Clinical trial NCT02444793
Conditions: Advanced/Metastatic Solid Tumors
Sponsor: Pfizer
Start date: 2015-05-01; Completion date: 2017-10-01
Enrollment: 24 participants; Allocation: ; Intervention model: 

Brief summary:
This study is a Phase 1b, open label, multi center, multi-dose trial designed to estimate the maximum tolerated dose (MTD) and select the recommended dose for phase 2 (RP2D) investigations of PF- 05082566 in combination with KW-0761 (mogamulizumab) in patients with advanced solid tumors. Once the MTD of PF-05082566 administered in combination with KW-0761 is estimated (dose finding), one or more expansion cohorts of patients with selected advanced solid tumors (dose-expansion ) will be enrolled to further characterize the combination in term of safety profile, anti tumor activity, pharmacokinetics, pharmacodynamics and biomarkers modulation.

Detailed description:

Arms: arm 1: During Parts 1 \& 2 Mogamulizumab and PF-05082566 will be administered at appropriate intervals. Part 1: PF-05082566 dose escalation; increased doses of PF-05082566 IV are administered with mogamulizumab IV. Part 2: patients will be treated with the maximum tolerated dose established in Phase 1 for the combination.
Interventions: intervention 1: PF-05082566 intervention 2: KW-0761
Intervention descriptions: intervention 1: Part 1: PF-05082566 dose escalation; Increased doses of PF-05082566 IV are administered at appropriate intervals. Part 2: MTD of PF-05082566 IV established in Part 1 is administered. intervention 2: Part 1: KW-0761 IV administered at appropriate intervals. Part 2: KW-0761 IV administered at appropriate intervals at the MTD dose for the combination.

Protocol documents:
Prot_000.pdf: 
PF-05082566
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Final Protocol Amendment 1, 04 February 2016
Page 1
A PHASE 1B STUDY OF PF-05082566 IN COMBINATION WITH 
MOGAMULIZUMAB (KW-0761) IN PATIENTS WITH ADVANCED SOLID 
TUMORS
Compound:
PF-05082566
Compound Name:
Not Applicable
United States (US) Investigational New 
Drug (IND) Number:
109,154
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
B1641004
Phase:
1b


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
04 February 2016
Protocol Summary: Secondary Endpoints

Endpoint 4 changed  Vd to Vss and added
AUCtau and deleted AUC∞.
Protocol Summary: Study Design: Dose Finding 
Portion:

Changed the maximum tested dose from 
10 mg/kg to 5 mg/kg.

Added the following in bold: Dose finding 
may stop if 9 DLT evaluable patients have 
been treated at the estimated MTD (6 if no 
DLT observed at any dose).

Added the 100 mg flat dose cohort to the dose 
finding portion of the trial which will only 
enroll SCCHN and/or squamous NSCLC 
patients.

Added that the 5.0 mg/kg cohort (if safe and 
tolerable) will enroll at least 6 squamous 
NSCLC patients.
Protocol Summary: Study Design: Dose 
Expansion Portion:

Added  that the expansion cohorts may 
include CRC, bladder, ovarian, squamous 
esophageal, SCCHN and squamous NSCLC. 
Schedule of Activities:

Removed the Baseline Signs and Symptoms 
CRF.

Updated, changed and clarified the timepoints 
for the PK, ADA and Cytokine blood draws. 

Footnote #19: Changed time period for 
reporting of pregnancy/breast feeding from 
28 days after last dose of PF-05082566 to 
60 days.


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Document
Version Date
Summary of Changes and Rationale

Footnotes # 29 and 30 added the following:
“Upon progression in patients that showed 
initial response and /or stable disease, a 
biopsy may be taken unless in the opinion of 
the Investigator it poses an unacceptable
safety risk to the patient”.

Footnote #32:Changed the definition of the 
end of study from “6 months from the date of 
the first dose of  the last patient enrolled” to 
“6 months from the date of the last dose of  
the last enrolled patient”.

Administrative and formatting changes were 
made to enhance the readability of this section 
and reduce confusion and redundancy.
1.2.4.1 Pharmacokinetics of PF-05082566 In 
Humans:

Added rationale for the addition of the 100 mg 
flat dose cohort in the dose finding portion of 
the trial. 
2.2 Endpoints: Secondary Endpoints:

Endpoint 4 changed Vd to Vss and added
AUCtau and deleted AUC∞.
3.1.1 Dose Finding Portion:

Added the 100 mg flat dose cohort to the dose 
finding portion of the trial which will only 
enroll SCCHN and/or squamous NSCLC 
patients.

Added that the 5.0 mg/kg cohort (if safe and 
tolerable) will enroll at least 6 squamous 
NSCLC patients to determine RP2D.
3.1.2 Dose Expansion Portion:

Added that the expansion cohorts may include
CRC, bladder, ovarian, squamous esophageal, 
SCCHN and squamous NSCLC.


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Document
Version Date
Summary of Changes and Rationale
3.1.3 Study Treatment:

Updated timing of the mogamulizumab 
infusion from starting “30 minutes (30 min) 
after completion of the PF-05082566 dose” to
“30 minutes (10 min) after completion of the 
PF-05082566 dose”. 
3.1.9 Criteria for Dose Escalation:

Changed the maximum tested dose from 
10 mg/kg to 5 mg/kg. 

Added the 100 mg flat dose cohort to the dose 
finding portion of the trial which will only 
enroll SCCHN and/ or squamous NSCLC 
patients.

Added that the 5.0 mg/kg cohort (if safe and 
tolerable) will enroll at least 6 squamous 
NSCLC patients.

Added the following in bold: Dose escalation 
may stop if 9 DLT evaluable patients have 
been treated at the estimated MTD (6 if no 
DLT observed at any dose).

Updated Table 6 to include the 100 mg flat 
dose and the 50 mg flat dose.

Added the following: “A 24 hr time window 
between dosing is not necessary between 
cohorts dosed simultaneously”.
3.5 Dose Expansion Portion:

Added that the expansion cohorts may include 
CRC, bladder, ovarian, squamous esophageal, 
SCCHN and squamous NSCLC.
4.1 Inclusion Criteria:

Criterion #1 Updated to specify that the dose 
finding  cohort will enroll squamous NSCLC 
patients and that the expansion cohorts may 
include CRC, bladder, ovarian, squamous 
esophageal,SCCHN and squamous NSCLC. 


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Document
Version Date
Summary of Changes and Rationale

Criterion #6 updated to: Platelet count 
decreased from ≥100,000/L to ≥75,000/L.
4.2 Exclusion Criteria:

Criterion #16 Updated to specify that except 
for adequately treated basal cell or squamous 
cell skin cancer, or carcinoma in situ of the 
breast or of the cervix no other malignancy 
diagnosis within the 2 years prior to 
registration is permitted.
5.4 Administration:

The following in bold was added for clarity:
“Patients will be observed in the clinic for at 
least 2 hours after the administration of 
study drug, throughout the duration of the 
study.”
5.4.2 Mogamulizumab:

Updated timing of the mogamulizumab 
infusion from starting “30 minutes (30 min) 
after completion of the PF-05082566 dose” to
“30 minutes (10 min) after completion of the 
PF-05082566 dose”.
5.4.5 Treatment After Initial Evidence of 
Radiologic Disease Progression:

Administrative and formatting changes were 
made to enhance the readability of this section 
and reduce confusion and redundancy.
5.4.9.1 Dose Modification Guidelines:

Table 7 updated to add the 50 mg flat dose to 
be used for dose reductions for those on the 
100 mg flat dose cohort.
7.1.2 Adverse Events:

Deleted mention that the baseline signs and 
symptoms will be recorded on the AE CRF.






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Document
Version Date
Summary of Changes and Rationale
9.5.1.1 Pharmacokinetics Analyses of PF-05082566 
and Mogamulizumab: 

Updated plasma to serum.

AUCinf deleted.

AUCtau added.
References:

Updated reference #27.

Added references # 34-37.
15.1 Communication of Results by Pfizer:

Updated with latest template language. 
Appendix 3:

Incorrect reference deleted and current
version of irRECIST added.
Administrative Changes:

Updates made to Abbreviation Section.
Administrative and formatting changes were 
made throughout the document to enhance the 
readability of the protocol and reduce 
redundancy.
Original 
protocol
19 December 
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
4-1BB
TNFRSF9, 
, ILA
4-1BBL
4-1BB Ligand, TNFSF9
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse Event
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
APC
Antigen presenting cell
AST
Aspartate aminotransferase
AUC
Area under the concentration - time curve
AUC0-last
Area under the  concentration-time curve from time zero to last measurable concentration
AUCtau
Area under the concentration-time curve over dosing interval   
BP
Blood pressure
BUN
Blood urea nitrogen 
CCR4
Chemokine (C-C motif) receptor 4; CD194
CCR7
Chemokine (C-C motif) receptor 7; CD197
CD3
Cluster of differentiation 3
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CD20
Cluster of differentiation 20
CD40
Cluster of differentiation 40, TNFRSF5
CD45
Cluster of differentiation 45, Protein tyrosine phosphatase, receptor type C (PTPRC),  leukocyte 
common antigen
CD134
Cluster of differentiation 134, TNFRSF4, OX-40
Cave
Average serum concentration (estimated)
Cmax
Maximum serum concentration 
Ctrough
Predose serum concentration during multiple dosing
CHF
Congestive heart failure
CL
Clearance
CNS 
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete Response
CRF
Case Report Form
CRM
Complete Reassessment Method
CT
Computed Tomography
CTCAE
Common terminology criteria for adverse events
DC
Dendritic cell
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DR
Duration of Response
EC
Ethic Committee
EC10
Concentration required to achieve 10% of the maximal response
CCI
CCI


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ECD
Extracellular domain
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
ED50
Dose required to achieve 50% of the maximal response
EDP
Exposure during pregnancy
ELISA
Enzyme linked immunosorbent assay
ERK
Extracellular signal-regulated kinase
FACS
Fluorescent-activated cell sorting; flow cytometry
Fc
Fragment crystallizable
FDA
Food and Drug Administration
FIP
First-In-Patient
FL
Follicular lymphoma
GCP
Good clinical practice
GGT
Gamma-glutamyl transpeptidase 
GTD
Greatest transverse diameter
Hb
Hemoglobin
HLA
Human leukocyte antigen
KHK
Kyowa Hakko Kirin Pharma, Inc. 
ICH
International Conference on Harmonization
ICOS
Inducible T-cell costimulator; CD278
IEC
Independent Ethics Committee
IFN-
Interferon-gamma
IgG1K
Immunoglobulin G subclass 1 Kappa
IgG2
Immunoglobulin G subclass 2
IHC
Immunohistochemistry
IL-1
Interleukin 1 beta
IL-2
Interleukin 2
IL-4
Interleukin 4
IL-6
Interleukin 6
IL-10
Interleukin 10
IL-12p70
Interleukin 12 ( bioactive 75 kDa heterodimer of IL-12p40 and IL-12 p35)
IRB
Institutional Review Board
irRC
Immune-Related Response Criteria
IV
Intravenous
Ki-67
Antigen identified by mAb Ki-67
LDH
Lactate dehydrogenase 
LFT
Liver function test
LOAEL
Lowest observed adverse effect level
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MPK
Milligrams per kilogram, mg/kg
MTD
Maximum tolerated dose
Nab
Neutralizing antibody
NCI
National Cancer Institute


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NF-kB
Nuclear Factor kappa B
NHL 
Non-Hodgkin's Lymphoma
NK
Natural killer cell
NKT
Natural killer T cell
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
OS
Overall survival
PBL
Peripheral blood leukocyte
PBMC
Peripheral blood mononuclear cells
PBS
Phosphate Buffered Saline
PD
Pharmacodynamics
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival 
PK
Pharmacokinetics
PR
Partial response
PT
Prothrombin time
RECIST
Response evaluation criteria in solid tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SC
Subcutaneous
SCID
Severe combined immunodeficiency
SAE
Serious adverse event
SD
Stable disease
SEM
Standard error of mean 
sFAsL
Soluble Fas Ligand
t1/2
Terminal elimination half-life
TGI
Tumor growth inhibition
TITE-CRM
Time-to-Event Continual Reassessment Method
TNF
Tumor necrosis factor
TNF
Tumor necrosis factor alpha
TNFR
Tumor necrosis factor receptor
TNFRSF
Tumor necrosis factor receptor super family
TRAF
TNFR associated factor
TSH
Thyroid Stimulating Hormone
TTR
Time To Response
Vss
Volume of distribution at steady state
CCI


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PROTOCOL SUMMARY
Indication
Advanced solid tumors. 
Study Rationale
PF-05082566 is a fully human IgG2 monoclonal antibody (mAb) that binds to human 4-1BB 
with high affinity and specificity.  PF-05082566 demonstrated in vitro and in vivo
immunomodulatory activity along with anti-tumor activity when administered as a single 
agent, in combination with antibody-dependent cellular cytotoxicity (ADCC) inducing 
antibodies, and significantly enhanced anti-tumor activity in combination with anti-PD-1 
antibodies.
The safety and tolerability of PF-05082566 is currently being evaluated in a First-in-Patient 
Phase 1 study as a single agent and in combination with rituximab (Study B1641001).  
PF-05082566 has been well tolerated up to a maximum tested dose of 10 mg/kg, when 
administered every 4-weeks (q4wks) as a single agent and in combination with rituximab 
without clinically significant adverse events (AEs) above Grade 1 severity attributed to 
PF-05082566.  The preliminary pharmacokinetic (PK) results from the ongoing Phase 1 
study suggest that exposure of PF-05082566 increases dose proportionally with a terminal 
half-life of approximately 10 days.  Additionally, a Phase 1 combination study of 
PF-05082566 and MK-3475, an anti PD-1 mAb (Study B1641003) has been recently 
activated.
POTELIGEO(mogamulizumab, KW-0761) is a humanized mAb of the IgG1/kappa isotype 
produced by applying POTELLIGENT, a technology to produce antibodies with enhanced 
ADCC activity, which was developed exclusively by Kyowa Hakko Kirin Co., Ltd. (KHK).  
Mogamulizumab binds to chemokine [C-C motif] receptor 4 (CCR4) that is overexpressed or 
expressed at high frequency on the surface of cells in several T-cell malignancies including 
peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and adult T-cell 
leukemia/lymphoma (ATL).  This drug was approved in 2012 by the Ministry of Heath, 
Labor and Welfare in Japan for the treatment of relapsed or refractory CCR4 positive ATL,
and subsequently CCR4+ treatment-naïve ATL, and relapsed or refractory PTCL and CTCL,
and it is currently under investigation as single agent in patients with advanced solid tumor.  
Mogamulizumab demonstrated an acceptable safety profile.  The AEs reported have 
generally been mild to moderate in severity, with the most frequent mogamulizumab-related 
AEs being infusion related reactions, nausea, pyrexia, fatigue, and drug eruption, all 
manageable through the administration of appropriate treatment. 
CCR4 has also been observed on the surface of regulatory T cells (Treg), a lymphocyte 
subpopulation that has been linked to suppression of anti-tumor immune responses.  In vitro
culture of mogamulizumab with peripheral blood mononuclear cells (PBMC) obtained from 
cancer patients, leads to depletion of CCR4+ Treg and expansion of anti-tumor T cells.  
In vivo experiments using a B16-F10 mouse melanoma model demonstrated that the 
antitumor activity of 4-1BB agonist can be significantly improved in combination with an 
anti-CD4 mAb, which depletes the CD4+ T cells, including Tregs.  It has not been possible 






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This clinical study will include:
1. Dose-Finding portion
In the dose-finding portion, the MTD of the combination will be estimated in patients with 
advanced solid tumors.
PF-05082566 1.2 mg/kg and mogamulizumab 1 mg/kg will be the starting dose level.  See 
Section 3.1.8 for further information on the Dose Escalation Strategy.  The dose levels to be
tested in the dose-finding portion are shown in Table 6 of Section 3.1.9. 
Dose escalation and MTD estimation for the PF-05082566 plus mogamulizumab 
combination will be conducted according to the following algorithm:
a.
Dose escalation and de-escalation of PF-05082566 will follow the Time-to-Event 
Continual Reassessment Method (TITE-CRM) up to a maximum dose of 5 mg/kg 
once every 4 weeks.
b. The MTD will be defined as the highest combination dose with a DLT rate 
<30% from the model estimate.
c.
Dose escalation may stop if: 

Maximum study sample size of 30 is reached; or 

9 DLT evaluable patients have been treated at the estimated MTD (6 if no DLT 
observed at any dose); or

All doses appear to be overly toxic and the MTD cannot be determined in the 
current trial. 
A flat dosing of PF-05082566 100 mg will be studied to confirm the safety and PK at a dose 
that may be used for the expansion cohorts. This cohort will only enroll SCCHN and/or
squamous NSCLC patients.
The 5.0 mg/kg cohort (if safe and tolerable) will enroll at least 6 squamous NSCLC patients.
It is estimated that approximately 30 patients would be required in the dose-finding portion to 
achieve the study objectives.
2. Dose Expansion portion
Once the MTD of PF-05082566 administered in combination with mogamulizumab has been 
estimated with confidence, one or more expansion cohorts of patients will be enrolled to 
further study the safety, tolerability, PK/PD, and preliminary anti-tumor activity for 
PF-05082566 in combination with mogamulizumab as well as to study 
 
.  Tumor types for the expansion cohorts will be selected from CRC, bladder, 
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ovarian, squamous esophageal, SCCHN and/or squamous NSCLC patients. Dose, tumor 
types, 
 for these cohorts will be selected based on emerging data from the 
dose-finding portion of the study or data obtained from ongoing studies testing PF-05082566. 
The total enrollment into all expansion cohorts will be up to 40 response-evaluable patients.
Study Treatment
In both portions, treatment will be administered in 4-week cycles.
PF-05082566 will be administered as a 1-hour intravenous (IV) infusion, every 4 weeks
(q4wks), on Day 1 of each cycle.  The starting dose of PF-05082566 will be 1.2 mg/kg.
Mogamulizumab will be given as a 1-hour IV infusion, every week (qwk), for 4 consecutive 
weeks (Days 1, 8, 15 and 22) followed by biweekly dosing (Days 1 and 15), at the dose of 
1 mg/kg.
On Day 1 of a dosing cycle, in which the drugs are co-administered, and PK samples are 
collected, the mogamulizumab infusion will start 30 minutes (10 min) after completion of 
PF-05082566 infusion and after the end of infusion PF-05082566 PK blood sample and 
pre-mogamulizumab PK blood sample are drawn. See Table 2.
Treatment with study drugs will continue until completion of 24 months of treatment 
(approximately 24 cycles), confirmed disease progression, patient refusal, unacceptable 
toxicity, whichever occurs first, or the study is prematurely terminated by the Sponsor, or for 
one of the other reasons for patient withdrawal as specified in Section 6.4.
Discontinuation from treatment may be considered at the investigator’s discretion for patients 
who have attained a confirmed complete response (CR), and have received at least two 
cycles of mogamulizumab and PF-05082566 after the date the CR was confirmed.  Patients 
who then experience radiologic disease progression will be eligible for re-treatment with both 
study drugs at the discretion of the investigator and by the approval of the Sponsor, if no 
anticancer treatment was administered since the last dose of study drugs, the patient meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is still open.  
Patients will resume therapy at the same dose and schedule as at the time of initial 
discontinuation.  Patients who completed the 24 months of treatment on-study and 
demonstrate clinical benefit with manageable toxicity and are willing to continue receiving 
the study treatment will be given the opportunity to continue treatment off-study upon 
agreement between investigator and Sponsor. 
Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as reported in Schedule of Activities (Table 1) and in Section 7.1, 
Safety Assessments.
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Approximately 70 patients are expected to be enrolled in the study overall (including 
dose-finding and expansion cohorts).
SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the ASSESSMENTS Section of the protocol for detailed information on each 
assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the patient.






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Footnotes for Schedules of Activities
1.
Screening: To be obtained within 28 days prior to registration.
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period.
3.
Tumor History: Includes oncology history; information on prior regimens (including dosing and duration of administration, description of best response observed, 
recurrence date), surgery and radiation therapy.
4.
Medical History: Includes history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 7 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment.  Height will be measured at baseline only.
6.
ECOG PS: ECOG performance scale is available as Appendix 1.
7.
Vital Signs: blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
8.
Hematology: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study 
medications unless otherwise indicated.  If during the first 2 cycles of treatment a Grade 4 hematologic event is evident, the hematology assessment should be repeated at 
least every other day to assess for events qualifying as DLT.  See Table 10 in Section 7.1.3, Laboratory Safety Assessments, for the list of the required Laboratory Tests.
9.
Blood Chemistry and Coagulation: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  On treatment, to be performed prior to 
dosing with study medications unless otherwise indicated.  See Table 10 in Section 7.1.3, Laboratory Safety Assessments, for the list of the required Laboratory Tests.
10. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semiquantitative method (eg, urine dipstick), protein will be quantified 
by 24 hour urine collection (see Table 10).  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
11. Serum/Urine Pregnancy Test (serum/urine): For female patients of childbearing potential, will be performed on 2 separate occasions prior to starting study treatment:  
once at the start of screening and once at the baseline visit, immediately before study drug administration.. Following a negative pregnancy result at screening, appropriate 
contraception must be commenced. Pregnancy tests to be routinely repeated on Day 1 every cycle.  Additional pregnancy test to be done whenever one menstrual cycle is 
missed or when potential pregnancy is suspected.  Additional pregnancy tests may also be done if requested by IRB/ECs or if required by local regulations.  See Section 4.3
for contraception guidelines.
12. 12-lead ECG: At each time point, 3 consecutive 12 lead ECGs will be performed approximately 2 minutes apart to determine mean QTc.  When coinciding with blood 
sample draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  On treatment 
ECGs will be performed on Day 1 of Cycles 1-4, before and at the end of PF-05082566 infusion and at the end of mogamulizumab infusion. Cycle s>4, ECGs to be 
performed only if clinically indicated. While pre-dose ECG assessments will be required for all patients, post-dose ECG assessments will be required only for patients in 
dose-finding cohorts.  See Section 7.1.5 for further details.
13. Hepatitis B and C Tests: Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other tests may be conducted per standard practice to confirm an 
active hepatitis infection.
14. Thyroid and other Endocrine Function Tests : On treatment, thyroid function tests will be performed in cases of clinical symptoms consistent with thyroiditis.  On 
treatment, other endocrine function tests (in addition to T3, FT4, and TSH) will be performed in cases of suspected hypoadrenalism or hypopituitarism See Table 10, in 
Section 7.1.3, Laboratory Safety Assessments, for the list of the required Laboratory Tests.
15. Registration: Patient number and dose level allocation operated by Pfizer Inc.  Study treatments administration should begin within 7 days of registration.  
16. PF-05082566 Administration: Treatment will be administered in a 4-week cycle (ie, 28-day cycle).  PF-05082566 will be administered as a 1-hour IV infusion on Day 1 of 
each cycle.  When both PF-05082566-and mogamulizumab are administered, PF-05082566 will be administered first. Treatment will continue until completion of 24 months 
of treatment (approximately 24 cycles), or for one of the reasons listed for patient withdrawal as specified in Section 6.4.




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26. Blood for Pharmacogenomics (RNA): Blood samples (2.5 mL whole blood at each time point) will be collected on Day 1 at pre-dose of Cycles 1, 2, 3, 5 and at the EOT.  
See Section 7.7 for details.
27. Blood for PF-05082566 Immunogenicity Testing: Blood samples (2 mL whole blood at each time point) for PF-05082566 immunogenicity testing will be collected on 
Day 1 at pre-dose of Cycles 1, 3, 5, 8, 12, 16, 20, 24 and EOT. If ADAs are detected, additional samples may be collected approximately every 8 weeks until ADA levels 
return to baseline.  See Section 7.5.1 for details.
28. Blood for Mogamulizumab Immunogenicity Testing: Blood samples (3 mL whole blood at each time point) for mogamulizumab immunogenicity testing will be collected 
Day 1 at pre-dose of Cycles 1, 3, 5, 8, 12, 16, 20, 24 and EOT.  If ADAs are detected, additional samples may be collected approximately every 8 weeks until ADA levels 
return to baseline.  See Section 7.5.2 for details.
31. End of Treatment: To be performed no later than 28 days (+7 days) after the last dose of study drug.  Obtain these assessments if not completed during the previous week 
on study, (during the previous 8 weeks on study, for tumor assessments).
32. Follow Up: Patients should be evaluated up to 60 days for safety (SAEs) after last dose of study treatment.  Refer to the protocol for specific guidelines.  Patients continuing 
to experience drug related toxicity following discontinuation of study 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.  PK and immunogenicity samples should be collected as described in the PK and 
Immunogenicity ASSESSMENTS Section in SOA (Table 2).  
Patients whose disease has not progressed at the end of treatment will enter into disease follow up.  During this follow up period, patients will have disease assessments 
performed every 8 weeks (7 days).  Once patients have exhibited disease progression or began a new anticancer therapy, or 6-month follow-up from the date of the last dose 
of the last enrolled patient, whichever occurs first, they will be withdrawn from the study.  See Section 4.3 for guidelines on contraception during this period.
Legend (X) = optional activity to be executed only if applicable; ADA= anti-drug antibodies; AE= adverse event; C=cycle; CRF= case report form: ECG= electrocardiogram; D=day; 
irRC= Immune-Related Response Criteria; PK=Pharmacokinetics; 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................29
LIST OF FIGURES .................................................................................................................29
APPENDICES .........................................................................................................................30
1. INTRODUCTION ...............................................................................................................31
1.1. Mechanism of Action/Indication.............................................................................31
1.2. Background and Rationale ......................................................................................31
1.2.1. 4-1BB Target Biology and Mechanism of Action......................................31
1.2.2. Preclinical Profile of PF-05082566 ............................................................32
1.2.2.1. In Vitro PF-05082566 Data.......................................................32
1.2.2.2. In Vivo Data: Functional Activity of PF-05082566 ..................33
1.2.2.3. Preclinical Anti-Tumor Activity of PF-05082566 ....................34
1.2.2.4. Preclinical Pharmacokinetics of PF-05082566 .........................34
1.2.2.5. Pharmacokinetics and Pharmacodynamics Relationship of 
PF-05082566 .....................................................................................34
1.2.2.6. Preclinical Toxicology of PF-05082566 ...................................35
1.2.3. Clinical Safety of PF-05082566 .................................................................35
1.2.4. Clinical Efficacy of PF-05082566..............................................................38
1.2.4.1. Pharmacokinetics of PF-05082566 in Humans.........................39
1.2.4.2. Immunogenicity of PF-05082566 .............................................39
1.2.5. Mogamulizumab.........................................................................................40
1.2.5.1. Clinical Safety Data for Mogamulizumab.................................41
1.2.5.2. Pharmacokinetics of Mogamulizumab......................................43
1.2.5.3. Immunogenicity of Mogamulizumab........................................43
1.2.6. Study Rationale...........................................................................................44
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................46
2.1. Objectives................................................................................................................46
2.2. Endpoints.................................................................................................................47
3. STUDY DESIGN.................................................................................................................48
3.1. Study Overview.......................................................................................................48
3.1.1. Dose-Finding portion..................................................................................48
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3.1.2. Dose Expansion portion..............................................................................48
3.1.3. Study Treatment..........................................................................................48
3.1.4. Safety Assessments.....................................................................................49
3.1.5. Efficacy Assessments .................................................................................49
3.1.6. Pharmacokinetic (PK)/Immunogenicity Assessments................................50
3.1.8. Starting Dose Selection Strategy ................................................................50
3.1.9. Criteria for Dose Escalation........................................................................51
3.2. DLT Definition........................................................................................................53
3.3. MTD Definition.......................................................................................................54
3.4. Dose for Expansion Cohorts ...................................................................................54
3.5. Dose Expansion Portion..........................................................................................54
3.6. Recommended Phase 2 Dose (RP2D) Definition ...................................................55
4. PATIENT SELECTION......................................................................................................55
4.1. Inclusion Criteria.....................................................................................................55
4.2. Exclusion Criteria....................................................................................................57
4.3. Lifestyle Guidelines ................................................................................................59
4.4. Sponsor’s Qualified Medical Personnel..................................................................60
5. STUDY TREATMENTS.....................................................................................................60
5.1. Allocation to Treatment ..........................................................................................60
5.2. Patient Compliance .................................................................................................61
5.3. Drug Supplies..........................................................................................................61
5.3.1. Dosage Form(s) and Packaging..................................................................61
5.3.1.1. PF-05082566.............................................................................61
5.3.1.2. Mogamulizumab........................................................................61
5.3.2. Preparation and Dispensing........................................................................61
5.4. Administration.........................................................................................................62
5.4.1. PF-05082566...............................................................................................62
5.4.2. Mogamulizumab.........................................................................................62
5.4.3. Food requirements ......................................................................................63
5.4.4. Treatment Duration.....................................................................................63
5.4.5. Treatment After Initial Evidence of Radiologic Disease Progression........63
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5.4.6. Recommended Dose Modifications............................................................64
5.4.7. Dose Interruptions ......................................................................................65
5.4.8. Dose Delays................................................................................................66
5.4.9. Dose Reductions .........................................................................................66
5.4.9.1. Dose Modification Guidelines ..................................................67
5.5. Drug Storage ...........................................................................................................69
5.6. Drug Accountability................................................................................................70
5.7. Concomitant Treatment(s).......................................................................................70
5.7.1. Prohibited Concomitant Medications .........................................................70
5.7.2. Concomitant Surgery..................................................................................71
5.7.3. Concomitant Radiotherapy.........................................................................72
5.8. Supportive Care.......................................................................................................72
5.8.1. Hematopoietic Growth Factors...................................................................72
5.8.2. Anti-Emetic Therapy ..................................................................................72
5.8.3. Anti-Diarrheal Therapy ..............................................................................72
5.8.4. Anti-Infective Therapy ...............................................................................72
5.8.5. Anti-Inflammatory Therapy........................................................................73
5.8.6. Corticosteroids............................................................................................73
5.8.7. Supportive Care Guidelines for Infusion Reactions to Either Study 
Drugs................................................................................................................73
6. STUDY PROCEDURES .....................................................................................................75
6.1. Screening.................................................................................................................75
6.2. Study Period ............................................................................................................75
6.3. Follow-up Visit .......................................................................................................75
6.4. Patient Withdrawal..................................................................................................76
7. ASSESSMENTS..................................................................................................................77
7.1. Safety Assessment...................................................................................................77
7.1.1. Pregnancy Testing ......................................................................................77
7.1.2. Adverse Events...........................................................................................78
7.1.3. Laboratory Safety Assessment ...................................................................78
7.1.4. Vital Signs and Physical Examination (PE) ...............................................79
7.1.5. Electrocardiogram (12-Lead)......................................................................79


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7.2. Tumor Assessments.................................................................................................80
7.3. Pharmacokinetics Assessments...............................................................................82
7.3.1. Blood for PK analysis of PF-05082566......................................................82
7.3.2. Blood for PK analysis of Mogamulizumab ................................................83
7.5. Immunogenicity Assessments.................................................................................85
7.5.1. Immunogenicity Tests for PF-05082566....................................................85
7.5.2. Immunogenicity Tests for Mogamulizumab ..............................................85
7.7. Banked Biospecimen...............................................................................................86
7.7.1. Markers of Drug Response.........................................................................86
7.7.2. Additional Research....................................................................................87
8. ADVERSE EVENT REPORTING......................................................................................88
8.1. Adverse Events........................................................................................................88
8.2. Reporting Period .....................................................................................................88
8.3. Definition of an Adverse Event...............................................................................89
8.4. Medication Errors....................................................................................................89
8.5. Abnormal Test Findings..........................................................................................90
8.6. Serious Adverse Events...........................................................................................90
8.6.1. Protocol-Specified Serious Adverse Events...............................................91
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................91
8.7. Hospitalization ........................................................................................................92
8.8. Severity Assessment................................................................................................93
8.9. Causality Assessment..............................................................................................94
8.10. Exposure During Pregnancy..................................................................................94
8.11. Occupational Exposure .........................................................................................96
8.12. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal) ........96
8.13. Eliciting Adverse Event Information ....................................................................96
8.14. Reporting Requirements........................................................................................96
8.14.1. Serious Adverse Event Reporting Requirements .....................................96
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8.14.2. Non Serious Adverse Event Reporting Requirements..............................97
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................97
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................97
9.1. Analysis sets............................................................................................................97
9.2. Statistical Methods for Dose Allocation: TITE-CRM ............................................98
9.2.1. Statistical Methods for Dose Escalation/De-Escalation ...........................100
9.3. Sample Size Determination...................................................................................101
9.4. Efficacy Analysis ..................................................................................................101
9.5. Analysis of Other Endpoints .................................................................................101
9.5.1. Analysis of Pharmacokinetics...................................................................101
9.5.1.1. Pharmacokinetics Analysis of PF-05082566 and 
Mogamulizumab..............................................................................101
9.5.1.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling................102
9.5.2. Analysis of Immunogenicity Data............................................................102
9.6. Safety Analysis......................................................................................................103
9.6.1. Analysis of Primary Endpoint ..................................................................103
9.6.2. Analysis of Secondary Safety Endpoints..................................................103
9.6.2.1. Adverse Events........................................................................103
9.6.2.2. Laboratory Tests Abnormalities..............................................103
9.6.2.3. ECG.........................................................................................103
9.7. Data Safety Monitoring Committee ......................................................................104
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................105
11. DATA HANDLING AND RECORD KEEPING ...........................................................105
11.1. Case Report Forms/Electronic Data Record .......................................................105
11.2. Record Retention.................................................................................................106
12. ETHICS............................................................................................................................106
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................106
12.2. Ethical Conduct of the Study ..............................................................................106
12.3. Patient Information and Consent.........................................................................107
12.4. Patient Recruitment.............................................................................................107
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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................107
13. DEFINITION OF END OF TRIAL.................................................................................108
13.1. End of Trial in All Participating Countries .........................................................108
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................108
15. PUBLICATION OF STUDY RESULTS........................................................................108
15.1. Communication of Results by Pfizer ..................................................................108
15.2. Publications by Investigators ..............................................................................109
16. REFERENCES ................................................................................................................110
LIST OF TABLES
Table 1.
Schedule of Activities: Safety and Efficacy Assessments (Dose-finding and 
Expansion Cohorts) ..............................................................................................19
Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments  (Dose-finding and Expansion Cohorts)...........20
Table 3.
In Vitro Properties of PF 05082566......................................................................33
Table 4.
Study B1641001- Portion A Treatment Emergent PF-05082566-Related 
Adverse Events Reported in at Least 1 Patient (Any CTC Grade).......................36
Table 5.
Study B1641001 - Portion B Treatment Emergent Treatment Related 
Adverse Events Reported in at Least 1 Patient (Any CTC Grade).......................37
Table 6.
Dose Escalation and De-Escalation Cohorts ........................................................53
Table 7.
Available Doses for Dose Reduction....................................................................67
Table 8.
Dose Modification Guidelines for Treatment Related Adverse Events ...............68
Table 9.
Infusion Reaction Treatment Guidelines for Either Study Drug..........................74
Table 10.
Laboratory Safety Assessments............................................................................78
Table 11.
Objective Response Status at each Evaluation...................................................117
Table 12.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................118
Table 13.
Overall Response Derived from Changes in Target, Non-target and New 
Lesions................................................................................................................120
LIST OF FIGURES
Figure 1.
Effect of PF-05082566 on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model .............................................................................................34


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Figure 2.
Antitumor Effects of Combined Therapy with Anti-4-1BB and Anti-CD4 
mAb in B16F10 Mouse Melanoma Model...........................................................45
Figure 3.
Example Plot of Prior Dose Toxicity Curve.......................................................100
APPENDICES
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............113
Appendix 2. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Guidelines...........................................................................................................114
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-05082566 is a novel fully human IgG2 monoclonal anti-body (mAb) agonist of 4-1BB 
(
, TNFRSF9) that is being developed in combination with Poteligeo
(mogamulizumab), a recombinant humanized mAb targeting C-C chemokine receptor 4, 
(CCR4, CD194) registered in Japan for CCR4 expressing adult T-cell leukemia/lymphoma 
(ATL), peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).  The 
proposed combination is being studied for the treatment of adult patients with advanced solid 
malignancies that are unresponsive to currently available therapies, or for whom no standard 
therapy is available.
1.2. Background and Rationale
1.2.1. 4-1BB Target Biology and Mechanism of Action
4-1BB (
, TNFRSF9), first identified as an inducible co-stimulatory receptor expressed 
on activated T cells, is a membrane spanning glycoprotein of the Tumor Necrosis Factor 
(TNF) receptor superfamily.  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 (Treg), 
dendritic cells (DC) including follicular DC, stimulated mast cells, differentiating myeloid 
cells, monocytes, neutrophils, eosinophils[1] and activated B cells.[2]  4-1BB expression has 
also been demonstrated on tumor vasculature[3,4] and atherosclerotic endothelium.[5]  The 
ligand that stimulates 4-1BB (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 naïve T cells but expression increases upon 
activation.  Based on homology to other members of the TNF receptor superfamily 
(TNFRSF), ligand binding is expected to induce receptor trimerization resulting in 
activation.[6]  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.[7,8,9]   
Upon 4-1BB activation, 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 NF-kB and the Mitogen Activated Protein (MAP) Kinase cascade including 
Erk, Jnk, and p38 MAP kinases.  NF-kB activation leads to upregulation 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.[10] 
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production.[11]  Reports have shown that 4-1BB 
agonist mAbs increase co-stimulatory 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 
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protective T cell memory responses.[12]  4-1BB agonists also inhibit autoimmune reactions in 
a variety of autoimmunity models.[13]  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.
Interaction of 4-1BB on activated normal human B cells with its ligand at the time of B cell 
receptor engagement stimulates proliferation and enhances survival.[2] The potential impact 
of 4-1BB engagement in B cell lymphoma has been investigated in two published studies.  
Evaluation of several types of human primary non-Hodgkin’s lymphoma (NHL) samples 
indicated that 4-1BB was expressed predominantly on infiltrating T cells rather than the 
lymphoma cells.[14]  The addition of 4-1BB agonists to in vitro cultures of B lymphoma cells 
with rituximab and NK cells resulted in increased lymphoma killing.[15] 
In addition, B cell immunophenotyping was performed in two experiments using 
PF-05082566 in cynomolgus monkeys with doses from 0.001-100 mg/kg; in these 
experiments peripheral blood B cell numbers were either unchanged or decreased.
1.2.2. Preclinical Profile of PF-05082566
PF-05082566, an intravenous (IV) fully human IgG2 monoclonal antibody (mAb), binds to 
the extracellular domain of human 4-1BB with high affinity and specificity and is capable of 
4-1BB agonism.  In a human xenograft tumor model, injection with PF-05082566 as a single 
agent has been shown to correlate with tumor cell line growth inhibition.  In addition, 4-1BB 
agonist mAbs demonstrate significant combinatorial efficacy with antibody-dependent 
cellular cytotoxicity (ADCC) antibodies in lymphoma models.  Preclinical studies support 
the use of this 4-1BB agonist mAb as a promising candidate for treatment of cancer, alone or 
in combination with ADCC-inducing mAbs.
1.2.2.1. In Vitro PF-05082566 Data
PF-05082566 has shown immunomodulatory activity in various in vitro assays.  In concert 
with a signal through the T-cell receptor, PF-05082566 has been shown to mediate ligation of 
4-1BB, which results in activation of NFkB culminating in T cell cytokine release and 
proliferation.  The in vitro properties of PF-05082566 are summarized in Table 3.














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In patients with B cell NHL treated with PF-05082566 in combination with rituximab 
(Portion B), there was evidence for anti-tumor activity in rituximab-refractory disease.  Out 
of 11 patients with rituximab-refractory disease (defined by lack of response or progression 
within 6 months of rituximab-containing therapy) 2 patients with follicular B cell lymphoma
(FL) achieved a complete response (CR), 1 patient each with FL and mantle cell lymphoma 
achieved a PR, and 1 patient achieved a mixed response with FL.
Two additional patients without a history of rituximab-refractory disease achieved PRs 
throughout the range of the PF-05082566 dose escalation, including a rituximab naïve patient 
with CD20 + nodular Hodgkin’s lymphoma treated at 1.2 mg/kg.
No efficacy data are available for the Phase 1b study testing PF-05082566 in combination 
with MK-3475 (an anti PD-1 mAb) in patients with solid tumors at the time of writing this 
document (B1641003 Study). 
1.2.4.1. Pharmacokinetics of PF-05082566 in Humans
As of September 1st, 2014, PK data have been analyzed from a total of 62 patients of study 
B1641001 (Portion A: 0.006-2.4 mg/kg doses and Portion B: 0.03-1.2 mg/kg doses).  The 
preliminary PK results from the ongoing Phase 1 study suggest that exposure of 
PF-05082566 increases dose proportionally.  In Cycle 1 of Portion A, following attainment 
of Cmax,  PF-05082566 serum concentrations showed a bi-exponential decline with a mean 
terminal elimination half-life of 135-280 hrs., a low systemic clearance 
(CL = 0.23- 0.34 mL/hr/kg) and a small volume of distribution (Vss = 68.7.-92.9 mL/kg).  In 
Portion B, PF-05082566 also showed a bi-exponential decline with a mean terminal 
elimination half-life of 170-332 hrs., a low systemic clearance (CL = 0.13-0.288 mL/hr/kg) 
and a small volume of distribution (Vss = 55-94.4 mL/kg). 
Preliminary population PK analysis showed that body weight accounts for only a small 
percentage (~7%) of the variability in PF-05082566 drug exposure. Simulations indicated 
that PF-05082566 exposure profiles are similar in both body weight and fixed PF-05082566 
dosing regimens. Therefore, it is suggested a fixed dosing regimen be utilized for ease of use 
and to minimize potential medication errors.
1.2.4.2. Immunogenicity of PF-05082566 
Based on the preliminary data obtained in Study B1641001, 26 out of 39 patients (66%) were 
positive for anti-drug antibodies (ADA) in Portion A, for at least one time point.  The impact 
of ADA on PK and efficacy of PF-05082566 is being characterized.  No immune mediated 
adverse events were reported and presence of ADA doesn’t seem to preclude anti-tumor 
activity.  No ADA’s were detected in Portion B, when PF-05082566 was administered in 
combination with rituximab.
Complete pre-clinical and clinical information for PF-05082566, including PK data in 
patients, may be found in the single reference safety document (SRSD), which for this study 
is the PF-05082566 IB.[16]


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1.2.5. Mogamulizumab
C-C chemokine receptor 4 (CCR4) is a cell surface receptor for the macrophage-derived 
chemokine (MDC), thymus and activation-regulated chemokine (TARC).  Chemokines are 
considered to play a role both in the recruitment of immune and inflammatory cells for 
anti-tumor response and in the selective homing of neoplastic B and T cells.  In normal 
tissue, CCR4 is known to be selectively expressed on a subset of activated T-helper (Th2)
type CD4 positive (CD4+) T cells that produce inflammatory cytokines such as interleukin 
(IL)-4, IL-5, and IL-13, and has garnered attention as a molecular target for the treatment of 
allergic disorders such as asthma, atopic dermatitis or allergic rhinitis.  CCR4 is also 
expressed on primed human T regulatory (Treg) cells, NK cells, basophils, monocytes, and 
platelets.
CCR4 is also overexpressed or expressed at high frequency on the surface of cells in several 
human T-cell malignancies including peripheral T-cell lymphoma (PTCL), cutaneous T-cell 
lymphoma (CTCL), and adult T-cell leukemia/lymphoma (ATL). 
Preclinical studies conducted using the defucosylated chimeric (murine-human) anti- CCR4 
mAb (KM2760), a precursor of the humanized mogamulizumab mAb, demonstrated a potent 
antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4 positive human 
T-cell leukemia and lymphoma cell lines by using human peripheral blood mononuclear cells 
(PBMC) as effector cells in vitro.  In addition, KM2760 showed significantly higher ADCC 
activity than the fucosylated antibody (KM3060) in in vivo T-cell leukemia mouse models. 
The potent ADCC activity of mogamulizumab was further confirmed in in vitro and in vivo
preclinical ATL and T-cell lymphoma models. 
POTELIGEO(Mogamulizumab, KW-0761) is a recombinant humanized monoclonal 
antibody (mAb) targeting CCR4-expressing cells.  It is being developed by Kyowa Hakko 
Kirin Pharma, Inc. (KHK) for the treatment of T-cell malignancies, including PTCL, CTCL, 
and adult ATL. 
Mogamulizumab was approved by the Ministry of Heath, Labor and Welfare in Japan in 
March 2012 for the treatment of relapsed or refractory CCR4 positive ATL and is the first 
POTELLIGENTantibody to receive marketing approval anywhere in the world. 
In March 2014, mogamulizumab received approval from Japan's Ministry of Health, Labour 
and Welfare for the additional indications relapsed or refractory CCR4-positive peripheral 
T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).
As of 31 December 2013, globally approximately 340 subjects have received at least one 
dose of mogamulizumab in clinical studies, and an estimated 800 patients with ATL have 
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1.2.5.1. Clinical Safety Data for Mogamulizumab
In the Phase 1 dose escalation study in patients with relapsed adult CCR4-positive T-cell 
leukemia/lymphoma (ATL), peripheral T-Cell lymphoma (PTCL) and cutaneous T-cell 
lymphoma (CTCL),[17] 16 patients received mogamulizumab once a week for 4 weeks by IV 
infusion at the doses of 0.01, 0.1, 0.5, and 1.0 mg/kg.  Mogamulizumab was well tolerated at 
all tested doses.  Neither the frequency nor the severity of toxicities increased with dose 
escalation.  Only one patient, at the 1.0 mg/kg dose, developed dose-limiting toxicities 
namely Grade 3 skin rash and febrile neutropenia, and Grade 4 neutropenia.  The total 
number of AEs was similar for all doses, demonstrating no dose relationship for AEs.
The most frequent treatment emergent AEs (TEAEs) considered to be at least possibly 
related to study drug were lymphocyte count decreased (94%), infusion related reaction 
(81%), pyrexia (69%), neutrophil count decreased (63%), white blood cell count decreased 
(63%), platelet count decreased (56%), and chills (50%).  The MTD was not reached.  
Therefore, the RP2D was determined to be 1.0 mg/kg.  The plasma maximum (Cmax) and 
trough (Ctrough), and the area under the curve of 0 to 7 days of mogamulizumab, tended to 
increase dose and frequency dependently.
The 1.0 mg/kg dose was used in all the following clinical studies Sponsored by Kyowa 
Hakko Kirin Co. Ltd. or Kyowa Hakko Kirin Pharma, Inc.
Clinical Studies Sponsored by Kyowa Hakko Kirin Co. Ltd. conducted in Japan
Mogamulizumab as monotherapy was administered weekly for 4 (Study 0761-0501 ) or 
8 weeks (Studies 0761-002 and 0761-004).  Sixteen patients with CCR4+ relapsed ATL, 
PTCL and CTCL were treated in Study 0761-0501, 27 patients with CCR4 relapsed ATL and 
37 with CCR4+ relapsed PTCL and CTCL were treated in studies Study 0761-002 and 
Study 0761-004, respectively.
The most frequently observed TEAEs (10% of patients) that were considered to be at least 
possibly related to mogamulizumab were: lymphocyte count decreased (90.8%), white blood 
cell count decreased (63.3%), neutrophil count decreased (56.9%), platelet count decreased 
(55.1%), pyrexia (54.%), infusion related reaction (33.9%), alanine aminotransferase 
increased (ALT, 30.3%), aspartate aminotransferase increased (AST, 24.8%), chills (22.9%), 
anemia and rash (22.9% each), alkaline phosphatase increased and febrile neutropenia 
(21.1% each), nausea (20.2%), decreased appetite (19.3%), albumin decreased and lactate 
dehydrogenase (LDH) increased (18.4% each), weight decreased (17.4%), rash papular 
(16.5%), malaise (15.6%), constipation and stomatitis (14.7% each), headache (13.8%), 
phosphorus decreased (12.8%), vomiting (12.8%), blood pressure increased and sodium 
decreased (11.9% each), pruritus, rash erythematous and diarrhea (11.0% each), and 
potassium decreased and tachycardia (10.1% each). 
The drug-related TEAEs that were Grade 3 in intensity and reported in at least 3 patients 
were: lymphocyte count decreased (78.0%), white blood cell count decreased (36.7%), 
neutrophil count decreased (35.8%), platelet count decreased (23.9%), febrile neutropenia 
(21.1%), anemia (20.2%), decreased appetite and popular rash (6.4% each), rash (5.5%),








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In vitro or in vivo anti-CCR4 mAb treatment selectively depleted eTreg cells and efficiently 
induced tumor-antigen-specific CD4+ and CD8+ T cells and cytokine production. Thus, 
cell-depleting anti-CCR4 mAb therapy is instrumental for evoking and enhancing tumor 
immunity in humans via selectively removing eTreg cells.[25]
The efficacy of 4-1BB agonist as a cancer therapy has been documented.  Its therapeutic 
effects are mediated by enhancing NK and CD8+ T-cell activation and IFN-production. 
In vivo experiments on a B16-F10 mouse melanoma model demonstrated that the antitumor 
activity of an anti- 4-1BB can be significantly improved by the combination with an 
anti-CD4 mAb.  When co-administered, anti-4-1BB and anti-CD4 mAbs were able to 
successfully inhibit tumor growth and induced increased survival (Figure 2).  Anti-4-1BB 
treatment resulted in the polyclonal expansion and differentiation of CD8+ T cells into 
effective tumor killers while the CD4+ T-cell depletion facilitated the infiltration of immune 
cells into the tumors and removed regulatory barriers such as Tregs.[26]
Figure 2.
Antitumor Effects of Combined Therapy with Anti-4-1BB and Anti-CD4 
mAb in B16F10 Mouse Melanoma Model
Antitumor effects of combined therapy with anti-4-1BB and anti-CD4 mAb.  B16F10 melanoma bearing 
mice 6 days after tumor cells sc injection (when the tumors were 3 to 5 mm in diameter) were injected i.p.  with
100 g anti-4-1BB (3E1) and/or 400 g anti-CD4 (GK1.5), or 100 g rat IgG as a control, five times every 5 d.
PF-05082566 is a fully human IgG2 agonist monoclonal antibody targeting 4-1BB.  The 
safety and tolerability of PF-05082566 is currently being evaluated in a Phase 1 study as a 
single agent in patients with advanced solid tumors or B cell lymphoma and in combination
with rituximab in patients with CD20+ NHL (Study B1641001).  PF-05082566, administered 
every 4 weeks, has been well tolerated (up to 10 mg/kg dose as single agent and up to 
2.4 mg/kg in combination with rituximab) with mostly Grade 1 TEAEs attributed to 
PF-05082566. 
Mogamulizumab is a humanized mAb of the IgG1/kappa isotype targeting CCR4-expressing 
cells approved in Japan for the treatment of relapsed or refractory CCR4 positive ATL,
PTCL and CTCL and currently under investigation as single agent in patients with advanced 
solid tumors.  Mogamulizumab demonstrated an acceptable safety profile.  The AEs reported 
have generally been mild to moderate in severity, with the most frequent 
mogamulizumab-related TEAEs being infusion related reactions, nausea, pyrexia, fatigue, 
and drug eruption, all easily manageable through the administration of appropriate treatment. 






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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and PD study designed 
to estimate the maximum tolerated dose (MTD), and select the Recommended Phase 2 Dose 
(RP2D) of PF-05082566 in combination with mogamulizumab in patients with advanced 
solid tumors. 
This clinical study will include:
3.1.1. Dose-Finding portion
In the dose-finding portion, MTD of the combination will be estimated in patients with 
advanced solid tumors (ie, locally advanced or metastatic disease based on the TITE-CRM 
design[28 and 33] and according to the algorithm detailed in Section 3.1.9.
PF-05082566 and mogamulizumab starting doses as well as the starting dose selection 
strategy are described in Section 3.1.8.
A flat dosing of PF-05082566 100 mg will be studied to confirm the safety and PK at a dose 
that may be used for the expansion cohorts. This cohort will only enroll SCCHN and/or
squamous NSCLC patients.
The 5.0 mg/kg cohort (if safe and tolerable) will enroll at least 6 squamous NSCLC patients.
It is estimated that approximately 30 patients would be required in the dose-finding portion to 
achieve the study objectives.
3.1.2. Dose Expansion portion
Once the MTD of PF-05082566 administered in combination with mogamulizumab has been 
estimated with confidence, expansion cohorts of patients will be enrolled to further study the 
safety, tolerability, PK/PD, and preliminary anti-tumor activity for PF-05082566 in 
combination with mogamulizumab, as well as to study 
  
Tumor types for the expansion cohorts will be selected from CRC, bladder, ovarian, 
squamous esophageal, SCCHN and/or squamous NSCLC. Dose, final tumor types, 
 
 for these cohorts will be selected based on emerging data from the dose-finding
portion of the study or obtained from ongoing studies testing PF-05082566.
The total enrollment into all expansion cohorts will be up to 40 response-evaluable patients.
3.1.3. Study Treatment
In both portions, treatment will be administered in a 4-week cycles.
PF-05082566 will be administered as a 1-hour intravenous infusion (IV), every 4 weeks
(q4wks), on Day 1 of each cycle.  The starting dose of PF-05082566 will be 1.2 mg/kg.
CCI
CCI


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Mogamulizumab will be given as a 1-hour IV infusion every week (qwk) for 4 consecutive 
weeks (Days 1, 8, 15 and 22) followed by biweekly dosing (Days 1 and 15), at the dose of 
1 mg/kg. 
On Day 1 of a dosing cycle, in which the drugs are co-administered, and PK samples are 
collected the mogamulizumab infusion will start 30 minutes (10 min) after completion of 
PF-05082566 infusion and after the end of infusion PF-05082566 PK blood sample and 
pre-mogamulizumab PK blood sample are drawn. See Table 2.
Treatment with study drugs will continue until completion of 24 months of treatment 
(approximately 24 cycles), confirmed disease progression, patient refusal, unacceptable 
toxicity, whichever occurs first or the study is prematurely terminated by the Sponsor or one 
of the reasons for patient withdrawal listed (for details see Section 6.4).
Discontinuation from treatment may be considered at the investigator’s discretion for patients 
who have attained a confirmed complete response (CR), and have received at least two 
cycles with mogamulizumab and PF-05082566 after the date the CR was confirmed.  Patients 
who then experience radiologic disease progression will be eligible for re-treatment with both 
study drugs at the discretion of the investigator and by the approval of the Sponsor, if no 
anticancer treatment was administered since the last dose of study drugs, the patient meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is still open.  
Patients will resume therapy at the same dose and schedule at the time of initial 
discontinuation. 
Patients who completed the 24 months of treatment on-study and demonstrate clinical benefit 
with manageable toxicity and are willing to continue receiving the study treatment will be 
given the opportunity to continue treatment off-study upon agreement between investigator 
and Sponsor.
3.1.4. Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as reported in Schedule of Activities (SOA) (Table 1) and in 
Section 7.1, Safety Assessments.
3.1.5. Efficacy Assessments
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline and on treatment every 8 weeks 7 days starting from Cycle 1 Day 1 up to 1 year, 
then every 3 months (7 days) as specified in the SOA Table 1.  In addition, radiological 
tumor assessments will also be conducted whenever disease progression is suspected (eg, 
Symptomatic deterioration), and at EOT (if not done in the previous 8 weeks) and during 
follow up visits (if applicable).  Assessment of response will be made using RECIST version 
1.1 (Appendix 2) and irRC (Appendix 3).  Further details are provided in Section 7.2, Tumor 
Assessments.




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However, in order to minimize the potential risk of synergistic toxicity due to the 
combination, the starting dose for PF-05082566 in this study will be set to 1.2 mg/kg.  
Exposure at 1.2 mg/kg is above the projected efficacious concentration and safety data 
supports this starting dose, as there were no severe PF-05082566 related AEs at this dose and 
at higher doses.
The starting dose of mogamulizumab will be 1 mg/kg.  The dose selected for this study is the 
dose approved for the treatment of relapsed or refractory CCR4 positive ATL, PTCL and 
CTCL.  This dose administered weekly for 4 weeks and then every other week (ie, biweekly) 
until disease progression, appeared to be safe in clinical trials conducted in more than 
152 ex-Japan patients with T cell lymphoma and in more than 800 patients with ATL.  The 
AEs reported have generally been mild to moderate in severity, with the most frequent 
mogamulizumab-related TEAEs being infusion related reaction, nausea, pyrexia, fatigue, and 
drug eruption, all easily manageable through the administration of specific treatment. 
3.1.9. Criteria for Dose Escalation
No dose escalation of mogamulizumab is foreseen for the estimation of the combination 
MTD.  Dose escalation and de-escalation of PF-05082566 will follow the Time-to-Event 
Continual Reassessment Method (TITE-CRM)[28,33] up to 5 mg/kg. 
A flat dosing of PF-05082566 100 mg will be studied to confirm the safety and PK at a dose 
that may be used for the expansion cohorts. The safety data at 100 mg flat dose (equivalent 
to 1.2 mg/kg) will be pooled together with the data at 1.2 mg/kg in the TITE-CRM model.
The 5.0 mg/kg cohort (if safe and tolerable) will enroll at least 6 squamous NSCLC patients 
to determine RP2D.
In each cohort, 3 to 9 patients evaluable for MTD determination may be enrolled.
The first 3 patients (Dose Level 1) will be treated at the starting dose.  For each subsequent 
patient, the probability of DLT is estimated for each level based on all the collected data 
from all treated patients up to that time and the prior expectations of toxicity, and the patient 
is assigned to the currently estimated target level (with escalation restrictions as indicated 
below), defined as the dose having an estimated probability of DLT closest to but not greater 
than the target rate (30%). 
The probabilities of toxicity are estimated based on a Bayesian statistical model to learn 
about the overall dose-toxicity relationship. 
Patients’ DLT data will be reported to the study statistician who will update the dose-toxicity 
model before the next enrolled patient is treated.
The MTD is defined as the highest combination dose with a DLT rate <30% from the model 
estimate (see Section 9.2).


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Dose escalation may stop if: 

Maximum sample size (n=30, see Section 9.2) is reached; or 

9 DLT evaluable patients have been treated at the estimated MTD (6 if no DLT 
observed at any dose); or

All doses appear to be overly toxic and the MTD cannot be determined in the current 
trial. 
In the TITE-CRM paradigm, patients who have enrolled in the trial, but have not experienced 
DLT, will be included in the probability calculation with an initial weight equal to the 
proportion of the 8-week (2 cycles of PF-05082566 and mogamulizumab) DLT observation 
period that the patients have completed (however, the weight function may be modified if 
accumulating safety data  suggest a different pattern). 
Patients who experience DLT or complete the observation period without DLT will be 
assigned full weight (=1). 
Details on the TITE-CRM method are provided in Section 9.2 and the Statistical Analysis 
Plan (SAP).
To avoid overly rapid escalation and to retain the efficiency of dose administration when 
enrollment is fast, the following restrictions and practical considerations will be followed.

Dose skipping in escalation to untested doses is not allowed (k −> k+1).  In particular, 
at least three patients should have been treated at dose level k before escalation to 
dose level k+1;

At least three patients should have been on treatment (for a minimum of 3 weeks) and 
observed DLT rate <33% at dose level k before a patient is assigned to dose level 
k+1 (Note that the waiting window depends on our knowledge in the time-to-event 
pattern of toxicity and accumulating safety data, and thereby the confidence in the 
associated weights.  However, intentional delay in enrollment in the absence of DLT
or serious AEs should be minimized and discouraged);

Dose escalation recommendation by the TITE-CRM algorithm may be overruled by 
the Sponsor if the nature of the existing data causes safety concern.
Dose escalation and de-escalation will be carried out according to Table 6. 




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
Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of 
38 degrees C (100.4 degrees F) for more than one hour;

Grade 3 neutropenic infection;

Grade 3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.
Non-Hematologic:

Grade 3 non laboratory toxicities (excluding infusion reactions), except those that 
have not been maximally treated (eg, nausea, vomiting, diarrhea).

Grade 3 laboratory abnormalities (other than AST/ALT) if:

Medical intervention is required to treat the patient, or

The abnormality leads to hospitalization.

Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
increase.
3.3. MTD Definition
The MTD is defined as the highest combination dose with a DLT rate <30% from the 
TITE-CRM model estimate (see details in Section 9.2).
Once the MTD is estimated, additional patients may be enrolled at this dosing level.  In the 
expansion cohort, patients’ DLT data will be entered into the Bayesian statistical model of 
the TITE-CRM procedure.  If the posterior distribution of the model incorporating the 
additional data from the expansion cohort suggest the estimated MTD is associated with a 
higher than expected DLT rate the next lower dose or an intermediate dose level will be 
expanded, and may be declared as the RP2D.
3.4. Dose for Expansion Cohorts
The expansion cohort(s) will be tested at either the estimated MTD or lower doses based on 
the emerging safety, efficacy and PK/PD data.
3.5. Dose Expansion Portion
Expansion cohort(s) will test PF-05082566 in combination with mogamulizumab in patients 
with select advanced solid tumors. Tumor types for the expansion cohorts will be selected 
from CRC, bladder, ovarian, squamous esophageal, SCCHN and/or squamous NSCLC. The 
PF-05082566 dose for expansion cohorts may be a flat dose of 100 mg. All patients in the 
expansion cohorts may be enrolled simultaneously.  The total number of patients enrolled 


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into one or more expansion cohorts will be determined based on the tumor type, and patient 
population emerging data from this study.  PK/ADA samples will be collected from all 
evaluable patients in the dose expansion cohorts.
3.6. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose chosen for further study based on Phase 1 results.  If the MTD proves 
to be clinically feasible for long term administration in a reasonable number of patients, such 
dose usually becomes the RP2D.  Further experience with the MTD may result in a RP2D 
dose lower than the MTD.
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 included in the study. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
Histological or cytological diagnosis of advanced/metastatic solid tumor malignancy. 
Dose Finding Cohorts: Tumor types will be limited to CRC, SCCHN, squamous 
NSCLC, bladder, or ovarian carcinomas which have progressed on standard therapy, 
or for which no standard therapy is available. Expansion Cohorts: Tumor types may
include: Histological or cytological diagnosis of either advanced/metastatic CRC, 
bladder, ovarian, squamous esophageal, SCCHN, or squamous NSCLC. NOTE:
Final determination of tumor types for expansion will be made based on emerging 
data from the dose-finding portion of the study or obtained from ongoing studies 
testing PF-05082566.
Measurable disease by RECIST version 1.1.
For Expansion Cohorts only: patients must have tumor accessible for biopsies (core 
needle biopsy or excision preferred). See Section 3.1.7.
Age 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Adequate bone marrow function, defined as follows:

absolute neutrophil count (ANC) 1.5 x 109/L (1,500/L);


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
platelet (PLT) count 75 x 109/L (75,000/L);

hemoglobin (Hb) 9.0 g/dL (5.6 mmol/L). 
Patients must be transfusion independent (ie, no blood product transfusions for a 
period of at least 14 days prior to study registration).
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.
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; 

Alkaline phosphatase 2.5 x ULN; (5 x ULN in case of bone metastasis).
Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 
1 except for AEs not constituting a safety risk by investigator judgment.
Serum/urine pregnancy test (for females of childbearing potential) negative at 
screening and before the patient will receive the study treatment.
Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two (2) highly effective methods of contraception throughout the study 
and for 60 days after the last dose of assigned study treatment. 
Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure; OR

Achieved post-menopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle stimulating hormone (FSH) level 
within the laboratory’s reference range for postmenopausal women. 
Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.


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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:
Central nervous system primary malignancies, active seizure disorder or spinal cord 
compression, or carcinomatous meningitis.  Patients with previously treated brain 
metastases may participate provided they are stable (without evidence of progression 
by imaging for at least 4 weeks prior to registration and any neurologic symptoms 
have returned to baseline), have no evidence of new or progressing brain metastases.  
This exception does not include carcinomatous meningitis, which is excluded 
regardless of clinical stability.
Systemic anticancer therapy within 28 days prior to registration.  In absence of 
persisting toxicity, 5 half-lives since completion of prior anti-cancer therapy is
acceptable.
Therapeutic or experimental monoclonal antibodies within 60 days prior to 
registration.
Systemic corticosteroid therapy or any other form of immunosuppressive therapy 
within 14 days prior to registration.  Patients that require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections will not be excluded from 
the study.
Major surgery within 28 days prior to registration.
Radiation therapy within 14 days prior to registration. 
History of, or active ethanol abuse or hepatitis (eg, alcohol or non-alcohol 
steatohepatitis [NASH], drug related, auto immune, virally related).
Live vaccine within 30 days prior to registration.
Active and clinically significant bacterial, fungal or viral infection including 
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) 
or acquired immunodeficiency syndrome (AIDS) related illness (HIV testing is not 
required), including patients who have an active infection requiring systemic therapy.  
Active herpes simplex or herpes zoster.  Patients on prophylaxis for herpes infection 
who started taking medication at least 30 days prior to study entry, and have no active 
signs of active infection, and whose last active infection was more than 6 months 
prior to registration, may enter the study, and should continue to take the prescribed 
medication for the duration of the study.


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Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations (including patients who are known to be positive for ADA to 
mogamulizumab or PF-05082566).
Patients who previously had a severe hypersensitivity reaction to treatment with 
another monoclonal antibody.
Patients with a history of autoimmune disease (eg, rheumatoid arthritis, Addison’s 
syndrome, multiple sclerosis, uveitis, systemic lupus erythematosus or Wegener’s 
granulomatosis).  Patients with vitiligo or alopecia are eligible.  Patients with Graves 
disease or psoriasis not requiring systemic treatment within the past 3 years are 
eligible.  Patients with hypothyroidism with stable hormone replacement are eligible.
Patients with known inflammatory bowel disease eg, ulcerative colitis, Crohn’s 
disease, or celiac disease.
Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
Any of the following within the 12 months prior to registration: myocardial 
infarction, congenital long QT syndrome, torsade de points, arrhythmias (including 
sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle 
branch block 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, ongoing cardiac dysrhythmias 
of NCI CTCAE Grade 2, atrial fibrillation of any grade, or QTcF interval >470 msec
at screening. 
Diagnosis of any other malignancy within 2 years prior to registration, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix.
Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant; male and female patients of childbearing potential who are 
unwilling or unable to use two (2) highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for 60 days after last dose of 
investigational product.
Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 


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Participation in other therapeutic studies within 4 weeks before the current study 
begins and/or during study participation.
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 or KHK employees directly involved in the 
conduct of the study.
4.3. Lifestyle Guidelines 
In this study, patients of childbearing potential will receive PF-05082566 and 
mogamulizumab, compounds for which the teratogenic risk in human is currently unknown.  
Two (2) methods of highly effective contraception must be used throughout the study and 
continued for at least 60 days after the last dose.  The investigator or his/her designee, in 
consultation with the patient, will select two appropriate methods of contraception for the 
individual patient from the list of permitted contraception methods (see below) and instruct 
the patient in their consistent and correct use.  
Patients need to affirm that they meet at least 2 of the selected methods of contraception.  
The investigator or his/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/her 
designee will instruct the patient to call immediately if a selected contraception method is 
discontinued or if pregnancy is known or suspected. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
Established use of oral, inserted, injected or implanted hormonal methods of 
contraception is allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
Correctly placed copper-containing intrauterine device (IUD).
Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
Male sterilization with absence of sperm in the post-vasectomy ejaculate.
Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).


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Patients will be advised to report any reaction to sun exposed skin.  In addition, special 
precautions will be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity ultraviolet B light (UVB) sources such as 
tanning beds, tanning booths and sunlamps.  Patients should be encouraged to apply 
sunscreen/sunblock daily.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual (ie, 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 help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. 
The help desk number can also be used by investigational staff if they are seeking advice on 
medical questions or problems; however, it should only be used in the event that the 
established communication pathways between the investigational site and the study team are 
not available. It is therefore intended to augment, but not replace, the established 
communication pathways between the investigational site and the study team for advice on 
medical questions or problems that may arise during the study. The help desk number is not 
intended for use by the patient directly, and if a patient calls that number, he or she will be 
directed back to the investigational site.
5. STUDY TREATMENTS
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
fax or email a complete Registration Form to the designated Sponsor study team member.  
The Sponsor will assign a patient identification number, which will be used on all Case 
Report Form (CRF) pages and other study-related documentation or correspondence 
referencing that patient and fax or /email to the site.
For the purposes of this protocol, study drug or study treatment refers to both PF-05082566 
and mogamulizumab.  No patient shall receive study drug until the investigator or designee 
has received the following information in writing from the Sponsor:

Confirmation of the patient’s enrollment;

Specification of the dose level for that patient; and


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
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 slot date.
5.2. Patient Compliance
There are no specific patient compliance guidelines for study drug administration, as the 
study drugs will be administered by designated study staff at the investigational site.
5.3. Drug Supplies
PF-05082566 and mogamulizumab will be supplied by Pfizer Global Clinical Supply Chain, 
Worldwide Research and Development.  Drug supplies will be shipped to the study sites with 
a Drug Shipment & Proof of Receipt form.  This form should be completed, filed, and the 
shipment confirmed as directed on the bottom of the Drug Shipment & Proof of Receipt 
form.
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. PF-05082566
PF-0508256 drug product will be supplied in clear glass vials at a 10 mg/mL concentration as 
sterile solution for intravenous administration and labeled as open supplies.  Each vial is 
packed in an individual carton. 
Each vial contains nominal 100 mg of PF-05082566 in a 10 mL solution.  To ensure that the 
exact volume can be withdrawn by syringe, there is a small amount of overfill in the vial.
5.3.1.2. Mogamulizumab
Mogamulizumab drug product will be supplied as a 4 mg/mL, sterile solution for dilution for 
intravenous infusion.  Each glass vial contains 20 mg of mogamulizumab.
5.3.2. Preparation and Dispensing
See the respective Dosage and Administration Instructions (DAI) for instructions on how to 
prepare the investigational products for administration.  Investigational products 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 
investigational agents.
The site will complete required dosage Preparation Record located in the study manual.  The 
use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor. 


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5.4. Administration
Study treatment administration should start no later than 7 days after registration.
A cycle is defined as the time from Day 1 dose to the next Day 1 dose of PF-05082566.  If 
there are no treatment delays, a cycle will be 4 weeks in duration. 
All trial treatments will be administered on an outpatient basis.  After Cycle 1, study drugs 
may be administered up to 2 days before or after the scheduled treatment day of each cycle 
for administrative reasons.  Patients will be observed in the clinic for at least 2 hours after the 
administration of study drug, throughout the duration of the study.
All patients should be weighed within 7 days 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 study drug required for dose preparation.  Decision to recalculate the study 
drug 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 study drug required for 
preparation and administration for the current cycle must be recalculated using this most 
recent weight obtained.
As with any antibody, allergic reactions to dose administration are possible.  Therefore,
appropriate drugs and medical equipment to treat allergic or anaphylactic reactions must
be immediately available, and study personnel must be trained to recognize and treat allergic 
and anaphylactic reactions.  Patients should be instructed to report any delayed reactions to 
the Investigator immediately.  If a patient experiences an infusion related reaction at any 
time during the study, premedication is recommended prior to subsequent infusions (see 
Section 5.4.2 for details on premedication to be used).
For both drugs, the exact duration of infusion should be recorded in both sources document 
and CRFs.  The infusion rate should be reduced or interrupted in the case of symptoms of 
infusion reaction, and symptomatic treatment administered.  The infusion may be continued 
at one-half the previous rate upon improvement of symptoms. If symptoms persist or 
worsen, the infusion should be discontinued. 
The study drug dose-escalation levels are shown in Table 6.  In addition, doses of 
PF-05082566 and mogamulizumab available for dose modification according to guidelines in 
Section 5.4.9, are shown below in Table 7.
5.4.1. PF-05082566
PF-05082566 will be administered first, as a 1-hour IV infusion, q4wks, on Day 1 of each 
cycle.  The starting dose of PF-05082566 will be 1.2 mg/kg. 
5.4.2. Mogamulizumab
Mogamulizumab will be given after PF-05082566 administration, as a 1-hour IV infusion, at 
a dose of 1 mg/kg.  Mogamulizumab will be administered weekly for 4 consecutive weeks in 
the first cycle (ie, on Days 1, 8, 15 and 22), followed by biweekly dosing in cycles 2 (ie, on 
Days 1 and 15). 


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The two study drugs are co-administered on Day 1 of each dosing cycle.  In such case, the 
mogamulizumab infusion will start 30 minutes (10 min) after completion of PF-05082566 
infusion and after the end of infusion PF-05082566 PK blood sample and 
pre-mogamulizumab PK blood sample are drawn. 
It is recommended that on Cycle 1 Day 1 administration of mogamulizumab, patients 
be premedicated according to the guidance below.
Premedication: Premedication with acetaminophen or paracetamol orally and 
diphenhydramine 50 mg IV (or equivalent antihistamine) to prevent hypersensitivity 
reactions is recommended before the first mogamulizumab infusion.
5.4.3. Food requirements 
PF-05082566 and mogamulizumab may be administered without regard to meals.
5.4.4. Treatment Duration
The treatment duration with both study drugs is 24 months (approximately 24 cycles) 
calculated from Cycle 1 Day 1. 
Patients may continue on treatment with both agents until disease progression (by RECIST 
v. 1.1 and/or irRC), patient refusal, unacceptable toxicity, whichever comes first, or the study 
is prematurely terminated by the Sponsor, or for one of the other reasons for patient 
withdrawal specified in Section 6.4.
Discontinuation from treatment may be considered at the investigator’s discretion for patients 
who have attained a confirmed CR, and have had at least two cycles with mogamulizumab
and PF-05082566 after the date the CR was confirmed.  Patients who then experience 
radiologic disease progression will be eligible for re-treatment with both study drugs at the 
discretion of the investigator and by the approval of the Sponsor, if no cancer treatment was 
administered since the last dose of study drugs, the patient meets the safety parameters listed 
in the Inclusion/Exclusion criteria, and the trial is still open.  Patients will resume therapy at 
the same dose and schedule at the time of initial discontinuation. 
Patients who completed the 24 months of treatment on-study and demonstrate clinical benefit 
with manageable toxicity and are willing to continue receiving the study treatment will be 
given the opportunity to continue treatment off-study upon agreement between investigator 
and Sponsor. 
5.4.5. Treatment After Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents such as mogamulizumab and PF-05082566 may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses.  The 
response patterns seen with such 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.  Based on the proposed 
mechanism of action of PF-05082566, new lesions may appear as enlargements in regional 
tumor-draining lymph nodes, which might reflect anti-tumor immune responses. 


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Therefore, if radiologic imaging shows progressive disease, in the absence of clinical 
deterioration, tumor assessment must be repeated 4 weeks later in order to confirm 
progressive disease. There is the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  
Note: Before continuation of treatment, the patient must be re-consented and informed that in 
order to continue receiving the investigational products on trial the patient may be foregoing 
Food and Drug Administration (FDA)-approved therapy with possible clinical benefit(s).
Patients may receive study treatment while waiting for confirmation of progressive disease if 
they are re-consented and are clinically stable as defined by the following criteria: 

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression. 

No decline in ECOG performance status. 

Absence of rapid progression of disease. 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
If repeat imaging shows a reduction in the tumor burden demonstrating CR, partial response 
(PR) or stable disease (SD) compared to the previous scan, treatment may be continued.  
If the repeat imaging confirms initially documented progressive disease, patients may be 
discontinued from the study.  However, according to the investigator’s judgment if a patient 
with evidence of disease progression is still experiencing clinical benefit, the patient will be 
eligible for continued treatment with PF-05082566 combined with mogamulizumab.  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.  
Biopsies should be considered, when clinically indicated, to clarify disease involvement in 
such cases.  In determining whether or not the tumor burden has increased or decreased, 
Investigators should consider all target lesions as well as non-target lesions (please refer to 
the Site Imaging Manual). 
5.4.6. Recommended Dose Modifications
Every effort should be made to administer study treatment (ie, PF-05082566 and 
mogamulizumab) at the planned dose and schedule.
In the event of significant toxicity dosing may be delayed and/or reduced as described below.  
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed.  Patients are to be instructed to notify investigators at the first occurrence of any 
adverse symptom.


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Patients who experience an AE meeting the definition of a DLT may be removed from 
treatment, based on the dose modification guidelines listed in Section 5.4.9 and in 
consultation with the Sponsor.
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. 
Investigators are encouraged to employ best supportive care according to local institutional 
clinical practices and according to the guidance for selected adverse events provided below.
Dose modifications will be reported in the CRF.
5.4.7. Dose Interruptions
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 2 toxicity despite supportive care, should have their treatment interrupted.
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
Section 5.4.8, Dose Delays.
Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in Section 5.4.9, Dose Reductions, unless expressly agreed 
otherwise following discussion between the investigator and the Sponsor.
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting >2 weeks, treatment resumption will be decided in consultation 
with the Sponsor.


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5.4.8. Dose Delays
Re-treatment at the start of any new cycle, intra cycle (when mogamulizumab only is 
administered), or following treatment interruption due to treatment related toxicity may not 
occur until all of the following parameters have been met:

ANC 1,000/L;

Platelet count 75,000/L;

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).
After all toxicities have recovered within the limits described above, treatment with 
PF-05082566 and/or mogamulizumab can be resumed. 
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
Intra cycle mogamulizumab dose delay due to treatment related toxicity is not allowed.  If, 
within a cycle, retreatment with mogamulizumab is not possible due to persistent toxicity, the 
dose/s should be considered as omitted.
Withhold scheduled dose for liver function test (LFT) related AEs (including asymptomatic) 
Grade 3 until return to baseline or Grade 1 severity.  In cases of potential liver injury, see 
Section 8.6.2.  In such cases, consultation with a hepatologist should be considered in the 
decision to initiate treatment with anti-inflammatory medications.
If hematological toxicities do not recover to the above values and non-hematologic toxicity 
does not resolve to baseline or Grade 1 (Grade 2 if not considered a safety risk for the 
patient) within 4 weeks of last infusion, consider permanent discontinuation after 
consultation with the Sponsor.  With investigator and Sponsor agreement, patients with a 
laboratory adverse event still at Grade 2 after 4 weeks may continue treatment in the trial 
only if asymptomatic and controlled. 
Permanent discontinuation of study treatment should be considered for any life-threatening 
event. 
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle. 
5.4.9. Dose Reductions
Dose reductions of PF-05082566 and/or mogamulizumab may be required based on the worst 
toxicity experienced in the previous administration or previous cycle (see Table 7). 


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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.
Patients experiencing recurrent and intolerable Grade 2 non-hematologic toxicity may 
resume dosing, with specific dose modifications detailed in Section 5.4.9.1, once recovery 
to Grade 1 or baseline is achieved.
Once a patient has a dose reduction in PF-05082566 and/or mogamulizumab for a 
drug-related toxicity, the dose will not be re-escalated.  Patients requiring more than one dose 
reduction will be withdrawn from treatment unless otherwise agreed between the investigator 
and the Sponsor. 
5.4.9.1. Dose Modification Guidelines
Table 7 below shows the PF-05082566 and mogamulizumab doses available for dose 
reduction in this study.  Suggested dose modification guidelines are presented in 
Table 8 below.  Both study drugs or mogamulizumab only should be held for the listed 
toxicities with dose modifications as suggested.
Table 7.
Available Doses for Dose Reduction
PF-05082566*
(mg/kg)
Mogamulizumab
(mg/kg)
2.4
0.5
1.2
50 mg flat dose**
0.6
*Intermediate doses could be used for dose-reduction based of 
DLTs observed.
** To be used for the 100 mg flat dose cohort.
Patients experiencing a DLT may resume dosing at the next lower dose level (if applicable) 
once adequate recovery is achieved. 
Recommended dose reductions are illustrated in Table 8.  The guidelines apply to both 
drugs when co-administered or to mogamulizumab alone (when applicable).  These 
recommendations are applicable for all cycles. 


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Table 8.
Dose Modification Guidelines for Treatment Related Adverse Events
Toxicity
Grade
Hold 
Treatment*
Criteria for 
Treatment Restart*
Dose 
Modification*
Discontinue Patient*
(after consultation with 
Sponsor)
Hematologic 
Toxicity meeting 
any of the criteria 
in Section 3.2.
3
Yes
Hold treatment until 
toxicity resolved to 
Grade 1 (Grade 2 for 
ANC)
Decrease dose 
by one dose 
level (based on 
Table 7). 
If toxicity does not 
resolve to Grade 1 or 
does not allow 
retreatment within 
4 weeks of last infusion, 
consider permanent 
discontinuation after 
consultation with the 
Sponsor.  
4 
Yes
Hold treatment until 
toxicity resolved to 
Grade 1 (Grade 2 for 
ANC)
Decrease dose 
by one dose 
level (based on 
Table 7). 
If toxicity does not 
resolve to Grade 1 or 
does not allow 
retreatment within 
4 weeks of last infusion, 
consider permanent 
discontinuation after 
consultation with the 
Sponsor. 
Non-Hematologic 
Toxicity
1
and 2
(if Grade 2 is 
not recurrent/
intolerable)
No
N/A
Continue at 
same dose level.
N/A
2
(only if 
recurrent/
intolerable)
Consider 
holding
Hold treatment until 
toxicity resolved to 
baseline or Grade 1
Continue at 
same dose level.
If toxicity does not 
resolve to baseline or
Grade 1 within 4 weeks 
of last infusion, consider 
permanent 
discontinuation after 
consultation with the 
Sponsor.  
3 
(if persisting 
when 
maximally 
treated)
Yes
Hold treatment until 
toxicity resolved to 
baseline or Grade 1 
(or, at the investigator 
discretion, to Grade 2 
if not considered a 
safety risk for the 
patient).
For laboratory AEs 
other than LFTs only: 
resolved to Grade 2 
and asymptomatic.
For LFTs: resolved to 
baseline or Grade 1.
Decrease dose 
by one dose 
level.
If toxicity does not 
resolve to baseline or 
Grade 1 (or, at the 
investigator discretion, 
to Grade 2 if not 
considered a safety risk 
for the patient) within 4 
weeks of last infusion, 
consider permanent 
discontinuation after 
consultation with the 
Sponsor (except as noted 
in Section 5.4.9.1 for 
laboratory AEs). 
Permanent 
discontinuation should 
be considered for any 
life-threatening event.


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Table 8.
Dose Modification Guidelines for Treatment Related Adverse Events
Toxicity
Grade
Hold 
Treatment*
Criteria for 
Treatment Restart*
Dose 
Modification*
Discontinue Patient*
(after consultation with 
Sponsor)
4
Yes
Hold treatment until 
toxicity resolves to 
baseline or Grade 1.
For laboratory AEs
other than LFTs only: 
resolved to Grade 2 
and asymptomatic.
For LFTs: resolved to 
baseline or Grade 1.
Decrease dose 
by one dose 
level 
If toxicity does not 
resolve to baseline or 
Grade 1 within 4 weeks 
of last infusion, consider 
permanent 
discontinuation after 
consultation with the 
Sponsor. 
Permanent 
discontinuation should 
be considered for any 
life-threatening event.
*Both drugs (Day 1 of each cycle) or mogamulizumab only (when applicable); 
PF-05082566 and mogamulizumab (if applicable) doses will be modified based on dose levels listed in 
Table 7.
5.5. Drug Storage
PF-05082566 will be stored at a temperature between 2C and 8C (36F to 46F). 
Mogamulizumab will be stored at a temperature between 2 and 8C (36 to 46F), protected 
from light.  The vials should not be vigorously shaken.
The investigator, or an approved representative (eg, pharmacist), will ensure that both 
PF-05082566 and mogamulizumab 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 DAI for storage conditions and stability of the diluted products.
Storage conditions stated in the SRSDs (ie, IBs of PF-05082566 and mogamulizumab), will
be superseded by the storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (eg, 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 study.  Even for continuous 
monitoring systems, a log or site procedure which ensures active daily evaluation for 
excursions should be documented.  The operation of the temperature monitoring device and 
storage unit (eg, refrigerator), as applicable, should be regularly inspected to ensure it is 
maintained in working order. 


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Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the Sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
5.6. Drug Accountability 
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.
Pfizer may supply drug accountability forms that must be used or may approve use of 
standard institution forms.  In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient by patient basis, 
including specific dates and quantities.  The forms must be signed by the individual who 
dispensed the drug and copies must be provided to Pfizer when directed.
At the end of the trial, the Sponsor or designee will provide guidance on the destruction of 
unused investigational product (eg, at the site).
5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s wellbeing may be given at 
discretion of the treating physician.
Medications intended solely for supportive care (ie, antiemetics, analgesics) are allowed. 
All concomitant medications and treatments, including prescription, over-the-counter (OTC), 
herbal supplements, IV medications and fluids, supportive care (antiemetic treatment and 
prophylaxis), drugs used to treat adverse events or chronic diseases, non-drug supportive 
interventions (transfusions) will be recorded in the CRF from 28 days prior to the start of 
study treatment and up to 28 days post the last dose of study treatment. 
Concomitant medications administered after 28 days after the last dose of trial treatment 
should be recorded for SAEs only as defined in Section 8.14.1. 
5.7.1. Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited at study entry as specified in the 
exclusion criteria are also not allowed during the study treatment period, except for
hematopoietic growth factors and steroids for symptomatic treatment (for details see 
Section 5.8, Supportive Care). 


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If there is an important medical condition requiring any medication specifically prohibited 
during the trial, discontinuation from study treatment may be considered.  The investigator 
should discuss the proposed course of action with the Sponsor Clinical Lead and/or Medical 
Monitor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician.  However, the decision to continue the 
patient on study treatment requires the mutual agreement of the Investigator, the Sponsor, 
and the patient. 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this clinical 
protocol: 

Anti-cancer systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol. 

Investigational agents other than mogamulizumab or PF-05082566. 

Live vaccines (flu vaccination allowed). 

Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology, except as agreed upon by the 
Sponsor. 
Consider withholding or discontinuing concomitant therapy with monoclonal antibodies of 
the same subclass as the study drugs (ie, IgGK and IgG2) in patients where anti-study drug 
antibodies are detected while on-study. 
The concurrent use of vitamins or herbal supplements should be considered with caution. 
5.7.2. Concomitant Surgery
No formal studies have been conducted to determine whether there is a risk to perform 
concomitant surgery in patients under treatment with either PF-05082566 or 
mogamulizumab.  As safety risks in this setting are unknown, it is suggested that the study 
drugs be withheld for 12 days before performing major surgery.  This will provide a margin 
of safety of one drug half-life (for mogamulizumab, which has the longer half-life of the two 
study drugs) before resuming therapy with the combination.
Postoperatively, the decision to reinitiate PF-05082566 and mogamulizumab treatment 
should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery.


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5.7.3. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease (eg, to a symptomatic solitary lesion or to 
the brain) is permitted if considered medically necessary by the treating physician and after 
consultation with the sponsor.  All attempts should be made to rule out disease progression in 
the event of increased localized pain.  It is suggested that the smallest radiation doses and 
smallest fields possible be used for palliation to minimize the inflammatory effects of 
radiotherapy.  It is suggested that PF-05082566 and mogamulizumab treatment be interrupted 
during palliative radiotherapy, in consultation with the Sponsor. 
5.8. 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. 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined in the following Sections. 
5.8.1. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first 2 cycles of treatment but they may be used to treat treatment emergent neutropenia 
as indicated by the current ASCO guidelines.[27]
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
5.8.2. Anti-Emetic Therapy
Primary prophylaxis of nausea and vomiting is permitted.  Nausea and vomiting should be 
treated aggressively, and consideration should be given in subsequent cycles to the 
administration of prophylactic antiemetic therapy according to standard institutional practice.  
Patients should be strongly encouraged to maintain liberal oral fluid intake. 
5.8.3. Anti-Diarrheal Therapy
Patients may receive prophylaxis of treatment-induced diarrhea.  Symptomatic care such as 
loperamide (Imodium) is recommended.  All patients who experience diarrhea should be 
advised to drink liberal quantities of clear fluids.  If sufficient oral fluid intake is not feasible, 
fluid and electrolytes should be substituted via IV infusion. 
5.8.4. Anti-Infective Therapy
Patients with a documented infectious complication should receive oral or IV antibiotics or 
other anti-infective agents as considered appropriate by the treating investigator for a given 
infectious condition, according to standard institutional practice.


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5.8.5. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming the drug is not 
included in Section 5.7.1, Prohibited Concomitant Treatment. There is no anticipated risk of
drug-drug interaction between mogamulizumab and PF-0582566.
Acetaminophen/paracetamol to a MAXIMUM total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.
5.8.6. Corticosteroids
Chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted.  
Use of corticosteroids as symptomatic treatment may be allowed on individual basis and 
upon discussion with the Sponsor. 
Acute emergency administration, topical applications, inhaled sprays, eye drops or local 
injections of corticosteroids are allowed and guidelines are provided in Section 5.4.9.
5.8.7. Supportive Care Guidelines for Infusion Reactions to Either Study Drugs
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs. 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: allergic reaction/hypersensitivity (including drug fever),
arthralgia, bronchospasm, cough, dizziness, dyspnea, fatigue/asthenia, lethargy, malaise,
headache, hypertension, hypotension, myalgia, nausea, pruritus/itching, rash/desquamation,
rigors/chills, sweating, tachycardia, tumor pain, urticaria (hives, welts, wheals) and vomiting. 
In the event that a site does not have established procedures for the treatment of study drug 
associated infusion reactions, guidelines are provided in Table 9.


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Table 9.
Infusion Reaction Treatment Guidelines for Either Study Drug
NCI CTCAE Grade§
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
Continue infusion as per protocol.
Increase monitoring of vital signs during the 
infusion as medically indicated until the 
patient is deemed medically stable in the 
opinion of the investigator.
To be considered upon Investigator 
discretion.
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment 
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
Stop infusion and monitor symptoms.
Appropriate medical therapy may include but 
is not limited to:
IV fluid
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the infusion rate (eg, from 
100 mL/hr to 50 mL/hr). 
If symptoms last more than 1 hour after
stopping infusion, dosing will be held.  The 
patient should be monitored until symptoms 
resolve or is deemed medically stable in the 
opinion of investigator.
Patients who develop prolonged symptoms
(>24 hrs.) despite premedication should be 
permanently discontinued from further 
trial treatment administration.
Patients may be premedicated 1.5 h 
(30 minutes) prior to infusion of 
mogamulizumab and/or 
PF-05082566) with:
Diphenhydramine 50 mg PO or IV 
(or equivalent dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of antipyretic eg, 
paracetamol).
Grades 3 or 4
Grade 3;
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; ventilator 
support indicated.
Stop infusion.
Appropriate medical therapy may include but 
is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Patient is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Note: Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration
§Classified per the Common Terminology Criteria for Adverse Events v. 4.03 (CTCAE) at http://ctep.cancer.gov


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6. STUDY PROCEDURES 
For screening, treatment period and follow up procedures, see Schedule of Activities.

Informed Consent must be obtained prior to undergoing any study specific procedure 
and may occur prior to the 28 day screening period.
For the treatment period discussed below, where multiple procedures are scheduled at the 
same nominal time point(s) relative to dosing, the following prioritization of events should be 
adhered to, where possible:

Blood pressure/pulse rate – may be obtained prior to or after electrocardiogram
(ECG) collection but must be obtained prior to blood specimen collection.

ECGs – obtain as close as possible to the scheduled time, but prior to blood specimen 
collection and within 30 minutes of the nominal time.

Clinical safety laboratory tests – obtain as close as possible to the scheduled time.

Pharmacokinetic blood specimens obtain at the scheduled time.

Other procedures – All other procedures should be obtained as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection, unless 
sampling is determined by the study personnel to potentially impact the results.
6.1. Screening
For screening procedures, see Schedule of Activities and ASSESSMENTS Sections.
Screening is to be performed within 28 days of registration.  Tumor history includes
information on prior regimens (including dosing and duration of administration, description 
of best response observed, recurrence date), surgery and radiation therapy.  Medical history, 
includes history of other diseases (active or resolved) and concomitant illnesses.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS Sections.
The EOT assessments are to be performed 28 days (+7 days) after the last dose of study 
treatment.  These assessments are to be performed if not completed during the previous week 
on study (during the previous 8 weeks on study for tumor assessments).
6.3. Follow-up Visit
For follow-up procedures, see Schedule of Activities and ASSESSMENTS Sections.
Patients continuing to experience treatment-related toxicity following discontinuation of 
study treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is 
expected.


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Only those patients whose disease has not progressed at the end of treatment will enter into 
disease follow-up.  During this follow-up period, patients will have disease assessments 
performed every 8 weeks 7 days.  Once patients have exhibited disease progression or 
began a new anti-cancer therapy (not including radiotherapy to a non-target tumor lesion), 
whichever occurs first, the date of progression or that of the new anticancer therapy initiation 
will be recorded on the appropriate CRF page, and the patients will be withdrawn from the 
study.  No further data will be collected from these patients. 
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or Sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for discontinuation of study treatment may include:

Disease progression according to RECIST v. 1.1 (Appendix 2) and/or irRC
(Appendix 3) (see Section 5.4.5 for details and exceptions);

Patients who have achieved a confirmed CR, and have had at least two additional 
cycles of mogamulizumab and PF-05082566 after the date the CR was confirmed;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment (follow up permitted by the patient);

Consent withdrawal (cessation of follow up);

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;


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
Start of another anticancer therapy;

Refusal for further follow-up;

Lost to follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient return for a final visit, if applicable, and 
follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, no further study specific evaluations should be performed, 
and no additional data should be collected.  The Sponsor may retain and continue to use any 
data collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, vital signs and physical examination, 
electrocardiogram (12-lead ECG), laboratory assessments, including pregnancy tests, and 
verification of concomitant treatments.
7.1.1. Pregnancy Testing
PF-05082566 has not been characterized for reproductive toxicology.
Toxicological studies indicated that mogamulizumab has no potential for embryo-fetal 
lethality, teratogenicity, or fetal growth retardation in animals.  However no data are 
available in humans.  The current mogamulizumab IB version[18] contains a full description 
of non-clinical reproductive and developmental toxicology. 


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See Section 8.10 for exposure during pregnancy.
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting study 
therapy (ie, once at the start of screening and once at the baseline 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 (ie, on Day 1) during 
the active treatment period, at the End of Treatment visit, 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 
Boards (IRBs)/Ethic Committee (ECs) or if required by local regulations.
7.1.2. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), 
seriousness, and relatedness.
7.1.3. Laboratory Safety Assessment
Hematology, blood chemistry, coagulation, urinalysis, thyroid and other endocrine function 
tests will be drawn at the time points described in the Schedule of Activities (Table 1) and 
analysed at local laboratories.  There is no need to repeat these tests on Cycle 1 Day 1 if 
screening assessment was performed within 7 days prior to that date.
Laboratory certifications and normal ranges with units must be provided to the Sponsor.  
Laboratory tests may be repeated also as clinically indicated.
Required tests are indicated in Table 10.
Table 10.
Laboratory Safety Assessments
Hematology
Hemoglobin (Hb) 
Platelets (PLTs)
White Blood Cells (WBCs)
Absolute Neutrophils
Absolute Lymphocytes
Absolute Monocytes
Absolute Eosinophils
Absolute Basophils


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Table 10.
Laboratory Safety Assessments
Chemistry
Alanine aminotransferase (ALT)
Aspartate Aminotransferase (AST)
Alkaline Phosphatase (ALP)
Lactate Dehydrogenase (LDH)
Sodium (Na)
Potassium (K)
Magnesium (Mg)
Total Calcium (Ca)
Phosphorus or Phosphate
Total bilirubin***
Creatinine or creatinine clearance
Albumin
Total proteins
Uric Acid
BUN or Urea
Immunoglobulin G
Glucose (fasted)
Coagulation
Partial thromboplastin time (PTT)
Prothrombin Time (PT) or International Normalized Ration (INR)
Urinalysis
Urine dipstick for urine protein.  If positive collect 24-hrs and microscopic 
(Reflex Testing)
Urine dipstick for urine blood.  If positive collect a microscopic (Reflex Testing)
Hepatitis B and C Tests
Hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other tests may 
be conducted per standard practice to confirm an active hepatitis infection.
Thyroid and other 
Endocrine Function 
Tests
Triiodothyronine (T3), Free-Thyroxine (FT4), Thyroid-Stimulating Hormone 
(TSH).
In the presence of clinical suspicion of hypopituitarism or hypoadrenalism, 
laboratory testing should include one or more of the following: 
Adrenocorticotropic hormone (ACTH), and cortisol levels (before and 30- 60 
minutes after corticotrophin stimulation).  
*** 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, PT/INR, 
and ALP.  
7.1.4. Vital Signs and Physical Examination (PE)
Patients will have a physical exam (PE) that will include major body systems, weight, vital 
signs (blood pressure and heart rate), assessment of ECOG performance status, and height; 
height will be measured at baseline only.  Each assessment will be performed at the time 
points described in the SOA Table 1.
7.1.5. Electrocardiogram (12-Lead)
ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  
It is preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  At each time point (see Table 1), three consecutive ECGs will be performed 
at approximately 2 minutes apart to determine the mean QTcF interval. 


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If the mean QTcF is prolonged (>500 msec, ie, NCI 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 >500 msec, prior to concluding that an episode of prolongation of 
the QTcF interval is due to study drug and is considered clinically significant, immediate 
correction of potential precipitating factors (including change in patient clinical condition, 
electrolyte abnormalities, hypoxia and concomitant administration of 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 470 msec (ie, inclusion criteria)  or is recovered to 480 msec 
(ie, NCI CTC AE Grade ≤1).  If QTcF interval reverts to less than 480 msec, and in the 
judgment of the investigator(s) and Sponsor is determined to be due to cause(s) other than 
study drug, treatment may be continued with regular ECG monitoring at the same dose level. 
If in this timeframe the QTcF intervals remains above 500 msec the study drug will be held 
until the QTcF interval decreases to 500 msec (NCI CTC AE Grade ≤2).  Patients will then 
re-start the study drug at the next lowest dose level according to Investigator’s judgment
therefore excluding that the event is considered clinically significant. 
If the QTcF interval has still not decreased to <500 msec after 2-weeks off treatment or if at 
any time a patient has a QTcF interval >515 msec (considered clinically significant) or 
becomes symptomatic, the study treatment will be permanently discontinued.
Additional triplicate ECGs may be performed as clinically indicated. 
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), ECGs (triplicate) should be obtained at the time of the event. 
Pre-dose ECG assessments will be required for all patients, post-dose ECG assessments will 
be required only for patients in dose-finding cohorts (see Table 1).
Clinically significant abnormal findings in baseline ECGs will be recorded as medical 
history. 
Clinically significant findings seen on the follow-up ECGs should be recorded as AEs. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
7.2. 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 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.


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The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, and on treatment every 8 weeks 7 days starting from Cycle 1 Day 1 up to 1 year, 
then every 3 months (7 days) as specified in Table 1.  Timing should follow calendar days
starting from C1D1 and should not be adjusted for treatment delays.
Follow up bone scans are required every 16 weeks (7 days) only if bone metastases are 
present at baseline and bone scan is used to follow bone lesions on treatment.  Otherwise 
bone imaging is required only if new bone metastasis are suspected and at the time of 
confirmation of complete response for patients who have bone metastases at baseline.  The 
same imaging technique used at baseline for bone lesions assessments should be used to 
assess the on treatment response to bones.
In addition, radiological tumor assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of EOT (if not done 
in the previous 8 weeks). 
Note that a lesion biopsied while on study, or a lesion that is irradiated during the study 
should no longer count as a target lesion.
Assessment of response will be made using RECIST version 1.1 (Appendix 2) and also by 
irRC (Appendix 3).
If radiologic imaging shows progressive disease, tumor assessment should be repeated 
4 weeks later in order to confirm progressive disease with the option of continuing 
treatment per Section 5.4.5 while awaiting radiologic confirmation of progression. 
In this trial, patients may be treated after initial progression by RECIST criteria and/or irRC,
and patient’s tumors will be subsequently assessed.  A patient who has initial progression 
may be assigned PR or CR at a later time point as long as the patient meets all criteria for PR 
or CR compared to the pretreatment tumor assessment.  If CR or PR is subsequently 
confirmed with respect to baseline, the patient’s overall assessment will be CR or PR 
regardless of early assessment of progressive disease.
In addition to on-study tumor response assessments, the history of responses to previous 
therapy will be collected.  This will include information on prior regimens, including dosing 
and duration of administration, plus a description of the best response observed for each prior 
regimen.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 














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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
Sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AEs that are
determined by the Sponsor to be serious will be reported by the Sponsor as a SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 60 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
Sponsor.
AEs (serious and nonserious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.
If a patient begins a new anticancer therapy, the AE reporting period for nonserious 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.
Pregnancy or breast feeding that occur during the trial, within 60 calendar days of 
discontinuing treatment with mogamulizumab, or within 60 days after the cessation of 
PF-05082566 if the patient begins a new anticancer therapy, whichever is earlier, should be 
reported as in Section 8.10 (Exposure During Pregnancy).


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8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;
Worsening of signs and symptoms of the malignancy under study should be reported as AEs
in the appropriate Section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong patient, at the wrong time, or at the wrong dosage strength Such 
medication errors occurring to a study participant are to be captured on the medication error 
case report form (CRF) which is a specific version of the AE page, and on the SAE form
when appropriate.  In the event of medication dosing error, the Sponsor should be notified 
immediately.


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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the 
AE page and, if applicable, any associated AEs are captured on an AE CRF page.
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for mogamulizumab or PF-05082566 by 20% over the prescribed dose for the dosing 
cohort under study.  No specific information is available on the treatment of overdose for 
either of the study drugs.  In the event of overdose, both study drugs should be discontinued 
and the patient should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
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 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;


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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria (CTC)
Grade 5 (see Section 8.8, 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.  In addition, an overdose of study 
medication should only be captured as an SAE when it meets one of the criteria listed above.
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 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 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;


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
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 to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;


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
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.
8.8. Severity Assessment
AEs will be reported using concise medical terminology (verbatim) as well as the Common 
Terminology Criteria (CTC) term for Adverse Events (Version 4.03, Publish Date: June 14, 
2010, http://ctep.cancer.gov/reporting/ctc.html) listed in the Cancer Therapy Evaluation 
Program.


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The investigator may use the following definitions of Severity in accordance with CTCAE 
Version 4.03 to describe the maximum intensity of the adverse event.   
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTC document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with 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 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For 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 
being exposed to the investigational product;


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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 Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure.  The information submitted should include 
the anticipated date of delivery (see below for information related to termination of 
pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, 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 exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study patient with the Pregnant Partner Release of 


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Information Form to deliver to his partner.  The investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. 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 adverse event.
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 investigative site file.
8.12. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of a SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. 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 exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.


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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 
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
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a SAP, which will be maintained by Pfizer.  This document may 
modify the plans outlined in the protocol; however, any major modifications of the primary 
endpoint and/or its analysis will also be reflected in a protocol amendment.
9.1. Analysis sets 
1. Full analysis set.
The full analysis set includes all enrolled patients.
2. Safety analysis set. 
The safety analysis set includes all enrolled patients who receive at least one dose of 
study medication.
3. DLT evaluable set. 
All enrolled patients who are eligible for the study and receive study treatment.  Note 
that every patient will contribute to the determination of the MTD including patients 
who are lost to follow-up prior to completion of the 2 cycles’ DLT observation 
period.


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4. PK/Immunogenicity and PK parameter analysis sets.
The PK/ADA concentration population is defined as all enrolled patients who have 
been treated and have at least one post dose concentration measurement of either 
PF-05082566 or mogamulizumab. 
The PK parameter analysis population is defined as all enrolled patients who have 
been treated and whose concentration-time data allows the estimation of at least 1 of 
the PK parameters of interest. 
5.
 
6. ECG/QTc Analysis set.
Treated patients who have baseline and at least 1 on study ECG/QTc measurement.
9.2. Statistical Methods for Dose Allocation: TITE-CRM
A number of alternative designs have been proposed to the standard 3+3 design for Phase I 
dose escalation trials that improve its accuracy, efficiency and statistical validity, including 
the continual reassessment method (CRM)[30] and its variants. 
Delayed-onset toxicities are a particular challenge for phase I trials of combination 
therapies.[31]  Most of the available dose-escalation designs, including the 3+3 design, the 
up-and-down designs and the CRM design, require all patients to have completed a fixed 
observation period for toxicity (eg, 1-2 cycles of the experiment regimen, or 6-8 weeks after 
start of treatment) before additional cohorts of patients can be enrolled. Thus, trial accrual is 
patient to opening and closing which may pose logistical risk on the success and completion 
of the study.  In addition, patients who are either lost to follow-up or die of events unrelated 
to treatment are usually required to be replaced.  Due to these reasons, the trial duration could 
be unacceptably long in case of prolonged observation window and unexpected high rate of 
patient drop-out.
The time-to-event continual reassessment method (TITE-CRM), a variant of the original 
CRM method, is open to accrual continually, and maintains other advantages of the CRM 
relative to the 3+3 design.  Like CRM, TITE-CRM seeks to determine the target MTD dose, 
defined as the dose most closely identified with the target rate, which is the largest acceptable 
DLT rate determined by the investigators based on the relative costs and benefits of the 
treatment.
TITE-CRM is to be implemented as described by Cheung et al.[28] and Huang et al.[33] for 
the dose-escalation and de-escalation of PF-05082566.  PF-05082566 may be administered 
intravenously at the following available dose levels of 1.2, 2.4, 100 mg flat dose (equivalent 
to the 1.2 mg/kg) and 5.0 mg/kg on an every 4 week schedule (q4wk).  
CCI


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PF-05082566 will be co-administered with mogamulizumab on Day 1 of each treatment 
cycle.  Mogamulizumab will be administered at 1 mg/kg, weekly on Cycle 1, biweekly from 
Cycle 2 onwards.  A lower mogamulizumab dose of 0.5 mg/kg may be tested if the starting 
dose is not tolerable.  Different doses and different dosing schedules of the combination may 
be investigated after the MTD is estimated.  The MTD is defined as highest dose that is 
associated with a DLT rate <30%.  A power function modeling DLT rate at each dose
di (i=1, …, 4) expressed as Pr (DLT | di) = Fi () will be used:
)
exp(
)
(


i
i
p
F

where pi is the prior estimate of DLT rate at dose level di, and p1p2…p4.  These estimates 
will be projected based model sensitivity to DLTs, together with single agent safety data for 
both study drugs.  is an unknown single parameter modeling the dose-toxicity relationship, 
with prior distribution 
)
,0
(
2
0

N
, where 
0
is the standard deviation of the normal prior 
distribution with mean=0.  At the beginning of the trial, the initial prior value of is set as 
0, the prior mean, which gives a prior dose-toxicity model of 
i
i
p
F

)
(
based on the power 
function. 
In the Bayesian paradigm, the prior distribution 
)
,0
(
2
0

N
expresses the researchers’ belief in 
the quality of the initial estimates pi.  The smaller the standard deviation
0
, the more 
confidence researchers have in the precision of pi. and vice versa.  As the trial progresses, 
this prior distribution is combined mathematically with the observed data to yield the 
posterior distribution of the parameter (the posterior mean of will be calculated to model 
the dose-toxicity relationship).  The prior distribution determines how responsive TITE-CRM 
is to the accumulated data.  With a small
0
upfront, the posterior toxicity probability 
estimates remain close to the prior estimates unless significantly discrepant data otherwise 
occur; with a large
0
, the model will tend to be more immediately responsive to data.  In this 
trial, 
0
=1, which provides a reasonably flat prior distribution of , with 90% Bayesian 
credible interval of 
)
exp(: [0.19, 5.21], sufficiently wide to cover a wide spectrum of 
dose-toxicity scenarios.  Figure 3 illustrates the dose-toxicity curve (blue curve) with 
90% upper and lower bounds (red curves) when the initial prior estimates
ip are (0.095, 
0.186, 0.300, 0.422).


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Figure 3.
Example Plot of Prior Dose Toxicity Curve
Prior dose-toxicity curve with 90% confidence limits
Dose Level of PF-05082566 (mg/kg)
DLT Rate
1.2(+moga 0.5)
1.2 (or 100mg)
2.4
5
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the TITE-CRM paradigm, patients who have enrolled in the trial but have not experienced 
a DLT will be included in the probability calculation with an initial weight equal to the 
proportion of the 8-week (2 cycles) DLT observation period the patients have completed.  
However the weight function will be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566.  An adaptive cyclical weight 
function as proposed by Huang et al.[33] will be implemented.
Patients who experience a DLT or complete the observation period without a DLT will be 
assigned full weight (=1). 
Extensive simulation results comparing the TITE-CRM using the adaptive cyclical weight 
function with the 3+3 design and other weight functions can be found in Huang et al.[33]
9.2.1. Statistical Methods for Dose Escalation/De-Escalation
Section 3.1.9 describes the dose escalation/de-escalation criteria, stopping rules and some 
restrictions and practical considerations on dose escalation.


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9.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
TITE-CRM approach cannot be determined in advance.  The maximum sample size is set 
as 30 for dose escalation cohorts in order to have a reliable and accurate estimate of the MTD 
based on simulation results.  Based on probability theory, a sample size of 30 will ensure the 
estimates of any binary variable (eg, objective response rate) have a 95% confidence interval 
of width <0.36.  A sample size of 30 also enables the detection of any unexpected toxicity 
that occurs at 5% rate (in a non-dose-dependent fashion) with a probability of 0.79, and that 
occurs at 10% rate with a probability of 0.96.
A stopping rule (see Section 3.1.9) will also be implemented for possible early stopping if 
there is strong confidence in the estimated MTD.
Additional patients will be required for expansion cohorts.  The total number of patients in 
expansion cohorts will be determined based on emerging data from this study, cancer 
indication, and the patient population of interest. 
9.4. Efficacy Analysis
In this Phase 1 study, anti-tumor activity is a secondary objective.  Only descriptive efficacy 
summaries will be performed for this part of the study.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, received (maximum) dose, overall tumor response at each visit, and 
best overall response.  In addition, disease progression date, death date, date of first response, 
and last tumor assessment date will be listed, together with DR and PFS for the expansion 
cohort.  Kaplan-Meier plot will be created for DR, TTR and PFS in the expansion cohort.  A 
bar plot for DR will also be created for confirmed responders defined by RECIST v 1.1
(Appendix 2) and Immune-Related Response Criteria (Appendix 3). 
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Pharmacokinetics Analysis of PF-05082566 and Mogamulizumab
Standard serum PK parameters including the maximum serum concentration (Cmax), time to 
maximum serum concentration (Tmax), and area under the serum concentration versus time 
curve (AUC) for PF-05082566 will be estimated using non-compartmental analysis, as data 
permits.  If data permit or if considered appropriate, minimum serum concentration (Cmin), 
average serum concentration (Cave),  terminal elimination half-life (t1/2),  clearance (CL), 
steady state volume of distribution (Vss), will be estimated.  Descriptive statistics will be 
provided for these PK parameters in tabular form (n, mean, SD, CV, median, minimum, 
maximum, geometric mean and its associated CV) by dose, cycle and day. 
Dose normalized AUCtau AUC0-last, and Cmax for PF-05082566 may be plotted against dose 
(using a logarithmic scale).  These plots will include individual patient values and the 
geometric means for each dose.  These plots will be used to help understand the dose 
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9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the per protocol 
analysis set.  Summaries and analyses of all other 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 Section 3, Study Design.  AEs constituting DLTs will be listed per 
dose level.
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Adverse Events
AEs will be graded by the investigator according to CTCAE version 4.03 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries 
will be on Treatment Emergent Adverse Events, those with initial onset or increasing in 
severity after the first dose of study medication.  The number and percentage of patients who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1, Cycle 2 and Cycles >2).
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, Cycle 2 
and Cycles >2).  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.
9.6.2.3. ECG
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. The most recent ECG collected prior to the first day of dosing 
will be considered the baseline ECG. 
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 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]. 


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Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, QTcF (and 
other correction factors, eg, QTcB as appropriate) 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 post-baseline QT 
value. 
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
Shift tables will be provided for baseline vs. worst on study QTc (one or more correction 
method will be used) using Maximum CTCAE Grade.  As well as tables of ECG abnormality 
at baseline (yes, no, not done: (n, %)).  Patients experiencing clinically-relevant 
morphological ECG changes will be summarized (including frequency and percentage).
9.7. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for this study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an
Internal Safety Review team consisting of physician, safety specialist, and statistician 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, laboratory test 
abnormalities, vital signs, and ECG findings observed at each dose level in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety 
profile and make a benefit/risk assessment and decide if further enrollment is 
appropriate; 

Findings having immediate implication for the management of patients on study will 
be communicated to all Principal Investigators in the timeframe associated with 
unexpected and drug-related SAEs.
During the dose escalation phase, a Dose Escalation Steering Committee (DESC) consisting 
of core clinical team members will be established to perform periodic review of the 
accumulating safety data, specifically, the DLTs.  The guidance for dosing and enrollment 
decisions is based on the Bayesian statistical model of TITE-CRM.  Other considerations 
may include lower grade AEs, nature and timing of the AEs, existing PK/PD data that may 


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cause safety concerns.  Following each review, the DESC will inform the study team and 
participating investigators on dosing and enrollment decisions.  A DESC Charter will be 
prepared and will be available before FSFV.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs 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.
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.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
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.


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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.
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 Good Clinical Practice (GCP) (International Conference on 
Harmonization (ICH) 1996), and the Declaration of Helsinki (World Medical Association 
1996 & 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.


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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 ethics committees and investigator databases may be used as 
recruitment procedures. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information 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.


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13. DEFINITION OF END OF TRIAL
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.
13.1. End of Trial in All 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-05082566 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 5 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 study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US basic results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
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 subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.


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EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (clinical study report synopses in which any data that 
could be used to identify individual patients have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug. 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 before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed. If any patent 
action is required to protect intellectual property rights, 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 (other than the study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, 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.


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16. REFERENCES
1.
Wang C, Lin GH, McPherson AJ, et al. Immune regulation by 4-1BB and 4-1BBL: 
complexities and challenges. Immunol Rev. 2009 May; 229(1):192-215.
2.
Zhang X, Voskens CJ, Sallin M, et al. CD137 promotes proliferation and survival of 
human B cells. J Immunol. 2010 Jan 15; 184(2):787-795. 
3.
Broll K, Richter G, Pauly S, et al. CD137 expression in tumor vessel walls. High 
correlation with malignant tumors. Am J Clin Pathol. 2001 Apr; 115(4):543-549.
4.
Seaman S, Stevens J, Yang MY, et al. Genes that distinguish physiological and 
pathological angiogenesis. Cancer Cell. 2007 Jun; 11(6):539-554.
5.
Olofsson PS, Söderström LA, Wågsäter D, et al. CD137 is expressed in human 
atherosclerosis and promotes development of plaque inflammation in 
hypercholesterolemic mice. Circulation. 2008 Mar 11; 117(10):1292-1301.
6.
Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of 
TNF receptor signaling. Cytokine. 2007 Feb; 37(2):101-107.
7.
Furtner M, Straub RH, Krüger S, Schwarz H. Levels of soluble CD137 are enhanced in 
sera of leukemia and lymphoma patients and are strongly associated with chronic 
lymphocytic leukemia. Leukemia. 2005 May;19(5):883-885.
8.
Hentschel N, Krusch M, Kiener PA, et al. Serum levels of sCD137 (4-1BB) ligand are 
prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin's 
lymphoma. Eur J Haematol. 2006 Aug; 77(2):91-101.
9.
Michel J, Langstein J, Hofstädter F, Schwarz H. A soluble form of CD137 
(ILA/4-1BB), a member of the TNF receptor family, is released by activated 
lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J 
Immunol. 1998 Jan; 28(1):290-295.
10.
Sabbagh L, Pulle G, Liu Y, et al. ERK-dependent Bim modulation downstream of the 
4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. 
J Immunol. 2008 Jun 15; 180(12):8093-8101.
11.
Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat 
Rev Immunol. 2009 Apr; 9(4):271-285.
12.
Lynch DH. The promise of 4-1BB (CD137)-mediated immunomodulation and the 
immunotherapy of cancer.  Immunol Rev. 2008 Apr; 222:277-286.
13.
Vinay DS, Cha K, Kwon BS. Dual immunoregulatory pathways of 4-1BB signaling. 
J Mol Med. 2006 Sep; 84(9):726-736.


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14.
Houot R, Goldstein MJ, Kohrt HE. Therapeutic effect of CD137 immunomodulation in 
lymphoma and its enhancement by Treg depletion. Blood. 2009 Oct 15; 
114(16):3431-3438.
15.
Kohrt HE, Houot R, Goldstein MJ.CD137 stimulation enhances the antilymphoma 
activity of anti-CD20 antibodies. Blood. 2011 Feb 24; 117(8):2423-32. Epub 2010 
Dec 30.
16.
PF-05082566 Investigator Brochure, September 2014.
17.
Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I study of KW-0761, a 
defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell 
leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 2010; 
28(9):1591-1598.
18.
POTELIGEOInvestigator Brochure Version 10, 05 March 2014.
19.
Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in 
patients with metastatic melanoma: Long-term survival update. Cancer J Sci Am. 2000; 
6 (Suppl. 1), S11–S14.
20.
Peterson AC, Harlin H, Gajewski TF, Immunization with Melan-A peptide-pulsed 
peripheral blood mononuclear cells plus recombinant human interleukin-12 induces 
clinical activity and T-cell responses in advanced melanoma. J Clin Oncol. 2003; 21: 
2342–2348.
21.
Tanimoto T, Hori A, Kami M. Sipuleucel-T immunotherapy for castration-resistant 
prostate cancer. N Engl J Med. 2010; 363:1966.
22.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med. 2010; 363:711–723.
23.
Page DB, Postov MA, Callahan, MK, et al. Immune modulation in cancer with 
antibodies. Annu. Rev. Med. 2014; 65:185–202.
24.
Sugiyamaa D, Nishikawaa H, Maedaa Y, et al. Anti-CCR4 mAb selectively depletes 
effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in 
humans. PNAS 2013;110:17945-50.
25.
Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the 
melanoma tumor microenvironment is driven by CD8+ T cells. Sci tran Med. 2013; 
5:1-11.
26.
Choi BK, Kim WJ, Kang WJ, et al. Mechanisms involved in synergistic anticancer 
immunity of anti-4-1BB and anti-CD4 therapy. Cancer Res. 2007; 67:8891-8899.


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27.
Smith TJ, Bohlke K, Lyman GH, et al. recommendations for the use of WBC growth 
factors: american society of clinical oncology clinical practice guideline update. J Clin 
Oncol. 2015 Oct 1; 33(28):3199-3212..
28.
Cheung YK, Chappell R. Sequential designs for phase 1 clinical trials with late-onset 
toxicities.  Biometrics 2000; 56(4):1177-1182.
29.
Wochok JD, Hoos A, O’Day S et al., Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 12: 
7412-7420.
30.
O’Quigley J, Pepe M, Fisher L: Continual reassessment method: A practical design for 
phase I clinical trials in cancer. Biometrics 1990; 46: 33-48.
31.
Muler J, McGinn C, Normolle D et al: Phase I trial using a time-to-event continual 
reassessment strategy for dose escalation of cisplatin combined with gemcitabine and 
radiation therapy in pancreatic cancer. J Clin Oncology 2004; 22: 238-243.
32.
Normolle D, Lawrence T: Designing dose-escalation trials with late-onset toxicities 
using the time-to-event continual reassessment method. J Clin Oncol 2006; 
24:4426-4433. 
33.
Huang B, Kuan PF. Time-to-event continual reassessment method incorporating 
treatment cycle information with application to an oncology phase I trial. Biom J 
2014;56(6):933-46. 
34.
Hodi FS, Bulter M, Oble DA, Seiden MV, haluska FG, Kruse A, et al. Immnologic and 
clinical effects of antibody blockade of cytotoic T lymphocyte-associated antigen 4 in 
previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008; 105:3005-10.
35.
Hoos A, Egermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst 2010; 102(18):1388-97.
36.
Wolchok JD, et al.: Guidelines for the Evaluation of Immune Therapy Activity in Solid 
Tumors: Immune-Related Response Criteria.  Clin Cancer Res  2009;15(23):7412-7420.
37.
Nishino M, Jagannathan JP, Krajewski KM, O'Regan K, Hatabu H, Shapiro G, Ramaiya 
NH. Personalized tumor response assessment in the era of molecular medicine: cancer-
specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR 
Am J Roentgenol. 2012;198(4):737–745.
38.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related 
tumor response assessment: does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab? Journal for Immunotherapy 
of Cancer. 2014;2:17.  




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


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


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Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

One or more target measurable lesions have not been assessed; 
or

Assessment methods used were inconsistent with those used at baseline;
or

One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or

One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 


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


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If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 12.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Appendix 3. Immune-related Response Criteria Derived from RECIST 1.1 (irRECIST)
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD1\anti 
PDL1 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.34, 35 Clinical observations of patients with advanced melanoma treated with 
ipilimumab, for example, suggested that conventional response assessment criteria such as 
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.36, 37
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.36, 37
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST 1.1 criteria (irRECIST).38
For irRECIST, only target and new measurable lesions are taken into account.  In contrast to 
the RECIST 1.1, the irRECIST criteria:

Require confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented, and 

Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm longest diameter per 
non-nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by 
20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial.
irRECIST criteria 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 diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
decreases 30%. 


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
Overall immune-related stable disease (irSD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions is 
neither irCR, irPR, (compared to baseline) or immune-related progressive disease 
(irPD, compared to nadir). 

Overall immune-related progressive disease (irPD): Sum of the diameters  (longest 
for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
increases 20% (compared to nadir), confirmed by a repeat, consecutive observation 
at least 4 weeks from the date first documented. 
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up 
to 5 new lesions in total can be added to the measurements.
New non-measurable lesions: Do not define progression but preclude irCR.
Overall responses derived from changes in target, non-target, and new lesions are outlined in 
Table 13.
Table 13.
Overall Response Derived from Changes in Target, Non-target and New 
Lesions
Measurable response
Non-measurable response
Overall response using 
irRECISTb
Target and New 
Measurable Lesions 
(Tumor Burden)a
Non-Target Lesions
New Non-Measurable 
Lesions
Decrease 100%
Absent
Absent
irCR
Decrease 100%
Stable
Any
irPR
Decrease 100%
Unequivocal progression
Any
irPR
Decrease 30%
Absent/stable
Any
irPR
Decrease 30%
Unequivocal progression
Any
irPR
Decrease <30% and 
increase <20%
Absent/stable
Any
irSD
Decrease <30% and 
increase <20%
Unequivocal progression
Any
irSD
Increase 20%
Any
Any
irPD
a.
Decrease assessed relative to baseline.
b.
Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive 
assessment at least 4 weeks apart.

SAP_001.pdf: 
PF-05082566
B1641004 Statistical Analysis Plan    
Page 1
A PHASE 1B STUDY OF PF-05082566 IN COMBINATION WITH 
MOGAMULIZUMAB (KW-0761) IN PATIENTS WITH ADVANCED SOLID 
TUMORS
STATISTICAL ANALYSIS PLAN
Compounds:
PF-05082566
Compound Name:
NA
Version:
Amendment 2
Date:
21-Sep-2017


PF-05082566
B1641004 Statistical Analysis Plan    
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoints...................................................................................................10
3.2. Secondary Endpoints...............................................................................................11
3.2.1. Safety Endpoints.........................................................................................11
3.2.2. Efficacy Endpoints......................................................................................11
3.2.3. Pharmacokinetic Endpoints ........................................................................12
3.2.4. Immunogenicity Endpoints.........................................................................13
3.4. Baseline Variables...................................................................................................13
3.4.1. Study Drug, Study Treatment and Baseline Definitions ............................13
3.4.2. Baseline Characteristics..............................................................................14
3.5. Safety Endpoints .....................................................................................................14
3.5.1. Adverse Events...........................................................................................14
4. ANALYSIS SETS ...............................................................................................................15
4.1. Full Analysis Set .....................................................................................................15
4.2. Safety Analysis Set..................................................................................................15
4.3. Other Analysis Set...................................................................................................15
4.3.1. DLT-evaluable Set......................................................................................15
4.3.2. PK Analysis Sets.........................................................................................15
4.3.4. Immunogenicity Analysis Set.....................................................................16
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.1.1. Hypotheses and Sample Size Determination..............................................16
5.1.2. Decision Rules Using the TITE-CRM Method ..........................................16
CCI
C
CCI


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5.2. General Methods .....................................................................................................19
5.2.1. Data Handling After the Cut-off Date ........................................................20
5.2.2. Pooling of Centers ......................................................................................20
5.2.3. Presentation of Continuous and Qualitative Variables...............................20
5.2.4. Definition of Study Day..............................................................................20
5.2.5. Definition of Start of New Anti-cancer Drug Therapy...............................20
5.2.6. Definition of Start of New Anti-cancer Therapy........................................21
5.2.7. Definition of On-treatment Period..............................................................21
5.2.8. Standard Derivations and Reporting Conventions .....................................21
5.2.9. Unscheduled Visits.....................................................................................22
5.2.10. Adequate Baseline Tumor Assessment ....................................................22
5.2.11. Adequate Post-baseline Tumor Assessment.............................................22
5.3. Methods to Manage Missing Data ..........................................................................22
5.3.1. Missing Data...............................................................................................22
5.3.1.1. Pharmacokinetic Concentrations...............................................23
5.3.1.2. Pharmacokinetic Parameters .....................................................23
5.3.2. Handling of Incomplete Dates....................................................................24
5.3.2.1. Disease History .........................................................................24
5.3.2.2. Adverse Events..........................................................................24
5.3.2.3. Prior and Concomitant Medications..........................................25
5.3.2.4. Exposure....................................................................................26
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments......26
5.3.3.1. Date of Last Contact..................................................................26
5.3.3.2. Death Date.................................................................................26
5.3.3.3. Tumor Assessments...................................................................27
5.3.3.4. Date of Start of New Anti-cancer Therapy ...............................27
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoints...................................................................................................28
6.1.1. DLT.............................................................................................................28
6.1.1.1. Primary Analysis.......................................................................28
6.2. Secondary Endpoint(s) ............................................................................................28
6.2.1. Safety Endpoints.........................................................................................28
6.2.2. Efficacy Endpoints......................................................................................28


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6.2.2.1. Objective Response as Assessed by the Investigator per 
RECIST v1.1 .....................................................................................28
6.2.2.2. Tumor Shrinkage from Baseline ...............................................30
6.2.2.3. Duration of Response................................................................30
6.2.2.4. Time to Response......................................................................31
6.2.2.5. Progression-free Survival (Expansion Cohort Only) ................31
6.2.3. Pharmacokinetic endpoints.........................................................................33
6.2.4. Population Pharmacokinetic Endpoints......................................................34
6.2.6. Endpoints for Immunogenicity Data of PF-05082566 and 
Mogamulizumab ..............................................................................................34
6.3. Other Endpoints.......................................................................................................35
6.3.1. irRECIST Endpoints...................................................................................35
6.4. Subset Analyses.......................................................................................................37
6.5. Baseline and Other Summaries and Analyses.........................................................37
6.5.1. Baseline Summaries....................................................................................37
6.5.1.1. Demographic Characteristics ....................................................37
6.5.1.2. Medical History.........................................................................38
6.5.1.3. Disease Characteristics..............................................................38
6.5.1.4. Prior Anti-cancer Therapies ......................................................39
6.5.2. Study Conduct and Patient Disposition......................................................40
6.5.2.1. Patient Disposition ....................................................................40
6.5.2.2. Protocol Deviations...................................................................40
6.5.3. Study Treatment Compliance and Exposure ..............................................40
6.5.3.1. Exposure to PF-05082566.........................................................42
6.5.3.2. Exposure to Mogamulizumab ...................................................44
6.5.3.3. Dose Reductions........................................................................45
6.5.3.4. Dose Delays...............................................................................45
6.5.3.5. Infusion Rate Reductions ..........................................................46
6.5.3.6. Infusion Interruptions................................................................46
6.5.4. Concomitant Medications and Non-Drug Treatments................................46
6.5.5. Subsequent Anti-cancer Therapies .............................................................47
6.6. Safety Summaries and Analyses .............................................................................47
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6.6.1. Adverse Events...........................................................................................47
6.6.1.1. All Adverse Events....................................................................48
6.6.1.2. Adverse Events Leading to Treatment Discontinuation............49
6.6.2. Deaths .........................................................................................................50
6.6.3. Serious Adverse Events ..............................................................................50
6.6.4. Other Significant Adverse Events ..............................................................50
6.6.5. Laboratory Data..........................................................................................52
6.6.5.1. Hematology and Chemistry Parameters....................................52
6.6.5.2. Other Laboratory Parameters ....................................................55
6.6.6. Vital Signs ..................................................................................................55
6.6.7. Electrocardiogram.......................................................................................56
6.6.8. Physical Examination .................................................................................58
6.6.9. ECOG Performance Status .........................................................................58
7. INTERIM ANALYSES.......................................................................................................58
7.1. Introduction .............................................................................................................58
7.2. Interim Analyses and Summaries............................................................................58
8. REFERENCES ....................................................................................................................59
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................6
Table 2.
PK Parameters to be Determined for PF-05082566 and Mogamulizumab..........12
Table 3.
Outcome and Event Dates for PFS and DR Analyses ..........................................32
Table 4. 
PFS Censoring Reasons and Hierarchy................................................................33
Table 5.
Summary Statistics of PK parameters ..................................................................34
Table 6.
Outcome and Event Date for irPFS and irDR Analyses......................................36
LIST OF FIGURES
Figure 1.
Example Plot of Prior Dose Toxicity Curve.........................................................18


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1641004 is based on the protocol 
amendment 1 dated 04-Feb-2016. The SAP amendment reflects updates to the imputation 
algorithms for missing data as applicable to the data collected in this study.
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version Date
Summary of Changes
1.0
06-Feb-2015
Not applicable (original SAP)
Amendment 1
08-Apr-2016
Re-structured the content of the SAP per Pfizer’s 
SAP template current as of 30-Jun-2015.
Aligned content with revisions from protocol 
amendment 1.
Revised the exploratory analysis based on 
irRECIST endpoints to be aligned with the new 
standard irRECIST criteria for IO.
Removed the Response Evaluable set.
Added more details on the analyses of secondary 
endpoints including safety, efficacy.
Added more details on the analyses of baseline 
and other summaries.
Refinements made in endpoint definition and 
description of analysis methods.
Amendment 2
21-Sep-2017
Throughout the document, replaced “start date” 
with first dose of study treatment.
Aligned the endpoints sections with the protocol.
Added definitions of start and end dates of study 
treatment in Section 3.4.1.
Section 3.5.1 and Section 6.6 revised to perform 
clinical review to identify Adverse Events of 
Special Interest.
Added Section 5.2.5 “Definition of start of new 
anti-cancer drug therapy” and Section 5.2.6 
“Definition of start of new anti-cancer therapy” to 
provide specific details regarding these 
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Version
Version Date
Summary of Changes
Added Section 5.2.10 “Adequate baseline tumor 
assessment” and 5.2.11 “Adequate post-baseline 
tumor assessment” to provide derivation details.
Section 5.3 “Methods to Manage Missing Data” 
and subsections - revised the imputation 
algorithms for missing data applicable to the data 
collected in the study.
Section 6.2.2 “Efficacy endpoints” – added 
definitions for BOR for patients without 
measurable disease at baseline and separated 
reasons for BOR of ‘no post-baseline assessment’ 
between death and other reasons; provided more 
details regarding censoring reasons for PFS and 
DR to take into account the change in schedule of 
tumor assessments and provided further details 
for the derivation of censoring reasons; Removed 
the OS subsection because it is not a study 
endpoint.
Section 6.2.3 “Pharmacokinetic endpoints” –
updated definitions and descriptions for 
consistency.
Section 6.3.1 “irRECIST endpoints” – provided 
more details regarding censoring reasons for 
irPFS and irDR to take into account the change in 
schedule of tumor assessments and provided 
further details for the derivation of censoring 
reasons.
Section 6.5.3 “Study treatment compliance and 
exposure” – added cycle definition and further 
details and corrections regarding derivations of DI 
and RDI; revised derivation for dose delays; 
added derivations for infusion interruptions; 
changed the definition of infusion rate reductions 
to take into account the first infusion rate.
Section 6.5.4 “Concomitant medications and non-
drug treatment” – deleted the summary tables for 
prior and concomitant non-drug treatment.
Section 6.6.2 “Deaths” – aligned the death
reasons with the wording in the associated eCRF.


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Version
Version Date
Summary of Changes
Section 6.6.4 “Other significant adverse events” –
replaced “SOC” with “Cluster” for irAEs.
Section 6.6.5 “Laboratory data” and Section 6.6.7 
“Electrocardiogram” provided further details 
regarding denominators used in the analyses.
Section 6.6.7 “Electrocardiogram” – changed the 
study-specific correction from linear regression to 
log-linear regression for consistency with other 
studies in the utomilumab program.
Deleted Appendix 1 since details are provided in 
Section 6.5.3.
Made edits to be aligned with the data collection
and for more accurate statistical descriptions.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B1641004.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data 
(ie,
PK data). The primary analysis will include all data up to a cut-off date 
corresponding to 24 months (104 weeks) after the last patient receives the first dose of study 
treatment.  The final analysis of the data will be performed after last patient last visit (LPLV).   
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
Primary Objectives

To estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 
Dose (RP2D) of PF-05082566 in combination with mogamulizumab in patients with 
advanced solid tumors.
Secondary Objectives

To evaluate the overall safety profile; 
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Dose-Expansion Phase
Once the MTD of PF-05082566 administered in combination with mogamulizumab has been 
estimated with confidence, expansion cohorts of patients will be enrolled to further study the 
safety, tolerability, PK/PD, and preliminary anti-tumor activity for PF-05082566 in 
combination with mogamulizumab, as well as to study 
.  
Tumor types for the expansion cohorts will be selected from CRC, bladder, ovarian, 
squamous esophageal, SCCHN and/or squamous NSCLC.  Dose, final tumor types, 
 
 for these cohorts will be selected based on emerging data from the dose-finding 
portion of the study or obtained from ongoing studies testing PF-05082566.
The total enrollment into all expansion cohorts will be up to 40 patients.
Treatment with study drugs will continue until completion of 24 months of treatment 
(approximately 24 cycles), confirmed disease progression, patient refusal, unacceptable 
toxicity, or the study is prematurely terminated by the Sponsor whichever occurs first.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints

First 2 cycles Dose-Limiting Toxicities (DLTs).
Severity of AEs will be graded according to National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE v. 4.03).  For the purpose of dose 
escalation, any of the following AEs occurring during the DLT observation period (first 
2 Cycles, ie, 8 weeks) that are attributable to one or both study drugs will be classified as 
DLTs:
Hematologic

Grade 4 neutropenia lasting >7 days;

Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of 
38 degrees C (100.4 degrees F) for more than one hour;

Grade 3 neutropenic infection; 

Grade 3 thrombocytopenia with bleeding;

Grade 4 thrombocytopenia.
Non-Hematologic:

Grade 3 non laboratory toxicities (excluding infusion reactions), except those that 
have not been maximally treated (eg, nausea, vomiting, diarrhea).
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
Grade 3 laboratory abnormalities (other than AST/ALT) if:

Medical intervention is required to treat the patient, or

The abnormality leads to hospitalization.

Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
increase.
3.2. Secondary Endpoints
3.2.1. Safety Endpoints

Adverse Events as characterized by type, frequency, severity [(as graded by NCI CTCAE 
v. 4.03)], seriousness and relationship to study therapy;

Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE v. 4.03);

Vital Signs (blood pressure and pulse rate), weight, Eastern Cooperative Oncology Group 
(ECOG) Performance Status.
3.2.2. Efficacy Endpoints

Objective tumor response;
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the first dose of study treatment until the date of the first documentation of 
progressive disease (PD). Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.
irOR is defined as immune-related CR (irCR) or immune-related PR (irPR) according to 
irRECIST from the first dose of study treatment until immune-related PD (irPD). Both 
irCR and irPR must be confirmed by repeat assessments performed no less than 4 weeks 
after the criteria for immune-related response are first met.  Also, irPD must be confirmed 
by a second, consecutive assessment at least 4 weeks apart.

Time-to-response (TTR, expansion cohorts only);
TTR is defined, for patients with an OR, as the time from the first dose of study treatment
to the first documentation of objective response (CR or PR) which is subsequently 
confirmed. 
irTTR is defined, for patients with an irOR, as the time from the first dose of study 
treatment to the first documentation of immune-related objective tumor response (irCR or 
irPR) which is subsequently confirmed. 


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
Duration of response (DR, expansion cohorts only);
DR is defined, for patients with OR, as the time from first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.  
irDR is defined, for patients with an immune-related objective response, as the time from 
the first documentation of immune-related objective response (irCR or irPR) to the date 
of first documentation of irPD (which is subsequently confirmed) or death due to any 
cause.  

Progression–free survival (PFS, expansion cohorts only);
PFS is defined as the time from the first dose of study treatment to the date of the first 
documentation of PD or death due to any cause, whichever occurs first.
irPFS is defined as the time from the first dose of study treatment to the date of first 
documentation of irPD (which is subsequently confirmed) or death due to any cause,
whichever occurs first.   
3.2.3. Pharmacokinetic Endpoints

PK parameters of PF-05082566 and mogamulizumab, including but not limited to Cmax, 
Ctrough, Tmax, AUC0-last, AUCtau, t1/2, CL and Vss, as data permits.
PK parameters will be determined from serum concentration-time data for Cycle 5 as 
shown in the following table:
Table 2.
PK Parameters to be Determined for PF-05082566 and Mogamulizumab
Parameter
Definition
Method of Determination
AUC 0-last
Area under the serum 
concentration-time profile from time 
zero to the time of the last 
measurable concentration (Clast)
Linear/Log trapezoidal method
AUC, tau
Area under the serum 
concentration-time over dosing 
interval 
Linear/Log trapezoidal method
Cmax
Maximum observed serum 
concentration 
Observed directly from data
Tmax
Time to first occurrence of Cmax
Observed directly from data 
t½
a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant calculated 
by a linear regression of the log-linear 
concentration-time curve.  Only those data points judged 
to describe the terminal log-linear decline were used in 
the regression.
Ctrough
Predose concentration during 
multiple dosing
Observed directly from data
CL
Clearance
Dose / AUCτ for steady state




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Definition of baseline: 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for heart rate (HR) and QT/QTc interval assessments will be derived from the visit 
where both HR and QT are not missing. Triplicate ECGs are collected in the study and the
baseline for each ECG measurement is the average of the pre-dose replicate measurements 
on the baseline day. Unscheduled assessments will not be included in the calculation of the 
average. QTcB and QTcF will be derived based on HR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline Characteristics
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6.
3.5. Safety Endpoints
3.5.1. Adverse Events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.




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4.3.4. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/Nab sample collected for either PF-05082566 or 
mogamulizumab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Determination
No formal statistical hypothesis testing is planned.
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
TITE-CRM approach cannot be determined in advance.  The maximum sample size is set 
as 30 for dose escalation cohorts in order to have a reliable and accurate estimate of the MTD 
based on simulation results.  Based on probability theory, a sample size of 30 will ensure the 
estimates of any binary variable (eg, objective response rate) have a 95% confidence interval 
(CI) with width <0.36.  A sample size of 30 also enables the detection of any unexpected 
toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with a probability of 
0.79, and that occurs at 10% rate with a probability of 0.96.
A stopping rule will also be implemented if:

Maximum sample size (n=30) is reached; or 

9 DLT evaluable patients have been treated at the estimated MTD (6 if no DLT observed 
at any dose); or

All doses appear to be overly toxic and the MTD cannot be determined in the current 
trial. 
Additional patients will be required for expansion cohorts (N=40).  The total number of 
patients in expansion cohorts will be determined based on emerging data from this study, 
cancer indication, and the patient population of interest. 
5.1.2. Decision Rules Using the TITE-CRM Method
The doses will be assigned to each enrolled patient using a TITE-CRM method with an 
adaptive cyclical weight function (Huang and Kuan, 2014), a modified version of the original 
method proposed by Cheung and Chappell (2000).
Delayed-onset toxicities are a particular challenge for phase I trials of combination therapies.  
Most of the available dose-escalation designs, including the 3+3 design, the up-and-down 
designs and the CRM design, require all patients to have completed a fixed observation 
period for toxicity (eg, 1-2 cycles of the experimental regimen, or 6-8 weeks after start of 
treatment) before additional cohorts of patients can be enrolled.  Thus, trial accrual is subject
to opening and closing which may pose logistical risk on the success and completion of the 
study.  In addition, patients who are either lost to follow-up or die of events unrelated to 


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treatment are usually required to be replaced.  Due to these reasons, the trial duration could 
be unacceptably long in case of prolonged observation window and unexpected high rate of 
patient drop-out.
The time-to-event continual reassessment method (TITE-CRM), a variant of the original 
CRM method, is open to accrual continually, and maintains other advantages of the CRM 
relative to the 3+3 design.  Like CRM, TITE-CRM seeks to determine the target MTD dose, 
defined as the dose most closely identified with the target rate, which is the largest acceptable 
DLT rate determined by the investigators based on the relative costs and benefits of the 
treatment.
TITE-CRM is to be implemented as described by Cheung and Chappell (2000) and Huang 
and Kuan (2014) for the dose-escalation of PF-05082566.
PF-05082566 may be administered intravenously at the available dose levels of 1.2, 2.4, 
100 mg flat dose (equivalent to the 1.2 mg/kg dose) and 5.0 mg/kg on q4wk schedule.
PF-05082566 will be co-administered with mogamulizumab on Day 1 of each treatment 
cycle.  
Mogamulizumab will be administered at 1 mg/kg, weekly during Cycle 1, and biweekly from 
Cycle 2 onwards.  A lower mogamulizumab dose of 0.5 mg/kg may be tested if the starting 
dose is not tolerable.  Different doses and different dosing schedules of the combination may 
be investigated after the MTD is estimated.  
The MTD is defined as highest dose that is associated with a DLT rate <30%.  A power 
function modeling DLT rate at each dose di (i=1, …, 4) expressed as Pr (DLT | di) = Fi () 
will be used:
)
exp(
)
(


i
i
p
F

where pi is the prior estimate of DLT rate at dose level di, and p1p2…p4.  These estimates 
will be projected based model sensitivity to DLTs, together with single agent safety data for 
both study drugs.  is an unknown single parameter modeling the dose-toxicity relationship, 
with prior distribution 
)
,0
(
2
0

N
, where 
0
is the standard deviation of the normal prior 
distribution with mean=0.  At the beginning of the trial, the initial prior value of is set as 
0, the prior mean, which gives a prior dose-toxicity model of 
i
i
p
F

)
(
based on the power 
function. 
In the Bayesian paradigm, the prior distribution 
)
,0
(
2
0

N
expresses the researchers’ belief in 
the quality of the initial estimates pi.  The smaller the standard deviation
0
, the more 
confidence researchers have in the precision of pi. and vice versa.  As the trial progresses, 
this prior distribution is combined mathematically with the observed data to yield the 
posterior distribution of the parameter (the posterior mean of will be calculated to model 
the dose-toxicity relationship).  The prior distribution determines how responsive TITE-CRM 
is to the accumulated data.  With a small
0
upfront, the posterior toxicity probability 


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estimates remain close to the prior estimates unless significantly discrepant data otherwise 
occur; with a large
0
, the model will tend to be more immediately responsive to data.  In this 
trial, 
0
=1, which provides a reasonably flat prior distribution of , with 90% Bayesian 
credible interval of 
)
exp(: [0.19, 5.21], sufficiently wide to cover a wide spectrum of 
dose-toxicity scenarios.  Figure1 illustrates the dose-toxicity curve (blue curve) with 
90% upper and lower bounds (red curves) when the initial prior estimates
ip are (0.095, 
0.186, 0.300, 0.422).
Figure 1.
Example Plot of Prior Dose Toxicity Curve
Prior dose-toxicity curve with 90% confidence limits
Dose Level of PF-05082566 (mg/kg)
DLT Rate
1.2(+moga 0.5)
1.2 (or 100mg)
2.4
5
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the TITE-CRM paradigm, patients who have enrolled in the trial but have not experienced 
a DLT will be included in the probability calculation with an initial weight equal to the 
proportion of the 8-week (2 cycles) DLT observation period the patients have completed.  
However the weight function will be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566.  An adaptive cyclical weight 
function as proposed by Huang et al. (2014) will be implemented.
Patients who experience a DLT or complete the observation period without a DLT will be 
assigned full weight (=1). 


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Extensive simulation results comparing the TITE-CRM using the adaptive cyclical weight 
function with the 3+3 design and other weight functions can be found in Huang et al. (2014).
To avoid overly rapid escalation and to retain the efficiency of dose administration when 
enrollment is fast, the following restrictions and practical considerations will be followed.

Dose skipping in escalation to untested doses is not allowed (k −> k+1).  In particular, at 
least three patients should have been treated at dose level k before escalation to dose level 
k+1;

At least three patients should have been on treatment (for a minimum of 3 weeks) and 
observed DLT rate <33% at dose level k before a patient is assigned to dose level 
k+1 (Note that the waiting window depends on our knowledge in the time-to-event 
pattern of toxicity and accumulating safety data, and thereby the confidence in the 
associated weights.  However, intentional delay in enrollment in the absence of DLT or 
serious AEs should be minimized and discouraged);

Dose escalation recommendation by the TITE-CRM algorithm may be overruled by the 
Sponsor if the nature of the existing data causes safety concern.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:

Dose Level -1: PF-05082566 1.2 mg/kg q4wks + mogamulizumab 0.5 mg/kg;

Dose Level 1: PF-05082566 1.2 mg/kg q4wks + mogamulizumab 1 mg/kg;

Dose Level 1a: PF-05082566 100 mg q4wks + mogamulizumab 1 mg/kg;

Dose Level 2: PF-05082566 2.4 mg/kg q4wks + mogamulizumab 1 mg/kg;

Dose Level 3: PF-05082566 5 mg/kg q4wks + mogamulizumab 1 mg/kg.
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group.
DLTs will be summarized based on the DLT-evaluable set by treatment group.
Other safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the safety analysis set by treatment group. 
PK data will be summarized based on the PK analysis sets by treatment group.
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group.
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5.2.1. Data Handling After the Cut-off Date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of Centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center.
5.2.3. Presentation of Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values, mean, median, standard deviation (SD), minimum, maximum and first and 
third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of Study Day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment +1. 
The study day for assessments occurring prior to the first dose of study treatment 
(eg, baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of Start of New Anti-cancer Drug Therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Systemic Therapy – for Cancer’ eCRF pages that is after 
the first dose of study treatment. When start date of anti-cancer drug therapy is missing or 
partially missing, the imputation rules described in Section 5.3.3.4 should be applied using 
only data from the ‘Follow-up Systemic Therapy – for Cancer’ eCRF pages.


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5.2.6. Definition of Start of New Anti-cancer Therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Systemic Therapy – for 
Cancer’ eCRF pages.

Start date of radiation therapy as identified by clinical review based on data recorded in 
the ‘Concomitant Radiation Therapy’ eCRF page. The following cases will not be 
considered as new anti-cancer therapy: ‘Type of Radiation Therapy’ = ‘Palliative’ and 
radiotherapy to a non-target tumor lesion. 

Surgery date recorded in ‘Concomitant Surgery’ when “Surgery Outcome’ = ‘Resected’ 
or ‘Partially Resected’.
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied.
5.2.7. Definition of On-treatment Period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 

(date of given informed consent - date of birth + 1) / 365.25;

In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth);

In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth).


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The integer part of the calculated age will be used for reporting purposes. 

BMI (kg/m2) = weight (kg)/[height (m)]2;

BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5.
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 
5.5 to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled Visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.
5.2.10. Adequate Baseline Tumor Assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 42 days prior to and including the first dose of 
study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesion status at baseline for non-target 
lesions).
5.2.11. Adequate Post-baseline Tumor Assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.2.2.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.


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Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic Concentrations
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.
Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.
5.3.1.2. Pharmacokinetic Parameters
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter 
cannot be derived from a patient’s concentration data, the parameter will be coded as NC
(ie, not calculated).  NC values will not be generated beyond the day that a patient 
discontinues.
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses.


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5.3.2. Handling of Incomplete Dates
5.3.2.1. Disease History
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:

If the day is missing, it will be imputed to the 1st day of the month. 

If both day and month are missing, the month and day will be imputed as January 1st.

If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse Events
Incomplete AE-related dates will be imputed as follows:

If only the day part of the AE onset date is missing, then the AE onset date will be 
replaced by 1st of the month. For example, if the AE onset date is --/JAN/2015, then the 
imputed AE onset date will be 01/JAN/2015.

If both the day and month of the AE onset date are missing, then the onset date will be 
replaced by January 1st of the year. For example, if AE onset date is --/---/2014, then the 
imputed AE onset date will be 01/JAN/2014.In all other cases the missing onset day or 
missing onset month will be replaced by 1.

If after above imputation, the imputed onset date with same month and year of the start of 
study treatment but less than the start of study treatment, and stop date is not less than the 
start of study treatment, then the imputed AE onset date will be re-assigned as the start of 
study treatment. 

If the AE onset date is missing completely, then the onset date will be imputed as 
following: If not missing the visit date and visit date is less than the start of study 
treatment and less than or equal to the stop date, then the visit date will be used to 
impute the onset date.

Else if previous visit date is greater than or equal to the start of study treatment and 
less than or equal to the stop date, then the previous visit date will be used to impute 
the onset date.

Else if previous visit date is less than the start of study treatment and the start of study 
treatment is less than or equal to stop date, then the start of study treatment will be 
used to impute the onset date.

Else Stop date will be used to impute the onset date.

Incomplete stop date will be replaced by the last day of the month (if day is missing only).


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
Incomplete stop date will be replaced by the last month of the year (if month is missing).

If the AE stop date is missing completely and still present, then the stop date will be 
imputed as following:

If not missing death date, then death date will be used to impute the stop date.

Else if not missing withdrawal date or Date Decision to Discontinue Treatment, the 
stop date will be imputed as the maximum of Withdrawal date, Date Decision to 
Discontinue Treatment, Onset date or AE visit date.

Else if missing withdrawal date and Date Decision to Discontinue Treatment, the stop 
date will be imputed as the maximum of subject summary visit date, Onset date or AE 
visit date.

Else the stop date will be imputed as the maximum of onset date or last dosing date.

If the AE stop date is missing completely and event resolved, then the stop date will be 
imputed as following:

If visit date is greater than onset date, then the visit date will be used to impute the 
stop date.

Else the onset date will be used to impute the stop date.

If after above imputation, the imputed stop date is less than the start of study treatment, 
then the imputed AE stop date will be re-assigned as the start of study treatment. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and Concomitant Medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, no imputation will be performed.

If the day of medication date is missing, then the medication date will be replaced by 1st
of the month. For example, if the medication start date is --/JAN/2015, then the imputed 
medication start date will be 01/JAN/2015. 

If both the day and month of medication start date are missing, then the medication date 
will be replaced by January 1st of the year. For example, if the medication start date is --
/---/2014, then the imputed medication start date will be 01/JAN/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.


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
Incomplete stop date will be replaced by the last day of the month (if day is missing). 

Incomplete stop date will be replaced by the last month of the year (if month is missing).

In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date or last dose date.  
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments
5.3.3.1. Date of Last Contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:

All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments).

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation.

AE start and end dates.

Study drug start and end dates.

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will 
not be applied to derive the last contact date.
5.3.3.2. Death Date
Partial death dates will be imputed based on the last contact date:

If the day or both the day and the month is missing, death will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact and the following:

Missing day:
1st day of the month and year of death.

Missing day and month:
January 1st of the year of death.


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5.3.3.3. Tumor Assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates 
(eg, X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of Start of New Anti-cancer Therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  

If the end date of new anti-cancer therapy is:

completely missing then it will be ignored in the imputations below.

partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy.

partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy.

If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is:

completely missing then it will be ignored in the imputations below.

partially missing with only year (YYYY) available then the imputations below will 
consider 01JANYYYY as the start date of the new anti-cancer therapy.


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
partially missing with only month and year available then the imputations below will 
consider the first day of the month for MMMYYYY as the start date of the new anti-
cancer therapy.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.
6.1. Primary Endpoints
6.1.1. DLT 
6.1.1.1. Primary Analysis
The primary analyses will be based on the DLT-evaluable set.  DLTs will be listed and 
summarized by treatment group.
6.2. Secondary Endpoint(s)
6.2.1. Safety Endpoints
Refer to Section 6.6.
6.2.2. Efficacy Endpoints
The following analyses will be based on the FAS by treatment group.   Assessment of 
response will be made using RECIST v1.1.
6.2.2.1. Objective Response as Assessed by the Investigator per RECIST v1.1
The following analyses will be based on the FAS by treatment group.  Assessment of 
response will be made using RECIST v1.1.
Best Overall Response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the first dose of study treatment until the first 
documentation of PD, according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD.

PR = at least two determinations of PR or better at least 4 weeks apart and before first 
documentation of PD (and not qualifying for a CR).

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥6 weeks after the first dose of study treatment and before first 
documentation of PD (and not qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥6 weeks after the first dose of study 
treatment and before first documentation of PD (and not qualifying for CR or PR).


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
PD = progression ≤12 weeks after the first dose of study treatment (and not qualifying for 
CR, PR, SD or non-CR/non-PD).

NE:  all other cases.
Only tumor assessments performed on or before the start of any further anti-cancer therapies
will be considered in the assessment of BOR.  Clinical deterioration will not be considered as 
documentation of disease progression.
Objective Response (OR) is defined as BOR of CR or PRaccording to RECIST v1.1
Patients who do not have a post-baseline radiographic tumor assessment (including due to 
early clinical progression), who receive anti-cancer therapies other than the study treatments 
prior to reaching a CR or PR, or who die, progress, or drop out for any reason prior to 
reaching a CR or PR will be counted as non-responders in the assessment of OR. Each 
patient will have an objective response status (0: no OR; 1: OR).  OR rate (ORR) is the 
proportion of patients with OR in the analysis set.
ORR by treatment group will also be calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).
In addition, the frequency (number and percentage) of patients with BOR of CR, PR, SD, 
non-CR/non-PD (applicable only to patients with non-measurable disease at baseline), PD 
and NE will be tabulated. Patients with BOR of NE will be summarized by reason for having 
NE status. The following reasons will be used:

Inadequate baseline assessment (includes missing assessment or non-measurable disease 
at baseline).

No post-baseline assessments due to death.

No post-baseline assessments due to other reasons.

All post-baseline assessments have overall response NE.

New anti-cancer therapy started before first post-baseline assessment.

SD of insufficient duration (<6 weeks after the first dose of study treatment).

PD too late (>12 weeks after the first dose of study treatment).
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’.


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6.2.2.2. Tumor Shrinkage from Baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100.
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100.
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created. This plot will display 
the best percentage change from baseline in the sum of the diameter of all target lesions for 
each patient with measurable disease at baseline and at least one post-baseline assessment.
6.2.2.3. Duration of Response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described below 
for PFS in Table 3.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group
together with a summary of associated statistics including the median DR time with 2-sided
95% CIs.  In particular, the DR rate at 3, 6 and 12 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed 
using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.


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6.2.2.4. Time to Response
Time to response (TTR) is defined, for patients with OR, as the time from the first dose of 
study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – first dose of study treatment +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.5. Progression-free Survival (Expansion Cohort Only)
Progression-Free Survival (PFS) is defined as the time from the first dose of study treatment
to the date of the first documentation of PD or death due to any cause, whichever occurs first.  
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), or for patients with an event after two or more missing 
tumor assessments. For patients who start a new anti-cancer therapy prior to an event, PFS 
data will be censored on the date of the last adequate tumor assessment prior to starting the 
new anti-cancer therapy. Patients who do not have an adequate baseline tumor assessment or 
who do not have an adequate post-baseline tumor assessment will be censored on the first 
dose of study treatment unless death occurred on or before the time of the second planned 
tumor assessment in which case the death will be considered an event (Table 3). 
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at baseline, on treatment every 8 weeks up to 1 year, then every 3 months and 
whenever disease progression is suspected (eg, symptomatic deterioration).  Assessments 
will be repeated at EOT only if not done in the previous 8 weeks.  The allowable time 
window for disease assessments is ±7 days while on treatment and whenever disease 
progression is suspected (eg, symptomatic deterioration).  
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 3.  
PFS (months) = [date of event or censoring– first dose of study treatment +1]/30.4375


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Table 3.
Outcome and Event Dates for PFS and DR Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
first dose of study treatment a
Censored a
PD or death 
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤ 16 weeks after the first dose of
study treatment
Date of PD or death
Event
PD or death after 2 or more missing or 
inadequate post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
No PD and no death
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived based on 
documented progression 
only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
a However if the patient dies ≤16 weeks after the first dose of study treatment the death is an event with date on 
death date.
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the first dose of study treatment; if the criteria were met the censoring will 
be on the ‘start date.’
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided
95% CIs.  In particular, the PFS rate at 3, 6, 9, 12 and 15 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed 
using Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 4 following the hierarchy shown.


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Table 4. 
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/ first dose of study treatment
Event after missing assessments a
4
No event and End of study (EOS) = Subject refused further 
follow-up 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and EOS present and no adequate post-baseline 
tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators.
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be conducted by treatment group.  
PF-05082566 and Mogamulizumab PK Concentrations:  
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, and the number of 
concentrations above the lower limit of quantification) of serum PK concentrations for 
PF-05082566 and mogamolizumab will be presented in tabular form by nominal visit, cycle, 
dose and nominal time.  
Linear and semi-log plots of median serum concentrations vs nominal time will be prepared 
for Cycle 5 by dose (all doses on the same plot). Similar plots will be prepared for each 
individual patient’s serum concentrations by dose (all subjects on the same plot).  
PF-05082566 and Mogamulizumab PK Parameters:  
The PF-5082566 and mogamulizumab PK parameters detailed in Section 3.2.3 for Cycle 5 
will be listed and summarized by dose using descriptive statistics as specified in Table 5.  PK
parameters with zero values will be excluded from the calculation of geometric means and 
geometric %CV. 




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6.3. Other Endpoints
6.3.1. irRECIST Endpoints
The irRECIST criteria will also be used in this study for exploratory assessments of anti-
tumor activity.   
The following analyses will be based on the FAS by treatment group based on Investigator 
assessment.
Immune-related progressive disease (irPD) needs to be confirmed by a second, consecutive 
assessment at least 4 weeks apart.  irPD is also considered to be confirmed if the patient.

dies within 12 weeks  after the initial observation of irPD, or 

discontinues treatment due to disease progression (clinical deterioration without 
radiological documentation) prior to or within 12 weeks after the assessment of irPD. 
Immune-related Best Overall Response (irBOR) will be derived based on reported lesion 
responses at different evaluation time points from the first dose of study treatment until 
immune-related disease progression per irRECIST, according to the following rules:

irCR = at least two determinations of irCR at least 4 weeks apart and before irPD;

irPR = at least two determinations of irPR or better at least 4 weeks apart and before irPD 
(and not qualifying for a irCR);

irSD = at least one irSD assessment (or better) ≥6 weeks after the first dose of study 
treatment and before irPD (and not qualifying for irCR or irPR);

irPD = at least two consecutive determinations of irPD at least 4 weeks apart;  

irNE:  all other cases.
Only tumor assessments performed before the start of any further anti-cancer therapies will 
be considered in the assessment of irBOR.  
Immune-related Objective Response (irOR) is defined as irBOR or irCR or irPR. 
Immune-related OR rate (irORR) is the proportion of patients with irOR in the analysis set. 
Immune-related Duration of Response (irDR) is defined, for patients with an immune-
related objective response, as the time from the first documentation of immune-related 
objective response (irCR or irPR) to the date of first documentation of irPD (which is 
subsequently confirmed) or death due to any cause.  If a patient has not had an event (irPD or 
death), irDR is censored at the date of last adequate tumor assessment. The censoring rules 
for irDR are as described below for irPFS.
irDR (months) = [date of event or censoring– first date of irOR +1]/30.4375


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Immune-related Time to response (irTTR) is defined, for patients with an irOR, as the 
time from the first dose of study treatment to the first documentation of immune-related 
objective tumor response (irCR or irPR) which is subsequently confirmed. 
irTTR (in months) = [first date of irOR – first dose of study treatment +1]/30.4375
Immune-related Progression-Free Survival (irPFS) is defined as the time from the first 
dose of study treatment to the date of first irPD (which is subsequently confirmed) or death 
due to any cause, whichever occurs first.  irPFS data will be censored on the date of the last 
adequate tumor assessment for patients who do not have an event (confirmed irPD or death), 
for patients who start a new anti-cancer therapy prior to an event or for patients with an event
after 2 or more missing tumor assessments.  Patients who do not have an adequate baseline 
tumor assessment or who do not have an adequate post-baseline tumor assessment will be 
censored on the first dose of study treatment unless death occurred on or before the time of 
the second planned tumor assessment in which case the death will be considered an event. 
The censoring and event date options to be considered for the irPFS and irDR analysis are 
presented in Table 6.
Table 6.
Outcome and Event Date for irPFS and irDR Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
first dose of study treatment
Censored a
irPD (subsequently confirmed) b or death 
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR 
-
≤ 16 weeks after the first dose of 
study treatment
Date of first irPD or death
Event
irPD (subsequently confirmed) b or death after 
2 or more missing or inadequate post-baseline 
tumor assessments 
Date of last adequate tumor 
assessment c documenting no irPD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ (clinical deterioration without 
radiological documentation) prior to or within 
12 weeks after the assessment of first irPD
Date of first irPD
Event
New anti-cancer therapy prior to confirmed 
irPD 
Date of last adequate tumor 
assessment c documenting no irPD 
before anti-cancer therapy is given 
or missed tumor assessments
Censored
(irPD not confirmed or no irPD) and no death
Date of last adequate tumor 
assessment c documenting no irPD 
before anti-cancer therapy is given 
or missed tumor assessments
Censored
a However if the patient dies ≤xx weeks after the first dose of study treatment the death is an event with date on 
death date
b irPD is also considered to be confirmed if the patient dies within 12 weeks after the initial documentation of 
irPD 
c If there are no adequate post-baseline assessments prior to irPD or death, then the time without adequate 
assessment should be measured from the first dose of study treatment; if the criteria were met the censoring will 
be on the first dose of study treatment.


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The analyses for irBOR, irOR, irDR, irTTR will follow the methodology outlined for the 
RECIST v1.1 endpoints as follows:

irOR will be summarized as described in Section 6.2.2.1 for OR and 95% CIs will be 
reported.

irBOR, irDR, irTTR and irPFS will be summarized by treatment group as described in
Sections 6.2.2.1, 6.2.2.3, 6.2.2.4, and 6.2.2.5 but irDR and irPFS will be analyzed using 
the censoring rules described in Table 6.
6.4. Subset Analyses
The number of patients expected in each treatment group is small and therefore no subset 
analyses are planned in this study.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following analyses will be based on the FAS overall and separately by treatment group.
6.5.1.1. Demographic Characteristics
Demographic characteristics and physical measurements will be summarized by treatment 
group using the following information from the ‘Screening/Baseline Visit’ eCRF pages.

Demographic characteristics:

Gender: Male, Female;

Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown;

Ethnic origin: Hispanic/Latino (‘Hispanic/Latino’, ‘Not Hispanic/Latino’, 
‘Unspecified’);

Age (years): summary statistics;

Age categories: 
-
<65 years, ≥65 years;
-
<65, 65-<75, 75-<85, ≥85 years.

Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4.

Physical measurements:

Height (cm);


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
Weight (kg);

Body Mass Index (BMI) (kg/m2);

Body Surface Area (BSA) (m2).
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (m2) and ECOG performance status.
6.5.1.2. Medical History
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
6.5.1.3. Disease Characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized overall and by treatment group. Summary statistics will be 
presented for the following.
From the ‘Primary Diagnosis’ eCRF page:

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page);

Time since initial diagnosis to first dose of study treatment (months), defined as (first 
dose of study treatment – date of initial diagnosis)/30.4375;

Time since diagnosis of local/regional recurrence of disease (months), defined as (first 
dose of study treatment – date of diagnosis of local/regional recurrence of disease or 
metastatic disease)/30.4375.
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No);

Involved tumor sites at baseline.


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6.5.1.4. Prior Anti-cancer Therapies
The prior anti-cancer therapies are collected under the ‘Previous Systemic Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy;

Patients with at least one prior anti-cancer drug therapy;

Patients with at least one prior anti-cancer radiotherapy;

Patients with at least one prior anti-cancer surgery.
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy;

Any prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4;

Prior anti-cancer immune therapy (including PD-1, PD-L1, anti-CTLA4, others);

Intent of Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic;

Best response: CR, PR, SD, PD, Unknown, Not applicable (Adjuvant only). Best 
response is derived from the last treatment regimen.
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used.
The listings of prior anti-cancer therapies will also be provided as follows. These will 
include the patient identification number, and all the relevant collected data-fields on the 
corresponding eCRF pages.

Listing of prior anti-cancer drug therapies;

Listing of prior anti-cancer radiotherapy;

Listing of prior anti-cancer surgeries.


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6.5.2. Study Conduct and Patient Disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group.
6.5.2.1. Patient Disposition
The percentages below will be calculated based on the number of patients in the FAS.

Number and percentage of treated patients in each of the analysis sets defined in
Section 4;

Number and percentage of patients with study drug ongoing (separately for each study 
drug when administered in combination);

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug when 
administered in combination);

Number and percentage of patients who entered safety follow-up.
In addition the following will be summarized:

Number and percentage of treated patients by center.
6.5.2.2. Protocol Deviations
All protocol violations that impact the safety of the patients and/or the conduct of a study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria;

Patients who develop withdrawal criteria whilst on the study but are not withdrawn;

Patients who receive the wrong treatment or an incorrect dose;

Patients who receive an excluded concomitant medication;

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study Treatment Compliance and Exposure
The following analyses will be based on the safety analysis set by treatment group.
All dosing calculations and summaries will be based on ‘Dose_ PF-05082566’ and ‘Dose_
mogamulizumab’ eCRFs pages. A listing of study drug administration will be created with 
the information collected on the ‘Dose_ PF-05082566’ and ‘Dose_mogamulizumab’ eCRF 
pages.


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Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is:

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit).

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date =  actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 28 days – 1 day.
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7.
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.
Exposure will be summarized (overall) as dose received (cumulative dose, actual dose 
intensity) and as dose received relative to intended dose (relative dose intensity [RDI]).  
The formulae below should be applied to each study drug separately.  In this study 1 cycle = 
4 weeks.
The derivations below are provided for the following:

PF-05082566 administered as a 1-hour IV infusion at a dose of 1.2 mg/kg, 2.4 mg/kg, 
5 mg/kg, or 100 mg flat dose once every 4 weeks in 4-week cycles.

Mogamulizumab will be administered as a 1-hour IV infusion at a dose of 1 mg/kg or 
0.5 mg/kg weekly for 4 consecutive weeks in the first cycle (ie, on Days 1, 8, 15 and 22), 
followed by biweekly dosing in cycles 2 (ie, on Days 1 and 15).
Analysis of exposure will be based on the calculated actual dose levels:

PF-05082566: total dose / weight, or total dose (for the flat dose cohort);

Mogamulizumab: total dose / weight.


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6.5.3.1. Exposure to PF-05082566
For weight-adjusted dose:
The dose level for PF-05082566 is calculated as actual dose administered/weight (mg/kg). 
The last available weight of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with PF-05082566 (weeks) =
(end date–date of first dose of PF-05082566 +1)/7,
where end date = start date of last cycle with non-zero dose of PF-05082566 + 28 – 1
Duration of exposure to PF-05082566 (weeks) = 
(last dose date of PF-05082566 – first dose date of PF-05082566 + 28)/7  
Cumulative dose overall is the sum of the actual doses of PF-05082566 received overall.  
Each cycle for PF-05082566 is defined by a 4-week period. The dose intensity (DI) and the 
relative dose intensity (RDI) will be calculated for each patient across all cycles.
Actual Dose Intensity (DI)

Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with PF-05082566 (weeks)/4].  
Relative Dose Intensity (RDI) 

Intended DI (mg/kg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [d (mg/kg)] / [1 (4-week cycle)] = d (mg/kg/4-week 
cycle).

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [d (mg/kg/4-week cycle)].
where d is 1.2 mg/kg, 2.4 mg/kg, or 5 mg/kg.
The summary of treatment exposure and compliance for PF-05082566 will include the 
following information:

Treatment duration (weeks);

Total number of infusions received;

Cumulative dose (mg/kg);

Dose intensity (mg/kg/cycle);


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
Relative dose intensity (%).
For flat dose:
The dose level for PF-05082566 is calculated as actual dose administered (mg).
Intended duration of treatment with PF-05082566 (weeks) =
(end date–date of first dose of PF-05082566 +1)/7,
where end date = start date of last cycle with non-zero dose of PF-05082566 + 28 – 1
Duration of exposure to PF-05082566 (weeks) = 
(last dose date of PF-05082566 – first dose date of PF-05082566 + 28)/7  
Cumulative dose overall is the sum of the actual doses of PF-05082566 received overall.  
Each cycle for PF-05082566 is defined by a 4-week period. The dose intensity (DI) and the 
relative dose intensity (RDI) will be calculated for each patient across all cycles.
Actual Dose Intensity (DI)

Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with PF-05082566 (weeks)/4].  
Relative Dose Intensity (RDI) 

Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [100 (mg)] / [1 (4-week cycle)] = 100 (mg/4-week 
cycle).

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [100 (mg/4-week cycle)].
The summary of treatment exposure and compliance for PF-05082566 will include the 
following information:

Treatment duration (weeks);

Total number of infusions received;

Cumulative dose (mg);

Dose intensity (mg/cycle);

Relative dose intensity (%).


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6.5.3.2. Exposure to Mogamulizumab
The dose level for mogamulizumab is calculated as actual dose administered/weight (mg/kg). 
The last available weight of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with mogamulizumab (weeks) =
(end date–date of first dose of mogamulizumab +1)/7,
where end date = start date of last cycle with non-zero dose of mogamulizumab +28 – 1.
Duration of exposure to mogamulizumab (weeks) = 
(last dose date of PF-05082566 – first dose date of PF-05082566 + d)/7  
where d is 7 days if the last dose is in Cycle 1 and 14 days if the last dose is beyond Cycle 1.
Cumulative dose overall is the sum of the actual doses of mogamulizumab received overall.  
Each cycle for mogamulizumab is defined by a 4-week period. The dose intensity (DI) and 
the relative dose intensity (RDI) will be calculated for each patient across all cycles.
Actual Dose Intensity (DI)

Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with mogamulizumab (weeks)/4].  
Relative Dose Intensity (RDI) 

For patients that discontinued mogamulizumab before C2D1, then 

Intended DI (mg/kg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [4×d mg/kg] / [1 (4-week cycle)]  = 4×d (mg/kg/4-
week cycle).

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [4×d (mg/kg/4-week cycle)] 
where d is 1 or 0.5.

For patients that were treated with mogamulizumab beyond C2D1, then

Intended DI (mg/kg/4-week cycle).
= [(n1×4×d (mg/kg) + n2×4×d/2 (mg/kg))/(n1+n2)] / [intended number of 4-weeks in a 
cycle] 
= [(n1×4×d (mg/kg) + n2×4×d/2 (mg/kg))/(n1+n2)] / [1 (4-week cycle)] 


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= [(n1×4×d + n2×4×d/2)/(n1+n2)] (mg/kg/4-week cycle)  
where, 

n1 = 1

n2 = intended duration of treatment with mogamulizumab (weeks)/4 – n1

n1+n2= intended duration of treatment with mogamulizumab (weeks)/4

d is 1 or 0.5.

Overall RDI (%) = 100 × [overall actual DI] / [intended DI].  
The summary of treatment exposure and compliance for mogamulizumab will include the 
following information:

Treatment duration (weeks);

Total number of infusions received;

Cumulative dose (mg/kg);

Dose intensity (mg/kg/cycle);

Relative dose intensity (%).
6.5.3.3. Dose Reductions
Dose reduction is defined as actual non-zero dose < 90% of the planned dose. 
Number and percentage of patients with at least one dose reduction as well as a breakdown of 
dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.4. Dose Delays
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days between 
two consecutive doses.
Dose delays will be grouped into the following categories.

No delay;

1-2 days delays;

3-6 days delay;


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
7 or more days delay.
No delay and 1-2 days delay will also be summarized together. 
For example, for PF-05082566, administered on a 4-week schedule, if one patient receives 
PF-05082566 on Day 1, then the next PF-05082566  administration date will be on Day 29; 
however, if the patient receives PF-05082566 at Day 30 or 31, this is considered as 1-2 days 
delay. 
Number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.5. Infusion Rate Reductions
The number and percentage of patients with at least one infusion rate reduction of 50% or 
more compared to the first infusion rate reported in the eCRF (first entry on the first dosing 
record page) as well as the frequency of patients with 1, 2, 3 or ≥4 infusion rate reductions of 
50% or more will be summarized.
6.5.3.6. Infusion Interruptions
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant Medications and Non-Drug Treatments
The following analyses will be based on the safety analysis set by treatment group.
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment. 
Prior and concomitant medications will be summarized from the ‘Prior and Concomitant 
Drug/Non-Drug Treatment’ eCRF page. 
Summary of prior and concomitant medications will include the number and percentage of 
patients by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred 
term. A patient will be counted only once within a given drug class and within a given drug 
name, even if he/she received the same medication at different times. If any prior or 
concomitant medication is classified into multiple ATC classes, the medication will be 
summarized separately under each of these ATC classes. The summary tables will be sorted 
on decreasing frequency of drug class and decreasing frequency of drug name in a given drug 
class. In case of equal frequency regarding drug class (respectively drug name), alphabetical 
order will be used. In case any specific medication does not have ATC classification level 2 
coded term, it will be summarized under ‘Unavailable ATC classification’ category. 


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A listing of concomitant medications will be created with the relevant information collected 
on the ‘Prior and Concomitant Drug Treatment’ eCRF page.
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘Prior and Concomitant Non-Drug Treatment’ eCRF page.
6.5.5. Subsequent Anti-cancer Therapies
The following analyses will be based on the FAS by treatment group.
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Systemic Therapy – for Cancer’, ‘Concomitant Radiation’, and ‘Concomitant Surgery’ eCRF 
pages. The earliest date of start of new anti-cancer drug therapy after first dose of study 
treatment will be used for the definition of the on-treatment period and the earliest date of 
start of new anti-cancer therapy after first dose of study treatment will be used for the 
censoring for efficacy analyses (see Sections 5.2.5 and 5.2.6). 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated based on the data collected from the ‘Follow-up Systemic Therapy – for Cancer’
eCRF page. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of
AEs and other safety parameters will be based on the safety analysis set by treatment group.  
Summaries of related AEs (PF-05082566 plus mogamulizumab) may further be presented as 
PF-05082566-related, mogamulizumab -related, or related to both study treatments.
All summaries described below by SOC and PT will further be presented by PT in decreasing 
frequency based on the frequencies observed in all treatment groups combined.
6.6.1. Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event occurs
during the on-treatment period as defined in Section 3.5.1.
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.

Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’).

Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).


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
Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).

Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified by clinical review based 
on the SRP prior to DB lock).

Infusion-related Reactions (IRR): IRRs (as identified by clinical review based on the 
SRP prior to DB lock) with onset on study drug dosing date (not prior to infusion of 
study drug) or the day following study drug infusion.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency observed in all treatment groups combined. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All Adverse Events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 

The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group:
-
TEAEs;
-
TEAEs, Grade ≥3;
-
Related TEAEs;
-
Related TEAEs, Grade ≥3;
-
TEAEs leading to permanent treatment discontinuation;
-
Related TEAEs leading to permanent treatment discontinuation;


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-
Serious TEAEs;
-
Related Serious TEAEs;
-
TEAEs leading to death;
-
Related TEAEs leading to death;
-
irAEs;
-
Related irAEs;
-
IRRs;
-
Related IRRs.

TEAEs by SOC and PT and worst grade;

Related TEAEs by SOC and PT and worst grade;

TEAEs leading to death by SOC and PT;

Related TEAEs leading to death by SOC and PT;

TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related TEAEs 
/ Grade ≥3 TEAEs / Related Grade ≥3 TEAEs;

TEAEs Excluding SAEs, with frequency ≥5% in any treatment group by SOC and PT.
6.6.1.2. Adverse Events Leading to Treatment Discontinuation
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment group:

TEAEs leading to discontinuation of PF-05082566 by SOC and PT;

Related TEAEs leading to discontinuation of PF-05082566 by SOC and PT;

TEAEs leading to discontinuation of mogamulizumab by SOC and PT;

Related TEAEs leading to discontinuation of mogamulizumab by SOC and PT;

TEAEs leading to permanent discontinuation of study treatment;

Related TEAEs leading to permanent discontinuation of study treatment. 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 


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6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days and within 60 days after last dose of study treatment as well as the 
cause of death, will be tabulated based on information from the ‘Notice of Death’ eCRFs, by 
treatment group. 

All deaths (within 30 days, and within 60 days);

Deaths (within 30 days, and within 60 days) after last dose of study treatment;

Cause of Death:
-
Disease under study;
-
Study treatment toxicity;
-
Unknown;
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5);

Flag for death ≤30 days and 31-60 days after last dose of study treatment.
6.6.3. Serious Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT;

Related SAEs by SOC and PT.
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other Significant Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:

irAEs leading to death, by cluster and PT;

Related irAEs leading to death, by cluster and PT;


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
irAEs, by cluster and PT;

irAEs, Grade ≥3, by cluster and PT;

Related irAEs, by cluster and PT;

Related irAEs, Grade ≥3, by cluster and PT;

irAEs leading to permanent treatment discontinuation, by cluster and PT;

Related irAEs leading to permanent treatment discontinuation, by cluster and PT;

Serious irAEs, by cluster and PT;

Related serious irAEs, by cluster and PT.
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:

IRRs leading to death, by PT;

Related IRRs leading to death, by PT;

IRRs, by PT;

IRRs, Grade ≥3, by PT;

Related IRRs, by PT;

Related IRRs, Grade ≥3, by PT;

IRRs leading to permanent treatment discontinuation, by PT;

Related IRRs leading to permanent treatment discontinuation, by PT;

Serious IRRs, by PT;

Related serious IRRs, by PT;

Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later).
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.


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6.6.5. Laboratory Data
6.6.5.1. Hematology and Chemistry Parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03.
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are 
only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories 
(ie, Low, Normal, High). 
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 
0 when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count ≥800/mm3.

Neutrophil count decreased:
-
derived absolute count does not meet Grade 2-4 criteria, and


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-
% value < % LLN value, and
-
derived absolute count ≥1500/mm3.
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows:
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group:

ALT ≥3×ULN, ALT ≥5xULN, ALT ≥10×ULN, ALT ≥20×ULN;

AST ≥3×ULN, AST ≥5xULN, AST ≥10×ULN, AST ≥20×ULN;

(ALT or AST) ≥3×ULN, (ALT or AST) ≥5×ULN, (ALT or AST) ≥10×ULN, (ALT or 
AST) ≥20×ULN;

TBILI ≥2×ULN;

Concurrent ALT ≥3×ULN and TBILI ≥2×ULN;

Concurrent AST ≥3×ULN and TBILI ≥2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP >2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and (ALP ≤2×ULN or 
missing).
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying.


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
peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥2×ULN, ALT≥3×ULN or AST ≥3×ULN will be provided.
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie, those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).

The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade(Grades 1-4), 
laboratory abnormalities during the on-treatment period.

The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:

Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased), Coagulation (activated 
partial thromboplastin time (aPTT) and prothrombin time (INR)).

Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase (CPK increased), Potassium (hypokalemia/ hyperkalemia), Sodium 
(hyponatremia/ hypernatremia), Magnesium (hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).


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Parameters with NCI-CTC grades not available:
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 

shifts from baseline normal to at least one result above normal during on-treatment 
period;

shifts from baseline normal to at least one result below normal during on-treatment 
period.
In this study, these apply to the following parameters: 

Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils;

Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH).
6.6.5.2. Other Laboratory Parameters
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF. 

Urinalysis: all urinalysis parameters (except for Proteinuria, which will be summarized 
with CTCAE grades);

Other parameters: hormone, and immunology parameters;

Pregnancy test.
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing. 
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided.
6.6.6. Vital Signs
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Weight will not be collected at End of Treatment. Height will 
be measured at screening only.


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Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed 
will be the differences from baseline. 
6.6.7. Electrocardiogram
ECG summaries will include all ECG assessments from screening and the on-treatment 
period.  All ECG assessments will be listed, and those collected outside the on-treatment 
period will be flagged in the listing. QTcB and QTcF will be derived based on HR and QT 
(see below). The average of the replicate measurements should be determined after the 
derivation of the individual parameter at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as:
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Both formula produce similar results when the range of heart rates is not extreme. If QTcB 
and QTcF methods do not adequately correct QT for heart rate, an empirical correction 
specific to the study population can be derived.
These corrections were obtained by starting with the simple power model:
QT = a × RRb                                 (1)


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and then used the natural log transformation to derive the equation:
ln(QT) = ln(a) + b ln(RR)              (2) 
The power model can be used to derive an empirical correction based on the reference group 
by fitting a linear mixed-effects regression model to the ln(QT) and ln(RR) data, estimating 
the slope b from Equation 2, and then applying that as a power in QTcP(msec) =
QT(msec)/RR(sec)b to correct all the singlet data (on-drug as well as off-drug.)
Data will be summarized using QTcF and QTcB. However, if these are not appropriate 
correction method for the data set, the results will also be summarized using QTcP.  
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category.

Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, QTcP) 
and HR using individual (non-averaged) baseline assessments.

For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point.

Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:           

QTc increase from baseline >30 ms, >60 ms;

QTc >450 ms, >480 ms, >500 ms;

HR ≤50 bpm and decrease from baseline ≥20 bpm;

HR ≥120 bpm and increase from baseline ≥20 bpm;

PR ≥220 ms and increase from baseline ≥20 ms;

QRS ≥120 ms.
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters.


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6.6.8. Physical Examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system at baseline.
6.6.9. ECOG Performance Status
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing.
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study. A Dose Escalation Steering 
Committee (DESC) was established to review safety data. Periodical DESC meetings will be 
scheduled to make decisions on escalation and de-escalation following the TITE-CRM 
design. 
7.1. Introduction
Not Applicable.
7.2. Interim Analyses and Summaries
Not Applicable.


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Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan;45(2):228-47.
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Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
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Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
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Lee S, Cheung YK (2009). Model calibration in the continual reassessment method. 
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Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related 
tumor response assessment: does reducing the number of lesions impact response 
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O’Quigley J, Pepe M, Fisher L (1990). Continual reassessment method: A practical 
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