Clinical trial NCT01307267
Conditions: Lymphoma, Non-Hodgkin Lymphoma, Follicular Lymphoma, Large B-Cell, Diffuse Carcinoma, Non-Small-Cell Lung Carcinoma, Renal Cell Carcinoma, Squamous Cell of Head and Neck Malignant Melanoma
Keywords: Phase 1 Non-Hodgkin's Lymphoma Advanced malignancies
Sponsor: Pfizer
Start date: 2011-06-21; Completion date: 2019-02-20
Enrollment: 190 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in patients with solid tumors or b-cell lymphomas, and in combination with rituximab in patients with CD20 positive Non-Hodgkin's Lymphoma (NHL).

Detailed description:

Arms: arm 1: PF-05082566 single agent in patients with advanced cancer arm 2: PF-05082566 in combination with rituximab in patients with Non-Hodgkin's Lymphoma
Interventions: intervention 1: PF-05082566 intervention 2: rituximab intervention 3: PF-05082566
Intervention descriptions: intervention 1: Intravenous, Dose escalation, once per month intervention 2: Intravenous, 375 mg/m2, once per week for 4 weeks intervention 3: IV, Dose escalation, once per month

Protocol documents:
Prot_000.pdf: 
PF-05082566
B1641001
Final Protocol Amendment 9, 06 January 2017
Page 1
A PHASE 1 STUDY OF PF-05082566 AS A SINGLE AGENT IN PATIENTS WITH 
ADVANCED CANCER, AND IN COMBINATION WITH RITUXIMAB IN 
PATIENTS WITH NON-HODGKIN’S LYMPHOMA (NHL)
Investigational Product Number:
PF-05082566
Investigational Product Name:
Utomilumab*
United States (US) Investigational New 
Drug (IND) Number:
109,154
European Clinical Trials Database 
(EudraCT) Number:
2011-002799-17
Protocol Number:
B1641001
Phase:
1
* Utomilumab is the proposed International Nonproprietary Name (INN) for 
PF-05082566 (4-1BB agonist monoclonal antibody)


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Document History
Document
Version Date
Summary of Changes
Amendment 9
06 January 2017
The Schedule of Activities for the expansion 
cohorts (Table 5) has been updated to include 
some additional assessments requested by the 
UK Medicines and Healthcare products 
Regulatory Agency (MHRA), to reduce the 
number of PK and ADA sample collection, to 
clarify the requirements for tumor tissue 
collection
 
The background section has been updated to 
provide updated clinical data from the present 
study and to introduce a paragraph presenting 
explicitly the benefit/risk assessment for 
PF-05082566 as a single-agent or in 
combination with rituximab.
The study objectives and endpoints have been 
updated to indicate that OR is the primary 
objective and endpoint for the expansion 
cohorts of Portion A and Portion B, 
 
The study design of the Expansion Cohort of 
Portion A has been updated to introduce a 
randomized cohort testing 3 different dose 
levels of PF-05082566 (0.24, 0.6 and 
1.2 mg/kg) in patients with melanoma who have 
had RECIST-defined disease progression on a 
previous treatment with an immune check-point 
inhibitor.  This cohort is intended to provide 
additional data in support of the RP2D selection 
for PF-05082566 as a single-agent in patients 
with advanced solid tumors.
The study design of the Expansion Cohort of 
Portion B has been updated to introduce the 
possibility to evaluate a lower dose level of 
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0.24 mg/kg of PF-05082566 in combination 
with rituximab in patients with follicular 
lymphoma (FL) refractory to treatment with 
rituximab.  The overall data from the expansion 
cohort of Portion B will be used to select the 
RP2D for PF-05082566 in combination with 
rituximab in patients with CD20-positive 
non-Hodgkin’s lymphoma.
The inclusion criteria have been updated to:

Define better the prior treatment history 
required for eligibility in the expansion 
cohorts of Portions A and B;

Require measurable disease at study entry 
for patients with advanced solid tumor;

Indicate that vaccine administration is not 
allowed within 4 weeks prior to study entry 
(not applicable to inactivated vaccines).
The administration section has been updated to 
allow the introduction of a different preparation
of PF-05082566.  Also the dose modification 
guidelines have been updated and simplified 
taking into account the clinical experience in 
the present study and that only 3 dose levels for 
PF-05082566 (0.24, 0.6 and 1.2 mg/kg) are 
currently under investigation.
Administration of rituximab starting at Cycle 
4 Day 0 until Cycle 10 Day 0 for patients 
enrolled in Portion B has been removed to 
obtain consistency with the rituximab dosing 
schedule among patients irrespective of whether 
local recommendations allow this re-treatment.
The study procedures and assessments sections 
have been updated to align with the 
modifications introduced to the other parts of 
the protocol.


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Document
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The data analysis/statistical methods section has 
been updated to align with and support the 
modifications introduced to the study design 
and to other parts of the protocol.
Administrative updates and wording 
modifications have been introduced to improve 
readability.
Amendment 8
16 September 2015
Portion A Expansion Cohort will include other 
tumor types in addition to melanoma as 
described in Section 4.1 Inclusion Criterion 1.
Under Section 4.1 Inclusion Criteria, Portion A 
Expansion Cohort patients must have 
documented disease progression on a 
checkpoint inhibitor (anti-CTLA-4, 
anti-PD1/PD-L1 antibodies) per RECIST 
criteria.  Rationale for focusing on checkpoint 
inhibitor refractory disease is detailed in 
Section 1.4.
Added a statement in the Inclusion Criterion 
2 to specify that Portion B Expansion Cohort 
includes patients with FL that are refractory to 
previous rituximab therapy or DLBCL with 
relapsed and/or refractory disease.
Total number of patients is increased to 
approximately 220.
The following inclusion criteria were modified 
as below:

Baseline renal function requirements 
were changed from creatinine 1.5 x 
ULN) or estimated creatinine clearance 
(CrCl) 60 mL/min to creatinine 2 x 
ULN or CrCl 50 mL/min. 

ALT/AST baseline value requirements 
were changed from ≤2.0 ULN to ≤
2.5 ULN

Removed baseline Alkaline phosphatase 
requirements


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Exclusion criteria were modified as below:
•
Systemic immunosuppressive regimens 
were reduced from 28 days to 14 days. 
•
Therapeutic or experimental monoclonal 
antibodies were reduced from 60 days to 
28 days. 
•
Radiation therapy was reduced from 
28 days to 14 days. 
•
Exclusion of patients with unstable or 
serious concurrent medical conditions in 
the previous 12 months is changed to 
previous 6 months.
•
In the exclusion #18, patients with prior 
therapy with any anti-PD-1, anti-PD-L1, 
anti-PD-L2, or anti-CTLA-4, was 
removed.
Pharmacokinetic sampling requirements were 
updated based on requirements according to 
escalation and expansion cohorts for both 
Portions. 
 
Off treatment follow up period and intervals 
were updated under Section 6.3, allowing 
1 month window for survival follow up.
Section 5.4.7 was added to allow palliative 
radiotherapy during study treatment.  Statement 
regarding palliative radiotherapy under 
Section 5.4.1 is removed.
Off treatment criteria is updated to clarify loss 
of clinical benefit, allowing patients to continue 
study treatment who continue to demonstrate 
clinical benefit despite disease progression.  
Patients must reconsent confirming 
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understanding that they may be forgoing 
approved therapy with possible clinical 
benefit(s) by continuing with the study 
treatment beyond objective disease progression. 
Under Portion B, rituximab maintenance dosing 
beginning at the 4th cycle is now optional and 
at the discretion of the investigator. 
 
 
Sample Size Determination was updated to 
include rationale for expansion cohort sample 
size.
 
 
Schedule of Activities (SOA) tables were 
updated to align with the changes described as 
above.
References and Appendix 1 list of abbreviations 
were updated.
Minor editorial changes were made for 
consistencies throughout the document. 
Amendment 7
29 April 2015
Schedule of Activities was revised as follows:
•
Study visits were reduced to q4 weeks
from Cycle 2 for expansion cohorts. 
•
On-treatment biopsy requirement was 
removed for the Portion B expansion 
cohort.  Baseline biopsy requirement 
was replaced with existing archival 
tissue sample. 
•
Portion B patients will repeat rituximab
dosing.  Rituximab (375 mg/m2) will be 
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administered every 8 weeks, in accord 
with the local and institutional Standard 
of Care, starting at Cycle 4 Day 0 until 
Cycle 10 Day 0 (or until discontinuation 
of study treatment due to progression, 
unacceptable toxicity, or consent 
withdrawal, whichever occurs earlier).
To better inform a decision on the RP2D, 
expansion cohort A will enroll patients with 
previously treated metastatic melanoma in each 
of 3 different doses (0.24 mg/kg, 1.2 mg/kg and 
10 mg/kg).  Patients enrolled under Portion B 
expansion cohort will receive 
PF-05082566 1.2 mg/kg in combination of 
rituximab.  Under this amendment, patients who 
are rituximab refractory or resistant CD-20+ FL 
or DLBCL will be enrolled.
 
 
Added clarification to Inclusion Criteria 1, 
2 and 3, and corrected Inclusion Criterion
13 from Amendment 6.
Exclusion criterion 1 was revised to allow 
enrollment of patients with stable brain 
metastases.  Exclusion criterion 3 was revised 
to provide clarity to the steroid administration 
prior to study entry.
Section 4.3, Lifestyle guidelines was updated to 
align with the current standard language. 
Dose hold, resumption and reduction scheme 
for expansion cohorts were added. 
To reduce radiation exposure, the frequency of 
tumor assessments were reduced for patients 
who remain on study therapy for >10 months.
 
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Added details on the analysis of 
immunogenicity data.
Clarification was made to specify Fridericia’s 
QT correction formula for exclusion criterion 
10.
Clarification was made to distinguish patients 
enrolled in Japan from Japanese (ethnic) 
patients who are enrolled from the sites outside 
of Japan.
 
 
Several administrative changes were made 
throughout the document to clarify language 
associated with the Schedule of Activities and
to resolve inconsistencies. 
Adverse Events and Communication of Results 
by Pfizer sections were updated to match 
current Pfizer standards.
Administrative changes were made to enhance 
readability.
Amendment 6
21 November 2014
Main changes are to add Japan cohort(s) in 
Portion A to evaluate safety, tolerability and PK 
profile of PF-05082566 as a single-agent in
patients enrolled in Japan.
<Japan specific changes>
General Study Design
Additional Japan cohorts with paired tumor 
biopsy in Portion A were added.  Standard 
3+3 design is applied to the Japan cohort(s).
Japan specific changes required by local 
regulation were added.
Patient Selection
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Japan specific changes required by local 
regulation were added.
<Common changes>
Exclusion of >4 cm liver lesions was removed 
for the patients who enrolled in expansion 
cohorts since no severe drug-related AEs 
related to hepatotoxicity have been observed 
based on current study safety data.
 
 
Mandatory study visits are reduced for patients 
in expansion cohorts to Day 1 of each cycle 
from Cycle 4, at the discretion of the 
investigator.
Administrative Changes
Multiple administrative changes were made 
throughout the document to clarify language 
associated with the Schedule of Activities to 
resolve inconsistencies and to incorporate 
changes in the Pfizer clinical protocol template.  
Amendment 5
05 February 2014
General Study Design
Added language to allow another Portion B 
expansion cohort at any of the previously tested 
dose escalation dose levels. 
Study Treatment
Exclusion Criterion 18 was changed to allow 
the inclusion of patients who have previously 
received treatment with an immunotherapy 
regimen (including anti-PD-1 and anti-CTLA4) 
if such treatment was not associated with 
clinically significant adverse events.
Based on current study safety data indicating 
that PF-05082566 infusion does not result in 
clinically significant infusion reactions. 
Therefore, after completion of the 0.6 mg/kg 
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dose level, there will no longer be a waiting 
period between the first dose of 
PF-05082566 for a patient and the first dose of 
rituximab for the next patient in the same dose 
cohort
Administrative Changes
Multiple administrative changes were made 
throughout the document to clarify language 
associated with the Schedule of Activities, 
resolve an inconsistency in stated dose levels in 
the Statistical Design section and to improve 
the readability of the protocol.
Amendment 4
24 May 2013
General Study Design
The protocol indication is more detailed to 
incorporate changes in Pfizer clinical protocol 
template instructions.
 
 
 
 
 
Study Treatment
For portions A and B, patients clinically 
benefiting from study treatment without 
unacceptable toxicity, objective disease 
progression, or withdrawal of consent will be 
given the opportunity to continue treatment 
after 8 cycles of therapy following approval 
from Pfizer.  Continued treatment will be on a 
reduced visit schedule, or as clinically 
indicated.
Patient Selection
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Inclusion Criterion 2 for Portion B the patient 
population for the expansion cohort will be 
CD20+ B cell NHL patients with a history of 
rituximab-refractory disease.
Inclusion Criterion 3 changed to accurately 
reflect the Cheson criteria for disease 
assessment with least one extranodal tumor 
mass >1.0 cm in the greatest transverse 
diameter or in the case of malignant lymph 
nodes >1.5cm in the greatest transverse 
diameter. 
Exclusion Criterion 15 changed to include 
recent (within the past year) or active suicidal 
ideation or behavior per the updated Pfizer 
protocol template.
Exclusion Criterion 17 added to exclude 
patients with a history of active ethanol abuse, 
hepatitis or liver lesions greater than 4 cm on 
the longest axis.
Exclusion Criterion 18 added to exclude 
patients with previous therapies containing 
drugs that specifically target T cell 
costimulation or checkpoint pathways.
Administrative
A risk/benefit statement was added to the end of 
the Introduction to conform to the Pifzer 
protocol guidance changes.
New Pfizer protocol Sections were added to 
incorporate changes in the Pfizer clinical 
protocol template changes.  These include 
Section 4.4 on sponsor qualified medical 
personnel, Section 5.4.4 on the use of 
anti-inflammatory therapies, Section 5.2.5 on 
dose interruptions was added, and 
Section 8.5.1 Protocol-Specified Serious 
Adverse Events (which clarifies that there are 
no protocol-specified AEs in this protocol).
In Section 8.2 and table footnotes, the SAE 


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active reporting period was increased to 60 days 
based on the Pfizer protocol template changes.
Section 9.2.2 (Simulations and Operating 
Characteristics in TITE-CRM) was removed as 
this material is covered in the Statistical 
Analysis Plan.
Other edits were made to enhance readability 
and to clarify language throughout the protocol.
Amendment 3
25 July 2012
Detailed rituximab dose administration 
guidelines are provided for Portion B.  
Guidelines for management of rituximab related 
infusion reactions are also provided. 
Additional pregnancy testing as indicated in 
Schedule of Activities per the updated protocol 
template and guidelines for testing are provided 
per the updated protocol template.
Clarification of measurable disease for 
Portion B.
Clarification on B-cell neoplasms excluded 
from the study.
Adequate bone marrow function, for Portion A 
defined as absolute neutrophil count (ANC)  
1.5 x 109/L (≥1,500/μL), platelet count 100 x 
109/L (≥100,000/μL), and hemoglobin 
>9.0 g/dL (>5.6 mmol/L), and for Portion B as 
ANC 1.0 x 109/L (1,000/uL), platelet count 
75 x 109/L (≥75000/μL), and hemoglobin 
>9.0 g/dL (>5.6 mmol/L). 
Lifestyle guidelines detailed per the updated 
protocol template.
Survival follow-up every 3 months.
Record retention guidelines updated per the 
protocol template.
Administrative changes due to the protocol 
template update and to enhance readability.
Amendment 2
13 February 2012
Definition of dose sought in Portion B 
redefined to be in line with Portion A (Optimal 


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Biological Dose revised to Recommended 
Phase 2 Dose).
 
 
Revision to PK schedule (addition of end of 
infusion draw).
Addition of hepatitis B core antibody 
assessment to hepatitis status panel at baseline.
Removal of several laboratory assessments in 
order to streamline data collection and review.
Addition of instructions in the cases of mixed 
response.
Revision of Adverse Event section to align with 
recently updated protocol template per 
CT3 guidance and US FDA Final Rule.
Administrative changes and clarifications made 
throughout.
Amendment 1
21 January 2011
Revisions made per the FDA’s request during 
the IND review period.  
Original protocol
09 December 2010
Not Applicable
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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PROTOCOL SUMMARY
Indication
PF-05082566, also known as utomilumab, as a single-agent is under investigation for the 
treatment of patients with advanced solid tumor malignancies or B cell lymphoma. 
PF-05082566 in combination with rituximab is also under investigation for the treatment of 
patients with relapsed or refractory CD20-positive non-Hodgkin’s lymphoma (NHL). 
Rationale
Study Rationale
PF-05082566 is a fully human IgG2 monoclonal antibody (mAb) and promising new 
molecular entity that binds to human 4-1BB with high affinity and specificity.  In vitro and in 
vivo data demonstrated significant immunomodulatory activity and anti-tumor activity of 
PF-05082566 when dosed as a single-agent and in combination with therapeutic mAbs that 
have the potential to induce antibody dependent cell mediated cytotoxicity (ADCC).  
Preclinical studies have shown favorable pharmacokinetics (PK) and metabolic properties 
which suggest that it may be well tolerated when administered intravenously (IV).  Based 
upon the above considerations, this first-in-human Phase 1 study will assess the safety and 
establish the maximum tolerated dose (MTD) and the Recommended Phase 2 Dose (RP2D) 
of single-agent PF-05082566 in patients with advanced solid tumors or B-cell lymphoma, 
and the MTD and RP2D of PF-05082566 given in combination with rituximab in patients 
with non-Hodgkin’s B-cell lymphoma. 
Consecutive cohorts of patients will receive PF-05082566 administered as a single-agent 
once every four weeks as an IV infusion (Portion A).  Based on preclinical studies, the 
dosing will begin at 0.006 mg/kg.  Once the safety of once every 4-week dosing of 
PF-05082566 as a single-agent is established at 0.06 mg/kg, dosing of PF-05082566 once 
every 4 weeks will be tested in combination with rituximab, given once weekly for 4 weeks, 
in patients with CD20-positive NHL (Portion B).  Patients will be assessed for dose-limiting
toxicities (DLTs) for the first 2 cycles of treatment in both Portions.  PK properties of 
PF-05082566 and rituximab will be assesse
 
.
 
 
 
 
 
 
 
 
  Taken 
these data together, 3 PF-05082566 dose levels will be further evaluated in Portion A 
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expansion cohorts: 0.24 mg/kg, 0.6 mg/kg and 1.2 mg/kg, and 2 dose levels may be further 
evaluated in Portion B expansion cohorts: 1.2 mg/kg and 0.24 mg/kg based on emerging 
data.
Portion A includes dose escalation cohorts and Japan cohort(s).  The Japan cohort(s) will be 
conducted in Japanese patients at Japanese sites following the completion of enrollment of 
the dose escalation cohorts in Portion A of this study. Patients enrolled into the Japan 
cohort(s) will receive PF-05082566 administered as a single-agent once every 4 weeks as an 
IV infusion.  Patients enrolled in Japan will follow the same eligibility criteria, study 
procedures (unless otherwise specified), and discontinuation criteria as those patients in the 
dose escalation cohort of Portion A.  As of June 2016, seven (7) patients have been enrolled 
in the 2 cohorts in Japanese patients and the 2 tested dose levels of PF-05082566 (5.0 and 
10 mg/kg) were well tolerated with no DLTs reported.  Japanese sites are currently 
participating in the expansion cohorts of Portion A and Portion B.
Portion A expansion cohorts include patients with solid tumors who have documented 
disease progression on a previous immune checkpoint inhibitor therapy (anti-CTLA-4, 
anti-PD-1/PD-L1 antibodies) per Response Evaluation Criteria in Solid Tumors (RECIST) 
version (v) 1.1 criteria (see Section 4.1 for the definition of disease that progressed from 
previous immune checkpoint inhibitor therapy).
Portion B expansion cohorts include patients with follicular lymphoma (FL) refractory to 
rituximab (see Section 4.1 for the definition of FL disease refractory to rituximab) or diffuse 
large B-cell lymphoma (DLBCL) with relapsed or refractory disease.
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Primary Objective – Dose Escalation Cohorts
Portion A:

To assess safety and tolerability at increasing dose levels of single-agent 
PF-05082566 in patients with advanced solid tumors or B-cell lymphoma in order to 
estimate the MTD and select the RP2D.
Portion B:

To assess safety and tolerability at increasing dose levels of PF-05082566 given in 
combination with rituximab in patients with relapsed or refractory CD20-positive 
NHL in order to estimate the MTD and select the RP2D.


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Secondary Objectives – Dose Escalation Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single-agent 
in patients with advanced solid tumors or B-cell lymphoma.
•
To evaluate the overall safety profile; 
•
To characterize the pharmacokinetics of PF-05082566;
•
To evaluate the immunogenicity of PF-05082566;
•
To characterize the effects of PF-05082566 on QTc;
•
To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL. 
•
To evaluate the overall safety profile; 
•
To characterize the pharmacokinetics of PF-05082566 and rituximab given in 
combination;
•
To evaluate the immunogenicity of PF-05082566 and rituximab;
•
To characterize the effects of PF-05082566 in combination with rituximab on QTc;
•
To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.
 
 
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Primary Objective – Expansion Cohorts
Portion A:
•
To estimate the objective response rate of PF-05082566.
Portion B:
•
To estimate the objective response rate of PF-05082566 in combination with 
rituximab.
Secondary Objectives – Expansion Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single agent 
in patients with advanced solid tumors or B cell lymphoma.
•
To evaluate the overall safety profile; 
•
To characterize pharmacokinetics of PF-05082566;
•
To evaluate the immunogenicity of PF-05082566;
•
To characterize the effects of PF-05082566 on QTc;
•
To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL.
•
To evaluate the overall safety profile;
•
To characterize pharmacokinetics of PF-05082566 and rituximab given in 
combination;
•
To evaluate the immunogenicity of PF-05082566 and rituximab;
•
To characterize the effects of PF-05082566 in combination with rituximab on QTc;
•
To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.
 
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Endpoints
Primary Endpoint – Dose Escalation Cohorts
•
First 2 cycles DLTs.
Secondary Endpoints – Dose Escalation Cohorts
Portion A:
•
Safety: Adverse events as characterized by type, frequency, severity [as graded by 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v.4.03], timing, seriousness and relationship to study therapy 
PF-05082566; Laboratory abnormalities as characterized by type, frequency, severity 
(as graded by NCI CTCAE v.4.03) and timing; Vital signs (blood pressure and pulse
rate);
•
PK: PF-05082566 [Cmax, Ctrough, Tmax, Area under the concentration vs time curve 
(AUC)0-last,, AUC0-∞, AUCtau, clearance (CL), and Vss, as data permits];
•
Anti-Drug Antibody levels for PF-05082566;
•
QTc interval;
•
Objective response as assessed by RECIST v1.1;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
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Portion B:
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566 in combination with rituximab; Laboratory abnormalities as 
characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and 
timing; Vital signs (blood pressure, pulse rate, and body temperature);
•
PK: PF-05082566 (Cmax, C trough, Tmax, AUC0-last,, AUC0-∞, AUCtau, CL and Vss, as 
data permits) and rituximab (Cmax and Ctrough);
•
Anti-Drug Antibody levels for PF-05082566 and rituximab;
•
QTc interval;
•
Objective response as assessed using the Cheson 2007 criteria;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
 
 
 
 
 
 
 
 
 
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Secondary Endpoints – Expansion Cohorts
Portion A:
•
First 2 cycles DLTs;
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566; Laboratory abnormalities as characterized by type, frequency, severity 
(as graded by NCI CTCAE v.4.03) and timing; Vital signs (blood pressure and pulse 
rate);
•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau,CL, and Vss, as 
data permits);
•
Anti-Drug Antibody levels for PF-05082566;
•
QTc interval;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
Portion B:
•
First 2 cycles DLTs;
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566 in combination with rituximab; Laboratory abnormalities as 
characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and 
timing; Vital signs (blood pressure, pulse rate, and body temperature);
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•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau, CL, and Vss, as 
data permits) and rituximab (Cmax and Ctrough);
•
Anti-Drug Antibody levels for PF-05082566 and rituximab;
•
QTc interval;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY DESIGN
This is a Phase 1, open label, multi-center, multiple-dose study of single-agent 
PF-05082566 in patients with advanced solid tumors or B-cell lymphoma, and of 
PF-05082566 in combination with rituximab in patients with relapsed or refractory 
CD20-positive NHL.  Approximately 270 patients are expected to be enrolled in the 
overall study.
There are 2 portions in this clinical study.  Portion A is designed to assess the safety and 
tolerability, PK 
 and to estimate the MTD/pharmacologically active dose and 
determine the RP2D of PF-05082566 administered as a single agent in patients with 
advanced solid tumors or B-cell lymphoma.  Two cohort(s) will be enrolled at clinical sites in 
Japan to evaluate safety, tolerability, and PK profile of PF-05082566 as a single agent in 
Japanese patients.  Portion B is designed to assess the safety and tolerability, PK 
 and 
to estimate the MTD and determine the RP2D of PF-05082566 in combination with 
rituximab in patients with relapsed or refractory CD20-positive NHL.  Acceptable safety of 
the single agent within the first 3 cohorts of Portion A will trigger the initiation of Portion B.  
Portions A and B will then escalate simultaneously and independently of each other. 
Dose Escalation: Portion A 
The criteria for dose escalation in Portion A will be based on the standard 3+3 design for 
dose escalation up to 0.3 mg/kg. For dose escalation above 0.3 mg/kg, doses of 
PF-05082566 will be assigned to each enrolled patient using a Time-to-Event Continual 
Reassessment Method (TITE-CRM) as this method has been found to be practical based on 
experience in Portion B. 
PF-05082566 will be administered in escalating doses with available dose levels including 
the following: 0.006, 0.03, 0.06, 0.12, 0.18, 0.24, 0.30 (using the 3+3 design), and 0.6, 1.2, 
2.4, 5.0, and 10 mg/kg (using the TITE-CRM design) by intravenous (IV) infusion of 1 hour
(-5/+15 min) every 4 weeks.  As of June 2016, the highest planned single-agent dose of
10 mg/kg was tested with no DLTs reported.  Patients tolerated PF-05082566 well at the 
highest planned dose of 10 mg/kg. If a dose reduction is needed for patients being treated 
with 0.6 to 10 mg/kg, a dose reduction may be made from the next highest planned dose level 
to one of the following specific dose levels: 0.45, 0.9, 1.8, 3.6, and 7.5 mg/kg.  In addition, 
these intermediate dose levels may be used for dose escalation if more than 1 DLT is 
observed at the preceding regular dose level. 
Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 Day 1 will start on Day 29.  Patients may continue treatment up to a 
maximum of 2 years from the first dose of study drug, or until one of the patient withdrawal
criteria under Section 6.4 becomes a reason to permanently discontinue study treatment.
Initially, 3 patients will be treated at each dose level.  For the first 3 cohorts 
(PF-05082566 given as a single agent at 0.006, 0.03, or 0.06 mg/kg), there will be a 
minimum 7-day time window between the first dose of a patient and the first dose of the next 
patient in the same cohort.  For all subsequent patients enrolled up to the 0.6 mg/kg dose 
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level, a minimum 72 hour window will apply between first doses. Current study safety data 
indicates that PF-05082566 infusion does not result in clinically significant infusion 
reactions. Therefore, after completion of the 0.6 mg/kg dose level, there will no longer be a 
waiting period between patients in the same dose cohort and in dose expansion cohorts. 
The dosing interval may be reconsidered and amended during the study based on the 
emerging safety and PK/
 data.
Japan Cohort(s) in Portion A:
The Japan cohort(s) will be conducted at Japanese sites following completion of enrollment 
of the dose escalation cohorts in Portion A of this study. Patients enrolled into the Japan 
cohort(s) will receive PF-05082566 administered as a single agent once every four weeks as 
an IV infusion.  Patients enrolled in Japan will follow the same eligibility criteria, study 
procedures (unless otherwise specified), and discontinuation criteria as those patients in the 
dose escalation cohort of Portion A.  The Japan cohort(s) will enroll approximately 9 patients 
in 2 cohorts.  These cohorts will consist of 3 patients at 1 dose level below the MTD and 
6 patients at the MTD based on non-Japanese population in Portion A.
Dose escalation in the Japan cohort(s) will be based on the standard 3+3 dose escalation
design at 2 dose levels, 5.0 mg/kg and 10 mg/kg.  Patients recruited in Japan will be enrolled 
and analysed to confirm safety, tolerability, and PK profile of PF-05082566 in Japanese 
patients. These patients will complete the first 2 cycles of PF-05082566 as a single-agent at 
a dose previously tested in non-Japan cohorts to evaluate potential DLTs. 
The 5 mg/kg dose (every 4 weeks) has been chosen as the starting dosage for the Japan
cohort. 5 mg/kg is well tolerated in a non-Japanese population, and there were no observed 
DLTs in Portion A at 5 mg/kg. PF-05082566 will be administered to 3 Japan cohort patients 
with advanced solid tumors or B cell lymphoma.  After enrollment is complete, safety data 
from at least 2 cycles will be obtained and analyzed.  If the 5 mg/kg dose level is found to be 
safe, escalation to 10 mg/kg dose level will occur.  Lower dose levels may be explored at any 
time during the study if this is clinically and scientifically warranted. Study centers will 
receive a notification if additional dose levels are explored.
Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 Day 1 will start on Day 29.  After completion of Cycle 2, patients will be 
asked to sign an additional consent document for confirmation of the patient’s willingness to 
continue participation in this study before starting Cycle 3. Patients clinically benefiting 
from study treatment will be given the opportunity to continue treatment up to a maximum of 
2 years from the first dose of study drug, or until one of the patient withdrawal criteria under 
Section 6.4 becomes a reason to discontinue study treatment.
Expansion Cohorts: Portion A
As of June 2016, the highest planned single-agent dose of 10 mg/kg PF-05082566 was tested 
with no DLTs reported in Portion A, and as of September 2016, 34 patients with advanced 
solid tumor, including 20 patients with melanoma, who had documented disease progression 
per RECIST v1.1 on a previous immune checkpoint inhibitor therapy (see Section 4.1 for the 
definition of disease that progressed from previous immune checkpoint inhibitor therapy) 
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have been enrolled in the expansion cohorts of Portion A and treated at the 0.24 or 1.2 mg/kg 
dose levels of PF-05082566.  Because the RP2D of PF-05082566 has not yet been 
determined in Portion A, approximately 40 additional patients with melanoma who had 
documented disease progression per RECIST v1.1 on a previous immune checkpoint 
inhibitor therapy will be randomized 2:1:1 to treatment with single agent PF-05082566 at the 
0.6, 0.24, or 1.2 mg/kg dose levels.  The objective of the expansion cohorts is to provide 
additional safety, tolerability, PK/
 and preliminary efficacy data for PF-05082566 in 
order to provide support for the selection of the RP2D. 
 
Dose Escalation: Portion B 
The doses of PF-05082566 will be assigned to each enrolled patient using a TITE-CRM. 
Safety of the single agent within the first 3 cohorts of Portion A will trigger the initiation of 
Portion B.  The initiation of Portion B may occur after all patients in the single-agent 
0.06 mg/kg cohort have completed Cycle 1 and received their second dose.  Enrollment will 
then begin with PF-05082566 at a dose of 0.03 mg/kg and escalating at the same dose 
intervals as listed for Portion A.  PF-05082566 will be given to patients IV (every 4 weeks) 
in combination with rituximab (375 mg/m2, every week x 4 weeks).  Patients clinically 
benefiting from study treatment without unacceptable toxicity, objective disease progression, 
or withdrawal of consent will be given the opportunity to continue treatment up to a 
maximum of 2 years from the first dose of study drug. 
The first dose of PF-05082566 will be given approximately 24 hours after the second weekly 
full dose of rituximab (defined as either the planned dose or in the case of infusion reactions, 
at least 50% of planned rituximab dose; see Section 5 for details).  For the first cohort 
(PF-05082566 given at 0.03 mg/kg) there will be a minimum 7 day window between the first 
dose of PF-05082566 for a patient and the first dose of rituximab for the next patient.  For all 
subsequent dose escalation/de-escalation cohorts, up to 0.6 mg/kg, a minimum 72 hour 
window will apply between the first dose of PF-05082566 for a patient and the first dose of 
rituximab for the next patient in the same cohort. Updated study safety data indicate that 
PF-05082566 infusion does not result in clinically significant infusion reactions. Therefore, 
after completion of the 0.6 mg/kg dose level, there will no longer be a waiting period 
between the first dose of PF-05082566 for a patient and the first dose of rituximab for the 
next patient in the same dose cohort.
Japan will not participate in Portion B until determination of the MTD of PF-05082566 as a 
single agent in Japan cohort.  Following the completion of Japan cohorts in Portion A, the 
combination of PF-05082566 with rituximab may also be tested in order to evaluate the 
safety of the combination therapy in patients enrolled in Japan.  Enrollment of Japan cohort
in Portion B is permitted and is dependent on the progress and status of the ongoing Portion 
B, as well as further development strategy.
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Expansion Cohorts: Portion B
As of June 2016, the highest planned dose of 10 mg/kg PF-05082566 in combination with 
rituximab was tested with no DLTs reported in Portion B, and as of September 2016, 
10 patients with rituximab-refractory FL (see Section 4.1 for definition of FL disease 
refractory to rituximab) and 4 patients with relapsed or refractory DLBCL have been enrolled 
in the expansion cohort of Portion B and treated at the 1.2 mg/kg dose level of PF-05082566.  
Because the RP2D of PF-05082566 administered in combination with rituximab has not yet 
been determined in Portion B, the expansion cohort of Portion B will enroll up to 
100 patients with rituximab-refractory FL who will be treated with rituximab in combination 
with PF-05082566 at the 1.2 mg/kg and, following an assessment of the tolerability, efficacy, 
and PK data collected for the combination of PF-05082566 at 1.2 mg/kg plus rituximab, 
at the 0.24 mg/kg dose level.  In the first cohort (FL-1), up to 20 patients will be treated with 
rituximab in combination with PF-05082566 at 1.2 mg/kg and in the second cohort (FL-2) up 
to 20 patients may receive rituximab in combination with PF-05082566 at 0.24 mg/kg.  The 
PF-05082566 dose level to be administered in the third cohort (FL-3) will be selected based 
on the overall evaluation of tolerability, efficacy, 
 and PK data collected for the 
combination of PF-05082566 plus rituximab in FL-1 and FL-2 (if this cohort is enrolled).  In 
FL-3, approximately 60 patients will receive rituximab in combination with 
PF-05082566 either at the 0.24 or 1.2 mg/kg dose level. The objective of this expansion 
cohort is to provide additional safety, tolerability, PK/
 and preliminary efficacy data for 
PF-05082566 given in combination with rituximab in order to provide support for the 
selection of the RP2D. 
 
 
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SCHEDULE OF ACTIVITIES: 
Table 1.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Escalation Only)
Screen1
CYCLE 1
CYCLE 2-8
>Cycle 822,24,31
End of 
Treatment29
Follow 
up30
Protocol Activity
Within 28 days 
prior to
enrollment
Day
1
Day
8
Day 
15
Day 
22
Day 
1
() 2
Day 
8
() 2
Day 
15
() 2
Day 
22
() 2
Day 1
() 2
Visit Window
Informed Consent2
X
Tumor History3
X
Medical History4
X
Physical Examination5
X
X
X
X
X
ECOG Performance 
Status6
X
X
X
X
Baseline Signs and 
Symptoms7
X
Vital Signs (BP and 
pulse)8
X
X
X
X
X
X
X
X
Safety 
Labs/Measurements
12-Lead ECG9
X
X
X
X
X
X
X
Hematology10
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry11
X
X
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
X
X
X
Urinalysis13
X
X
X
Pregnancy test14
X
X
X
X
X
Hepatitis B and C 
testing [hepatitis B 
surface antigen and core 
antibody; anti-hepatitis 
C antibody]
X
Endocrine function 
assessment15
X
As clinically indicated
LVEF assessment16
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Table 1.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Escalation Only)
Screen1
CYCLE 1
CYCLE 2-8
>Cycle 822,24,31
End of 
Treatment29
Follow 
up30
Protocol Activity
Within 28 days 
prior to
enrollment
Day
1
Day
8
Day 
15
Day 
22
Day 
1
() 2
Day 
8
() 2
Day 
15
() 2
Day 
22
() 2
Day 1
() 2
Registration and 
Treatment 
Registration17
X
Administration of
PF-0508256618
X
X
X
Tumor assessments 
CT or MRI scan or 
equivalent19
X
To be assessed every 8 weeks (1 week) for the first 
10 months on study treatment, then subsequently every 
16 weeks (1 week)
X
X
Other clinical 
assessments
AEs20
Monitored and Recorded Continuously
X
Review 
Prior/Concomitant 
Medication21
X
Monitored and Recorded Continuously
X
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Table 2.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Escalation Only): Pharmacokinetic, 
 Assessments
Cycle 1 and Cycle 2
Cycle 3
Cycle 4
Cycle 
>4
End of 
Treatment29
Follow 
up30
Assessments
[(±) 2 days
for cycles >1]
Day 
1
Day 
3
Day 
8
Day 
15
Day 
22
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
3
Day 
28
Day 1
Blood for PF-05082566 PK22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
 
Blood for Immunogenicity (ADA) 
testing27
X
X
X
X
X
X
X
X
X
 
                 
Footnotes for Schedule of Activities – Portion A (PF-05082566 Alone) Table 1 and Table 2.
*Patients enrolled into the Japan cohort(s) should follow the same schedule of assessments as non-Japanese patients in Portion A dose escalation cohort.
1.
Screening: To be performed within 28 days prior to enrollment (Pfizer signature of the enrollment form).
2.
Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period.  In Japan, after completion of 
cycle 2, patients will be asked to sign an additional consent document for confirmation of the patient’s willingness to continue participation in this study before starting 
cycle 3.
3.
Tumor History: To be collected within 28 days prior to enrollment.  Includes oncology history; information on prior regimens, including dosing and duration of administration 
plus description of best response observed and treatment failure based on Disease Specific Guidelines. 
4.
Medical History: To be collected within 28 days prior to enrollment. Includes history of other diseases (active or resolved) and concomitant illnesses.
5.
Physical Examination: Includes major body systems.  Weight for the purposes of dose calculation must be recorded at Screening and within 7 days pre-dose Day 1 of each 
cycle.  Height will be measured at baseline only. 
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6.
ECOG Performance Status: ECOG performance scale is available in Appendix 4.
7.
Baseline signs and symptoms: Patients will be asked about any signs and symptoms experienced within the past 14 days prior to enrollment.  During trial treatment any new 
or worsened conditions since baseline should be reported on the Adverse Event (AE) CRF.
8.
Vital Signs: Blood pressure and pulse rate will be recorded.
9.
Triplicate 12-Lead electrocardiogram (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.  ECGs will be collected as follows: a) at Screening; b) On Cycle 1 Day 1 (C1D1), at pre-dose, 1.5 hr post start of infusion and 24 hrs post-dose; c) On Cycle 1/ 
Days 8 and 15; d) On Cycles ≥2 Day 1, at 1.5 hr post start of infusion f) at End of Treatment.  If the mean QTc interval is prolonged (>500 msec corrected by Fridericia’s 
formula), then the ECGs should be re-evaluated by a qualified person at the center for confirmation.  Additional triplicate ECGs may be performed as clinically indicated.
10. Hematology: No need to repeat on C1D1 if the screening assessment is performed within 7 days prior to that date.  To be performed weekly.  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
8 for Laboratory Tests list.
11. Blood Chemistry: No need to repeat on C1D1 if the screening assessment is performed within 7 days prior to that date.  To be performed weekly.  See Table 8 for Laboratory 
Tests list.
12. Coagulation: No need to repeat on C1D1 if the screening assessment is performed within 7 days prior to that date.  To be performed weekly for Cycle 1 and on Day 1 for all 
remaining cycles.  See Table 8 for Laboratory Tests list.
13. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick is abnormal.  No need to repeat on C1D1 if the screening assessment is performed within 7 days prior to 
that date.  To be performed at baseline and end of treatment.  See Table 8 for Laboratory Tests list.
14. Serum/Urine Pregnancy Test: For female patients of childbearing potential, who do not fit for the definition of “female patients who are not of childbearing potential” in 
inclusion criterion 11, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting administration of study 
treatment: once at the start of screening and once at the baseline visit, immediately before administration of the first dose of study treatment.  Pregnancy tests will also be 
routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by 
local regulations.
15. Endocrine function assessment during treatment to be performed in cases of suspected hypoadrenalism or hypopituitarism.  See Table 8 for Laboratory Tests list.
16. LVEF assessment: measurement of ejection fraction by echocardiogram (ECHO), multigated acquisition (MUGA) scan, or an equivalent methodology.
17. Registration: Patient number and dose level allocation operated by Pfizer.
18. PF-05082566 administration: PF-05082566 will be administered once in 4 weeks as a 1-hour (-5/+15 min) IV infusion (each cycle =28 days).  Refer to Section 5.4.
19. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Brain scans 
and bone scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease.  Baseline CNS imaging is not required with the exception 
of symptomatic patients to rule out CNS metastases.  CT or MRI scans to be done once every 8 weeks (1 week) for the first 10 months on study treatment, then subsequently 
every 16 weeks (1 week) until objective disease progression.  Confirmation of response (CR/PR) should be done at least 4 weeks after the initial response for patient with 
advanced solid tumors. Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation.  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 16 weeks
(1 week).


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20. AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03. Patients must be followed for AEs for 28 days after the last treatment 
administration or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy in the 
meantime. For serious adverse events (SAE)s, 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.  Serious adverse events occurring to a patient after the active reporting period has 
ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.
21. Concomitant Medications: All concomitant medications including supportive care drugs (eg, Anti-emetic treatment and prophylaxis), and the drugs used to treat AEs or 
chronic diseases should be recorded in the CRF.
22. Blood for PF-05082566 Pharmacokinetics: Blood samples will be collected during Cycle 1 and Cycle 2 on (a) Day 1 at pre-dose, end of infusion, and at 1.5, 2, 6 and 24 hrs
post start of infusion; (b) on Days 3, 8, 15, and 22.  During Cycle 3 on (c) Day 1 at pre-dose, end of infusion, 1.5 and 24 hrs post start of infusion; (d) on Days 8, 15, and 22.  
During Cycle 4 on (e) Day 1 at pre-dose, end of infusion, and at 1.5 hr post start of infusion; (f) on Days 3 and 28 after the last dose administration.  The PK sample for 
Day28 following the Cycle 4 dose of PF-05082566 need not be collected if a patient undergoes PF-05082566 dosing for additional cycles or if the patient starts another cancer 
therapy.  If a patient continues with additional cycles of therapy (up to 2 years), PK samples will be collected pre-dose, end of infusion, and at 1.5 hours post start of infusion 
in each cycle.  Timing of sampling may be modified based on emerging PK data.  For patients ending from the study, a PK sample should be collected at the End of 
Treatment assessment. In Japan, patients will be hospitalized for PK sampling for at least the first 2 days of the first cycle of dosing of PF-05082566.
 
  
 
 
 
 
 
27. Blood for Immunogenicity (ADA) testing: Blood for immunogenicity testing will be collected at a) in Cycle 1 and Cycle 2 Day 1 at pre-dose and Days 8 and 15; b) in 
Cycle 3 at Day 1 pre-dose and Day 15; c) in Cycle 4 at Day 1 pre-dose.  If a patient continues with additional treatment cycles (Cycle >4), ADA samples will be collected at 
pre-dose in the higher cycles.  For patients ending from the study therapy, immunogenicity samples should be collected at the End of Treatment assessment day.  If ADAs are 
detected, additional samples may be collected every 3 months until ADA levels return to baseline.  For patients who remain positive for ADA during the follow-up phase, 
Immunogenicity (ADA) samples should be collected at the same time as disease assessments are being performed until ADA levels return to baseline or until the patient 
enters the survival follow phase. 
29. End of Treatment: To be performed approximately 28 days after the last dose of study treatment.  Obtain these assessments if not completed during the previous week (during 
the previous 6 weeks for tumor assessments).
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30. Follow up period: Patients should be evaluated for serious adverse events up to 60 days after last dose of study treatment.  Patients continuing to experience toxicity at this 
point 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.  Immunogenicity (ADA) samples should be collected beyond 28 days for patients who are positive for ADA (Refer to Footnote 27). During the follow-up phase, 
Immunogenicity (ADA) samples should be collected at the same time as disease assessments are being performed until ADA levels return to baseline or until the patient 
enters the survival follow phase.  Thereafter, 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 16 weeks (±1 week).  Once patients have exhibited disease progression, they will enter into survival follow-up for 
assessment of survival only.  A new anti-cancer therapy will be reported on the CRF.  Follow-up for survival will be conducted every 12 weeks (+/- 4 weeks) for up to 2 years 
from first dose of study treatment for the last enrolled patient (telephone calls acceptable).
31. For patients continuing on study beyond 8 cycles of therapy, continued treatment will be on a reduced visit schedule (Day 1 of each cycle), or as clinically indicated, until 
disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of consent up to a maximum of 2 years from the first dose of study drug.
 
 
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Table 3.
Schedule of Activities: Portion B (PF-05082566 + Rituximab) Assessments (Dose Escalation Only)
Screen1
CYCLE 1
CYCLE 2-835
>Cycle
8 23,26,35
End of 
Treatment32
Follow 
up33
Protocol Activity 
(Cycle Day relative to 
PF-05082566 dosing)
Within 
28 days 
prior to 
enrollment
Day 
(-7)34
Day 
(0)
Day 
1
Day 
7
Day 
14
Day 
22
Day 
1
() 2
Day 
8
() 2
Day 
15
() 2
Day 
22
() 2
Day 1
() 2
Visit Window
Informed Consent2
X
Tumor History3
X
Medical History4
X
Physical 
Examination5
X
X
X
X
X
X
ECOG Performance 
Status6
X
X
X
X
X
Baseline Signs and 
Symptoms7
X
Vital Signs (BP,  
pulse, and body 
temperature)8
X
X
X
X
X
X
X
X
X
X
Safety 
Labs/Measurements
12-Lead ECG9
X
X
X
X
X
X
X
Hematology10
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry11
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
X
X
X
X
X
Urinalysis13
X
X
X
Pregnancy test14
X
X
X
X
X
X
X
Hepatitis B and C 
testing [hepatitis B 
surface antigen and 
core antibody; 
anti-hepatitis C 
antibody]
X
Endocrine function 
assessment15
X
As clinically indicated


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Table 3.
Schedule of Activities: Portion B (PF-05082566 + Rituximab) Assessments (Dose Escalation Only)
Screen1
CYCLE 1
CYCLE 2-835
>Cycle
8 23,26,35
End of 
Treatment32
Follow 
up33
Protocol Activity 
(Cycle Day relative to 
PF-05082566 dosing)
Within 
28 days 
prior to 
enrollment
Day 
(-7)34
Day 
(0)
Day 
1
Day 
7
Day 
14
Day 
22
Day 
1
() 2
Day 
8
() 2
Day 
15
() 2
Day 
22
() 2
Day 1
() 2
LVEF assessment16
X
As clinically indicated
Registration and 
Treatment 
Registration17
X
Administration of 
PF-0508256618
X
X
X
Administration of 
Rituximab19
X
X
X
X
Tumor assessments 
X
CT or MRI scan or 
equivalent20
X
To be assessed approximately every 8 weeks
(1 week) for the first 10 months on study 
treatment, then subsequently every 16 weeks 
(1 week)
X
X
Other clinical 
assessments
AEs21
Monitored and Recorded Continuously
X
Review
Prior/Concomitant 
Medication22
X
Monitored and Recorded Continuously
X
X


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Table 4.
Schedule of Activities: Portion B (PF-05082566 + Rituximab: Dose Escalation Only): Pharmacokinetic, 
 
 
 Assessments
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 
>4
End 
of 
Treat-
ment32
Follow
up33
Assessments
(Cycle Day relative to 
PF-05082566 dosing)
Day
(-7)
Day
(0)
Day 
1
Day 
3
Day 
7
Day 
14
Day 
22
Day 
1
(±)2
Day 
8
(±)2
Day 
15
(±)2
Day 
22
(±)2
Day 
1
(±)2
Day 
22
(±)2
Day 
1
(±)2
Day 
28
(±)2
Day 
1
(±)2
Blood for 
PF-05082566 PK23
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for Rituximab PK24
X
X
X
X
X
X
X
X
X
X
 
 
Blood for 
PF-05082566 Immunogenicity (ADA) 
testing27
X
X
X
X
X
X
X
Blood for Rituximab immunogenicity 
(ADA) testing28
X
X
X
X
X
X
 
 
 
 
Footnotes for Schedule of Activities – Portion B (PF-05082566 + Rituximab) Table 3 and Table 4.
1.
Screening: To be performed within 28 days prior to enrollment (Pfizer signature of the enrollment form).
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: To be collected within 28 days prior to enrollment.  Includes oncology history, information on prior regimens, including dosing and duration of 
administration plus description of best response observed and treatment failure based on Disease Specific Guidelines. 
4.
Medical History: To be collected within 28 days prior to enrollment.  Includes history of other diseases (active or resolved) and concomitant illnesses.
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
Physical Examination: Includes major body systems.  Weight for the purposes of dose calculation must be recorded at Screening and within 7 days at pre-dose on Day 1 of 
each cycle to ensure the patient did not experience either a weight loss or gain >10% from the weight used for the last dose calculation.  For weight change less than 10% the 
decision to recalculate the PF-05082566 dose can be in accordance with institutional practice. If the patient experienced either a weight loss or gain >10% compared to the 
weight used for the last dose calculation, the PF-05082566 dose must be recalculated using the actual weight at that visit.  Height will be measured at baseline only.

ECOG Performance Status: ECOG performance scale is available in Appendix 4.

Baseline signs and symptoms: Patients will be asked about any signs and symptoms experienced within the past 14 days prior to enrollment.  During trial treatment any new 
or worsened conditions since baseline should be reported on the AE CRF page.

Vital Signs: Blood pressure, pulse rate, and body temperature will be recorded.

Triplicate 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.  ECGs will 
be collected as follows: a) at Screening; b) On Day (-7) prior to the dose of Rituximab and at end of infusion; c) On Cycle 1 Day 1 (C1D1), prior to the dose of 
PF-05082566 and 1.5 hours post start of infusion; d) On Cycle 1 Day 14; e) On Cycles ≥2 Day 1 at 1.5 hours post start of infusion and f) at End of Treatment.  If the mean 
QTc interval is prolonged (>500 msec using any correction method), then the ECGs should be re-evaluated by a qualified person at the center for confirmation.  Additional 
ECGs may be performed as clinically indicated.
Hematology: No need to repeat on Cycle 1 Day -7 [C1D(-7)] if the screening assessment is performed within 7 days prior to that date.  To be performed weekly.  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 8 for Laboratory Tests list.
Blood Chemistry: No need to repeat on C1D(-7) if the screening assessment is performed within 7 days prior to that date.  To be performed weekly. See Table 8 for 
Laboratory Tests list.
Coagulation: No need to repeat on C1D(-7) if the screening assessment is performed within 7 days prior to that date.  To be performed weekly for Cycle 1 and on Day 1 for 
all remaining cycles.  See Table 8 for Laboratory Tests list.
Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal. To be performed at screening, Cycle 1 Day 1, and at the end of treatment.  See Table 8 for 
Laboratory Tests list.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, who do not fit for the definition of “female patients who are not of childbearing potential” in 
inclusion criterion 11, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting administration of study 
treatment: once at the start of screening and once at the baseline visit, immediately before administration of the first dose of study treatment.  Pregnancy tests will also be 
routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required 
by local regulations.
Endocrine function assessment during treatment to be performed in cases of suspected hypoadrenalism or hypopituitarism.  See Table 8 for Laboratory Tests list.
LVEF assessment: measurement of ejection fraction by echocardiogram (ECHO), multigated acquisition (MUGA) scan, or an equivalent methodology.
Registration: Patient number and dose level allocation operated by Pfizer.
PF-05082566 administration: PF-05082566 will be administered once in 4 weeks as a 1-hour (-5/+15 min) IV infusion (each cycle =28 days).
Rituximab administration: rituximab (375 mg/m2) will be administered as an IV infusion once weekly for 4 doses during Cycle 1 starting on Cycle 1 Day -7.  Refer to 
Section 5.4 on administration and management of infusion related AEs and to the rituximab package insert.  Also refer to Footnote 1.
Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Brain scans 
will be performed at baseline if disease is suspected and on-study as appropriate to follow disease.  Baseline CNS imaging is not required with the exception of symptomatic 
patients to rule out CNS metastases.  CT or MRI scans to be done once every 8 weeks (1 week) for the first 10 months on study treatment, then subsequently every 


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16 weeks (±1 week) until objective disease progression.  Confirmation of response (CR/PR) is not required per Cheson 2007 response criteria.  Tumor assessment should be 
repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation.  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 16 weeks (±1 week).
21. AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03.  Patients must be followed for AEs for 28 days after the last 
treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy
in the meantime. For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 
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 study drug 
are to be reported to the Sponsor.
22. Concomitant Medications: All concomitant medications including supportive care drugs (eg, Anti-emetic treatment and prophylaxis), and the drugs used to treat AEs or 
chronic diseases should be recorded in the CRF.
23. Blood for PF-05082566 Pharmacokinetics: Blood samples will be collected during Cycle 1 on (a) Day 1 at pre-dose, the end of infusion, and at 1.5, 2, 6 and 24 hrs post start 
of infusion; (b) on Days 3, 7 (matched with rituximab pre-dose PK sample), 14 (matched with rituximab pre-dose PK sample) and 22.  During Cycle 2 on (c) Day 1 at 
pre-dose, end of infusion, and at 1.5 and 24 hrs post start of infusion; (d) on Days 8, 15, and 22.  During Cycle 3 on (e) Day 1 at pre-dose, end of infusion, and at 1.5 hr post 
start of infusion; (f) on Days 22.  During Cycle 4 on (g) Day 1 at pre-dose, end of infusion, and at 1.5 hr post start of infusion; (h) on Day 28 post the Cycle 4 dose.  The PK 
sample for Day 28 following the Cycle 4 dose of PF-05082566 need not be collected if a patient undergoes PF-05082566 dosing for additional cycles or if the patient starts 
another cancer therapy.  If a patient continues with additional cycles of therapy (up to 2 years), PK samples will be collected pre-dose, end of infusion, and at 1.5 hours post 
start of infusion in each cycle.  Timing of sampling may be modified based on emerging PK data.  For patients ending/withdrawing from the study, PK samples should be 
collected at the End of Treatment/Withdrawal assessment day. 
24. Blood for Rituximab Pharmacokinetics (NOTE: All days are numbered relative to PF-05082566 dosing): Blood samples will be collected on (a) Day (-7) at pre-dose and at 
15 min post end of infusion, 6 and 24 hrs post start of infusion; (b) on Day (0) at pre-dose and 15 min post end of infusion; (c) on Cycle 1 Day 1 at 2 and 24 hrs post start of 
infusion of PF-05082566; (d) Cycle 1 Day 3; (e) on Cycle 1 Day 7 at pre-dose and 15 min post end of infusion; (f) on Cycle 1 Day 14 at pre-dose and 15 min post end of 
infusion; (g) on Cycle 1 Day 22; (h) on Cycle 2 Day 1 before the dose of PF-05082566; (i) on Cycle 2 Day 15.  Timing of sampling may be modified based on emerging PK 
data.  For patients ending/withdrawing from the study, PK samples should be collected at the End of treatment/Withdrawal assessment day.  Note that whenever rituximab 
PK samples are collected on days when PF-05082566 PK samples are collected, they should be time matched to avoid multiple sticks.
27. Blood for PF-05082566 Immunogenicity (ADA) testing: Blood for immunogenicity testing will be collected at a) All Cycles on Day 1 prior to the dosing of PF-05082566.  
If a patient undergoes additional treatment cycles (Cycle >4), ADA samples will be collected at pre-dose in the higher cycles.  For patients ending from the study, 
immunogenicity samples should be collected at the End of Treatment assessment day.  For patients who are remaining positive for ADA during the follow-up phase, 
Immunogenicity (ADA) samples should be collected at the same time as disease assessments are being performed until ADA levels return to baseline or until the patient 
enters the survival follow phase. 
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28. Blood for Rituxim
 Immunogenicity (ADA) testing (NOTE: All days are numbered relative to PF-05082566 dosing): Blood for immunogenicity testing will be collected at 
a) Cycle 1 On Day -7, Day 0, Day 7 and Day 14 prior to the dosing of Rituximab; (b) On Cycle 2 Day 15.
 
 
.
32. End of Treatment: To be performed approximately 28 days after the last dose of study treatment.  Obtain these assessments if not completed during the previous week 
(during the previous 6 weeks for tumor assessments).
33. Follow up period: Patients should be evaluated for adverse events up to 60 days after last dose of study treatment.  Patients continuing to experience toxicity at this point 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.  
Immunogenicity (ADA) samples should be collected beyond 28 days for patients who are positive for ADA (Refer to Footnote 27).  During the follow-up phase, 
Immunogenicity (ADA) samples should be collected at the same time as disease assessments are being performed until ADA levels return to baseline or until the patient 
enters the survival follow phase.  Thereafter, 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 16 weeks (±1 week).  Once patients have exhibited disease progression, they will enter into survival 
follow-up for assessment of survival only.  A new anti-cancer therapy will be reported on the CRF.  Survival follow-up will be conducted within 12 weeks (+/- 4 weeks) 
from the last survival follow-up for up to 2 years from first dose of study treatment for the last enrolled patient (telephone calls acceptable).
34. For infusion reactions to rituximab where a partial dose (<50% of the full dose) is administered, either the Day -7 dose OR the Day 0 administration of Cycle 1 and the 
associated procedures may be repeated one time based on the rituximab label guidelines, local practice, and eligibility for retreatment as detailed in Section 5.4.
35. For patients continuing on study beyond 8 cycles of therapy, continued treatment will be on a reduced visit schedule (Day 1 of each cycle), or as clinically indicated, until 
disease progression, unacceptable toxicity, or withdrawal of consent up to a maximum of 2 years from the first dose of study drug.
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Table 5.
Schedule of Activities for Expansion Cohorts (Portions A and B)
Screen1
CYCLE 1
CYCLE 2
End of 
Treatment2
Follow 
up3
Protocol Activity 
(Cycle Day relative to 
PF-05082566 dosing)
Within 28 days 
prior to
randomization 
OR enrollment
Day -74
(Portion 
B  Only)
Day 04
(Portion 
B  Only)
Day 1
Day 7
(Portion B  
Only)
Day 14
(Portion B  
Only)
Day 1
() 2
Informed Consent
X
Tumor History5
X
Medical History6
X
Physical Examination7
X
X
X
X
X
ECOG Performance Status8
X
X
X
X
X
Baseline Signs and Symptoms9
X
Vital Signs (BP, pulse, body 
temperature for Portion B)10
X
X
X
X
X
X
X
X
Neurological Examination 
(Portion B)29
As clinically indicated
Central histopathology review of FL 
diagnosis (Portion B)30
X
Safety Labs /Measurements
12-Lead ECG11
X
X
X
X
(C2, C3, C4)
X
Hematology and Blood Chemistry12
X
X
X
X
X
X
X
X
Coagulation13
X
X
X
X
X
X
X
X
Urinalysis14
X
X
X
Pregnancy test14
X
X
X
X
Hepatitis B and C testing [hepatitis B 
surface antigen and core antibody; 
anti-hepatitis C antibody]
X
Endocrine function assessment16
X
X
X
LVEF assessment17
X
As clinically indicated
Registration and Treatment 
Registration18
X
X
Administration of  PF-0508256619
X
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Table 5.
Schedule of Activities for Expansion Cohorts (Portions A and B)
Screen1
CYCLE 1
CYCLE ≥2
End of 
Treatment2
Follow 
up3
Protocol Activity 
(Cycle Day relative to 
PF-05082566 dosing)
Within 28 days 
prior to
randomization 
OR enrollment
Day -74
(Portion 
B  Only)
Day 04
(Portion 
B  Only)
Day 1
Day 7
(Portion B  
Only)
Day 14
(Portion B  
Only)
Day 1
(±) 2
Administration of Rituximab (Portion 
B)20
X
X
X
X
X21
Tumor assessments 
CT or MRI scan or equivalent22
X
To be assessed every 8 weeks (±1 week) for the first 10 months on 
study treatment, then subsequently every 16 weeks (±1 week)
X
X
Bone marrow (BM) biopsy or 
aspirate32
X
To be assessed in patients with potential CR by radiological 
assessments to determine the response category
Other clinical assessments
AEs23
Monitored and Recorded Continuously
X
Review Prior/Concomitant 
Medication24
X
Monitored and Recorded Continuously
X
X
 
 
 
 
 
Footnotes for Schedule of Activities – Expansion Cohorts (Portions A and B) Table 5.
1.
Screening: To be performed within 28 days prior to randomization for the randomized cohorts and to enrollment (Pfizer signature of the enrollment form) for the 
non-randomized cohorts.
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
End of Treatment: To be performed approximately 28 days after the last dose of study treatment.  Obtain these assessments if not completed during the previous week 
(during the previous 6 weeks for tumor assessments).

Follow-up period: Patients should be evaluated for adverse events up to 60 days after last dose of study treatment.  Patients continuing to experience toxicity at this point 
following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the Investigator, that 
no further improvement is expected.  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 16 weeks (1 week).  Once patients have exhibited disease progression, they will enter into survival follow-up for 
assessment of survival only.  Any new anti-cancer therapy will be reported on the CRF.  Survival follow-up will be conducted every 12 weeks (+/- 4 weeks) for survival 
status and subsequent anti-cancer treatment, up to 2 years from the first dose of study treatment for the last treated patient (for the non-randomized cohorts) or from the 
randomization date for the last randomized patient (for the randomized cohorts).  Telephone calls are acceptable. 

Portion B only.  For infusion reactions to rituximab where a partial dose (<50% of the full dose) is administered, either the Day -7 dose OR the Day 0 administration of 
Cycle 1 and the associated procedures may be repeated one time based on the rituximab label guidelines, local practice, and eligibility for retreatment as detailed in 
Section 5.4.

Tumor History: To be collected within 28 days prior to randomization for the randomized cohorts and to enrollment for the non-randomized cohorts.  Includes oncology 
history, information on prior regimens, including dosing and duration of administration plus description of best response observed and treatment failure based on Disease 
Specific Guidelines.  For patients enrolled in Portion B includes current Ann Arbor staging (Lister et al. 1989)32, and for patients with FL, current FL grade and current 
Follicular Lymphoma International Prognostic Index (FLIPI) score (Solal-Celigny et al. 2004)31.

Medical History: To be collected within 28 days prior to randomization for the randomized cohorts and to enrollment for the non-randomized cohorts. Includes history of 
other diseases (active or resolved) and concomitant illnesses.

Physical Examination: Includes major body systems.  Weight for the purposes of dose calculation must be recorded at Screening and within 7 days at pre-dose on Day 1 of 
each cycle to ensure the patient did not experience either a weight loss or gain >10% from the weight used for the last dose calculation.  For weight change less than 10% the 
decision to recalculate the PF-05082566 dose can be in accordance with institutional practice. If the patient experienced either a weight loss or gain >10% compared to the 
weight used for the last dose calculation, the PF-05082566 dose must be recalculated using the actual weight at that visit.  Height will be measured at baseline only.

ECOG Performance Status: ECOG performance scale is available in Appendix 4.

Baseline signs and symptoms: Patients will be asked about any signs and symptoms experienced within the past 14 days prior to randomization for the randomized cohorts 
and to enrollment for the non-randomized cohorts.  During trial treatment, any new or worsened conditions since baseline should be reported on the AE CRF page.
Vital Signs: Blood pressure, body temperature (only for patients in Portion B), and pulse rate will be recorded.
Triplicate 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.  ECGs will 
be collected as follows: a) at Screening; b) On Day -7, prior to the dose of Rituximab and at end of infusion (Portion B only); c) On Cycle 1 Day 1 (C1D1), prior to the dose 
of PF-05082566 and 1.5 hours post start of infusion; d) On Cycle 2-4 Day 1 at 1.5 hours post start of infusion; and e) at End of Treatment.  Additional triplicate ECGs may 
be performed as clinically indicated.  If the QTc interval is prolonged (>500 msec by any correction method), then the ECGs should be re-evaluated by a qualified person at 
the center for confirmation.  A subset of approximately 30 FL patients enrolled at selected sites in the FL-3 expansion cohort of Portion B will be assessed using an ECG 
machine provided by central vendor to allow central review of ECG.
Hematology and Chemistry: No need to repeat on C1D1 for Portion A or Cycle 1 Day -7 [C1D(-7)] for Portion B if the screening assessment is performed within 7 days 
prior to that date.  To be performed weekly only for portion B patients during Cycle 1, and on Day 1 for all subsequent cycles.  See Table 8 for Laboratory Tests list.
Coagulation: No need to repeat on C1D1 (Portion A) or C1D(-7) (Portion B) if the screening assessment is performed within 7 days prior to that date.  To be performed 
weekly only for portion B patients during Cycle 1, and on Day 1 of all subsequent cycles.  See Table 8 for Laboratory Tests list.


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14. Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D1 (Portion A) if the screening assessment is performed within 
7 days prior to that date.  To be performed at screening, Cycle 1 Day 1, and at the end of treatment.  See Table 8 for Laboratory Tests list.
15. Serum/Urine Pregnancy Test: For female patients of childbearing potential, who do not fit for the definition of “female patients of nonchildbearing potential” in inclusion 
criterion 11, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting administration of study treatment: 
once at the start of screening and once at the baseline visit, immediately before administration of the first dose of study treatment.  Pregnancy tests will also be routinely 
repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or when potential pregnancy 
is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local 
regulations.
16. Endocrine function assessment: thyroid function testing should be performed at screening, on Cycle 3 Day 1, every 12 week thereafter, and at the end of treatment; ACTH
and cortisol levels should be assessed in cases of suspected hypoadrenalism or hypopituitarism.  See Table 8 for Laboratory Tests list.
17. LVEF assessment: measurement of ejection fraction by echocardiogram (ECHO), multigated acquisition (MUGA) scan, or an equivalent methodology.
18. Registration: In the randomized cohorts of Portion A for patients with advanced melanoma, patient enrollment and assignment of PF-05082566 dose level is managed 
through the use of an interactive response technology (IRT) system.  In the non-randomized cohorts of Portion A and Portion B patient number and dose level allocation is 
operated by Pfizer. 
19. PF-05082566 administration: PF-05082566 will be administered once every 4 weeks as a 1 hour (-5/+15 min) IV infusion (each cycle =28 days).  For the randomized 
cohorts in Portion A patients will be randomized 2:1:1 to the 0.6 mg/kg, 1.2 mg/kg and 0.24 mg/kg dose levels of PF-05082566, respectively.  Patients enrolled in the 
non-randomized cohorts of Portion A and Portion B will receive either the 1.2 mg/kg or 0.24 mg/kg dose level of PF-05082566. 
20. Rituximab administration (Portion B only): rituximab (375 mg/m2) will be administered as an IV infusion once weekly for 4 doses during Cycle 1 starting on Cycle 
1 Day -7. Refer to Section 5.4 of the protocol on administration and management of infusion related AEs and to the rituximab package insert. 
21. In Portion B only, patients may have received additional doses of rituximab (375 mg/m2) starting at Cycle 4, in accord with the local and institutional Standard of Care, and 
at the discretion of the investigator.  A single dose of rituximab will be administered on Day 0 starting on Cycle 4 and will be repeated every 2 cycles up to a maximum of 
4 additional doses (up to Cycle 10 Day 0).
22. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  Brain scans 
and will be performed at baseline for patients with CNS disease or if disease is suspected, and on study as appropriate to follow disease.  Baseline CNS imaging is not 
required unless to confirm stability of existing CNS metastases or for symptomatic patients to rule out CNS metastases.  Bone scans will be performed at baseline if disease
is suspected only for patients enrolled in Portion A, and on study (every 16 weeks ±1 week) as appropriate to follow disease. CT or MRI scans to be done once every 
8 weeks (±1 week) for the first 10 months on study treatment, then subsequently every 16 weeks (±1 week) until objective disease progression.  Confirmation of response 
(CR/PR) should be done at least 4 weeks after the initial response, per RECIST v1.1
  Confirmation of response 
(CR/PR) is not required for patients with NHL per Cheson 2007 response criteria.  Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks 
have passed since the last evaluation.  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 16 weeks (±1 week).  All radiographic images from patients with rituximab refractory FL enrolled in the expansion 
cohorts Portion B must be collected and sent to a central radiology laboratory for potential future independent review.  See the study manual for more details
23. AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03.  Patients must be followed for AEs for 28 days after the last 
treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 28 days should the patient commence another anticancer therapy 
in the meantime.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure and/or receiving investigational product, through and including 
60 calendar days after the last administration of the investigational product.  SAEs experienced by a patient after the active reporting period has ended should be reported to 
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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 study 
drug are to be reported to the Sponsor.
24. Concomitant Medications: All concomitant medications including supportive care drugs (eg, Anti emetic treatment and prophylaxis), and the drugs used to treat AEs or 
chronic diseases should be recorded in the CRF.
30. Central Histopathology Review of FL Diagnosis (Portion B only): Slides from the archival (tissue collected within the last 6 months) OR a baseline (tissue collected de novo
during the screening period prior to the first dose of PF-05082566) tumor biopsy must be sent to a central pathology laboratory for independent review.  Confirmation of the 
FL diagnosis is not required for patient enrollment.  See the study manual for more details.
32. Bone marrow (BM) biopsy or aspirate: Required for patients with potential CR by radiological assessments to determine the response category.
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Table 6.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Expansion Cohorts): Pharmacokinetic assessments
Cycle 1
Cycle 2 and 3
Cycle 4
Cycle ≥5
End of 
Treatment
Assessments
[() 2 days
for cycles >1]
Day 
1
Day 
7
Day 
14
Day 
1
Day 
1
Day 
7
Day 
14
Day 1
Blood for PF-05082566 PK1
X
X
X
X
X
X
X
X
(every 
4 cycles)
X
Blood for Immunogenicity 
(ADA) testing2
X
X
X
X
(every 
4 cycles)
X
Blood for PF-05082566 Pharmacokinetics: Blood samples will be collected for at least 5 patients in each dose expansion cohort with the following schedule: during 
Cycle 1 on (a) Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hrs post start of infusion; (b) 1 sample on Days 7 and 14, respectively.  During Cycle 2 and Cycle 
3 on (c) Day 1 at pre-dose, and end of infusion.  During Cycle 4 on (d) Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hrs post start of infusion; (e) 1 sample on 
Days 7 and 14, respectively.  After Cycle 4, PK samples will be collected on Day 1 at pre dose every 4 cycles.  For the remaining patients, PK samples will be collected 
on Day 1 of Cycles 1 to 4 at pre-dose and end of infusion.  After Cycle 4, PK samples will be collected on Day 1 at pre-dose every 4 cycles.  A PK sample should be 
collected at the End of Treatment assessment.  In Japan, patients will be hospitalized for PK sampling for at least the first two days of the first cycle of dosing of 
PF-05082566.
Blood for Immunogenicity (ADA) testing: Blood for immunogenicity testing will be collected at a) Day 1 at pre-dose from Cycle 1 to Cycle 4; b) after Cycle 4, ADA 
samples will be collected on Day 1 at pre-dose every 4 cycles.  Immunogenicity samples should be collected at the End of Treatment assessment day.


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Table 7.
Schedule of Activities: Portion B (PF-05082566 + Rituximab: Dose Expansion): Pharmacokinetic Assessments
Cycle 1
Cycle 
2 and 3
Cycle 4
Cycle ≥5
End of 
Treatment
Assessments
(Cycle Day relative to 
PF-05082566 dosing)
Day
(-7)
Day
(0)
Day 
1
Day 
7
Day 
14
Day 1
Day 
1
Day 
7
Day
14
Day 1
Blood for 
PF-05082566 PK1
X
X
X
X
X
X
X
X
(every 4 cycles)
X
Blood for Rituximab PK2
X
X
X
X
X
X
(C2 only)
X
Blood for 
PF-05082566 Immunogeni
city (ADA) testing3
X
X
X
X
(every 4 cycles)
X
Blood for Rituximab 
immunogenicity (ADA) 
testing4
X
X
X
X
X
(C2 only)
X

Blood for PF-05082566 Pharmacokinetics: Blood samples will be collected for at least 5 patients in each dose expansion cohort (dosed with PF-05082566 at 1.2 mg/kg OR 
0.24 mg/kg) with the following schedule: during Cycle 1 on (a) Day 1 at pre-dose, end of infusion, and at 2, 6 and 24 hr post start of infusion; (b) 1 sample on Days 7 and 14, 
respectively.  During Cycle 2 and Cycle 3 on (c) Day 1 at pre-dose, end of infusion.  During Cycle 4 on (d) Day 1 at pre-dose, end of infusion, and at 2, 6 and 24 hr post start 
of infusion; (e) 1 sample on Days 7 and 14, respectively.  After Cycle 4, PK samples will be collected on Day 1 at pre-dose every four cycles.  For the remaining patients, PK 
samples will be collected on Day 1 of Cycles 1 to 4 at pre-dose and end of infusion.  After Cycle 4, PK samples will be collected on Day 1 at pre-dose every 4 cycles.  A PK 
sample should be collected at the End of Treatment assessment. 

Blood for Rituximab Pharmacokinetics (NOTE: All days are numbered relative to PF-05082566 dosing): Blood samples will be collected for at least 5 patients enrolled in
the dose expansion cohort dosed with PF-05082566 at 1.2 mg/kg on (a) Day -7) and Day (0) at pre- dose and end of infusion of rituximab (b) on Cycle 1 Day 1 at 2 and 
24 post start of infusion of PF-05082566; (c) on Cycle 1 Day 7 and Day 14 at pre-dose and end of infusion of rituximab; (f) 1 sample on Cycle 2 Day 1 before the dose of 
PF-05082566; PK samples should be collected at the End of treatment/Withdrawal assessment day.  For the remaining patients, PK samples for rituximab will NOT be 
collected.  Note that whenever rituximab PK samples are collected on days when PF-05082566 PK samples are collected, they should be time matched to avoid multiple 
sticks. 

Blood for PF-05082566 Immunogenicity (ADA) testing: Blood for immunogenicity testing will be collected at a) Day 1 at pre-dose from Cycle 1 to Cycle 4 b) after Cycle 4, 
ADA samples will be collected on Day 1 at pre-dose every four cycles (Cycle 8, Cycle 12, etc.).  Immunogenicity samples should be collected at the End of Treatment 
assessment day. 
4.
Blood for Rituximab Immunogenicity (ADA) testing (NOTE: All days are numbered relative to PF-05082566 dosing): Blood for immunogenicity testing will be collected at 
a) Cycle 1 On Day (-7), Day 0, Day 7 and Day 14 prior to the dosing of rituximab; (b) On Cycle 2 Day 1 prior to the dosing of PF-05082566; (d) end of treatment.


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Table 8
Safety Laboratory Tests
SAFETY LABORATORY REQUIREMENTS 
- May be performed up to 48 hours prior to scheduled cycle Day 1 visits to facilitate 
availability of results to the investigator at the time of the clinic visit.
Assessments
Hematology Panel:
Chemistry Panel:
Absolute Neutrophil Count
Sodium
Hemoglobin
Potassium
Calcium
Platelet Count
Creatinine
WBC with differential (5-part if available)
Albumin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Glucose
Phosphorus
Magnesium
Bilirubin: total
Blood urea nitrogen (BUN)
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Total protein
Uric acid (or urate)
Coagulation Panel: international normalized ratio 
(INR) or prothrombin time (PT), Partial 
thromboplastin time (PTT)
Hepatitis Screening: hepatitis B surface 
antigen and core antibody; anti-hepatitis C 
antibody.


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Table 8
Safety Laboratory Tests
SAFETY LABORATORY REQUIREMENTS 
- May be performed up to 48 hours prior to scheduled cycle Day 1 visits to facilitate 
availability of results to the investigator at the time of the clinic visit.
Assessments
Urinalysis: measurement of pH, specific gravity, 
protein/albumin, glucose, blood/hemoglobin, 
ketones/acetone, Urine dipstick for urine protein: if 
positive collect 24-hr and microscopic (Reflex 
Testing), Urine dipstick for urine blood: if positive 
collect a microscopic (Reflex Testing). No need to 
repeat on C1D1 if baseline assessment performed 
within 7 days prior to that date. 
Pregnancy Test (serum or urine): Conducted for 
women of childbearing potential only.
Endocrine Function Assessments: 
baseline assessments including but not 
limited to: TSH, Free T4. In the presence 
of clinical suspicion of hypopituitarism or 
hypoadrenalism, laboratory testing should 
include one or more of the following: TSH, 
ACTH, and cortisol levels before and 
30-60 minutes after corticotropin 
stimulation.  


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................53
LIST OF FIGURES .................................................................................................................53
APPENDICES .........................................................................................................................54
1. INTRODUCTION ...............................................................................................................55
1.1. Mechanism of Action/Indication.............................................................................55
1.2. Background and Rationale ......................................................................................55
1.2.1. Scientific Rationale: Target Biology and Mechanism of Action................55
1.2.2. Pre-Clinical Development of PF-05082566 ...............................................56
1.2.2.1. In Vitro Data..............................................................................56
1.2.2.2. In Vivo Data: Functional Activity of PF-05082566..................57
1.2.2.3. Anti-Tumor Activity of PF-05082566 ......................................58
1.2.2.4. Combination Studies .................................................................58
1.4. Study Rationale .......................................................................................................62
1.5. Summary of Benefit/Risk Assessment....................................................................63
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................64
2.1. Objectives................................................................................................................64
2.1.1. Primary Objective – Dose Escalation Cohorts ...........................................64
2.1.2. Secondary Objectives – Dose Escalation Cohorts......................................64
2.1.4. Primary Objective – Expansion Cohorts ....................................................65
2.1.5. Secondary Objectives – Expansion Cohorts...............................................65
2.2. Endpoints.................................................................................................................66
2.2.1. Primary Endpoint – Dose Escalation Cohorts ............................................66
2.2.2. Secondary Endpoints – Dose Escalation Cohorts.......................................66
2.2.4. Primary Endpoint – Expansion Cohorts .....................................................68
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2.2.5. Secondary Endpoints – Expansion Cohorts................................................68
3. STUDY DESIGN.................................................................................................................70
3.1. Study Overview.......................................................................................................70
3.1.1. Portion A Expansion Cohorts.....................................................................71
3.1.2. Portion B Expansion Cohorts .....................................................................72
3.1.3. Study Treatment Duration ..........................................................................72
3.2. Starting Dose...........................................................................................................73
3.2.1. Portion A.....................................................................................................73
3.2.1.1. Japan cohort(s) in Portion A......................................................73
3.2.2. Portion B.....................................................................................................73
3.3. Criteria for Dose Escalation ....................................................................................73
3.3.1. Portion A (Single Agent PF-05082566 ) ....................................................73
3.3.1.1. Japan cohort(s) in Portion A (PF-05082566 as a Single
Agent)................................................................................................75
3.3.2. Portion B (PF-05082566 + Rituximab) ......................................................76
3.4. DLT Definition........................................................................................................79
3.5. MTD Definition (Portion A and Portion B)............................................................80
3.6. RP2D (Portions A and B)........................................................................................80
4. PATIENT SELECTION......................................................................................................80
4.1. Inclusion Criteria.....................................................................................................80
4.2. Exclusion Criteria....................................................................................................82
4.3. Life Style Guidelines...............................................................................................84
4.4. Sponsor Qualified Medical Personnel.....................................................................85
5. STUDY TREATMENTS.....................................................................................................85
5.1. Allocation to Treatment ..........................................................................................87
5.1.1. Allocation to Treatment for Patients Enrolled in the Randomized 
Expansion Cohorts of Portion A......................................................................87
5.1.2. Allocation to Treatment for Patients Enrolled in the Non 
Randomized Expansion Cohorts of Portion A and Portion B..........................88
5.2. Patient Compliance .................................................................................................88
5.3. Investigational Product Supplies.............................................................................88
5.3.1. Dosage Form(s) and Packaging..................................................................88
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5.3.1.1. PF-05082566 .............................................................................88
5.3.1.2. Rituximab..................................................................................89
5.3.2. Preparation and Dispensing........................................................................89
5.4. Administration.........................................................................................................89
5.4.1. Recommended Dose Modifications for PF-05082566 ...............................91
5.4.2. Dosing Interruptions for PF-05082566.......................................................91
5.4.3. Dose Delays for PF-05082566....................................................................92
5.4.4. Dose Modifications for PF-05082566 ........................................................92
5.5. Investigational Product Storage ..............................................................................93
5.6. Investigational Product Accountability...................................................................94
5.6.1. Destruction of Investigational Product Supplies ........................................94
5.7. Concomitant Medication(s).....................................................................................94
5.7.1. Other Anticancer or Experimental Drugs...................................................94
5.7.2. Supportive Care ..........................................................................................94
5.7.3. Hematopoietic Growth Factors...................................................................95
5.7.4. Anti-Inflammatory Therapy........................................................................95
5.7.5. Corticosteroids............................................................................................95
5.7.6. Surgery........................................................................................................95
5.7.7. Radiation Therapy ......................................................................................95
6. STUDY PROCEDURES .....................................................................................................95
6.1. Screening.................................................................................................................96
6.2. Treatment Period.....................................................................................................96
6.3. Follow-up Visit .......................................................................................................96
6.4. Patient Withdrawal..................................................................................................96
7. ASSESSMENTS..................................................................................................................98
7.1. Safety Assessment...................................................................................................98
7.1.1. Pregnancy Testing ......................................................................................98
7.1.2. Adverse Events...........................................................................................98
7.1.2.1. Adverse Events of Special Interest............................................99
7.1.3. Laboratory Safety Assessments..................................................................99
7.1.4. Vital Signs and Physical Examinations......................................................99
7.1.5. ECG Assessments.......................................................................................99


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7.2. Pharmacokinetics Assessments.............................................................................100
7.2.1. Portion A: Single Agent PF-05082566 (Dose Escalation, and Japan 
Cohort(s)).......................................................................................................100
7.2.2. Portion B: PF-05082566 + Rituximab (Dose Escalation) ........................101
7.2.2.1. PF-05082566 ...........................................................................101
7.2.2.2. Rituximab................................................................................101
7.2.3. Dose Expansion Cohorts – Portion A and Portion B................................102
7.2.3.1. PF-05082566 PK Sampling for Dose Expansion Cohorts 
(Portions A and B)...........................................................................102
7.2.3.2. Rituximab PK Sampling for Dose Expansion Cohort 
(Portion B Only)..............................................................................103
 
 
7.3.3. Immunogenicity Assessments ..................................................................105
7.3.3.1. Portion A: Single Agent PF-05082566 (Dose Escalation 
and Japan cohort(s)..........................................................................105
7.3.3.2. Portion B: PF-05082566 + Rituximab (Dose Escalation).......105
7.3.3.3. Immunogenicity Assessments for Expansion Cohorts 
(Portion A and Portion B)................................................................106
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8. ADVERSE EVENT REPORTING....................................................................................110
8.1. Adverse Events......................................................................................................110
8.2. Reporting Period ...................................................................................................110
8.3. Definition of an Adverse Event.............................................................................110
8.4. Abnormal Test Findings........................................................................................111
8.5. Serious Adverse Events.........................................................................................112
8.5.1. Protocol-Specified Serious Adverse Events .............................................112
8.5.2. Potential Cases of Drug-Induced Liver Injury..........................................112
8.6. Hospitalization ......................................................................................................113
8.7. Severity Assessment..............................................................................................115
8.8. Causality Assessment............................................................................................115
8.9. Exposure During Pregnancy..................................................................................115
8.10. Occupational Exposure .......................................................................................117
8.11. Withdrawal Due to Adverse Events (See also the section on Patient 
Withdrawal).............................................................................................................117
8.12. Eliciting Adverse Event Information ..................................................................117
8.13. Reporting Requirements......................................................................................117
8.13.1. Serious Adverse Event Reporting Requirements ...................................117
8.13.2. Non-Serious Adverse Event Reporting Requirements ...........................118
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............118
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................118
9.1. Analysis Sets .........................................................................................................118
9.2. Statistical Methods for Dose Allocation: TITE-CRM ..........................................119
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9.3. Sample Size Determination...................................................................................122
9.4. Efficacy Analysis ..................................................................................................123
9.5. Analysis of Other Endpoints .................................................................................124
9.5.1. Analysis of Pharmacokinetics...................................................................124
9.5.1.1. Single- and Multiple-Dose PF-05082566 and Rituximab 
PK Analysis.....................................................................................124
9.5.1.3. Analysis of Immunogenicity Data...........................................124
9.6. Safety Analysis......................................................................................................126
9.6.1. Analysis of Primary Endpoint in the Dose Escalation Cohorts................126
9.6.2. Analysis of Secondary Safety Endpoints..................................................126
9.7. Data Safety Monitoring Committee ......................................................................128
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................128
11. DATA HANDLING AND RECORD KEEPING ...........................................................128
11.1. Case Report Forms/Electronic Data Record .......................................................128
11.2. Record Retention.................................................................................................129
12. ETHICS............................................................................................................................129
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........129
12.2. Ethical Conduct of the Study ..............................................................................130
12.3. Patient Information and Consent.........................................................................130
12.4. Patient Recruitment.............................................................................................130
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................130
13. DEFINITION OF END OF TRIAL.................................................................................131
13.1. End of Trial in a Member State...........................................................................131
13.2. End of Trial in all Participating Countries ..........................................................131
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................131
15. PUBLICATION OF STUDY RESULTS........................................................................131
15.1. Communication of Results by Pfizer ..................................................................131
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15.2. Publications by Investigators ..............................................................................132
16. REFERENCES ................................................................................................................134
LIST OF TABLES
Table 1.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Escalation 
Only).....................................................................................................................26
Table 2.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Escalation
Only): Pharmacokinetic,
Table 3.
Schedule of Activities: Portion B (PF-05082566 + Rituximab) Assessments 
(Dose Escalation Only).........................................................................................32
Table 4.
Schedule of Activities: Portion B (PF 05082566 + Rituximab: Dose 
Escalation Only): Pharmacokinetic
Table 5.
Schedule of Activities for Expansion Cohorts (Portions A and B) ......................38
Table 6.
Schedule of Activities: Portion A (PF-05082566 Alone: Dose Expansion 
Cohorts): Pharmacokinetic assessments...............................................................43
Table 7.
Schedule of Activities: Portion B (PF-05082566 + Rituximab: Dose 
Expansion): Pharmacokinetic Assessments..........................................................44
Table 8
Safety Laboratory Tests........................................................................................45
Table 9.
In Vitro Properties of PF-05082566 .....................................................................57
Table 10.
PF 05082566 Presentations to be Administered in the Expansion Cohorts .........89
Table 11.
Available Dose Levels for PF-05082566 (mg/kg)................................................93
Table 12.
Objective Response Status at each Evaluation...................................................144
Table 13.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................145
Table 14.
Overall Response Derived from Changes in Target, Non-Target and New 
Lesions................................................................................................................153
LIST OF FIGURES
Figure 1.
Effect of PF 05082566 on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model .............................................................................................58
Figure 2.
Combinatorial Efficacy of 4 1BB and CD20 Surrogate mAbs in 
Lymphoma Models...............................................................................................59
Figure 3.
Study Design of the Expansion Cohort of Portion A ...........................................71
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Figure 5.
Example Plot of Prior Dose-Toxicity Curve ......................................................121
APPENDICES
Appendix 1. Abbreviations....................................................................................................137
Appendix 2. Determination of Efficacy – Solid Tumors.......................................................141
Appendix 3. Determination of Efficacy – Non-Hodgkin’s Lymphoma ................................146
Appendix 4. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............150
 
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1. INTRODUCTION
This is the first-in-patient study of PF-05082566, also known as utomilumab, designed to 
evaluate the safety, pharmacokinetics (PK) 
 of 
PF-05082566 administered IV as a single-agent or in combination with rituximab.
1.1. Mechanism of Action/Indication
PF-05082566 is a novel fully human IgG2 monoclonal antibody (mAb) agonist of 4-1BB 
(CD137, TNFRSF9), an inducible costimulatory receptor expressed on activated lymphocyte 
cells, being developed for cancer therapy.  Stimulation of the immune response by a 4-1BB 
agonist has the potential to enhance anti-tumor responses, as a single-agent or in combination 
with therapeutic mAbs that have the potential to induce ADCC.  In this study, 
PF-05082566 as a single-agent is under investigation for the treatment of patients with 
advanced solid tumor malignancies or B-cell lymphoma (Portion A) and PF-05082566 in 
combination with rituximab is under investigation for the treatment of patients with relapsed 
or refractory CD20-positive non-Hodgkin’s lymphoma (NHL; Portion B).
1.2. Background and Rationale
1.2.1. Scientific Rationale: Target Biology and Mechanism of Action
4-1BB (CD137, TNFRSF9), first identified as an inducible costimulatory 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 NK and Natural killer T (NKT) cells, regulatory T cells, dendritic cells (DC) 
including follicular DC, stimulated mast cells, differentiating myeloid cells, monocytes, 
neutrophils, eosinophils (Wang et al. 2009),27 and activated B cells (Zhang et al. 
2009).26 4-1BB expression has also been demonstrated on tumor vasculature (Broll et al. 
2001, Seaman et al. 2007)2,25 and atherosclerotic endothelium (Olofsson et al. 2008).21 The 
ligand that stimulates 4-1BB (4-1BBL) is expressed on activated antigen-presenting cells 
(APCs), myeloid progenitor cells, and hematopoietic stem cells. 
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 (Zhang et al. 
2009).29 The potential impact of 4-1BB engagement in B-cell lymphoma has been 
investigated in 2 published studies.  Evaluation of several types of human primary NHL 
samples indicated that 4-1BB was expressed predominantly on infiltrating T cells rather than 
the lymphoma cells (Houot et al. 2011).8 The addition of 4-1BB agonists to in vitro cultures 
of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing 
(Kohrt et al. 2010).11 Also, combination of an agonistic mAb against CD137 with a mAb 
with the potential to induce ADCC should result in enhanced ADCC as suggested in 
NHL11 and breast cancer models30.  In addition, B-cell immunophenotyping was performed 
in 2 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.
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4-1BB is undetectable on the surface of naive T cells but expression increases upon 
activation. Based on homology to other members of the tumor necrosis factor receptor super 
family (TNFRSF), ligand binding is expected to induce receptor trimerization resulting in 
activation (Chan et al. 2007).3 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 
(Michel et al. 1998; Furtner et al. 2005; Hentschel et al. 2006).6,7,14
Upon 4-1BB activation, tumor necrosis factor receptor (TNFR) associated factor (TRAF)
1 and TRAF 2, pro-survival members of the TRAF family are recruited to the 4-1BB
cytoplasmic tail resulting in downstream activation of Nuclear Factor kappa B (NFkB) and 
the Mitogen Activated Protein (MAP) Kinase cascade including Erk, Jnk, and p38 MAP 
kinases.  NFkB 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 
extracellular signal regulated kinase (Erk) dependent manner (Sabbagh et al. 2008).24
Numerous studies of murine and human T cells indicated that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production (Croft 2009).5 Reports have shown 
that 4-1BB agonist mAbs increase costimulatory molecule expression and markedly enhance 
cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models.  4-1BB
agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings and both 
monotherapy and combination therapy tumor models and have established durable anti-tumor 
protective T cell memory responses (Lynch 2008).13 4-1BB agonists also inhibit 
autoimmune reactions in a variety of autoimmunity models (Vinay et al. 2006).26 This dual 
activity of 4-1BB offers the potential to provide anti-tumor activity while dampening 
autoimmune side effects that can be associated with immunotherapy approaches that break
immune tolerance.
1.2.2. Pre-Clinical Development 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.  Injection with PF-05082566 has been shown to correlate with tumor cell 
line growth inhibition in xenogenic tumor models as a single agent. In addition, 4-1BB
agonist mAbs demonstrate significant combinatorial efficacy with 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 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 9.


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Table 9.
In Vitro Properties of PF-05082566
In vitro Assay
Activity (nM)
Affinity for 4-1BB
Biacore
     Affinity (KD)
     On rate (Ka)
     Off rate (Kd)
8.71.0
1.40.06 x106 M-1 s-1
0.0120.001s-1
Saturation Binding 
4-1BB ECD binding ELISA (EC50; n=3)
    Human
    Cyno
0.1240.041
0.1980.024
4-1BB expressing 300.19 cells (FACS EC50; n=2)
     Human
     Cyno
1.8
4.2
PHA stimulated primary cells
     Human PBMC (FACS EC50; n=12)
     Cyno PBMC (FACS EC50; n=7)
     Dog, rat, mouse (FACS; n=2)
48.924
14968
No binding up to 100 nM
Inhibition of ligand binding
Ligand competition ELISA (IC50; n=2)
0.2000.003
In vitro stimulation
4-1BB transfected cells (NF-kB luciferase reporter) (EC50)
     Human (n=3)
     Cyno (n=3)
0.150.04
0.40.039
Augmentation of primary human T cell activity
     CD3 induced IL-2 production (EC50{range max fold induction}; n=12)
22.67.63 {2-20}
Selectivity (FACS)
CD40, CD134
No binding up to 1000 nM
ECD = Extracellular Domain
ELISA = Enzyme Linked Immunosorbent Assay
FACS = Fluorescence Activated Cell Sorting
PHA = Phytohemagglutinin
PBMC = Peripheral Blood Mononuclear Cell
NF-kB = Nuclear Factor kappa B
IL-2 = Interleukin-2
1.2.2.2. In Vivo Data: Functional Activity of PF-05082566
In pre-clinical studies, PF-05082566 has exhibited the ability to increase lymphocyte 
proliferation. In small animal models developed to test the in vivo function of PF-05082566, 
PF-05082566 was able to enhance expansion of human leukocytes in a dose dependent 
manner as evidenced by an increase in the proportion of human CD45+ cells in the peripheral 
blood of engrafted mice.  Similarly, a dose-dependent increase in the proportion of human 
leukocytes expressing the proliferation marker Ki-67 was noted. In addition, 
PF-05082566 treatment of cynomolgus monkeys in single or multiple dose studies increased 
proliferation among cytotoxic central memory T cells (CD8 TCM) in PBMC samples. Taken 
together, these data demonstrated evidence of PF-05082566’s ability to enhance lymphocyte 
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1.2.2.3. Anti-Tumor Activity of PF-05082566
PF-05082566 has demonstrated anti-tumor activity in pre-clinical studies. Tumor cell lines 
representing melanoma, colon, and prostate tumor types were tested in a xenogenic tumor 
model. None of the tumor lines expressed 4-1BB; therefore, tumor cells were mixed with 
primary human PBMC from a healthy volunteer donor prior to injection in all cases.  Once 
tumors were established, animals were treated with PF-05082566.  PF-05082566 was found 
to be efficacious against all 3 tumor types. An example growth curve demonstrating the 
response to a prostate carcinoma is shown in Figure 1.
Figure 1.
Effect of PF-05082566 on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model
PF-05082566 inhibits the growth of the PC3 prostate carcinoma in vivo Panel A: mean 
tumor volume at each time point measured.  Panel B: volume of each tumor on the final 
study day (Day 21).  The mean and standard error of the mean (SEM) are indicated by bars. 
*p<0.05, ** p<0.005. 
1.2.2.4. Combination Studies
Antibody-dependent cellular cytotoxicity (ADCC) has been hypothesized as a mechanism of 
tumor destruction resulting in direct antigen presentation and in the induction of tumor 
antigen-specific T-cell responses (‘cross-priming”) (Weiner et al. 2009).28 This was
supported by preclinical experiments demonstrating that the therapeutic efficacy of an 
anti-HER2/neu antibody depends on both innate and adaptive immunity (Park et al. 2010).23
The combinatorial anti-tumor activity of ADCC inducing mAb with 4-1BB agonist mAbs 
was assessed. A mouse anti-mouse CD20 antibody with ADCC inducing activity was 
selected as a surrogate mAb for rituximab (Ahuja et al. 2007).1 MAB9371 was selected as a 
surrogate for PF-05082566, as PF-05082566 does not cross react with murine 4-1BB. 
MAB9371 is a commercially available rat anti-mouse 4-1BB agonist mAb (R & D Systems, 
Minneapolis MN). The binding affinity of MAB9371 for murine 4-1BB is similar to the 
affinity of PF-05082566 for human 4-1BB. In both models, treatment with a combination of 
surrogate mAbs at concentrations with limited single-agent efficacy, showed significant 
tumor growth inhibition (A20 model) and/or enhanced survival (E-myc model) (Figure 2).
control
0.01mg/kg
0.1mg/kg
1mg/kg
0
200
400
600
800
1000
*
**
Tumor volume (mm3)
0
5
10
15
20
25
0
200
400
600
800
Vehicle control
PF-05082566 1.0 mg/kg
PF-05082566 0.1 mg/Kg
PF-05082566 0.01mg/kg
Day Post Implant
Tumor volume (mm3)
A
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Figure 2.
Combinatorial Efficacy of 4 1BB and CD20 Surrogate mAbs in Lymphoma 
Models
4-1BB agonist antibodies demonstrate significant combinatorial efficacy with ADCC 
antibodies in transplantable and spontaneous lymphoma models. A) A20 murine 
lymphoma cells were implanted on the flank of Balb/C mice.  Group mean tumor volume 
measurements at the indicated times are shown above. Error bars represent SEM. Untreated 
vs. single agent p= not significant, untreated vs. combination p<0.01.  B) Survival days post 
treatment.  Median survival was: CD20=15 days, 1mpk 4-1BB =23.5 days, CD20+0.1mpk 
4-1BB=25.5 days, CD20+1mpk 4-1BB= 34 days. Statistical significance of the 4-1BB 
treatment or combination treatment versus CD20 group was determined using a Log Rank 
(Mantel-Cox) test: CD20 vs. 4-1BB p<0.02, CD20 vs. CD20 + 0.1mpk 4-1BB p= not 
significant, CD20 vs. CD20 + 1mpk 4-1BB p<0.001.
 
 
 
 
 
 
 
 
 
 
 
 
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1.4. Study Rationale
PF-05082566 is a promising new molecular entity that binds to human 4-1BB with high 
affinity and specificity. In vitro and in vivo data demonstrated significant 
immuno-modulatory activity and anti-tumor activity of PF-05082566 when dosed as a single 
agent and in combination with ADCC inducing antibodies. Preclinical studies have shown 
favorable PK and metabolic properties which suggest that it may be well tolerated when 
administered IV. Based upon the above considerations, this first-in-human Phase 1 study 
will assess the safety and establish the maximum tolerated dose (MTD) and the
Recommended Phase 2 Dose (RP2D) of single-agent PF-05082566 in patients with advanced
solid tumor or B-cell lymphoma, and the MTD and the RP2D of PF-05082566 in 
combination with rituximab in patients with CD20-positive NHL.
As of June 2016, 133 patients with advanced solid tumors and hematological malignancies 
received PF-05082566 in a dose range between 0.006 and 10 mg/kg in this study.  Eight-six 
(86) patients (Portion A), mainly with advanced solid tumors, received single-agent 
PF-05082566 and 47 patients (Portion B) with NHL received PF-05082566 in combination 
with rituximab.  No DLTs were reported either in Portion A or Portion B, and 
treatment-related adverse event (AE)s were generally mild or moderate in severity.  In 
Portion A, 2 Grade 3 AEs (hyponatremia and fatigue) and 3 serious adverse events (SAE)s 
(enterocolitis, decreased appetite and pneumonitis reported in 2 patients) were assessed as 
related to treatment with single-agent PF-05082566. In Portion B no Grade ≥3 AEs and no 
SAEs were reported as related to PF-05082566.  In Portion A 1 confirmed complete response 
(CR) and 1 confirmed partial response (PR) in Merkel cell carcinoma patients who were 
treated at 0.24 mg/kg and 0.6 mg/kg respectively were reported.  In addition, 1 patient with 
anti-PD-1 refractory melanoma treated at 0.24 mg/kg had a PR that was not yet confirmed,
and 1 patient with anti-PD-1 refractory melanoma treated at 0.24 mg/kg had a greater than 
30% reduction in the diameters of multiple target tumors and achieved prolonged disease 
stabilizatio
 
In Portion B, 8 patients with FL (7 patients were 
refractory to prior rituximab-containing regimen) achieved an objective response: 4 patients 
achieved a CR (2 treated at 1.2 mg/kg, 1 treated at 0.12 mg/kg, and 1 treated at 0.03 mg/kg) 
and 4 patients achieved a PR (2 treated at 0.18 mg/kg, 1 treated at 1.2 mg/kg, and 1 treated at 
5.0 mg/kg).  One (1) patient with CD20-positive nodular lymphocyte-predominant Hodgkin’s 
lymphoma treated at 1.2 mg/kg achieved a PR and 1 patient with mantle cell lymphoma 
treated at 2.4 mg/kg achieved a PR. 
Additional information for PF-05082566 may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure. 
The SRSD for rituximab is the United States Prescribing Information for Rituxan®.
The Sponsor considers that the above reported nonclinical toxicity and safety pharmacology 
studies and clinical data support the development of PF-05082566 for the treatment of 
advanced cancers and the conduct of this Phase 1 clinical study B1641001.
Because the RP2D of PF-05082566 has not yet been optimized, enrollment into expansion 
cohorts for both Portion A and Portion B will be continued.  The objectives of the dose 
expansion cohorts are to provide additional safety, tolerability, PK/
 and preliminary 
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efficacy data for PF-05082566 in order to support the selection of the RP2D.  
 
 
Portion A expansion cohort will focus on patients with advanced solid tumors who have had 
documented disease progression on a previous immune checkpoint inhibitor therapy 
(anti-CTLA-4, anti-PD1/PD-L1 antibodies) per Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v) 1.1 criteria. Targeted blockade of CTLA-4 or PD-1 with 
antagonist monoclonal antibodies (mAbs) releases the “brakes” on T cells to boost anti-tumor 
immunity.  Generating optimal T cell responses also requires T cell co-stimulation, which 
can be provided through ligation of tumor necrosis factor receptor family members, including 
4-1BB (CD137) (Linch et al., 2015).14 Upregulation of 4-1BB has been observed in an in 
vitro model of T-cell exhaustion caused by tonic signaling of chimeric antigen receptors 
(CARs), and inclusion of a 4-1BB endodomain in the CAR prevented exhaustion (Long et 
al., 2015).12 This finding suggests that 4-1BB agonists such as PF-05082566 may reverse 
exhaustion mediated by tonic T-cell receptor signaling in the tumor.  The exhausted 
phenotype has been reported in mouse models of PD-1 deficiency and may be expected in at 
least some patients treated with PD-1 and/or PD-L1 inhibitors (Odorizzi et al., 2015).20 The 
preliminary evidence of clinical activity observed in 2 patients with melanoma that
progressed on previous anti-PD-1 therapy enrolled in this study who achieved a PR that was 
not yet confirmed at the time of the June 2016 data cut, 
 
 
 Thus, Portion A expansion cohorts will 
include patients with advanced solid tumors who have had documented disease progression 
on a previous immune checkpoint inhibitor therapy per RECIST v1.1 criteria.
Portion B expansion cohorts include patients with follicular lymphoma (FL) that are 
refractory to previous rituximab therapy or DLBCL with relapsed or refractory disease.  
Patients with FL disease that is refractory to rituximab represent an unmet medical need with 
very limited therapeutic options, and the preliminary evidence of clinical activity observed in 
this study support further evaluation of PF-05082566 in combination with rituximab in this 
patient population. 
1.5. Summary of Benefit/Risk Assessment
The benefit/risk relationship has been carefully considered in the planning of this clinical
trial.  PF-05082566 has demonstrated clinical activity as monotherapy in patients with 
advanced solid tumors and in combination with rituximab in patients with CD20-positive 
NHL.  The clinical safety profile of PF-05082566 is tolerable and supports its use as both a 
single agent and in combination with rituximab.
Based on the above reported nonclinical and clinical data for PF-05082566, the conduct of 
this clinical trial is considered justifiable using the dose and frequency of administration of 
PF-05082566 (1.2, 0.6, and 0.24 mg/kg IV every 4 weeks) as specified in this clinical trial 
protocol.  Of note, the highest PF-05082566 dose to be administered in the dose expansion 
cohorts of this study is considerably lower than the highest dose tested (10 mg/kg).
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Thus, the projected benefit/risk of PF-05082566 as a single agent or in combination with 
rituximab is anticipated to be favorable for investigation in this population of patients with 
advanced solid tumor malignancies who had documented disease progression on a previous
immune checkpoint inhibitor therapy or relapsed or refractory CD20-positive NHL, 
respectively.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective – Dose Escalation Cohorts
Portion A:

To assess safety and tolerability at increasing dose levels of single agent 
PF-05082566 in patients with advanced solid tumors or B cell lymphoma in order to 
estimate the MTD and select the RP2D.
Portion B:

To assess safety and tolerability at increasing dose levels of PF-05082566 given in 
combination with rituximab in patients with relapsed or refractory CD20-positive 
NHL in order to estimate the MTD and select the RP2D.
2.1.2. Secondary Objectives – Dose Escalation Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single agent 
in patients with advanced solid tumors or B cell lymphoma.

To evaluate the overall safety profile;

To characterize the pharmacokinetics of PF-05082566;

To evaluate the immunogenicity of PF-05082566;

To characterize the effects of PF-05082566 on QTc;

To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL.

To evaluate the overall safety profile;

To characterize the pharmacokinetics of PF-05082566 and rituximab given in 
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•
To evaluate the immunogenicity of PF-05082566 and rituximab;
•
To characterize the effects of PF-05082566 in combination with rituximab on QTc;
•
To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.
 
 
2.1.4. Primary Objective – Expansion Cohorts
Portion A:
•
To estimate the objective response rate of PF-05082566.
Portion B:
•
To estimate the objective response rate of PF-05082566 in combination with 
rituximab.
2.1.5. Secondary Objectives – Expansion Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single agent 
in patients with advanced solid tumors or B cell lymphoma.
•
To evaluate the overall safety profile; 
•
To characterize the pharmacokinetics of PF-05082566;
•
To evaluate the immunogenicity of PF-05082566;
•
To characterize the effects of PF-05082566 on QTc;
•
To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL.
•
To evaluate the overall safety profile;
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•
To characterize the pharmacokinetics of PF-05082566 and rituximab given in 
combination;
•
To evaluate the immunogenicity of PF-05082566 and rituximab;
•
To characterize the effects of PF-05082566 in combination with rituximab on QTc;
•
To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.
 
 
 
 
 
2.2. Endpoints
2.2.1. Primary Endpoint – Dose Escalation Cohorts
•
First 2 cycles DLTs.
2.2.2. Secondary Endpoints – Dose Escalation Cohorts
Portion A:
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566; Laboratory abnormalities as characterized by type, frequency, severity 
(as graded by NCI CTCAE v.4.03) and timing; Vital signs (blood pressure and pulse 
rate);
•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau,CL, and Vss, as 
data permits);
•
Anti-Drug Antibody levels for PF-05082566;
•
QTc interval;
•
Objective response as assessed by using the RECIST v1.1;
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•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
Portion B:
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566 in combination with rituximab; Laboratory abnormalities as 
characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and 
timing; Vital signs (blood pressure, pulse rate, and body temperature);
•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau, CL, and Vss, as 
data permits) and rituximab (Cmax and Ctrough);
•
Anti-Drug Antibody levels for PF-05082566 and rituximab;
•
QTc interval;
•
Objective response as assessed by using the Cheson 2007 criteria;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
 
 
 
 
 
 
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2.2.4. Primary Endpoint – Expansion Cohorts
•
For Portion A: Objective response as assessed by using the RECIST v1.1.
•
For Portion B: Objective response as assessed by using the Cheson 2007 criteria.
2.2.5. Secondary Endpoints – Expansion Cohorts
Portion A:
•
First 2 cycles DLTs;
•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566; Laboratory abnormalities as characterized by type, frequency, severity 
(as graded by NCI CTCAE v.4.03) and timing; Vital signs (blood pressure and pulse 
rate);
•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau,CL, and Vss, as 
data permits);
•
Anti-Drug Antibody levels for PF-05082566;
•
QTc interval;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
Portion B:
•
First 2 cycles DLTs;
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•
Safety: Adverse events as characterized by type, frequency, severity (as graded by 
NCI CTCAE v.4.03), timing, seriousness and relationship to study therapy 
PF-05082566 in combination with rituximab; Laboratory abnormalities as 
characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and 
timing; Vital signs (blood pressure, pulse rate, and body temperature);
•
PK: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, AUCtau, CL, and Vss, as 
data permits) and rituximab (Cmax and Ctrough);
•
Anti-Drug Antibody levels for PF-05082566 and rituximab;
•
QTc interval;
•
Duration of response;
•
Time to tumor response;
•
Progression-free survival;
•
Overall survival.
 
 
 
 
 
 
 
 
 
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open label, multi-center, multiple-dose study of single agent 
PF-05082566 in patients with advanced solid tumors or B cell lymphoma, and of 
PF-05082566 in combination with rituximab in patients with refractory or relapsed
CD20-positive NHL. Approximately 270 patients are expected to be enrolled in the overall 
study.
There are 2 portions in this clinical study. Portion A is designed to assess the safety and 
tolerability, PK 
 and to estimate the MTD/pharmacologically active dose and
determine the RP2D of PF-05082566 administered as a single agent in patients with 
advanced solid tumors or B-cell lymphoma. Two cohort(s) will be enrolled at clinical sites in 
Japan to evaluate safety, tolerability and PK profile of PF-05082566 as a single agent in 
Japanese patients. 
Portion B is designed to assess the safety and tolerability, PK 
 and to estimate the 
MTD and determine the RP2D of PF-05082566 in combination with rituximab in patients 
with relapsed or refractory CD20-positive NHL. Acceptable safety of the single agent within 
the first 3 cohorts of Portion A will trigger the initiation of Portion B.  Portions A and B will 
then escalate simultaneously and independently of each other.
As of June 2016, the dose escalation components of Portion A and Portion B have been 
completed with no DLTs reported for PF-05082566 administered either as single agent or in 
combination with rituximab. Patients tolerated well PF-05082566 administration at the 
highest planned dose of 10 mg/kg in both Portions of the study and no further dose escalation 
was performed (see Section 1.4, 1.5, and the PF-05082566 Investigator Brochure for 
additional details).
Because the RP2D of PF-05082566 administered as a single-agent or in combination with 
rituximab has not yet been determined, enrollment at several dose levels of PF-05082566 will 
be continued in expansion cohorts for both Portion A and Portion B. 
 
 
  In addition, 
early signs of clinical activity were reported with single-agent PF-05082566 dose levels 
between 0.24 mg/kg to 0.6 mg/kg in patients with MCC and melanoma and responses were 
also observed with the combination of PF-05082566 and rituximab in NHL at dose levels as
low as 0.03 mg/kg with the majority of responses observed at dose levels ≤1.2 mg/kg.  
Finally, exploratory exposure (dose) response analyses indicated that better efficacy is 
expected at PF-05082566 dose levels ≤1.2 mg/kg.  Taken these data together, 
3 PF-05082566 dose levels will be further evaluated in Portion A expansion cohorts: 
0.24 mg/kg, 0.6 mg/kg and 1.2 mg/kg, and 2 dose levels may be further evaluated in Portion 
B expansion cohorts: 1.2 mg/kg and 0.24 mg/kg based on emerging data.
Because no significant toxicities were observed during dose escalation, patients enrolled into 
the expansion cohorts will have a modified visit schedule (see Table 5).
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3.1.1. Portion A Expansion Cohorts
As of September 2016, 34 patients with advanced solid tumor, including 20 patients with 
melanoma, who had documented disease progression per RECIST v1.1 on a previous 
immune checkpoint inhibitor therapy (see Section 4.1 for the definition of disease that 
progressed from previous immune checkpoint inhibitor therapy) have been enrolled in the 
expansion cohorts of Portion A and treated at the 0.24 or 1.2 mg/kg dose levels of 
PF-05082566.  These two dose levels will be further expanded and an intermediate dose level 
(0.6 mg/kg) will also be evaluated.  Approximately 40 additional patients with melanoma 
who had documented disease progression per RECIST v1.1 on a previous immune 
checkpoint inhibitor therapy will be randomized 2:1:1 to treatment with single agent 
PF-05082566 at the 0.6, 0.24, or 1.2 mg/kg dose levels.  The study design of the Portion A 
expansion cohorts is illustrated in Figure 3.
Figure 3.
Study Design of the Expansion Cohort of Portion A
For each cohort the primary diagnosis, the PF-05082566 dose levels (0.24, 0.6, or 1.2 mg/kg), the 
PF-05082566 drug preparation to be used (10 mg/mL or 25 mg/mL) and the enrollment status are illustrated.  
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3.1.2. Portion B Expansion Cohorts
As of September 2016, 10 patients with rituximab-refractory FL (see Section 4.1 for the 
definition of FL disease refractory to rituximab) and 4 patients with relapsed or refractory 
DLBCL have been enrolled in the expansion cohort of Portion B and treated at the 1.2 mg/kg 
dose level of PF-05082566. The expansion cohort of Portion B will enroll up to 100 patients 
with rituximab-refractory FL who will be treated with rituximab in combination with 
PF-05082566 at the 1.2 mg/kg and, following an assessment of the tolerability, efficacy, 
 
and PK data collected for the combination of PF-05082566 at 1.2 mg/kg plus rituximab, at 
the 0.24 mg/kg dose level.  In the first cohort (FL-1), up to 20 patients will be treated with 
rituximab in combination with PF-05082566 at 1.2 mg/kg and in the second cohort (FL-2) up 
to 20 patients may receive rituximab in combination with PF-05082566 at 0.24 mg/kg.  The 
PF-05082566 dose level to be administered in the third cohort (FL-3) will be selected based 
on the overall evaluation of tolerability, efficacy, 
 PK data collected for the 
combination of PF-05082566 plus rituximab in FL-1 and FL-2 (if this cohort is enrolled).  In 
FL-3, approximately 60 patients will receive rituximab in combination with 
PF-05082566 either at the 0.24 or 1.2 mg/kg dose level.  The study design of the Portion B 
expansion cohort is illustrated in Figure 4.
Figure 4.
Study Design of the Expansion Cohort of Portion B
For each cohort the primary diagnosis, the PF-05082566 dose levels (0.24, or 1.2 mg/kg), and the 
PF-05082566 drug preparation to be used (10 mg/mL or 25 mg/mL) are illustrated.  No switch between the 
2 different preparations is allowed during study treatment.  FL-2 opens to enrollment following an assessment 
of the tolerability, efficacy, 
 PK data collected in FL-1.  The PF-05082566 dose level to be administered 
in the FL-3 will be selected based on the overall evaluation of tolerability, efficacy, 
 PK data collected in 
FL-1 and FL-2 (if this cohort is enrolled).
3.1.3. Study Treatment Duration
Patients clinically benefiting from study treatment will be given the opportunity to continue 
treatment for up to 2 years from the first dose of study drug, or until one of the patient 
withdrawal criteria under Section 6.4 becomes a reason to discontinue study treatment.  
Evidence of benefit includes objective responses, mixed responses, immune-related 
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responses, or stable disease.  See Tumor Response Assessment Section 7.7 for description 
and cases of mixed response
 
Patients whose disease has not progressed at the end of study treatment will enter into disease 
follow-up.  During this follow-up period, patients will have disease assessments performed 
every 16 weeks (±1week).  Once patients have exhibited disease progression, they will enter 
into survival follow-up for assessment of survival only.
3.2. Starting Dose
3.2.1. Portion A
The starting dose for PF-05082566 in Portion A was 0.006 mg/kg. This dose is based on the 
MABEL approach. This starting dose is 50 times lower than the observed LOAEL 
(0.3 mg/kg) in the cynomolgus monkey multiple dose toxicity study.
3.2.1.1. Japan cohort(s) in Portion A
The starting dose for PF-05082566 in Japan cohort was 5 mg/kg. This doses has been well 
tolerated in a non-Japanese population and no non-Japanese patients have experienced DLTs 
at 5 mg/kg in Portion A. 
3.2.2. Portion B
Initiation of Portion B dose cohort 1 commenced after the third dose level of Portion A 
(0.06 mg/kg) was determined to be safe. The starting dose for PF-05082566 in Portion B 
was 0.03 mg/kg, equal to one half of the single-agent, multiple dose (SAMD) cohort 3 (ie, 
0.06 mg/kg) in Portion A.
3.3. Criteria for Dose Escalation
3.3.1. Portion A (Single Agent PF-05082566 )
The criteria for dose escalation in Portion A will be based on the standard 3+3 design for 
dose escalation up to 0.3 mg/kg. For dose escalation above 0.3 mg/kg, doses of 
PF-05082566 will be assigned to each enrolled patient using a Time-to-Event Continual 
Reassessment Method (TITE-CRM), as this method has been found to be practical based on 
experience in Portion B. 
PF-05082566 will be administered in escalating doses with available dose levels including 
the following: 0.006, 0.03, 0.06, 0.12, 0.18, 0.24, 0.30 using the 3+3 design, and 0.6, 1.2, 2.4,
5.0 and 10 mg/kg using the Time-to-Event Continual Reassessment Method (TITE-CRM 
design)4 by IV infusion of 1 hour (-5/+15 min) every 4 weeks.  As of June 2016, the highest 
planned single agent dose of 10 mg/kg was tested with no DLTs reported in Portion A and no 
further dose escalation was performed.  Patients tolerated PF-05082566 well at the highest 
planned dose of 10 mg/kg.
If a dose reduction is needed for patients being treated with 0.6 to 10 mg/kg, a dose reduction 
may be made from the next highest planned dose level to one of the following specific dose 
levels: 0.45, 0.9, 1.8, 3.6, and 7.5 mg/kg. In addition, these intermediate dose levels may be 
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used for dose escalation if more than one dose limiting toxicity is observed at the preceding 
regular dose level
Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 Day 1 will start on Day 29. Patients clinically benefiting from study 
treatment without unacceptable toxicity, objective disease progression, or withdrawal of 
consent will be given the opportunity to continue treatment up to a maximum of 2 years from 
the first dose of study drug.
For the 3+3 method, the following algorithm is followed:
If a DLT is observed in 1 of the initial 3 treated patients, 3 additional patients will be enrolled 
and treated at the same dose level. 
If no further DLT is observed, the next dose level will be opened. 
Subsequent dose levels will not be opened until all patients entered at the current dose level 
have been treated and observed for at least 28 days after the second dose is given (ie, through 
the end of Cycle 2), and the number of DLTs among those patients in their first 2 cycles has 
been determined.  If a patient in a cohort drops out of study during the DLT observation 
period due to reasons other than a dose limiting toxicity (eg, progression of disease, no 
longer willing to participate, etc.), another patient will be enrolled. 
Dose escalation will continue until DLTs are observed in at least 2 of the 3-6 patients treated 
at a dose level, leading to the conclusion that the MTD has been exceeded and ending dose 
escalation. When a dose exceeding the MTD has been identified, the next lower dose is 
declared the MTD, provided that 6 patients have already been treated at that dose with 0 or 
1 DLTs experienced in total. (3 additional patients may need to be enrolled at this dose level 
for a total of 6). If 2 or more patients are deemed to have DLTs, the dose will be further 
de-escalated and the dosing interval will be adjusted based on the observed
DLTs.
Initially, 3 patients will be treated at each dose level.  For the first 3 cohorts 
(PF-05082566 given as a single agent at 0.006, 0.03, or 0.06 mg/kg), there will be a 
minimum 7 day time window between the first dose of a patient and the first dose of the next 
patient in the same cohort. For all subsequent patients enrolled up to the 0.6 mg/kg dose 
level, a minimum 72 hour window will apply between first doses. Updated safety
information in patients indicates that PF-05082566 infusion has thus far not resulted in 
clinically significant infusion reactions.  Therefore, there will be no longer be a waiting 
period between patients in the same dose cohort and in dose expansion cohorts.
The dosing interval may be reconsidered and amended during the study based on the 
emerging safety and PK/
 data.
For dose escalation above 0.3 mg/kg, the doses of PF-05082566 will be assigned to each 
enrolled patient using the modified TITE-CRM (Cheung et al., 2000),4 as described in detail 
for Portion B in Sections 3.3.2 and Section 9.2.
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As of June 2016, the highest planned single-agent dose of 10 mg/kg PF-05082566 was tested 
with no DLTs reported in the dose escalation cohorts of Portion A and, as of September 2016, 
34 patients with advanced solid tumor, including 20 patients with melanoma, who had 
documented disease progression per RECIST v1.1 on a previous immune checkpoint 
inhibitor therapy (see Section 4.1 for the definition of disease that progressed from previous 
immune checkpoint inhibitor therapy) have been enrolled in the expansion cohorts of Portion 
A and treated at the 0.24 or 1.2 mg/kg dose levels of PF-05082566.  Because the RP2D of 
PF-05082566 has not yet been determined in Portion A, approximately 40 additional patients 
with melanoma who had documented disease progression per RECIST v1.1 on a previous 
immune checkpoint inhibitor therapy will be randomized 2:1:1 to treatment with single agent 
PF-05082566 at the 0.6, 0.24, or 1.2 mg/kg dose levels.
The expansion cohorts will provide additional safety, tolerability, PK/
 and preliminary 
efficacy data for PF-05082566 in order to support the selection of the RP2D.  
 
 Cumulative safety data will continue to be 
evaluated using the Bayesian statistical model.  Should emerging data in the expansion 
cohort indicate that any of the dose levels tested in the expansion cohort is more toxic than 
previously estimated (>25% DLT rate), or in the case of a clear exposure plateau or 
the next lower dose level may be explored, and may be 
declared as the RP2D for PF-05082566 as a single agent.
3.3.1.1. Japan cohort(s) in Portion A (PF-05082566 as a Single Agent)
The Japan cohort(s) will be conducted at Japanese sites following the completion of 
enrollment of the dose escalation cohorts in Portion A of this study. Patients enrolled into 
the Japan cohort(s) will receive PF-05082566 administered as a single agent once every four 
weeks as an IV infusion.  Patients enrolled in Japan will follow the same eligibility criteria, 
study procedures (unless otherwise specified) and discontinuation criteria as those patients in 
the dose escalation cohorts of Portion A.  The Japan cohort(s) will enroll approximately 
9 patients in 2 cohorts.  These cohorts will consist of 3 patients at one dose level below the 
MTD and 6 patients at the MTD based on non-Japanese population in Portion A.
Dose escalation in the Japan cohort(s) will be based on the standard 3+3 dose escalation 
design at 2 dose levels: 5.0 mg/kg and 10 mg/kg.  Patients recruited in Japan will be enrolled 
and analysed to confirm safety, tolerability and PK profile of PF-05082566 in Japanese 
patients.  These patients will complete the first 2 cycles of PF-05082566 as a single agent at a 
dose previously tested in non-Japan cohorts to evaluate potential dose-limiting toxicities 
(DLTs).
The 5 mg/kg dose (every 4 weeks) has been chosen as the starting dosage for the Japan
cohort(s).  5 mg/kg is well tolerated in non-Japanese population and there were no observed 
DLT’s in Portion A at 5 mg/kg. PF-05082566 will be administered to 3 Japan cohort patients
with advanced solid tumors and B cell lymphoma. After enrollment is complete, safety data 
from at least 2 cycles will be obtained and analyzed.  If the 5 mg/kg dose level is found to be 
safe, escalation to 10 mg/kg dose level will occur.  Lower dose levels may be explored at 
any time during the study if this is clinically and scientifically warranted.  Study centers will 
receive a notification if additional dose levels are explored.
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Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 Day 1 will start on Day 29.  After completion of Cycle 2, patients will be 
asked to sign an additional consent document for confirmation of the patient’s willingness to 
continue participation in this study before starting Cycle 3.  Patients clinically benefiting 
from study treatment without unacceptable toxicity, objective disease progression, or 
withdrawal of consent will be given the opportunity to continue treatment on a reduced visit 
schedule (Day 1 of each cycle), or as clinically indicated, until disease progression, 
unacceptable toxicity, or withdrawal of consent up to a maximum of 2 years from the first 
dose of study drug, or until one of the patient withdrawal criteria under Section 6.4 becomes 
a reason to discontinue study treatment.  Dose escalation will follow the 3+3 algorithm 
described in Section 3.3.1.
Patients discontinuing from the study before the second dose is given (Cycle 2 Day 1) for 
reasons other than treatment-related toxicity will be replaced in order to complete the cohort 
and have an adequate assessment.
Patients that discontinue from the study after the completion of second dose of therapy for 
reasons other than treatment-related toxicity will be discussed on a per patient basis between 
the sponsor and the investigator in terms of whether the patient requires replacement or can 
continue to be observed off study for the duration of the DLT observation period (ie, total 
8 week period). 
If the above replacement occurs, the patients who are lost to follow-up due to reasons 
unrelated to treatment related adverse events (AEs) are not evaluable for DLT. See
Section 9.1.
Updated safety information in non-Japanese patients indicate that PF-05082566 infusion has 
thus far not resulted in clinically significant infusion reactions.  Therefore, there will not be a 
waiting period in the same dose cohort between adjacent patients.
The dosing interval may be reconsidered and amended during the study based on the 
emerging safety and PK
 data.
Seven (7) patients have been enrolled in the 2 cohorts described above and the 2 tested dose 
levels of PF-05082566 (5.0 mg/kg and 10 mg/kg) were well tolerated in patients recruited in 
Japan with no DLTs reported.  Japanese sites are currently participating in the expansion 
cohort of Portion A and Portion B.
3.3.2. Portion B (PF-05082566 + Rituximab)
Safety of the single agent within the first 3 cohorts of Portion A will trigger the initiation of 
Portion B.  The initiation of Portion B may occur after all patients in the single agent 
0.06 mg/kg cohort have completed Cycle 1 and received their second dose.  Enrollment will 
then begin with PF-05082566 at a dose of 0.03 mg/kg and escalating at the same dose 
intervals as listed for Portion A. PF-05082566 will be given to patients IV (every 4 weeks) 
in combination with rituximab (375 mg/m2, every week during Cycle 1).  Patients clinically 
benefiting from study treatment without unacceptable toxicity, objective disease progression, 
or withdrawal of consent will be given the opportunity to continue treatment up to a 
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maximum of 2 years from the first dose of study drug. The first dose of PF-05082566 will be 
given approximately 24 hours after the second weekly, full dose of rituximab (defined as 
either the planned dose or in the case of infusion reactions, at least 50% of planned rituximab 
dose; see Section 5 for details). For the first cohort (PF-05082566 given at 0.03 mg/kg) there 
will be a minimum 7 day window between the first dose of PF-05082566 for a patient and 
the first dose of rituximab for the next patient.
For all subsequent dose escalation/de-escalation cohorts, up to 0.6 mg/kg, a minimum 
72 hour window will apply between the first dose of PF-05082566 for a patient and the first 
dose of rituximab for the next patient in the same cohort.  Updated safety information in 
patients indicates that PF-05082566 infusion has thus far not resulted in clinically significant 
infusion reactions.  Therefore, there will be no longer be a waiting period between patients in 
the same dose cohort and in dose expansion cohorts.
The proposed doses and schedule may be reconsidered and amended during the study based
on the emerging safety and PK
 data.
See the additional rules below for more details regarding dose escalation. Patients in 
Portion B will be replaced only if they discontinue prior to receiving the first dose of 
PF-05082566.
The doses of PF-05082566 will be assigned to each enrolled patient using the modified 
TITE-CRM (Cheung et al., 2000).4 The goal of the trial is to determine the dose of 
PF-05082566 associated with a 25% probability of a DLT (a target DLT rate of 0.25).  In 
Portion B, the first 3 patients (first cohort) will be treated at 0.03 mg/kg. For each 
subsequent patient eligible for enrollment, 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 (25%). The probabilities of 
toxicity are estimated based on a Bayesian statistical model with prior distribution (projected 
from the Portion A single agent data and pre-clinical data) 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.
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) DLT observation period the patients 
have completed (however the weight function may be modified if the Portion A safety data 
suggest different weight (toxicity) patterns in Cycle 1 and Cycle 2+ of PF-05082566, and/or 
accumulating safety data in Portion B 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.
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.
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•
Dose skipping in escalation to untested doses is not allowed (k −> k+1). In particular, 
at least 3 patients should have been treated at dose level k before escalation to dose 
level k+1;
•
At least 3 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 (but 
frequency should be minimized) by the sponsor if the nature of the existing data 
causes safety concern;
•
If the most recent 3 patients have been treated at dose level k, the next enrolled 
patient will not be treated at the same dose until at least 2 of the most recent 3 patients 
have completed 3-week follow-up in order to collect timely safety information.
Dose finding (dose escalation and de-escalation) of the trial stops if: (1) the maximum 
sample size has been reached (45 in total, see Section 9.3 for details), (2) at least 9 patients 
have been treated at a dose that is predicted to be the MTD or (3) all doses appear to be 
overly toxic and the MTD cannot be determined in the current trial. The final posterior 
probability and 90% posterior probability interval estimates of DLT at each dose level will be 
calculated, with data from all patients. 
As of June 2016, the highest planned dose of 10 mg/kg PF-05082566 in combination with 
rituximab was tested with no DLTs reported in Portion B and no further dose escalation was 
performed.  As of September 2016, 10 patients with rituximab-refractory FL (see 
Section 4.1 for definition of FL disease refractory to rituximab) and 4 patients with relapsed 
or refractory DLBCL have been enrolled in the expansion cohort of Portion B and treated at 
the 1.2 mg/kg dose level of PF-05082566. Because the RP2D of PF-05082566 administered 
in combination with rituximab has not yet been determined in Portion B, enrollment will be
expanded to enroll up to 100 patients with rituximab-refractory FL.  Patients with 
rituximab-refractory FL will be treated with rituximab in combination with PF-05082566 at 
the 1.2 mg/kg and, following an assessment of the tolerability, efficacy
 and PK data 
collected for the combination of PF-05082566 at 1.2 mg/kg plus rituximab, at the 0.24 mg/kg 
dose level.  In the first cohort (FL-1), up to 20 patients will be treated with rituximab in 
combination with PF-05082566 at 1.2 mg/kg and in the second cohort (FL-2) up to 
20 patients may receive rituximab in combination with PF-05082566 at 0.24 mg/kg.  The 
PF-05082566 dose level to be administered in the third cohort (FL-3) will be selected based 
on the overall evaluation of tolerability, efficacy,
 and PK data collected for the 
combination of PF-05082566 plus rituximab in FL-1 and FL-2 (if this cohort is enrolled).  In 
FL-3, approximately 60 patients will receive rituximab in combination with 
PF-05082566 either at the 0.24 or 1.2 mg/kg dose level.
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The objective of the expansion cohorts is to provide additional safety, tolerability, PK
 
and preliminary efficacy data for PF-05082566 in combination with rituximab, in order to 
support the selection of the RP2D.  
 
Cumulative safety data will continue to be evaluated using the Bayesian statistical model. 
Should emerging data indicate that any of the dose levels tested in the expansion cohort is 
more toxic than previously estimated (>25% DLT rate),
 
and may be 
declared as the RP2D for PF-05082566 in combination with rituximab.
Japanese sites are currently participating in Portion B following the evaluation of the 
PF-05082566 safety profile in Japanese patients enrolled in Portion A.
3.4. DLT Definition
Severity of AEs will be graded according to CTCAE v 4.03. AEs meeting the following 
definition occurring in the first two cycles of treatment (up to 28 days post second dose) 
which are not related to progressive disease and attributable to PF-05082566 alone (Portion 
A) or to PF-05082566 in combination with rituximab (Portion B) will be classified as DLTs:
Hematologic:
•
Grade 4 neutropenia [absolute neutrophil count (ANC) <500/mm3 or <0.5 x 109/L]
lasting >7 days;
•
Febrile neutropenia (defined as neutropenia ≥Grade 3 [ANC <1000 cells/mm3] and a 
body temperature ≥38.5°C);
•
Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection);
•
Grade ≥3 thrombocytopenia (<50,000 - 25,000/mm3 or <50.0 – 25.0 x 109/L) with 
bleeding;
•
Grade 4 thrombocytopenia (<25,000/mm3 or <25.0 x 109/L) >3 days;
•
Grade 4 anemia (hemoglobin <6.5 g/dL or 4.0 nmol/L);
•
Grade ≥3 hemolysis (>2 gm decrease in hemoglobin requiring medical intervention 
[transfusion or steroids]).
Non-Hematologic:
•
Grade ≥3 toxicities, except those grade 3 events that respond to treatment (eg, grade 
3 nausea, vomiting, diarrhea that responds to standard medical supportive care within 
48 hours would not be considered a DLT).
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3.5. MTD Definition (Portion A and Portion B)
The MTD estimate is the dose level associated with ≤25% of patients experiencing a 
dose-limiting toxicity. Due to the discreteness of the dose levels and in the interest of safety 
of patients, the estimated MTD is the highest dose level with DLT rate closest to but no more 
than 0.25 per the TITE-CRM method (for Portion A in which the 3+3 design was used for 
PF-05082566 doses of up to 0.3 mg/kg and for Japan cohorts, the MTD estimate is the dose 
level at which 0/6 or 1/6 evaluable patients experience a DLT during the first two treatment 
cycles with the next higher dose having at least 2 of 3 to 6 patients experiencing DLTs).
3.6. RP2D (Portions A and B)
The RP2D will be chosen for further clinical development based on data for the primary and 
secondary endpoints of this study.  Given the broad active dose range for many 
immunotherapies, significant clinical activity observed at lower doses will also be a factor in 
choosing the RP2D.
To be declared the RP2D, the MTD should also prove to be clinically feasible in a higher 
number of patients for long term administration. Once the MTD is identified, additional
patients may be enrolled at this dosing level. In the expansion cohort, patients’ DLT data 
will still 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 suggests the estimated MTD is associated with a DLT rate, or in the case of a clear 
exposure plateau 
the next lower dose or an 
intermediate dose level will be explored, and may be declared as the RP2D. 
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Portion A: Histological diagnosis of advanced solid tumor malignancy or B-cell 
lymphoma, for which no curative therapy is available.  For patients to be enrolled in 
the expansion cohorts:
•
Diagnosis of melanoma, renal cell carcinoma (RCC), non-small cell lung 
carcinoma (NSCLC), or squamous cell carcinoma of the head and neck 
(SCCHN);
•
Documented disease progression per RECIST v1.1 on a previous systemic 
immune checkpoint inhibitor therapy (anti-CTLA-4, anti-PD-1/PD-L1) 
administered as a single agent OR in combination;
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
Measurable disease with at least 1 target lesion by RECIST v1.1 that has not been 
previously irradiated.
2. Portion B: Histological diagnosis of relapsed or refractory CD20-positive NHL for 
which no curative therapy is available, including small lymphocytic lymphoma 
(SLL)/chronic lymphocytic leukemia (CLL) with nodal disease (not including 
SLL/CLL with >10,000 lymphocytes/l, prolymphocytic leukemia, hairy cell 
leukemia, heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, 
extraosseous plasmacytoma, lymphomatoid granulomatosis, and large B-cell 
lymphoma arising in Castleman disease).  For patients to be enrolled in the expansion 
cohorts:

Diagnosis of FL or DLBCL;

Measurable disease with at least 1 extranodal tumor mass >1.0 cm in the greatest 
transverse diameter (GTD) or in the case of malignant lymph nodes >1.5cm in the 
GTD and the product of the diameters ≥2.25cm2 as measured by Computerized 
Tomography (CT) or Magnetic Resonance Imaging (MRI);

FL disease (Grade 1, 2, or 3a) refractory to rituximab defined as:

Lack of a CR or PR during a previous rituximab containing regimen 
comprising at least 2 doses of 375 mg/m2, OR

Occurrence of PD within 6 months of completion of a previous rituximab 
containing regimen comprising at least 2 doses of 375 mg/m2

Treatment with ≥2 prior regimens for FL.
3. Availability of an archival (tissue collected within the last 6 months) OR baseline 
tumor biopsy (tissue collected de novo during the screening period); this tissue 
sample must be available also for a central pathology laboratory for independent 
review.
4. Age 18 years or older (or ≥20 years of age if required by local regulation).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 1.
6. Adequate bone marrow function, for Portion A defined as absolute neutrophil count 
(ANC) 1.5 x 109/L (≥1,500/μL), platelet count 100 x 109/L (≥100,000/μL), and 
hemoglobin >9.0 g/dL (>5.6 mmol/L), and for Portion B as ANC 1.0 x 109/L 
(1,000/uL), platelet count 75 x 109/L (≥75000/μL), and hemoglobin 8.0 g/dL 
(5.0 mmol/L) or 8.5 mmol/L (5.3 mmol/L) for Japanese patients.  In both cases, 
patients must be transfusion independent [ie, no blood product transfusions for a 
period of at least 14 days prior to enrollment (Portion B) or randomization (Portion 
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7. Adequate Renal Function, including serum creatinine 2 x upper limit of normal 
(ULN) or estimated creatinine clearance 50 mL/min as calculated using the method 
standard for the institution.
8. Adequate Liver Function, including: a) Total serum bilirubin 1.5 x ULN unless the 
patient has documented Gilbert syndrome; b) Aspartate and Alanine 
Aminotransferase (AST and ALT) 2.5 x ULN.
9. Adequate Cardiac Function, as measured by left ventricular ejection fraction (LVEF) 
that is greater than 40%, or the presence of New York Heart Association (NYHA) 
classification of no greater than stage II congestive heart failure.
10. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE 
v. 4.03 except for AEs not constituting a safety risk by investigator judgment.
11. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.  Female patients of nonchildbearing potential must meet at least 1 of the 
following criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause;

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential. 
12. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two highly effective method(s) of contraception throughout the study and 
for at least 90 days (180 days if required by local regulation) after the last dose of 
assigned treatment.
13. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
14. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Patients with known symptomatic brain metastases requiring steroids. Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
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prior to enrollment (Portion B) or randomization (Portion A), have discontinued 
corticosteroid treatment for these metastases for at least 4 weeks and are 
neurologically stable.
2. Prior allogeneic hematopoietic stem cell transplant.
3. Chemotherapy, growth factors, or investigational agents within 28 days before the 
first dose of study treatment (for the purposes of this protocol, study treatment 
includes rituximab in Portion B). Immunosuppressive regimens involving systemic 
corticosteroids within 14 days before the first dose of study treatment. 
4. Therapeutic or experimental monoclonal antibodies in last 28 days prior to enrollment 
(Portion B) or randomization (Portion A).
5. Prior therapy with a compound of the same mechanism of action.
6. Vaccination within 4 weeks prior to enrollment (Portion B) or randomization (Portion 
A) except for administration of inactivated vaccines (for example, inactivated 
influenza vaccines).
7. Major surgery within 28 days prior to enrollment (Portion B) or randomization 
(Portion A).
8. Radiation therapy within 14 days prior to enrollment (Portion B) or randomization 
(Portion A).
9. Autoimmune disorders (eg, Crohn’s Disease, rheumatoid arthritis, scleroderma, 
systemic lupus erythematosus) and other diseases that compromise or impair the 
immune system.
10. Active and clinically significant bacterial, fungal or viral infection including 
tuberculosis, hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness (HIV 
testing is not required).
11. Unstable or serious concurrent medical conditions in the previous 6 months, eg,
pancreatitis, severe/unstable angina, prolonged QT interval corrected by Fridericia’s 
formula (QTcF) >470 msec (calculated as average of triplicate readings, taken no 
greater than 2 minutes apart, and no history of Torsades de Pointes or symptomatic 
QTc abnormality), symptomatic congestive heart failure, myocardial infarction and/or 
pulmonary hypertension, ongoing maintenance therapy for life-threatening ventricular 
arrhythmia, stroke, and uncontrolled major seizure disorder.
12. Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in 
situ of the cervix.
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14. Patients with intolerance to or who have had a severe allergic or anaphylactic reaction 
to antibodies or infused therapeutic proteins, or patients who have had a severe 
allergic or anaphylactic reaction to any of the substances included in the study drug 
(including excipients).
15. 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.
16. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
4.3. Life Style Guidelines
Patients who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use 2 methods of highly effective contraception 
throughout the study and for at least 90 days (180 days if required by local regulation) after 
the last dose of PF-05082566.  Women of childbearing potential who received rituximab 
during the study should use effective contraception for 12 months following the last dose of 
rituximab.  The investigator or his or her designee, in consultation with the patient, will 
confirm that the patient has selected 2 appropriate methods of contraception for the 
individual patient and his or her partner(s) from the list of permitted contraception methods 
(see below) and will confirm that the patient has been instructed in their consistent and 
correct use.  The investigator or designee, at each study visit, will inform the patient of the 
need to use 2 highly effective methods of contraception consistently and correctly and 
document the conversation, and the patient’s affirmation, in the patient’s chart.  In addition, 
the investigator or designee will instruct the patient to call immediately if 1 or both of the 
selected contraception methods is discontinued or if pregnancy is known or suspected in the 
patient or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected*, implanted*, transdermal), provided the patient 
or male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).


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3. Male condom or female condom used WITH a separate spermicide product* (ie, 
foam, gel, film, cream, or suppository).  For countries where spermicide is not 
available or condom plus spermicide is not accepted as highly effective contraception, 
this option is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
*Not commercially available in Japan.
NOTE:  Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the patient. 
All sexually active male patients must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 90 days (180 days if 
required by local regulation) after the last dose of PF-05082566.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study manual.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems, however it 
should be used in the event that the established communication pathways between the 
investigational site and the study team are not available.  It is therefore intended to augment, 
but not replace the established communication pathways between the investigational site and 
study team for advice on medical questions or problems that may arise during the study.  The 
contact center number is not intended for use by the patient directly and if a patient calls that 
number they will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).


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For this study, the investigational products is PF-05082566. Rituximab is considered to be 
an investigational product in some countries and not others, according to local regulations.
Portion A:
During the dose escalation phase, PF-05082566 will be administered in escalating doses with 
available dose levels including the following: 0.006, 0.03, 0.06, 0.12, 0.18, 0.24, 0.30 (using 
the 3+3 design), and 0.6, 1.2, 2.4, 5.0 and 10 mg/kg (using the TITE-CRM design) by IV
infusion of 1 hour (-5/+15 min) every 4 weeks.  If a dose reduction is needed for patients 
being treated with 0.6 to 10 mg/kg, a dose reduction may be made from the next highest 
planned dose level to one of the following specific dose levels: 0.45, 0.9, 1.8, and 3.6 mg/kg. 
If the 10 mg/kg dose is not well tolerated, there is an option to de-escalate to 7.5 mg/kg.
Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 will start on Day 29.
In the expansion cohort, PF-05082566 will be administered at either 0.24 mg/kg, 0.6 mg/kg, 
or 1.2 mg/kg by IV infusion of 1 hour (-5/+15 min) every 4 weeks.  If a dose reduction is 
required due to the treatment-related toxicity, this may be allowed as an alternative to 
discontinuation of treatment. No dose reduction is allowed for patients treated at the 
0.24 mg/kg dose level.  See Section 5.4.4 for details.
Japan cohort(s) in Portion A:
PF-05082566 will be administered at 2 planned dose escalation levels (5.0 mg/kg and 
10 mg/kg ) by IV infusion of 1 hour (-5/+15 min) every 4 weeks.  Each patient will initially 
receive the first dose on Cycle 1 Day 1 with a 28-day observation period.  Cycle 2 Day 1 will 
start on Day 29.  After completion of Cycle 2, patients will be asked to sign an additional 
consent document for confirmation of the patient’s willingness to continue participation in 
this study before starting Cycle 3.  Lower dose levels, as described above for Portion A, may 
be explored at any time during the study if this is clinically and scientifically warranted based 
on the emerging safety data in Japanese patients.  Study centers will receive a notification if 
additional dose levels are explored.
Portion B:
PF-05082566 will be administered by IV infusion of 1 hour (-5/+15 min) every four weeks at
dose levels as shown for Portion A, with the exception that the Portion B dose escalation 
starts at 0.03 mg/kg.
In the expansion cohort, patients enrolled in Portion B will receive a dose of PF-05082566 at 
0.24 mg/kg or 1.2 mg/kg in combination with 375 mg/m2 rituximab.  If a PF-05082566 dose 
reduction is required due to the PF-05082566-related toxicity, this may be allowed as an 
alternative to discontinuation of treatment.  No dose reduction is allowed for patients treated 
at the 0.24 mg/kg dose level.  See Section 5.4.4 for details.
Rituximab will be administered in Cycle 1 at a fixed dose of 375 mg/m2, once per week for a 
total of 4 weeks.  The first dose of rituximab will be administered on Cycle 1 Day (-7) 
followed by the second dose a week later on Day (0). 


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The first dose of PF-05082566 will be given approximately 24 hours after the second weekly, 
full dose of rituximab (Cycle 1 Day 1).  This allows for the observance of any potential 
reactions to rituximab treatment prior to the initiation of PF-05082566 dosing.  In this study, 
full dose of rituximab is defined as either the planned dose, or for those patients who develop 
an infusion reaction, as at least 50% of the planned dose.  Continuation with protocol 
activities as scheduled, following administration of less than the planned rituximab dose, 
requires confirmation of dose acceptability from the Sponsor.
The proposed schedule and duration of infusion may be reconsidered and amended during 
the study based on the emerging safety and PK
 data.
Duration of Treatment
Patients clinically benefiting from study treatment will be given the opportunity to continue 
treatment for up to 2 years, unless one of the patient withdrawal criteria under Section 
6.4 becomes a reason to permanently discontinue study treatment earlier.  Evidence of 
benefit includes objective responses, mixed responses, immune-related responses, or stable 
disease.  See Tumor Response Assessment Section 7.7 for descriptions and cases of mixed 
response
Patients who have objective disease progression and are receiving clinical benefit from the 
study treatment will be given an opportunity to continue up to 2 years, after being 
reconsented and informed that the patient may be foregoing other therapies with possible 
clinical benefit(s) by continuing with study treatment.
5.1. Allocation to Treatment
5.1.1. Allocation to Treatment for Patients Enrolled in the Randomized Expansion 
Cohorts of Portion A
Allocation of patients with advanced melanoma to treatment groups will proceed through the 
use of an interactive response technology (IRT) system (interactive Web based response 
[IWR]).  The site staff (study coordinator or specified designee) will be required to have an 
active or valid account and password with the IRT system, enter or select information 
including but not limited to the protocol number, specific protocol entrance criteria indicated 
in the system and the screening number.  The site staff will then be provided with, at a 
minimum, a treatment assignment and a randomization number.  The IRT system will 
provide a confirmation report containing the patient number and the randomization number.  
The confirmation report must be stored in the site’s files.  The study specific IRT reference 
manual will provide the contact information and further details on the use of the IRT system.
Eligible patients will be randomized in a 2:1:1 ratio to receive PF-05082566 at the 0.6, 
0.24 or 1.2 mg/kg dose levels, respectively.  Study treatment must start within 3 days after 
patient randomization.
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues.  The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system.
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5.1.2. Allocation to Treatment for Patients Enrolled in the Non Randomized Expansion 
Cohorts of Portion A and Portion B
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/and email) a complete Registration Form to the designated Sponsor study team 
member. The Sponsor will assign a patient identification number, which will be used on all 
Case Report Form (CRF) pages and other trial-related documentation or correspondence 
referencing that patient and (fax or/and email) to the site.
No patient shall receive the investigational products 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;

Permission to proceed with dosing the patient. 
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Patient Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigational site.  The site will complete required dosage Preparation 
Record located in the Investigational Product manual (IP manual).  The use of the 
Preparation Record is preferred but it does not preclude the use of an existing appropriate 
clinical site documentation system.  The existing clinical site's documentation system should 
capture all pertinent /required information on the preparation and administration of the dose.  
This may be used in place of the Preparation Record after approval from the sponsor and/or 
designee.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. PF-05082566
PF-05082566 drug product will be supplied by the sponsor or designee.  PF-05082566 drug 
product is a solution and should be stored refrigerated at 2-8°C.  PF-05082566 drug product 
will be supplied in glass vials at a 10 mg/mL (100 mg/vial) and 25 mg/mL (125 mg/vial) 
concentration and labeled as open supplies.  Each vial is packed in an individual carton.  For 
packaging and labeling information on rituximab, refer to the most recent version of the local 
product labeling.  The administration of each preparation in the Portion A and Portion B 
expansion cohorts should follow Table 10 below; see Section 3.1 for additional details about 
the different expansion cohorts.  No switch between the 2 different preparations is 
allowed during study treatment.  See the IP manual for additional information.


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Table 10.
PF-05082566 Preparations to be Administered in the Expansion Cohorts
Portion
Cohort
PF-05082566
dose level
Preparation to Use
10 mg/mL
(100 mg/vial
25 mg/mL
(125 mg/vial)
A 
Non 
Randomized
Other 
Histology
1.2 or 0.24 mg/kg
X
A 
Randomized
Melanoma
1.2 mg/kg
X
Melanoma
0.6 mg/kg
X
Melanoma
0.24 mg/kg
X
B
FL-1
1.2 mg/kg
X
FL-2
0.24 mg/kg
X
FL-3
1.2 mg/kg or 0.24 mg/kg
X
DLBCL
1.2 mg/kg
X
Grey Shading: close to enrollment; No shading: Open to enrollment.  No switch between the 2 different 
preparations is allowed during study treatment.
5.3.1.2. Rituximab
Rituximab is commercially available.  Central supply or locally obtained commercial 
supplies of this drug will be used in accordance with local regulations and the package insert.
5.3.2. Preparation and Dispensing
See the PF-05082566 IP manual and the rituximab package insert for instructions on how to 
prepare the investigational product for administration.  Investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of investigational products.
5.4. Administration
Patients will receive doses of PF-05082566 IV once every 4weeks (1 cycle). A cycle is 
defined as the time from the Day 1 dose to the next Day 1 dose.  If there are no treatment 
delays, a cycle will be 4 weeks in duration. 
Premedication is recommended for all patients, and may include an antihistamine, an 
anti-inflammatory agent, or a pain reliever.
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The duration of infusion is 1 hour (-5/+15 minutes). 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 permanently.
Patients on Portion B of the study will receive doses of rituximab IV once every week for the 
first cycle of treatment at a fixed dose of 375 mg/m2. Initiation of PF-05082566 will 
commence approximately 24 hours after the second weekly on study full dose of rituximab
has been administered. For additional details about the administration of rituximab, refer to 
rituximab package insert.
Medication errors may result in this study from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dose strength, or 
administration of a study drug at the wrong study visit day. 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 adverse event (AE) page and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product. 

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE) CRF page.
Given the known side effects of rituximab and the pre-clinical and clinical safety data for 
PF-05082566 (see the PF-05082566 Investigator Brochure for additional details), it is not 
anticipated that overlapping side effects will occur. Patients will be treated with two doses of 
rituximab prior to the initiation of PF-05082566 to assess for rituximab specific side effects. 
Patients should be monitored carefully, however, for potential infusion reactions, particularly 
for the earlier doses of PF-05082566. Rituximab can cause severe, including fatal, infusion 
reactions.  Severe reactions have typically occurred during the first infusion with time to 
onset of 30-120 minutes.  Rituximab-induced infusion reactions and sequelae include 
urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute 
respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic 
shock, anaphylactoid events, or death.  Refer to the rituximab package insert for additional 
details.
Guidance for prevention and management of infusion reactions to rituximab: Premedicate 
patients with an antihistamine and acetaminophen prior to dosing.  For patients with 
rheumatoid arthritis or a previous history of rituximab-associated infusion reactions it is 


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suggested to administer a glucocorticoid (such as methylprednisolone) IV 30 minutes prior to 
each infusion.  Institute medical management (eg, glucocorticoids, epinephrine, 
bronchodilators, or oxygen) for infusion reactions as needed.  Depending on the severity of 
the infusion reaction and the required interventions, temporarily or permanently discontinue 
rituximab.  Resume infusion at a minimum 50% reduction in rate after symptoms have 
resolved.  Closely monitor the following patients: those with pre-existing cardiac or 
pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and 
those with high numbers of circulating malignant cells.  Refer to the rituximab package insert 
for additional details.
Delay of rituximab dosing before Day 1 of Cycle 1: for patients who undergo interruption of 
dosing of rituximab such that dosing cannot be completed within 24 hours, repeat dosing 
may be acceptable in certain cases.  A repeat of the rituximab dose is contingent upon 
communication with the Sponsor that, in the opinion of the investigator the patient is a 
candidate for retreatment, and only if a patient has already received less than 50% of the 
planned rituximab dose.  Repeated dosing of rituximab will only be allowed for Day -7 or 
Day 0 of Cycle 1 for a maximum of one repeated rituximab infusion, and allowed only if the 
reasons for interruption do not include persistence of a Grade 3 or Grade 4 AE attributed to 
rituximab. 
Delay of rituximab dosing after Day 1 of Cycle 1: Patients who have dose interruptions of 
rituximab that preclude completion of the infusion within 24 hours will permanently 
discontinue the study treatment, including treatment with PF-05082566.
Patients who develop progressive multifocal leukoencephalopathy (PML) should 
permanently discontinue study treatment (see Section 7.1.2.1 for more details).
5.4.1. Recommended Dose Modifications for PF-05082566
Every effort should be made to administer PF-05082566 on the planned dose and schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse symptom.
Dose modifications may occur in 2 ways:

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
5.4.2. Dosing Interruptions for PF-05082566
Patients experiencing a DLT according to the definitions provided in Section 3.4 or 
intolerable Grade 2 toxicity should have their treatment interrupted (Note for Portion B: AEs 
attributed to rituximab only do not meet the DLT definition).


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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 5.4.3.
Doses may be held as needed until toxicity resolution.  Depending on when the AE resolves, 
a treatment interruption may lead to delay the initiation of the subsequent cycle.
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in Section 5.4.4, 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 >8 weeks, treatment resumption will be decided in consultation with 
the Sponsor.
5.4.3. Dose Delays for PF-05082566
A new cycle of treatment may begin only if:

ANC 500/µL;

Platelet count 50,000/µL;

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).
Note: withhold scheduled dose for liver function test related AEs (including asymptomatic) 
Grade 3 until return to baseline or Grade 1 severity. In cases of potential liver injury, see
Section 8.5.2.  In such cases, consultation with a hepatologist should be considered in the 
decision to initiate treatment with anti-inflammatory medications.
If the above conditions are not met, treatment must be delayed. If, within 8 weeks all 
toxicities have recovered within the limits described above, treatment with PF-05082566 can 
be resumed. If persisting toxicity does not allow for the resumption of treatment after 
8 weeks of delay, the patient will be permanently discontinued from study treatment.
5.4.4. Dose Modifications for PF-05082566
Following dosing interruption or cycle delay due to toxicity (see Section 5.4.2 and 5.4.3), the 
PF-05082566 dose may need to be reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Patients experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the 
next lower dose level, if possible, once recovery to Grade 1 or baseline is achieved.


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Patients experiencing an AE meeting the DLT definition (see Section 3.4 for DLT definition) 
may resume dosing at the next lower dose level, if possible, once adequate recovery is 
achieved (see Section 5.4.3).
Dose reduction of PF-05082566 by 1 and, if needed, 2 dose levels (Table 11) will be 
allowed depending on the type and severity of toxicity encountered.  Patients requiring more 
than 2 dose reductions will be permanently discontinued from the study treatment and 
entered into the follow-up phase.  Once a patient has a dose reduction of PF-05082566 for a 
PF-05082566 related toxicity, the dose will not be re-escalated.  All dose modifications and 
adjustments must be clearly documented in the patient's source notes and CRF.
Patients treated with PF-05082566 at 0.24 mg/kg requiring a dose reduction should be 
permanently withdrawn from study treatment.
Table 11.
Available Dose Levels for PF-05082566 (mg/kg)
1.2
0.6
0.24
5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  See the IP manual, package insert, or equivalent for storage conditions of the 
product once reconstituted and/or diluted.  Any storage conditions stated in the SRSD will be 
superseded by the storage conditions stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.


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Once an excursion is identified, the investigational product must be quarantined and not used 
until the Pfizer provides permission to use the investigational product.  It will not be 
considered a protocol deviation if Pfizer approves the use of the investigational product after
the temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.6. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.6.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Medication(s)
Concomitant treatment considered necessary for the patient’s well being may be given at 
discretion of the treating physician.
All concomitant medications, blood products, as well as interventions (eg, paracentesis, etc.) 
received by patients from screening until the end of study visit will be recorded on the CRF.
5.7.1. Other Anticancer or Experimental Drugs
No additional anticancer therapy will be permitted while patients are receiving study therapy.
Additionally, the concurrent use of vitamins or herbal supplements should be considered with 
caution.
Palliative and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion.
5.7.2. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines. 


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5.7.3. Hematopoietic Growth Factors
The use of hematopoietic growth factors is at the discretion of the treating physician in line 
with local guidelines.  Erythropoietin* may be used at the investigator’s discretion for the 
supportive treatment of anemia.
*Use of erythropoietin for the treatment of anemia with cancer patients is not approved in 
Japan.
5.7.4. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed.  Systemic 
anti-inflammatory therapies may be used to treat SAEs potentially related to the study drug.  
However, in such cases it is suggested that Investigators consult with a specialist based on 
the involved organ systems before instituting treatment.
5.7.5. Corticosteroids
Chronic, systemic corticosteroid use for palliative or supportive purpose, except for the use 
of systemic corticosteroids according to the rituximab prescribing information, 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.  
Physiologic use for replacement in cases of adrenal insufficiency at doses equivalent to 
≤10 mg of prednisone daily is acceptable.
5.7.6. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-05082566 required to minimize the risk
of impaired wound healing and bleeding has not been determined.  Stopping PF-05082566 is 
recommended at least 14 days prior to surgery.  Postoperatively, the decision to reinitiate 
PF-05082566 treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
5.7.7. Radiation Therapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically
necessary by the treating physician.  All attempts should be made to rule out disease
progression in the event of increased localized pain.  If palliative radiotherapy is needed to
control bone pain, the sites of bone disease should be present at baseline, otherwise, bone
pain requiring radiotherapy will be considered as a sign of disease progression.
6. STUDY PROCEDURES
For screening, treatment period and follow-up procedures, see Schedule of Activities 
(Table 1-7).
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, in order of the most important to the least important:


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•
 
•
Pharmacokinetic blood specimens - obtain at the scheduled time.
•
ECGs – obtain as close as possible to the scheduled time, but prior to PK blood 
specimen collection and within 30 minutes of the nominal time.
•
Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must 
be obtained prior to PK blood specimen collection and within 60 minutes of the 
nominal time.
•
Clinical safety lab tests – obtain as close as possible to 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 (Table 1-7).
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities (Table 1-7).
6.3. Follow-up Visit
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 16 weeks (±1 week). Once patients have exhibited disease progression,  they will enter 
into survival follow-up for assessment of survival only.  A new anti-cancer therapy will be 
reported on the CRF. 
Patients will be followed for at least 2 years after first dose of the last patient unless lost to 
follow-up, consent withdrawal, or study discontinued by the Sponsor, whichever occurs 
first. Patients will be contacted every 12 weeks (+/- 4 weeks) for survival status and 
subsequent anti-cancer treatment.
Patients continuing to experience toxicity at this point following discontinuation of treatment 
will continue to be followed at least every 4 weeks until resolution or determination, in the 
clinical judgment of the Investigator, that no further improvement is expected.
For follow-up procedures see Schedule of Activities (Table 1-7).
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, behavioral, or 
administrative reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given investigative site. 
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Reasons for discontinuation of study treatment may include:
•
 
•
Global deterioration of health status requiring discontinuation;
•
Unacceptable toxicity (including PML, clinically significant opportunistic infections 
and tuberculosis);
•
Pregnancy;
•
Significant protocol violation;
•
Lost to follow-up;
•
Patient refused further treatment;
•
Study terminated by Sponsor;
•
Death.
 
 
 
 
 
 
 
 
 
 
 
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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, neurological examination, ECG (12-lead), laboratory assessments, including 
pregnancy tests and verification of concurrent medications.  A neurological examination will 
be performed as clinically indicated because of the risk of progressive multifocal 
leukoencephalopathy with rituximab.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting 
administration of study treatment: once at the start of screening and once at the baseline visit, 
immediately before administration of the first dose of study treatment.  Following a negative 
pregnancy test result at screening, appropriate contraception must be commenced and a 
second negative pregnancy test result will be required at the baseline visit before the patient 
may receive the investigational product.  Pregnancy tests will be repeated at every treatment 
cycle during the active treatment period, at the end of study treatment, and additionally 
whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by institutional review 
boards (IRBs)/ethics committees (ECs) or if required by local regulations.  In the case of a 
positive confirmed pregnancy, the patient will be withdrawn from administration of 
investigational product but may remain in the study.
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) 
timing, seriousness, and relatedness.
AEs that occur during the study, including baseline signs and symptoms, will be recorded on 
the AEs CRF page.


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7.1.2.1. Adverse Events of Special Interest
Due to pre-clinical results and human experience with compounds of a similar nature, 
patients should be carefully monitored for endocrine (including but not limited to
hypopituitarism and hypoadrenalism) and hepatic events. Evaluation of hypopituitarism or 
hypoadrenalism should be considered in patients who develop signs and symptoms that may 
include unexplained loss of body and facial hair, decreased blood pressure, and hyponatremia 
with hyperkalemia; in the presence of clinical suspicion, laboratory testing should include 
one or more of the following: thyroid-stimulating hormone (TSH), adrenocorticotropic 
hormone (ACTH), and cortisol levels before and 30-60 minutes after corticotropin 
stimulation.  See Study Flowcharts, Table 3, Table 5, and Safety Lab table (Table 8) for 
guidance.
John Cunningham virus infection resulting in PML and death can occur in rituximab treated 
patients with hematologic malignancies.  The majority of patients with hematologic 
malignancies diagnosed with PML received rituximab in combination with chemotherapy or 
as part of a hematopoietic stem cell transplant.  Most cases of PML were diagnosed within 
12 months of their last infusion of rituximab.  Consider the diagnosis of PML in any patient 
presenting with new-onset neurologic manifestations.  Evaluation of PML includes, but is not 
limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 
7.1.3. Laboratory Safety Assessments
Hematology and blood chemistry (Table 8) will be drawn at the time points described in the 
Schedule of Activities (Table 5) and analyzed at local laboratories.
Blood and/or urine for hematology, chemistry, coagulation, hepatitis B and C, endocrine 
function, urinalysis and pregnancy testing will be collected at the time points described in the 
Schedule of Activities, Table 3, and Table 5, and analyzed at local laboratories.
7.1.4. Vital Signs and Physical Examinations
Patients will have a physical exam to include weight, blood pressure, heart rate, body 
temperature (Portion B only), assessment of ECOG status and height; height will be
measured at baseline only. Physical exams will be performed at the time points described in 
the Schedule of Activities, Table 3 and Table 5.
7.1.5. ECG Assessments
Electrocardiogram (ECG): Triplicate 12-lead (with a 10-second rhythm strip) tracing in the 
supine position will be used for all ECGs.  It is preferable that the machine used has a 
capacity to calculate the standard intervals automatically. At each time point (see the 
Schedule of Activities, Table 3, and Table 5), 3 consecutive ECGs will be performed at 
approximately 2 minutes apart to determine the mean QTc interval.  If the mean QTc is 
prolonged (>500 msec by any correction method, ie, CTCAE Grade 3), then the ECGs 
should be re-evaluated by a qualified person at the site for confirmation as soon as the 
finding is made, including verification that the machine reading is accurate. If manual 
reading verifies a QTcF of >500 msec, immediate correction for reversible causes (including 
electrolyte abnormalities, hypoxia and concomitant medications for drugs with the potential 
to prolong the QTc interval) should be performed. In addition, repeat ECGs should be 


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immediately performed hourly for at least 3 hours until the QTc interval resolves to Grade 
1 or less. If QTc interval reverts to less than 500 msec, and in the judgment of Investigator(s) 
and Sponsor is determined to be due to cause(s) other than study drug, treatment may be 
continued with regular ECG monitoring. If in that timeframe the QTc intervals rise above 
500 msec the study drug will be held until the QTc interval decreases to Grade 1 or less.  
Patients will then re-start the study drug at the next lowest dose level. If the QTc interval has 
still not decreased to <500 msec after 2 weeks, or if at any time a patient has a QTc interval 
>515 msec or becomes symptomatic, the patient will be removed from the study. Additional 
triplicate ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
If an ECG assessment is 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 overrides the timing of the ECG collections).
7.2. Pharmacokinetics Assessments
7.2.1. Portion A: Single Agent PF-05082566 (Dose Escalation, and Japan Cohort(s))
Blood samples will be collected for PK of PF-05082566 at the following times:

During Cycle 1 and Cycle 2 on (a) Day 1 at pre-dose, end of infusion, and at 1.5, 2, 
6 and 24 hrs post start of infusion; (b) on Days 3, 8, 15 and 22;

During Cycle 3 on (c) Day 1 at pre-dose, end of infusion, and at 1.5 and 24 hrs post 
start of infusion; (d) on Days 8, 15 and 22;

During Cycle 4 on (e) Day 1 at pre-dose, end of infusion, and at 1.5 hr post start of 
infusion; (f) on Day 3 and Day 28 after administration of the last dose.
For patients ending the study, PK samples should be collected at the End of Treatment 
assessment day. 
The PK sample for Day 28 following the Cycle 4 dose of PF-05082566 need not be 
collected if a patient undergoes PF-05082566 dosing for additional cycles or if the patient 
starts another cancer therapy.  If a patient continues with additional cycles of therapy (up to 
2 years), PK samples will be collected pre-dose, end of infusion and at 1.5 hours post start of 
infusion in each cycle.
In Japan, patients will be hospitalized for PK sampling for at least the first 2 days of the first 
cycle of dosing of PF-05082566 (Note: this is a planned hospitalization and thus is not 
considered a serious adverse event (SAE) unless prolonged due to study drugs.  See section 
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7.2.2. Portion B: PF-05082566 + Rituximab (Dose Escalation)
7.2.2.1. PF-05082566
Blood samples will be collected for PK of PF-05082566 at the following times:

During Cycle 1 on (a) Day 1 at pre-dose, end of infusion, and at 1.5, 2, 6, and 24 hrs
post start of infusion; (b) on Days 3, 7, 14 and 22;

During Cycle 2 on (c) Day 1 at pre-dose, end of infusion, and at 1.5 and 24 hrs post 
start of infusion; (d) on Days 8, 15 and 22;

During Cycle 3 on (e) Day 1 at pre-dose, end of infusion and at 1.5 hrs post start of 
infusion; (f) on Day 22;

During Cycle 4 on (g) Day 1 at pre-dose, end of infusion and at 1.5 hrs post start of 
infusion; (h) and on Day 28 post Cycle 4 dose.
For patients ending from the study, PK samples should be collected at the End of Treatment 
assessment day. 
The PK sample for Day 28 following the Cycle 4 dose of PF-05082566 need not be 
collected if a patient undergoes PF-05082566 dosing for additional cycles or if the patient 
starts another cancer therapy. If a patient continues with additional cycles of therapy up to 
2 years, PK samples will be collected pre-dose, end of infusion and at 1.5 hours post start of 
infusion in each cycle.
7.2.2.2. Rituximab
Blood samples will be collected for PK of rituximab at the following times (NOTE: All days 
are numbered relative to the start of PF-05082566 dosing): 

On Day (-7) at pre-dose and at 15 min post end of infusion, 6 and 24 hrs post start of 
infusion;

On Day (0) at pre-dose and 15 min post end of infusion;

During Cycle 1 on: Day 1 at 2 and 24 hrs post start of infusion of PF-05082566; Day 
3; Day 7 at pre-dose and 15 min post end of infusion; Day 14 at pre-dose and 15 min 
post end of infusion; and Day 22;

During Cycle 2 on: Day 1 prior to the dose of PF-05082566 and Day 15. 
For patients ending from the study, PK samples should be collected at the End of treatment 
assessment day. 
Note that whenever rituximab PK samples are collected on days where PF-05082566 PK 
samples are being collected, these collections should be time matched to avoid multiple 
needle sticks.  The time matched collections are shown in the above list in italics.


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For both Portion A and Portion B, PK sampling schedule may be modified based on 
emerging PK data.
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time 
documented in the CRF.
  All efforts will be made to obtain the PK samples at the scheduled 
nominal time relative to dosing. However, samples obtained within 10% of the nominal time 
(eg, within 6 minutes of a 60 minute sample) will be considered protocol complaint, and the 
exact time of the sample collection noted on the CRF. If a scheduled blood sample collection 
cannot be completed for any reason, the missed sample time may be re-scheduled with 
agreement of clinical investigators, patient and Sponsor.
PK samples will be assayed for PF-05082566 and rituximab using a validated analytical 
method in compliance with Pfizer standard operating procedures. Details regarding the 
collection, processing, storage and shipping of the blood samples will be provided in the 
study manual.
7.2.3. Dose Expansion Cohorts – Portion A and Portion B
7.2.3.1. PF-05082566 PK Sampling for Dose Expansion Cohorts (Portions A and B)
For patients enrolled into each of the expansion cohorts for Portions A and B, blood samples 
will be collected for PK of PF-05082566 for at least 5 patients in each dose cohort at the 
following times:
•
During Cycle 1 on (a) Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hrs post 
start of infusion; (b) one sample on Days 7 and 14, respectively;
•
During Cycles 2 and 3 on (c) Day 1 at pre-dose, and end of infusion;
•
During Cycle 4 on (d) Day 1 at pre-dose, and end of infusion, and 2, 6, and 24 hrs
post start of infusion; (e) one sample on Days 7 and 14, respectively;
•
Subsequently, every 4 cycles on Day 1 at pre-dose (Cycles 8, 12, 16, etc.);
•
At the End of Treatment visit.
For the remaining patients in Portions A and B expansion cohorts, PK samples will be 
collected on Day 1 of Cycles 1 to 4 at pre-dose and end of infusion. After Cycle 4, PK 
samples will be collected on Day 1 at pre-dose every 4 cycles (Cycles 8, 12, 16, etc.).  A final 
PK sample should be collected at the End of Treatment visit.
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7.2.3.2. Rituximab PK Sampling for Dose Expansion Cohort (Portion B Only)
Blood samples will be collected for PK of rituximab for at least 5 patients enrolled in the 
expansion cohort for FL at the following times (NOTE: All days are numbered relative to the 
start of PF-05082566 dosing): 
•
On Day (-7) and Day (0) at pre-dose and end of infusion of rituximab;
•
During Cycle 1 on: (a) Day 1 at 2 and 24 hrs post start of infusion of PF-05082566; 
(b) Day 7 and Day 14 at pre-dose and end of infusion of rituximab;
•
During Cycle 2 on: Day 1 prior to the dose of PF-05082566;
•
A final PK sample should be collected at the End of treatment visit. 
For the remaining patients in Portion B expansion cohorts, PK samples for rituximab will not 
be collected.
Note that whenever rituximab PK samples are collected on days where PF-05082566 PK 
samples are being collected, these collections should be time matched to avoid multiple 
needle sticks. 
 
 
 
 
 
 
 
 
 
 
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All efforts should be made to time match the PK samples with the biomarker samples 
whenever these samples are collected together.
 
 
Flow cytometry of peripheral blood mononuclear cells (PBMCs) will also be conducted to 
determine the absolute counts of key cell types, including T cells B cells, and NK cells.  
These measurements will be used to detect changes in PBMC composition after treatment 
and will be conducted in parallel with the PK assessment as in Section 7.2.1 and 7.2.2.
 
 
 
 
 
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7.3.3.3. Immunogenicity Assessments for Expansion Cohorts (Portion A and Portion B)
7.3.3.3.1. Immunogenicity to PF-05082566
Blood for PF-05082566 immunogenicity testing will be collected at
•
Day 1 prior to the dosing of PF-05082566 for Cycles 1-4;  
•
After Cycle 4, ADA samples will be collected on Day 1 at pre-dose every 4 cycles
(Cycles 8, 12, 16, etc.);
•
End of Treatment visit.
Samples will be analyzed by a laboratory to be identified by Pfizer.  See the Laboratory 
Manual for additional details. 
7.3.3.3.2. Immunogenicity to Rituximab (Portion B Only)
Blood for rituximab immunogenicity testing (NOTE: All days are numbered relative to 
PF-05082566 dosing) will be collected at:
•
Cycle 1 Day -7, Day 0, Day 7 and Day 14 prior to the dosing of rituximab;
•
Cycle 2 Day 1 prior to the dosing of PF-05082566;
•
End of treatment.
 
 
 
 
 
 
 
 
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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 a
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE. To 
assist in the determination of case seriousness further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or
receiving investigational product, through and including 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 non-serious) should be recorded on the case report form (CRF) from the 
time the patient has taken at least one dose of investigational product through the patient’s 
last visit.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;


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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational Exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or


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
Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.5. Serious Adverse Events
A SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a 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 a 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 adverse event and as a SAE with common terminology criteria 
for adverse events (CTCAE) Grade 5 (see the section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on SAE Reporting Requirements). 
8.5.2. 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. 


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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range
who subsequently present with AST or ALT values ≥3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For patients with preexisting ALT OR, AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal range:
AST or ALT values ≥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 one time the upper 
limit of normal or if the value reaches 3 times the upper limit of normal (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 and for oncology studies, 
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
(GGT), 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 serious AEs.
8.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 


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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;

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 a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up 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;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.7. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a 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. 
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see 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.
8.9. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (eg, because of treatment or environmental exposure) to the 
investigational product; or the female becomes, or is found to be pregnant after 
discontinuing and/or being exposed to the investigational product.  An example of 


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environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to 
the investigational product prior to or around the time of conception and/or is 
exposed during his partner’s pregnancy.
If a 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 in Utero (EIU) 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 EIU Form.  
This must be done irrespective of whether an adverse event 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 EIU 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 EIU Supplemental Form.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for the termination should be specified and, if clinically possible, the structural integrity of 
the terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for a serious adverse event (ie, ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly [in a live born baby, a terminated fetus, an intrauterine fetal demise or a neonatal 
death]), the investigator should follow the procedures for reporting serious adverse events.
Additional information about pregnancy outcomes that are reported as serious adverse events 
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 serious adverse events.  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 
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 
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8.10. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to 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 subject enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE report form is maintained in the investigator site file.
8.11. Withdrawal Due to Adverse Events (See also the section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page.
When a patient withdraws because of a SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If a SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If a SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the serious adverse event is fatal or life-threatening, notification to 
Pfizer must be made immediately, irrespective of the extent of available adverse event 
information.  This timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of EDP,
exposure via breastfeeding, and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of a SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.  For all SAEs, the investigator is obligated to pursue 
and provide information to Pfizer in accordance with the timeframes for reporting specified 
above.  In addition, an investigator may be requested by Pfizer to obtain specific additional 
follow-up information in an expedited fashion.  This information collected for SAEs is more 
detailed than that captured on the AE case report form.  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 


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causes of the event, such as concomitant medications, vaccines, and/or illnesses must be 
provided.  In the case of a patient death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of serious AE 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 serious AE information.
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (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.
Japan cohort(s) data will be summarized separately from the patients enrolled outside of 
Japan in Portion A of the study.
9.1. Analysis Sets 
According to ICH E9 only analysis sets needed for main analysis are indicated here.  Other 
analysis sets are indicated in the SAP.
1. Safety analysis set.
For the randomized cohorts: The safety analysis set will include all patients who receive 
at least 1 dose of study drug.  Patients will be classified according to the treatment 
assigned at randomization unless the incorrect treatment(s) was/were received throughout 
the dosing period, in which case patients will be classified according to the first study 
treatment received. 
For non-randomized cohorts: The safety analysis set will include all patients who receive 
at least 1 dose of study drug.  Patients will be classified according to the study treatment 
actually received.  If a patient receives more than 1 study treatment, the patient will be 
classified according to the first treatment received.
2. Full analysis set.
For the randomized cohorts: The full analysis set (FAS) will include all randomized 
patients.  Patients will be classified according to the treatment assigned at randomization.


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For non-randomized cohorts: The FAS will include all patients who receive at least 
1 dose of study drug.  Patients will be classified according to the study treatment actually 
received.  If a patient receives more than 1 treatment, the patient will be classified 
according to the first treatment received.  In the non-randomized cohorts of the study, the 
FAS and the safety analysis set are identical.
3. Per protocol analysis set (DLT-evaluable set).
The per protocol analysis set is a subset of the safety analysis set, and it includes all 
patients who received at least 1 dose of study treatment (for Portion A: at least 1 dose of 
PF-05082566; for Portion B: at least 1 dose of PF-05082566 and 1 dose of rituximab).  
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.
4. PK analysis sets.
The PK concentration population is defined as all treated patients who have at least 
1 concentration.
The PK parameter analysis population is defined as all treated patients who have at least 
1 of the PK parameters of interest. 
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) (O’Quigley et al., 1990)22, and its variants. 
Delayed-onset toxicities are a particular challenge for phase I trials of combination therapies 
(Muler et al., 2004).22 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 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 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 
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TITE-CRM is to be implemented as described by Cheung et al. (2000) and Normolle et al. 
(2006)19 for the dose escalation of PF-05082566.  PF-05082566 will be administered IV at 
escalating doses of 0.60, 1.2, 2.4, 5 mg/kg as a single agent in Portion A (the standard 
3+3 method is used for doses up to 0.30 mg/kg), and at escalating doses of 0.03, 0.06, 0.12, 
0.18, 0.24, 0.30, 0.60, 1.2, 2.4, 5 mg/kg given once every 4 weeks in Portion B in 
combination with rituximab, which will be administered at a fixed dose of 375 mg/m2, once 
per week for 4 weeks total (Cycle 1).  If 5 mg/kg of PF-05082566 is well tolerated, the 
sponsor may investigate the 10 mg/kg level for the estimation of the MTD.  The following 
dose levels are available for the dose ranges bracketed between 0.6 and 5 mg/kg based on the 
TITE-CRM indicated dose reduction from the next highest planned dose level: 0.45, 0.9, 1.8, 
3.6, and 7.5 mg/kg). However, they will not be tested if a dose reduction is not 
recommended by the statistical model.  In addition, these intermediate dose levels may be 
used for dose escalation if one dose limiting toxicity is observed at the preceding regular 
dose level
We define the MTD to be the highest dose that is associated with a DLT rate ≤25%. A 
power function modeling DLT rate at each dose di (i=1, …, 14) 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≤…≤p14. These 
estimates will be projected based on the Portion A single-agent PF-05082566 safety profile 
in the first 3 dose levels, together with the pre-clinical animal data.  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 our 
trial, we set 
0
=0.97, which provides a reasonably flat prior distribution of , with 
95% Bayesian credible interval of 
)
exp( : [0.15, 6.67], sufficiently wide to cover a wide 
spectrum of dose-toxicity scenarios.  Figure 5 illustrates the dose-toxicity curve with 
95% upper and lower bounds when the initial prior estimates
ip are (1.4e-05, 1.4e-04, 
9.0e-04, 3.8e-03, 0.01, 0.03, 0.06, 0.11, 0.17, 0.25, 0.33, 0.42, 0.50, 0.58).


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Figure 5.
Example Plot of Prior Dose-Toxicity Curve
Prior dose-toxicity curve with 95% upper and lower bounds
Dose Level of PF-05082566 (mg/kg)
DLT Rate
0.03
0.06
0.12
0.18
0.24
0.3
0.45
0.6
0.9
1.2
1.8
2.4
3.6
5
0
0.1
0.2
0.25
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the trial conduct, the first 3 patients will be treated at the lowest dose level. For each 
subsequent patient eligible for enrollment, 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 MTD, defined 
as the dose having an estimated probability of DLT closest to but not greater than the target 
rate (25%). The probabilities of toxicity are estimated based on the Bayesian power model 
with prior distribution of the parameter to learn about the overall dose-toxicity relationship. 
Patients’ DLT data will be reported in real time to the study statistician who will estimate the 
MTD before the next enrolled patient is treated.
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 a weight equal to the proportion of 
the 8-week (2 cycles of PF-05082566) DLT observation period the patients have completed 
(however the weight function may be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566, or an adaptive weight function if 
ongoing safety data suggest different toxicity patterns in Cycle 1 and Cycle 2 of 
PF-05082566); patients who experience DLT or complete the observation period without 
DLT will be assigned full weight (=1) (for details see the Statistical Analysis Plan).
Section 3.3.2 describes stopping rules and some restrictions and practical considerations on 
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9.3. Sample Size Determination
The sample sizes planned for the study arise from logistic feasibility and past experience with 
first in human (FIH) studies in oncology and are not driven by statistical considerations. It is 
expected that approximately 270 patients will be required (including dose escalation and 
expansion cohorts of Portion A and Portion B). 
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
TITE-CRM approach can not be determined in advance. The maximum sample size is set 
as 45 in order to have a reliable and accurate estimate of the MTD based on simulation 
results. Based on probability theory, a sample size of 45 will ensure the estimates of any 
binary variable (eg, objective response rate)  have a 95% confidence interval of width <0.30. 
A sample size of 45 also enables us to detect any unexpected toxicity that occurs at 5% rate 
(in a non-dose-dependent fashion) with a probability of 0.90, and that occurs at 10% rate 
with a probability of 0.99. 
A stopping rule (Section 3.3.2) will also be implemented for possible early stopping if there 
is strong confidence in the estimated MTD.
Portion A expansion cohorts include patients with solid tumors of interest who progressed 
after treatment with an immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1/PD-L1).  The 
target sample size is approximately 20 patients with advanced melanoma at each tested dose 
(0.24 mg/kg, 0.6 mg/kg, 1.2 mg/kg) and approximately 20 patients, including other tumor 
types as described in Section 4.1, Inclusion Criteria (Criterion 1).  With 20 patients with 
advanced melanoma, the maximum standard error of the objective response rate (ORR) is 
0.11.
Number of Patients with 
Responses/Sample Size (Advanced 
Melanoma)
Objective Response Rate (ORR)
and Estimated 95% CI (%)* 
2/20
10% (1.2, 31.7)
4/20
20% (5.7, 43.74)
6/20
33% (11.9, 54.3)
10/20
50% (27.2, 72.8)
*Clopper-Pearson CI
Portion B expansion cohorts include approximately 100 patients with FL refractory to 
rituximab (see Section 4.1 for definition of FL disease refractory to rituximab) with 
80 patients treated at the selected RP2D (1.2 mg/kg or 0.24 mg/kg) dose level of 
PF-05082566.  With 80 patients, the maximum standard error of the ORR is 0.06.


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Responses/Sample size (FL 
Refractory to Rituximab)
Objective Response Rate (ORR)
and Estimated 95% CI (%)*
40/80
50% (38.6, 61.4)
44/80
55% (43.5, 66.2)
48/80
60% (48.4, 70.8)
56/80
70% (58.7, 79.7)
*Clopper-Pearson CI
9.4. Efficacy Analysis
In this first-in-human study anti-tumor activity is a secondary objective in the dose escalation 
cohorts and a primary objective in the expansion cohorts and will be evaluated separately in 
Portion A and Portion B. 
The detailed definitions of objective response (OR), best overall response (BOR), objective 
ORR, duration of response (DR), time to tumor response (TTR), progression-free survival 
(PFS), and overall survival (OS) will be provided in a Statistical Analysis Plan (SAP).
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, progression date, death date, date of first response and last 
tumor assessment date will be listed, together with Duration of Response, Progression Free 
Survival and Overall Survival. If any responses are observed for patients with measurable 
disease at baseline, tumor responses will be tabulated by dose level(s). 
ORR by treatment group will be calculated along with the two-sided 95% CI using the 
Clopper-Pearson method.
DR, PFS, and OS will be analysed using Kaplan-Meier methods and descriptive statistics.  
Point estimates will be presented with their 95% confidence intervals.
TTR will be summarized using simple descriptive statistics (eg median and range).
 
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9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Single- and Multiple-Dose PF-05082566 and Rituximab PK Analysis
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), pre-dose serum concentration during multiple dosing 
(Ctrough), area under the serum concentration versus time curve from 0 to infinity (AUCinf), 
area under the serum concentration versus time curve over dosing interval (AUCtau), terminal
elimination half-life (t1/2), total systemic clearance (CL), steady state volume of distribution 
(Vss), accumulation ratio (Rac) will be estimated. For rituximab, Cmax and Ctrough will be 
summarized.  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.
For PF-05082566 and rituximab concentrations, individual values and descriptive statistics 
(n, mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) will 
be presented by dose, cycle, day of assessment, and nominal time in tabular form. Individual
patient and median profiles of the concentration-time data will be plotted by dose, cycle and
day. Median profiles will be presented on both linear-linear and log-linear scales.  AUCinf
(AUCtau at steady state), AUClast 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 
proportionality for PF-05082566.
 
 
 
 
9.5.1.3. Analysis of Immunogenicity Data
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies (Nab) will be summarized by dose.  For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit.  The effect of ADA/Nab on PF-05082566 PK and safety will be evaluated if data 
permit.
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9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint(2-cycle DLT) in the dose escalation 
cohorts will be based on the per protocol analysis set.  DLT will continue to be monitored as 
a secondary endpoint in the expansion cohorts 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 in the Dose Escalation Cohorts
First 2 cycles DLTs 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 MTDs of 
PF-05082566 with or without rituximab as described in Section 4.4. AEs constituting DLTs 
will be listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). The focus of AE 
summaries will be on Treatment Emergent Adverse Events, those with initial onset or 
increasing in severity after the first dose of study medication. The number and percentage of 
patients who experienced any AE, SAE, treatment related AE, and treatment related SAE 
will be summarized according to worst toxicity grades. The summaries will present AEs 
both on the entire study period and by cycle (Cycle 1 and Cycles ≥1). 
C
C
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Laboratory Tests Abnormalities
The number and percentage of patients who experience laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay. The 
analyses will summarize laboratory tests both on the entire study period and by cycle (Cycle 
1, Cycle 2, and Cycles 2). 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal or not done.
Electrocardiograms
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.  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, 
Bazett’s, Fridericia’s and possibly a study specific factor). The adequacy of the correction 
method will be assessed graphically (plots of QT and QTc versus RR) and supplementary
transformations may be considered, as appropriate. Data will be summarized and listed for 
QT, HR, RR, PR, QRS, QTcF and QTcB by treatment and dose. Individual QTc (all 
evaluated corrections) intervals will be listed by compound, 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 QTc value and changes from baseline in QTc after treatment by compound, dose 
and by time point. For each patient and by treatment, the maximum change from baseline 
will be calculated as well as the maximum post-baseline value across time-points. Outlier 
analysis of the QTc data will be conducted and summarized as follows:

The number of patients with maximum change from baseline in QTc (<30, 30-<60, 
and 60 msec);

The number of patients with maximum post-dose (post-baseline) QTc (450, 
>450-480, >480- 500, and >500 msec).
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).


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The effect of drug concentrations on QTc change from baseline will be explored graphically. 
Additional concentration-QTc analyses may be performed.  Data may be pooled with other 
study results and/or explored further with PK
 models.
9.7. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team 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;
•
The Investigators and Sponsor will discuss results, AEs, clinical laboratory tests seen 
at each dose level in an ongoing manner at regular teleconferences and/or meetings to 
determine the safety profile and benefit/risk ratio and decide if further enrollment is 
appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP)s are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.
The study site may be patient to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry”.
In most cases, the source documents are the hospital's or the physician’s patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence 
(eg, letters, meeting minutes, telephone calls reports).  The records should be retained by the 
investigator according to ICH, local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  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)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, Molecular Profiling Supplement, informed consent forms, and other 
relevant documents, eg, recruitment advertisements, if applicable, from the IRB/IEC.  All 
correspondence with the IRB/IEC should be retained in the Investigator File.  Copies of 
IRB/IEC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Patient names, address, birth date and other identifiable data will be replaced by an 
alpha-numerical code consisting of a numbering system provided by Pfizer and year of birth.
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of patient personal data.
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient's legal representative before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent form.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Study Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Patient Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-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 trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.


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Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, patient 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.


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Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled 
Publications by Investigators, the defined terms shall have the meanings given to them in the 
Clinical Study Agreement.


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16. REFERENCES
1.
Ahuja A, Shupe J, Dunn R, et al. Depletion of B cells in murine lupus: efficacy and 
resistance. J Immunol. 2007 Sep 1;179(5):3351-61.
2.
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):543-9.
3.
Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of 
TNF receptor signaling. Cytokine. 2007 Feb;37(2):101-7.
4.
Cheung YK, Chappell R. Sequential designs for phase 1 clinical trials with late-onset 
toxicities.  Biometrics 2000; Dec; 56(4):1177-82.
5.
Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat 
Rev Immunol. 2009 Apr;9(4):271-85.
6.
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):883-5.
 
 
 
 
10.
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):3431-8. 
Epub 2009 Jul 29.
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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.
12.
Long AH, Haso WM, Shern JF et al. 4-1BB costimulation ameliorates T cell exhaustion 
induced by tonic signaling of chimeric antigen receptors. Nature Med. 2015;21:581-90.
13.
Lynch DH. The promise of 4-1BB (CD137)-mediated immunomodulation and the 
immunotherapy of cancer.  Immunol Rev. 2008 Apr;222:277-86.
14.
Linch SN et al., OX40 agonists and combination immunotherapy: putting the pedal to 
the metal. Front Oncol. 2015 Feb 16;5:34.
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15.
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):290-5.
16.
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 22: 238-243, 2004.
 
 
 
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Normolle D, Lawrence T: Designing dose-escalation trials with late-onset toxicities 
using the time-to-event continual reassessment method. J Clin Oncol 24: 4426-4433, 
2006.
21.
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):1292-301.
22.
O’Quigley J, Pepe M, Fisher L: Continual reassessment method: A practical design for 
phase I clinical trials in cancer. Biometrics 46: 33-48, 1990.
23.
Park S, Jiang Z, Mortenson ED, et al. The therapeutic effect of anti-HER2/neu 
antibodydepends on both innate and adaptive immunity. Cancer Cell. 2010 Aug 
9;18(2):160-70.
24.
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):8093-101.
25.
Seaman S, Stevens J, Yang MY, et al. Genes that distinguish physiological and 
pathological angiogenesis. Cancer Cell. 2007 Jun;11(6):539-54.
26.
Vinay DS, Cha K, Kwon BS. Dual immunoregulatory pathways of 4-1BB signaling. J 
Mol Med. 2006 Sep;84(9):726-36.
CCI
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27.
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.
28.
Weiner LM, Dhodapkar MV, Ferrone S. Monoclonal antibodies for cancer 
immunotherapy. Lancet. 2009 Mar 21;373(9668):1033-40.
29.
Zhang X, Voskens CJ, Sallin M, et al. CD137 promotes proliferation and survival of 
human B cells. J Immunol. 2010 Jan 15;184(2):787-95. Epub 2009 Dec 11.
30.
Kohrt HE, Houot R, Weiskopf K, et al. Stimulation of natural killer cells with a CD137-
specific antibody enhances trastuzumab efficacy in xenotransplant models of breast 
cancer. J Clin Invest. 2012 Mar;122(3):1066–75.
31.
Solal-Celigny P, Roy P, Colombat P, White J, et al. Follicular lymphoma international 
prognostic index. Blood 2004 Sep;104 (5):1258-65.
32.
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss 
the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J 
Clin Oncol. 1989 Nov;7(11):1630-6.


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Appendix 1. Abbreviations
4-1BB
TNFRSF9,  CD137,  ILA
4-1BBL
4-1BB Ligand, TNFSF9
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
APC
Antigen presenting cell
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the concentration vs time curve
AUC0-168
area-under-the-curve from time zero to 168 hours
AUC0-672
area-under-the-curve from time zero to 672 hours
AUC0-last
area-under-the-curve from time zero to last measurable concentration
BM
Bone marrow
BOR
Best overall response
BUN
Blood urea nitrogen 
CARs
Chimeric antigen receptors
CD20
Cluster of differentiation 20
CD40
Cluster of differentiation 40, TNFRSF5
 
CD45RA
CD45 (PTPRC) RA isoform
CD134
Cluster of differentiation 134, TNFRSF4, OX-40
Cave
Estimated average serum concentration
CI
Confidence interval
CL
Clearance
CLL
Chronic lymphocytic leukemia
Cmax
Maximum observed serum concentration 
CR
Complete response
CRF
Case report form
CRM
Continual reassessment method
CRP
C reactive protein
CT
Computerized Tomography 
CTA
Clinical study application
CTCAE
Common Terminology Criteria for Adverse Events
CXCR6
Chemokine (C-X-C motif) receptor 6; CD186
CTLA-4
Cytotoxic T-Lymphocyte-Associated protein 4
DC
Dendritic cell
DLBCL
Diffuse Large B-Cell Lymphoma
DLT
Dose limiting toxicity
CCI
CCI
CCI
CCI
CCI
CCI
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DR
Duration of response
EC
Ethics committee
EC10
Concentration required to achieve 10% of the maximal response
ECD
Extracellular domain
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
ED50
Dose required to achieve 50% of the maximal response
EIU
Exposure in Utero
ELISA
Enzyme linked immunosorbent assay
ERK
Extracellular signal-regulated kinase
EUDRACT
European Union Drug Regulating Authorities Clinical Trials
EQ-VAS
Visual analogue scale
FAS
Full analysis set
FACS
Fluorescent-activated cell sorting; flow cytometry
Fc
Fragment crystallizable
FDA
Food and Drug Administration
FIH
First in human
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
GCPs
Good Clinical Practices
GGT
Gamma-glutamyl transferase
GTD
Greatest transverse diameter
Hb
Hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
ICH
International Code of Harmonization
IEC
Independent ethics committee
IgG
Immunoglobulin G
IgG2
Immunoglobulin G subclass 2
IHC
Immunohistochemistry
IND
Investigational new drug
INN
International non-proprietary name
INR
International normalized ratio
IP
Investigational product
IRB
Institutional review board
IRT
Interactive response technology
ITGB7
Integrin beta 7
IUD
Intrauterine device
IV
Intravenous(ly)
LFT
Liver function test
LDH
Lactate dehydrogenase 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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LOAEL
Lowest observed adverse effect level
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MABEL
Minimal anticipated biological effect level
MAP
Mitogen activated protein
MCL
Mantle cell lymphoma
MCC
Merkel cell carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
UK Medicines and Healthcare products Regulatory Agency
MRI
Magnetic Resonance Imaging
MUGA
Multigated acquisition
MPK
Milligrams per kilogram, mg/kg
MTD
Maximum tolerated dose
Nab
Neutralizing antibodies
NCI
National Cancer Institute
NF-kB
Nuclear Factor kappa B
NHL 
Non-Hodgkin's Lymphoma
NK
Natural killer cell
NKT
Natural killer T cell
NSCLC
Non-small cell lung carcinoma
NOAEL
No observed adverse effect level
NYHA
New York Heart Association
OBD
Optimal biological dose
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PBL
Peripheral blood leukocyte
PD-1
Programmed cell Death-1
PD-L1
Programmed cell Death- Ligand 1
PET
Positron emission tomography
PR
Partial response
PFS
Progression-free survival 
PK
Pharmacokinetics
PML
progressive multifocal leukoencephalopathy
POM
Proof of mechanism
PR
Partial response
PT
Prothrombin time
QTcF
QT interval corrected by Fridericia’s formula
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
SAMD
Single agent, multiple dose
SAP
Statistical analysis plan
SC
Subcutaneous
SCCHN
Squamous cell carcinoma of the head and neck
sCD25
Soluble CD25
SCID
Severe combined immunodeficiency
SAE
Serious Adverse Event
SEM
Standard error of the mean
CCI
CCI
CCI
CCI
CCI
C
CI
CCI


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sFasL
Soluble Fas Ligand
SLL
Small lymphocytic lymphoma
SOP
Standard Operating Procedures
SDP
Sum of the product diameters
SPR
Surface plasmon resonance 
SRSD
Single reference safety document
t1/2
Half-life
TCR
T-Cell Receptor
TGI
Tumor growth inhibition
TITE-CRM
Time-to-Event Continual Reassessment Method
TNF
Tumor necrosis factor
TNFR
Tumor necrosis factor receptor
TNFRSF
Tumor necrosis factor receptor super family
TRAF
TNFR associated factor
TSH
Thyroid-stimulating hormone
TTR
Time to tumor response
ULN
Upper limit of normal
US
United States
USA
United States of America
Vss
Volume of distribution at steady state
WHO
World Health Organization
CCI
CCI
CCI


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Appendix 2. Determination of Efficacy – Solid Tumors
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.

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.


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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 2 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. 
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 12.
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 13.
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

Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009 Jan;45(2):228-47.


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Appendix 3. Determination of Efficacy – Non-Hodgkin’s Lymphoma
Efficacy will be assessed using the International Working Group response criteria (Cheson 
Criteria Version 2007).  Tumor responses are determined using information from objective 
measurements from CT scans, as well as clinical information including B-symptom 
evaluation, physical examination, ECOG performance status, assessment of liver and spleen, 
laboratory assessments such as bone marrow biopsies and/or aspirates, biochemical markers 
of disease activity (ie, LDH) and hematology results.
Tumor and clinical assessments will be performed as described in the Tumor Assessment 
flowchart.  Treatment delays should not alter the schedule of tumor and clinical assessment 
evaluations and should continue at the frequency outlined in the flowchart.
For patients to be considered evaluable for efficacy, they must have completed at least 
1 follow-up radiological tumor assessment post randomization, they must have received 
sufficient investigational product (at least one cycle of PF-05082566) and they must not have 
had any major protocol violations as determined by the sponsor.
Measurable/Abnormal Lesions
A nodal site of disease is considered measurable/abnormal if:

Any nodal lesion can have a single diameter of >15 mm in the GTD, and the 
perpendicular dimension to the GTD must have a diameter >10 mm in order to be 
considered abnormal and measurable.

Any nodal lesion can have >10 mm through ≤15 mm in the GTD, and the 
perpendicular dimension to the GTD must have a diameter >10 mm to be considered 
abnormal.
A nonnodal site of disease is considered measurable/abnormal if it measures ≥10 mm in 
2 perpendicular dimensions.
Nonmeasurable Lesions
All non nodal sites of disease that that measure 10 mm in a single GTD are considered non 
measurable.  Other sites of disease that are considered evaluable, but not measurable include 
pleural effusions, ascites and bone lesions.
Index Lesions
Up to 6 measurable/abnormal lesions should be selected as index lesions.  Lesions can be 
selected as index lesions if they are clearly measurable in 2 perpendicular dimensions.  
Lesions cannot be selected as index lesions if they have been in an area of prior radiotherapy 
without evidence of progression.  These lesions should be selected from disparate regions of 
the body as possible and should include mediastinal and retroperitoneal sites if these sites are 
involved.  The greatest transverse diameter and the greatest perpendicular transverse 
diameter will be recorded for each index lesion.  The product of these 2 dimensions will be 
recorded and the sum of the product diameters (SPD) of the index lesions will be the baseline 
value used in determining response.


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Non-Index Lesions
All other lesions, either measurable or non measurable, are considered non index lesions.  
Multiple lesions may be grouped together as a non-index lesion (ie, multiple bony lesions in 
scapula).  The status of the non index lesion will be recorded on the CRF.
Method of Measurement

At a minimum, conventional CT or MRI should be performed with contiguous slices 
of 10 mm or less in thickness.  Spiral CT should be performed by use of 8 mm or less 
contiguous reconstruction interval.  The same method of measurement should be used 
throughout.

CT scans with contrast should be performed for radiographic assessments.  If a chest 
CT is not feasible with contrast, a non contrast CT should be performed.  If CT 
abdomen/pelvis with contrast is not feasible, then an MRI of the abdomen/pelvis 
should be performed.

Positron emission tomography (PET) scans should not be used for the determination 
of response, however, may be obtained if clinically indicated.  Additionally, 
ultrasounds should not be used for purposes of measuring or evaluating disease in this 
study.
Clinical Assessments
In addition to radiographic tumor measurements, other clinical assessments should be 
obtained when evaluating disease.  These include:

Physical examination findings, evaluation presence, absence or any new lymph 
nodes.  Additionally, an assessment of ECOG performance status will be obtained.

Evaluation of B-symptoms.

Bone marrow biopsies and/or aspirates.

Evaluation of the liver and spleen.

Biochemical markers of disease, including LDH.


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Response Criteria
Evaluation of Index Lesions
Term
Definition
Complete 
Response
Complete disappearance of all detectable clinical and radiographic evidence 
of disease.
All lymph nodes must have returned to normal size.  If a lymph node GTD 
was 15 mm, it must have returned to 15 mm.  If the short axis was >10 mm 
and the GTD was >11 mm, it must have returned to 10 mm.
The spleen and/or liver, if enlarges prior to therapy on PE or CT, should no 
longer be palpable on PE and normal by imaging.
Partial Response
50% decrease in the SPD of up to 6 index lesions.
No increase in size of other nodes, liver or spleen.
Stable Disease
Failure to attain a CR/PR or PD.
Progressive 
Disease/Relapsed 
Disease
50% increase in SPD of previously involved sites from nadir.
Unable to Evaluate
Incomplete data (ie, missing scans or unreadable images).
Not all index lesions evaluated.
Index lesions not assessed.
Evaluation of Non-Index Lesions
Term
Definition
Complete Response
Complete disappearance of all non-index lesions.
Stable 
Disease/Incomplete 
Response
Persistence of one or more non-index lesion not qualifying for CR or PD.  
Progressive 
Disease
Any new nonnodal lesion.
Any new nodal lesion ≥15 mm in GTD.
Unequivocal progression of existing non-index lesions.
Bone marrow that was negative and is now positive.
Any new circulating lymphoma cells in blood cell count and/or pleural fluid.
Any new circulating blasts in the blood cell count.
Unable to Evaluate
Incomplete data (ie, missing scans or unreadable images).
Not all non-index lesions evaluated.
Non-index lesions not assessed.
Not Applicable
No non-index lesions at baseline.


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Overall Response
Index Lesions
Non-Index lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
SD/IR
No
PR
CR
UE
No
CR
CR
NA
No
CR
PR
CR
No
PR
PR
SD/IR
No
PR
PR
UE
No
PR
PR
NA
No
PR
SD
CR
No
SD
SD
SD/IR
No
SD
SD
UE
No
SD
SD
NA
No
SD
RD/PD
Any
Yes/No
RD/PD
Any
RD/PD
Yes/No
RD/PD
Any
Any
Yes
RD/PD
UE
Non-PD
No
UE

Adapted from: Cheson B, Pfistner B, Juweid M, et al. Revised Response for Malignant 
Lymphoma. Journ Clin Onc. 2007;25(5):579-586.


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Appendix 4. Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG 
Grade
Description
Karnofsky 
Score*
0
Fully active, able to carry on all predisease performance without 
restriction
100
1
Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature, ie, light house work, 
office work.
80 or 90
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours
60 or 70
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
40 or 50
4
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair.
20 or 30
* Karnofsky Performance Score is provided for reference.  Please record corresponding ECOG grade only.


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SAP_001.pdf: 
PF-05082566
B1641001 Statistical Analysis Plan    
Page 1
B1641001
A PHASE 1 STUDY OF PF-05082566 AS A SINGLE AGENT IN PATIENTS WITH 
ADVANCED CANCER, AND IN COMBINATION WITH RITUXIMAB IN 
PATIENTS WITH NON-HODGKIN’S LYMPHOMA (NHL)
STATISTICAL ANALYSIS PLAN
Compounds:
PF-05082566
Compound Name:
Utomilumab
Version:
Amendment 2
Date:
2-Mar-2017


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................9
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................15
3.1. Primary Endpoint – Dose Escalation Cohorts.........................................................15
3.2. Secondary Endpoints – Dose Escalation Cohorts ...................................................16
3.2.1. Safety Endpoints.........................................................................................16
3.2.2. Efficacy Endpoints......................................................................................16
3.2.3. Pharmacokinetic Endpoints ........................................................................16
3.2.4. Immunogenicity Endpoints.........................................................................17
3.4. Primary Endpoint – Expansion Cohorts..................................................................18
3.5. Secondary Endpoints – Expansion Cohorts ............................................................18
3.5.1. Safety Endpoints.........................................................................................18
3.5.2. Efficacy Endpoints......................................................................................19
3.5.3. Pharmacokinetic Endpoints ........................................................................19
3.5.4. Immunogenicity Endpoints.........................................................................19
 
 
3.7. Baseline Variables...................................................................................................20
3.7.1. Study Drug, Study Treatment and Baseline Definitions ............................20
3.7.2. Baseline Characteristics..............................................................................22
3.8. Safety Endpoints .....................................................................................................22
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3.8.1. Adverse Events...........................................................................................22
4. ANALYSIS SETS ...............................................................................................................22
4.1. Full Analysis Set .....................................................................................................22
4.2. Safety Analysis Set..................................................................................................23
4.3. Other Analysis Set...................................................................................................23
4.3.1. DLT-evaluable Set......................................................................................23
4.3.2. PK Analysis Set ..........................................................................................23
4.3.4. Immunogenicity Analysis Set.....................................................................23
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................24
5.1. Hypotheses and Decision Rules ..............................................................................24
5.1.1. Hypotheses and Sample Size Determination..............................................24
5.1.2. Decision Rules Using the TITE-CRM Method ..........................................25
5.2. General Methods .....................................................................................................28
5.2.1. Data Handling After the Cut-off Date ........................................................29
5.2.2. Pooling of Centers ......................................................................................29
5.2.3. Presentation of Continuous and Qualitative Variables...............................29
5.2.4. Definition of Study Day..............................................................................29
5.2.5. Definition of Start of New Anti-cancer Drug Therapy...............................30
5.2.6. Definition of Start of New Anti-cancer Therapy........................................30
5.2.7. Definition of On-treatment Period..............................................................30
5.2.8. Standard Derivations and Reporting Conventions .....................................31
5.2.9. Unscheduled Visits.....................................................................................31
5.2.10. Adequate Baseline Tumor Assessment ....................................................31
5.2.11. Adequate Post-baseline Tumor Assessment.............................................32
5.3. Methods to Manage Missing Data ..........................................................................32
5.3.1. Missing Data...............................................................................................32
5.3.1.1. Pharmacokinetic Concentrations...............................................32
5.3.1.2. Pharmacokinetic Parameters .....................................................33
5.3.2. Handling of Incomplete Dates....................................................................33
5.3.2.1. Disease History .........................................................................33
5.3.2.2. Adverse Events..........................................................................33
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5.3.2.3. Prior and Concomitant Medications..........................................35
5.3.2.4. Exposure....................................................................................35
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments......35
5.3.3.1. Date of Last Contact..................................................................35
5.3.3.2. Death Date.................................................................................36
5.3.3.3. Tumor Assessments...................................................................36
5.3.3.4. Date of Start of New Anti-cancer Therapy ...............................37
6. ANALYSES AND SUMMARIES ......................................................................................37
6.1. Primary Endpoints...................................................................................................37
6.1.1. DLT (Dose-escalation Cohorts)..................................................................37
6.1.1.1. Primary Analysis.......................................................................37
6.1.2. Objective Response as Assessed by the Investigator (Expansion 
Cohorts)............................................................................................................37
6.1.2.1. Primary Analysis.......................................................................37
6.2. Secondary Endpoint(s) ............................................................................................37
6.2.1. Safety Endpoints.........................................................................................37
6.2.2. Efficacy Endpoints......................................................................................38
6.2.2.1. Objective Response as Assessed by the Investigator................38
6.2.2.2. Tumor Shrinkage.......................................................................40
6.2.2.3. Duration of Response................................................................41
6.2.2.4. Time to Response......................................................................42
6.2.2.5. Progression-free Survival..........................................................42
6.2.2.6. Overall Survival ........................................................................44
6.2.3. Pharmacokinetic Endpoints ........................................................................45
6.2.3.1. Non-compartmental Analysis....................................................45
6.2.3.2. Population Pharmacokinetic Analysis.......................................46
6.2.4. Endpoints for Immunogenicity Data of PF-05082566 and Rituximab.......46
 
6.4. Subset Analyses.......................................................................................................49
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6.5. Baseline and Other Summaries and Analyses.........................................................49
6.5.1. Baseline Summaries....................................................................................49
6.5.1.1. Demographic Characteristics ....................................................49
6.5.1.2. Medical History.........................................................................51
6.5.1.3. Disease Characteristics..............................................................51
6.5.1.4. Prior Anti-cancer Therapies ......................................................51
6.5.2. Study Conduct and Patient Disposition......................................................53
6.5.2.1. Patient Disposition ....................................................................53
6.5.2.2. Protocol Deviations...................................................................54
6.5.3. Study Treatment Compliance and Exposure ..............................................55
6.5.3.1. Exposure to PF-05082566.........................................................56
6.5.3.2. Exposure to Rituximab..............................................................56
6.5.3.3. Dose Reductions........................................................................57
6.5.3.4. Dose Delays...............................................................................57
6.5.3.5. Infusion Rate Reductions ..........................................................58
6.5.3.6. Infusion Interruptions................................................................58
6.5.4. Concomitant Medications and Non-drug Treatments.................................58
6.5.5. Subsequent Anti-cancer Therapies .............................................................59
6.6. Safety Summaries and Analyses .............................................................................59
6.6.1. Adverse Events...........................................................................................60
6.6.1.1. All Adverse Events....................................................................60
6.6.1.2. Adverse Events Leading to Treatment Discontinuation............61
6.6.2. Deaths .........................................................................................................62
6.6.3. Serious Adverse Events ..............................................................................62
6.6.4. Laboratory Data..........................................................................................63
6.6.4.1. Hematology and Chemistry Parameters....................................63
6.6.4.2. Other Laboratory Parameters ....................................................66
6.6.5. Vital Signs ..................................................................................................66
6.6.6. Electrocardiogram.......................................................................................67
6.6.7. Physical Examination .................................................................................69
6.6.8. ECOG Performance Status .........................................................................69
7. INTERIM ANALYSES.......................................................................................................69
7.1. Introduction .............................................................................................................69


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7.2. Interim Analyses and Summaries............................................................................69
8. REFERENCES ....................................................................................................................70
LIST OF TABLES
Table 2.
PK Parameters to be Determined for PF-05082566 and Rituximab.....................17
Table 3.
Outcome and Event Dates for PFS and DR Analyses ..........................................43
Table 4.
PFS Censoring Reasons and Hierarchy................................................................44
Table 5.
OS Censoring Reasons and Hierarchy..................................................................45
LIST OF FIGURES
Figure 1.
Study Design of the Expansion Cohort of Portion A ...........................................13
Figure 2.
Study Design of the Expansion Cohort of Portion B............................................15
Figure 3.
Example Plot of Prior Dose Toxicity Curve.........................................................27
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1641001 is based on the protocol 
amendment 9 dated 6 Jan 2016.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B1641001.  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,
 data, PK data). The primary analysis will include all data up to a clinical cut-
off date corresponding to 24 months (104 weeks) after the last patient is randomized (for 
randomized cohorts) or treated (for non-randomized cohorts).  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.
Throughout this document ‘start date’ refers to date of randomization for randomized cohorts 
and first dose of study treatment for non-randomized cohorts.
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2.1. Study Objectives
Primary Objective – Dose Escalation Cohorts
Portion A:

To assess safety and tolerability at increasing dose levels of single agent 
PF-05082566 in patients with advanced solid tumors or B-cell lymphoma in order to 
estimate the MTD and select the RP2D.
Portion B:

To assess safety and tolerability at increasing dose levels of PF-05082566 given in 
combination with rituximab in patients with relapsed or refractory CD20-positive 
NHL in order to estimate the MTD and select the RP2D.
Secondary Objectives – Dose Escalation Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single agent 
in patients with advanced solid tumors or B-cell lymphoma.

To evaluate the overall safety profile; 

To characterize the pharmacokinetics of PF-05082566;

To evaluate the immunogenicity of PF-05082566;

To characterize the effects of PF-05082566 on QTc;

To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL.

To evaluate the overall safety profile;

To characterize the pharmacokinetics of PF-05082566 and rituximab given in 
combination;

To evaluate the immunogenicity of PF-05082566 and rituximab;

To characterize the effects of PF-05082566 in combination with rituximab on QTc;

To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.


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Primary Objective – Expansion Cohorts
Portion A:
•
To estimate the objective response rate of PF-05082566.
Portion B:
•
To estimate the objective response rate of PF-05082566 in combination with 
rituximab.
Secondary Objectives – Expansion Cohorts
Portion A:
All secondary objectives listed below are to be evaluated for PF-05082566 as a single agent 
in patients with advanced solid tumors or B cell lymphoma.
•
To evaluate the overall safety profile; 
•
To characterize the pharmacokinetics of PF-05082566;
•
To evaluate the immunogenicity of PF-05082566;
•
To characterize the effects of PF-05082566 on QTc;
•
To evaluate the anti-tumor effect of PF-05082566.
Portion B:
All secondary objectives listed below are to be evaluated for PF-05082566 in combination 
with rituximab in patients with relapsed or refractory CD20-positive NHL.
•
To evaluate the overall safety profile;
•
To characterize the pharmacokinetics of PF-05082566 and rituximab given in 
combination;
•
To evaluate the immunogenicity of PF-05082566 and rituximab;
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•
To characterize the effects of PF-05082566 in combination with rituximab on QTc;
•
To evaluate the anti-tumor effect of PF-05082566 in combination with rituximab.
 
  
 
 
2.2. Study Design
This is a Phase 1, open label, multi-center, multiple-dose study of single-agent 
PF-05082566 in patients with advanced solid tumors or B-cell lymphoma, and of 
PF-05082566 in combination with rituximab in patients with relapsed or refractory CD20-
positive NHL.
There are 2 portions in this clinical study.  
Portion A is designed to assess the safety and tolerability, PK and PD, and to estimate the 
MTD/pharmacologically active dose and determine the RP2D of PF-05082566 administered 
as a single agent in patients with advanced solid tumors or B-cell lymphoma.  Two cohort(s) 
will be enrolled at clinical sites in Japan to evaluate safety, tolerability, and PK profile of 
PF-05082566 as a single agent in Japanese patients.  
Portion B is designed to assess the safety and tolerability, PK and PD, and to estimate the 
MTD and determine the RP2D of PF-05082566 in combination with rituximab in patients 
with relapsed or refractory CD20-positive NHL.  Acceptable safety of the single agent within 
the first 3 cohorts of Portion A will trigger the initiation of Portion B.  
Portions A and B will then escalate simultaneously and independently of each other. 
Patients may continue treatment up to a maximum of 2 years from the first dose of study 
drug, or until one of the patient withdrawal criteria becomes a reason to permanently 
discontinue study treatment.
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Dose Escalation: Portion A 
The criteria for dose escalation in Portion A will be based on the standard 3+3 design for 
dose escalation up to 0.3 mg/kg.  For dose escalation above 0.3 mg/kg, doses of 
PF-05082566 will be assigned to each enrolled patient using a Time-to-Event Continual 
Reassessment Method (TITE-CRM). 
PF-05082566 will be administered in escalating doses with available dose levels including 
the following: 0.006, 0.03, 0.06, 0.12, 0.18, 0.24, 0.30 (using the 3+3 design), and 0.6, 1.2, 
2.4, 5.0, and 10 mg/kg (using the TITE-CRM design) by intravenous (IV) infusion of 1 hour
(-5/+15 min) every 4 weeks.  
As of June 2016, the highest planned single-agent dose of 10 mg/kg was tested with no DLTs 
reported.  Patients tolerated PF-05082566 well at the highest planned dose of 10 mg/kg. If a 
dose reduction is needed for patients being treated with 0.6 to 10 mg/kg, a dose reduction 
may be made from the next highest planned dose level to one of the following specific dose 
levels: 0.45, 0.9, 1.8, 3.6, and 7.5 mg/kg.  In addition, these intermediate dose levels may be 
used for dose escalation if more than 1 DLT is observed at the preceding regular dose level. 
Each patient will initially receive the first dose on Cycle 1 Day 1 with a 28-day observation 
period.  Cycle 2 Day 1 will start on Day 29.  
Initially, 3 patients will be treated at each dose level.  For the first 3 cohorts 
(PF-05082566 given as a single agent at 0.006, 0.03, or 0.06 mg/kg), there will be a 
minimum 7-day time window between the first dose of a patient and the first dose of the next 
patient in the same cohort.  For all subsequent patients enrolled up to the 0.6 mg/kg dose 
level, a minimum 72 hour window will apply between first doses.
Current study safety data indicates that PF-05082566 infusion does not result in clinically 
significant infusion reactions.  Therefore, after completion of the 0.6 mg/kg dose level, there 
will no longer be a waiting period between patients in the same dose cohort and in dose 
expansion cohorts. 
Japan Cohort(s) in Portion A:
The Japan cohort(s) will be conducted at Japanese sites following completion of enrollment 
of the dose escalation cohorts in Portion A of this study. Patients enrolled into the Japan 
cohort(s) will receive PF-05082566 administered as a single agent once every four weeks as 
an IV infusion.  Patients enrolled in Japan will follow the same eligibility criteria, study 
procedures (unless otherwise specified), and discontinuation criteria as those patients in the 
dose escalation cohort of Portion A.  The Japan cohort(s) will enroll approximately 9 patients 
in 2 cohorts.  These cohorts will consist of 3 patients at 1 dose level below the MTD and 
6 patients at the MTD based on non-Japanese population in Portion A.


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Dose escalation in the Japan cohort(s) will be based on the standard 3+3 dose escalation 
design at 2 dose levels, 5.0 mg/kg and 10 mg/kg.  Patients recruited in Japan will be enrolled 
and analysed to confirm safety, tolerability, and PK profile of PF-05082566 in Japanese 
patients.  These patients will complete the first 2 cycles of PF-05082566 as a single-agent at 
a dose previously tested in non-Japan cohorts to evaluate potential DLTs. 
The 5 mg/kg dose (every 4 weeks) has been chosen as the starting dosage for the Japan 
cohort.  5 mg/kg is well tolerated in a non-Japanese population, and there were no observed 
DLTs in Portion A at 5 mg/kg. PF-05082566 will be administered to 3 Japan cohort patients 
with advanced solid tumors or B cell lymphoma.  After enrollment is complete, safety data 
from at least 2 cycles will be obtained and analyzed.  If the 5 mg/kg dose level is found to be 
safe, escalation to 10 mg/kg dose level will occur.  Each patient will initially receive the first 
dose on Cycle 1 Day 1 with a 28-day observation period.  Cycle 2 Day 1 will start on Day 29.  
After completion of Cycle 2, patients will be asked to sign an additional consent document 
for confirmation of the patient’s willingness to continue participation in this study before 
starting Cycle 3. 
Expansion Cohorts: Portion A
Figure 1.
Study Design of the Expansion Cohort of Portion A


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As of June 2016, the highest planned single-agent dose of 10 mg/kg PF-05082566 was tested 
with no DLTs reported in Portion A, and as of September 2016, 34 patients with advanced 
solid tumor, including 20 patients with melanoma, who had documented disease progression 
per RECIST v1.1 on a previous immune checkpoint inhibitor therapy have been enrolled in 
the expansion cohorts of Portion A and treated at the 0.24 or 1.2 mg/kg dose levels of 
PF-05082566.  Because the RP2D of PF-05082566 has not yet been determined in Portion A, 
approximately 40 additional patients with melanoma who had documented disease 
progression per RECIST v1.1 on a previous immune checkpoint inhibitor therapy will be
randomized 2:1:1 to treatment with single agent PF-05082566 at the 0.6, 0.24, or 1.2 mg/kg 
dose levels.  
Dose Escalation: Portion B 
The doses of PF-05082566 will be assigned to each enrolled patient using a TITE-CRM. 
The initiation of Portion B may occur after all patients in the single-agent 0.06 mg/kg cohort 
have completed Cycle 1 and received their second dose.  Enrollment will then begin with 
PF-05082566 at a dose of 0.03 mg/kg and escalating at the same dose intervals as listed for 
Portion A.  PF-05082566 will be given to patients IV (every 4 weeks) in combination with 
rituximab (375 mg/m2, every week x 4 weeks).  
The first dose of PF-05082566 will be given approximately 24 hours after the second weekly 
full dose of rituximab (defined as either the planned dose or in the case of infusion reactions, 
at least 50% of planned rituximab dose).  For the first cohort (PF-05082566 given at 
0.03 mg/kg) there will be a minimum 7 day window between the first dose of 
PF-05082566 for a patient and the first dose of rituximab for the next patient.  For all 
subsequent dose escalation/de-escalation cohorts, up to 0.6 mg/kg, a minimum 72 hour 
window will apply between the first dose of PF-05082566 for a patient and the first dose of 
rituximab for the next patient in the same cohort.  Updated study safety data indicate that 
PF-05082566 infusion does not result in clinically significant infusion reactions.  Therefore, 
after completion of the 0.6 mg/kg dose level, there will no longer be a waiting period 
between the first dose of PF-05082566 for a patient and the first dose of rituximab for the 
next patient in the same dose cohort.
Japan will not participate in Portion B until determination of the MTD of PF-05082566 as a 
single agent in Japan cohort.  Following the completion of Japan cohorts in Portion A, the 
combination of PF-05082566 with rituximab may also be tested in order to evaluate the 
safety of the combination therapy in patients enrolled in Japan.  Enrollment of Japan cohort
in Portion B is permitted and is dependent on the progress and status of the ongoing Portion 
B, as well as further development strategy.


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Expansion Cohorts: Portion B
Figure 2.
Study Design of the Expansion Cohort of Portion B
As of June 2016, the highest planned dose of 10 mg/kg PF-05082566 in combination with 
rituximab was tested with no DLTs reported in Portion B, and as of September 2016, 
10 patients with rituximab-refractory FL and 4 patients with relapsed or refractory DLBCL 
have been enrolled in the expansion cohort of Portion B and treated at the 1.2 mg/kg dose 
level of PF-05082566.  Because the RP2D of PF-05082566 administered in combination with 
rituximab has not yet been determined in Portion B, the expansion cohort of Portion B will 
enroll up to 100 patients with rituximab-refractory FL who will be treated with rituximab in 
combination with PF-05082566 at the 1.2 mg/kg and, following an assessment of the 
tolerability, efficacy, PD and PK data collected for the combination of PF-05082566 at 
1.2 mg/kg plus rituximab, at the 0.24 mg/kg dose level. In the first cohort (FL-1), up to 
20 patients will be treated with rituximab in combination with PF-05082566 at 1.2 mg/kg and 
in the second cohort (FL-2) up to 20 patients may receive rituximab in combination with 
PF-05082566 at 0.24 mg/kg.  The PF-05082566 dose level to be administered in the third 
cohort (FL-3) will be selected based on the overall evaluation of tolerability, efficacy, PD 
and PK data collected for the combination of PF-05082566 plus rituximab in FL-1 and 
FL-2 (if this cohort is enrolled).  In FL-3, approximately 60 patients will receive rituximab in 
combination with PF-05082566 either at the 0.24 or 1.2 mg/kg dose level. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint – Dose Escalation Cohorts

First 2 cycles Dose-Limiting Toxicities (DLTs).


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3.2. Secondary Endpoints – Dose Escalation Cohorts
3.2.1. Safety Endpoints

Adverse events as characterized by type, severity (as graded by NCI CTCAE v.4.03), 
timing, seriousness and relationship to study therapy PF-05082566 for Portion A and in 
combination with rituximab for Portion B; 

Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03) and timing;

Vital signs (blood pressure, and pulse rate);

QTc interval.
3.2.2. Efficacy Endpoints

Best Overall Response (BOR), Duration of Response (DR), Time to Tumor Response 
(TTR), Progression-free survival (PFS), per RECIST v1.1 for solid tumors and Cheson 
2007 criteria for NHL based on Investigator assessment;
BOR is defined as the best response recorded from ‘start date’ until documented disease 
progression. Only tumor assessments performed before the start of any further anti-
cancer therapies will be considered in the assessment of BOR.     
DR is defined, for patients with an objective response (BOR of complete response [CR] 
or partial response [PR]), as the time from first documentation of objective response (CR 
or PR) to the date of first documentation of objective progression of disease (PD) or 
death due to any cause.  For solid tumors, both CR and PR per RECIST v1.1 must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.
TTR is defined, for patients with an objective response, as the time from the ‘start date’
to the first documentation of objective response (CR or PR).  For solid tumors, 
confirmation of response per RECIST v1.1 is required.
PFS is defined as the time from ‘start date’ to the date of the first documentation of PD or 
death due to any cause, whichever occurs first.

Overall Survival (OS);
OS is defined as the time from ‘start date’ to the date of death due to any cause.
3.2.3. Pharmacokinetic Endpoints

Pharmacokinetic parameters: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, 
AUCtau, CL, and Vss, as data permits) and rituximab (Cmax, Ctrough).


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Table 2.
PK Parameters to be Determined for PF-05082566 and Rituximab
Parameter
Definition
Method of Determination
AUC0-last
Area under the serum 
concentration-time curve from time 
zero to the time of the last measurable 
concentration (Clast)
Log-Linear trapezoidal method
AUCtau
a
Area under the serum 
concentration-time curve over dosing 
interval τ
Log-Linear trapezoidal method
AUC0-∞
a
Area under the serum concentration-
time curve from time 0 to infinity
Log-Linear trapezoidal method
Cmax
Maximum observed serum 
concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data 
t½
a
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression during the terminal phase 
of the natural log-transformed 
concentration-time profile 
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
CLa
Clearance
Dose / AUC0-∞after single dose
Dose / AUCtau after multiple doses
Vss
a
Steady state volume of distribution
CL•MRTiv, where MRTiv is mean 
residence time after intravenous 
administration
AUC0-
last(dn)
Dose normalized AUC0-last
AUC0-last / Dose
AUC0-∞(dn)a
Dose normalized AUC0-∞
AUC0-∞/ Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
Rac
Accumulation ratio
AUCtau after multiple 
dosing/AUCtau after single dose
a If data permit
3.2.4. Immunogenicity Endpoints
•
Anti-drug Antibody (ADA)/neutralizing antibody (Nab) titers for PF-05082566 and
rituximab.
 
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3.4. Primary Endpoint – Expansion Cohorts
•
For Portion A: Objective response (confirmed CR or PR) as assessed by using the 
RECIST v1.1.
•
For Portion B: Objective response (CR or PR) as assessed by using the Cheson 2007 
criteria.
3.5. Secondary Endpoints – Expansion Cohorts
3.5.1. Safety Endpoints
•
First 2 cycles of DLTs;
•
Adverse events as characterized by type, severity (as graded by NCI CTCAE v.4.03), 
timing, seriousness and relationship to study therapy PF-05082566 for Portion A and in 
combination with rituximab for Portion B; 
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03) and timing;
•
Vital signs (blood pressure, and pulse rate);
•
QTc interval.
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3.5.2. Efficacy Endpoints
•
DR, TTR, PFS, per RECIST v1.1 for solid tumors and Cheson 2007 criteria for NHL 
based on Investigator assessment;
•
OS.
3.5.3. Pharmacokinetic Endpoints
•
Pharmacokinetic parameters: PF-05082566 (Cmax, Ctrough, Tmax, AUC0-last,, AUC0-∞, 
AUCtau, CL, and Vss, as data permits) and rituximab (Cmax and Ctrough).  Refer to Table 2
for definitions and methods of PK parameters.
3.5.4. Immunogenicity Endpoints
•
Anti-Drug Antibody levels for PF-05082566 and rituximab.
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.7. Baseline Variables
3.7.1. Study Drug, Study Treatment and Baseline Definitions
In this study, ‘study drug’ refers to PF-05082566 or rituximab and ‘study treatment’ (or 
‘treatment group’) refers to one of the following:
•
PF-05082566 0.006 mg/kg q4wks;
•
PF-05082566 0.03 mg/kg q4wks;
•
PF-05082566 0.06 mg/kg q4wks;
•
PF-05082566 0.12 mg/kg q4wks;
•
PF-05082566 0.18 mg/kg q4wks;
•
PF-05082566 0.24 mg/kg q4wks;
•
PF-05082566 0.3 mg/kg q4wks;
•
PF-05082566 0.6 mg/kg q4wks;
•
PF-05082566 1.2 mg/kg q4wks;
•
PF-05082566 2.4 mg/kg q4wks;
•
PF-05082566 5 mg/kg q4wks;
•
PF-05082566 10 mg/kg q4wks;
•
PF-05082566 0.03 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.06 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.12 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.18 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.24 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.3 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 0.6 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 1.2 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
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•
PF-05082566 2.4 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 5 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;
•
PF-05082566 10 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4.
Start and end dates of study treatment:
For single agent PF-05082566:
The date/time of first dose of study treatment is the earliest date/time of non-zero dosing of 
the study drug.
The date/time of last dose of study treatment is the latest date/time of non-zero dosing of the 
study drug.
For PF-05082566 + rituximab:
The date/time of first dose of study treatment in a combination arm is the earliest date/time of 
the first non-zero dose date/time for each of the study drugs. 
The date/time of last dose of study treatment in a combination arm is the latest date/time of 
the last non-zero dose date/time for each of the study drugs.
Definition of baseline: 
Definition of baseline for efficacy analyses in randomized cohorts
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy analyses. If such a value is missing, the last measurement prior to the first dose of 
study treatment will be used as the baseline measurement except for analyses of tumor 
assessment data where the baseline assessment would be considered as missing. 
Definition of baseline for efficacy 
 and for 
safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for safety, efficacy
 
  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.
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Patients who start treatment and discontinue from the study treatment 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 and QT/QTc interval assessments will be derived from the visit where 
both heart rate 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 heart rate and QT.  The average of the 
replicate measurements will be determined after the derivation of the individual parameter at 
each time point.
3.7.2. 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.
3.8. Safety Endpoints
3.8.1. 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.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
For the randomized cohorts: The full analysis set (FAS) will include all randomized patients.  
Patients will be classified according to the treatment assigned at randomization. 


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For non-randomized cohorts: The FAS will include all patients who receive at least one dose 
of study drug.  Patients will be classified according to the study treatment actually received.  
If a patient receives more than one treatment the patient will be classified according to the 
first treatment received.
4.2. Safety Analysis Set
For the randomized cohorts: The safety analysis set will include all patients who receive at 
least one dose of study drug. Patients will be classified according to the treatment assigned 
at randomization unless the incorrect treatment(s) was/were received throughout the dosing 
period in which case patients will be classified according to the first study treatment 
received. 
For non-randomized cohorts: The safety analysis set will include all patients who receive at 
least one dose of study drug.  Patients will be classified according to the study treatment 
actually received.  If a patient receives more than one study treatment, the patient will be 
classified according to the first treatment received. For the non-randomized cohorts of the 
study, the FAS and the safety analysis set are identical.
4.3. Other Analysis Set
4.3.1. DLT-evaluable Set
The DLT-evaluable set is a subset of the safety analysis set, and it includes all patients who 
receive at least 1 dose of study treatment (for Portion A: at least 1 dose of PF-05082566; for 
Portion B: at least 1 dose of PF-05082566 and 1 dose of rituximab).  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.
4.3.2. PK Analysis Set
The PK concentration population is defined as all treated patients (subset of the safety 
analysis set) who have at least 1 concentration.
The PK parameter analysis population is defined as all treated patients (subset of the safety 
analysis set) who have at least 1 of the PK parameters of interest. 
 
 
 
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 
rituximab.
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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.
The sample sizes planned for the study arise from logistic feasibility and past experience with 
First in Human (FIH) studies in oncology and are not driven by statistical considerations.  It 
is expected that approximately 277 patients will need to be enrolled to achieve the objectives 
of the study. 
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 45 in order to have a reliable and accurate estimate of the MTD based on simulation 
results.  Based on probability theory, a sample size of 45 will ensure the estimates of any 
binary variable (eg, objective response rate) have a 95% confidence interval (CI) of width 
<0.30.  A sample size of 45 also enables detection of any unexpected toxicity that occurs 
at 5% rate (in a non-dose-dependent fashion) with a probability of 0.90, and that occurs 
at 10% rate with a probability of 0.99. 
A stopping rule will also be implemented if:
•
Maximum sample size (N=45) is reached; or 
•
9 DLT-evaluable patients have been treated at the estimated MTD; or
•
all doses appear to be overly toxic and the MTD cannot be determined in the current 
trial. 
Portion A expansion cohorts include patients with solid tumors of interest who progressed 
after treatment with an immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1/PD-L1).  The 
target sample size is approximately 20 patients with advanced melanoma at each tested dose 
(0.24 mg/kg, 0.6 mg/kg, 1.2 mg/kg) and approximately 20 patients, including other tumor 
types. With 20 patients with advanced melanoma, the maximum standard error of the ORR 
is 0.11.
Portion B expansion cohorts include approximately 80 patients with FL refractory to 
rituximab and to an alkylating agent at either 1.2 mg/kg or 0.24 mg/kg of PF-05082566. 
With 80 patients, the maximum standard error of the ORR is 0.06.
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5.1.2. Decision Rules Using the TITE-CRM Method
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) (O’Quigley et al., 1990), and its variants. 
Delayed-onset toxicities are a particular challenge for phase I trials of combination therapies 
(Muler et al., 2004). 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 
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 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. (2000) and Huang et al. 
(2014) for the dose escalation of PF-05082566.  PF-05082566 will be administered IV at 
escalating doses of 0.60, 1.2, 2.4, 5 mg/kg as a single agent in Portion A (the standard 
3+3 method is used for doses up to 0.30 mg/kg), and at escalating doses of 0.03, 0.06, 0.12, 
0.18, 0.24, 0.30, 0.60, 1.2, 2.4, 5 mg/kg given once every 4 weeks in Portion B in 
combination with rituximab, which will be administered at a fixed dose of 375 mg/m2, once 
per week for 4 weeks total (Cycle 1).  If 5 mg/kg of PF-05082566 is well tolerated, the 
sponsor may investigate the 10 mg/kg level for the estimation of the MTD.  The following 
dose levels are available for the dose ranges bracketed between 0.6 and 5 mg/kg based on the 
TITE-CRM indicated dose reduction from the next highest planned dose level: 0.45, 0.9, 1.8, 
3.6, and 7.5 mg/kg).  However, they will not be tested if a dose reduction is not 
recommended by the statistical model.  In addition, these intermediate dose levels may be 
used for dose escalation if one dose limiting toxicity is observed at the preceding regular 
dose level.
We define the MTD to be the highest dose that is associated with a DLT rate ≤25%.  A 
power function modeling DLT rate at each dose di (i=1, …, 14) 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≤…≤p14.  These 
estimates will be projected based on the Portion A single-agent PF-05082566 safety profile 
in the first 3 dose levels, together with the pre-clinical animal data.  is an unknown single 


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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 our trial, we set 
0
=0.97, which provides a reasonably flat prior distribution of , with 95% Bayesian 
credible interval of 
)
exp( : [0.15, 6.67], sufficiently wide to cover a wide spectrum of 
dose-toxicity scenarios.  Figure 3 illustrates the dose-toxicity curve with 95% upper and 
lower bounds when the initial prior estimates
ip are (1.4e-05, 1.4e-04, 9.0e-04, 3.8e-03, 0.01, 
0.03, 0.06, 0.11, 0.17, 0.25, 0.33, 0.42, 0.50, 0.58).


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Figure 3.
Example Plot of Prior Dose Toxicity Curve
Prior dose-toxicity curve with 95% upper and lower bounds
Dose Level of PF-05082566 (mg/kg)
DLT Rate
0.03
0.06
0.12
0.18
0.24
0.3
0.45
0.6
0.9
1.2
1.8
2.4
3.6
5
0
0.1
0.2
0.25
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
target
In the trial conduct, the first 3 patients will be treated at the lowest dose level.  For each 
subsequent patient eligible for enrollment, 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 MTD, defined 
as the dose having an estimated probability of DLT closest to but not greater than the target 
rate (25%).  The probabilities of toxicity are estimated based on the Bayesian power model 
with prior distribution of the parameter to learn about the overall dose-toxicity relationship.  
Patients’ DLT data will be reported in real time to the study statistician who will estimate the 
MTD before the next enrolled patient is treated.
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 a weight equal to the proportion of 
the 8-week (2 cycles of PF-05082566) DLT observation period the patients have completed 
(however the weight function may be modified if safety data suggest different weight 
(toxicity) patterns in Cycle 1 and Cycle 2 of PF-05082566, or an adaptive weight function if 
ongoing safety data suggest different toxicity patterns in Cycle 1 and Cycle 2 of 
PF-05082566); patients who experience DLT or complete the observation period without 
DLT will be assigned full weight (=1).


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5.2. General Methods
As described in Section 3.7.1, in this study ‘treatment group’ refers to one of the following:

PF-05082566 0.006 mg/kg q4wks;

PF-05082566 0.03 mg/kg q4wks;

PF-05082566 0.06 mg/kg q4wks;

PF-05082566 0.12 mg/kg q4wks;

PF-05082566 0.18 mg/kg q4wks;

PF-05082566 0.24 mg/kg q4wks;

PF-05082566 0.3 mg/kg q4wks;

PF-05082566 0.6 mg/kg q4wks;

PF-05082566 1.2 mg/kg q4wks;

PF-05082566 2.4 mg/kg q4wks;

PF-05082566 5 mg/kg q4wks;

PF-05082566 10 mg/kg q4wks;

PF-05082566 0.03 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.06 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.12 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.18 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.24 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.3 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 0.6 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 1.2 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 2.4 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 5 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4;

PF-05082566 10 mg/kg q4wks + rituximab 375 mg/m2  q1wk x4.
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.


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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 set by treatment group.
 
 
 
.
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group.
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 randomized/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 and number of missing values [ie, n (missing)], 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.
CCI
CCI
CCI
CCI


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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’ 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’ eCRF pages.
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 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment for non-randomized cohorts or after the date of randomization for randomized 
cohorts amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Systemic Therapy’ 
eCRF pages.

Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’ with 
‘Treatment Type’ not equal to ‘Palliative’.

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 using ‘Follow-up Systemic Therapy’, 
‘Concomitant Radiation Therapy’ and ‘Concomitant Surgery’ eCRF pages.
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.


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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)
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. E.g., 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 28 days prior to and including ‘start date’.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions (for patients with solid tumor) or index lesions (for 
patients with NHL) and non-missing lesions status at baseline for non-target lesions (for 
patients with solid tumor) or non-index lesions (for patients with NHL)).


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
Computerized tomography (CT) or magnetic resonance imaging (MRI) is required at 
baseline and may include chest, abdomen and pelvis. Brain scans will be performed at 
baseline for patients with CNS disease or if disease is suspected, and on study as 
appropriate to follow disease.  Baseline CNS imaging is not required unless to confirm 
stability of existing CNS metastases or for symptomatic patients to rule out CNS 
metastases.  Bone scans will be performed at baseline if disease is suspected only for 
patients enrolled in Portion A, and on study as appropriate to follow disease.  
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 6.1.2.1).  Time points where 
the response is 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.
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.


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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.
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


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
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).

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 withdraw 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 withdraw 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.


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
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.

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.

Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’).


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
Study drug start and end dates.

Randomization date for the randomized cohorts and enrollment date for the non-
randomized cohorts.

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.
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.


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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) 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.

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 (Dose-escalation Cohorts)
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.
6.1.2. Objective Response as Assessed by the Investigator (Expansion Cohorts)
6.1.2.1. Primary Analysis
Refer to Section 6.2.2.1.
6.2. Secondary Endpoint(s)
6.2.1. Safety Endpoints
Refer to Section 6.6.


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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 for solid tumors and Cheson 2007 criteria for 
NHL.
6.2.2.1. Objective Response as Assessed by the Investigator
BOR will be assessed based on reported overall lesion responses at different evaluation time 
points from the ‘start date’ until documented disease progression, according to the following 
rules. Only tumor assessments performed before the start of any further anti-cancer therapies 
will be considered in the assessment of BOR.  Clinical deterioration will not be considered as 
documented disease progression.
BOR Based on Confirmed Responses for Solid Tumors

CR = at least two determinations of CR at least 4 weeks apart and before progression.

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before progression (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 ‘start date’ and before progression (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 ‘start date’ and before 
progression (and not qualifying for CR or PR).

PD = progression ≤ 12 weeks after ‘start date’ (and not qualifying for CR, PR, SD or 
non-CR/non-PD).

Not Evaluable (NE):  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR. A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have an on-treatment radiographic tumor assessment due to early 
progression, who receive anti-tumor 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.


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ORR by treatment group will 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 confirmed BOR of CR, 
PR, SD, PD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), 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:

No baseline assessment.

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 or non-CR/non-PD of insufficient duration (<6 weeks after ‘start date’).

PD too late (>12 weeks after ‘start date’).
Special and rare cases where BOR is NE due to both early SD or non-CR/non-PD and late 
PD will be classified as ‘SD too early’.
BOR Based on Unconfirmed Responses for NHL: 

CR = one objective status of CR documented before progression. 

PR = one objective status of PR documented before progression (and not qualifying for 
CR).

SD = at least one SD assessment (or better) ≥6 weeks after ‘start date’ and before 
progression (and not qualifying for CR or PR).

PD = progression ≤12 weeks after ‘start date’ (and not qualifying for CR, PR, or SD). 

NE:  all other cases.  
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 50% from the nadir, but enough that a previously 
documented 50% decrease from baseline no longer holds (see Section 6.2.2.2 on details of 
tumor change).  
OR is defined as BOR of CR or PR according to Cheson 2007 criteria.


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Patients who do not have an on-treatment radiographic tumor assessment due to early 
progression, who receive anti-tumor 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 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 a BOR of CR, PR, SD, 
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:

No baseline assessments.

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 ‘start date’).

PD too late (>12 weeks after ‘start date’).
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’.
6.2.2.2. Tumor Shrinkage
Tumor Shrinkage for Solid Tumors:
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 anticancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100.


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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 adequate post-baseline 
assessment.
Tumor Shrinkage for NHL:
The greatest transverse diameter and the greatest perpendicular transverse diameter will be 
recorded for each index lesion.  The product of these 2 dimensions will be recorded and the 
sum of the product diameters (SPD) of the index lesions will be the baseline value used in 
determining response and tumor shrinkage.
Tumor shrinkage will be summarized as the percent change from baseline in index lesions 
(SPD) per time point. It will be derived as:

((SPD at week XX – SPD at baseline)/SPD at baseline) × 100.
The maximum reduction in index lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anticancer therapy, as:

Minimum of ((SPD at week XX – SPD at baseline)/SPD at baseline) × 100.
A waterfall plot of maximum percent reduction in the SPD from baseline will be created. 
This plot will display the best percentage change from baseline in the SPD for each patient 
with measurable disease at baseline and at least one adequate post-baseline assessment.
6.2.2.3. Duration of Response
Duration of Response (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 
objective progression of disease (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.


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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.
6.2.2.4. Time to Response
Time to response (TTR) is defined, for patients with OR, as the time from the ‘start date’ to 
the first documentation of objective response (CR or PR).  For RECIST-defined response in 
solid tumors confirmation of response is required. 
TTR (in months) = [first date of OR – ‘start date’ +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
Progression-Free Survival (PFS) is defined as the time from ‘start date’ to the date of the first 
documentation of objective progression of disease (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 2 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 ‘start 
date’ unless death occurred on or before the time of the second planned tumor assessment (ie,
≤16 weeks after ‘start date’) 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 screening and every 8 weeks until disease progression regardless of initiation of 
subsequent anti-cancer therapy. After 10 months from ‘start date’, tumor assessments will be 
conducted less frequently, ie, at 16-week intervals.
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– ‘start date’ +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
‘Start date’ a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after ‘start date’
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 ‘start date’ the death is an event with date on death date.
b  If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate assessment 
should be measured from the ‘start date’; if the criteria were met the censoring will be on the ‘start date’
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 before event. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ ‘start date’ OR 
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 OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
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.
6.2.2.6. Overall Survival
Overall survival (OS) is defined as the time from ‘start date’ to the date of death due to any 
cause. Patients last known to be alive will be censored at date of last contact.
OS (months) = [date of death or censoring– ‘start date’ +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 OS time with 2-sided 
95% CIs.  In particular, the OS rate at 3, 6, 9, 12, 15, and 18 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.  


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Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 5 following the hierarchy shown.
Table 5.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [End of study (EOS) = Subject refused 
further follow-up] 
Subject refused further follow-up
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 16 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators.
6.2.3. Pharmacokinetic Endpoints
6.2.3.1. Non-compartmental Analysis
Standard pharmacokinetic parameters (eg, Ctrough, Cmax, Tmax, t1/2,  AUC0-last, AUC0-, AUCtau, 
CL, Vss and Rac) will be estimated using non-compartmental methods. Pharmacokinetic 
parameters for PF-05082566 and rituximab will be evaluated.
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its 
associated 95% CI and geometric %CV) of serum concentrations for PF-05082566 and 
rituximab will be presented in tabular form by study day, cycle, dose and nominal time.  
Concentrations with zero values will be excluded from the calculation of geometric means, 
its associated 95% CI and geometric %CV. Linear and semi-log plots of median serum 
concentrations vs nominal time will be prepared by study day, cycle and dose. Similar plots 
will be prepared for each individual patient’s serum concentrations.  
Pharmacokinetic parameters will be listed and summarized by cycle and dose using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, and geometric 
mean, its associated 95% CI and geometric %CV).  Dose-normalized parameters (eg, Ctrough, 
Cmax and AUC) will also be listed and summarized. Pharmacokinetic parameters with zero 
values will be excluded from the calculation of geometric means, its associated 95% CI and 
geometric %CV. 


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AUC0-∞(AUCtau at steady state), 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 
proportionality for PF-05082566.
6.2.3.2. Population Pharmacokinetic Analysis
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between PF-05082566 and rituximab exposure and 
 or significant 
safety/efficacy endpoints.  The results of these analyses, if performed, may be reported 
separately.
6.2.4. Endpoints for Immunogenicity Data of PF-05082566 and Rituximab
ADA/ Nab data will be listed and summarized for PF-05082566 and rituximab by dose and 
for the entire study population. The percentage of patients with positive ADA and Nab will 
be summarized by dose and overall study population (eg. at baseline, post-dose, treatment-
induced, treatment-boosted or anytime of the study). For patients with positive ADA, the 
magnitude (titer), time of onset, and duration of ADA response will also be described, if data 
permit. The impact of ADA/Nab on PK, safety/efficacy will also be assessed, if data permit.
 
 
  
 
 
 
 
 
 
 
 
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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 (Yes/No).
•
Age (years): summary statistics.
•
Age categories: 
•
< 65 years, ≥ 65 years.
•
< 65, 65-<75, 75-<85, ≥ 85 years.
CCI


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
Pooled Geographical Region (as applicable): 

North America.

Europe.

Asia.

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including >10% of the 
overall randomized population).

Geographic Region (as applicable):

North America.

Latin America.

Western Europe.

Eastern Europe.

Middle East.

Australasia.

Asia.

Africa.

Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4.

Physical measurements:

Height (cm).

Weight (kg).

Body Mass Index (BMI) (kg/m2).

Body Surface Area (BSA) (m2).
Site codes will be used for the determination of the patient’s geographic region.
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.


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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’, RECIST, and 
IWGRC eCRF pages will be summarized overall and by treatment group. Summary statistics 
will be presented for the following.
From the ‘Primary Diagnosis’ eCRF page:

Site of primary tumor;

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page);

Time since initial diagnosis to ‘start date’ (months), defined as (‘start date’ – date of 
initial diagnosis)/30.4375;

For Portion A solid tumors: Time since diagnosis of local/regional recurrence of disease 
(months), defined as (‘start date’ – date of diagnosis of local/regional recurrence of 
disease)/30.4375.
From the RECIST tumor assessment eCRF page:

Measurable disease (lesions) at baseline (Yes, No);

Involved tumor sites at baseline.
From the IWGRC tumor assessment eCRF page:

Involved tumor sites at baseline.
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.


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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 treatment;

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;

Number of prior anti-cancer drug therapy regimens: missing / 1 / 2 / 3 / ≥4;

Type of prior anti-cancer therapy;

For Portion A solid tumors: Prior anti-cancer immune therapy (including PD-1, PD-L1, 
anti-CTLA4, others);

Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Unknown / Not applicable. Best response is derived from the 
last treatment regimen.

For the expansion cohort patients:

Response to prior checkpoint inhibitor therapy (patients with melanoma in 
Portion A): Refractory / Relapsed, collected on the ‘Subject Stratification’ page.

Response to prior rituximab therapy (patients with FL in Portion B): Refractory / 
Relapsed, collected on the ‘Subject Stratification’ page.
The prior anti-cancer drugs 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.
Prior anti-cancer treatments and procedures will be included in the listings that follow with a 
flag to identify prior therapies. 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;


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
Listing of prior anti-cancer radiotherapy;

Listing of prior anti-cancer surgeries.
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
For randomized cohorts
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall;

Number of patients who discontinued from the study prior to randomization overall and 
by the main reason for discontinuation;

Number and percentage of randomized patients in each of the analysis sets defined in
Section 4;

Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug when administered in combination);

Number and percentage of randomized 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 follow-up;

Number and percentage of patients who discontinued the study overall and by the main 
reason for discontinuation.
The results of the randomization algorithm (according to IRT) will be summarized as 
follows:

Number and percentage of randomized patients overall, by region (Europe, EEA 
(required by EudraCT), North America, Latin America, Middle East, Asia, Australasia, 
Africa), by country within region;

Number and percentage of randomized patients by center;

Cross tabulation: patients randomized (Arm A/Arm B/none) vs. patients treated (Arm 
A/Arm B/none).


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For non-randomized cohorts
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall.

Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation.

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 follow-up.

Number and percentage of patients who discontinued the study overall and by the main 
reason for discontinuation.
In addition the following will be summarized:

Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia, Africa), by 
country within region.

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.


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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.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  I.e., 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 CRF 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 may be summarized (overall) as dose received (cumulative dose, actual dose 
intensity) and as dose received relative to intended dose (relative dose intensity [RDI]).  
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily, oral cyclical).  
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination.
The derivations below are provided assuming 1 cycle = 4 weeks and for the following study 
drugs (administered alone or in combination):

PF-05082566 administered as a 1-hour IV infusion (mg/kg) once every 4 weeks in 4-
week cycles. 


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
Rituximab administered as a 1-hour IV infusion at a fixed dose of 375 mg/m2 once every 
week (Day -7, Day 0, Day 7, Day 14) for the first cycle of treatment. 
6.5.3.1. Exposure to PF-05082566
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.  
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 ranges from 0.006 mg/kg to 10 mg/kg (see Section 3.7.1).
6.5.3.2. Exposure to Rituximab
The dose level for rituximab is calculated as actual dose administered/BSA (mg/m2). The last 
available BSA of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with rituximab (weeks) = 4 weeks
Duration of exposure to rituximab (weeks) = 
(last dose date of rituximab – first dose date of rituximab + 7)/7.  
Cumulative dose overall is the sum of the actual doses of rituximab received overall.  


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Actual Dose Intensity (DI)

Overall actual DI (mg/m2/4-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with rituximab (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [375×4 (mg/m2)] / [1 (4-week cycle)] = 375×4
(mg/m2/4-week cycle).

Overall RDI (%) = 100 × [overall actual DI] / [intended DI] 
= 100 ×  [overall actual DI] / [375×4 (mg/m2/4-week cycle)].
6.5.3.3. Dose Reductions
Applicable to PF-05082566 and rituximab.  
Dose reduction is defined as actual non-zero dose < 90% of the planned dose. 
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized.
6.5.3.4. Dose Delays
Applicable to PF-05082566 and rituximab.
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. 
PF-05082566 in Portion A
Dose delay in Cycle x (days) = Date of first dose of PF-05082566 in Cycle x – Date of first 
dose of PF-05082566 in Cycle (x-1) – 28, where x >1.
PF-05082566 in Portion B
In Cycle 1, 
Dose delay (days) = Study day of first dose of PF-05082566 – 9  [Note: Cycle 1 starts on 
Day -7 and the first dose of PF-05082566 is scheduled for Cycle 1 Day 1].
In Cycle x,
Dose delay in Cycle x (days) = Date of first dose of PF-05082566 in Cycle x – Date of first 
dose of PF-05082566 in Cycle (x-1) – 28, where x >1.


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Rituximab
Dose delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – 7, where x >1.
Dose delays will be grouped into the following categories:

No delay.

1-2 days delay.

3-6 days delay.

7 or more days delay.
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 will be summarized in the 
1-2 days delay category. 
The 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
Applicable to PF-05082566 and rituximab.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the CRF (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% 
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. 


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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. 
A listing of concomitant medications will be created with the relevant information collected 
on the ‘Prior and Concomitant Drug Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘Prior and Concomitant Non-Drug Treatment’. 
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’, ‘Concomitant Radiation Therapy’ and ‘Concomitant Surgery’ eCRF 
pages. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up anti-
cancer Therapy’ 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.  
All summaries of related AEs (PF-05082566 plus rituximab) will further be presented as 
PF-05082566-related, rituximab -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.


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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 3.8.1.
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).

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).
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.


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
TEAEs, Grade ≥3.

Related TEAEs.

Related TEAEs, Grade ≥3.

TEAEs leading to permanent treatment discontinuation.

Related TEAEs leading to permanent treatment discontinuation.

Serious TEAEs.

Related Serious TEAEs.

TEAEs leading to death.

Related TEAEs leading to death.

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 rituximab by SOC and PT;

Related TEAEs leading to discontinuation of rituximab by SOC and PT;

TEAEs leading to permanent discontinuation of study treatment;

Related TEAEs leading to permanent discontinuation of study treatment. 


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The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
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 
primary reason for death, will be tabulated based on information from the ‘Notice of Death’
and ‘Survival Follow-Up’ eCRFs, by treatment group. 

All deaths;

Deaths within 30 days after last dose of study treatment;

Deaths within 60 days after last dose of study treatment;

Reason for 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);

Flags 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.


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6.6.4. Laboratory Data
6.6.4.1. 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 5.2.7). 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).
6.6.4.2. 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.
6.6.5. Vital Signs
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 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. 
6.6.6. 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)
and then used the natural log transformation to derive the equation:


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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 RR, QTc (QTcB, QTcF and, if applicable, QTcP) 
and RR 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:           

QT/QTc increase from baseline >30 ms, >60 ms.

QT/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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6.6.7. Physical Examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.8. 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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Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
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O’Quigley J, Pepe M, Fisher L (1990). Continual reassessment method: A practical 
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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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Lee S, Cheung YK (2009). Model calibration in the continual reassessment method. 
Clinical Trials. 6: 227-238.
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Huang B, Kuan P. (2014). Time-to-event continual reassessment method incorporating 
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CCI