of free OX40 receptor expressed on T cells in peripheral blood.
 
 
 
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•
Levels of serum cytokines (including, but not limited to IFNγ, IL-2, IL-6, IL-10, and 
TNF-α), chemokines (including, but not limited to MIP-1 α, MIP-1β and MCP-1) 
and soluble OX40.
2.2.1.2. Endpoints for Part A2 Monotherapy Dose Expansion
Primary Endpoints:
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to study therapy PF-04518600.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA and NAb against PF-04518600.
 
 
 
 
 
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2.2.2. Endpoints for Part B Combination Therapy
2.2.2.1. Endpoints for Part B1 Combination Therapy Dose Escalation
Primary Endpoints:
•
DLTs observed in each patient during the first 98 days in order to determine the 
MTD.
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to PF-04518600/utomilumab combination.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 years.
•
Pharmacokinetic parameters of PF-04518600 and utomilumab:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA against PF-04518600 and utomilumab.
 
 
 
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2.2.2.2. Endpoints for Part B2 Combination Therapy Dose Expansion
Primary Endpoints:
•
AEs as characterized by type, frequency, severity (as graded by NCI CTCAE v 4.03), 
timing, seriousness and relationship to PF-04518600/utomilumab combination.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
Secondary Endpoints:
•
Objective tumor response, as assessed using the RECIST version 1.1 and irRECIST.
•
Anti-tumor activity assessments of: PFS, TTP, SD, DR by RECIST version 1.1 and 
irRECIST and OS.
•
Overall survival rates at 6 months, 1 year and 2 year.
•
Pharmacokinetic parameters of PF-04518600 and utomilumab:
SDo - Cmax, AUCsdo,τ, AUCinf, t1/2, as data permit.  MD (assuming steady-state is 
achieved) - Css,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, and Rac (AUCss,τ/AUCsdo,τ) 
as data permit.
•
Incidence of ADA against PF-04518600 and utomilumab.
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open label, multi-center, multiple dose, dose escalation, safety, 
pharmacokinetic, and pharmacodynamic study of PF-04518600 monotherapy (Part A) and 
PF-04518600 plus utomilumab combination therapy (Part B).  Both Part A and Part B will be 
further divided into a dose escalation phase, and a dose expansion phase (see Figure 4). 
Figure 4.
Study Schematic
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A maximum of approximately 210 patients are expected to be enrolled into the study.  
Patients will complete up to 4 weeks of screening.  Patients in Parts A1 and B1 who are part 
of the expansion of any dose level and all patients in Parts A2 and B2 will undergo 
mandatory pre- and on-treatment biopsies.  If the Investigator judges the risk of certain 
on-treatment biopsies unacceptable for the patient (eg, based on site of tumor, potential for 
complications during/after procedure, etc.) the medical monitor must be consulted (see 
Section 1.4 Rationale for Pre Treatment and On Treatment Biopsies).  Patients will receive 
doses of PF-04518600 intravenously (IV) over 60 minutes (-5 to +15 minutes) every 
2 weeks.  Patients in Part B will also receive doses of utomilumab intravenously (IV) over 
60 minutes (-5 to +15 minutes) every 28 days.  Following the initial dose, treatment with 
investigational product will continue until disease progression by irRECIST (see 
Section 0 Treatment after Initial Evidence of Radiological Disease Progression), patient 
refusal, unacceptable toxicity occurs, or the end of the study, whichever comes first.  Patients 
will be allowed to stay on study, if the treating physician feels that it is in the patient’s best 
interest, in the case of radiological progression and in the absence of clear clinical 
progression.  A follow-up visit after approximately 4 weeks after the last dose for AE and 
SAE collection will be conducted.  Assessment of late immune related responses will be 
evaluated up to 98 days after the first dose of Cycle 1. Because atypical tumor responses 
after growth of pre-existing lesions or appearance of new lesions have been observed with 
immune checkpoint inhibitors, study B0601002 will assess tumor response based on both 
response evaluation criteria in solid tumor (RECIST) and Immune-related Response Criteria 
Derived from RECIST v1.1 (irRECIST). Survival data will be collected (by phone, every 
8 weeks, see Section 6.3 Follow-up Visit, Section 7.4 Tumor Response Assessments and 
Appendix 5).85-87 The time on study can vary depending on the observed toxicity and 
potential benefit an individual patient derives.  It is estimated that patients will remain on 
treatment for approximately 12-18 weeks, making total study duration approximately 
20-26 weeks (exclusive of 2-year survival follow-up).  Actual duration can be longer, if a 
patient derives benefit from study treatment.  However, 2 years from the time of the first dose 
of investigational product of the last patient enrolled or last surviving patient (whichever is 
later) the study will be closed.
Patients having an unresolved adverse event that is possibly related to ADA formation will 
be asked to return 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 concurs with that the investigator’s assessment, up to 6 months 
from the end of treatment (EOT) or the day of early withdrawal.
3.1.1. Part A Monotherapy
3.1.1.1. Part A1 Dose Escalation
Part A1 will study doses of PF-04518600 in sequential dose levels (0.01, 0.1, 0.3, 1.5, 3 and 
10 mg/kg) of adult patients with advanced or metastatic HCC, melanoma, clear cell RCC or 
HNSCC who are unresponsive to currently available therapies or for whom no standard 
therapy is available.  Each dose level will include an initial cohort of 2-4 patients that may be 
expanded to approximately 10 patients based on peripheral pharmacodynamic data.
Approximately 3 patients enrolled in Japan will be included for at least 2 dose levels for 
safety evaluation (see Section 3.1.1.3 Japan Only).

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Approximately 58 patients will be enrolled into Part A1, which includes the 48 patients 
already enrolled in Cohorts 1-5 (see Section 1.2.1.3 for details), and ~10 patients enrolled 
into Cohort 7.  The actual number of patients enrolled will therefore depend on the observed 
safety and tolerability profile of PF-04518600 monotherapy, the number of dose levels that 
will be explored or expanded to characterize the pharmacodynamic effects, the number of 
dose levels required to identify the MTD or OBD. All Japanese patients in Part A1 should be 
hospitalized until 2nd dosing.
A modified toxicity probability interval (mTPI) method, targeting a DLT rate of 25% and an 
acceptable DLT interval (20%-30%),88 will be utilized. 
When a dose level is deemed safe following a DLT observation period of 28 days or 2 cycles
for the initial cohort of 2 to 4 patients, escalation will occur to the next dose level.  The study 
may be stopped if the drug is deemed not tolerable at the lowest dose level.  For safety 
reasons, a staggered start will be employed at all dose levels; 1 patient in each cohort of 
2-4 patients will be dosed, and observed for 48 hours before subsequent patients can be 
dosed.  If no safety concerns arise during this 48 hr period, a second patient will be enrolled 
into the same dose level.  A staggered start will not be implemented for the expansion phase 
of a dose level; that is, the first patient within the expansion cohort will not need to be 
observed for 48 hours before additional patients are enrolled into the same dose level.
Peripheral pharmacodynamic assessments of any given dose may be completed after the dose 
is deemed safe, and escalation to the next dose level has already occurred.  When peripheral 
monitoring indicates immune modulation in the first 2-4 patients, the dose level will be 
expanded to approximately 10 patients allowing better characterization of pharmacodynamic 
effects and reducing variability due to small sample size.  If no peripheral pharmacodynamic 
effects are observed for the first 2-4 patients in any dose level, the dose level will not be 
expanded. 
Patients who are part of the expansion of any dose level will undergo mandatory pre- and 
on-treatment biopsies (See Schedule of Activities for specifics).  To better estimate the OBD, 
tumor pharmacodynamic data from all patients will be evaluated at the end of Part A1.
Safety information provided by additional patients enrolled into each dose expansion cohort 
will be taken into account for RP2D determination.  If the DLT rate is estimated to reach 
30% or more at any dose level, enrollment at that level and all higher levels will be 
temporarily stopped and the safety data will be analyzed.  Decision on moving forward will 
follow the same DLT target as described previously.  Dose escalation will continue until an 
MTD has been established, maximum dose level (20 mg/kg, please see Section 3.1.5 Criteria 
for Dose Escalation) has been reached or until three sequential dose levels show a similar 
pharmacodynamic signal. 
Late immune related DLTs that occur during the first 98 days (or first 7 cycles if patient 
remains on treatment) will be taken into account for MTD determination (see 
Section 3.2.1 Late Immune Related DLTs and Section 6.3 Follow-up Visit).  If late immune 
related DLTs occur, all safety data will be reviewed and a decision will be made whether or 
not to permanently stop enrollment in the higher cohorts and declare the MTD, to continue 
enrollment in the cohort, to increase the number of patients evaluated in that cohort or to stop 
the study. 

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Dose levels selected for Part A2 are based on data from Part A1.
The proposed doses, schedule(s) and PK time points may be reconsidered and amended 
during the study based on the emerging safety and pharmacokinetic data.  Lower, 
intermediate and higher dose cohorts (maximum of 20 mg/kg, refer to Section 3.1.5 Criteria
for Dose Escalation) can be added.  Higher dose cohorts can only be initiated if the next 
lowest level is deemed safe.
3.1.1.2. Part A2 Dose Expansion
Part A2 monotherapy dose expansion phase will randomize HCC patients 1:1 to flat dose 
levels of either 30 mg (Arm 1) or 250 mg (Arm 2) of PF-04518600 given every 2 weeks up 
to 20 patients per arm. These are doses chosen based on the following preliminary data from 
Part A1.
1. Partial responses were observed in 1 melanoma and 1 HCC patient at 0.1 (n=10) and 
0.3 mg/kg (n=11) dose levels. Full receptor occupancy in peripheral T cells was 
observed in both responders. 
2. Full receptor occupancy was achieved for all patients at doses ≥0.3 mg/kg. 
The flat dose that is equivalent to 0.3 mg/kg was determined to be 25 mg in terms of 
matching the center of the distributions based on the population PK/PD analysis using 
preliminary data from Part A1 of this study. However, 30 mg was chosen as the low dose 
(Arm 1) for Part A2 to ensure the 5th percentile of trough concentrations (Ctrough) to be at or 
above which the full receptor occupancy was observed. 
Although no responses were observed in the 3 mg/kg cohort, increases in peripheral blood 
central memory CD4 T cell proliferation and activation similar to the increases found at the 
0.1 mg/kg were observed at 3 mg/kg. Therefore, Arm 2 will evaluate a 3 mg/kg flat dose 
equivalent of 250 mg.
An additional flat dose level of 800 mg, approximately equivalent to 10 mg/kg, may be 
added after initiation of enrollment into Arms 1 and 2 if this is supported by emerging data 
from the 10 mg/kg cohort of Part A1.
All patients in A2 will undergo mandatory pre- and on-treatment biopsies (See Schedule of 
Activities for specifics).
If preliminary sign of efficacy from Part A1, or emerging data from other OX40 agonist 
programs indicate a rationale for exploration of a different tumor type, these may be added or 
substituted for HCC patients. 
 
 
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3.1.2. Part B Combination Therapy
3.1.2.1. Part B1 Dose Escalation
After initial safety data have been evaluated and deemed safe for the first 3 dose levels in 
Part A1, Part B will be initiated.  Part B1, the combination therapy dose escalation phase, 
will enroll approximately 55 patients. At least 6 patients must have been evaluated for the 
28 day DLT observation period at the 0.3 mg/kg dose level in Part A1 OX40 monotherapy
before Part B1 can be initiated.  Part B1 will study sequential dose levels of 
PF-04518600 (0.1, 0.3, 1.0 and 3 mg/kg, with an option of 10 mg/kg pending data from 
Part A1) combined with 20 mg or 100 mg of utomilumab in adult patients with NSCLC, 
HNSCC, melanoma, bladder, gastric or cervical cancer who are unresponsive to currently 
available therapies or for whom no standard therapy is available. The starting dose level will 
be 0.1 mg/kg of PF-04518600 and 20 mg of utomilumab, given no sooner than 30 minutes 
apart (for dosing schedule, please see Section 5.4.2 Administration Part B Combination 
Therapy). Based on emerging data in the 10 mg/kg Part A1 cohort, an optional cohort of 
10 mg/kg PF-04518600 in combination with 100 mg of utomilumab may be evaluated. If 
patients at the 0.3 mg/kg dose level in Part A1 OX40 monotherapy experiences 
≥Grade 2 immune related toxicities or cytokine release syndrome, starting dose of 
PF-04518600 will be 0.01 mg/kg combined with 20 mg of utomilumab. 
The mTPI method for dose escalation adopted for PF-04518600 monotherapy in Part A1 will 
also be used in PF-04518600/utomilumab combination therapy in Part B1, and targets a dose 
limiting toxicities (DLT) rate of 25% and an acceptable DLT interval (20%-30%),7 will be 
utilized for dose escalation (see Section 3.1.5 Criteria for Dose Escalation).88
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Figure 5.
Dose Escalation Scheme based on the Proposed Doses for PF-04518600 and 
Utomilumab
Y (500)
100
3
4
5
**6
20
1*
1
2
10
-1*
-1
0.01
0.1
0.3
1
3
10
Utomilumab (mg)
PF-04518600 (mg/kg)
* If first 6 patients at the 0.3 mg/kg dose level in Part A1 OX40 monotherapy experience Grade 2 immune 
related toxicities or cytokine release syndrome, starting dose of PF-04518600 will be 0.01 mg/kg combined 
with 20 mg of utomilumab in Part B1. 
** Based on emerging data in the 10 mg/kg Part A1 cohort, an optional cohort of 10 mg/kg PF-04518600 in 
combination with 100 mg of utomilumab may be evaluated.
An initial 2 to 4 patient may be enrolled initially into each dose level combination.  Fresh 
biopsies will not be required for these patients.  The mTPI model performs dose escalation by 
increasing or decreasing the dose of either PF-04518600, utomilumab or both based on the 
observed number and/or nature of DLTs at the current dose combination level (see Figure 5). 
The starting dose combination level will be 0.1 mg/kg PF-04518600 combined with 20 mg of 
utomilumab.  If no DLTs are observed, the next dose combination level will be 0.3 mg/kg 
PF-04518600 combined with 20 mg of utomilumab.  If no toxicity is observed, the dose of 
PF-04518600 will continue to be increased (see Figure 5).  If toxicity is observed at the 
starting dose combination level, 0.1 mg/kg PF-04518600 combined with 10 mg of 
utomilumab will be evaluated.  Subsequent to the initial dose, if dose de-escalation is 
recommended after evaluation, intermediate dose levels between the previous dose 
combination and current dose combination may be studied.  Using the observed data, 1 or 
more dose combination levels of PF-04518600 and utomilumab with toxicity rate closest to, 

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but not exceeding, the predefined target rate of 25% will be identified.  If the starting dose is 
deemed not tolerable, the next dose combination level will be 0.1 mg/kg 
PF-04518600 combined with 10 mg of utomilumab.
When a dose combination level is deemed safe following a DLT observation period of 
28 days or 2 cycles (of PF-04518600), escalation will occur to the next dose combination
level.  A staggered start will be employed for all dose combination levels; that is, the first 
patient for any dose combination level will be dosed, and observed for 48 hours before 
subsequent patients can be dosed.  If no safety concerns arise during this 48 hr period, a 
second patient will be enrolled into the same dose combination level. 
Peripheral pharmacodynamic assessments of any given dose combination level may be 
completed after the dose combination level is deemed safe, and escalation to the next dose 
combination level has already occurred.  When peripheral monitoring indicates immune 
modulation in the first 2-4 patients, the dose level will be expanded to approximately 
10 patients allowing better characterization of pharmacodynamic effects and reducing 
variability due to small sample size.  To allow for better characterization of 
pharmacodynamic effects, these additional patients will undergo mandatory pre-treatment 
and on treatment biopsies (See Schedule of Activities for specifics).  If no peripheral 
pharmacodynamic effects are observed for the first 2-4 patients in any dose combination
level, the dose combination level will not be expanded. 
3.1.2.2. Part B2 Dose Expansion
Part B2 combination therapy dose expansion phase will further evaluate safety and 
anti-tumor activity of the combination with a dosing regimen selected based on results of 
Part B1 with flat dose equivalents of PF-04518600. 
From the results of Part B1, the selected dose for PF-04518600 in the B2 combination 
therapy dose expansion cohorts is 30 mg (a flat dose equivalent to 0.3 mg/kg) intravenously 
(IV) Q2W in combination with PF-05082566 20 mg IV every 28 days.
Part B2 will be divided into 2 arms:
Arm 1 will enroll melanoma patients who have either:
a.
Ocular melanoma patients with advanced/metastatic disease; or,
b. Cutaneous/acral melanoma patients with advanced/metastatic disease who have 
received checkpoint inhibitor (anti-PD-L1, anti-PD-1, or anti-CTLA4) based 
treatment on which disease progressed. [Note:  Checkpoint inhibitor may have been 
part of a combination therapy, as long as the combination did not contain OX40 or 
4-1BB agonist.]  Any questions on prior treatment may be discussed with the 
Sponsor.

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Arm 2 will enroll NSCLC patients who have: 
a.
Histological or cytological diagnosis of NSCLC with advanced/metastatic disease.  
Patients must have previously received prior anti-PD-L1 or anti-PD-1 mAb on which 
disease progressed. [Note:  Previous anti-PD-L1 or anti-PD-1 mAb may have been 
part of a combination therapy, eg in combination with chemotherapy, as long as the 
combination did not contain OX40 or 4-1BB agonist.]
Part B2 will initially enroll up to 20 patients in each arm (including approximately 5 ocular 
melanoma patients in Arm 1), and all patients will undergo mandatory pre- and on-treatment 
tumor biopsies. If the Investigator judges the risk of certain on-treatment biopsies 
unacceptable for the patient (eg, based on site of tumor, potential for complications 
during/after procedure, etc.) the medical monitor must be consulted (see 
Section 1.4 Rationale for Pretreatment and On-treatment Biopsies).
The dose level of PF-04518600 and the dose level of utomilumab within the dose 
combination level will be selected from MTD or OBD established in Part B1. If the MTD is 
not reached, the maximum administered dose (MAD) maybe selected. A flat dosing strategy 
for PF-04518600, similar to one implemented for Part A2, will be implemented if supported 
by PK data.
Based on emerging data from Parts B1 and B2, if no response has been seen by the time the 
10th patient enrolls in either arm in B2, enrollment may pause until a patient experiences a 
response or after the 16 week tumor assessment for the 10th patient, whichever is first. If at 
least 1 response does not occur in the first 10 patients in an arm, then enrollment may stop in 
that arm. Enrollment will continue in any arm that has at least 1 responder in the first 
10 patients. If there are responders in both arms before the 10th patient enrolls, then 
enrollment will continue to the full 20 patients for each arm.
3.1.2.3. Japan participation in Part B Combination Therapy
Japan will participate in Part B after safety of PF-04518600 of at least 2 dose levels as a 
single agent has been evaluated in Japanese patients (See Section 3.1.1.3 Japan Cohorts in 
Part A Monotherapy).  Following the completion of the safety assessment of at least 2 dose 
levels for Japanese patients in Part A1, and if deemed acceptable by the local health 
authorities, the combination of PF-04518600 with utomilumab may also be tested in order to 
evaluate the safety of the combination therapy in patients enrolled in Japan. 
3.1.3. Enrollment Prioritization
3.1.3.1. Dose Escalation Phase
For both Part A1 monotherapy and Part B1 combination therapy dose escalation phases
(except for Japan), once a monotherapy dose level or combination dose level is open for 
enrollment, first priority will be given to the recruitment of the first 2-4 patients into that 
dose level. If a DLT occurs in the first 2-4 patients at a dose level, second recruitment 
priority will be given to the expansion of that dose level. Third recruitment priority will be 
given to the expansion of any dose level (monotherapy or combination) based on 
pharmacodynamic assessment trigger.  During expansion of multiple dose levels for 
pharmacodynamic assessments, patients will be recruited into the lowest available dose level 
first. 

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3.1.4. Starting Dose
The initial starting dose for monotherapy PF-04518600 (Part A1) is 0.01 mg/kg.  In Part B1, 
the starting dose combination level will be 0.1 mg/kg PF-04518600 combined with 20 mg of 
utomilumab.  PF-04518600 will be given once in 2 week cycles, and utomilumab will be 
given once every other cycle.
3.1.5. Criteria for Dose Escalation
3.1.5.1. Part A Monotherapy
A mTPI method, targeting a DLT rate of 25% and an acceptable DLT interval 
(20%-30%),88 will be utilized in Part A1 dose escalation phase.  Initial 2 to 4 patients will be 
enrolled in each cohort with a target size of 3 patients.  In dose cohorts with 2 patients 
enrolled, an additional patient may be enrolled for dose escalation assessment if one of the 
two patients has a DLT event observed.  Decisions to escalate to the next dose level will be 
determined using safety assessments obtained from these initial 2-4 patients. 
The dose levels to be evaluated are listed in Table 2. Beginning with the starting dose of 
0.01 mg/kg, if either a DLT related to PF-04518600 or a grade 2 cytokine release syndrome, 
infusion reaction, or allergic reaction is observed, subsequent dosages will not be increased 
by more than 3-fold, or one- half a log (eg, increases from 0.01 mg/kg will be to 0.03 mg/kg,
and increases from 0.3 mg/ kg will be to 1.0 mg/kg). If dosages greater than 3 mg/kg are 
evaluated, if DLTs are absent, subsequent dose levels may include a maximum of 5-fold 
increase.  If a DLT considered related to PF-04518600 is observed, the next dose level will 
not be greater than 3-fold the previous dose level.  Up to a maximum of 20 mg/kg may be 
evaluated.  If a high DLT rate is observed at the starting dose, the study may be stopped. 
Table 2.
Table of Potential Dose Levels
Cohort
Dose
(mg/kg)
1
0.01
2
0.1
3
0.3
4
1.5
5
3
6
TBD: maximum 6.0 (optional)
7
10
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in prior and current cohorts at the same dose level to determine where future cohorts 
should be on dose escalation, no change in dose, or dose de-escalation. 
The algorithm will stop if any of the following criteria is met:
1. The maximum sample size has been achieved (approximately 58 patients total).

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2. A minimum of 9 patients have been accumulated on a dose that is predicted to be the 
MTD or MAD; or,
3. All doses explored appear to be overly toxic and the MTD cannot be determined.
All clinically relevant AEs and SAEs will be reviewed by the sponsor and investigators to 
determine if the dose allocation schedule requires modification. 
Table 3.
Decision Rules
Number of Patients Treated at a Dose level
Number of 
Patients 
Having DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10 n=11 n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
n/a
S
S
S
E
E
E
E
E
E
E
2
U
D
D
S
S
S
S
S
S
S
S
3
U
U
D
D
S
S
S
S
S
S
4
U
U
U
D
D
D
D
D
S
5
U
U
U
U
U
D
D
D
6
U
U
U
U
U
U
D
7
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; 
U: Unacceptable toxicity; n/a: Not applicable
Patients experiencing a DLT may be managed with dose modification (after dose 
interruption) or discontinuation.  Subsequent dose levels may not be opened until the first 
2-4 patients entered at the current dose level have been treated and observed for at least two 
complete cycles and the number of DLTs among those patients in their first two cycles has 
been determined. 
If a patient withdraws from the study before Day 28 for reasons other than investigational 
product-related toxicity (see Section 3.2 DLT Definition), another patient may be enrolled to 
replace that patient at the current dose level.  In principle, all patients must be evaluated for 
28 days.  However, if a patient withdraws close to Day 28 for reasons other than toxicity and 
is due to a clear unrelated drug event (eg, traffic accident, clear disease progression), the 
patient may be deemed evaluable for safety if safety assessments have been unremarkable, 

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and the investigator and sponsor’s medical monitor both agree that the patient is evaluable 
for DLT safety observation.
The dose escalation portion of the study is completed when at least 9 evaluable patients have 
been treated at the highest dose associated with a mean DLT rate of 25%. 
3.1.5.2. Part B Combination Therapy
The dose escalation scheme based on mTPI method described in Section 3.1.5.1 will also be 
used in Part B Combination Therapy. The potential dose combination level of 
PF-04518600 and utomilumab are depicted in Figure 5.
Similar to Part A, the dose escalation portion of Part B is completed when at least 9 evaluable 
patients have been treated at the highest dose combination level(s) associated with a DLT 
rate of 25%. 
Selected dose for PF-04518600 in the B2 combination therapy dose expansion cohorts is 
30 mg (a flat dose equivalent to 0.3 mg/kg) intravenously (IV) Q2W in combination with 
PF-05082566 20 mg IV every 28 days.
3.2. DLT Definition
Severity of adverse events will be graded according to CTCAE version 4.03 (see 
Appendix 2).  For the purpose of dose escalation, any of the following adverse events 
occurring in the first two cycle of treatment (28 days) will be classified as DLTs, unless there 
is a clear alternative explanation (eg, related to underlying disease/progression):
Hematologic:

Grade 4 neutropenia lasting >7 days.

Febrile neutropenia (defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.5C (101.3F) or a sustained temperature of 38C 
(100.4F) for more than 1 hour.

Grade 3 neutropenic infection.

Grade 3 thrombocytopenia with clinically significant bleeding or requiring medical 
intervention [eg, transfusion].

Grade 4 thrombocytopenia.

any <10.000;

10.000-25.000 for >5 days*.

Grade 4 anemia.

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
Grade ≥3 anemia related to hemolysis or autoimmune disease (>2 g/dL decrease in 
hemoglobin requiring medical intervention [transfusion or steroids]).

Non-hematologic:

Grade 3 toxicities that are considered clinically significant, including cytokine 
release syndrome, infusion reactions and allergic reactions, except those that have not 
been maximally treated (eg, nausea, vomiting, diarrhea) or can be easily treated 
(eg, electrolyte abnormalities).
In addition, clinically important or persistent toxicities (eg, toxicities responsible for 
significant dose delay as described in Section 5.4.5.5 Dose Delay) that are not included in the 
above criteria may be considered a DLT following review by Pfizer and the investigators.  
All DLTs need to represent a clinically significant shift from baseline.
*Specifically for HCC patients entering with a lower baseline value of platelets, change from 
baseline needs to be taken into consideration.
Information regarding DLT observation period can be found in Section 3.1.5 (Criteria for 
Dose Escalation). Whilst DLT observation for 28 days is required for dose escalation, safety 
and tolerability assessment for the first 98 days (or completion of 7 cycles) will be taken into 
account for MTD and RP2D selection (see Section 3.3, MTD definition). During the 98 day 
assessment period, specific attention will be paid to late immune-related AEs (see 
Section 3.2.1 Late Immune Related DLTs).  Late immune-related AE information will be 
collected from patients who withdraw after 1 to 6 cycles of treatment during follow up visits
(see Section 6.3 Follow-up Visit). 
3.2.1. Late Immune Related DLTs
Late immune related DLTs are immune-related AEs that meet the same grading criteria as 
DLT criteria and occur from Day 29 through the 98 day assessment period (or completion of 
first 7 cycles if patient remains on treatment).  If late immune related DLTs occur, enrollment 
into any higher dose level cohorts will be placed on temporarily hold. All safety data will be 
reviewed, and a decision will be made to either:

Continue enrollment in higher dose level cohorts.

Increase the number of patients in the cohort in which the immune-related DLT
occurred to 6 total patients.  If the cohort has already recruited 6 patients, the number 
of patients should be increased to 9 total patients.  All patients will be followed for at 
least 98 days to reassess safety at this dose level.  If no other late immune-related 
DLTs are observed (total late immune-related DLT rate is 1 out of 6 or 1 out of 9), 
enrollment in higher dose level cohorts may resume.  If after the enrollment of 
additional patients the late immune-related DLT rate increases to 2 or more patients 
out of 6, this dose level will be considered above the MTD.  In this case, the next 
lower dose level cohort will be expanded to 6 then 9 total patients to reassess safety at 
that dose level. 

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•
Permanently stop enrollment in higher dose level cohorts, and declare the dose level 
to be above MTD.  Increase the number of patients in the next lowest dose level 
cohort to 6 then 9 total patients and follow all patients for at least 98 days to reassess 
safety at this dose level. 
•
Stop the study. 
For any given patient that is on-treatment at dose levels that are subsequently considered to 
be above the MTD, the option to dose reduce will be discussed (see Section 5.4.5.6 Dose
Reductions, Interruptions and Discontinuation Criteria).  If a patient tolerated the above 
MTD dose level well and is benefiting, continuation of treatment at the above MTD dose 
level will require re-consenting.
3.3. Maximum Tolerated Dose (MTD) Definition
The estimated MTD is the dose level associated with approximately 25% of patients 
experiencing DLT.  The target interval for the DLT rate is 20%-30%.  Due to the discreteness 
of the dose levels and in the interest of safety of patients, the estimated MTD is the highest 
tested dose level with mean DLT rate ≤0.25 in at least 9 DLT evaluable patients.  This is with 
the exception of Grade 4 and 3 cytokine release syndrome, infusion reaction or allergic 
reaction.  If ≥1 patient out of 6 (or ≥17%) experiences a Grade 4 cytokine release syndrome, 
infusion reaction or allergic reaction, or if 2 patients out of 6 (33%) experiences 
Grade 3 cytokine release syndrome, infusion reaction or allergic reaction, the dose level will 
be considered to be above the MTD.  All safety data will be evaluated and a decision will be 
made whether or not to permanently stop enrollment in the higher cohorts and declare the 
MTD, to continue enrollment in the cohort, to increase the number of patients evaluated in 
that cohort or to stop the study (see Section 3.2.1 Late Immune Related DLTs).  The 
cumulative incidence of all late immune related DLTs will be taken into account for 
determination of the MTD/RP2D. An interim safety analysis will be triggered if the overall 
cumulative incidence of late immune related DLTs increases above 25% across all dose 
levels.  If a clear dose response is observed, the study may resume enrollment at the lowest 
dose level with incidence in 1 or less patients out of 6. If the incidences of late immune 
related DLTs do not appear to have a dose response relationship (ie, consistently observed in 
all dose levels), the option to terminate the study will be considered. 
3.4. Optimal Biological Dose (OBD) Definitions
The Optimal Biological Dose (OBD) is the lowest dose that can produce a pharmacodynamic 
effect that is consistent with the proposed mechanism with an acceptable toxicity.  
 
 
 
 
 
 
3.5. Maximum Administered Dose (MAD)
The Maximum Administered Dose (MAD) is the highest dose administered.
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3.6. Recommended Phase 2 Dose (RP2D) Definition
The Recommended Phase 2 Dose (RP2D) is the dose chosen for further study based on 
Phase 1 results.  If the MTD proves to be clinically feasible for long term administration in a 
reasonable number of patients, such dose usually becomes the RP2D.  Further experience 
with the MTD may result in a RP2D dose lower than the MTD.  Next to safety assessment, 
careful consideration will be given to pharmacodynamic effects.  If an OBD can be 
determined, this will be a key factor in the determination of the RP2D.
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.
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are enrolled in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
4.1.1. Part A Monotherapy
1. Part A1 only: Patients with histological or cytological diagnosis of HNSCC, HCC, 
melanoma, or clear cell RCC who progressed on or are intolerant to standard therapy, 
for which no standard therapy is available or who decline standard therapy.
2. Part A2 only: Patients with histological or cytological diagnosis of 
advanced/metastatic HCC who are treatment naïve and have declined standard of 
care, or have had at least 1 prior line of systemic therapy.  Prior 
anti-PD-L1/PD-1 therapy is allowed. 
3. Patients must have at least one measurable lesion as defined by RECIST version 1.1,
be willing to undergo the mandatory biopsies and there is no excessive risk from 
biopsy as judged by the Investigator.
4. Adults (men and women) age 18 years (for Japan only: 20 years of age). 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
6. Adequate Bone Marrow Function, including:

ANC 1,500/mm3 or 1.5 x 109/L.

ANC for HCC only ≥1,000/mm3 or 1.0 x 109/L.

Platelets 100,000/mm3 or 100 x 109/L.

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
Platelets for HCC only: 60,000/mm3. 

Hemoglobin 9 g/dL.  Limited transfusions to reach this value are allowed, after 
discussion with sponsor’s medical monitor.  There should not be a chronic need 
for transfusions in the recent (approximately 3 month) past.
7. Adequate Renal Function, including:

Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 60 ml/min as calculated using the method standard for the institution.  
If an estimated creatinine clearance is believed to be inaccurate for a patient, 24 hr 
urine collection with actual assessment of creatinine clearance is allowed.
8. Adequate Liver Function (all patients, except HCC, see Inclusion Criteria 9), 
including:

Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome.

Aspartate and alanine aminotransferase (AST & ALT) 2.5 x ULN; 5.0 x ULN 
if there is liver involvement secondary to tumor.
9. Inclusion for HCC patients only:

Child-Pugh Class A or B with a score of 7 (see Appendix 3) and no prior history 
of hepatic encephalopathy.

Serum bilirubin 3 mg/dL.

Serum Albumin 2.8 g/dL.

AST and ALT 5.0 x ULN.

International Normalized Ratio (INR) 2.3 or Prothrombin Time (PT) 6 seconds 
above control.
10. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE 
except for AEs not constituting a safety risk by investigator judgment.
11. Serum or urine pregnancy test (for women of childbearing potential) negative at 
screening and at the baseline visit before the patient may receive the investigational 
product).
12. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two highly effective method(s) of contraception throughout the study and 
for at least 90 days after the last dose of assigned treatment.

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Female patients, who are not of childbearing potential as defined below, are eligible 
to be included (ie, meet at least one of the following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy.

Have medically confirmed ovarian failure; or,

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women. 
13. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
14. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures.
4.1.2. Part B Combination Therapy
1. Part B1 only: Patients with histological or cytological diagnosis of NSCLC, HNSCC, 
melanoma, urothelial bladder carcinoma (including renal pelvis, ureters, urinary 
bladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix who 
progressed on or are intolerant to standard therapy, for which no standard therapy is 
available, or who decline standard therapy.
2. Part B2 Arm 1 only:
a.
Ocular melanoma patients with advanced/metastatic disease; or,
b. Cutaneous/acral melanoma patients with advanced/metastatic disease who have 
received checkpoint inhibitor (anti-PD-L1, anti-PD-1, or anti-CTLA4) based 
treatment on which disease progressed. [Note:  Checkpoint inhibitor may have 
been part of a combination therapy, as long as the combination did not contain 
OX40 or 4-1BB agonist.]  Any questions on prior treatment may be discussed 
with the Sponsor.
3. Part B2 Arm 2 only: Histological or cytological diagnosis of NSCLC with 
advanced/metastatic disease.  Patients must have previously received prior 
anti-PD-L1 or anti-PD-1 mAb on which disease progressed. [Note: Previous 
anti-PD-L1 or anti-PD-1 mAb may have been part of a combination therapy, eg, in 
combination with chemotherapy, as long as the combination did not contain OX40 or 
4-1BB agonist.]
4. Patients must have at least one measurable lesion as defined by RECIST version 1.1,
be willing to undergo the mandatory biopsies and there is no excessive risk from a 
biopsy as judged by the Investigator.

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5. Adults (men and women) age 18 years (for Japan only: 20 years of age). 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
7. Adequate Bone Marrow Function, including:

ANC 1,500/mm3 or 1.5 x 109/L.

Platelets 100,000/mm3 or 100 x 109/L.

Hemoglobin 9 g/dL.  Limited transfusions to reach this value are allowed, after 
discussion with sponsor’s medical monitor.  There should not be a chronic need 
for transfusions in the recent (approximately 3 month) past.
8. Adequate Renal Function, including:

Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 60 ml/min as calculated using the method standard for the institution.  
If an estimated creatinine clearance is believed to be inaccurate for a patient, 24 hr 
urine collection with actual assessment of creatinine clearance is allowed.
9. Adequate Liver Function including:

Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome.

Aspartate and alanine aminotransferase (AST & ALT) 2.5 x ULN.
10. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE 
except for AEs not constituting a safety risk by investigator judgment.
11. Serum or urine pregnancy test (for women of childbearing potential) negative at 
screening and at the baseline visit before the patient may receive the investigational 
product).
12. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two highly effective method(s) of contraception throughout the study and 
for at least 90 days after the last dose of assigned treatment. 
Female patients, who are not of childbearing potential as defined below, are eligible 
to be included (ie, meet at least one of the following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy.

Have medically confirmed ovarian failure; or,

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
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women.
13. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
14. Patients who are willing and able to comply with 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:
4.2.1. Part A Monotherapy
1. Patients with known symptomatic brain metastases requiring systemic corticosteroids.  
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.  Mild neurological deficits are allowed, if they do not interfere 
with the ability to judge the safety profile of PF-04518600.
2. History of or active autoimmune disorders (including but not limited to: Crohn’s 
Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave’s 
disease) and other conditions that compromise or impair the immune system.
3. Active bacterial, fungal or viral infection including hepatitis B (HBV, see exception 
below for patients with HCC), hepatitis C (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS) -related illness.
For Part A1 patients with HCC only: after the safety profile of a cohort has been 
established in 2-4 patients, and escalation to the next higher dose level has taken 
place, HCC patients enrolled into the expansion lower dose cohort meeting the 
following criteria can be enrolled: patients infected with the HBV or HCV but with 
minimal viral load (<20 IU/ml) at the moment of screening and who are being treated 
with either entecavir or tenofovir during the full study period.
For Part A2 HCC patients: patients with chronic HCV infection are allowed; 
however, patients with chronic HBV infection must be receiving effective antiviral 
therapy (viral load <100 IU/ml).  Patients with active coinfection with HBV and 
HCV, active coinfection with HBV and hepatitis D virus are excluded.  The following 
HCC subtypes are also exclusionary: fibrolamellar HCC, sarcomatoid HCC, and 
mixed cholangiocarcinoma.
4. Bleeding esophageal or gastric varices <2 months prior to informed consent 
document (ICD) date.

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5. Unmanageable ascites (limited medical treatment to control ascites is permitted, but 
all patients with ascites will require review by sponsor’s medical monitor).
6. Major surgery within 4 weeks of starting study treatment.
7. Patients who have undergone solid organ or hematopoietic transplant.
8. Systemic anti-cancer therapy within 4 weeks of starting study treatment (6 weeks for 
mitomycin C or nitrosoureas).  If systemic anti-cancer therapy was given within 
4 weeks, patient may be included if 4-5 times elimination half-life of drug has passed.
9. Radiation therapy within 4 weeks of starting study treatment, except: palliative 
radiotherapy to a limited field is allowed after consultation with sponsor’s medical 
monitor at any time during study participation, including during screening. 
10. Previous high dose chemotherapy requiring stem cell rescue.
11. Prior treatment with an OX40 agonist.
12. Currently require doses of systemic immune suppressive medication [eg, 10 mg of 
prednisone or equivalent (1.5 mg of dexamethasone)]. 
13. History of Grade 3 or higher immune-mediated adverse event (including AST/ALT 
elevations that where considered drug related and cytokine release syndrome) that 
was considered related to prior immune-modulatory therapy (eg, checkpoint 
inhibitors, co-stimulatory agents etc.) or any grade immune-related AEs that required 
immune suppressive therapy.
14. Patients with intolerance to or who have had a severe (Grade 3) allergic or 
anaphylactic reaction to antibodies or infused therapeutic proteins, or patients who 
have had a severe allergic or anaphylactic reaction to any of the substances included 
in the investigational product (including excipients).
15. Patients with a previous history of anthracycline treatment and are at risk of cardiac 
failure (New York Heart Association [NYHA] Class II or above).
16. Any one of the following currently or in the previous 6 months: myocardial 
infarction, congenital long QT syndrome, torsade’s de points, arrhythmias (including 
sustained ventricular tachyarrhythmia and ventricular fibrillation), and left anterior 
hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (CHF New York Heart Association 
class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic 
pulmonary embolism or other clinical significant episode of thrombo-embolic 
disease*.  Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, atrial fibrillation 
of any grade, or QTcF interval >470 msec at screening (except in case of right bundle 
branch block, these cases must be discussed with sponsor’s medical monitor).  *Cases 
must be discussed in detail with sponsor’s medical monitor to judge eligibility.  

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Anticoagulation (heparin and trypsin-like serine protease (factor Xa) inhibitors only, 
no vitamin-K antagonists) will be allowed if indicated. 
17. Participation in other interventional studies within 28 days before the current study 
begins and/or during study participation. Before joining Study B0601002, at least 
28 days must have passed from last systemic study therapy administration.  
Participation in long term follow up is allowed if no procedures which may interfere 
with the interpretation of study results will be performed.
18. Patients in the 0.01 mg/kg cohort must not be 50 kg in weight.
19. Pregnant female patients; breastfeeding female patients (including patients who are 
weaning their infants).
20. 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 or sponsor’s medical monitor, 
would make the patient inappropriate for entry into this study.
21. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
4.2.2. Part B Combination Therapy
1. Patients with known symptomatic brain metastases requiring systemic corticosteroids.  
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.  Mild neurological deficits are allowed, if they do not interfere 
with the ability to judge the safety profile of PF-04518600/utomilumab.
2. History of or active autoimmune disorders (including but not limited to: Crohn’s 
Disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave’s 
disease) and other conditions that compromise or impair the immune system.
3. Active bacterial, fungal or viral infection including HBV, HCV, known human HIV 
or AIDS -related illness.
4. Bleeding esophageal or gastric varices <2 months prior to ICD date.
5. Unmanageable ascites (limited medical treatment to control ascites is permitted, but 
all patients with ascites will require review by sponsor’s medical monitor).

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6. Major surgery within 4 weeks of starting study treatment.
7. Patients who have undergone solid organ or hematopoietic transplant.
8. Systemic anti-cancer therapy within 4 weeks of starting study treatment (6 weeks for 
mitomycin C or nitrosoureas).  If systemic anti-cancer therapy was given within 
4 weeks, patient may be included if 4-5 times elimination half-life of drug has passed.
9. Radiation therapy within 4 weeks of starting study treatment, except: palliative 
radiotherapy to a limited field is allowed after consultation with sponsor’s medical 
monitor at any time during study participation, including during screening. 
10. Previous high dose chemotherapy requiring stem cell rescue.
11. Prior treatment with an OX40 agonist or a 4-1BB agonist.
12. Currently require doses of systemic immune suppressive medication [eg, 10 mg of 
prednisone or equivalent (1.5 mg of dexamethasone)]. 
13. History of Grade 3 or higher immune-mediated adverse event (including AST/ALT 
elevations that where considered drug related and cytokine release syndrome) that 
was considered related to prior immune-modulatory therapy (eg, checkpoint 
inhibitors, co-stimulatory agents etc.) or any grade immune-related AEs that required 
immune suppressive therapy.
14. Patients with intolerance to or who have had a severe (Grade 3) allergic or 
anaphylactic reaction to antibodies or infused therapeutic proteins, or patients who 
have had a severe allergic or anaphylactic reaction to any of the substances included 
in the investigational products (including excipients).
15. Patients with a previous history of anthracycline treatment and are at risk of cardiac 
failure (NYHA Class II or above).
16. Any one of the following currently or in the previous 6 months: myocardial 
infarction, congenital long QT syndrome, torsade’s de points, arrhythmias (including 
sustained ventricular tachyarrhythmia and ventricular fibrillation), and left anterior 
hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (CHF New York Heart Association 
class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic 
pulmonary embolism or other clinical significant episode of thrombo-embolic 
disease*.  Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, atrial fibrillation 
of any grade, or QTcF interval >470 msec at screening (except in case of right bundle 
branch block, these cases must be discussed with sponsor’s medical monitor).  *Cases 
must be discussed in detail with sponsor’s medical monitor to judge eligibility.  
Anticoagulation (heparin and factor Xa inhibitors only, no vitamin-K antagonists) 
will be allowed if indicated. 

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17. Participation in other interventional studies within 28 days before the current study 
begins and/or during study participation. Before joining Study B0601002, at least 
28 days must have passed from last systemic study therapy administration.  
Participation in long term follow up is allowed if no procedures which may interfere 
with the interpretation of study results will be performed. 
18. Pregnant female patients; breastfeeding female patients (including patients who are 
weaning their infants).
19. Patients that will receive 0.01 mg/kg PF-04518600 must not be 50 kg in weight.
20. 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 or sponsor’s medical monitor, 
would make the patient inappropriate for entry into this study.
21. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
4.3. Lifestyle Guidelines
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive PF-04518600 or PF-04518600 in combination with 
utomilumab, which is a compound for which the teratogenic risk is currently unknown.  Two 
(2) methods of highly effective contraception must be used throughout the study and 
continued for 90 days after the last dose.  The investigator or his/her designee, in consultation 
with the patient will confirm the patient has selected two appropriate methods of 
contraception for the individual patient from the list of permitted contraception methods (see 
below) and will confirm the patient has been instructed in their consistent and correct use.  
Patients need to affirm that they meet the criteria for correct use of at least 2 of the selected 
methods of contraception.  The investigator or his or her designee will discuss with the 
patient the need to use highly effective contraception consistently and correctly according to 
the Schedule of Activities and document such conversation in the patient’s chart.  In addition, 
the investigator or his or her designee will instruct the patient to call immediately if a 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
patient or the patient’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:

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1. Established use of oral, inserted, injected (not available in Japan), implanted (not 
available in Japan) or transdermal hormonal (not available in Japan) methods of 
contraception is allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available (for example in 
Japan) or condom plus spermicide is not accepted as highly effective contraception, 
this option is not appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or,

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range 
for postmenopausal women.
All sexually active male patients must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for 90 days after the last dose.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study coordinator’s manual. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 

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only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).  Eligible patients will be enrolled 
to receive PF-04518600 (and utomilumab for Part B patients) in an open-labeled, unblinded 
manner.  Patients will be registered and successively assigned to the next available treatment 
slot at a dose level or dose combination level decided on after the previous cohort’s safety 
evaluation and ongoing observations of earlier enrolled patients.  For monotherapy, patients 
will be dosed at 0.01 mg/kg PF-04518600 in the first cohort.  For combination therapy, 
patients will be dosed at 0.1 mg/kg PF-04518600 and 20 mg utomilumab in the first dose 
combination level.  Selected dose for PF-04518600 in the B2 combination therapy dose 
expansion cohorts is 30 mg (a flat dose equivalent to 0.3 mg/kg) intravenously (IV) Q2W in 
combination with PF-05082566 20 mg IV every 28 days.
5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will
e-mail 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 study-related documentation or correspondence referencing that 
patient and e-mail to the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

Confirmation of the patient’s enrollment.

Specification of the dose level for that patient; and 

Permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.

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5.2. Patient 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 Pfizer 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 mediation use.
5.3. Investigational Product Supplies
PF-04518600 and utomilumab will be supplied for the study by Pfizer.  No patients or 
third-party payers will be charged for investigational product.
Study centers will receive a supply of Clinical Trial Material upon 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.
5.3.1. Dosage Forms and Packaging
5.3.1.1. PF-04518600
PF-04518600 10 mg/mL injection is presented as a sterile solution for intravenous 
administration.  Each vial contains 108 mg of PF-04518600 in 10.8 mL of aqueous buffered 
solution, with a nominal volume of 10 mL, is sealed with a coated stopper and an overseal, 
and labeled according to local regulatory requirements.  The vial is designed for single use.
PF-04518600 will be shipped under refrigerated conditions (2-8C) and should be stored 
under refrigerated conditions (2-8C).
5.3.1.2. Utomilumab
Utomilumab drug product will be supplied in glass vials at a 10 mg/mL concentration and 
labeled as open supplies.  Each vial is packed in an individual carton.
5.3.2. Preparation and Dispensing
See the investigational product (IP) Manual located in the Study Manual for instructions on 
how to prepare the investigational product for administration.  Investigational product should 
be prepared and dispensed by an appropriately qualified and experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, practitioner, pharmacist, or medical 
assistant) as allowed by local, state, and institutional guidance.  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 biologic agents.

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5.4. Administration
5.4.1. Part A1 Monotherapy
PF-04518600 will be administered intravenously with adjustment for body weight at every 
cycle.  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 2 weeks in duration.  PF-04518600 will be administered on 
Day 1 of each 2 week cycle per the IP Manual as an intravenous (IV) infusion over 
60 minutes (-5 to +15 minutes and should include the time needed to flush the infusion line) 
on an outpatient basis.  If infusion reaction occurs, infusion rate maybe reduced (refer to 
Section 5.4.5.1 Infusion Reactions and Appendix 4 for management of infusion reactions).
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. 
Each patient may receive PF-04518600 until disease progression by irRECIST (see Section 
5.4.6 Treatment After Initial Evidence of Radiological Progression), patient refusal, or 
unacceptable toxicity occurs, or end of study, whichever occurs first. 
The dose level will be assigned by the sponsor (Section 5.1 Allocation to Treatment).  Patient 
actual body weight will be used to calculate the mg/kg dose, and the calculated dose will be 
rounded off to the second decimal point.  All patients should be weighed within 72 hours 
prior to dosing for every cycle to ensure they did not experience either a weight loss or gain 
>10% from the prior weight used to calculate the amount of PF-04518600 required for dose 
preparation.  Decision to recalculate PF-04518600 dose based on the weight obtained at each 
cycle can be in accordance with institutional practice, however if the patient experienced 
either a weight loss or gain >10% compared to the weight used to calculate the initial dose, 
the amount of PF-04518600 required for investigational product preparation and 
administration for the current cycle must be recalculated using this most recent weight 
obtained. 
5.4.2. Part A2 Monotherapy
PF-04518600 will be administered intravenously as a flat dose.  A cycle is defined as the 
time from current Day 1 dose to the next Day 1 dose.  If there are no treatment delays, a 
cycle will be 2 weeks in duration.  PF-04518600 will be administered on Day 1 of each 
2 week cycle per the IP Manual as an intravenous (IV) infusion over 60 minutes (-5 to 
+15 minutes and should include the time needed to flush the infusion line) on an outpatient 
basis.  If infusion reaction occurs, infusion rate maybe reduced (refer to 
Section 5.4.5.1 Infusion Reactions and Appendix 4 for management of infusion reactions). 
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 IP 
manual for infusion rate and duration.
Each patient may receive PF-04518600 until disease progression by irRECIST (see Section 
5.4.6 Treatment After Initial Evidence of Radiological Progression), intolerability, death, or 
until end of study, whichever comes first.

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The dose level will be assigned by the sponsor (Section 5.1 Allocation to Treatment). 
5.4.3. Part B1 Combination Therapy
In Part B1, utomilumab will be administered on Day 1 of every other cycle (every 28 days) 
per IP Manual as an intravenous (IV) infusion over 60 minutes (-5 to +15 minutes and should 
include the time needed to flush the infusion line).  Utomilumab will be administrated 
intravenously using a flat dose.
Per monotherapy, PF-04518600 will be administered on Day 1 of each 2 week cycle per the 
IP Manual as an intravenous (IV) infusion over 60 minutes (-5 to +15 minutes and should 
include the time needed to flush the infusion line) on an outpatient basis.  PF-04518600 will 
be administered intravenously with adjustment for body weight at every cycle.  On cycles 
whereby both PF-04518600 and utomilumab are to be administered on the same day, 
PF-04518600 will be administered after, but no sooner than 30 minutes after completion of 
the utomilumab infusion in absence of infusion reaction and after post-utomilumab and 
pre-PF-04518600 pharmacokinetic blood draws (see Section 5.4.5.6.2 Dose Reductions, 
Interruptions, and Discontinuation Criteria Part B Combination).  All blood draws should be 
taken from the contra-lateral arm of the infusion. Furthermore, separate infusion bags, 
infusion lines, and filters must be used for each investigational product. Indwelling catheters
should be flushed prior to infusion of each investigational product.
A cycle is defined as the time from Day 1 dose of PF-04518600 to the next Day 1 dose.  If 
there are no treatment delays, a cycle will be 2 weeks.  Each patient may receive 
PF-04518600 and utomilumab until disease progression by irRECIST (see Section 5.4.6
Treatment After Initial Evidence of Radiological Progression), intolerability, death, or until 
end of study, whichever comes first. 
If infusion reaction occurs, refer to Section 5.4.5.1 Infusion Reactions and Appendix 4 for 
management of infusion reactions.  If premedication is required for the management of 
infusion reactions, administration of PF-04518600 not sooner than 30 minutes before 
utomilumab administration may be considered.
5.4.4. Part B2 Combination Therapy
In Part B2, utomilumab will be administered on Day 1 of every other cycle (every 28 days) 
per IP Manual as an intravenous (IV) infusion over 60 minutes (-5 to +15 minutes and should 
include the time needed to flush the infusion line).  Utomilumab will be administrated 
intravenously using a flat dose.
PF-04518600 will be administered intravenously as a flat dose on Day 1 of each 2 week 
cycle per the IP Manual as an intravenous (IV) infusion over 60 minutes (-5 to +15 minutes 
and should include the time needed to flush the infusion line).  On cycles whereby both 
PF-04518600 and utomilumab are to be administered on the same day, PF-04518600 will be 
administered after, but no sooner than 30 minutes after completion of the utomilumab
infusion in absence of infusion reaction and after post-utomilumab and 
pre- PF-04518600 pharmacokinetic blood draws (see Section 5.4.5.6.2 Dose Reductions, 
Interruptions, and Discontinuation Criteria Part B Combination).  All blood draws should be 

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taken from the contra-lateral arm of the infusion.  Furthermore, separate infusion bags, 
infusion lines, and filters must be used for each investigational product.  Indwelling catheters 
should be flushed prior to infusion of each investigational product.
A cycle is defined as the time from Day 1 dose of PF-04518600 to the next Day 1 dose.  If 
there are no treatment delays, a cycle will be 2 weeks.  Each patient may receive 
PF-04518600 and utomilumab until disease progression by irRECIST (see Section 5.4.6
Treatment After Initial Evidence of Radiological Progression), intolerability, death, or until 
end of study, whichever comes first. 
If infusion reaction occurs, refer to Section 5.4.5.1 Infusion Reactions and Appendix 4 for
management of infusion reactions.  If premedication is required for the management of 
infusion reactions, administration of PF-04518600 not sooner than 30 minutes before 
utomilumab administration may be considered.
5.4.5. 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 highest-grade 
toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom.
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 persisting toxicity 
when a new cycle is due to start.

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
5.4.5.1. Infusion Reactions
Following the first infusion of some monoclonal antibody therapeutics, some patients 
experience fever, headache, nausea, vomiting or hypotension.  These adverse events (AEs) 
are generally ascribed to lysis of cellular targets, cytokine release, or complement activation. 
In the case of infusion reaction, characterized by fever and chills, and less commonly 
hypotension, either experienced by a particular patient or if seen in other patients, 
pretreatment medication should be administered to reduce the incidence and severity.  A 
regimen is suggested here; however, if local standard of care is a different regimen, this will 
be allowed.  In cases of infusion reactions, patients should be pretreated with acetaminophen 
and diphenhydramine (or other antihistamine) approximately 0.5 to 2 hours before 
investigational product administration.  The pretreatment medications will not be supplied by 
Pfizer.  Suggested starting doses are 650 to 1000 mg acetaminophen and 50 mg 

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diphenhydramine (or equivalent for other antihistamines) either IV or oral.  Two (2) 
additional doses of acetaminophen may be administered approximately every 4-6 hours after 
the initial pretreatment or as needed.
5.4.5.2. Hypersensitivity Types 1 and 3
Type 1 hypersensitivity or allergic (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) reactions are theoretically possible in response to any injected protein.  Immune 
complex mediated Type 3 hypersensitivity reactions are similar to the adverse events (AEs) 
of Type 1 reactions but are likely to be delayed from the time of infusion and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
All patients should be closely observed while receiving investigational product infusions and 
monitoring for clinical signs of a systemic reaction will continue thereafter for clinical signs 
of allergic reactions/hypersensitivity. 
In the case of a hypersensitivity reaction, the patient will be treated symptomatically with 
supportive care, further monitoring, and treatment with anti-histamines and/or 
corticosteroids.  Study infusions may be stopped and the patient will be followed until the 
end of the study. 
Detailed guidance on treatment, dose interruptions and potential retreatment is provided in
Appendix 4.
5.4.5.3. Extravasation
In the event of extravasation infusion should be stopped immediately and the investigator 
needs to be consulted immediately.  Treatment of extravasation should follow local standard 
of care. 
5.4.5.4. Immune-Related Adverse Events (irAEs)
Although the mechanism of OX40 and 4-1BB are different from check point inhibitors, both 
OX40 and 4-1BB do stimulate the immune system and thus immune-related AEs (irAEs) can 
occur.  Immune mediated etiology of an AE will be adjudicated by the investigator.  
Treatment of irAEs is mainly dependent upon severity (NCI CTCAE grade v4.03):

Grade 1 or 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring;

Persistent Grade 2: manage similar to Grade 3 to 4 AE;

Grade 3 or 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in Table 4.

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Table 4.
Management of Immune-Related Adverse Events (irAEs)
Gastrointestinal irAEs
Diarrhea / Colitis
(NCI CTCAE v4.03)
Management
Follow-up
Grade 1
Diarrhea: <4 stools/day over baseline;
Colitis: asymptomatic 
Continue investigational product 
therapy
Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening symptoms
Educate patient to report worsening 
immediately
If worsens:
Treat as Grade 2 or 3/4
Grade 2
Diarrhea: 4 to 6 stools per day over 
baseline; IV fluids indicated 
<24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Delay investigational product 
therapy
Symptomatic treatment
If improves to Grade 1: 
Resume investigational product therapy
If persists >5-7 days or recur:
0.5 to 1.0 mg/kg/day methylprednisolone or 
equivalent 
When symptoms improve to Grade 1, taper
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume investigational product 
therapy per protocol.
If worsens or persists >3 to 5 days with oral 
steroids:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): 7 stools per day 
over baseline; incontinence; IV fluids 
24 hrs; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Discontinue investigational product 
therapy per protocol
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, then taper 
over at least 1 month
If persists >3 to 5 days, or recur after 
improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should not 
be used in cases of perforation or sepsis
Dermatological irAEs
Rash
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1 to 2
Covering 30% body surface area 
Symptomatic therapy 
(eg, antihistamines, topical 
steroids) 
Continue investigational product 
therapy
If persists >1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay investigational product therapy
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral equivalent.  
Once improving, taper steroids over at least 
1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume 
investigational product therapy
If worsens: 
Treat as Grade 3 to 4

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Table 4.
Management of Immune-Related Adverse Events (irAEs)
Grade 3 to 4
Covering >30% body surface area; 
life threatening consequences 
Delay or discontinue 
investigational product therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections 
Resume investigational product therapy
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of investigational 
product therapy 
Monitor for symptoms every 2 to 
3 days 
Consider Pulmonary and Infectious 
Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4
Grade 2
Mild to moderate new symptoms
Delay investigational product therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization 
1.0 mg/kg/day methyl-prednisolone 
IV or oral equivalent 
Consider bronchoscopy, lung biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near baseline, taper 
steroids over at least 1 month and then resume 
investigational product therapy and consider 
prophylactic antibiotics
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4
Grade 3 to 4
Severe new symptoms; New / 
worsening hypoxia; life-threatening 
Discontinue investigational product 
therapy
Hospitalize 
Pulmonary and Infectious Disease 
consults
2 to 4 mg/kg/day methylprednisolone 
IV or IV equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung biopsy 
If improves to baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
Add additional immunosuppression (eg, 
infliximab, cyclophosphamide, intravenous 
immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Liver Function Tests (LFT) 
Increase
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue investigational product 
therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4

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Table 4.
Management of Immune-Related Adverse Events (irAEs)
Grade 2
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to
3 x ULN 
Delay investigational product therapy
Increase frequency of monitoring to 
every 3 days 
If returns to baseline: 
Resume routine monitoring, resume 
investigational product therapy
If elevations persist >5 to 7 days or worsen: 
0.5 to 1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to Grade 
1 or baseline, taper steroids over at least 
1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume 
investigational product therapy
Grade 3 to 4
AST or ALT >5 x ULN and /or 
total bilirubin >3 x ULN 
Discontinue investigational product 
therapy 
Increase frequency of monitoring to 
every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, worsens or
rebounds: 
Add mycophenolate mofetil 1 gram (g) twice 
daily 
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines 
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Asymptomatic TSH abnormality 
Continue investigational product therapy 
If TSH <0.5 x LLN, or TSH >2 x ULN, or consistently out of range in 2 subsequent 
measurements: include free T4 at subsequent cycles as clinically indicated; consider 
endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider pituitary MRI scan 
Symptomatic with abnormal lab / 
pituitary scan: 
Delay investigational product 
therapy
1 to 2 mg/kg/day 
methylprednisolone IV or by mouth 
equivalent 
Initiate appropriate hormone 
therapy 
No abnormal lab / pituitary MRI 
scan but symptoms persist: 
Repeat labs in 1 to 3 weeks / MRI 
in 1 month 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month and 
consider prophylactic antibiotics for 
opportunistic infections 
Resume investigational product therapy 
Patients with adrenal insufficiency may need 
to continue steroids with mineralocorticoid 
component 

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Table 4.
Management of Immune-Related Adverse Events (irAEs)
Suspicion of adrenal crisis (eg, severe 
dehydration, hypotension, shock out 
of proportion to current illness) 
Delay or discontinue investigational product therapy 
Rule out sepsis 
Stress dose of IV steroids with mineralocorticoid activity 
IV fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic endocrinopathy 
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
irAE=immune-related adverse event, IV=intravenous, LLN=lower limit of normal, MRI=magnetic resonance 
imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs, T4=thyroxine, TSH=thyroid-stimulating hormone, 
ULN=upper limit of normal.
5.4.5.5. Dose Delay
Re-treatment following treatment interruption for treatment related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:

ANC 1,000/mm3.

Platelets count 50,000/mm3.  HCC only: based on investigator judgment, after 
consultation with sponsor’s medical monitor, change from baseline will be 
considered, and levels of 25,000/mm3 may be acceptable.

Non-hematologic toxicities have returned to baseline or Grade 1 severity (or, at the 
investigator discretion, Grade 2 if not considered a safety risk for the patient).
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.  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 (or until deemed 
irreversible) occurs as assessed by the Investigator.
If these conditions are met within 2 weeks of treatment interruption or cycle delay, 
PF-04518600 or PF-04518600/utomilumab may be resumed.  For monotherapy, please refer 
to Section 5.4.5.6.1 (Dose Reductions, Interruptions and Discontinuation Part A 
Monotherapy) for adverse events requiring dose reduction at the time of treatment 
resumption. For combination therapy, intrapatient dose reduction will not be permitted (see 
Section 5.4.5.6.2 Dose Reductions, Interruptions and Discontinuation Part B Combination 
Therapy).
If these conditions are not met, treatment resumption must be delayed up to a maximum of 
4 weeks.  If these parameters have not been met after 4 weeks of dose interruption or 4 weeks 
of new cycle delay, permanent discontinuation of treatment with PF-04518600 or 
PF-04518600/utomilumab should be considered.  Treatment resumption for patients 

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recovering from treatment-related toxicity after 4 weeks of treatment interruption or cycle 
delay can be considered only if the patient is deemed to be deriving obvious clinical benefit 
per the investigator’s best medical judgment and needs to be agreed between the investigator 
and the sponsor.
If a treatment interruption continues beyond Day 14 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle. 
5.4.5.6. Dose Reductions, Interruptions and Discontinuation Criteria
5.4.5.6.1. Part A Monotherapy
Following dose interruption, cycle delay due to toxicity, or observation of late immune 
related DLTs such that the current dose of treatment is now considered to be above the MTD 
(see Section 3.2.1 Late Immune Related DLTs), the PF-04518600 dose may need to be 
reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Dose reduction of PF-04518600 by 1 and, if needed, 2 dose levels will be allowed depending 
on the type and severity of toxicity observed.  Patients enrolled in the first (0.01 mg/kg) 
cohort should be discontinued from the study if dose reduction is required.  Patients requiring 
more than 2 (or 1 for the first cohort) dose reductions will be discontinued from the treatment 
and entered into the follow-up phase, unless otherwise agreed between the investigator and 
the sponsor.  For example, if a patient has clear signs of clinical benefit, and if the 
investigator considered it to be in the best interest of the patient, they may be allowed to stay 
on study at a further reduced dose after recovery and appropriate dose interruption.  All dose 
modifications/adjustments must be clearly documented in the patient's source notes and CRF. 
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is not allowed.
Patients experiencing a DLT may resume dosing at the next lower dose level once adequate 
recovery is achieved.  No dose reductions are planned for patients experiencing toxicities 
other than those listed as DLTs.  However, patients experiencing recurrent and intolerable 
Grade 2 toxicity may resume dosing at the next lower dose level once recovery to 
Grade 1 or baseline is achieved. 
Recommended dose reductions are illustrated in Table 5.

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Table 5.
Dose Modification for Drug Related Toxicity at Start of Subsequent Cycle in 
Part A
Event
Action
Grade 3 or 4 non-hematologic toxicity considered 
related to PF-04518600 per investigator judgment 
(including persistent nausea, vomiting, diarrhea 
despite optimal medical therapy), excluding 
clinically manageable electrolyte abnormalities.

Hold PF-04518600 infusion until recovery to 
Grade 0-1 or baseline and reduce by 1 dose level.

If toxicity (Grade 3-4) reoccurs despite reduction, 
patient may be dose reduced again by 1 more 
dose level upon recovery to Grade 0-1 or 
baseline. 

Prompt palliative and supportive measures 
mandated per local standard of care 
(eg, antiemetic). 

Patients who experience Grade 4 non hematologic 
toxicities despite intervention should be 
discontinued from the study, unless restarting 
treatment at reduced dose level is in the patient’s 
best interest per investigator judgment and after 
consultation with Pfizer’s medical monitor (eg, 
clear clinical benefit and no alternative treatment 
options).
Hematologic toxicity considered related to 
PF-04518600 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 >38.3oC or a 
sustained temperature of 38oC (100.4oF)  
with ANC <1000/mm3;
or,

Grade 4 Thrombocytopenia, ie, PLTS 
25,000 mm3 (25.0 x 109/L);
or,

Grade 3 Thrombocytopenia, ie, PLTS 
50,000 mm3 (50.0 x 109/L) with bleeding.

Hold PF-04518600 until recovery of ANC to 
1.0 x 109/L (1,000 cells/mm3) and platelets 
75 x 109/L (75,000 cells/mm3).  For HCC 
patients, a lower threshold for platelets can be 
considered after discussion with the sponsor’s 
medical monitor (eg, 40,000 cells/mm3), 
depending on the shift from baseline.

Reduce PF-04518600 by 1 dose level.

If toxicity reoccurs (grades a described on the left 
side) despite dose reduction, patient may either be 
held until recovery and continuation at same dose, 
or undergo further dose reduction by 1 more dose 
level.
Other grade 4 hematologic toxicity considered 
related to PF-04518600 per investigator judgment.

Hold PF-04518600 until recovery to Grade 0-1 or 
baseline and reduce PF-04518600 dose by 1 dose 
level.

If toxicity reoccurs (Grade 4) despite dose 
reduction, patient may either be held until 
recovery and continuation at same dose, or 
undergo further dose reduction by 1 more dose 
level.
No recovery of toxicities within 4 weeks of 
scheduled PF-04518600 infusion.

Discontinue treatment, unless restarting treatment 
at reduced dose level (either lowest dose level 
tested or more than 2 dose level reduced) is in the 
patient’s best interest per investigator judgment 
and after consultation with Pfizer’s medical 
monitor (eg, clear clinical benefit and no 
alternative treatment options).
Please refer to Section 9.6.3 for (12-Lead) Electrocardiogram (ECG) events that may lead to 
dose reductions or discontinuations.

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5.4.5.6.2. Part B Combination Therapy 
Intrapatient dose reductions are not permitted during the combination therapy with 
PF-04518600 and utomilumab unless, in discussion with the sponsor, a dose combination 
level is deemed to be above the determined MTD for the combination. 
Given the expected similarities of side effect profile and mechanism between the two 
co-stimulation monoclonal antibodies, both treatments must be interrupted or discontinued 
together. Patients will not be permitted to continue treatment with one agent, while the other 
agent is either interrupted or permanently discontinued.  If infusion related reactions are 
observed following the administration of the first agent, administration of the second agent 
will be withheld until symptoms resolve (see Section 5.4.5.1 Infusion Reactions).
Treatment of irAEs should follow guidelines set forth in Table 4 in 
Section 5.4.5.4 Recommended dose modifications for any other drug-related toxicity are 
illustrated in Table 6.
Table 6.
Treatment Interruptions/ Discontinuations for Drug Related Toxicity at 
Start of Subsequent Cycle
Toxicity
NCI CTCAE 
Severity Grade
Treatment Modifications
Hematologic abnormalities.
Grade 3
Withhold until recovery to Grade 1 or better.
If toxicity does not resolve to Grade 1 or better within 
4 weeks of last infusion, consider permanent 
discontinuation after consultation with the sponsor.
Upon the second occurrence of the same 
Grade 3 toxicity that does not resolve to Grade 1 by 
the next administration, treatment must be permanently 
discontinued.
Grade 4
Permanent discontinuation.
Exceptions are:
Single laboratory values out of normal range that are 
unlikely related to investigational product (s) as 
assessed by the Investigator, do not have any clinical 
correlate, and resolve within 7 days with adequate 
medical management.
Infusion-related reaction.
Grade 1-4
See Section 5.4.5.1 and Appendix 4.
Hypersensitivity reaction.
Grade 1-4
See Section 5.4.5.2 and Appendix 4.
Other non-hematologic 
toxicities and laboratory 
abnormalities.
Grade 2
If toxicity resolves to Grade 1 by the next 
administration, treatment may continue.
If toxicity does not resolve to Grade 1 by the next 
administration despite optimal treatment, the next 
infusion should be omitted.  If at the end of 4 weeks of 
dose holding, the event has not resolved to Grade 1, 
the patient should permanently discontinue treatment 
(except for hormone deficiencies that can be managed 
by replacement therapy and for which up to 
2 additional subsequent doses may be omitted). 

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Table 6.
Treatment Interruptions/ Discontinuations for Drug Related Toxicity at 
Start of Subsequent Cycle
Toxicity
NCI CTCAE 
Severity Grade
Treatment Modifications
Grade 3
Permanent discontinuation, Exceptions are:

Transient (6 hours) flu-like symptoms or fever, 
which is controlled with medical management.

Transient (24 hours) fatigue, local reactions, 
headache that resolves to Grade 1.

Nausea and vomiting controlled by medical 
therapy.

Diarrhea, skin toxicity, or liver function test 
(ALT, AST, or Gamma-glutamyltransferase 
[GGT]) that resolves to Grade 1 in less than 
7 days after medical management (eg, 
immunosuppressant treatment) has been 
initiated.

Amylase or lipase abnormality that is not 
associated with symptoms or clinical 
manifestations of pancreatitis.

Tumor flares phenomenon defined as local pain, 
irritation, or rash localized at sites of known or 
suspected tumor.

Non hematologic laboratory abnormality that do 
not require medical intervention or 
hospitalization.

Single non hematologic laboratory values out of 
normal range that are unlikely related to 
treatment as assessed by the Investigator, do not 
have any clinical correlate, and resolve to 
Grade 1 within 7 days with adequate medical 
management.
Grade 4
Permanent discontinuation, Exceptions are:

Non hematologic laboratory abnormality that 
does not require medical intervention or 
hospitalization.  Single non hematologic 
laboratory values out of normal range that are 
unlikely related to treatment as assessed by the 
Investigator, do not have any clinical correlate, 
and resolve within 7 days with adequate medical 
management.

Amylase or lipase abnormality that is not 
associated with symptoms or clinical 
manifestations of pancreatitis.

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5.4.6. Treatment after Initial Evidence of Radiological Disease Progression
Immunotherapeutic agents such as PF-04518600 and/or utomilumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses.  The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with cytotoxic agents, and can manifest as a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions.
If radiologic imaging shows disease progression, tumor assessment should be repeated 
4 weeks later in order to confirm the progression (See Appendix 6).  Assigned study 
treatments may be continued at the Investigator’s discretion while awaiting radiologic 
confirmation of disease progression.
Patients may receive study treatments while waiting for confirmation of progressive disease 
(PD) if they are clinically stable as defined by the following criteria:

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression.

No decline in ECOG performance status.

Absence of rapid progression of disease by radiographic imaging.

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
If repeat imaging no longer shows PD but rather CR, PR or SD compared to the initial scan, 
treatment may be continued/resumed.  In determining whether or not the tumor burden has 
increased or decreased, Investigators should consider all target as well as non-target lesions 
(refer to the Appendix 6).
If the repeat imaging confirms PD, patients should be considered for discontinuation from 
both investigational products.  However, according to the Investigator’s clinical judgment 
and after discussion between the Investigator and the Sponsor, if a patient with evidence of 
PD is still experiencing clinical benefit, the patient may be eligible for continued treatment 
with both investigational products.  The Investigator’s judgment should be based on the 
overall benefit-risk assessment and the patient’s clinical condition, including performance 
status, clinical symptoms, adverse events and laboratory data. 
Patients who stop treatment for reasons other than toxicity with either or both investigational 
products and then experience radiologic disease progression shortly thereafter will be eligible 
for re-treatment with either or both investigational products at the discretion of the 
Investigator and after discussion with the Sponsor.

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5.5. Drug Storage 
The investigator, or an approved representative, eg, pharmacist will ensure that the 
investigational products PF-04518600 and utomilumab are stored in a secured area with 
controlled access under recommended storage conditions and in accordance with applicable 
regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
drug label.  See the IP Manual, package insert or equivalent for storage conditions of the 
product once reconstituted and/or diluted.
Storage conditions stated in the single reference safety document (SRSD) (ie, investigator 
brochure [IB]) will be superseded by the storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the labeled storage 
conditions, as described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined while 
maintaining appropriate storage conditions (2-8C) and not used until the sponsor provides 
documentation of permission to use the investigational product.  It will not be considered a 
protocol deviation if the sponsor approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to sponsor approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. The Investigational Product Manual should 
be referenced for any additional guidance on storage conditions and actions to be taken when 
conditions are outside the specified range.
5.6. Drug Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  The sponsor or designee will 
provide guidance on the destruction of unused investigational product (eg, at the site).
To ensure adequate records, all PF-04518600 and utomilumab will be accounted for in the 
case report form and drug accountability inventory forms as instructed by Pfizer.  Unless 
otherwise authorized by Pfizer, 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 

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[CRO]).  If Pfizer 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 Pfizer.  Destruction must be 
adequately documented.
Under no circumstances should the investigator or other site personnel supply investigational 
product to other investigators, patients, or clinics, or allow supplies to be used other than 
directed by this protocol without prior authorization from Pfizer.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
All concomitant treatments, blood products and saline infusions, as well as non-drug 
interventions (eg, analgesic use for paracentesis) received by patients from screening until 
the end of study visit will be recorded on the CRF (including the name of the procedure or 
medication, route and duration of treatment and reason (eg, AE).
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anticancer treatment including chemotherapy, hormonal therapy (see 
Section 4.2 Exclusion Criteria, and Section 5.7.2 Supportive Care), or experimental 
anticancer medications will be permitted while patients are receiving study treatment.  
Additionally, the concurrent use of herbal supplements for an anti-cancer treatment is not 
permitted.
5.7.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines or local standard of care.
5.7.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors (G-CSF) is not permitted 
during the first two cycles but they may be used to treat treatment emergent neutropenia as 
indicated by the current American Society of Clinical Oncology (ASCO) guidelines.93 For
Japan only: since the indications and dosages of G-CSF compounds approved in Japan may 
differ, please refer to Japanese guidelines.

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Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia, except during the DLT observation period. Note that use of erythropoietin for the 
treatment of anemia in cancer patients is not approved in Japan.
5.7.4. 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 the drug is not included in the Concomitant Treatment(s)
section, as well as the duration of treatment assuming there is no known or expected 
drug-drug interaction.  If so it must be approved by the sponsor.
5.7.5. Anti-inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatment(s) section. 
5.7.6. Corticosteroids 
Chronic, systemic corticosteroid use (prednisone 10 mg/day or dexamethasone 
1.5 mg/day) for palliative or supportive purpose is not permitted.  Acute emergency and 
short term administration, topical applications, inhaled sprays, eye drops, or local injections 
of corticosteroids are allowed.  If immune-related AEs occur, immune-suppressive treatment 
should be administered according to local standards or practice.
5.7.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-04518600/utomilumab administration, 
required to minimize the potential risk of impaired wound healing, risk of infection and 
bleeding, has not been determined.  Stopping PF-04518600/utomilumab administration is 
recommended at least 7 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-04518600/utomilumab treatment should be based on a clinical assessment of satisfactory 
wound healing and recovery from surgery.
5.7.8. Anticoagulation 
Anticoagulation (heparin and factor Xa inhibitors only, no vitamin-K antagonists) will be 
allowed if indicated. However, perioperative anticoagulant use must be in alignment with 
the institutional standards for perioperative biopsy procedures.
5.7.9. Radiotherapy
There has been tumor regression observed in a non-irradiated tumor following palliative 
radiotherapy in a melanoma patient treated with 10 mg/kg of PF-04518600 who had initially 
met criteria for PD by RECIST. It is possible that radiation may have benefited the 
anti-tumor immune response from PF-04518600 similar to what has been reported in a 
preclinical study evaluating the anti-tumor activity of OX40 agonist and radiation.122

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Consideration may be given for optional radiotherapy administered at palliative doses to a 
tumor between time of first progression by RECIST and when the patient has confirmed
disease progression by irRECIST. The irradiated tumor should preferably be a non-target 
lesion. If a target lesion is selected for irradiation, there should be other target lesions that 
can be followed for measurements. Palliative radiotherapy on study is permitted (eg, for the 
treatment of painful bony or skin lesions) if clinically indicated at any time. 
In view of the current lack of data about the interaction of PF-04518600 and/or utomilumab
with concurrent radiotherapy, study drug treatment should be interrupted during
radiotherapy, stopping 1 day before and resuming treatment at least 1 day after. Planned 
dosing schedule, treatment fields and technique need to be discussed with and approved by 
the sponsor’s medical monitor before start of treatment.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see Schedule of Activities and Section 7 Assessments.
All patients being considered for the study and eligible for screening must sign an 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 12.3 on Patient Information and Informed Consent.
All 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.
The required screening assessments and laboratory tests are summarized in the Schedule of 
Activities and Section 7.  Following completion of the screening assessments and 
confirmation of eligibility, patients may be enrolled.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and Assessments Section 7.
6.3. Follow-up Visit
For follow-up procedures see Schedule of Activities and Assessments Section 7.
At least 28 days and no more than 35 days after discontinuation of treatment, patients will 
return to undergo the assessments outlined in the Schedule of Activities as well as a review 
of concomitant medications, 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.  Late immune related DLT information will also be collected
during this visit.

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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.
Independent to time of disease progression, all patients (unless patients are lost to follow up, 
consent is withdrawn, or study is discontinued by the sponsor) will be followed for survival 
for at least 2 years from the time of their first dose of investigational product (s). After the 
completion of end of treatment visits, Patients will be contacted by phone every 2 months for 
survival status. However, 2 years from the time of the first dose of investigational product of 
the last patient enrolled or last surviving patient (whichever is later) the study will be closed.
6.3.1. Follow-Up for Late Immune-Related Events
As outlined in Section 3.2.1 (Late Immune Related DLTs), safety and tolerability assessment 
for the first 98 days (or completion of 7 cycles) will be taken into account for MTD and 
RP2D selection.  To collect late immune related DLT information, any patient who 
discontinues after 1 to 4 or 6 cycles of treatment will be contacted by phone as part of the 
follow up visit.  For patients who discontinue after receiving 5 cycles of treatment, late 
immune information will be collected during the 28 to 35 day follow up visit.  If the patient 
discontinues after receiving 6 cycles of treatment, they will be contacted by phone 14 days 
(2 days) after end of treatment (EOT).  If the patient discontinues after receiving 4 cycles of 
treatment, they will be contacted by phone 42 days (2 days) after EOT.  If the patient 
discontinues after receiving 3 cycles of treatment, they will be contacted by phone 56 days 
(2 days) after EOT. If the patient discontinues after receiving 2 cycles of treatment, they 
will be contacted by phone 70 days (2 days) after EOT. If the patient discontinues after 
receiving 1 cycle of treatment, they will be contacted by phone 84 days (2 days) after EOT.  
If any concern arises, patient will be called in for an inpatient follow up visit within 
5 calendar days of initial phone call. For this inpatient follow up visit, the Schedule of 
Activities will be similar to the follow up visit completed 28 to 35 days after end of 
treatment.  Patients continuing to experience late immune-related toxicity will continue to be 
followed at least every 4 weeks until resolution or determination, in the clinical judgment of 
the Investigator, that no further improvement is expected.
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 
investigational product 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. 
1. Reasons for withdrawal of study treatment may include:

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
Objective disease progression according to irRECIST* (see Appendix 5 and 
Appendix 6),85-87

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
2. Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refusal for further follow-up for survival;

Death.
*In the case of radiological progression (especially per standard RECIST) but in the absence 
of clinical deterioration, if investigator deem it is in the best interest of the patient, the patient 
will be allowed to stay on study.
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, requests the patient to return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.

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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, electrocardiogram (ECG [12-lead]), laboratory assessments, including 
pregnancy tests and verification of concomitant treatments.
7.1.1. Pregnancy Testing
For female patients of childbearing potential (that is, patients who are not defined as a patient 
of non-child bearing potential, see Section 4.3 [Lifestyle Guideline]), a serum or urine 
pregnancy test, with sensitivity of at least 25 mIU/mL will be performed on 2 occasions prior 
to starting study treatment-once at the start of screening and once at the baseline (C1D1) 
visit, immediately before investigational product administration.  Following a negative 
pregnancy result at screening, appropriate contraception must be commenced and a further 
negative pregnancy result will then be required at the baseline visit before the patient may 
receive the investigational product.  Pregnancy tests will also be routinely repeated at every 
cycle during the active treatment period, at the end of study treatment, and additionally 
whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
In the case of a positive hCG test, the patient will be withdrawn from study medication but 
may remain in the study.  Additional pregnancy tests may also be undertaken if requested by 
institutional review board (IRB)/institutional ethics committee (IECs) or if required by local 
regulations.
Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required 
by local regulations.
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 adverse events 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. 

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Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C 
antibody (HCV Ab) and human immunodeficiency virus (HIV) serology testing should be 
conducted at screening.  All Part A2 HCC patients with detectable viral load for hepatitis B 
at screening must also be tested for hepatitis D by antibody (HDV Ab) or polymerase chain 
reaction (PCR). All Part A2 HCC patients with detectable viral load for HCV or HBV at 
screening, must be retested for viral load every 3 months (ie, Cycle 7 Day 1, Cycle 13 Day 1, 
Cycle 19 Day 1, etc) and at the EOT visit. Other tests may be conducted per standard 
practice to confirm an active hepatitis or HIV infection.  In Part B, history of human 
papilloma virus (HPV) will be recorded for HNSCC patients. 
All laboratory safety assessments conducted on Cycle 1 Day 1 (C1D1) must be completed 
within 48 hours prior to dosing.  Prior to dosing a patient, safety assessments (hematology, 
chemistry, coagulation and urinalysis) must be reviewed by a physician.  If screening
assessments are performed within 72 hours prior to C1D1, there is no need to repeat 
hematology, chemistry or coagulation assessments on C1D1.  If screening assessments are 
performed within 7 days of C1D1, there is no need to repeat urinalysis assessments on C1D1.  
Assessments performed on Cycle 2 Day 1 (C2D1) and each subsequent cycle should be 
performed within 48 hours prior to dosing.  Investigators may have additional blood tests 
performed for the purpose of planning treatment administration, dose modification, or 
following AEs.
If abnormalities are observed in Thyroid-stimulating hormone (TSH) values, a T4 thyroxine 
test will be performed.
For HCC patients, alpha fetoprotein levels will be evaluated at screening and every 6 weeks 
until confirmed progressive disease in Part A1, every 8 weeks until Week 48 and then every 
12 weeks until confirmed progressive disease in Part A2.
For patients with previous history of anthracycline treatment and who are not at high risk of 
cardiac failure (ie, those patients that have NYHA Class I), troponin I (troponin T is allowed 
if the assay utilized can be verified to have cardiac specificity) and N-terminal of the 
prohormone brain natriuretic peptide (Nt-proBNP) levels will be evaluated every other cycle 
and when clinically indicated.

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Hematology
Chemistry
Coagulation
Serology
Urinalysis
Pregnancy 
Test
Cardiac 
Enzymes
Hemoglobin
ALT
PT or INR
HBsAg, 
HBcAb
Urine dipstick 
for urine 
protein: If 
positive 
collect 24-hr 
and 
microscopic 
(Reflex 
Testing)
For female 
patients of 
childbearing 
potential, 
serum or 
urine (to be 
specified in 
the protocol)
Troponin I or 
T (if verified)
Platelets
AST
PTT
HCV Ab
Nt-proBNP  
WBC
Alk Phos
HIV 
serology
Neutrophils
GGT
HDV Ab or 
PRC
Lymphocytes
Sodium
Hepatitis B 
quantitative 
test
Monocytes
Potassium
Hepatitis C 
quantitative 
test
Eosinophils
Magnesium
Urine dipstick 
for urine 
blood: If 
positive 
collect a 
microscopic 
(Reflex 
Testing)
Basophils
Chloride
Hematocrit
Total 
Calcium
Total 
Bilirubin***
BUN or 
Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous 
or Phosphate
lipase
amylase
TSH
Alpha 
fetoprotein 
for HCC 
patients
*** 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, alkaline phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels. 
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination to include weight, vital signs, assessment of ECOG 
performance status and height; height will be measured at screening only.
7.1.5. (12-Lead) Electrocardiogram
Electrocardiogram (ECG): A single 12-lead (with at least a 10-second rhythm strip) tracing 
will be used for the screening ECG. Triplicate 12-lead (with at least a 10-second rhythm 
strip) tracing will be used for all other scheduled ECGs.  Unscheduled visits do not require 
triplicate ECGs.  It is preferable that the machine used has a capacity to calculate the 

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standard intervals automatically.  All 12-lead ECGs will be reviewed by a central laboratory.  
At each time point (see the Schedule of Activities) three consecutive ECGs will be performed 
at approximately 1-5 minutes apart to determine the mean QTcF interval.  Fridericia’s 
formula (QTcF) is calculated as follows:
QTcF= QT / (RR)0.33
If the mean QTcF is prolonged (>501 msec, ie, CTC AE Grade 3), then the ECGs should 
be re-evaluated by a qualified person at the site for confirmation as soon as the finding is 
made, including verification that the machine reading is accurate.  If manual reading verifies 
a QTcF of >501 msec, immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong 
the QTcF interval) should be performed.  In addition, repeat ECGs should be immediately 
performed hourly for at least 3 hours until the QTcF interval falls below 501 msec.  If QTcF 
interval reverts to less than 501 msec, and in the judgment of the investigator(s) and sponsor 
is determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring.  If in that timeframe the QTcF intervals rise above 
501 msec the investigational product will be held until the QTcF interval decreases to 
480 msec.  Patients will then re-start the investigational product at the next lowest dose level.  
If the QTcF interval has still not decreased to 480 msec after 2-weeks, or if at any time a 
patient has a QTcF interval >515 msec or becomes symptomatic, the patient will be removed 
from study drug.  Additional triplicate ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If 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 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). 
7.1.6. Echocardiogram or Multigated Acquisition (MUGA) Scan
Echocardiogram or multigated acquisition (MUGA) will be evaluated in patients with 
previous history of anthracycline treatment.  For these patients, an echocardiogram or 
MUGA will be performed at screening and every 3 months whilst on treatment and when 
clinically indicated.  An echocardiogram or MUGA will be performed at the end of treatment 
(EOT) visit if not performed within 3 months of discontinuation.  The following parameters 
will be evaluated: ventricular function (including left ventricular ejection fraction [LVEF], 
end systolic volume [ESV] and end diastolic volume [EDV]), qualitative evaluation of 
chamber size, and wall motion.  A Doppler examination will be completed and should 
include an assessment of mitral valve, atria, right ventricle, tricuspid valve, aortic valve, 
pulmonic valve, great vessels, and pericardium. 

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7.2. Pharmacokinetics Assessments
7.2.1. Blood for PK Analysis of PF-04518600 and Utomilumab
For both Part A Monotherapy and Part B Combination Therapy, blood samples for the 
analysis of PF-04518600 concentrations will be collected into appropriately labeled tubes at 
times specified in the Schedule of Activities of the protocol.  For each analysis, 5 mL of 
blood samples will be collected to provide approximately 2 mL serum.  The PK sampling 
schedule may be modified based on emerging PK data.
For Part B Combination Therapy only, blood samples (2 mL whole blood at each time point) 
will be collected to provide serum for PK analysis of utomilumab as outlined in the Schedule 
of Activities.  The PK sampling schedule may be modified based on emerging PK data.
The 1 hr samples should be collected immediately before the infusion ends for the 
corresponding investigational agent from the contra-lateral arm of the infusion.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs and the date and time of 
blood sample collection and of last dosing prior to PK collection documented in the CRF.
Where noted in the Schedule of Activities, blood samples for PF-04518600 (both Part A and 
Part B) and utomilumab (Part B only) concentrations will be collected at approximately the 
same time as pharmacodynamic samples whenever possible. 
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time 
relative to dosing.  However, the exact time of the sample collection will always be noted on 
the CRF.  Samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60 minute sample) from dosing will be not be captured as a protocol deviation.  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.  
Additional instructions for sample collection, processing, storage and shipping will be 
provided in the lab manual.
PK samples will be assayed for PF-04518600 (both Part A and Part B) and utomilumab
(Part B only) using validated analytical methods in compliance with Pfizer standard 
operating procedures.  Details regarding the collection, processing, storage and shipping of 
the blood samples will be provided in the study manual.
 
 
 
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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.
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the subsequent tumor assessments.
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Anti-tumor clinical activity will be assessed through radiological tumor assessments 
conducted at baseline, during treatment as specified in the applicable Schedule of Activity, 
whenever disease progression is suspected (eg, symptomatic deterioration), until confirmed 
progressive disease or start of subsequent anticancer therapy whichever comes first.
Assessment of tumor response will be made using RECIST version 1.1 (Appendix 5)85 and
irRECIST response criteria (Appendix 6).86,87
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.6. Immunogenicity Evaluations
Bioanalysis to assess for anti-drug (PF-04518600 or utomilumab) antibodies (ADA) will be 
performed.  All samples that are positive in a screening assay will be further characterized in 
terms of antibody specificity.  A tiered approach to screening, confirmation and 
titer/quantitation will be utilized. The screening assay with competitive confirmatory steps 
followed by the titer assay will be used.  Samples may also be analyzed in neutralization 
assays (NAb).  Patients having an unresolved adverse event that is possibly related to ADA 
formation will be asked to return for ADA and drug concentration blood sampling at 
approximately 3 month intervals until the adverse event or its sequelae resolve or stabilize at 
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a level acceptable to the investigator, and sponsor concurs with that the investigator’s 
assessment, up to 6 months from the EOT or the day of early withdrawal.
Blood samples (10 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 of this protocol.
Additional instructions for sample collection, processing, storage, and shipping will be 
provided in the lab manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
As part of understanding the immunogenicity of the investigational product, samples may be 
used for additional characterization of an observed immunogenicity response and/or 
evaluation of the bioanalytical method.  These data will be used for internal exploratory 
purposes and will not be included in the clinical report.  Samples collected for this purpose 
will be retained in accordance to local regulations and if not used within this timeframe, will 
be destroyed.
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 sequela 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 AEs that are 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through 98 calendar days from first administration of the 
investigational product, or up to 60 days after last administration of investigational product, 
whichever is later.  SAEs occurring to a patient after the active reporting period has ended 
should be reported to the sponsor if the investigator becomes aware of them; at a minimum, 

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all SAEs that the investigator believes have at least a reasonable possibility of being related 
to investigational product are to be reported to the sponsor.
If a serious adverse event occurs after informed consent is signed and before investigational 
product is administered, this information will be reported on a Serious Adverse Event Form 
and will be recorded in the safety database.
AEs (non-serious) should be recorded on the CRF from the time the patient has taken at least 
1 dose of study treatment through 28 days after the last treatment administration or until all 
drug related toxicities have resolved, whichever is later. However, late immune-related 
DLTs that are not SAEs need to be collected consistent with Section 3.2.1.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs 
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

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
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. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an adverse event (AE) CRF page. 
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
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8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE Grade 5 (see Section 8.8 on 
Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see Section 8.14.1 on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (x ULN) concurrent with a total bilirubin value 2 x ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 x ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value 2 times the baseline values and 3 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 level increased from baseline by an amount of at least 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 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time, should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
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however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.

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8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see Section 8.14 on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a an SAE report form and an 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 baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
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8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however a copy of the completed SAE Report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See also Section 6.4 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 an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 

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allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Analysis Sets
a.
Safety analysis set. 
The safety analysis set includes all enrolled patients who receive at least one dose of 
study medication.
b. Full analysis set.
The full analysis set includes all enrolled patients.
c.
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 and who do not have major treatment deviations during first 
cycle.  Patients with major treatment deviations in DLT observation period are not 
evaluable for the MTD assessment and will be replaced as needed to permit MTD 
estimation.  Major treatment deviations include:

Administration of less than 75% of the planned dose of PF-04518600 provided 
that the reduction is not due to toxicity attributable to PF-04518600.

Administration of more than 150% of the planned dose of PF-04518600.
d. 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.

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e.
Immunogenicity assessment sets.
The immunogenicity assessment population is defined as all enrolled patients who 
receive at least one dose of study medication and have ADA results reported for at 
least one time point.
9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation/De-Escalation
9.2.1.1. Part A Monotherapy
For the monotherapy portion of the study, a mTPI design88 will be adopted for dose 
escalation and de-escalation determination.  The mTPI design uses a Bayesian statistics 
framework and a beta-binomial hierarchical model with prior distribution of DLT set as a 
beta (0.75, 0.65) to compute the posterior probability of three dosing intervals that reflect the 
relative difference between the toxicity rate of each dose level to the target rate (pT=0.25, 
where pT is the target probability).  If the toxicity rate of the currently used dose level is far 
smaller than pT, the mTPI will recommend escalating the dose level; if it is close to target 
probability (pT), the mTPI will recommend continuing at the current dose; if it is far greater 
than pT, the mTPI will recommend de-escalating the dose level. 
Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the under 
dosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2;1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of PF-04518600 as a single-agent in Study B0601002, both e1 and e2 are 
selected as 0.05.  Therefore, the target interval for the DLT rate is (0.20, 0.30).
The three dosing intervals and the penalty functions are associated with three different 
dose-escalation decisions.  The under-dosing interval corresponds to a dose escalation (E), 
over-dosing corresponds to dose de-escalation (D), and proper-dosing corresponds to 
remaining at the current dose (R).  Given a dosing interval and a probability distribution, the 
unit probability mass (UPM) of that dosing interval is defined as the probability of a patient 
belonging to that dosing interval divided by the length of the dosing interval.  The mTPI 
design calculates the UPMs for the three dosing intervals, and the one with the largest UPM 
informs the corresponding dose-finding decision, which is the dose level to be used for future 
patients.  For example, if the under-dosing interval has the largest UPM, the decision will be 
to escalate, and the next cohort of patients will be treated at the next higher dose level.  Ji et 
al.88 have demonstrated that the decision based on UPM is optimal in that it minimizes a 
posterior expected loss (ie, minimizes the chance of making a wrong dosing decision). 
The dose-finding portion of the study is terminated when either approximately 40 DLT 
evaluable patients have been enrolled or when at least 9 evaluable patients have been treated 
at the highest dose with mean DLT rate 30%, whichever comes first.  Refer to 
Table 3 (Decision Rules) in Section 3.1.5.1 (Criteria for Dose Escalation Part A 
Monotherapy).

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9.2.1.2. Part B Combination Therapy
The dose escalation scheme based on mTPI method described in Section 9.2.1.1 will also be 
used in Part B Combination Therapy.88
9.2.2. Statistical Method for Estimating the MTD
9.2.2.1. Part A Monotherapy
As previously described, the estimated MTD is the highest tested dose level with mean DLT 
rate 0.25 in at least 9 DLT evaluable patients.  It is also assumed that at the estimated MTD, 
less than 17% patients will experience Grade 4 cytokine release syndrome, infusion reaction 
or allergic reaction during the 28 day DLT observation period, and the first 98 days after 
initial treatment.  It is also assumed that at the estimated MTD less than 33% of patients will 
experience grade 3 cytokine release syndrome, infusion reaction, or allergic reaction during 
the first 98 days after treatment.  We assume that higher doses of either PF-04518600 result 
in higher toxicity rates.  But, due to the relatively low number of patients that may be 
potentially allocated to any dose combination, this assumption may be violated.
9.2.2.2. Part B Combination Therapy
The estimated MTD is the highest tested dose combination level with mean DLT rate 
≤0.25 in at least 9 DLT evaluable patients.  It is also assumed that at the estimated MTD the
toxicity of PF-04518600/utomilumab combination follows the monotonicity assumption that 
a higher dose level of either PF-04518600 or utomilumab will result in a higher toxicity rates. 
9.3. Sample Size Determination
A maximum of approximately 210 patients are expected to be enrolled into the study.  The 
total sample size is not based on formal hypothesis testing considerations.
9.3.1. Part A Monotherapy
The number of patients to be enrolled in the study will depend upon the observed safety 
profile, which will determine the number of patients at each dose level and the number of 
dose levels explored.
At least 9 patients will be treated at the dose declared as the MTD.  If MTD was not reached 
by definition of safety criteria, this statement will apply for highest tested dose level.
The sample size using the mTPI approach cannot be determined in advance.  It is estimated 
the number of DLT evaluable patients to be enrolled in the dose escalation stage will allow a 
reliable and accurate estimate of the MTD. 
The exact sample size of the mTPI design in Part A1 cannot be pre specified in advance 
because it is a dynamic feature of the design.  The maximum sample size after which the 
Part A1 will be stopped and MTD declared is 58 patients.  Also, a minimum of 9 patients is 
required to establish the MTD.  The actual sample size of Part A1 will depend on the 
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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 A1, this number will be at least 9 patients. 
The planned sample size for Part A2 expansion cohort is up to 40 evaluable patients.  An 
evaluable patient will have both a baseline and on-treatment tumor biopsy. Aggregate 
toxicity will be monitored for patients in Part A2.  DLT will continue to be assessed in 
Part A2, and data acquired in Part A1 dose-escalation phase and Part A2 dose expansion 
phase will be combined to assess the toxicity (as suggested by Lasonos and O’Quigley, 
2014).89 In the event the observed toxicity exceeds 30%, a revised MTD may be 
recommended.
Although the A2 sample size is not based on any statistical considerations, the study would 
have 69% power to assess an overall response rate of 10% with 20 patients assuming the 
overall response rate of current therapy is 2%,96 using a one-sample test under a two-sided 
level of 0.1.  The study would have about 93% power if the true response rate is 20%. A 
table of 90% confidence intervals based on observed number of responders is provided below 
for reference:
Table 7.
90% Confidence Intervals of Overall Response Rate
N=20
90% Confidence Interval
Observed  
Responders
ORR
Lower Limit
Upper 
Limit
0*
0
0
5.6%
1
5%
0
15.5%
2
10%
0
23.5%
4
20%
2.8%
37.2%
6
30%
10.6%
49.4%
8
40%
19.5%
60.5%
*: with 0.005 continuity correction for confidence interval calculation
9.3.2. Part B Combination Therapy
The number of patients to be enrolled in the study will depend upon the observed safety 
profile, which will determine the number of patients at each dose combination level and the 
number of dose levels explored.  The maximum sample size after which the Part B1 will be 
stopped and MTD declared is 55 patients.  The total planned sample size for 
Part B2 expansion cohort is approximately 40 evaluable patients.

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At least 9 patients each will be treated at the dose combination level(s) identified as MTD.  If 
MTD was not reached by definition of safety criteria, this statement will apply for highest 
tested dose combination level.
9.4. Efficacy Analysis
In this FIP study, anti-tumor clinical activity is a secondary objective.
Tumor response in terms of time to progression, tumor progression, duration of response, and 
best objective response by RECIST and irRECIST will be summarized. Summary tables of 
response rates, median time to progression and corresponding confidence intervals will be 
provided Summary tables and figures will be generated by dose levels and/or tumor types. 
Data will be presented in the form of patient data listings that include, but are not limited to, 
tumor type, starting dose, tumor response at each visit, and best overall response.  In 
addition, progression date, death date, date of first response and last tumor assessment date, 
and date of last contact will be listed.
9.5. Analysis of Pharmacokinetics
9.5.1. PF-04518600 and Utomilumab PK Analysis
Serum pharmacokinetic parameters including the maximum concentration (Cmax), and area
under the concentration versus time curve within a dose interval (AUCτ) for 
PF-04518600 (Parts A and B) and utomilumab (Part B only) will be estimated using 
non-compartmental analysis.  If data permit or if considered appropriate, minimum 
concentration (Cmin), average concentration (Cav), AUC from time zero extrapolated to 
infinity (AUCinf), terminal elimination half-life (t1/2), clearance (CL), apparent volume of 
distribution (Vss), and accumulation ratio (Rac) will be also estimated.  The PK parameters 
will be summarized descriptively by dose, and cycle.
The concentrations of PF-04518600 (Parts A and B) and utomilumab (Part B only) will be 
summarized descriptively by dose, cycle, and nominal time.  Individual patient and median 
profiles of the concentration-time data will be plotted by dose and cycle using nominal times.  
Median profiles will be presented on both linear-linear and log-linear scales.
 
 
 
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9.5.3. Immunogenicity
ADA samples will be analyzed for the presence or absence of anti- PF-04518600 and 
anti-utomilumab antibodies following a tiered approach using screening, confirmation and 
titer/quantitation using a validated assay.  Samples tested positive for ADA will be further 
analyzed for NAb using a validated assay.  Listings and summary tabulations of the time 
course data on immune response endpoints will be generated.  Potential impact of 
immunogenicity on PK and clinical response including 
 
safety/tolerability and efficacy of ADA will be explored, if data is warranted.
9.5.4. Statistical Analysis of Biomarker Endpoint
For biopsy samples, summary statistics (eg, the mean and standard deviation, median, and 
minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment.  For each pair of 
specimens, the percent change from baseline of these same parameters will also be 
calculated.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
The percentage change from baseline for 
 over the period of 
the study will be tabulated by individual. The mean change from baseline values over time 
per cohort will also be tabulated.  Data will be presented in tabular and/or graphical format 
and summarized descriptively. 
 
 
 
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
9.6.1. Analysis of Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study.  The occurrence of DLTs observed in the dosing cohorts is used to estimate the 
MTD as described in the Study Design Section 3.  Adverse Events constituting DLTs will be 
listed per dose level.
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9.6.2. Analysis of Secondary Endpoints
9.6.2.1. Adverse Events
Adverse Events (AEs) will graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of study 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). 
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 lab assay.  The analyses will 
summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and 
Cycles beyond 1).  Shift tables will be provided to examine the distribution of laboratory 
toxicities.
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done. 
9.6.3. ECG
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. Baseline is defined as results collected at C1D1 prior to dosing.  
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF (and other correction factors, eg, QTcB as appropriate), and by dose.  Individual QT` 
(all evaluated corrections) intervals will be listed by time and dose.  The most appropriate 
correction factor will be selected and used for the following analyses of central tendency and 
outliers and used for the study conclusions.  Descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) will be used to summarize the absolute corrected QT 
value and changes from baseline in corrected QT after treatment by dose and time point.  For 
each patient and by treatment, the maximum change from baseline will be calculated as well 
as the maximum post-baseline value across time-points.  Categorical analysis will be 
conducted for the maximum change from baseline in corrected QT and the maximum 
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Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction method will be used) using maximum CTC AE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/ pharmacodynamic 
models.
9.7. Analysis of Anti-drug Antibody (ADA) for PF-04518600 and Utomilumab
Summary of number of patients developed ADA for PF-04518600 and utomilumab will be 
tabulated by dose group.  Subgroup analysis may be performed to assess the PK or 
pharmacodynamic response if data warrant. 
 
 
 
 
 
9.9. Interim Analysis
There is no planned formal interim analysis. 
9.10. 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.
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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The study site and investigator will 
promptly resolve any discrepancies that are identified between the study data and the 
patient's medical records.  The investigator will promptly provide copies of the inspection 
findings to Pfizer or its agent.  Before response submission to the regulatory authorities, the 
investigator will provide Pfizer or its agents with an opportunity to review and comment on 
responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
10.1. GCP Training
Prior to enrollment of any patients, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the Study will 
complete the Pfizer GCP Training or equivalent before performing Study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the Study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
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.

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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital'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, and telephone call reports).  The records should 
be retained by the investigator according to International Conference on Harmonization 
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.

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The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with 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 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data is compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients.  The study 
site will maintain a confidential list of patients who participated in the study linking their 
numerical code to the patient’s actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of patient personal data consistent with 
applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRB/EC and investigator databases may be used as recruitment 
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Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as Last Patient Last Visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-04518600 or 
PF-04518600 plus utomilumab 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 2 business days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), 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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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
EudraCT
Pfizer posts European (EU) Basic Results on EudraCT for all Pfizer-sponsored interventional 
studies that are in scope of EU requirements.  EU Basic Results are submitted for posting 
within 1 year of the primary completion date for studies in adult populations or within 
6 months of the primary completion date for studies in pediatric populations.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.

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

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Inman BA, Frigola X, Dong H, et al. Costimulation, coinhibition and cancer. Curr 
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Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer 
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Vetto JT, Lum S, Morris A, et al. Presence of the T-
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Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo 
enhances antitumor immunity. J Immunol 2000;164(4):2160-9.
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Petty JK, He K, Corless CL, et al. Survival in human colorectal cancer correlates with 
expression of the T-cell costimulatory molecule OX-40 (CD134). Am J Surg 2002; 
183(5):512-8.
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Ramstad T, Lawnicki L, Vetto J, et al. Immunohistochemical analysis of primary breast 
tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule 
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141. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and 
carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results 
from a randomized, double-blind, multicenter phase II study. J Clin Oncol 
2012;30:2046-54.
142. Zatloukal P, Heo DS, Park K, et al. Randomized phase II clinical trial comparing 
tremelimumab (CP-675,206) with best supportive care (BSC) following first-line 
platinum-based therapy in patients (pts) with advanced non-small cell lung cancer 
(NSCLC). Journal of Clinical Oncology 2009; 27(15S): 8071-8071.

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Appendix 1. 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, 1982.90

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Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (Version 4.03 date June 14, 2010) has been placed in the Study Manual for 
this protocol.  Alternatively, the NCI CTCAE may be reviewed on-line at the following NCI 
website: 
http://ctep.cancer.gov/reporting/ctc.html

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Appendix 3. Child-Pugh Score
Factor
1 point
2 points
3 points
Total bilirubin (μmol/L)
<34
34-50
>50
Serum albumin (g/L)
>35
28-35
<28
PT INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed with 
medication)
Grade III-IV (or refractory)
The total point score will be used to determine the patient’s Child-Pugh class outlined below: 
Class A
Class B
Class C
Total points
5-6
7-9
10-15
1-year survival
100%
80%
45%

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Appendix 4. 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 (>100.4F/38.0C) occur, the infusion should be interrupted.  Patients may 
be treated symptomatically (as described in Section 5.4.5.5 Dose Delay) and the infusion 
should be restarted at 50% of the original rate. 
Hypersensitivity reactions:
1. NCI-CTCAE Grade 1 allergic reaction or cytokine release syndrome.

Monitor for worsening condition.  If the reaction worsens, stop the infusion.  
Institute premedication for subsequent infusions as per Section 5.4.5.5 Dose
Delay. 
2. NCI-CTCAE Grade 2 allergic reaction or cytokine release syndrome.

Stop PF-04518600 or PF-05082566 infusion.

Administer bronchodilators, oxygen, acetaminophen, etc. as medically indicated.

Resume infusion at 50% of previous rate once reaction has decreased to 
Grade 1 in severity.  Monitor closely for any worsening.  If the reaction recurs, 
stop infusion.  Institute premedication for subsequent infusions as per 
Section 5.4.5.5 Dose Delay.
3. 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.
4. Treatment of Grade 3 or Grade 4 allergic reaction, cytokine release syndrome or 
anaphylaxis.

Stop the PF-04518600 or PF-05082566 infusion immediately and disconnect 
infusion tubing from the patient.

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
Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, 
intravenous fluids, vasopressor agents, oxygen, etc. as medically indicated.

Telephone Sponsor or designated representative to report an SAE as per 
Section 8 Adverse Event Reporting.

For a NCI-CTCAE Grade 3 or 4 hypersensitivity reaction, study treatment will be 
discontinued.
5. Re-treatment following Grade 1 or Grade 2 allergic reactions or cytokine release 
syndrome.

Once the PF-04518600 or PF-05082566 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-04518600 or 
PF-04518600/PF-05082566.

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-04518600 or PF-04518600/PF-05082566.

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, pharmacodynamic and ADA sampling should continue as long as the sampling does not 
interfere with the medical treatment of the patient.
In cases of suspected cytokine release syndrome, a serum sample should be provided for 
cytokine release assay analysis by the central lab so as long as the sampling does not interfere 
with the medical treatment of the patient.

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Appendix 5. RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228-247.85
A. Categorizing Lesions at Baseline:
1. 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. 
2. Non-measurable Disease:

Non-measurable disease includes lesions too small to be considered measurable
(including nodes with short axis between 10 and 14.9 mm) and truly non-measurable 
disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, 
leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions 
that cannot be accurately measured with calipers, abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion patientive to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
3. 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.
4. Recording Tumor Assessments:
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
5. Target Lesions:
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

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.
6. Non-target Disease:
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).

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B. Objective Response Status at Each Evaluation:
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
1. 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. 
2. Non-target Disease:

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

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
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
3. 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.
4. 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. 
5. Subjective Progression:
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 8.
Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New 
Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:

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Table 9.
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 6. Immune-related Response Criteria Derived From RECIST 
v1.1 (irRECIST)
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA-4, anti-PD-1 and 
anti PD-L1 which exert the antitumor activity by augmenting activation and proliferation of 
T-cells, thus leading to tumor infiltration by T-cells and tumor regression rather than direct 
cytotoxic effects.86,91 Clinical observations of patients with advanced melanoma treated with 
ipilimumab, for example, suggested that conventional response assessment criteria such as 
Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria are not sufficient 
to fully characterize patterns of tumor response to immunotherapy because tumors treated 
with immunotherapeutic agents may show additional response patterns that are not described 
in these conventional criteria.87,92
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have 
been reported as not capturing the existence of a subset of patients who have an OS similar to 
those who have experienced CR or PR but were flagged as PD by WHO criteria.
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses and designated Immune-related Response Evaluation Criteria 
In Solid Tumors (irRECIST).86
For irRECIST, only target and measurable lesions are taken into account.
In contrast to RECIST 1.1, irRECIST:

Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented; and,

Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum 
of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not 
increase by 20%.
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial.
irRECIST responses are defined as follows:

Overall immune-related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions. All measurable lymph nodes 
also must have a reduction in short axis to <10 mm.

Overall immune-related partial response (irPR): Sum of the longest diameters of 
target and new measurable lesions decreases 30%.

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
Overall immune-related stable disease (irSD): Sum of the longest diameters of 
target and new measurable lesions neither irCR, irPR, (compared to baseline) or 
immune-related progressive disease (irPD, compared to nadir).

Overall immune-related progressive disease (irPD): Sum of the longest diameters 
of target and new measurable lesions increases 20% (compared to nadir) with a 
minimum absolute increase of 5 mm, confirmed by a repeat, consecutive observation 
at least 4 weeks from the date first documented.
New measurable lesions: Incorporated into tumor burden.
In order to be selected as new measurable lesions (2 lesions per organ, 5 lesions total, per 
timepoint), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm 
in short axis for new measurable lymph nodes. New measurable lesions shall be prioritized 
according to size, and the largest lesions shall be selected as new measured lesions.
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively.
New non-measurable lesions: Do not define progression but preclude irCR.
Table 10.
Overall Responses derived from Changes in Index, Non-index, and New 
Lesions
Measurable 
Response
Tumor burdena
Non-Measurable Response
Overall Response 
using irRECISTb
Non-index lesions
New, 
non-measurable 
lesions
100%
Absent
Absent
irCR
100%
Stable
Any
irPR
100%
Unequivocal 
Progression
Any
irPR
30%
Absent/ stable
Any
irPR
30%
Unequivocal 
Progression
Any
irPR
<30% and <20% 
Absent/ Stable
Any
irSD
<30% and <20%
Unequivocal 
Progression
Any
irSD
20%
Any
Any
irPD
a Decreases assessed relative to baseline.
b Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive assessment at 
least 4 weeks part.