Conditions: Advanced Cancer
Keywords: anti PD-L1 anti 4-1BB OX40 agonist anti M-CSF TLR9 agonist Non-small cell lung cancer (NSCLC) melanoma squamous cell carcinoma of head and neck (SCCHN) triple negative breast cancer (TNBC) gastric cancer Small cell lung cancer (SCLC) bladder cancer platinum resistant ovarian cancer TGCT/PVNS
Allocation: RANDOMIZED | Intervention model: 
Enrollment: 409
Healthy volunteers: no

Brief summary:
This is a Phase 1b/2 dose-optimization study to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of avelumab (MSB0010718C) in combination with other cancer immunotherapies in patients with locally advanced or metastatic solid tumors. The primary purpose is to assess the safety and early signs of efficacy of various avelumab combinations with other cancer immunotherapies, optimizing dosing regimens as appropriate, in a limited series of indications.

Detailed description:
This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, clinical activity, PK, and PD study of avelumab in combination with other immune modulators in adult patients with locally advanced or metastatic solid tumors (eg, non-small cell lung cancer (NSCLC), melanoma, squamous cell carcinoma of the head and neck (SCCHN), triple-negative breast cancer (TNBC), gastric cancer, platinum resistant ovarian cancer, bladder cancer, small cell lung cancer (SCLC) and progressing tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS) . In Phase 1b, this includes patients whose disease has progressed on standard of care therapy or for whom no standard therapy is available. In Phase 2, enrollment criteria regarding prior treatment(s) received varies by tumor type. Incorporation of the other immune modulators into this study is based on preclinical and clinical data supportive of single-agent tolerability and potential clinical benefit, as well as non-clinical data suggesting safety, tolerability and clinical benefit of the agent(s) in combination with avelumab. Combinations of avelumab plus other immune modulator(s) to be evaluated are as follows:

* Combination A: avelumab plus utomilumab (4-1BB agonist mAb)
* Combination B: avelumab plus PF-04518600 (OX40 agonist mAb)
* Combination C: avelumab plus PD 0360324 (M-CSF mAb)
* Combination D: avelumab plus utomilumab plus PF-04518600
* Combination F: avelumab plus CMP-001 (TLR9 agonist) and avelumab plus CMP-001 plus utomilumab and avelumab plus CMP-001 and PF-04518600 Each combination will be studied individually in 2 study parts: 1) a Phase 1b Lead-in part to evaluate safety, and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and RP2D (if applicable), of the combination, and 2) a Phase 2 part to evaluate efficacy and further evaluate safety of the selected dose from the Phase 1b portion in pre-specified patient populations.

Arms:
arm 1: NSCLC patients treated with avelumab + utomilumab (Dose level 1) arm 2: NSCLC patients treated with avelumab + utomilumab (Dose level 2) arm 3: NSCLC patients treated with avelumab + utomilumab (Dose level 3) arm 4: Melanoma patients treated with avelumab +utomilumab arm 5: SCCHN patients treated with avelumab + utomilumab arm 6: TNBC patients treated with avelumab + utomilumab arm 7: SCLC that has progressed after at least 1 line of platinum-containing therapy treated with avelumab +utomilumab arm 8: NSCLC first-line Stage IV treated with avelumab +PF-05082566 arm 9: PF-04518600 + avelumab in selected tumor types arm 10: PF-04518600 + avelumab in selected tumor types arm 11: PD 0360324 + avelumab in selected tumor types arm 12: PD 0360324 + aveluamb in selected tumor types arm 13: PF-05082566 + PF-04518600 + avelumab in selected tumor types arm 14: PF-05082566 + PF-04518600 + avelumab in selected tumor types arm 15: NSCLC first-line Stage IV treated with avelumab +utomilumab (sequential starting with utomilumab monotherapy followed by combination) arm 16: NSCLC first-line Stage IV treated with avelumab + utomilumab (sequential starting with avelumab monotherapy followed by combination) arm 17: CMP-001 +avelumab in SCCHN arm 18: CMP-001+avelumab+utomilumab in SCCHN arm 19: CMP-001 +avelumab+PF-04518600 in SCCHN

Interventions: intervention 1: Avelumab intervention 2: Utomilumab intervention 3: PF-04518600 intervention 4: PD 0360324 intervention 5: CMP-001
Intervention descriptions: intervention 1: Anti-PD-L1 antibody intervention 2: Anti-4-1BB antibody intervention 3: OX40 Agonist intervention 4: Anti-M-CSF intervention 5: TLR9 agonist

Protocol document:
Prot_000.pdf: 
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A PHASE 1B/2 OPEN-LABEL STUDY TO EVALUATE SAFETY, CLINICAL 
ACTIVITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF 
AVELUMAB (MSB0010718C) IN COMBINATION WITH OTHER CANCER 
IMMUNOTHERAPIES IN PATIENTS WITH ADVANCED MALIGNANCIES
JAVELIN MEDLEY
Compounds:
MSB0010718C
PF-05082566
PF-04518600
PD 0360324
CMP-001
Compound Name:
Avelumab (MSB0010718C)
Utomilumab (PF-05082566)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-002552-27
Protocol Number:
B9991004
Phase:
1b/2
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
CCI


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Document History
Document
Version 
Date
Summary of Changes
Original 
Protocol
09 June 2015
Not applicable (N/A)
Protocol 
Amendment 1
31 August 
2015
The following are FDA directed changes to the original 
Protocol:
Table 2 of the Schedule of Activities was revised to 
include 2 additional PK blood samples for PF-05082566 
and avelumab on Cycle 1 Day 8 and Cycle 1 Day 15.
Protocol Section 1.2.2.3 was revised to include safety 
data from patients receiving 10 mg/kg of PF-05082566.
Protocol Summary, Protocol Sections 3.1.3, Figure 3, 
Section 9.2 and Table 9, the wording for stopping a dose 
level cohort based on the number of DLTs in the 
Phase 1b portion of the study was changed from 3 out of 
6 patients to 2 out of 6 patients with DLTs.
In Protocol Section 3.2, the definition of Grade 3 diarrhea 
was revised to place a restriction on the time before it is 
considered a DLT.  The definition of DLT for liver 
function tests was revised to reflect Hy’s Law. 
In Protocol Section 4.1, inclusion criterion 1 was revised 
so that patients with ALK-rearranged or EGFR-mutated 
NSCLC have received and are refractory to or intolerant 
of standard treatment options. 
Protocol Section 5.3.5.3 was revised to require 
investigators to re-consent patients who will continue on 
therapy after initial progression of disease.
Table 5 in Protocol Section 5.3.7.2 was revised to remove 
“single value out of normal range that are likely related to 
treatment as assessed by the Investigator” under 
“Exceptions to permanent discontinuation”.
In addition, compound number MSB0010718C has been 
corrected throughout the document, Section 1.2.2 heading 
was revised to “anti-4-1BB”, and Section 3.1.2 was 
revised to remove wording not required per protocol 
template and was redundant with Section 3.1.3.


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Protocol 
Amendment 2
29 February 
2016
Amendment 2 is 1) adding a triple-negative breast cancer 
(TNBC) cohort to Combination A (avelumab and 
PF-05082566), and 2) adding a new combination to the 
study (Combination B; avelumab and PF-04518600).  
Changes to specific sections of the protocol are listed 
below.
Schedule of Activities for Combination A (avelumab and 
PF-05082566) and Section 7.1.4 updated to remove 
ANA, ANCA, and RF tests. 
Schedule of Activities for Combination A (avelumab and 
PF-05082566): physical examination, hematology, blood 
chemistry, and vital signs have been removed from
Day 8 and Day 22 of Cycles 3. 
Schedule of Activities for Combination A: Contraceptive 
check added to Day 1 of each cycle, to EOT, and end of 
contraception requirement period.  Concomitant 
treatment collection added to Follow-Up. 
Schedule of Activities for Combination A: TCR Analysis 
added. 
Schedule of Activities for Combination A:
Footnote 22 replaced with wording from Section 8.2 to 
clarify previous inconsistencies.
Schedule of Activities for Combination A:
Footnotes 28 and 29 revised to clarify requirements for 
archival and de novo biopsies.
Schedule of Activities for Combination B (avelumab and 
PF-04518600) added.
Section 1: Triple-negative breast cancer (TNBC) and 
colorectal cancer tumor types and description of 
Combination B (avelumab and PF-04518600) were 
added.
Section 1.2.2.3: Section on pre-clinical combination 
studies moved in front of clinical safety and efficacy to 
improve readability. 




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Section 4.3: Lifestyle guidelines revised to include details 
for Combination B.
Section 5: Updated throughout to include information on 
PF-04518600.
Section 5:1: Updated to include information for 
allocation to treatment for Combination B. 
Section 5.3.3: Added supplies of PF-04518600. 
Section 5.3.4.3: Added formulation and packaging of 
PF-04528600. 
Section 5.3.5.3: Added preparation of PF-04518600. 
Section 5.3.6: Updated wording for premedication for 
infusions for clarity. 
Section 5.3.6.1: Updated to include a +20 minute time 
window, if needed, in between infusions of avelumab and 
PF-05082566 or PF-04518600. 
Section 5.3.6.3: Added details of administration of 
PF-04518600.
Section 6.1.1: Text revised for clarification of 
requirements for archival and de novo biopsies. 
Section 7.2.3: Added PK analysis of PF-04518600. 
Section 7.3.3: Added immunogenicity assessment of 
PF-04518600.
Section 7.4: Updated to include a table of biomarker 
collections and analyses.
Section 7.5.1: Revised to include specifics for 
Combination B.
Section 7.6: Updated to include blood samples for 
carcinoembryonic antigen (CEA) testing in CRC patients 
in Combination B when tumor assessments are 
performed.  MRI added as an option for bone imaging. 


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Section 9: Updated throughout to include specific details 
for Combination B.
Section 9.1: Analysis sets updated to include those for 
Combination B. 
Section 9.2.2: Added with statistical methods for 
Combination B.
Section 9.3: Updated to include sample size 
determination for the TNBC cohort for Combination A 
and sample size determination for Combination B. 
Section 9.4: Updated to include Combination B in 
efficacy analysis.
Section 9.5.1.1: Revised analysis of biomarker endpoints. 
Section 16: Updated references 22 and 27.  Added 
references 34-49 related to anti-OX40 and the addition of 
Combination B. 
Appendix 1: The RECIST v1.1 appendix was 
re-formatted to maintain consistency across avelumab 
studies.  The content and meaning of this appendix has 
not changed.
Appendix 4: The irRECIST appendix was revised to 
reflect the most recent publication from Nishino, et al.  
There are 3 differences from the original Appendix 4: up 
to 2 new target lesions per organ are allowed instead of 
up to 5 new target lesions per organ; up to 5 target lesions 
total are allowed instead of up to 10 target lesions total; 
and lymph nodes are measured on the short axis and must 
be 15 mm.
Other administrative changes have been incorporated 
throughout the document.


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Protocol 
Amendment 3
22 April 
2016
Section 3.1.5: Table 8 regarding the decision rules of the 
mTPI design was revised to reflect a target DLT rate 
change from 30% to 25% per FDA request.
Section 3.3: The definition of MTD for PF-04518600 in 
combination with avelumab was revised to clarify that 
MTD decision making is dependent on the higher dose of 
PF-04518600 tested in combination with 10 mg/kg 
avelumab.
Section 4.1: Inclusion criterion #1 for Combination A 
Phase 2 was revised to not include patients with PD-1 or 
PD-L1 refractory disease (best response of PD).
Section 9.2.2:  The target probability rate was changed 
from 0.3 to 0.25, and the DLT interval was changed to 
(0.16, 0.33) per FDA request.
Protocol
Amendment 4
11 August 
2016
Section 3.1.5: Wording added to allow flexibility in the 
timing and the number of patients in dose escalation 
cohorts.
Protocol 
Amendment 5
30 
September 
2016  
Major changes to the protocol included the following: 

“PF-05082566” replaced with the proposed 
International Nonproprietary Name (INN), 
“utomilumab”, throughout the protocol.

Avelumab and utomilumab clinical experience data 
(safety, PK, and immunogenicity) updated in the 
Introduction section.

Combination A (avelumab plus utomilumab):  cohorts 
of patients with SCLC (n=20) and first-line NSCLC 
(n=20) added to the Phase 2 part.  In addition, the 
sample size for the TNBC cohort was reduced to 
20, and sample size justifications for the 
tumor-specific cohorts were added or modified, as 
applicable.

Combination B: patient population modified to 
specify that the Phase 2 tumor-specific cohorts to be 
evaluated will include a total of 25 patients each, 
including at least 20 anti-PD-1/PD-L1 
treatment-naïve patients and up to 5 patients who 
have previously received anti-PD-1/PD-L1 therapy. 


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
Two new combinations of avelumab plus other cancer 
immunotherapies were added: 1) Combination C 
(avelumab plus PD 0360324) and 2) Combination D 
(avelumab plus utomilumab plus PF-04518600).  Due 
to the addition of these new combinations, several 
sections of the protocol were modified.  A high-level 
summary of the major changes made by section are as 
follows: 

Protocol Summary updated;

Schedule of Activities (SOAs) updated;

New SOA Tables 5 – 8 added;

Section 1, Introduction, updated;

Background information for the new 
combination agent (PD 0360324) added;

Study rationale for Combinations C and D 
added.

Section 2, Study Objectives and Endpoints, 
updated to include objectives and endpoints 
specific to Combinations C and D;

Section 3, Study Design, updated to include 
details specific to Combinations C and D.  In 
addition, the Study Design section was revised to 
minimize redundancies across the various 
combinations included in the study;

Section 4, Patient Selection, updated to include 
details specific to Combinations C and D;

Section 5, Study Treatments, updated to include 
investigational product details 
(appearance/packaging, preparation, 
administration) for PD 0360324 (Combination C).  
In addition, dose modification guidelines for 
PD 0360324 and considerations specific to 
Combination D were added;


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
Section 7, Assessments, updated to include details 
regarding PK, immunogenicity, and 
biomarker/pharmacodynamic (PD) sample 
collections for Combinations C and D;

Section 9, Data Analysis/Statistical Methods, 
updated to describe sample size determinations 
for Combinations C and D;

Appendix 3, Abbreviations and Definition of 
Terms, updated. 

In addition, several changes were made to the overall 
protocol structure to reduce redundancies and other 
administrative changes made to improve clarity.
Protocol 
Amendment 6
16 May 2017
The primary purpose of Protocol Amendment 6 was to 
add a new combination treatment of avelumab plus 
PF-06840003 for evaluation in patients with advanced 
solid tumors (Combination E).  A high-level summary of 
changes made to the protocol specific to Combination E 
by section is as follows:

Protocol Summary updated;

Schedule of Activities (SOA) updated (Tables 9 and 
10 added);

Section 1, Introduction, updated;

Background information for the new combination 
agent (PF-06840003) added;

Study rationale for Combination E added.

Section 3, Study Design, updated to include details 
specific to Combination E;

Section 4, Patient Selection, updated to include 
details specific to Combination E;

Section 5, Study Treatments, updated to include 
investigational product details for PF-06840003;  


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
Section 7, Assessments, updated to include details 
regarding PK, immunogenicity, ECG, and biomarker 
assessments specific to Combination E;

Section 9, Data Analysis/Statistical Methods, updated 
to describe statistical methods specific to 
Combination E.
In addition to Combination E, the following changes 
were also made as part of Protocol Amendment 6:
Added two new cohorts (Cohort A9 and Cohort A10) of 
patients with 1st-line NSCLC to Combination A to 
evaluate sequenced administration of avelumab and 
utomilumab. 
Modified specific tumor-type inclusion criteria for each 
of the Combinations to improve overall clarity, and 
ensure homogenous patient population enrollment.
Allowed Tenosynovial giant cell tumor/pigmented 
villonodular synovitis (TGCT/PVNS) patients in 
combination C.
Instructions for treatment modifications for drug-related 
toxicities and management of immune-related adverse 
events were updated as per latest avelumab Investigator’s 
Brochure (IB) and reorganized for clarity.  
An overview of these and other additional changes by 
section are as follows:

Schedule of Activities, Tables 1 and 2 (SOA for 
Combination A) modified to include evaluations 
specific to new Cohorts A9 and A10.

Section 1, Introduction, updated;

Current clinical experience data (safety, PK, 
immunogenicity, and preliminary efficacy) 
updated for avelumab, PF-04518600, and 
utolimumab;

Study rationale specific to Cohorts A9 and 
A10 added;




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Protocol 
Amendment 7
18 Sep 2017
The primary purpose of Protocol Amendment 7 was to 
remove a new combination treatment of avelumab plus 
PF-06840003 for evaluation in patients with advanced 
solid tumors (Combination E) sections.  A high-level 
summary of changes made to remove the Combination E 
by section is as follows:

Protocol Summary;

Schedule of Activities (SOA) updated (Tables 9 and 
10 has been removed);

Section 1, Introduction, has been updated and all 
information pertaining to Combination E has been 
removed including;

Background information for the new combination 
agent (PF-06840003);

Study rationale for Combination E.

Section 3, Study Design, updated to remove details 
specific to Combination E;

Section 4, Patient Selection, updated to remove 
details specific to Combination E;

Section 5, Study Treatments, updated to remove 
investigational product details for PF-06840003;

Section 7, Assessments, updated to remove details 
regarding PK, ECG, and biomarker assessments 
specific to Combination E;

Section 9, Data Analysis/Statistical Methods, updated 
to remove section on statistical methods specific to 
Combination E.
Other minor administrative and/or editorial changes were 
also incorporated to improve overall document clarity and 
accuracy.
Protocol 
Amendment 8
27 Feb 2019
The primary purpose of Protocol Amendment 8 was to
add new combination treatments for evaluation in 
patients with SCCHN: Cohort F1, avelumab plus 
CMP-001; Cohort F2, avelumab plus CMP-001 and 




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Summary of Changes

Section 3, Study Design, updated; 

Study Design, updated to include details specific 
to Combination F; 

The frequency of tumor assessments updated for 
visits after 24 months from randomization;

Current status of combination A, B and C 
updated.

Section 4, Patient Selection; 

Added selection criteria specific to Combination 
F;

Updated the requirements regarding 
lifestyle/contraceptive requirement guidance.

Section 5, Study Treatments; 

Added investigational product details for 
CMP-001, edits to text pertaining to the 
management of infusion-related reactions, and 
addition of information pertaining to management 
of cytokine release syndrome and injection site 
reactions;

Updated premedication and observation 
period-related requirements for avelumab
infusion.  

Section 6, Study Procedures; 

Updated to include details of an on-treatment 
biopsy specific to Combination F;

Updated to specify the maximum duration of 
study treatment; 

Updated the follow-up visit procedures and 
laboratory tests included in the standard safety 
CCI




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who participate in the study for more than 2 years. 
Other minor administrative and/or editorial changes were 
also incorporated to improve overall document clarity and 
accuracy.
The following changes were made as a result of program
level protocol deviation alert letter (PDAL dated 
09 August 2018):

Section 7.1.4, Laboratory Safety Assessments, 
addition of text describing the requirement to review 
laboratory test results prior to study drug 
administration
Protocol
Amendment 9
13 Dec 2019
The primary purpose of Protocol Amendment 9 was to 
modify the inclusion criteria for Combination F and to 
update the current status of Combination D. A high-level 
summary of changes made to the protocol, by section, is 
as follows:

SOA updated for Combination F (Tables 11 and
12).

Section 4, Patient Selection:
Modified inclusion criterion specific to prior 
immunotherapy in Combination F;
Modified inclusion criterion specific to eligibility 
for intralesional administration in Combination F;
Modified exclusion criterion specific to prior 
radiotherapy.

Section 5, Study Treatments:
Addition of Section 5.3.3.2.5 detailing CMP-001 
diluent;
Updated Section 5.3.5.2 Timing of Investigational 
Product Administration to allow investigational 
product administration to be spread over two 
consecutive days for Combination F;


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Premedication guidance for Combination F 
updated for when dosing is spread over 2 days;
Stress dose steroids prophylaxis for patients who 
have experienced CRS updated to align with dose 
modification requirement to discontinue study 
treatment for CRS of Grade 3 lasting >24 hours 
and CRS ≥Grade 4.

Appendix 4, CMP-administration:
Details on tumor lesion selection criteria for 
injectable lesions added. 
Other minor administrative and/or editorial changes were 
also incorporated to improve overall document clarity and 
accuracy.
The following changes were made as a result of PACLs 
dated 8 April 2019, 30 July 2019, and 26 September 
2019:
PACL dated 8 April 2019: 
SOA updated Combination A, B, C and D 
Footnote(s) 15 & Combination F Footnote 14 and
Section 7.1.6 to clarify single ECG requirement at 
End of Treatment Visit;
SOA updated Combination D Footnote 16 & 
Combination F Footnote 15 to clarify hepatitis B 
blood tests requirements;
SOA Combination F Footnote 1 updated to clarify 
screening period definition;
Sections 5.3.2 Other Immune Modulators and 
Section 5.3.3 Formulation Dosage/Forms and 
Packaging updated to add CMP-001 diluent;
Section 5.3.5.2 Combination F observation period 
updated to correct typo error;
Section 13 Definition of End of Trial duplicate 


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paragraph deleted.  
PACL dated 30 July 2019: 
Protocol Summary updated and Section 3, Study 
Design updated to document current status of 
Combination D.
PACL dated 26 September 2019: 
SOA updated (Tables 6, 8, and 10, Combination 
B to D) to remove the requirement of immune cell 
phenotyping at the End of Treatment/Withdrawal 
Visit;
SOA updated (Tables 5 and 9, Combination B and
D) to clarify PF-04518600 administration on Day 
15 of Cycles ≥24; 
SOA table formatting corrected (Tables 3, 5, 7, 9 
and 11) to show Cycles ≥24 visits in On 
Treatment column. 
These amendments incorporate 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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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................27
LIST OF FIGURES .................................................................................................................28
LIST OF APPENDICES..........................................................................................................29
PROTOCOL SUMMARY.......................................................................................................31
SCHEDULE OF ACTIVITIES................................................................................................47
1. INTRODUCTION ...............................................................................................................87
1.1. Indication.................................................................................................................88
1.2. Background and Rationale ......................................................................................88
1.2.1. Avelumab....................................................................................................88
1.2.1.1. Avelumab Clinical Experience..................................................88
1.2.1.2. Pharmacokinetics of Avelumab in Humans..............................91
1.2.2. Utomilumab (4-1BB Agonist)....................................................................92
1.2.2.1. In Vivo Data: Functional Activity of Utomilumab....................93
1.2.2.2. In Vivo Data: Anti-Tumor Activity of Utomilumab..................93
1.2.2.3. Pre-Clinical Combination Studies.............................................94
1.2.2.4. Utomilumab Clinical Experience..............................................95
1.2.2.5. Pharmacokinetics of Utomilumab in Humans ..........................98
1.2.2.6. Immunogenicity of Utomilumab in Humans ............................98
1.2.3. PF-04518600 (OX40 Agonist) ...................................................................99
1.2.3.1. PF-04518600 Nonclinical Efficacy.........................................100
1.2.3.2. PF-04518600 Nonclinical Toxicology....................................102
1.2.3.3. In Vitro Cytokine Release Assays (Avelumab plus 
Utomilumab plus PF-04518600).....................................................102
1.2.3.4. PF-04518600 Clinical Experience ..........................................102
1.2.3.5. Pharmacokinetics of PF-04518600 .........................................104
1.2.3.6. Immunogenicity of PF-04518600 ...........................................105
1.2.4. PD 0360324 (Anti-M-CSF)......................................................................105
1.2.4.1. Preclinical Studies...................................................................105
1.2.4.2. Preclinical Combination Studies .............................................105
1.2.4.3. Clinical Safety and Efficacy....................................................106
1.2.4.4. Pharmacokinetics of PD 0360324...........................................107


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1.2.4.5. Immunogenicity of PD 0360324.............................................108
1.2.5. CMP-001 (QbG10) ...................................................................................108
1.2.5.1. Preclinical Studies...................................................................108
1.2.5.2. Preclinical Combination Studies.............................................109
1.2.5.3. Clinical Safety and Efficacy....................................................110
1.2.5.4. Pharmacokinetics of CMP-001 ...............................................114
1.2.5.5. Immunogenicity of CMP-001 .................................................114
1.2.6. Study Rationale.........................................................................................115
1.2.6.1. Rationale for the Individual Combinations Under 
Evaluation........................................................................................115
1.2.7. Rationale for the Tumor Types to be Evaluated.......................................118
1.2.7.1. Combination A (Avelumab plus Utomilumab).......................118
1.2.7.2. Combination B (Avelumab plus PF-04518600)......................120
1.2.7.3. Combination C (Avelumab plus PD 0360324) .......................120
1.2.7.4. Combination D (Avelumab plus Utomilumab plus 
PF-04518600)..................................................................................120
1.2.7.5. Combination F1 (Avelumab plus CMP-001); F2 
(Avelumab plus CMP-001 and utomilumab); F3 (Avelumab 
plus CMP-001 and PF-04518600)...................................................120
1.2.8. Rationale for Investigational Product Doses ............................................121
1.2.8.1. Avelumab ................................................................................121
1.2.8.2. Utomilumab.............................................................................121
1.2.8.3. PF-04518600 ...........................................................................122
1.2.8.4. PD 0360324.............................................................................122
1.2.8.5. CMP-001.................................................................................122
1.3. Summary of Benefit/Risk Assessment..................................................................123
1.4. Biomarker Rationale .............................................................................................126
1.4.1. Specific Features of Combination A: Avelumab plus Utomilumab.........127
1.4.2. Specific Features of Combination B: Avelumab plus PF-04518600........127
1.4.3. Specific Features of Combination C: Avelumab plus PD 0340324 .........127
1.4.4. Specific Features of Combination D: Avelumab plus Utomilumab 
plus PF-04518600..........................................................................................127
1.4.5. Specific Features of Combination F: Avelumab plus CMP-001 and 
Utomilumab or PF-04518600).......................................................................128


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2. STUDY OBJECTIVES AND ENDPOINTS.....................................................................128
2.1. Objectives..............................................................................................................128
2.2. Endpoints...............................................................................................................129
3. STUDY DESIGN...............................................................................................................130
3.1. Study Overview.....................................................................................................130
3.1.1. Tumor Assessments..................................................................................131
3.1.2. Safety Assessments...................................................................................131
3.1.3. Pharmacokinetic/Immunogenicity Assessments ......................................131
3.1.4. Biomarker Assessments............................................................................132
3.1.5. Modified Toxicity Probability Interval Dose Escalation Design 
(Combinations B, C, and D) ..........................................................................132
3.2. Study Designs for Each Combination ...................................................................134
3.2.1. Combination A (Avelumab plus Utomilumab) ........................................134
3.2.2. Combination B (Avelumab plus PF-04518600).......................................137
3.2.3. Combination C (Avelumab plus PD 0360324).........................................138
3.2.4. Combination D (Avelumab plus Utomilumab plus PF-04518600)..........140
3.2.5. Combination F (Avelumab plus CMP-001 and Utomilumab or 
PF-04518600) ................................................................................................142
3.3. Dose-Limiting Toxicity Definition .......................................................................144
3.4. Maximum Tolerated Dose Definitions..................................................................146
3.5. Maximum Administered Dose Definitions ...........................................................146
3.6. Recommended Phase 2 Dose Definition...............................................................146
4. PATIENT SELECTION....................................................................................................146
4.1. Inclusion Criteria...................................................................................................147
4.2. Exclusion Criteria..................................................................................................152
4.3. Lifestyle Guidelines ..............................................................................................154
4.4. Sponsor’s Qualified Medical Personnel................................................................156
5. STUDY TREATMENTS...................................................................................................156
5.1. Allocation to Treatment ........................................................................................157
5.2. Patient Compliance ...............................................................................................158
5.2.1. Parenterally Administered Investigational Products ................................158
5.3. Investigational Product Supplies...........................................................................158
5.3.1. Avelumab (MSB0010718C).....................................................................158


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5.3.2. Other Immune Modulators .......................................................................158
5.3.3. Formulation/Dosage Forms and Packaging..............................................158
5.3.3.1. Avelumab (MSB0010718C) ...................................................158
5.3.3.2. Other Investigational Products................................................158
5.3.4. Preparation and Dispensing......................................................................159
5.3.4.1. Parenterally Administered Investigational Products...............159
5.3.5. Administration..........................................................................................160
5.3.5.1. Parenterally Administered Investigational Products...............160
5.3.5.2. Timing of Investigational Product Administration .................162
5.3.5.3. Treatment after Initial Evidence of Radiological Disease 
Progression ......................................................................................164
5.3.5.4. Treatment after Confirmed Complete Response.....................165
5.3.6. Food Requirements...................................................................................165
5.3.7. Recommended Dose Modifications..........................................................165
5.3.7.1. Dose Delays.............................................................................165
5.3.7.2. Study Treatment Modifications for Investigational 
Products Drug-Related Toxicity......................................................166
5.3.7.3. Special Precautions for Avelumab, Utomilumab, 
PF-04518600, PD 0360324, and CMP-001 Administration ...........166
5.4. Investigational Product Storage ............................................................................178
5.5. Investigational Product Accountability.................................................................178
5.5.1. Destruction of Investigational Product Supplies ......................................178
5.6. Concomitant Medications .....................................................................................178
5.6.1. Hematopoietic Growth Factors.................................................................179
5.6.2. Concomitant Surgery................................................................................179
5.6.3. Concomitant Radiotherapy.......................................................................180
5.6.4. Other Prohibited Concomitant Medicines and Therapies.........................180
5.7. Rescue Medications and Supportive Care.............................................................181
5.7.1. Supportive Care Guidelines......................................................................181
6. STUDY PROCEDURES ...................................................................................................182
6.1. Screening...............................................................................................................182
6.1.1. Tumor Biospecimens................................................................................182
6.1.1.1. Combination A, B, C and D ....................................................182


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6.1.1.2. Combination F.........................................................................182
6.1.1.3. Sample Processing and Submission Requirements.................183
6.1.1.4. Selection of Lesion for Biopsy................................................183
6.2. Treatment Period...................................................................................................183
6.3. Follow-up ..............................................................................................................184
6.4. Patient Withdrawal................................................................................................185
7. ASSESSMENTS................................................................................................................186
7.1. Safety Assessments ...............................................................................................186
7.1.1. Pregnancy Testing ....................................................................................186
7.1.2. Contraceptive Check.................................................................................187
7.1.3. Adverse Events .........................................................................................187
7.1.4. Laboratory Safety Assessments................................................................187
7.1.5. Vital Signs and Physical Examination......................................................188
7.1.6. (12-Lead) Electrocardiogram....................................................................188
7.2. Pharmacokinetics Assessments.............................................................................189
7.2.1. All Combinations: Blood for PK Analysis of Avelumab .........................190
7.2.2. Combination A: Blood for PK Analysis of Utomilumab .........................190
7.2.3. Combination B: Blood for PK Analysis of PF-04518600........................190
7.2.4. Combination C: Blood for PK Analysis of PD 0360324..........................190
7.2.5. Combination D: Blood for PK Analysis of Utomilumab and 
PF-04518600..................................................................................................190
7.2.6. Combination F: Blood for PK Analysis of CMP-001, Utomilumab 
and PF-04518600...........................................................................................190
7.3. Immunogenicity Assessments...............................................................................191
7.3.1. All Combinations: Immunogenicity Assessment of Avelumab ...............191
7.3.2. Combination A: Immunogenicity Assessment of Utomilumab................191
7.3.3. Combination B: Immunogenicity Assessment of PF-04518600 ..............191
7.3.4. Combination C: Immunogenicity Assessment of PD 0360324................191
7.3.5. Combination D: Immunogenicity Assessment of Utomilumab and 
PF-04518600..................................................................................................191
7.3.6. Combination F: Immunogenicity Assessment of CMP-001, 
Utomilumab and PF-04518600......................................................................192
7.4. Biomarker and Pharmacodynamic Assessments...................................................192


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7.4.1. Combination A: Avelumab plus Utomilumab (4-1BB/CD136 
Agonist mAb)\ ...............................................................................................194
7.4.2. Combination B: Avelumab plus PF-04518600 (OX40/CD134 
Agonist mAb).................................................................................................194
7.4.3. Combination C: Avelumab plus PD 0360324 (Anti-M-CSF)..................194
7.4.4. Combination D: Avelumab plus Utomilumab plus PF-04518600 ...........194
7.4.5. Combination F: Avelumab and CMP-001 with Utomilumab or 
PF-04518600..................................................................................................194
7.4.6. Archived Tumor Biospecimens and De Novo Tumor Biopsies...............194
7.4.7. Peripheral Blood.......................................................................................195
7.5. Banked Biospecimens ...........................................................................................195
7.5.1. Markers of Drug Response.......................................................................195
7.5.2. Additional Research..................................................................................196
7.6. Tumor Response Assessments ..............................................................................196
8. ADVERSE EVENT REPORTING....................................................................................197
8.1. Adverse Events......................................................................................................197
8.1.1. Avelumab Adverse Events of Special Interest .........................................198
8.2. Reporting Period ...................................................................................................198
8.3. Definition of an Adverse Event.............................................................................198
8.4. Medication Errors..................................................................................................199
8.5. Abnormal Test Findings........................................................................................200
8.6. Serious Adverse Events.........................................................................................200
8.6.1. Protocol-Specified Serious Adverse Events.............................................201
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................201
8.7. Hospitalization ......................................................................................................202
8.8. Severity Assessment..............................................................................................204
8.9. Causality Assessment............................................................................................204
8.10. Exposure During Pregnancy................................................................................205
8.11. Occupational Exposure .......................................................................................206
8.12. Withdrawal Due to Adverse Events (See also Section 6.4 on Patient 
Withdrawal).............................................................................................................206
8.13. Eliciting Adverse Event Information ..................................................................206
8.14. Reporting Requirements......................................................................................206


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8.14.1. Serious Adverse Event Reporting Requirements ...................................207
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................207
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............207
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................207
9.1. Analysis Sets .........................................................................................................208
9.1.1. Full Analysis Set.......................................................................................208
9.1.2. Safety Analysis Set...................................................................................208
9.1.3. Evaluable for DLT Analysis Set...............................................................208
9.1.4. PK/Immunogenicity Analysis Sets...........................................................209
9.1.5. Biomarker Analysis Set............................................................................209
9.2. Statistical Methods and Properties ........................................................................209
9.2.1. Combination A..........................................................................................209
9.2.2. Combinations B, C, and D........................................................................209
9.2.3. Combination F ..........................................................................................211
9.3. Sample Size Determination...................................................................................211
9.3.1. Combination A..........................................................................................211
9.3.1.1. Sample Size Determination for Utomilumab and 
Avelumab for NSCLC Cohorts A1, A2, and A3.............................212
9.3.1.2. Sample Size Determination for Utomilumab and 
Avelumab for Melanoma Cohort A4...............................................212
9.3.1.3. Sample Size Determination for Utomilumab and 
Avelumab for SCCHN Cohort A5 ..................................................212
9.3.1.4. Sample Size Determination for Utomilumab and 
Avelumab for TNBC Cohort A6, SCLC Cohort A7, and 
First-Line NSCLC Cohorts A8, A9 and A10 ..................................213
9.3.2. Combination B: Sample Size Determination for PF-04518600 and 
Avelumab.......................................................................................................213
9.3.3. Combination C: Sample Size Determination for PD 0360324 and 
Avelumab.......................................................................................................214
9.3.4. Combination D: Sample Size Determination for Utomilumab and 
PF-04518600 and Avelumab .........................................................................215
9.3.5. Combination F: Sample Size Determination for CMP-001 and 
Avelumab and Utomilumab or PF-04518600................................................215
9.4. Efficacy Analysis ..................................................................................................216
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................217


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9.5.1. Analysis of Pharmacokinetics of Study Drugs .........................................217
9.5.2. Analysis of Biomarker Endpoints.............................................................217
9.5.3. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic Modeling .............................................218
9.5.4. Analysis of Immunogenicity Data of Avelumab and Other Study 
Drugs..............................................................................................................218
9.6. Safety Analysis......................................................................................................218
9.6.1. Analysis of the Primary Endpoint in the Phase 1b Lead-in......................218
9.6.2. Analysis of Secondary Safety Endpoints..................................................218
9.6.2.1. Adverse Events........................................................................219
9.6.2.2. Laboratory Test Abnormalities ...............................................219
9.6.2.3. Electrocardiograms..................................................................219
9.7. Analysis of Other Endpoints .................................................................................220
9.8. Data Safety Monitoring Committee ......................................................................220
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................220
11. DATA HANDLING AND RECORD KEEPING ...........................................................221
11.1. Case Report Forms/Electronic Data Record .......................................................221
11.2. Record Retention.................................................................................................221
12. ETHICS............................................................................................................................222
12.1. Institutional Review Board/Ethics Committee....................................................222
12.2. Ethical Conduct of the Study ..............................................................................222
12.3. Patient Information and Consent.........................................................................222
12.4. Patient Recruitment.............................................................................................223
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................223
13. DEFINITION OF END OF TRIAL.................................................................................223
13.1. End of Trial in a Member State...........................................................................223
13.2. End of Trial in All Other Participating Countries...............................................223
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................223
15. PUBLICATION OF STUDY RESULTS........................................................................224
15.1. Communication of Results by Pfizer ..................................................................224
15.2. Publications by Investigators ..............................................................................225
16. REFERENCES ................................................................................................................226


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LIST OF TABLES
Table 1.
Combination F (Avelumab Plus CMP-001 and Utomilumab or 
PF-04518600) Study Treatments..........................................................................43
Table 2.
CMP-001 Administration and Requirements .......................................................46
Table 3.
Schedule of Activities: Combination A (Avelumab and 
Utomilumab) - Safety and Efficacy Assessments (Phase 1b and Phase 2) ..........48
Table 4.
Schedule of Activities: Combination A (avelumab and 
Utomilumab) - Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments...........................................................................50
Table 5.
Schedule of Activities: Combination B (Avelumab and PF-04518600) –
Safety and Efficacy Assessments (Phase 1b and Phase 2) ...................................55
Table 6.
Schedule of Activities: Combination B (Avelumab and 
PF-04518600) - Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments...........................................................................57
Table 7.
Schedule of Activities: Combination C (Avelumab + PD 0360324) – Safety 
and Efficacy Assessments (Phase 1b and Phase 2) ..............................................62
Table 8.
Schedule of Activities: Combination C (Avelumab and PD 
0360324) - Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Assessments..........................................................................................................64
Table 9.
Schedule of Activities: Combination D (Avelumab, Utomilumab, and 
PF-04518600) – Safety and Efficacy Assessments ..............................................69
Table 10.
Schedule of Activities: Combination D (Avelumab, Utomilumab, and 
PF-04518600) - Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments...........................................................................71
Table 11.
Schedule of Activities: Combination F (F1: Avelumab plus CMP-001, F2: 
Avelumab plus CMP-001 and Utomilumab, F3: Avelumab plus CMP-001 
and PF-04518600) – Safety and Efficacy Assessments (Phase 1b and Phase 
2)...........................................................................................................................76
Table 12.
Schedule of Activities: Combination F (F1: Avelumab + CMP-001, F2: 
Avelumab + CMP-001 + Utomilumab, F3: Avelumab + CMP-001 + PF-
04518600) - Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic 
Assessments (Phase 1b and Phase 2)....................................................................79
Table 13.
Detailed Dose Escalation/De Escalation Scheme...............................................133
Table 14.
Combination A (Avelumab Plus Utomilumab) Phase 1b Study Treatments 
– NSCLC Only ...................................................................................................134
Table 15.
Combination B Phase 1b Study Treatments (Avelumab plus PF-04518600) ....137
Table 16.
Combination C Phase 1b Study Treatments (Avelumab Plus PD 0360324)......139


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Table 17.
Combination D (Utomilumab Plus PF-04518600 Plus Avelumab) Phase 1b 
Study Treatments................................................................................................140
Table 18.
Combination F (Avelumab Plus CMP-001 Plus Utomilumab or
PF-04518600) Study Treatments........................................................................144
Table 19.
Study B9991004 Investigational Products..........................................................157
Table 20.
CMP-001 Administration and Requirements .....................................................161
Table 21.
Avelumab, Utomilumab, PF-04518600, PD 0360324, and CMP-001 
Treatment Modifications for Drug-Related Toxicity .........................................166
Table 22.
Treatment Modification for Symptoms of Infusion-Related Reactions .............167
Table 23.
Cytokine Release Syndrome Revised Grading system.......................................169
Table 24.
High-Dose Vasopressors (All Doses Are Required for ≥3 hours) .....................170
Table 25.
Management of Immune-Related Adverse Events.............................................171
Table 26.
Laboratory Tests .................................................................................................187
Table 27.
Examples of Biomarker Analyses and Intended Uses........................................193
Table 28.
Combination A: Probability of Expanding Dose Level......................................209
Table 29.
Combination F: Probability of Expanding Dose Level ......................................211
Table 30.
Sample Size and Exact 90% CI for ORR in Combination A,  Cohort A6-
A10. ....................................................................................................................213
Table 31
Sample Size and Exact 90% CI for ORR in Combinations B, C, and D............214
Table 32
Sample Size and Exact 90% Confidence Intervals for Objective Response 
Rate in Combination F (Cohorts F1 to F3).........................................................216
Table 33.
CMP-001 Injection Volumes..............................................................................247
Table 34.
CMP-001 Administration and Requirements .....................................................247
LIST OF FIGURES
Figure 1.
Combination A Phase 1b and Phase 2 Study Design Schema - NSCLC 
Only (Cohorts A1, A2, A3) ..................................................................................36
Figure 2.
Combination A Phase 2 Study Design Schema - Melanoma (Cohort A4), 
SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort A7), and 
First-Line NSCLC (Cohort A8)............................................................................36
Figure 3.
Combination A Phase 2 Study Design Schema – Sequenced Administration 
in Patients with First-Line NSCLC (Cohort A9 and  Cohort A10)......................37
Figure 4.
Combination B Phase 1b and Phase 2 Study Design Schema..............................38
Figure 5.
Combination C Phase 1b and Phase 2 Study Design Schema..............................39


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Figure 6.
Combination D Phase 1b and Phase 2 Study Design Schema*............................41
Figure 7.
Combination F Phase 1b and Phase 2 Study Design Schema ..............................43
Figure 8.
Effect of Utomilumab on the Growth of PC3 Prostate Carcinoma in a 
huPBL SCID Model .............................................................................................94
Figure 9.
Combinatorial Efficacy of Surrogate Anti-4-1BB Combined with Surrogate 
Anti-PD-1 in a Colorectal Carcinoma Model.......................................................95
Figure 10. Mouse Surrogate Antibody OX86 mIgG1 Prevented Growth of CT26 
Colon Carcinoma................................................................................................100
Figure 11. Mouse Surrogate Antibody OX86 mIgG2a plus Avelumab Prevented 
Growth of CT26 Colon Carcinoma ....................................................................101
Figure 12. Inhibition of Tumor Growth by the Triplet Combination of 
Avelumab/Utomilumab/PF-04518600 in Melanoma and Colorectal 
Carcinoma Models..............................................................................................101
Figure 13. Inhibition of Tumor Growth by the Combination of Avelumab and 
anti-M-CSF in a Colorectal Carcinoma Model ..................................................106
Figure 14. Anti-tumor Efficacy of CMP-001 Regimen and Route of Administration in 
A20 Syngeneic Mouse Lymphoma Model - Study 160263: Injected Tumor 
- Right Flank.......................................................................................................110
Figure 15. Combination A Phase 1b and Phase 2 Study Design Schema - NSCLC 
Only (Cohorts A1, A2, A3) ................................................................................135
Figure 16. Combination A Phase 2 Study Design Schema - Melanoma (Cohort A4), 
SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort A7), and 
First-Line NSCLC (Cohort A8)..........................................................................136
Figure 17. Combination A Phase 2 Study Design Schema – Sequenced Administration
in Patients with First-Line NSCLC (Cohort A9 and Cohort A10).....................136
Figure 18. Combination B Phase 1b and Phase 2 Study Design Schema............................138
Figure 19. Combination C Phase 1b and Phase 2 Study Design Schema............................140
Figure 20. Combination D Phase 1b and Phase 2 Study Design Schema*..........................142
Figure 21. Combination F Phase 1b and Phase 2 Study Design Schema ............................143
Figure 22
Recommended Treatment Algorithm for Cytokine Release Symptoms ............169
Figure 23. Method for CMP-001 Intratumoral Injection .....................................................249
LIST OF APPENDICES
Appendix 1. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines .......................................................................................235
Appendix 2. ECOG Performance Status................................................................................240


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Appendix 3. Abbreviations and Definitions of Terms...........................................................241
Appendix 4. CMP-001 Administration..................................................................................246


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PROTOCOL SUMMARY
Indication
Avelumab is a fully human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody 
(mAb) of the immunoglobulin (Ig) G1 isotype that is currently being investigated in 
combination with other cancer immunotherapies to enhance anti-tumor activity over that 
expected by avelumab alone in patients with locally advanced or metastatic solid tumors.  
Avelumab is expected to increase the effectiveness of anti-tumor T cells by preventing 
inhibition of T cell activation.  This effect is expected to be enhanced by agents that promote 
anti-tumor immunity by complementary mechanisms such as promotion of T cell survival or 
removal of inhibitory myeloid cells.
Background
This is a Phase 1b/2 dose-finding study to evaluate safety, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary antitumor activity of avelumab (MSB0010718C), 
a PD-L1 mAb, in combination with other cancer immunotherapies in patients with locally 
advanced or metastatic solid tumors.  Avelumab reversal of T cell inhibition via PD-L1 
blockade is only one potential mechanism which can augment anti-tumor immunity.  
However, in many patients, blocking this single resistance pathway is insufficient to trigger a 
robust anti-tumor response.  As will be detailed in this protocol, mouse tumor modeling 
suggests that combining avelumab with 4-1BB or OX40 (CD134) agonist mAbs as doublets 
leads to increased anti-tumor activity compared with mice treated with any of the single 
agents.  In addition, macrophage-colony stimulating factor (M-CSF) blocking antibodies 
when combined with 4-1BB agonist mAbs and avelumab as a triplet, in models where 
myeloid suppressive cells may be important, exhibits greater anti-tumor activity than the 
respective doublets.  Furthermore, triplet combinations of 4-1BB and OX40 agonist mAbs or 
4-1BB agonist showed a marked increase in anti-tumor activity in these models compared 
with the respective doublets.  It is thought that triplets may be more effective compared with 
doublets as it is likely that doublet therapies, while potentially effective, do not address 
resistance mechanisms tied to immune homeostasis as well as select triplets.  Therefore, after 
the evaluation of respective doublets in this study for safety and preliminary clinical activity, 
triplet combinations may be explored in specific clinical settings where these combinations 
might be more effective.
While the above combinations address mechanisms thought to be active in tumors harboring 
a pre-existing immune response, they do not address the growing unmet medical need of 
patients who progress on PD-1/PD-L1 therapy due to absent or inactive immune responses.  
Preclinical studies detailed in this protocol suggest a Toll-like Receptor 9 (TLR9) receptor 
agonist may initiate immune responses that could be further enhanced by a PD-L1 pathway 
inhibitor in settings where single agent inhibition of the PD-L1 pathway is less effective.  
These preclinical studies also support the hypothesis that 4-1BB and OX40 agonist mAbs 
may further enhance T cell responses activated by the TLR9/PD-L1 combination.


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The primary purpose of this study is to assess the safety and early signs of activity of the 
above mentioned avelumab doublet and triplet combinations.  The proposed combinations 
are as follows: 

Combination A: avelumab plus utomilumab (PF-05082566), a fully human Ig 
G2 mAb agonist of 4-1BB (CD137, TNFRSF9) that promotes survival and function 
of T cells, especially CD8+ T cells. 

Combination B: avelumab plus PF-04518600, a fully human IgG2 mAb agonist of 
OX 40 (CD134) that promotes survival and function of T cells, especially CD4+ T 
cells.

Combination C: avelumab plus PD 0360324, a fully human IgG2 mAb directed 
against M-CSF that may inhibit tumor infiltration by immunosuppressive 
macrophages.  (Sites in the United Kingdom [UK] will not participate in this 
combination).

Combination D: avelumab plus utomilumab and PF-04518600 that is expected to 
provide complementary support for CD8+ and CD4+ T cells.

Combination F: avelumab plus CMP-001, an encapsulated TLR9 agonist that is 
expected to activate tumor-infiltrating plasmacytoid dendritic cells (pDCs) leading to 
activation and recruitment of anti-tumor T-cells to the tumor microenvironment.  
CMP-001 is expected to elicit T cell priming and infiltration into the tumor 
microenvironment, whereas avelumab is expected to block T cell inhibition by PD-L1 
that is induced by CMP-001.  Utomilumab or PF-04518600 will be evaluated in 
combination with avelumab and CMP-001 for the promotion of survival and function 
of T-cells activated by the combination.  (Only sites in the United States [US] will 
participate in this combination).
Study Objectives and Endpoints:
Primary Objectives

Phase 1b lead-in: To assess safety and tolerability of a single dose level of avelumab 
in combination with increasing dose levels of other immune modulators in patients 
with locally advanced or metastatic solid tumors in order to select the Recommended 
Phase 2 Dose(s) (RP2D)/schedule for the combination. 

Phase 2: To assess objective response (OR) of avelumab in combination with other 
immune modulators in patients with locally advanced or metastatic solid tumors.
Secondary Objectives

To assess the overall safety and tolerability of avelumab and other immune 
modulators when given in combination; 






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
Combination F: avelumab plus CMP-001 (TLR9 agonist) and utomilumab or 
PF-04518600:

Cohort F1: avelumab plus CMP-001; 

Cohort F2: avelumab plus CMP-001 and utomilumab; 

Cohort F3: avelumab plus CMP-001 and PF-04518600.
For Phase 1b dose escalation and Phase 2 expansion cohorts, patients may be enrolled into 
different combinations in parallel.  In non-randomized cohorts, slot assignments will be 
managed by the study team and sites will be notified in advance of cohort initiations.  
Patients are not allowed to crossover between the different combinations evaluated in this 
study.
Each combination will be studied individually in 2 study parts: 1) a Phase 1b Lead-in part to 
evaluate safety, and determine the maximum tolerated dose (MTD) or maximum 
administered dose (MAD) and RP2D (if applicable), of the combination, and 2) a 
Phase 2 part to evaluate efficacy and further evaluate safety of the selected dose from the 
Phase 1b portion in prespecified patient populations.  Enrollment of patients in different 
combinations may be staged in order of combination alphabetical order and by tumor type.  
Therefore, in Phase 1b dose escalation cohorts and Phase 2 expansion cohorts, staging of 
patient recruitment will be communicated to clinical sites in advance of the opening of new 
cohorts.  Study design details for each combination are provided below.
Additional combinations of avelumab with other immune modulators may be added to this 
protocol based on emerging preclinical and clinical data. 
Combination A (Avelumab plus Utomilumab)
Combination A includes a Phase 1b lead-in part and a Phase 2 part (Figure 1 and Figure 2).  
During Phase 1b, up to 18 NSCLC patients will be randomized 1:1:1 to 1 of 3 cohorts 
(6 patients each) to receive utomilumab at 500 mg (Cohort A1), 100 mg (Cohort A2), or 
20 mg (Cohort A3) administered intravenously (IV) every 4 weeks (Q4W) in combination 
with 10 mg/kg of avelumab administered IV every 2 weeks (Q2W) for 2 cycles (ie, 8 weeks).  
If a DLT is observed in at least 2 of 6 DLT-evaluable patients treated within a cohort, further 
evaluation of the cohort will be stopped (DLT definitions are provided in
Section 3.3).  Patients treated in Phase 1b who are not considered DLT evaluable will be 
replaced for the assessment of the DLT rate in the cohort to which they were randomized. 


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Figure 1.
Combination A Phase 1b and Phase 2 Study Design Schema - NSCLC Only 
(Cohorts A1, A2, A3)
For each utomilumab dose level that is tolerated (ie, not meeting the DLT criteria) in the 
Phase 1b lead-in, the corresponding dose level cohort(s) will continue enrollment in 
Phase 2 with up to 22 additional patients each.  Therefore, all 3 cohorts could potentially 
enroll additional patients. 
In addition to potential expansion of enrollment of patients with NSCLC to Cohorts A1, A2, 
or A3, Phase 2 will also enroll patients with melanoma (Cohort A4; N=28), SCCHN 
(Cohort A5; N=35), TNBC (Cohort A6; N=20), SCLC (Cohort A7; N=20), and first-line 
(1L) advanced  NSCLC (Cohort A8; N=20, up to 26 patients will be enrolled to achieve a 
minimum of 20 PD-L1-positive patients). 
Figure 2.
Combination A Phase 2 Study Design Schema - Melanoma (Cohort A4),
SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort A7), and 
First-Line NSCLC (Cohort A8)
* Utomilumab dose = 100 mg (may be modified based on emerging data).


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Sequenced administration of single agent avelumab or utomilumab for 1 cycle followed by 
administration of combination (avelumab plus utomilumab) will be evaluated in 2 additional 
cohorts.  Both cohorts will enroll 20 patients each with PD-L1 positive, first-line advanced 
NSCLC.  Cohort A9 will evaluate utomilumab single-agent administration, one month prior 
to initiation of combination treatment on Cycle 2 Day 1 (28 days after start of the 
single-agent treatment).  Cohort A10 will evaluate avelumab single-agent administration, one 
month prior to initiation of combination treatment on Cycle 2 Day 1 (28 days after start of 
the single-agent treatment).  Enrollment into Cohorts A9 and A10 will be randomized 1:1.    
Figure 3.
Combination A Phase 2 Study Design Schema – Sequenced Administration 
in Patients with First-Line NSCLC (Cohort A9 and 
Cohort A10)
In Phase 2, efficacy and safety will be assessed separately for each cohort of 
utomilumab plus avelumab in the NSCLC Cohorts A1, A2, and A3, as well as for Cohorts 
A4 (melanoma), A5 (SCCHN), A6 (TNBC), A7 (SCLC), and A8–A10 (first-line NSCLC).
Originally, approximately 253 patients with solid tumors were planned to be enrolled in 
Combination A across all cohorts.  Enrollment of patients into Cohorts A1 to A6 and A8 
were completed as planned.  In Cohort A7, 10 SCLC patients were enrolled.  However, the 
level of clinical activity observed in Cohort A7 does not support further clinical development 
and further enrollment in this cohort is not planned.  In addition, due to recent improvements 
in the standard of care for 1L NSCLC patients, the level of clinical activity observed in 
Cohort A10 does not support further development.  Given that Cohort A9 and A10 use 1:1 
randomization for enrollment, further enrollment in Cohort A9 alone would not conform with 
the study design.  Therefore, further enrollment in Cohorts A7, A9, and A10 is not planned.  
Combination B (Avelumab plus PF-04518600)
Combination B includes a Phase 1b dose-escalation part and Phase 2 part.  In the Phase 1b 
part for Combination B, patients with locally advanced or metastatic solid tumors as defined 
in Section 4.1 will be evaluated to identify the MTD or MAD of avelumab plus PF-04518600 
using the modified toxicity probability interval (mTPI) design.  Patients will receive 
PF-04518600 IV Q2W in combination with 10 mg/kg avelumab Q2W for 2 cycles (8 weeks). 
The starting dose level (B12) for Combination B is 0.3 mg/kg PF-04518600 Q2W plus 
10 mg/kg avelumab Q2W.  Initially 3 patients will be enrolled, treated, and monitored during 
the 8-week DLT period.  If recommended by the mTPI design, the dose level can be 
a) expanded in cohorts of up to 3 patients and then up to an additional 6 patients, b) escalated 


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to the next dose level, or c) de-escalated to a lower dose level.  A total of 12 patients will be 
treated at the RP2D.  If at any point the mTPI requires a de-escalation, the next 3 patients 
will be enrolled at the lower dose level.  Dose escalation will be allowed as long as the next 
highest dose level has not been determined to have exceeded the MTD. 
Following the 8-week DLT observation period, if no patients experience DLTs, the next 
higher dose level cohort may be initiated.  Initially 3 patients will be assigned to a new open
dose level.  Up to 3 patients can be added at the same dose level if no DLTs are observed 
after 4 weeks of observation.  After the first 3 patients enrolled in a dose escalation cohort 
have completed the 8-week DLT period, additional cohorts of up to 6 patients each may be 
enrolled into any dose level that has been deemed safe (if recommended by the mTPI design) 
for a total of 12 patients to obtain additional safety and PD data.  See the subsection for all 
combinations in Inclusion Criterion 1 (Section 4.1) for biopsy requirements. 
Once the Phase 1b part is completed and the MTD or MAD is determined, the Phase 2 
portion of Combination B will be initiated.  During Phase 2, patients with NSCLC, 
melanoma, SCCHN will be enrolled into 3 separate cohorts of 25 patients each to evaluate 
safety and efficacy at the RP2D determined during Phase 1b for those tumor types.  Each 
cohort will provide preliminary estimates for objective response rate (ORR) to help inform 
future trials.  The overall study schema for Combination B, including study treatments to be 
evaluated during Phase 1b, is presented in Figure 4). 
Figure 4.
Combination B Phase 1b and Phase 2 Study Design Schema
Originally, approximately 105 patients were planned to be enrolled in Combination B.  
Enrollment in Phase 1 was completed and enrollment in the Phase 2 SCCHN cohort was also
completed.  The safety profile of this combination was acceptable and there was evidence of 
pharmacodynamic activity.  However, the observed clinical activity does not support further 
development.  Therefore, the completion of patient enrollment into the Phase 2 NSCLC 
cohort and the initiation of enrollment into the Phase 2 melanoma cohort are not planned.  


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Combination C (Avelumab plus PD 0360324)
Combination C includes a Phase 1b sequential dose-escalation lead-in part and Phase 2 part.  
In the Phase 1b lead-in part for Combination C, patients with locally advanced or metastatic 
solid tumors as defined in Section 4.1 will be evaluated to identify the MTD or MAD of 
avelumab plus PD 0360324 using the mTPI design.  Patients will receive PD 0360324 IV 
Q2W in combination with 10 mg/kg avelumab Q2W for 2 cycles (8 weeks). 
If recommended by the mTPI design, a dose level may be a) expanded in cohorts of up to 
3 patients and then up to an additional 4 patients, b) escalated to the next dose level, or 
c) de-escalated to a lower dose level. 
The starting dose level (C11) of Combination C is 50 mg PD 0360324 Q2W plus 10 mg/kg 
avelumab Q2W.  Starting with dose level C11, 3 patients will be enrolled, treated, and
monitored during the 8-week DLT period.  Fresh biopsies will not be required for the first 
3 patients enrolled in each dose level.  If at any point the mTPI requires a de-escalation, the 
next 3 patients will be enrolled at the lower dose level.  Dose escalation will be allowed as 
long as the next highest dose level has not been determined to have exceeded the MTD. 
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is reconfirmed per mTPI design. 
During Phase 1b, if allowed by the mTPI design, a cohort may be expanded to approximately 
10 patients total to collect additional safety, clinical activity, and biomarker related data. 
Once the Phase 1b is completed and the MTD or MAD is determined, the Phase 2 portion of 
Combination C will be initiated to evaluate safety and efficacy at the RP2D determined 
during Phase 1b.  Up to 2 tumor types among the following will be selected for evaluation: 
ovarian cancer, SCCHN, NSCLC, or gastric cancer.  The overall study schema for 
Combination C, including study treatments to be evaluated during Phase 1b, is presented in 
Figure 5.
Figure 5.
Combination C Phase 1b and Phase 2 Study Design Schema


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Originally, approximately 80 patients were planned to be enrolled in Combination C.  
However, the level of clinical activity observed in cohorts C11, C12, and C13, did not 
support development beyond Phase 1b.  Therefore, Phase 2 is not planned. 
Combination D (Avelumab plus Utomilumab plus PF-04518600)
Combination D includes a Phase 1b sequential dose escalation part and a Phase 2 part. In the 
Phase 1b part for Combination D, patients with locally advanced or metastatic solid tumors 
as defined in Section 4.1 will be evaluated to identify the MTD or MAD of avelumab plus 
utomilumab plus PF-04518600 using the mTPI design.  Patients will receive utomilumab 
plus PF-04518600 in combination with avelumab Q2W for 2 cycles (8 weeks) and be 
evaluated for DLT. 
The starting dose level (D11) for Combination D is 20 mg utomilumab Q4W plus 0.1 mg/kg
PF-04518600 Q2W plus 10 mg/kg avelumab Q2W.  The initiation of patient recruitment at 
D11 is dependent upon the observation of no more than 1 DLT out of 6 patients treated in 
Phase 1b Combinations A and B at 500 mg utomilumab and 1 mg/kg PF-04518600, 
respectively.  As of 30 September 2016, this study has completed the Phase 1b part of 
Combination A with no DLTs observed and, for the Phase 1b part of Combination B, no 
DLTs have been observed at the starting dose level of 0.3 mg/kg PF-04518600 (B12) with 
evaluation of the 1 mg/kg PF-04158600 dose level ongoing.  Since no DLTs were observed 
during Phase 1b of Combination A, Combination D will be initiated once the safety of the 
1 mg/kg PF-04518600 dose level of Combination B is confirmed (eg, dose is acceptable per 
mTPI design following treatment of at least 6 patients treated at that dose or higher). 
If recommended by the mTPI design, a dose level may be a) expanded in cohorts of up to 
3 patients and then up to an additional 4 patients, b) escalated to the next dose level, or 
c) de-escalated to a lower dose level. 
Starting with dose level D11, 3 patients will be enrolled, treated, and monitored during the 
8-week DLT period.  Fresh biopsies will not be required for the first 3 patients enrolled in 
each dose level.  If at any point mTPI requires de-escalation, the next 3 patients will be 
enrolled at the lower dose level.  Dose escalation will be allowed as long as the dose level 
satisfies the mTPI criteria. 
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is re-confirmed per mTPI design.  During Phase 1b, if allowed by 
the mTPI design, a cohort may be expanded to approximately 10 patients total to collect 
additional safety, clinical activity, and biomarker related data. 
Once the Phase 1b lead-in is completed and the MTD or MAD is determined, the 
Phase 2 portion of Combination D may be initiated to evaluate the safety and efficacy at the 
RP2D (one or more dose levels) determined during Phase 1b, if the safety and clinical 
activity are supportive of further development.  Up to 2 tumor types among the following 
may be selected for evaluation: NSCLC, melanoma, SCCHN, or bladder cancer.  The overall 


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study schema for Combination D, including study treatments to be evaluated during Phase
1b, is presented in Figure 6.
Figure 6.
Combination D Phase 1b and Phase 2 Study Design Schema*
* A solid arrow to a dose level implies that only the dose level from which the arrow is originating needs to be 
safe (escalate per mTPI design) for that dose level to be opened.  For example, D21 may be opened if D11 is 
safe, and D31 may be opened if D21 is safe.  A dashed arrow to a dose level implies that more than 1 dose level 
is required to be safe (escalate per mTPI design for more than 1 dose level) for that dose level to be opened.  For 
example, D12 and D21 both need to be safe (escalate per mTPI design for both) for D22 to be opened, and 
D31 and D22 both need to be safe for D32 to be opened.  Cohorts D12 and D21 and Cohorts D22 and D31 may 
be opened and enroll patients in parallel since only either utomilumab or PF-04518600 is escalated at a time. 
Originally, approximately 122 patients were planned to be enrolled into Combination D.  
However, the level of clinical activity observed in cohorts D11 to D32 did not support 
development beyond Phase 1b.  Therefore, Phase 2 is not planned. Overall 71 patients were 
enrolled for Combination D treatment.
Combination F (Avelumab plus CMP-001 with or without Utomilumab or 
PF-04518600)
Combination F includes a Phase 1b safety lead-in part and a Phase 2 part.  Eligible patients 
will have recurrent or metastatic SCCHN, will have been previously treated with an 
anti-PD-1 or anti-PD-L1 containing therapy, and will have experienced disease progression 
prior to study entry (see Inclusion Criteria in Section 4.1).  
In the Phase 1b safety lead-in part, patients will initially be randomized 1:1:1 into each of 
Cohorts F1, F2, and F3.  Six DLT evaluable patients are needed to assess safety in each 
cohort. Patient who are not evaluable for DLTs, might be replaced by enrolling a patient 
without randomization.  


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Up to 12 patients will be randomized into each cohort in the Phase 1b safety lead-in and 
evaluated for DLT during the first treatment cycle (4 weeks) as follows:

If 1 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
14 additional patients in the Phase 2 cohort expansion.

If 2 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
6 additional DLT-evaluable patients in the Phase 1b lead-in part of the study:

If 3 of 12 patients experience DLT, the cohort will be expanded to enroll up to 
8 additional patients in the Phase 2 cohort expansion;

If 4 of up to 12 patients experience DLT, enrollment in the specific cohort will 
be discontinued. 

If 3 of up to 6 patients experience DLT, enrollment in the specific cohort will be 
discontinued.
If one cohort is discontinued, patients will be randomized to the remaining cohorts in a 1:1 
ratio.  Therefore, the total number of possible enrolled patients per cohort may be 
approximately 20 patients for cohorts that do not meet the DLT stopping criteria and the total 
number of patients enrolled for this combination may be approximately 60 patients. 
In addition to the rules for the continuation of a cohort based on DLTs, the Sponsor will 
monitor DLTs across the cohorts and may elect to pause or discontinue patient enrollment at 
any time based on emerging safety and efficacy data from the current study or other studies 
with CMP-001. 
The following 3 cohorts will be evaluated (see Figure 7):

Cohort F1: avelumab plus CMP-001;

Cohort F2: avelumab plus CMP-001 and utomilumab;

Cohort F3: avelumab plus CMP-001 and PF-04518600.
The following doses of study drugs will be administered: 

CMP-001 at 10 mg for an initial 7 doses (2 subcutaneous [SC] administrations at 
weekly intervals, followed by 5 intratumoral administrations [IT] at weekly intervals) 
and then IT administration every 2 weeks (Q2W) (all cohorts).

Avelumab at 10 mg/kg administered IV every 2 weeks (Q2W) (All cohorts);

Utomilumab at 100 mg administered IV every 4 weeks (Q4W) (F2);

PF-04518600 at 0.3 mg/kg administered IV every 2 weeks (Q2W) (F3).  


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The overall study schema for Combination F, including study treatments to be evaluated, is 
presented in Figure 7.
Figure 7.
Combination F Phase 1b and Phase 2 Study Design Schema
The dose levels of the study treatments to be evaluated during Combination F are presented 
in Table 1.  
Table 1.
Combination F (Avelumab Plus CMP-001 and Utomilumab or 
PF-04518600) Study Treatments
Cohort
CMP-001
(SC and IT)
Utomilumab Dose 
(IV)
PF-04518600 Dose 
(IV)
Avelumab Dose 
(IV)
F1
10 mg
NA
NA
10 mg/kg Q2W
F2
10 mg
100 mg Q4W
NA
10 mg/kg Q2W
F3
10 mg
NA
0.3 mg/kg Q2W
10 mg/kg Q2W
IV=intravenous; SC=subcutaneous; NA=not applicable; IT=intratumoral.
Study Design Elements Common to All Combinations
For all combinations, treatment with investigational products will continue until disease 
progression is confirmed by the Investigator, patient refusal, unacceptable toxicity, or until 
the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details 
of treatment after initial determination of radiological disease progression.
Patients who stop avelumab or the other immune modulator(s) may continue on treatment 
with the investigational product(s) that is/are not considered to be responsible for any severe 
adverse event (AE) in consultation with the Sponsor’s Medical Monitor. 
It is recommended that patients who have experienced a confirmed complete response (CR) 
should continue to be treated with investigational products at the discretion of the 
Investigator after discussion with the Sponsor. 


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Patients who stop treatment for reasons other than toxicity and experience radiologic disease 
progression shortly thereafter will be eligible for re-treatment with either avelumab or the 
other immune modulator(s) at the discretion of the Investigator and after discussion with the 
Sponsor.
Tumor Assessment: Anti-tumor activity will be assessed by radiological tumor assessments 
at 8-week intervals using RECIST v1.1.  In case partial response (PR), CR, or progressive 
disease (PD) is observed according to RECIST v.1.1, tumor assessments should be repeated 
at least 4 weeks after initial documentation.  After 1 year from randomization in the study 
(randomized cohorts) or the first dose (non-randomized cohorts), tumor assessments will be 
conducted less frequently, ie, at 12-week (after 1 year) and 16-week (after 2 years) intervals, 
respectively.  In addition, radiological tumor assessments will also be conducted whenever 
disease progression is suspected (eg, symptomatic deterioration) and at the End of 
Treatment/Withdrawal (if not done in the previous 4 weeks and prior response is other than 
confirmed PD).  Details of the treatment after initial evidence of radiological disease 
progression are provided in Section 5.3.5.3.
Further specific guidance on tumor imaging is provided in Section 7.6.
Safety Assessments: Safety will be monitored at regular intervals throughout the study by 
means of laboratory tests and clinical visits as described in the Schedule of Activities and 
described in Section 7.1.  The hematology, blood chemistry, and pregnancy test (if 
applicable) results must be available and reviewed by the treating physician prior to study 
treatment administration.  Further details are presented in Section 5.3.7.
PK/Immunogenicity Assessments: PK/immunogenicity blood sampling will be collected as 
described in the Schedule of Activities for each combination and described in Section 7.2. 
The proposed doses, schedule(s), and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
Biomarker Assessments: A key objective of the biomarker analyses that will be performed in 
this study is to investigate biomarkers that are potentially predictive of treatment benefit with 
the combination of avelumab and other immune modulator(s).  In addition, biomarker studies 
of tumor and blood biospecimens will be carried out to help further understand the 
mechanism of action of the combinations of avelumab plus other immune modulator(s), as 
well as potential mechanisms of resistance.  Biomarkers that correlate with 
pharmacodynamic effects may be considered when prioritizing dose levels for further 
exploration.  Biomarker assessments are described in Section 7.4.
Investigational Products:
All investigational products will be administered at the investigational site on an outpatient 
basis.  After Cycle 1, investigational products may be administered up to 2 days before or 
after the scheduled treatment day of each cycle for administrative reasons.  However, if the 
administration is given 2 days before or after the scheduled treatment day, and multiple 


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investigational products are to be administered, all scheduled investigational products should 
be given on the same day. 
Avelumab will be administered at 10 mg/kg as a 1-hour IV infusion Q2W on Day 1 and 
Day 15 of each cycle. 
Utomilumab (Combination A, Combination D, and Combination F) will be administered as a 
1-hour IV infusion Q4W on Day 1 of each cycle. 
PF-04518600 (Combination B, Combination D, and Combination F) will be administered as 
a 1-hour IV infusion, Q2W on Day 1 and Day 15 of each cycle.
PD 0360324 (Combination C) will be administered as a 30-minute IV infusion Q2W on 
Day 1 and Day 15 of each cycle. 
For Combination D, on days when 3 investigational products are to be administered, 
utomilumab will be administered first, followed at least 30 minutes (+20-minute time 
window, if needed) later by the PF-04518600 infusion (second), followed at least 30 minutes 
(+20-minute time window, if needed) later by the avelumab infusion (third).  On days when 
only avelumab and PF-04518600 are administered, PF-04518600 will be administered first,
followed by the avelumab infusion at least 30 minutes (+20-minute time window, if needed) 
after the end of the PF-04518600 infusion.
CMP-001 will be administered initially as 2 weekly SC doses, followed by IT dosing at 
weekly intervals for 5 additional doses.  After the first 7 doses, CMP-001 will be 
administered IT every 2 weeks (Q2W) (all cohorts). From C2D1, if IT is not feasible then 
CMP-001 should be administered in the peritumoral region.  If peritumoral administration is 
not feasible, then SC administration in an area of the draining lymph node where primary 
disease exists should be implemented.  If any of the above is not feasible, then SC (either 
arm, thigh or anterior abdominal wall) administration should be implemented.  For 
Combination F, on days when 3 investigational products are to be administered, either 
utomilumab (Cohort F2) or PF-04518600 (Cohort F3) will be administered first, followed by 
avelumab and then followed by CMP-001.  CMP-001 administration and requirements are 
summarized in Table 2.


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Table 2.
CMP-001 Administration and Requirements
Visit/Dose
CMP-001 Administrationa
Premedications
Post injection 
Observation Period
C1D1 and C1D8
SC (either arm, 
thigh or 
anterior 
abdominal 
wall)
Weekly
Mandated
Required (4 hrs)
C1D15, C1D22, 
C2D1, C2D8
ITb
Weekly
Mandated
Required (4 hrs)
C2D15 onwards
ITb
Every 2 
weeks
Recommended
Required (can be reduced 
up to 1 hr based on 
reactions to prior
injections and clinical 
judgement).
C=cycle; D=day; hr=hour; IT=intratumoral; SC=subcutaneous.
a. CMP-001 will be administered initially as 2 weekly SC doses, followed by IT dosing at weekly intervals for 
5 additional doses.  After the first 7 doses, CMP-001 will be administered IT every 2 weeks (Q2W) (all 
cohorts).
b. From C2D1, if IT is not feasible then CMP-001 should be administered in peritumoral region. If peritumoral
administration is not feasible, then SC administration in an area of the draining lymph node where primary 
disease exists should be implemented.  If any of the above is not feasible, then SC (either arm, thigh or anterior 
abdominal wall) should be implemented.
Detailed instructions for CMP-001 administration, including tumor lesion selection and dose 
splitting, are provided in Appendix 4 and in the Injection Manual. 
Statistical Analyses
DLT is the primary endpoint for Phase 1b lead-in.  The DLT-evaluable data set includes all 
enrolled patients in Phase 1b who are eligible for the study, receive at least 1 dose of study 
treatment, and either experience DLT or complete the DLT observation period.  For 
Combinations A, B, C, and D, the DLT observation period is the first 2 cycles (8 weeks) of 
treatment.  For Combination F, the DLT observation period will be 4 weeks including the 
first two weekly SC injections and the subsequent two weekly IT administrations. 
Patients without DLTs who withdraw from study treatment before receiving at least 75% of
the prescribed doses for all investigational products in the combination for reasons other than 
treatment-related toxicity (eg, missed appointments or development of rapidly progressing 
disease) are not evaluable for DLT.
Analyses of DLT are based on the DLT-evaluable set.  The occurrence of DLTs and AEs 
constituting DLTs will be summarized and listed per cohort for patients in the Phase 1b 
lead-in (Combination A and Combination F) and summarized and listed for all patients in the 
Phase 1b lead-in (Combinations B, C, and D).


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OR is the primary endpoint for Phase 2.  OR is defined as CR or PR per RECIST v1.1 from 
the randomization in the study (randomized cohorts) or first dose (non-randomized cohorts) 
until disease progression or death due to any cause.  Both CR and PR must be confirmed by 
repeat assessments performed no less than 4 weeks after the criteria for response are first 
met.  Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
CR or PR per Investigator’s assessment according to RECIST v.1.1.  The two-sided exact 
90% CIs for ORR will be calculated.
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to the ASSESSMENTS section of the protocol for detailed information on each 
assessment required for compliance with the protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table in order to conduct evaluations or assessments required to 
protect the well-being of the patient.








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Footnotes for Schedule of Activities (Combination A)
1.
Screening: To be obtained within 28 days prior to randomization for the non-small cell lung cancer (NSCLC) cohorts or first dose for the melanoma, squamous cell 
carcinoma of the head and neck (SCCHN), and triple-negative breast cancer (TNBC) cohorts.
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 randomization for the NSCLC cohorts or first dose for the melanoma, SCCHN, SCLC, and TNBC cohorts.  
Includes oncology history, information on prior regimens (including dosing and duration of administration, best response observed, and recurrence date), surgery, and 
radiation therapy.
4.
Medical History: To be collected within 28 days prior to randomization for the NSCLC cohorts or first dose for the melanoma, SCCHN, SCLC, and TNBC cohorts.  
Includes history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment.  Height will be measured at screening only.  Starting on C24D1, on-treatment physical 
examination to be performed only when clinically indicated.
6.
Baseline Signs/Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry (Study entry is randomization date for 
randomized cohorts and first dose date for non-randomized cohorts) and recorded on the Medical History case report form (CRF) page.  During treatment any new or 
worsening conditions since baseline should be reported on the Adverse Event (AE) CRF.
7.
ECOG PS: ECOG performance scale is available as Appendix 2.
8.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
9.
Contraceptive Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of the selected method of contraception.  The investigator or his or her designee will discuss with the patient the need to use at least 1 highly effective 
contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if selected contraception method is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner. See Section 4.3).
10. Hematology: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study 
treatments unless otherwise indicated.  If, during the first 2 cycles of treatment, a Grade 4 hematologic event is evident, the hematology assessment should be repeated at 
least every other day to assess for events qualifying as dose-limiting toxicity (DLT).  See Section 7.1.4 for the list of the required Laboratory Tests.
11. Blood Chemistry: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study treatments 
unless otherwise indicated.  Results should be available for review prior to infusion of investigational products.  See Section 7.1.4 for the list of the required Laboratory 
Tests.
12. Coagulation: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, starting on C3D1, coagulation test to be performed when 
clinically indicated.  See Section 7.1.4 for the list of the required Laboratory Tests.
13. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semi-quantitative method (eg, urine dipstick), protein will be 
quantified by 24-hour urine collection.  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
14. Serum/Urine Pregnancy Test (serum/urine): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed and assayed in a certified laboratory on two occasions prior to starting study treatments, once at the start of screening and once at the baseline visit immediately 
before investigational products administration. Additional pregnancy tests (serum or urine) will also be routinely repeated at every treatment cycle, prior to dosing, during 
the active treatment period, at the end of study therapy, during follow-up (up to 90 days after last study treatment), 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 (See Section 7.1.1).


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15. 12-Lead ECG: All patients require a single ECG measurement at screening and End of Treatment (EoT) visit.  On-treatment ECGs will be performed on Day 1 of Cycles 1 
and 2, before and at the end of utomilumab infusion and at the end of avelumab infusion. For Cohorts A9 and A10, triplicate ECG measurements are not required and may 
be performed as clinically indicated. At each time point, three (3) consecutive 12 lead ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean 
QTc (average of triplicates).  When coinciding with blood sample draws for PK, the ECG assessment should be performed prior to blood sample collection, such that the 
blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should 
be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation and 
repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
16. Hepatitis B and C Virus Tests: Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Reflexive testing and other supporting tests may be 
conducted per standard practice to confirm an active hepatitis infection.
17. ACTH and Thyroid Function Tests: Thyroid function tests (ACTH, free T4 [FT4], thyroid stimulating hormone [TSH]) will be performed at Screening, Cycle 3 
Day 1 and every 12 weeks thereafter, End of Treatment (EOT) visit, and 30 days after last investigational product administration, and if clinically indicated.  See 
Section 7.1.4 for the list of the required Laboratory Tests.
18. Randomization/Enrollment: Patient number and dose level allocation via interactive response technology (IRT) operated by Pfizer Inc.  Investigational product 
administration should begin within 7 days after randomization/enrollment.
19. Avelumab Administration: Treatment will be administered every 2 weeks in 4-week cycles (ie, 28-day cycles).  Avelumab will be administered as a 1-hour intravenous 
infusion every 2 weeks (eg, on Days 1, 15 of a cycle).  For all cohorts except Cohort A9, avelumab administration will start on Cycle 1 Day 1.  For patients randomized to 
Cohort A9, avelumab administration will begin on Cycle 2 Day 1.  Avelumab infusion will start at least 30 minutes (+20 minute time window, if needed) after completion of 
utomilumab infusion.  On days when PK samples are taken, avelumab infusion will start after the post- utomilumab and pre-avelumab pharmacokinetic blood samples are 
drawn.  Treatment will continue until disease progression is confirmed by the investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the 
Sponsor, whichever occurs first.  See Section 5.3.5.3 for details of treatment after initial determination of radiological disease progression. 
20. Utomilumab Administration: Treatment will be administered in a 4-week cycle (ie, 28-day cycle).  Utomilumab will be administered as a 1-hour intravenous infusion on 
Day 1 of a cycle.  For all cohorts except Cohort A10, utomilumab administration will start on Cycle 1 Day 1.  For patients randomized to Cohort A10, utomilumab 
administration will begin on Cycle 2 Day 1.  When both utomilumab-and avelumab are administered, utomilumab will be administered first, followed by the avelumab 
infusion at least 30 minutes (+20 minute time window, if needed) after the end of the utomilumab infusion.  Treatment will continue until disease progression is confirmed 
by the investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details of treatment 
after initial determination of radiological disease progression.
21. Tumor Assessments: The decision for body areas to be scanned will depend on disease under study and extent of disease.  Imaging may include chest, abdomen and pelvis 
CT or MRI scans; brain CT or MRI scan, and bone scans (or CT/18F-FDG-PET/MRI for bone imaging).  The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons.  The minimum recommended body areas to be scanned depending on malignancy are detailed in the Imaging Manual.  The same 
imaging technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments.  Antitumor activity will be 
assessed through radiological tumor assessments conducted at screening and every 8 weeks until disease progression regardless of initiation of subsequent anticancer 
therapy.  The allowable time window for disease assessments is 7 days while on treatment and whenever disease progression is suspected (eg, symptomatic deterioration).  
In case partial response (PR), complete response (CR), or Progressive Disease (PD) is observed according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, 
tumor assessments should be repeated at least 4 weeks after initial documentation.  Tumor assessments should be repeated at End of Treatment/Withdrawal if not done in the 
previous 4 weeks and prior response is other than confirmed PD.  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  After 1 year 
from randomization in the study (randomized Cohorts A1-A3, A9 and A10) or first dose (non-randomized Cohorts A4-A8), tumor assessments will be conducted less 
frequently, ie, at 12-week (after 1 year) and 16-week (after 2 years) intervals, respectively.  Bone scans (or CT/18F-FDG-PET/MRI) are required at baseline only if bone 
metastases are known or suspected outside the body areas scanned, then every 16 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is required 
only if new bone metastasis are suspected and at the time of confirmation of complete response for patients who have bone metastases.  Assessment of response will be 
made using RECIST version 1.1 (see Section 7.6, Appendix 1).  


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22. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the subject provides informed consent, which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a subject 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 treatment are to be reported to the sponsor.  AEs serious or non-serious, suspected to be related to the study treatment based 
on investigator’s assessment, should be recorded on the CRF.  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 study treatment, irrespective of any intervening treatment 
(See Section 8.2).
23. Concomitant Treatments: Concomitant treatments will be recorded from 28 days prior to the start of study treatment and up to 90 days after the last dose of investigational 
products.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to 
treat AEs or chronic diseases, and non-drug supportive interventions (eg, transfusions).  Concomitant treatments will not be collected for patients who initiate subsequent 
anticancer therapy.
24. Subsequent Anti-Cancer Treatment: Subsequent anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue 
in follow up, and during survival follow up.
25. Survival: Patients will be followed for survival, independently of time of disease progression or initiation of subsequent anticancer therapy, for at least 2 years after 
randomization of the last patient in the randomized cohorts and for at least 2 years after first dose of the last patient for the non-randomized cohorts unless lost to follow-up, 
consent withdrawal, or study discontinued by the Sponsor.  Patients will be contacted every 3 months for survival status and subsequent anti-cancer treatment. 
26. Blood for Utomilumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
(ie, at the end of infusion) on Day 1 of Cycles 1, 3, 5, 8, and Cycle 12.  A sample will also be collected on Days 8 and 15 of Cycle 1 (non-dosing visit).  For patients 
randomized to Cohort A9, PK samples will begin on Cycle 1 Day 1.  For patients randomized to Cohort A10, PK samples will begin on Cycle 3 Day 1.  
27. Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will also be collected on Day 8 of 
Cycle 1 (non-dosing visit).  For patients randomized to Cohort A9, PK samples will begin on Cycle 2 Day 1.  For patients randomized to Cohort A10, PK samples will begin
on Cycle 1 Day 1.  
28. Archival FFPE Tumor Tissue Block: Patients in Phase 1b should provide archival FFPE tumor tissue if available.  Patients in Phase 2 must provide FFPE tissue from the 
most recent primary or metastatic tumor biopsy or resection prior to study entry, taken within one year of start of study treatment, with no intervening systemic anti-cancer 
therapy; if such tissue is not available then a de novo biopsy prior to study entry is required.  The requirement for archival tissue may be waived if a de novo biopsy will be 
collected.  See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue samples.
29. De Novo Tumor Biopsy: A mandatory baseline de novo tumor biopsy from a locally recurrent or metastatic tumor site must be obtained for all patients except for the first
3 patients (including replacements) enrolled in each dose level in Phase 1b, if archival tissue meeting the specifications in footnote 28 and Section 6.1.1 is not available.  On 
treatment biopsies are required except in instances where the procedure poses unacceptable risks per investigator documentation.  See Inclusion Criteria (Section 4.1) for 
biopsy requirements.  At end of treatment, if a patient discontinues due to disease progression, a de novo tumor sample is required except in instances where the procedure 
poses unacceptable risks per investigator documentation. See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue 
samples.  The Cycle 2 Day 1 de novo biopsy should be performed at any time between 21 days after first dose of study drug(s) 4 days BEFORE dosing on
Cycle 2 Day 1.  
30. TCR Analysis from Peripheral Blood: A 6 mL sample of whole blood will be collected at screening, Day 1 (pre-dose) and Day 15 (pre-dose) of Cycles 1 and 2; 
Day 1 (pre-dose) of Cycles 3 and 5; and at End of Treatment/Withdrawal.
31. Whole Blood for DNA Analysis: A 4 mL blood biospecimen will be collected prior to dosing on Day 1 of Cycles 1, 2, 3, 5 and at End of Treatment/Withdrawal. See
Section 7.4 for details.
32. Serum for pharmacogenomic/proteomic/metabolomic analysis: A 10 mL blood biospecimen will be collected prior to dosing on Day 1 of Cycles 1, 2, 3, 5 and at End of 
Treatment/Withdrawal.  See Section 7.4 for details.


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33. Plasma for pharmacogenomic/proteomic/metabolomic analysis: A 20 mL blood biospecimen will be collected at screening, prior to dosing on Day 1 of Cycles 1, 2, 3, 
and at End of Treatment/Withdrawal.  See Section 7.4 for details.
34. PAXGene whole blood collection optimized for RNA analysis: A 2.5 mL blood biospecimen will be collected prior to dosing on Day 1 of Cycles 1, 2, 3, 5 and at End of 
Treatment/Withdrawal.  See Section 7.4 for details.
35. Banked Biospecimens: A 4 mL blood biospecimen Prep D1 (K2 ethylenediaminetetraacetic acid [EDTA] whole blood collection optimized for DNA analysis) will be 
collected on Day 1 of Cycle 1 prior to dosing and retained in a biobank for possible pharmacogenomic assessments, unless prohibited by local regulations or by decision of 
the IRB or EC (see also Section 7.5 of the protocol).
36. Blood for Utomilumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for utomilumab immunogenicity testing will be 
collected on Cycles 1, 3, 5,8, and 12 on Day 1 at pre-dose.  For patients randomized to Cohort A9, ADA samples will begin on Cycle 1 Day 1.  For patients randomized to 
Cohort A10, ADA samples will begin on Cycle 3 Day 1.  
37. Blood for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for avelumab immunogenicity testing will be collected on 
Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.  For patients randomized to Cohort A9, ADA samples will begin on Cycle 2 Day 1.  For patients randomized to
Cohort A10, ADA samples will begin on Cycle 1 Day 1.  
38. End of Treatment: Obtain these assessments if not completed during the previous week on study, except for tumor assessments, which need not be repeated if performed 
within the prior 4 weeks.  The EOT visit should occur within 7 days after discontinuation criteria are met.
39. Follow-Up: Patients should be evaluated for safety up to 90 days (30 days, 60 days, and 90 days) after last dose of investigational products.  See Section 6.3.  Patients 
continuing to experience toxicity following discontinuation of investigational products will continue to be followed at least every 4 weeks regardless of initiation of new 
anticancer treatment 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 time of study treatment discontinuation will enter into disease follow-up. (For tumor assessment).  Physical examination, ECOG status, vital signs, and 
safety laboratory measurements are not required for patients who initiate new anticancer treatment, unless the patient continues to experience toxicity following 
discontinuation of the investigational products. Contraception check and serum/urine pregnancy tests are required for all patients who enter Follow-up regardless of 
initiation of subsequent anticancer therapy.  
Abbreviations: ACTH = adrenocorticotropic hormone, ADA = anti-drug antibodies; AE = adverse event; C=Cycle; CT = computed tomography; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = end of treatment; FFPE = formalin-fixed paraffin-embedded; 
HBV = hepatitis B virus; 
HCV = hepatitis C virus; MRI = magnetic resonance imaging; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; TCR = 
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Footnotes for Schedule of Activities (Combination B)
1.
Screening: To be obtained within 28 days prior to study entry (first dose).
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 start of treatment.  Includes oncology history, information on prior regimens (including dosing and duration of 
administration, best response observed, and recurrence date), surgery, and radiation therapy.  Human papilloma virus (HPV) status will be collected for patients with 
squamous cell carcinoma of the head and neck (SCCHN).
4.
Medical History: To be collected within 28 days prior to study entry.  Includes history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment.  Height will be measured at screening only.  Starting on C24D1, on-treatment physical 
examination to be performed only when clinically indicated.
6.
Baseline Signs/Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry and recorded on the Medical History 
case report form (CRF) page.  During treatment any new or worsening conditions since baseline should be reported on the Adverse Event (AE) CRF.
7.
ECOG PS: ECOG performance scale is available as Appendix 2.
8.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
9.
Contraceptive Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of the selected method of contraception.  The investigator or his or her designee will discuss with the patient the need to use at least 1 highly effective 
contraception method consistently and correctly and document such conversation the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if selected contraception method is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner (See Section 4.3).
10. Hematology: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study 
treatments unless otherwise indicated.  If, during the first 2 cycles of treatment, a Grade 4 hematologic event is evident, the hematology assessment should be repeated at least 
every other day to assess for events qualifying as dose-limiting toxicity (DLT).  See Protocol Section 7.1.4 for the list of the required Laboratory Tests.
11. Blood Chemistry: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study treatments 
unless otherwise indicated.  Results should be available for review prior to infusion of investigational products.  See Section 7.1.4 for the list of the required Laboratory Tests.
12. Coagulation: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, starting on C3D1 coagulation test to be performed when 
clinically indicated.  See Section 7.1.4 for the list of the required Laboratory Tests.
13. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semi-quantitative method (eg, urine dipstick), protein will be quantified 
by 24-hour urine collection.  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
14. Serum/Urine Pregnancy Test (serum/urine): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed and assayed in a certified laboratory on two occasions prior to starting study treatments, once at the start of screening and once at the baseline visit immediately 
before investigational products administration. Additional pregnancy tests (serum or urine) will also be routinely repeated at every treatment cycle, prior to dosing, during the 
active treatment period, at the end of study therapy, during follow-up (up to 90 days after last study treatment), 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 (See Section 7.1.1).
15. 12-Lead ECG: All patients require a single ECG measurement at screening and End of Treatment (EoT) visit.  On-treatment ECGs will be performed on Day 1 of Cycles 1 
and 2, before PF-04518600 infusion and at the end of avelumab infusion. At each time point, three (3) consecutive 12 lead ECGs (triplicates) will be performed 
approximately 2 minutes apart to determine mean QTc (average of triplicates).  When the ECG coincides with blood sample draws for PK, the PK sample should be taken as 
close as possible to the end of infusion time for the investigational product with an allowance of ±10 minutes.  The ECG assessment should be performed prior to blood 
sample collection, such that the blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or 
stroke) triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
16. Hepatitis B and C Virus Tests: Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other tests may be conducted per standard practice to 
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17. ACTH and Thyroid Function Tests: Thyroid function tests (ACTH, free T4 [FT4], thyroid stimulating hormone [TSH]) will be performed at Screening, Cycle 3 Day 1 and 
every 12 weeks thereafter, End of Treatment (EOT) visit, and 30 days after last investigational product administration, and if clinically indicated.  See Section 7.1.4 for the 
list of the required Laboratory Tests.
18. Enrollment: Patient number and allocation to treatment groups will be done via interactive response technology (IRT) operated by Pfizer Inc.  Investigational product 
administration should begin within 7 days after enrollment. 
19.
Avelumab Administration: Avelumab will be administered as a 1-hour intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  Avelumab infusion will be 
administered at least 30 minutes (+20 minute time window, if needed) after the PF-04518600 infusion.  Treatment will continue until disease progression is confirmed by the 
investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Protocol Section 5.3.5.3 for details of treatment
after initial determination of radiological disease progression.
20.
PF-04518600 Administration: PF-04518600 will be administered as a 1-hour intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  PF-04518600 will be 
administered first, followed by the avelumab infusion at least 30 minutes (+20 minute time window, if needed) after the end of the PF-04518600 infusion.  On days when PK
samples are taken, avelumab infusion will start after the post-PF-04518600 and pre-avelumab PK blood samples are drawn.  Treatment will continue until disease progression 
is confirmed by the investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details 
of treatment after initial determination of radiological disease progression.
21. Tumor Assessments: The decision for body areas to be scanned will depend on disease under study and extent of disease.  Imaging may include chest, abdomen and pelvis 
CT or MRI scans; brain CT or MRI scan, and bone scans (or CT/18F-FDG-PET /MRI for bone imaging).  The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons.  The minimum recommended body areas to be scanned depending on malignancy are detailed in the Imaging Manual.  The same imaging 
technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments.  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.  The 
allowable time window for disease assessments is 7 days while on treatment and whenever disease progression is suspected (eg, symptomatic deterioration).  In case partial 
response (PR), complete response (CR), or Progressive Disease (PD) is observed according to Response Evaluation Criteria for Solid Tumors (RECIST) v.1.1, tumor 
assessments should be repeated at least 4 weeks after initial documentation.  Tumor assessments should be repeated at End of Treatment/Withdrawal if not done in the 
previous 4 weeks and prior response is other than confirmed PD.  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  After 1 year from 
first dose, tumor assessments will be conducted less frequently, ie, at 12-week (after 1 year) and 16-week (after 2 years) intervals, respectively.  Bone scans (or CT/18F-FDG-
PET/MRI) are required at baseline only if bone metastases are known or suspected outside the body areas scanned, then every 16 weeks only if bone metastases are present at 
baseline.  Otherwise bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for patients who have bone 
metastases.  Assessment of response will be made using RECIST version 1.1 (See Section 7.6, Appendix 1).  
22. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the subject provides informed consent, which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a subject 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 treatment are to be reported to the sponsor.  AEs serious or non-serious, suspected to be related to the study treatment based on 
investigator’s assessment, should be recorded on the CRF.  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 study treatment, irrespective of any intervening treatment (see 
Section 8.2).
23. Concomitant Treatments: Concomitant treatments will be recorded from 28 days prior to the start of study treatment and up to 90 days after the last dose of investigational 
products.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to treat 
AEs or chronic diseases, and non-drug supportive interventions (eg, transfusions).  Concomitant treatments will not be collected for patients who initiate subsequent 
anticancer therapy.
24. Subsequent Anti-Cancer Treatment: Subsequent anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue 
in follow up, and during survival follow up.


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25. Survival: Patients will be followed for survival, independently of time of disease progression or initiation of subsequent anticancer therapy, for at least 2 years after 
enrollment of the last patient unless lost to follow-up, consent withdrawal, or study discontinued by the Sponsor.  Patients will be contacted every 3 months for survival status 
and subsequent anti-cancer treatment.
26.
Blood for PF-04518600 Pharmacokinetics: Blood samples (5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will also be 
collected on Day 8 of Cycle 1 (non-dosing visit).
27.
Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-infusion (ie., at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will also be 
collected on Day 8 of Cycle 1 (non-dosing visit).
28. Archival FFPE Tumor Tissue Block: Patients in Phase 1b should provide archival FFPE tumor tissue if available.  Patients in Phase 2 must provide FFPE tissue from the 
most recent primary or metastatic tumor biopsy or resection prior to study entry, taken within one year of start of study treatment, with no intervening systemic anti-cancer 
therapy; if such tissue is not available then a de novo biopsy prior to study entry is required.  The requirement for archival tissue may be waived if a de novo biopsy will be 
collected.  See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue samples.
29. De Novo Tumor Biopsy: A mandatory baseline de novo tumor biopsy from a locally recurrent or metastatic tumor site must be obtained for all patients except for the first 
3 patients (including replacements) enrolled in each dose level in Phase 1b, if archival tissue meeting the specifications in footnote 28 and Section 6.1.1 is not available.  
On-treatment biopsies are required except in instances where the procedure poses unacceptable risks per investigator documentation.  See Inclusion Criteria (Section 4.1) for 
biopsy requirements.  At end of treatment, if a patient discontinues due to disease progression, a de novo tumor sample is required except in instances where the procedure 
poses unacceptable risks per investigator documentation. See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue.  
See Section 6.1.1 of the protocol and Laboratory Manual for additional details on the selection of lesions and preparation of tissue samples.  The Cycle 2 Day 1 de novo 
biopsy should be performed at any time between 21 days after first dose of study drug(s) 4 days BEFORE dosing on Cycle 2 Day 1.  
30. Banked Biospecimens: A 4-mL blood sample will be collected on Day 1 of Cycle 1 prior to dosing and retained in a biobank for possible pharmacogenomic assessments, 
unless prohibited by local regulations or by decision of the institutional review board or ethics committee (see also Section 7.5 of the protocol). 
31. Immune Cell Phenotyping: A 6 mL whole blood sample will be collected at screening, Day 1 (pre-dose), Day 8, Day 15, and Day 22 of Cycle 1, Day 1 and Day 15 of 
Cycle 2 and Day 1 of Cycle 4.  Immune cell phenotypes associated with anti-tumor immunity and immune regulation will be measured by flow cytometry.
32. TCR Analysis from Peripheral Blood: A 6 mL whole blood sample will be collected into a tube optimized for deoxyribonucleic acid (DNA) preservation at screening, 
Day 1 pre-dose and Day 15 of Cycle 1, Day 1 of Cycles 2 and 4, and at End of Treatment/Withdrawal.  DNA will be submitted to TCR sequencing analysis.
33. Plasma for pharmacogenomic/proteomic/metabolomic analysis: A 20 mL blood biospecimen will be collected at screening and at End of Treatment/Withdrawal.  See 
Section 7.4 for details.
34. RNA Profiling of Peripheral Blood: Two 2.5 mL whole blood samples will be collected into PAXgene (RNA) tubes at screening, Day 1 (pre-dose) and end of infusion 
(EOI) of the last investigational product (IP) administered and Day 8, and 15 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4 and at End of 
Treatment/Withdrawal.  RNA will be analyzed for expression profile of immune- and tumor-related transcripts.
35. Cytokine, Chemokine and Soluble Receptor: A 4 mL blood sample will be collected into plasma collection tubes at Day 1 (pre-dose) and EOI, Day 8, 15 and 22 of 
Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4 and at End of Treatment/Withdrawal.  Samples be will be analyzed for soluble factors associated with immune 
activation, regulation and potential pharmacodynamics activity of avelumab.
36. Blood for PF-04518600 Immunogenicity (ADA) Testing: Blood samples (5 mL whole blood at each time point) for PF-04518600 immunogenicity testing will be collected 
on Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.
37. Blood for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for avelumab immunogenicity testing will be collected on 
Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.
38. End of Treatment: Obtain these assessments if not completed during the previous week on study, except for tumor assessments, which need not be repeated if performed 
within the prior 4 weeks.


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39. Follow-Up: Patients should be evaluated for safety up to 90 days (30 days, 60 days, and 90 days) after last dose of investigational products (see Section 6.3).  Patients 
continuing to experience toxicity following discontinuation of investigational products will continue to be followed at least every 4 weeks regardless of initiation of new 
anticancer treatment 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 time of study treatment discontinuation will enter into disease follow-up (for tumor assessment).  Physical examination, ECOG status, vital signs, and safety 
laboratory measurements are not required for patients who initiate new anticancer treatment, unless the patient continues to experience toxicity following discontinuation of 
the investigational products.  Contraception check and serum/urine pregnancy tests are required for all patients who enter Follow-up regardless of initiation of subsequent 
anticancer therapy.  
Abbreviations: ACTH = adrenocorticotropic hormone, ADA = anti-drug antibodies; AE = adverse event; C=Cycle; CT = computed tomography; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; FFPE = formalin-fixed paraffin-embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; 
MRI = magnetic resonance imaging; PK = pharmacokinetics RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; TCR=T-cell receptor.








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Footnotes for Schedule of Activities (Combination C)
1.
Screening: To be obtained within 28 days prior to study entry (first dose).
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 start of treatment.  Includes oncology history, information on prior regimens (including dosing and duration of 
administration, best response observed, and recurrence date), surgery, and radiation therapy. 
4.
Medical History: To be collected within 28 days prior to study entry.  Includes history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment.  Height will be measured at screening only.  Starting on C24D1, on-treatment physical 
examination to be performed only when clinically indicated.
6.
Baseline Signs/Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry and recorded on the Medical History 
case report form (CRF) page.  During treatment any new or worsening conditions since baseline should be reported on the Adverse Event (AE) CRF.
7.
ECOG PS: ECOG performance scale is available as Appendix 2.
8.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
9.
Contraceptive Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of the selected method of contraception.  The investigator or his or her designee will discuss with the patient the need to use at least 1 highly effective 
contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if selected contraception method is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner (See Section 4.3).
10. Hematology: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study 
treatments unless otherwise indicated.  If, during the first 2 cycles of treatment, a Grade 4 hematologic event is evident, the hematology assessment should be repeated at 
least every other day to assess for events qualifying as dose-limiting toxicity (DLT).  See Protocol Section 7.1.4 for the list of the required Laboratory Tests.
11. Blood Chemistry: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study treatments 
unless otherwise indicated.  Results should be available for review prior to infusion of investigational products.  See Section 7.1.4 for the list of the required Laboratory 
Tests.  
12. Coagulation: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, starting on C3D1, coagulation test to be performed when 
clinically indicated.  See Section 7.1.4 for the list of the required Laboratory Tests.
13. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semi-quantitative method (eg, urine dipstick), protein will be quantified 
by 24-hour urine collection.  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
14. Serum/Urine Pregnancy Test (serum/urine): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed and assayed in a certified laboratory on two occasions prior to starting study treatments, once at the start of screening and once at the baseline visit immediately 
before investigational products administration.  Additional pregnancy tests (serum or urine) will also be routinely repeated at every treatment cycle, prior to dosing, during 
the active treatment period, at the end of study therapy, during follow-up (up to 90 days after last study treatment), 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 (See Section 7.1.1).
15. 12-Lead ECG: All patients require a single ECG measurement at screening and End of Treatment (EoT) visit.  On-treatment ECGs will be performed on Day 1 of Cycles 1 
and 2, before PD 0360324 infusion and at the end of avelumab infusion.  At each time point, three (3) consecutive 12 lead ECGs (triplicates) will be performed 
approximately 2 minutes apart to determine mean QTc (average of triplicates).  When the ECG measurements coincide with blood sample draws for PK, the PK sample 
should be taken as close as possible to the end of infusion time for the investigational product, with an allowance of 10 minutes.  ECG assessment should be performed prior 
to blood sample collection, such that the blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke) triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
16. Hepatitis B and C Virus Tests: Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other tests may be conducted per standard practice to 
confirm an active hepatitis infection.


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17. ACTH and Thyroid Function Tests: Thyroid function tests (ACTH, Free T4 [FT4], thyroid stimulating hormone [TSH]) will be performed at Screening, Cycle 3 Day 1 
and every 12 weeks thereafter, End of Treatment (EOT) visit, and 30 days after last investigational product administration, and if clinically indicated.  See Section 7.1.4 for 
the list of the required Laboratory Tests.
18. Enrollment: Patient number and allocation to treatment groups will be done via interactive response technology (IRT) operated by Pfizer Inc.  Investigational product 
administration should begin within 7 days after enrollment.  
19. Avelumab Administration: Avelumab will be administered as a 1-hour intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  Avelumab infusion will be 
administered at least 30 minutes (+20 minute time window, if needed) after the PD 0360324 infusion.  Treatment will continue until disease progression is confirmed by the 
investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Protocol Section 5.3.5.3 for details of 
treatment after initial determination of radiological disease progression.
20. PD 0360324 Administration: PD 0360324 will be administered as a 30 minute intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  PD 0360324 will be 
administered first, followed by the avelumab infusion at least 30 minutes (+20 minute time window, if needed) after the end of the PD 0360324 infusion.  On days when PK 
samples are taken, avelumab infusion will start after the post- PD 0360324 and pre-avelumab PK blood samples are drawn.  Treatment will continue until disease 
progression is confirmed by the investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See 
Section 5.3.5.3 for details of treatment after initial determination of radiological disease progression.
21. Tumor Assessments: The decision for body areas to be scanned will depend on disease under study and extent of disease.  Imaging may include chest, abdomen and pelvis 
CT or MRI scans; brain CT or MRI scan, and bone scans (or CT/18F-FDG-PET /MRI for bone imaging).  The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons.  The minimum recommended body areas to be scanned depending on malignancy are detailed in the Imaging Manual.  The same 
imaging technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments.  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.  The allowable time window for disease assessments is 7 days while on treatment and whenever disease progression is suspected (eg, symptomatic deterioration).  
In case partial response (PR), complete response (CR), or Progressive Disease (PD) is observed according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, 
tumor assessments should be repeated at least 4 weeks after initial documentation.  Tumor assessments should be repeated at End of Treatment/Withdrawal if not done in the 
previous 4 weeks and prior response is other than confirmed PD.  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  After 1 year 
from first dose, tumor assessments will be conducted less frequently, ie, at 12-week (after 1 year) and 16-week (after 2 years) intervals, respectively.  Bone scans (or CT/18F-
FDG-PET/MRI) are required at baseline only if bone metastases are known or suspected outside the body areas scanned, then every 16 weeks only if bone metastases are 
present at baseline.  Otherwise bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for patients who 
have bone metastases.  Assessment of response will be made using RECIST version 1.1 (See Section 7.6, Appendix 1).  For patients with ovarian cancer and ascites, a
50 mL aliquot of ascites fluid will be collected to evaluate the effect of PD 0360324 on the macrophage content of tumor-associated ascites fluid during the course of 
clinical management.  
22. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that 
the subject provides informed consent, which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a subject 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 treatment are to be reported to the sponsor.  AEs serious or non-serious, suspected to be related to the study treatment based 
on investigator’s assessment, should be recorded on the CRF. 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 study treatment, irrespective of any intervening treatment 
(see Section 8.2).
23. Concomitant Treatments: Concomitant treatments will be recorded from 28 days prior to the start of study treatment and up to 90 days after the last dose of investigational 
products.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to 
treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).  Concomitant treatments will not be collected for patients who initiate 
subsequent anticancer therapy.


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24. Subsequent Anti-Cancer Treatment: Subsequent anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue 
in follow up, and during survival follow up.
25. Survival: Patients will be followed for survival, independently of time of disease progression or initiation of subsequent anticancer therapy, for at least 2 years after 
enrollment of the last patient unless lost to follow-up, consent withdrawal, or study discontinued by the Sponsor.  Patients will be contacted every 3 months for survival 
status and subsequent anti-cancer treatment.
26. Blood for PD 0360324 Pharmacokinetics: Blood samples (3 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 30 min 
post-infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will also be 
collected on Day 8 of Cycle 1 (non-dosing visit).
27. Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will also be 
collected on Day 8 of Cycle 1 (non-dosing visit).
28. Archival FFPE Tumor Tissue Block: Patients in Phase 1b should provide archival FFPE tumor tissue if available.  Patients in Phase 2 and additional patients enrolled 
during expansion of dose levels(s) determined to be safe during Phase 1b must provide FFPE tissue from the most recent primary or metastatic tumor biopsy or resection 
prior to study entry, taken within one year of start of study treatment, with no intervening systemic anti-cancer therapy; if such tissue is not available then a de novo biopsy
prior to study entry is required.  The requirement for archival tissue may be waived if a de novo biopsy will be collected.  See Section 6.1.1 and Laboratory Manual for 
additional details on the selection of lesions and preparation of tissue samples.
29. De Novo Tumor Biopsy: A mandatory baseline de novo tumor biopsy from a locally recurrent or metastatic tumor site must be obtained for all patients except for the first 
3 patients (including replacements) enrolled in each dose level in Phase 1b, if archival tissue meeting the specifications in footnote 28 and Section 6.1.1 is not available.  
On-treatment biopsies are required except in instances where the procedure poses unacceptable risks per investigator documentation.  At end of treatment, if a patient 
discontinues due to disease progression, a de novo tumor sample is required except in instances where the procedure poses unacceptable risks per investigator documentation. 
See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue.  The Cycle 2 Day 1 de novo biopsy should be performed 
at any time between 21 days after first dose of study drug(s) 4 days BEFORE dosing on Cycle 2 Day 1.  
30. Banked Biospecimens: A 4-mL blood sample will be collected on Day 1 of Cycle 1 prior to dosing and retained in a biobank for possible pharmacogenomic assessments, 
unless prohibited by local regulations or by decision of the IRB or EC (see also Section 7.5 of the protocol).
31. Immune Cell Phenotyping: A 6 mL whole blood sample will be collected at screening, Day 1 (pre-dose), Day 8, Day 15, and Day 22 of Cycle 1, Day 1 and Day 15 of 
Cycle 2 and Day 1 of Cycle 4.  Immune cell phenotypes associated with anti-tumor immunity and immune regulation will be measured by flow cytometry.
32. TCR Analysis from Peripheral Blood: A 6 mL whole blood sample will be collected into a tube optimized for deoxyribonucleic acid (DNA) preservation at screening, 
Day 1 pre-dose and Day 15 of Cycle 1, Day 1 of Cycles 2 and 4, and at End of Treatment/Withdrawal.  DNA will be submitted to TCR sequencing analysis.
33. RNA Profiling of Peripheral Blood: Two 2.5 mL whole blood samples will be collected into PAXgene (RNA) tubes at screening, Day 1 (pre-dose) and end of infusion 
(EOI) and Day 8, and 15 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4, and at End of Treatment/Withdrawal.  RNA will be analyzed for expression profile of 
immune- and tumor-related transcripts.
34. Cytokine, Chemokine and Soluble Receptor: A 4 mL blood sample will be collected into plasma collection tubes at screening, Day 1 (pre-dose) and end of infusion (EOI), 
Day 8, 15 and 22 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4 and at End of Treatment /Withdrawal.  Samples be will be analyzed for soluble factors 
associated with immune activation, regulation and potential pharmacodynamics activity of avelumab.
35. Blood for PD 0360324 Immunogenicity (ADA) Testing: Blood samples (5 mL whole blood at each time point) for PD 0360324 immunogenicity testing will be collected 
on Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.
36. Blood for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for avelumab immunogenicity testing will be collected on 
Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.
37. End of Treatment: Obtain these assessments if not completed during the previous week on study, except for tumor assessments, which need not be repeated if performed 
within the prior 4 weeks.


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38. Follow-Up: Patients should be evaluated for safety up to 90 days (30 days, 60 days, and 90 days) after last dose of investigational products.  See Section 6.3.  Patients 
continuing to experience toxicity following discontinuation of investigational products will continue to be followed at least every 4 weeks regardless of initiation of new 
anticancer treatment 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 time of study treatment discontinuation will enter into disease follow-up. (For tumor assessment).  Physical examination, ECOG status, vital signs, and 
safety laboratory measurements are not required for patients who initiate new anticancer treatment, unless the patient continues to experience toxicity following 
discontinuation of the investigational products.  Contraception check and serum/urine pregnancy tests are required for all patients who enter Follow-up regardless of initiation 
of subsequent anticancer therapy.  
Abbreviations: ACTH = adrenocorticotropic hormone, ADA = anti-drug antibodies; AE = adverse event; C=Cycle; CT = computed tomography; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; FFPE = formalin-fixed paraffin-embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; 
M-CSF = macrophage-colony stimulating factor; MRI = magnetic resonance imaging; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; 
RNA = ribonucleic acid; TCR=T-cell receptor.








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Footnotes for Schedule of Activities (Combination D)
1.
Screening: To be obtained within 28 days prior to study entry (first dose).
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 start of treatment.  Includes oncology history, information on prior regimens (including dosing and duration of
administration, best response observed, and recurrence date), surgery, and radiation therapy. 
4.
Medical History: To be collected within 28 days prior to study entry.  Includes history of other diseases (active or resolved) and concomitant illnesses. 
5.
Physical Examination: Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment.  Height will be measured at screening only.  Starting on C24D1, on-treatment physical 
examination to be performed only when clinically indicated.
6.
Baseline Signs/Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to study entry and record on the Medical History case 
report form (CRF) page.  During treatment any new or worsening conditions since baseline should be reported on the Adverse Event (AE) CRF.
7.
ECOG PS: ECOG performance scale is available as Appendix 2.
8.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
9.
Contraceptive Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of the selected method of contraception.  The investigator or his or her designee will discuss with the patient the need to use at least 1 highly effective 
contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if selected contraception method is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner (See Section 4.3.
10. Hematology: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study
treatments unless otherwise indicated.  If, during the first 2 cycles of treatment, a Grade 4 hematologic event is evident, the hematology assessment should be repeated at least 
every other day to assess for events qualifying as dose-limiting toxicity (DLT).  See Protocol Section 7.1.4 for the list of the required Laboratory Tests.
11. Blood Chemistry: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study treatments 
unless otherwise indicated.  Results should be available for review prior to infusion of investigational products.  See Section 7.1.4 for the list of the required Laboratory Tests.
12. Coagulation: It is not necessary to repeat on C1D1 if performed within 7 days prior to that date.  On treatment, starting on C3D1, coagulation test to be performed when 
clinically indicated.  See Section 7.1.4 for the list of the required Laboratory Tests.
13. Urinalysis: During the treatment period to be performed when clinically indicated.  If protein 2+ by semi-quantitative method (eg, urine dipstick), protein will be quantified 
by 24-hour urine collection.  Urine reflex microscopy is required whenever urine multitest dipstick is positive for blood or protein. 
14. Serum/Urine Pregnancy Test (serum/urine): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed and assayed in a certified laboratory on two occasions prior to starting study treatments, once at the start of screening and once at the baseline visit immediately 
before investigational products administration.  Additional pregnancy tests (serum or urine) will also be routinely repeated at every treatment cycle, prior to dosing, during 
the active treatment period, at the end of study therapy, during follow-up (up to 90 days after last study treatment), 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 (See Section 7.1.1).
15. 12-Lead ECG: All patients require a single ECG measurement at screening and End of Treatment (EoT) visit.  On-treatment ECGs will be performed on Day 1 of Cycles 1 
and 2, before utomilumab infusion and at the end of avelumab infusion. At each time point, three (3) consecutive 12 lead ECGs (triplicates) will be performed approximately 
2 minutes apart to determine mean QTc (average of triplicates).  When the ECG measurements coincide with blood sample draws for PK, the PK sample should be taken as 
close as possible to the end of infusion time for the investigational product, with an allowance of ±10 minutes. The ECG assessment should be performed prior to blood 
sample collection, such that the blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or 
stroke) triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
16. Hepatitis B and C Virus Tests: Conduct tests for hepatitis B surface antigen, and anti-hepatitis C.  Other tests may be conducted per standard practice to confirm an active 
hepatitis infection.
17. ACTH and Thyroid Function Tests: Thyroid function tests (ACTH, FT4, TSH) will be performed at Screening, Cycle 3 Day 1 and every 12 weeks thereafter, EOT visit, 
and 30 days after last investigational product administration, and if clinically indicated.  See Section 7.1.4 for the list of the required Laboratory Tests.


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18. Enrollment: Patient number and allocation to treatment groups will be done via interactive response technology (IRT) operated by Pfizer Inc.  Investigational product 
administration should begin within 7 days after enrollment. 
19. Avelumab Administration: Avelumab will be administered as a 1-hour intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  Avelumab infusion will be 
administered at least 30 minutes (+20 minute time window, if needed) after the PF-04518600 infusion.  Treatment will continue until disease progression is confirmed by the 
investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Protocol Section 5.3.5.3 for details of 
treatment after initial determination of radiological disease progression.
20. Utomilumab Administration: Treatment will be administered in a 4-week cycle (ie, 28-day cycle).  Utomilumab will be administered as a 1-hour intravenous infusion on 
Day 1 of each cycle.  When all 3 IPs are administered, utomilumab will be administered first, followed by the PF-04581600 infusion (second), followed by the avelumab 
infusion (third) at least 30 minutes (+20 minute window, if needed) after the end of the PF-04518600 infusion.  Treatment will continue until disease progression is 
confirmed by the investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details of 
treatment after initial determination of radiological disease progression.
21. PF-04518600 Administration: PF-04518600 will be administered as a 1-hour intravenous infusion every 2 weeks on Day 1 and Day 15 of each cycle.  When all 3 IPs are 
administered, utomilumab will be administered first, followed by the PF-04581600 infusion (second), followed by the avelumab infusion (third) at least 30 minutes 
(+20 minute window, if needed) after the end of the PF-04518600 infusion.  On days when avelumab and PF-04518600 are administered, PF-04518600 will be administered 
first, followed by the avelumab infusion at least 30 minutes after the end of the PF-04518600 infusion.  Treatment will continue until disease progression is confirmed by the 
investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details of treatment after 
initial determination of radiological disease progression.
22. Tumor Assessments: The decision for body areas to be scanned will depend on the disease under study and extent of disease.  Imaging may include chest, abdomen and 
pelvis CT or MRI scans; brain CT or MRI scan, and bone scans (or CT/18F-FDG-PET /MRI for bone imaging).  The CT scans should be performed with contrast agents 
unless contraindicated for medical reasons.  The minimum recommended body areas to be scanned depending on malignancy are detailed in the Imaging Manual.  Baseline 
tumor assessment must be performed within 28 days prior to enrollment.  The same imaging technique used to characterize each identified and reported lesion at baseline will 
be employed in the following tumor assessments.  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.  The allowable time window for disease assessments is 7 days while on treatment and 
whenever disease progression is suspected (eg, symptomatic deterioration).  In case partial response (PR), complete response (CR), or Progressive Disease (PD) is observed 
according to RECIST v.1.1, tumor assessments should be repeated at least 4 weeks after initial documentation.  Tumor assessments should be repeated at End of 
Treatment/Withdrawal if not done in the previous 4 weeks and prior response is other than confirmed PD.  Timing should follow calendar days and should not be adjusted for 
delays in cycle starts. After 1 year from first dose, tumor assessments will be conducted less frequently, ie, at 12-week (after 1 year) and 16-week (after 2 years) intervals, 
respectively.  Bone scans (or CT/18F-FDG-PET/MRI) are required at baseline only if bone metastases are known or suspected outside the body areas scanned, then every 
16 weeks only if bone metastases are present at baseline.  Otherwise bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of 
complete response for patients who have bone metastases.  Assessment of response will be made using RECIST version 1.1 (See Section 7.6, Appendix 1).  
23. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  For SAEs, the active reporting period 
to Pfizer or its designated representative begins from the time that the subject provides informed consent, which is obtained prior to the subject’s participation in the study, 
ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 90 calendar days after the last administration of the study
treatment. SAEs occurring to a subject 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 treatment are to be reported to the sponsor AEs serious or non-serious, 
suspected to be related to the study treatment based on investigator’s assessment, should be recorded on the CRF.  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 
study treatment, irrespective of any intervening treatment (see Section 8.2).
24. Concomitant Treatments: Concomitant treatments will be recorded from 28 days prior to the start of study treatment and up to 90 days after the last dose of investigational 
products.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). Concomitant treatments will not be collected for patients who initiate 
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25. Subsequent Anti-Cancer Treatment: Subsequent anti-cancer therapy will be documented and recorded for patients who discontinue investigational products and continue 
in follow up, and during survival follow up.
26. Survival: Patients will be followed for survival, independently of time of disease progression or initiation of subsequent anticancer therapy, for at least 2 years after 
enrollment of the last patient unless lost to follow-up, consent withdrawal, or study discontinued by the Sponsor.  Patients will be contacted every 3 months for survival status 
and subsequent anti-cancer treatment. 
27. Blood for Utomilumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-start of infusion (ie, at the end of infusion) on Day 1 of Cycles 1, 3, 5, 8, and Cycle 12.  A sample will also be collected on Days 8 and 15 of Cycle 1 (non-dosing visit).
28. Blood for PF-04518600 Pharmacokinetics: Blood samples (5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-start of infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will 
also be collected on Day 8 of Cycle 1 (non-dosing visit).
29. Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each time point) will be collected from all patients in the study at pre dose and 1 hour 
post-start of infusion (ie, at the end of infusion) on Days 1 and 15 of Cycle 1, and then pre-dose and end of infusion on Day 1 of Cycles 2, 4, 6, and Cycle 10.  A sample will 
also be collected on Day 8 of Cycle 1 (non-dosing visit).
30. Archival FFPE Tumor Tissue Block: Patients in Phase 1b should provide archival formalin-fixed paraffin-embedded (FFPE) tumor tissue if available.  Patients in
Phase 2 and additional patients enrolled during expansion of dose levels(s) determined to be safe during Phase 1b must provide FFPE tissue from the most recent primary or 
metastatic tumor biopsy or resection prior to study entry, taken within one year of start of study treatment, with no intervening systemic anti-cancer therapy; if such tissue is 
not available then a de novo biopsy prior to study entry is required.  The requirement for archival tissue may be waived if a de novo biopsy will be collected.  See 
Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue samples.
31. De Novo Tumor Biopsy: A mandatory baseline de novo tumor biopsy from a locally recurrent or metastatic tumor site must be obtained for all patients except for the first 
3 patients (including replacements) enrolled in each dose level in Phase 1b, if archival tissue meeting the specifications in footnote 28 and Section 6.1.1 is not available.  
On-treatment biopsies are required except in instances where the procedure poses unacceptable risks per investigator documentation. At end of treatment, if a patient 
discontinues due to disease progression, a de novo tumor sample is required except in instances where the procedure poses unacceptable risks per investigator documentation.  
See Section 6.1.1 and Laboratory Manual for additional details on the selection of lesions and preparation of tissue.  The Cycle 2 Day 1 de novo biopsy should be performed 
at any time between 21 days after first dose of study drug(s) 4 days BEFORE dosing on Cycle 2 Day 1.  
32. Banked Biospecimens: A 4-mL blood sample will be collected on Day 1 of Cycle 1 prior to dosing and retained in a biobank for possible pharmacogenomic assessments, 
unless prohibited by local regulations or by decision of the institutional review board or ethics committee (see also Section 7.5 of the protocol).
33. Immune Cell Phenotyping: A 6 mL whole blood sample will be collected at screening, Day 1 (pre-dose), Day 8, Day 15, and Day 22 of Cycle 1, Day 1 and Day 15 of 
Cycle 2 and Day 1 of Cycle 4.  Immune cell phenotypes associated with anti-tumor immunity and immune regulation will be measured by flow cytometry.
34. TCR Analysis from Peripheral Blood: A 6 mL whole blood sample will be collected into a tube optimized for DNA preservation at screening, Day 1 pre-dose and Day 15 
of Cycle 1, Day 1 of Cycles 2 and 4 and at End of Treatment/Withdrawal.  DNA will be submitted to TCR sequencing analysis.
35. Plasma for pharmacogenomic/proteomic/metabolomic analysis: A 20 mL blood biospecimen will be collected at screening, Cycle 2 Day 1, and at End of 
Treatment/Withdrawal.  See Section 7.4 for details.
36. RNA Profiling of Peripheral Blood: Two 2.5 mL whole blood samples will be collected into PAXgene (RNA) tubes at screening, Day 1 (pre-dose) and end of infusion 
(EOI) and Day 8, and 15 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4, and at End of Treatment/Withdrawal.  RNA will be analyzed for expression profile of 
immune- and tumor-related transcripts.
37. Cytokine, Chemokine and Soluble Receptor: A 4 mL blood sample will be collected into plasma collection tubes on Screening, Day 1 (pre-dose) and end of infusion 
(EOI), Day 8, 15 and 22 of Cycle 1, Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 4 and the End of Treatment/Withdrawal.  Samples be will be analyzed for soluble factors 
associated with immune activation, regulation and potential pharmacodynamics activity of avelumab.
38. Blood for Utomilumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for utomilumab immunogenicity testing will be collected 
on Cycles 1, 3, 5,8, and 12 on Day 1 at pre-dose.
39. Blood for PF-04518600 Immunogenicity (ADA) Testing: Blood samples (5 mL whole blood at each time point) for utomilumab immunogenicity testing will be collected 
on Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.


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40. Blood for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5 mL whole blood at each time point) for avelumab immunogenicity testing will be collected on 
Cycles 1, 2, 4, 6, and 10 on Day 1 at pre-dose.
41. End of Treatment: Obtain these assessments if not completed during the previous week on study, except for tumor assessments, which need not be repeated if performed 
within the prior 4 weeks.
42. Follow-Up: Patients should be evaluated for safety up to 90 days (30 days, 60 days, and 90 days) after last dose of investigational products.  See Section 6.3.  Patients 
continuing to experience toxicity following discontinuation of investigational products will continue to be followed at least every 4 weeks regardless of initiation of new 
anticancer treatment 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 time of study treatment discontinuation will enter into disease follow-up. (For tumor assessment).  Physical examination, ECOG status, vital signs, and 
safety laboratory measurements are not required for patients who initiate new anticancer treatment, unless the patient continues to experience toxicity following 
discontinuation of the investigational products. Contraception check and serum/urine pregnancy tests are required for all patients who enter Follow-up regardless of initiation 
of subsequent anticancer therapy.  
Abbreviations: ACTH = adrenocorticotropic hormone, ADA = anti-drug antibodies; AE = adverse event; C=Cycle; CT = computed tomography; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; FFPE = formalin-fixed paraffin-embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; 
MRI = magnetic resonance imaging; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; TCR = T-cell receptor.
























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1. INTRODUCTION
This is a Phase 1b/2 dose-finding study to evaluate safety, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary antitumor activity of avelumab (MSB0010718C), 
a programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) in combination with 
other cancer immunotherapies in patients with locally advanced or metastatic solid tumors 
(eg, non-small cell lung cancer [NSCLC], melanoma, squamous cell carcinoma of the head 
and neck [SCCHN]), and triple-negative breast cancer [TNBC]).  Avelumab reversal of T 
cell inhibition via PD-L1 is only one potential mechanism which can augment anti-tumor 
immunity and it appears that in many patients simply blocking this resistance pathway is 
insufficient to trigger a robust anti-tumor response.  As detailed in this protocol, mouse tumor 
modeling suggests that combining avelumab with 4-1BB or OX40 agonist mAbs as doublets 
leads to increased anti-tumor activity compared with mice treated with any of the single 
agents.  In addition, macrophage-colony stimulating factor (M-CSF) blocking antibodies 
when combined with 4-1BB agonist mAbs and avelumab as a triplet in models where 
myeloid suppressive cells may be important exhibits greater anti-tumor tumor activity than 
the respective doublets.  Furthermore, triplet combinations of 4-1BB and OX40 agonist 
mAbs showed a marked increase in anti-tumor activity in these models compared with the 
respective doublets.  It is thought that triplets may be more effective compared with doublets 
as it is likely that doublet therapies, while potentially effective, do not address mechanisms of 
immune homeostasis as well as select triplets.  Therefore, after the evaluation of respective 
doublets in this study for safety and preliminary clinical activity, triplet combinations may be 
explored in specific clinical settings where these combinations might be more effective.
While the above combinations address mechanisms thought to be active in tumors harboring 
a pre-existing immune response, they do not address the growing unmet medical need of 
patients who progress on PD-1/PD-L1 therapy due to absent or inactive immune responses.  
Preclinical studies detailed in this protocol suggest a Toll-like Receptor 9 (TLR9) receptor 
agonist may initiate immune responses that could be further enhanced by a PD-L1 pathway 
inhibitor in settings where single agent inhibition of the PD-L1 pathway is less effective.  
These preclinical studies also support the hypothesis that 4-1BB and OX40 agonist mAbs 
may further activate T cell responses activated by the TLR9/PD-L1 combination.
The primary purpose of this study is to assess the safety and early signs of efficacy of the 
above mentioned avelumab doublet combinations followed by the evaluation of a triplet 
combination of these agents based on the safety of the respective doublets. The proposed 
combinations are as follows:

Combination A: avelumab plus utomilumab, a fully human immunoglobulin (Ig) 
G2 isotype mAb agonist of 4-1BB (CD137, TNFRSF9) that promotes survival and 
function of T cells, especially CD8+ T cells. 

Combination B: avelumab plus PF-04518600, a fully human IgG2 mAb agonist of 
OX40 (CD134) that promotes survival and function of T cells, especially CD4+ T 
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
Combination C: avelumab plus PD 0360324, a fully human IgG2 mAb directed 
against M-CSF that may inhibit tumor infiltration by immunosuppressive 
macrophages.  (Sites in the United Kingdom [UK] will not participate in this 
combination).

Combination D: avelumab plus utomilumab and PF-04518600 that is expected to 
provide complementary support for CD8+ and CD4+ T cells.

Combination F: avelumab plus CMP-001, an encapsulated TLR9 agonist that is 
expected to activate tumor-infiltrating plasmacytoid dendritic cells (pDCs) leading to 
activation and recruitment of anti-tumor T-cells to the tumor microenvironment.  
CMP-001 is expected to elicit T cell priming and infiltration into the tumor 
microenvironment, whereas avelumab is expected to block T cell inhibition by PD-L1 
that is induced by CMP-001.  Utomilumab or PF-04518600 will be evaluated in 
combination with avelumab and CMP-001 for the promotion of survival and function 
of T-cells activated by the combination. (Only sites in the United States [US] will 
participate in this combination).
Additional combinations of avelumab with other immune modulators may be incorporated
into this protocol, based on emerging preclinical and clinical data. 
1.1. Indication
Avelumab is a fully human anti-PD-L1 mAb of the Ig G1 isotype that is currently being 
investigated in combination with other cancer immunotherapies to enhance anti-tumor 
activity over that expected by avelumab alone in patients with locally advanced or metastatic 
solid tumors.  Avelumab is expected to increase the effectiveness of anti-tumor T cells by 
preventing inhibition of T cell activation.  This effect is expected to be enhanced by agents 
that promote anti-tumor immunity by complementary mechanisms such as promotion of 
T cell survival or removal of inhibitory myeloid cells.
1.2. Background and Rationale
1.2.1. Avelumab 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with 
programmed death protein-1 (PD-1).  Compared with anti-PD-1 antibodies that target 
T-cells, avelumab targets tumor cells and therefore expected to have fewer side effects, 
including a lower risk of autoimmune-related safety issues, as blockade of PD-L1 leaves the 
programmed death-ligand 2 (PD-L2)/PD-1 pathway intact to promote peripheral 
self-tolerance.1  For complete details of the in vitro and nonclinical studies, refer to avelumab 
Investigator’s Brochure (IB).2
1.2.1.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in Phase 1, 2, and 3 clinical protocols in a wide variety of cancers, including 
non-small cell lung cancer, gastric cancer, Merkel cell carcinoma (MCC), renal cell 










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lymphoma cells.17 The addition of 4-1BB agonists to in vitro cultures of B lymphoma cells 
with rituximab and NK cells resulted in increased lymphoma killing.18
Utomilumab is a novel fully human IgG2 mAb agonist of 4-1BB (CD137, TNFRSF9).  In 
addition to the studies described above to characterize 4-1BB, B cell immunophenotyping 
was performed in two experiments using utomilumab in cynomolgus monkeys with doses 
from 0.001-100 mg/kg; in these experiments peripheral blood B cell numbers were either 
unchanged or decreased.
1.2.2.1. In Vivo Data: Functional Activity of Utomilumab
In pre-clinical studies, utomilumab has exhibited the ability to increase lymphocyte 
proliferation.  In small animal models developed to test the in vivo function of utomilumab, 
utomilumab 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, 
utomilumab treatment of cynomolgus monkeys in single or multiple dose studies increased 
proliferation among cytotoxic central memory T-cells (CD8 TCM) in peripheral blood 
mononuclear cell (PBMC) samples.  Taken together, these data demonstrate evidence of 
utomilumab’s ability to enhance lymphocyte response in vivo.
1.2.2.2. In Vivo Data: Anti-Tumor Activity of Utomilumab
Single-agent utomilumab has demonstrated the ability to promote anti-tumor immune activity 
in pre-clinical studies.  Human tumor cell lines representing melanoma, colon, and prostate 
tumor types were tested in a xenogenic transplant model.  Utomilumab does not bind to 
murine 4-1BB; therefore, primary human PBMC from a healthy volunteer donor were mixed 
with tumor cells to set up the animal model.  Once tumors were established, animals were 
treated with utomilumab.  Utomilumab 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 8.




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Figure 9.
Combinatorial Efficacy of Surrogate Anti-4-1BB Combined with Surrogate
Anti-PD-1 in a Colorectal Carcinoma Model
Combination of a 4-1BB agonist antibody with a PD-1 antagonist antibody shows significant inhibition 
tumor growth in a colon carcinoma model. C57BL6 mice were subcutaneously (SC) implanted with 
1x106 MC38 murine colon carcinoma cells.  Tumor growth was monitored and animals randomized to four 
groups of 8 each when the tumors reached an average size of 150 mm3 and intraperitoneal (IP) dosed with 
vehicle (phosphate-buffered saline; PBS), 1 mg/kg anti-mouse 4-1BB agonist (MAB9371), 10 mg/kg 
anti-mouse PD-1 antagonist (RMP1-14), or the simultaneous combination of the two once every 5 days for a 
total of two doses.  The study was terminated when tumor sizes of the controls reached 1000 mm3.  
Combination treatment of animals with 4-1BB agonist plus PD-1 antagonist resulted in 63.2% reduction in 
tumor growth when compared to vehicle controls (unpaired t test *p = 0.0125).  Significant tumor growth 
inhibition by either agent dosed individually was not observed.
1.2.2.4. Utomilumab Clinical Experience
The anti-tumor activity of single-agent utomilumab in patients with advanced malignancies, 
including MCC, melanoma, and NSCLC, and utomilumab in combination with rituximab in 
patients with B-cell NHL is being assessed in ongoing Study B1641001.  In addition, Study 
B1641003, a Phase 1b study of utomilumab in combination with pembrolizumab and Study 
B1641004, a Phase 1b study of utomilumab in combination with mogamulizumab (an 
anti-CCR4 mAb), are ongoing in patients with advanced solid tumors.
1.2.2.4.1. Safety and Efficacy
Study B1641001
As of 06 June 2016, a total of 133 patients have been treated in Study B1641001: 86 patients 
in Portion A have received utomilumab in dose levels between 0.006 and 10 mg/kg and 
47 patients in Portion B have received with utomilumab in dose levels between 0.03 and 
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Among patients treated in Portion A, the most frequently reported TEAEs (10% of patients,
all grades) regardless of causality were fatigue (24.4%), nausea (18.6%), decreased appetite 
(16.3%), vomiting (16.3%) abdominal pain (15.1%), diarrhea (11.6%), dizziness (11.6%), 
constipation (10.5%), and pyrexia (10.5%).  There were 2 Grade 5 AEs reported (malignant 
neoplasm progression and death), which were considered not related to the study drug.  
Treatment-related TEAEs were mostly Grade 1 or Grade 2 with only three Grade 3 AEs 
reported (fatigue, ALT elevation, and hyponatremia).  Note: After the data cut-off date 
causality of the Grade 3 ALT elevation was re-assessed as not related to utomilumab by the 
Investigator.  The reported Grade 3 fatigue was of limited duration approximately 20 days 
and seen at the highest dose tested of 10 mg/kg of utomilumab.  No Grade 4 treatment-
related AEs were observed.  Only 1 patient permanently discontinued treatment with 
PF-05082566 for a Grade 2 treatment-related AE of enterocolitis.  Only 3 treatment-related 
serious AEs (SAEs) were reported in 2 patients: enterocolitis, decreased appetite and 
pneumonitis.
Among patients treated in Portion B, the most frequently reported TEAEs (10% of patients; 
all grades) regardless of causality were fatigue (31.9%), infusion-related reaction (21.3%), 
upper respiratory tract infection (14.9%), diarrhea (12.8%), pyrexia (12.8%), chills (10.6%), 
cough (10.6%), and headache (10.6%).  There was one Grade 5 AE (death) reported (due to 
disease progression), which was considered not related to the study drug.  The most 
commonly reported treatment-related TEAEs (10% of patients; all grades) that were 
considered treatment-related were fatigue (23.4%) and infusion-related reaction (21.3%). 
Treatment-related TEAEs were mostly Grade 1 or Grade 2. Grade 3 AEs were reported in 
4 patients: infusion-related reaction (2 patients), lymphocyte count decreased and 
neutropenia (1 patient each).  All Grade 3 AEs were related to rituximab treatment only, per 
Investigator assessment.  None of the Grade 3 AEs were related to utomilumab.  No 
Grade 4 treatment-related AEs were observed.
Overall, the safety profile of utomilumab, based on a data cutoff date of 
06 June 2016, supports its use as both a single agent and in combination with rituximab.  
Treatment-related AEs were generally mild or moderate with only two Grade 3 AEs 
(hyponatremia and fatigue) reported as related to utomilumab in Portion A.
Study B1641003 
As of 06 June 2016, a total of 23 solid tumor patients have been treated with the combination 
of utomilumab and pembrolizumab at the fixed dose of 2 mg/kg.  Utomilumab doses 
administered include 0.45 mg/kg (n=5); and 0.9 mg/kg, 1.8 mg/kg, and 3.6 mg/kg
(n=3 patients each); and 5 mg/kg (n=9).  
The most frequently reported TEAEs (10% of patients; all grades) regardless of causality, 
were fatigue (43.5%), cough (34.8%), decreased appetite (30.4%), nausea (30.4%), 
constipation, pruritus, rash maculo-papular (26.1% each), pyrexia and vomiting (21.7% 
each), anemia, dyspepsia, rash, and upper respiratory tract infection (17.4%, each), arthralgia, 
asthenia, back pain, dry mouth, dry skin, dyspnea, fall, haemoptysis, hypokalaemia, 
hyponatraemia, muscle spasms, oedema peripheral, pleural effusion, pneumonia, sinusitis, 


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and stomatitis (13.0% each).  There was one Grade 5 AE (death) reported (due to disease 
progression) which was considered not related to the study drug.
The most frequently observed treatment-related TEAEs (≥10% of patients; all grades) were 
fatigue (34.8%), rash maculo-papular (26.1%), pruritus (21.7%), pyrexia (17.4%), nausea, 
decreased appetite, dry skin, dry mouth (13.0% each) and are shown in 
Table 6.2-14. Treatment-related TEAEs were mostly Grade 1 or Grade 2.  There were only 
2 treatment-related (utomilumab and pembrolizumab) Grade 3 AEs reported in 2 patients:
adrenal insufficiency (no evidence of associated hypophysitis reported) and hypokalaemia 
(1 patient each).  No Grade 4 or 5 treatment-related AEs were observed.
In summary, the observed safety profile, based on a data cut-off date of 06 June 2016 for 
B1641003, supports utomilumab use in combination with pembrolizumab.  Treatment-related 
AEs were generally mild or moderate with only two Grade 3 AEs reported as treatment-
related to both utomilumab and pembrolizumab.
Study B9991004
In the B9991004 study, the DLT observation period in Phase 1b portion of Combination A is 
complete.  All 3 dose levels utomilumab at 500 mg (Cohort A1), 100 mg (Cohort A2), or 
20 mg (Cohort A3) in combination with 10 mg/kg have been well tolerated and no DLT has 
been observed in 18 enrolled patients.  Including Phase 2, 273 patients with NSCLC, 
SCCHN, melanoma, TNBC, and SCLC received utomilumab at dose levels of 20 mg, 
100 mg, and 500 mg in combination with avelumab 10 mg/kg Q2W.  The combination is 
well tolerated.  The AE profile of the combination therapy is consistent with either of the 
single agent therapies in terms of incidence and severity of the adverse events (unpublished 
data).
Efficacy
Study B1641001
As of the data cut-off date 06 June 2016, in Portion A, 1 confirmed CR and 1 confirmed PR 
in MCC were reported in patients who were treated at 0.24 mg/kg and 0.6 mg/kg 
respectively.  In addition, 1 patient with anti-PD-1 refractory melanoma treated at 0.24 mg/kg 
had a PR that was not yet confirmed at the time of data cut-off date; however, this response 
was confirmed at a subsequent assessment.  In addition, 1 patient with anti-PD-1 refractory 
melanoma treated at 0.24 mg/kg had a greater than 30% reduction in the diameters of 
multiple target tumors but was considered to have stable disease (irSD) per Immune-related 
Response Criteria derived from Response Evaluation Criteria for Solid Tumors (RECIST) 
version (v) 1.1.  After the IB cutoff date, one out of 5 NSCLC patients treated with single 
agent utomilumab at 0.24 mg/kg experienced partial response (pending confirmation).
In Portion B, 8 patients with follicular lymphoma (7 patients were refractory to prior 
rituximab-containing regimen) achieved an objective response: 4 patients achieved a CR 
(2 treated at 1.2 mg/kg, 1 at 0.12 mg/kg, and 1 at 0.03 mg/kg) and 4 patients achieved a PR
(2 treated at treated at 0.18 mg/kg, 1 treated at 1.2 mg/kg, and 1 treated at 5.0 mg/kg).  One 


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(1) patient with CD20 + Hodgkin’s lymphoma treated at 1.2 mg/kg achieved a PR and 
1 patient with Mantle Cell Lymphoma (MCL) treated at 2.4 mg/kg achieved a PR.
Study B1641003
As of 06 June 2016, among the 23 patients treated in Study B1641003, 6 had confirmed 
objective response providing an ORR of 26.0%.  Two (2) patients had a confirmed CR 
(1 patient with RCC treated at 1.8 mg/kg and 1 patient with SCLC treated at 5.0 mg/kg).  
Four (4) patients achieved a PR: 1 patient with RCC and 1 patient with NSCLC treated at 
0.45 mg/kg; 1 patient with anaplastic thyroid disease treated at 3.6 mg/kg, and 1 patient with 
SCCHN treated at 5 mg/kg.
1.2.2.5. Pharmacokinetics of Utomilumab in Humans
Study B1641001
Preliminary PK data following single-dose treatments are available for 81 patients (46 in 
Portion A and 35 in Portion B) in Study B1641001.  Following the attainment of Cmax, 
utomilumab serum concentrations showed a bi-exponential decline, with a mean terminal 
elimination half-life (t1/2) of 208-349 hrs, a low systemic clearance (CL = 0.265 to 
0.389 mL/hr/kg) and a small volume of distribution (Vss = 83.3-231 mL/kg) in Cycle 1 of 
Portion A.  In Portion B, utomilumab also showed a bi-exponential decline with a mean 
terminal elimination half-life of 274-550 hrs, a low systemic clearance (CL = 0.175 to 
0.335 mL/hr/kg) and a small volume of distribution (Vss = 88.4-164 mL/kg).  A dose 
proportional increase in utomilumab exposure was observed.  
Study B1641003
Blood samples were collected for characterizing the PK and ADA of both utomilumab and 
pembrolizumab.  The utomilumab exposure appeared to increase with increasing doses.  The 
utomilumab t1/2 ranged from 136 to 179 hours.
1.2.2.6. Immunogenicity of Utomilumab in Humans
Study B1641001
Based on preliminary data from Study B1641001, 9 of 61 (14.8%) patients in Portion A 
exhibited positive ADAs prior to treatment with utomilumab.  Thirty-five out of 61 patients 
(57.4%) were positive for ADA for at least one time point regardless of baseline ADA status. 
Among 35 ADA-positive patients, 7 (20%) exhibited positive neutralizing antibody (Nab) 
against PF- 05082566 In Portion B, 2 out of 41 (4.9%) patients exhibited positive ADA 
against utomilumab prior to treatment with utomilumab plus rituximab.  Three of 41 patients 
(7.3%) were positive for ADA for at least one time point regardless of baseline ADA status 
when administered in combination with rituximab. Among 3 ADA-positive patients, 
1 (33.3%) exhibited positive Nab against utomilumab.


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The impact of ADA on PK of utomilumab was also characterized.  The utomilumab CL was 
similar in ADA negative and ADA positive patients suggesting that ADA status has minimal 
impact on the PK of utomilumab.
Study B1641003
Preliminary ADA data show 2 of 23 (8.7%) patients exhibited positive ADA against 
utomilumab prior to treatment with utomilumab plus pembrolizumab.  Seventeen of 
23 patients (73.9%) were positive for ADA for at least one time point regardless of baseline 
ADA status when administered in combination with pembrolizumab.  Among 14 ADA 
positive patients who were tested for Nab analysis, 5 (35.7%) patients had a positive Nab 
against utomilumab.  Complete pre-clinical and clinical information for utomilumab, 
including PK data in patients, may be found in the SRSD, which for this study is the 
utomilumab IB.20
1.2.3. PF-04518600 (OX40 Agonist)
OX40 (CD134) is a co stimulatory receptor that acts on antigen stimulated T-cells but not 
native T-cells.36,37  OX40 expression is transient, and peaks 48 to 72 hours following T-cell 
receptor (TCR) stimulation.  High numbers of OX40 positive infiltrating T-cells have been 
found within tumor biopsies, and lymph nodes of primary melanoma, breast, colon and head 
and neck cancer patients.38-41  OX40 plays a key role in T-cell survival, proliferation, and 
activation.  Following binding to OX40 ligand (also known as OX40L, CD252 or TNFSF4), 
OX40 signaling activates both the canonical and noncanonical NF-κB (nuclear factor kappa 
light chain enhancer of activated B cells) survival pathways, leading to an upregulation of 
anti-apoptotic molecules including Bcl-2, Bcl-xL, and surviving.42  Furthermore, 
OX40 engagement may enhance IL-2, IL-4, IL-5, IFNcytokine secretion by activated
CD4 T-cells.  It is interesting to note that OX40 activation has been shown to not require 
co-stimulation from other co-stimulatory receptors.43  OX40L is usually expressed on
activated B cells and dendritic cells, but due to the immunosuppressive environment within a 
tumor, OX40L was not detected in the tumor mass of several syngeneic mouse models.52  
Mechanistically, it is therefore possible that an agonistic mAb to OX40 may reverse T-cell’s 
anergic state, and enhance tumor immunity.  Indeed, eradication of tumor growth has been 
observed by using agonistic OX40 mAbs and OX40 agonists in preclinical models of 
melanoma, sarcoma, and glioma, and colon, breast, prostate, and renal cancers.37,39,44,45  
Given the potential for OX40 agonistic mAbs to enhance anti-tumor T-cell responses, and 
induce tumor regression, a Phase 1 clinical trial with a murine anti OX40 antibody has been 
completed.46  In this study, tumor regression was observed in 12 of 30 advanced cancer 
patients, as well as an acceptable toxicity profile.  Pfizer has generated a fully human 
IgG2 monoclonal antibody specific for the human OX40 (PF-04518600). 
PF-04518600 has been demonstrated to be an agonistic antibody against OX40.  
Furthermore, PF-04518600 can selectively and reversibly bind to human OX40 with a high 
affinity, and in conjunction with TCR signals, is able to functionally co stimulate T-cells as 
measured by IL-2, IL-6, tumor necrosis factor (TNF) and IFNrelease in vitro.  In a 
syngeneic mouse model, a murine surrogate anti OX40 agonistic antibody 
(OX86) demonstrated growth inhibition of colon tumors (see Section 1.2.3.1).


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1.2.3.1. PF-04518600 Nonclinical Efficacy
PF-04518600 is a fully human IgG2 mAb that is highly selective for human 
OX40 (CD134).  PF-04518600’s agonistic potential was demonstrated in a luciferase reporter 
assay, and selectivity studies using a Biacore assay also showed PF-04518600 to be highly 
selective for OX40, with no cross activity with other members of the TNFR super family, 
including CD40 receptor, 4 1BB receptor (CD137), and glucocorticoid-induced TNFR 
family-related gene (GITR).51
1.2.3.1.1. Single-Agent Studies
To determine in vivo efficacy, a murine surrogate agonist antibody against 
OX40, OX86, was utilized in murine tumor models.  In a syngeneic tumor model, 
OX86 inhibited the growth of CT26 colon tumor cells (Figure 10).51  Dosing of 10, 1, 0.1, or 
0.01 mg/kg OX86 mIgG1 every 4 days for 3 doses starting 12 days after the implantation of 
0.2 million CT26 cells led to a 63.5%, 68.9%, 48.0%, and 42.6% decrease in tumor volume 
respectively.
Figure 10. Mouse Surrogate Antibody OX86 mIgG1 Prevented Growth of CT26 Colon 
Carcinoma


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1.2.3.1.2. Combination Studies
In a syngeneic tumor model, the murine surrogate anti OX40 agonistic antibody 
OX86 combined with avelumab inhibited the growth of CT26 colon tumor cells 
(Figure 11).  Doses of 0.3 mg/kg OX86 mIgG2a in combination with 10 mg/kg avelumab 
were used.  Treatment was started when the tumors reached an average of 230-252 mm3 in 
size.  Animals were dosed twice per week for 3 doses.  The combination of avelumab and 
anti-OX40 led to a decrease in tumor volume of 67.9% 11 days post-treatment (p<0.05), 
76.8% 14 days post-treatment (p<0.0001), and 77.2% 18 days post-treatment (p<0.0001). 
Figure 11. Mouse Surrogate Antibody OX86 mIgG2a plus Avelumab Prevented 
Growth of CT26 Colon Carcinoma
The triple combination of the surrogate mouse OX40 mAb and surrogate 4-1BB mAb with 
avelumab led to significant tumor growth inhibition in the established colon carcinoma 
MC38 model and the less immunogenic melanoma model B16-F10 (Figure 12), in 
comparison with the single-agent and double combination treatments.  Animals were dosed
twice per week for 3 doses.
Figure 12. Inhibition of Tumor Growth by the Triplet Combination of 
Avelumab/Utomilumab/PF-04518600 in Melanoma and Colorectal 
Carcinoma Models
4-1-BB: 1 mg/kg; avelumab: 20 mg/kg (B16-F10 melanoma model), 10 mg/kg (MC38 colon carcinoma model); 
4-1BB: 1 mg/kg.  **p=0.002; ***p=0.0006.


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1.2.3.2. PF-04518600 Nonclinical Toxicology
The nonclinical safety profile of PF-04518600 has been well characterized in nonclinical 
toxicology studies that are described in the PF-04518600 IB.51  Repeated administration of 
PF-04518600 was well tolerated in male and female cynomolgus monkeys when 
administered intravenously once weekly for 1 month (5 times in total) at dosages up to 
100 mg/kg.  Toxicology results revealed that systemic exposure to PF-04518600 increased 
with increasing doses, and there were no apparent gender-related differences in exposure. 
The potential for PF-04518600 to stimulate cytokine release was tested at concentrations 
ranging from 1-100 g/mL in human whole blood from healthy volunteers.  In addition, plate 
bound PF-04518600 was tested at concentrations ranging from 1-100 g/mL for stimulation 
of pro inflammatory cytokine release from human PBMCs from healthy volunteers.  
PF-04518600 did not induce significant release of TNF, IL-6 or IFNin the human whole 
blood or PBMCs.51
1.2.3.3. In Vitro Cytokine Release Assays (Avelumab plus Utomilumab plus 
PF-04518600)
The potential for PF-04518600 and avelumab together with utomilumab to stimulate 
cytokine release was tested at concentrations ranging from 1-100 g/mL in human whole 
blood from 8 healthy volunteers.  In addition, plate bound PF-04518600, avelumab, and 
utomilumab were tested at concentrations ranging from 1-100 g/mL for stimulation of pro 
inflammatory cytokine release from human peripheral blood mononuclear cells (PBMCs) 
from 8 healthy volunteers.  The combination of PF-04518600, avelumab, and 
utomilumab did not induce significant release of TNF, IL-6 or IFNin the human whole 
blood or PBMCs.
1.2.3.4. PF-04518600 Clinical Experience
PF-04518600 is currently being evaluated in an ongoing, Phase 1, open-label, 2-part dose 
escalation and expansion study in patients with select advanced solid tumors (Study 
B0601002).  As of 31 August 2018, a total of 163 patients have received PF-04518600 as 
either single agent at doses between 0.01 and 10 mg/kg (Part A; n=81) or as the combination 
of PF-0418600 (0.1 or 3 mg/kg) plus utomilumab (Part B; n=82).  
1.2.3.4.1. Safety and Efficacy
Safety
Study B0601002 (Part A: PF-04518600 Single Agent, Part B: PF-04518600 Plus 
Utomilumab) 
Part A: As of the data cut-off date of 31 August 2018, 81 patients were treated with 
PF-04518600 across 6 dose levels (0.01, 0.1, 0.3, 1.5, 3 and 10 mg/kg) in Part A of Study 
B0601002.  


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The most frequent AEs that occurred in ≥10% of patients are: fatigue (33.3%), nausea 
(22.2%), decreased appetite (23.5%), pruritus (19.8%), aspartate aminotransferase increased 
(21.0%), anemia (17.3%), abdominal pain (18.5%), constipation (14.8%), dyspnea (18.5%), 
headache (11.1%), chills (11.1%), pyrexia (17.3%), diarrhea (13.6%), vomiting (14.8%), 
alanine aminotransferase increased (11.1%), cough (13.6%), rash (13.6%), back pain 
(12.3%), hypertension (11.1%), and blood bilirubin increased (11.1%).
The most frequent treatment related AE experienced by ≥10% of patients in Part A was 
fatigue (18.5%).  The majority of treatment-related AEs reported were Grade 3 or below 
except for two Grade 4 AEs (preferred term [PT]: lipase increased).  Two (2) patients 
discontinued treatment with PF-04518600 for treatment-related AEs: one patient for 
congestive cardiac failure and one patient for aspartate aminotransferase increased.
Part B: As of the data cut-off date of 31 August 2018, 82 patients were treated with 
PF-04518600 across 4 dose levels of PF-04518600 (0.1,0.3, 1 and 3 mg/kg) in combination 
with 20 mg or 100 mg utomilumab or 30 mg PF-04518600 in combination with 20 mg 
utomilumab.  The most frequently reported AEs that occurred in ≥10% of patients included: 
decreased appetite (26.8%), fatigue (26.8%), anaemia (26.8%), nausea (19.5%), pyrexia 
(15.9%), abdominal pain (12.2%), constipation (18.3%), diarrhea (14.6%), cough (12.2%), 
dyspnea (13.4%), and aspartate aminotransferase increased (11.0%).
The most frequent treatment-related AE experienced by 2 or more patients include fatigue 
(12.2%), anaemia (8.5%), nausea, pruritus, and decreased appetite (6.1% each), alanine 
aminotransferase increased, rash, and vomiting (4.9% each).  The majority of 
treatment-related AEs reported were Grade 3 or below except for a single Grade 4 AE (PT: 
lipase increased).  One (1) patient discontinued due to treatment-related infusion related 
reaction (patient treated at 1 mg/kg PF-04518600 plus 100 mg utomilumab).
In summary, the safety profile of PF-04518600, based on a data cut-off date of 31 August 
2018 for Study B0601002, shows a manageable safety profile as single agent and in 
combination with utomilumab.  Grade 1/2 fatigue represents the most common (33.3%) AE 
related to PF-04518600 monotherapy, and the most common (26.8%) AE related to 
PF-04518600 plus utomilumab.  The majority of treatment-related AEs were Grade 3 or 
below except two cases of Grade 3 lipase increased (PF-04518600 monotherapy) and one 
case of Grade 4 lipase increase (PF-04518600 plus utomilumab). 
Study B9991004
In study B9991004, the Phase 1b part of Combination B is completed.  All three dose levels 
of PF-04518600 at 0.3 mg/kg (Cohort B12), 1.0 mg/kg (Cohort B13) and 3.0 mg/kg (Cohort 
B14) in combination with avelumab 10 mg/kg have been well tolerated and no DLT has been 
observed.  The PF-04518600 0.3 mg/kg IV Q2W dose in combination with avelumab 
10 mg/kg has been selected for Phase 2.  A total of 71 patients have been treated with 0.3 mg, 
1 mg, or 3 mg/kg PF-04518600 Q2W combined with 10 mg/kg avelumab.  The combination 
is well tolerated.  The AE profile of the combination therapy is consistent with the either of 
the single agent therapies in terms of incidence and severity of the AEs (unpublished data).  


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Efficacy
Study B0601002
Part A1 (PF-04518600 monotherapy)
As of the data cutoff date of 19 August 2018 (Part A1 efficacy only), 3 partial responses 
(PRs) were reported in Study B0601002 Part A1 confirmed by RECIST; 1 PR was reported 
in a cutaneous melanoma patient treated at the 0.1 mg/kg dose level who had a duration of 
response of 10.3 weeks, an additional PR was reported in a hepatocellular carcinoma (HCC) 
patient treated at the 0.3 mg/kg dose level who had a duration of response of 93.1 weeks, and 
the other PR was in a cutaneous melanoma patient treated at the 10 mg/kg dose level who has 
a duration of response of 35.9 weeks.  A total of 26/52 (50%) patients treated in Part A1, 
experienced a best overall response of stable disease (SD).
Part B1 (PF-04518600 plus Utomilumab)
As of the data cutoff date of 19 August 2018 (Part B1 efficacy only), 2 PRs reported during 
Part B1 were confirmed by RECIST; 1 PR was reported in a malignant melanoma patient 
treated at 0.3 mg/kg PF-04518600 + 20 mg utomilumab who had a duration of response of at 
least 56.1 weeks, and a second PR was reported in an ocular melanoma patient treated at 
0.3 mg/kg PF-04518600 + 100 mg utomilumab who had a duration of response of 
12.1 weeks.  A third patient with cutaneous melanoma treated at 0.3 mg/kg PF-04518600 + 
100 mg utomilumab dose level developed an unconfirmed PR after initial progression.  A 
total of 18/57 (31.6%) patients treated in Part B1, experienced a best overall response of SD.
1.2.3.5. Pharmacokinetics of PF-04518600
As of 27 October 2017, preliminary PK data were available for 52 patients at the 0.01, 0.1, 
0.3, 1.5, 3, and 10 mg/kg dose levels from the monotherapy dose escalation phase (Part A1) 
of the B0601002 study. 
Following single IV infusion of PF-04518600, PF-04518600 peak concentrations were 
observed at the end of infusion or at 3 hours after the end of infusion, followed by a decline 
in PF-04518600 concentrations exhibiting multiphasic disposition characteristics.  At the 
0.1 mg/kg dose, PF-04518600 PK profiles exhibited a pattern consistent with target mediated 
drug disposition compared with higher doses.  The exposure (AUCτ) during the first cycle 
following PF-04518600 administration increased with increasing dose levels in an 
approximately dose-proportional manner between the doses of 0.3 and 10 mg/kg.  The mean 
t½ values ranged from 4 to 10.1 days at the dose range of 0.1 to 10 mg/kg.
Following multiple IV infusions of PF-04518600 once every 14 days, the mean (± standard 
deviation) accumulation ratios (calculated as AUCτ, Cycle 3/AUCτ, Cycle 1) were 1.4 ± 0.5, 
1.7 ± 0.4, 1.8 ± 0.2, 2.0 ± 0.2, and 2.0 ± 0.3 at the dose levels of 0.1, 0.3, 1.5, 3, and 
10 mg/kg, respectively, based on a total of 28 patients with full PK profiles from both Cycle 
1 and Cycle 3.


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1.2.3.6. Immunogenicity of PF-04518600
As of 30 October 2017, preliminary data were available for 49 patients who had the baseline 
and at least one post-dose ADA sample analyzed from the monotherapy dose escalation 
phase (Part A1) of the B0601002 study.  A total of 4 patients (8.2%) tested positive for ADA 
at baseline.  A total of 16 patients (33%) were ADA positive at a minimum of one post-dose
time point.  The majority of ADA titers were low with no noticeable effect on the PK of 
PF-04518600, except for 2 patients at the 0.1 mg/kg dose level; these 2 patients had the 
highest titers in that group and the Ctrough of PF-04518600 appeared to be lower compared to 
the expected profiles at later cycles.
Complete pre-clinical and clinical information for PF-04518600 may be found in the SRSD, 
which for this study is the PF-04518600 IB.51
1.2.4. PD 0360324 (Anti-M-CSF)
M-CSF, also known as colony-stimulating factor -1 (CSF-1), is a pleiotropic cytokine that is 
produced by a wide range of cells, including several tumor types.  It is the primary regulator 
of the survival, proliferation, and differentiation of mononuclear phagocytes such as 
monocytes and tumor/tissue macrophages.53  M-CSF delivers a signal through the M-CSF 
receptor (also referred to as M-CSFR, CSF 1R, or CD115), a type III receptor tyrosine kinase 
that is mainly restricted to cells of the mononuclear phagocyte lineage.54  Blockade of 
M-CSF/M-CSFR signaling pathway by mAbs to the ligand M-CSF or the receptor M CSFR, 
and small molecule antagonists to the M-CSFR tyrosine kinase inhibitor (TKI), has been the 
subject of extensive preclinical investigations.53,55  Tumor-associated macrophage (TAM) 
reduction or re-programming and the resulting delayed tumor growth have been shown in 
many murine tumor models.53,55,56  Clinically, administration of a monoclonal antibody 
(RG7155) that inhibits CSF-1 receptor (CSF-1R) activation to patients led to striking 
reductions of tumor macrophages and objective responses in patients with diffuse-type giant 
cell tumors.57
PD 0360324 is a fully human IgG2 mAb that binds M-CSF with high affinity (dissociation
constant [KD] = 281 pM) and selectivity, and prevents the binding of M-CSF to its receptor 
(>100-fold potency for M-CSF over c-fms). 
1.2.4.1. Preclinical Studies
PD 0360324 does not cross-react with murine M-CSF, therefore, a surrogate antibody was 
used in murine models of arthritis and lupus.  In these studies, the surrogate antibody was 
efficacious in reducing paw swelling and reducing proteinuria and macrophage infiltration, 
respectively.  In addition, a rat anti-mouse M-CSF surrogate (Clone 5A1) was utilized in a 
mouse MC-38 tumor model.  Antibody treatment led to a reduction of tumor-associated 
macrophages, resulting in delayed tumor growth.
1.2.4.2. Preclinical Combination Studies
In a syngeneic tumor model, the anti-M-CSF antibody combined with avelumab inhibited the
growth of MC38 colon carcinoma cells, although not significantly more than anti-M-CSF by 
itself (Figure 13).  A dose of 15 mg/kg anti-M-CSF antibody in combination with 10 mg/kg 




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antibodies, performed when PD 0360324 levels reached the lower limit of quantitation, were 
negative. 
Periorbital soft tissue swelling related events have been observed in a total of 13 patients who 
received M-CSF at doses ranging from 50 mg to 300 mg IV.  It included periorbital edema 
and eyelid swelling, which appears to be a class effect of M-CSF/CSF-1 inhibitors.  The 
observed time of onset of the soft tissue swelling has ranged from shortly after dosing 
(Day 2) in one subject to several weeks or more for most subjects.  All of these swelling 
events resolved spontaneously with approximate durations ranging from 1 day to 157 days.  
The intensity of the periorbital soft tissue swelling was mild to moderate in all cases except 
for one subject with a severe event.  The severity decreased to moderate within 3 days and 
subsequently resolved within 32 days.  All the events resolved subsequently, 6 of the 
13 events required discontinuation of therapy.  Most of the events were observed at dose of 
100 mg and above.  The significance of these soft tissue swelling findings are not clear, but 
may be related to deposition of hyaluronic acid (HA) in the connective tissue spaces, 
including around extra ocular tissue.  It is known that macrophages have a significant role in 
the turnover of HA, and increased HA in interstitial matrix would be consistent with 
decreased tissue macrophage presence due to M-CSF inhibition.
In the clinical studies, transient, dose- and treatment-related elevations in AST, ALT, and CK
have been observed and were generally mild.  Transient changes in creatine kinase – muscle 
and brain subunits (CK-MB) have been associated with mild to moderate CK elevations.  No 
associated cardiac troponin 1 changes or electrocardiogram (ECG) abnormalities have been 
observed.  Mild increases in AST and CK from baseline are expected in subjects receiving 
PD 0360324 as a decrease in tissue macrophages may lead to decreased clearance of these 
enzymes.
The 300 mg dose of PD 0360324 in Protocol A6261001 was determined to have exceeded 
the limits of acceptable safety and tolerability due to severe periorbital edema, CK elevation, 
and myoglobinemia in healthy adults.  This dose will not be used in the B9991004 study.  
Doses as high as 150 mg were tolerated in patients with lupus erythematosis in Study 
A6261008.
The clinical efficacy of PD 0360324 in cancer patients is being studied for the first time in 
this study.  However, M-CSF/CSF-1R inhibition was reported to have significant clinical 
activity in patients with tenosynovial giant tumor.64  This is a tumor that is driven in most 
cases by a gene translocation that results in most tumor cells expressing M-CSF. 
1.2.4.4. Pharmacokinetics of PD 0360324
The PK of PD 0360324 has been evaluated in healthy subjects following a single IV dose at 
3 mg to 300 mg, in patients with rheumatoid arthritis following multiple IV doses from 
20 mg to 100 mg Q4W, and in patients with cutaneous lupus erythematosus following 
multiple IV doses at 100 mg and 150 mg Q2W.
After a single IV dose over the range of 3 mg to 300 mg, the concentration-time profiles of 
PD 0360324 indicated concentration-dependent (saturable) elimination, possibly due to 


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target-mediated disposition.  The increase in PD 0360324 dose from 3 mg to 300 mg led to a
more than dose proportional increase in systemic exposure.  There was minimal 
accumulation in exposure after multiple dosing Q4W.  The peak (Cmax) and trough (Ctrough) 
concentrations after multiple dosing increased in a greater than dose proportional manner as 
doses increased from 100 mg to 150 mg Q2W.
1.2.4.5. Immunogenicity of PD 0360324
In healthy subjects (Study A6261001), ADA against PD 0360324 was not detected following 
a single IV dose over the range of 3 mg to 300 mg.  In patients with rheumatoid arthritis 
(Study A6261002), no ADA was detected after multiple IV dosing from 20 mg to 100 mg.  
In patients with cutaneous lupus erythematosus (Study A6261008), 2 (1 patient from each of 
the 100-mg and 150-mg dose groups) out of 22 patients tested positive for ADA. In both 
patients, ADA appeared to be transient.  There was no obvious effect of positive ADA on PK 
levels, safety or efficacy.  The positive ADA samples tested negative for neutralizing 
activity.
1.2.5. CMP-001 (QbG10)
The active drug substance of CMP-001 is designated QbG10, a virus-like particle (VLP) 
composed of a Toll-Like Receptor 9 (TLR9) agonist (G10, an oligodeoxynucleotide [ODN]) 
containing a cytosine linked to a guanine by a phosphate bond (CpG) encapsulated in 
bacteriophage Qbeta capsid proteins.  Qbeta serves as a biological carrier for G10 and 
protects the TLR9 agonist from immediate degradation by nucleases in vivo.
CMP-001 is designed to activate pDCs via TLR9.  The TLR9-dependent activation of pDCs 
causes secretion of very large quantities of type I interferons, increased expression of 
costimulatory molecules, and recruitment and activation of other dendritic cell (DC) subsets 
to enhance tumor antigen presentation to T cells, culminating in the generation of effective
anti-tumor T cell responses.  
Subcutaneous administration of CMP-001 leads to formation of anti-Qbeta antibodies that 
enable fragment crystallizable gamma receptor (FcR)-mediated CMP-001 delivery to 
tumor-resident pDC after subsequent IT injections.  As the TLR9 receptors are intracellular, 
uptake of the TLR9 agonist leads to tumor-associated pDC activation and release of 
interferon alpha (IFNα), with the induction of T-helper cell type 1 (Th1)-biased innate and
adaptive antitumor immune responses.
CMP-001 is currently under development by Checkmate Pharmaceuticals (Checkmate) for
the treatment of multiple tumor types in combination with checkpoint inhibitors (eg, 
pembrolizumab) and/or other anticancer agents and cancer treatment modalities.  
QbG10 has been previously studied in nonclinical and clinical trials under the name CYT003. 
1.2.5.1. Preclinical Studies
The ability of QbG10 to affect TLR9 dependent activation of DCs has been investigated in 
several in vitro pharmacodynamic studies using mouse, rat, and human cells. QbG10


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efficiently induced secretion of interleukin 12 (IL-12) in mouse bone marrow-derived
dendritic cells (BMDCs) in vitro.  No such effect was observed when BMDCs were treated 
with QbpGlu component (Qb reassembled in the presence of polyglutamic acid thus devoid
of nucleic acids) demonstrating that G10 nucleotide is critical for TLR9-dependent activation
of DCs. 
The in vitro studies also confirmed the crucial role of anti-Qb antibodies that are induced 
during treatment in the QbG10 uptake by pDCs.  Upon treatment of PBMCs with QbG10,
high levels of IFNα were only detected in the samples incubated with QbG10 in the presence
of immune serum or a monoclonal Qb-specific antibody (Qb5IgG1) while incubation of 
PBMCs with QbG10 in the presence of naïve serum did not induce IFNα.  Blood DC
antigen-4 (BDCA-4) positive CD11c-negative pDCs appeared to be the main source of
IFNα expression in human PBMCs treated with QbG10 in the presence of immune serum.
In vivo pharmacodynamic studies evaluated the efficacy of QbG10 in a mouse allergy and
asthma model and in rats to characterize the dominant antibody response.  
1.2.5.2. Preclinical Combination Studies
The preclinical anti-tumor efficacy of CMP-001 when combined with anti-PD-1 was tested in
vivo in BALB/cAnN mice bearing syngeneic A20 lyphoma tumor (Checkmate CMP Study 
No. 160263).  The 300 µg CMP-001 dose with two different dosing regimens (a total of 2 or 
4 doses given every 5 days) and routes of administration (SC and IT) when combined with
anti-PD-1 (intraperitoneal twice a week for 2 weeks at 10 mg/kg) was evaluated in
9 treatment groups (including untreated control and anti-PD-1 alone) of 12 female mice each
(n=108).  At Day -14 a SC priming dose of CMP-001 was given to all mice to initiate an
anti-Qb immune response. A20 tumors were implanted in the right flanks of the mice at Day 
0 and in the left flanks at Day 3.  Treatments began on Day 5.  IT administration was into
right flank tumors and SC dosing was either in the nape of the neck or the base of each limb.  
The delayed implantation of left flank tumor was to increase the window of time for
evaluation of abscopal effects from IT injections.  Systemic antitumor immunity was
observed with all IT administration groups, regardless of CMP-001 concentration or number
of administrations.  SC administration also demonstrated significant systemic anti- tumor
efficacy (Figure 14).65


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Figure 14. Anti-tumor Efficacy of CMP-001 Regimen and Route of Administration in 
A20 Syngeneic Mouse Lymphoma Model - Study 160263: Injected Tumor -
Right Flank
Abbreviations: D = day; IT = intratumoral; PD-1 = programmed cell death protein; Q = every; 
SC = subcutaneous; TW = twice weekly.
In a separate study using a syngeneic CT-26 colon tumor model, IT administered CMP-001 
in combination with an intraperitoneally administered PD-1 antagonist and an OX40 agonist 
resulted in cures of both treated and untreated CT-26 tumors in 40% of the mice 
demonstrating direct and abscopal/systemic anti-tumor activity of the triplet.  The median 
survival time was increased for animals treated with the triplet compared to those treated 
with only vehicle or one or two immune modulators (50 days versus 18 days versus 21 or 
23-28 days, respectively).  Similar results were observed in the syngeneic MBT-2 bladder 
tumor model (and to a lesser extent in renal cancer RenCa model) though no complete 
responses were recorded.  These data support the clinical investigation of these combinations 
in cancer patients.66
1.2.5.3. Clinical Safety and Efficacy
CMP-001 in combination with a PD-L1 agonist or as monotherapy is currently being 
evaluated in three Checkmate Pharmaceuticals Inc. phase 1b studies: 
CMP-001-001(NCT02680184), CMP-001-002 (NCT03084640) and CMP-001-003 
(NCT03438318).67


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As of 31 October 2018, a total of 159 patients have received at least one IT or SC dose of 
CMP-001.  
Safety
Study CMP-001-001
Study CMP-001-001 is evaluating CMP-001 alone or in combination with pembrolizumab in 
patients with advanced melanoma resistant/refractory to checkpoint inhibitors.
As of 31 October 2018, 128 patients have received at least one CMP-001 by IT
administration including, 113 patients who have received CMP-001 in combination with 
pembrolizumab 200 mg Q3W and 15 patients who have received CMP-001 alone.  
In the Part 1 Dose Escalation and Part 1 Dose Expansion phases, patients have received 
CMP-001 at doses of 1 mg (n=3), 3 mg (n=16), 5 mg (n=70), 7.5 mg (n=6) and 10 mg (n=18)
in combination with pembrolizumab (2 mg/kg Q3W) at 2 different dosing schedules 
(Schedule A: CMP-001 administered IT once a week for 7 weeks [Prime Phase] followed by 
Q3W administration [Boost Phase] and Schedule B: CMP-001 administered IT once a week
for 2 weeks, then 5 times Q3W [Prime Phase] followed by Q3W [Boost Phase]).  Fifteen 
(15) patients who have received CMP-001 in the Part 2 Monotherapy Arm have received 
CMP-001 at 5 mg (n=14) and 10 mg (n=1) doses. 
As of 31 October 2018, 112 of the 113 (99.1%) patients enrolled in the Part 1 Dose 
Escalation and Part 1 Dose Expansion Phases of the CMP-001-001 study have experienced at 
least 1 TEAE, and 56 (49.6%) patients have experienced Grade 3 or higher TEAEs.  The 
most commonly occurring TEAEs for all grades include chills (80 patients; 70.8%), fever 
(pyrexia) (67 patients; 59.3%), nausea (61 patients; 54.0%), fatigue (56 patients; 49.6%), 
vomiting (45 patients; 39.8%), headache (37 patients; 32.7%), hypotension, diarrhea, and 
decreased appetite (30 patients, 26.5%, each event), constipation (28 patients; 24.8%), 
injection site pain (24 patients; 21.2%), and cough and back pain (23 patients; 20.4%, each 
event).  The only Grade 3 or higher TEAE occurring in 5% or more of patients is 
hypotension (10 patients; 8.8%).
Treatment-related TEAEs have been reported in 109 (96.5%) patients.  The most commonly 
occurring treatment-related TEAEs for all grades include chills (79 patients; 69.9%); fever 
(pyrexia) (66 patients; 58.4%), nausea (53 patients; 46.9%), fatigue (50 patients; 44.2%), 
vomiting (34 patients; 30.1%), headache (32 patients; 28.3%), decreased appetite and 
injection site pain (24 patients; 21.2%, each event), and diarrhea (23 patients; 20.4%).  The 
only Grade 3 or higher treatment-related TEAE occurring in 5% or more of patients is 
hypotension (9 patients; 8.0%).
Thirty-seven (32.7%) patients have experienced at least 1 SAE.  Serious AEs reported in 
more than 1 patient include hypotension (7 patients; 6.2%), sepsis (3 patients; 2.7%), and 
fever (pyrexia), cytokine release syndrome, encephalopathy, hypoxia, and respiratory failure 
(2 patients; 1.8%, each event).  Most SAEs are not considered related to study treatment, 
however, SAEs that are considered related to combination study treatment reported in more 


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than 1 patient include hypotension (6 patients; 5.3%) and cytokine release syndrome 
(2 patients; 1.8%).  
Study CMP-001-002
Study CMP-001-002, is evaluating CMP-001 administered as a SC injection in Part 1 and as 
a SC and IT injection in Part 2 in combination with pembrolizumab in patients with advanced 
melanoma.
As of 31 October 2018, 18 patients have received at least 1 dose of CMP-001 by SC or IT 
injection in the Part 1 Dose Escalation Phase of the CMP-001-002 study.  Patients received 
CMP-001 at starting doses of 5 mg (n=10) or 10 mg (n=8; note: 2 of these 8 patients enrolled 
in the 10 mg dosing cohort were initially dosed with 5 mg) in combination with 
pembrolizumab 200 mg Q3W.  No patients have been enrolled in the Part 1 Dose Expansion 
Phase or Part 2.  
In the Part 1 Dose Escalation Phase, all 18 (100%) patients have experienced at least 1 TEAE 
and 11 (61.1%) patients have experienced Grade 3 or higher TEAEs.  The most commonly 
occurring TEAEs for all grades include fatigue (11 patients; 61.1%), nausea (8 patients; 
44.4%), chills (6 patients; 33.3%), fever (pyrexia) (5 patients; 27.8%), and diarrhea, 
headache, and rash (4 patients; 22.2%, each event).  Grade 3 or higher TEAEs of anemia and 
tumor pain have been reported in 2 (11.1%) patients each.  
Treatment-related TEAEs have been reported in 16 (88.9%) patients.  The most commonly 
occurring treatment-related TEAEs for all grades include fatigue (11 patients; 61.1%), chills 
(6 patients; 33.3%), nausea and fever (pyrexia) (5 patients; 27.8%, each event), and headache 
and rash (4 patients, 22.2%, each event).  No Grade 3 or higher treatment-related TEAEs 
have been reported in 2 or more patients.  
Nine (50.0%) patients have experienced at least 1 SAE.  Serious AEs reported in more than 
1 patient include tumor pain (2 patients; 11.1%).  Only 1 of the SAEs of tumor pain (5.6%) is 
considered treatment-related and resulted in treatment delay.  
Study CMP-001-003
Study CMP-001-003 is evaluating CMP-001 administered SC and IT in combination with 
atezolizumab with and without radiation therapy in patients with advanced NSCLC. 
In Part A Stage 1 of the Study, 13 patients have received at least 1 dose of CMP-001 by SC 
injection at a dose of 5 mg in combination with atezolizumab 1200 mg Q3W.
As of 31 October 2018, 12 (92.3%) of 13 patient have experienced at least 1 TEAE, and 
8 (61.5%) patients have experienced Grade 3 or higher TEAEs.  The most commonly 
occurring TEAEs for all grades include fatigue (6 patients; 46.2%), fever (pyrexia) 
(5 patients; 38.5%), hypotension (5 patients; 38.5%), chills, decreased appetite, headache, 
and hyponatremia (4 patients; 30.8%, each event), and anemia, nausea, blood creatinine 
increased, platelet count decreased, back pain, and rash (3 patients, 23.1%, each event).  


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Grade 3 or higher TEAEs reported in 2 or more patients include pneumonia, decreased 
appetite, and hypotension (2 patients; 15.4%, each event).  
Treatment-related TEAEs have been reported in 12 (92.3%) patients.  The most commonly 
occurring treatment-related TEAEs for all grades include fever (pyrexia) (5 patients; 38.5%) 
and fatigue, headache, and hypotension (4 patients; 30.8%, each event).  Grade 3 or higher 
treatment-related TEAEs have been reported in 4 (30.8%) patients.  
Nine (69.2%) patients have experienced at least 1 SAE.  Serious AEs reported in more than 
1 patient include fever (pyrexia), pneumonia, and dyspnea (2 patients; 15.4%, each event).  
Most SAEs are considered not related to study treatment, but both SAEs of fever (pyrexia) 
(15.4%) are considered related to study treatment. 
Safety Summary
Preliminary analysis of safety data appears to demonstrate an acute toxicity profile for all 
3 studies that consists predominately of Grade 1 to Grade 2 AEs including fever (pyrexia), 
chills, nausea, vomiting, diarrhea, headache, rash, and hypotension resembling 
interferon-related toxicities as well as symptoms associated with cytokine release.  The most 
common Grade 3 or higher TEAE is hypotension.  These AEs typically present within 1 to 
4 hours after the third CMP-001 dose and generally resolve within a few hours with standard
supportive care and/or stress dose steroids. 
Mild to moderate injection site reactions following IT injections, such as pain, itching, 
erythema, swelling, and induration have been reported. These injection site reactions were 
mostly grade 1 or 2 events. 
Efficacy
Study CMP-001-001
Preliminary efficacy data across the Part 1 Dose Escalation and Part 1 Dose Expansion 
Phases show an objective response rate (ORR) in 18 of 113 melanoma patients of 15.9% and 
is comprised of 2 CRs and 16 PRs.  The 95% CI is 9.7% to 24.0%.  The ORR using the 
combination of RECIST/immune-related Response Evaluation Criteria in Solid Tumors 
(irRECIST) is 19.5% (22 of 113 patients; 95% CI = 12.6% to 28.0%).  An additional 
4 patients are included as responders based on the irRECIST assessment due to achieving a 
PR after initial progression.  There are 30 (26.3%) patients with a RECIST best response of 
SD, 50 (44.2%) patients with a RECIST best response of PD, and 11 (9.7%) patients who 
discontinued prior to having a follow-up scan.  
Of the 18 patients with RECIST responses, 8 patients have responses of at least 48 weeks in 
duration, with 1 of these patients having an ongoing response at Week 108 and another 
patient with an ongoing response at Week 84.  Three patients have a response duration of 
24 weeks, 2 patients have a response duration of 12 weeks, and 1 elderly patient discontinued 
treatment after the Week 12 tumor assessment scan.  As of the data cutoff date, 8 of the 
18 patients with RECIST responses remain on treatment and 10 patients are off treatment.


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Study CMP-001-002
Preliminary efficacy data across the Part 1 Dose Escalation Phase in the CMP-001-002 study 
show an ORR of 11.8% in 2 of 17 melanoma patients with a 95% CI of 1.5% to 36.5%.  
Overall, there are 5 (29.4%) patients with a RECIST best response of SD, 7 (41.2%) patients 
with a RECIST best response of PD, and 3 (17.6%) patients who discontinued prior to having 
a follow-up tumor assessment (1 patient discontinued due to an AE of tumor pain, 1 patient 
discontinued to enter hospice, and 1 patient discontinued because of Investigator decision).  
Both patients with a RECIST best response of PR continue to have a response at the time of 
the data cutoff, with their latest tumor assessments confirming response performed at 
Week 24 for 1 patient and Week 36 for the other patient.  As of the database cut-off, 1 patient 
is still pending their first follow-up tumor assessment. 
Study CMP-001-003
There are no patients with a response across the preliminary efficacy data in Part A Stage 1.  
To date, 3 (23.1%) NSCLC patients have a RECIST best response of SD, 8 (61.5%) patients 
have a RECIST best response of PD, and 2 (15.4%) patients discontinued from the study 
before having a follow-up tumor assessment (1 patient died and 1 patient discontinued due to 
an unrelated SAE of pneumonitis.  
Additional information for this compound may be found in the SRSD, which for this study is 
the IB.  
1.2.5.4. Pharmacokinetics of CMP-001
The PK studies performed in mice and rats demonstrate that QbG10 blood concentrations
peaked between 6 and 24 hours after SC dosing; declined in a monoexponential manner; and 
have a t1/2 of 7 to 10 hours.  Following SC injection, the QbG10 VLPs nanoparticles (30 nm 
in size) circulate rapidly through the lymphatic vessels into the draining lymph nodes, and 
subsequently into the systemic circulation.68  Intratumoral injection of QbG10 is expected to
behave with similar PK to the SC route because, although tumors generally have poorly 
developed lymphatic vessels, they also have compensating elevated oncotic pressures that
lead to nanoparticle circulation into the draining lymph nodes.69
Based on PK results in the rat model, concentrations of CMP-001 are expected to be low and 
below the lower limit of quantification (LLOQ), therefore, conventional PK parameters of
CMP-001 cannot be determined in humans.
To date, CMP-001 has not been studied in formal clinical drug-drug interaction studies. 
Pharmacokinetic interactions between CMP-001 and checkpoint inhibitors are not expected 
and have not been observed to date. 
1.2.5.5. Immunogenicity of CMP-001 
Anti-Qb antibodies reach levels above 100 g/mL by the third CMP-001 dose.  Based on
evaluation of IgG levels from 24 patients in the Checkmate Dose Escalation Phase of 


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CMP-001-001 study who received IT CMP-001 doses of 1, 3, 5, 7.5 or 10 mg, there is no
demonstrable relationship between CMP-001 dose and the level of anti-Qb antibodies.  The
mean level of IgG across tested patients at timepoints beyond 3 weeks of treatment was
575 g/mL, and the median level was 442 g/mL.  The IgG antibody levels were
significantly higher than the IgM. There has been no association observed between levels of
anti-Qb antibody and either CMP-001 treatment efficacy or toxicity.
1.2.6. Study Rationale
1.2.6.1. Rationale for the Individual Combinations Under Evaluation
Immunomodulators are proposed for combination with avelumab based on clinical safety and 
anti-tumor activity for the individual agents and at least one the following considerations: 
(a) pre-clinical data suggesting increased efficacy of the combination without noticeable 
toxicity, (b) gene expression profiling data from human tumors suggesting coexpression of 
the respective target with PD-L1 and genes associated with effective immune responses to 
tumors, (c) proposed complementary mechanisms of action that might lead to increased 
anti-tumor activity.
1.2.6.1.1. Combination A (Avelumab plus Utomilumab)
As noted in Section 1.2.2.2 and Section 1.2.2.3, murine tumor experiments demonstrated 
significant immune-modulatory activity and anti-tumor activity of utomilumab and surrogate 
anti-mouse 4-1BB mAbs when dosed as a single agent in some tumor models.  Combinations 
of agonist anti 4-1BB antibodies with antagonists of PD-1/PD-L1 have shown significantly 
improved anti-tumor activity compared with either single agent.  These data are consistent 
with the hypothesis that addition of 4-1BB agonism to PD-L1 blockade results in a more
robust anti-tumor immune response following PD-L1 blockade.  The implication is that 
combining an agonist mAb (utomilumab) with an anti-PD-L1 mAb (avelumab) will increase 
the proportion of objective responses and increase the clinical benefit.  Available non-clinical 
safety data indicates that the addition of an anti PD-1 antibody did not add to the toxicity of 
an anti-4-1BB agonist antibody. 
1.2.6.1.2. Combination B (Avelumab plus PF-04518600)
Ribonucleic acid (RNA)-seq data generated by the cancer genome atlas (TCGA) research 
network (http://cancergenome.nih.gov/) across multiple tumor types was used to assess 
potential utility of the combination of avelumab and PF-04518600.  Given that the RNA-seq 
data is generated from bulk tumors, spearman correlations of mRNA expression of target of 
interest (avelumab or OX40) to mRNA expression of markers of specific immune cell 
subsets was completed.  This correlation was used as a guide for the determination of 
OX40 or PD1-IFNinflammatory immune gene signature expression levels within different 
immune cells.48  For PD-1/PD-L1 mAbs such as avelumab, response to PD-1 blockade with 
pembrolizumab is associated with an interferon inflammatory immune gene signature, 
correlation of PD-1 expression to the expression of the IFN inflammatory immune gene 
signature (predictive of response and including the following 10 genes: HLA-DRA, 
CXCL9, GZMA, PRF1, CCR5, IFN, CXCL10, IDO1, STAT1, CXCL11) was completed.  
For OX40, since anti-OX40 agonists are expected to stimulate CD4 cells, correlation of 


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OX40 expression to CD4 expression was completed.  Scatter plot of OX40-CD4 correlations 
and PD-1-IFNsignature correlations across all the TCGA tumor types were computed.  The 
correlation between PD-L1, OX40, and the IFN inflammatory immune gene signature 
suggests that OX40 agonism may be effective in the majority of patients with targetable 
PD-L1.
1.2.6.1.3. Combination C (Avelumab plus PD 0360324)
In multiple mouse tumor models, the combination of a blocking CSF-1R/M-CSFR antibody 
with an anti-PD-1 antibody significantly enhanced anti-tumor activity.59  In a preclinical 
model of colon carcinoma, anti-M-CSF in combination with avelumab inhibited tumor 
growth and appeared to be most potent when combined with a 4-1BB agonist antibody 
(Figure 13).  Myeloid cell reduction represents an active area of clinical investigation for the 
treatment of solid tumors, with multiple clinical studies under way with other agents that 
either block M-CSF or the M-CSFR. 
1.2.6.1.4. Combination D (Avelumab plus Utomilumab plus PF-04518600)
In mouse tumor modeling experiments, addition of both surrogate 4-1BB and OX40 agonists 
to avelumab led to greater tumor inhibition than was achievable by the component doublet
combinations (Figure 12).  Importantly,  the addition of a triplet combination of 
avelumab/utomilumab/PF-04518600 to vitro cytokine release assays with normal human
blood cells indicated that the concentrations of cytokines (TNF-, IL-6, IFN-) induced by 
the combination of all 3 antibodies were similar to or lower than avelumab alone in assays 
using whole blood or PBMCs (see Section 1.2.3.3).  This assay is used to assess the potential 
for cytokine release syndrome and the results indicate that the potential for this type of AE is 
low. 
Clinical safety and PK data from Combination A (utomilumab plus avelumab) and 
Combination B (avelumab plus PF-04518600) will be evaluated on an ongoing basis to 
confirm safety of each of the doublets.  At least 6 patients will be evaluated for DLTs in 
Combination B at the 1 mg/kg PF-04518600 dose level before the first dose level for 
Combination D (D11), 0.1 mg/kg PF-04518600 plus 20 mg utomilumab plus 10 mg/kg 
avelumab) can be initiated.
In this study, as of 30 September 2016, the utomilumab plus avelumab doublet 
(Combination A) was found to be well tolerated at all utomilumab dose levels evaluated in 
Phase 1b with no DLTs and the PF-04518600 and avelumab doublet (Combination B) has 
also been well tolerated at the first dose level, B12 (0.3 mg/kg PF-04518600), with no DLTs.  
Based on monotherapy data, this is considered to be within a pharmacologically-active dose 
range.  The initiation of the utomilumab plus PF-04518600 plus avelumab triplet 
(Combination D) is dependent upon an adequate safety profile at the next dose level (ie, no 
more than 1 DLT) of Combination B, B13 (1 mg/kg PF-04518600), in 6 patients (see 
Sections 1.2.2.4.1 and 1.2.3.4.1 for updated safety information for Combination A and 
Combination B, respectively). 


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1.2.6.1.5. Combination F (Avelumab plus CMP-001)
Intratumoral injection of TLR9 agonists have elicited strong cytotoxic T cell (CTL) 
responses in human clinical trials in patients with melanoma, but the CTL responses are 
transient and objective tumor responses are rare.  T cells, induced following TLR9 agonist 
therapy in humans, express high levels of PD-170, 71, 72 suggesting that PD-1 may inhibit CTL 
activity mobilized by TLR9.  Adding anti-PD-1 to TLR9 treatment increased tumor growth 
inhibition and survival in mouse tumor models, including bladder73 and ovarian cancer 
models.74  Combination of TLR9 agonist and anti-PD1 was associated with increased tumor-
specific CD8+ T cells, activated CD4 T cells, and decreased regulatory T cells in the tumor 
area.  As noted in Section 1.2.5.2, combination benefit was observed following 
co-administration of CMP-001 and anti-PD1 to mice bearing A20 lymphoma tumors.  In 
vitro culture with anti-PD-1 antibodies significantly increased cytokine production by CD8+ 
T cells from melanoma patients treated with a TLR9 agonist, suggesting that potentially a 
similar additive benefit might be seen in humans.70  As discussed in Section 1.2.5.3, this has 
been clinically validated based on preliminary efficacy data obtained in patients with PD-1 
refractory melanoma treated with pembrolizumab (anti-PD-1) and CMP-001.  
A different investigational synthetic TLR9 agonist, SD-101, has been investigated in SCCHN 
patients.  SD-101 stimulates human pDCs to release IFNand mature into efficient 
antigen-presenting cells, enhancing both innate and adaptive immune responses.  The 
combination of IT SD-101 and pembrolizumab (anti-PD-1) was tested in an ongoing Phase 
1b/2, study (NCT02521870, SYNERGY-001 DV3-MEL-01/Keynote-184) in 
33 advanced/metastatic SCCHN patients.  The treatment was well tolerated with no evidence 
of an increased incidence or severity of AEs over pembrolizumab monotherapy.  No increase 
in immune-related AEs over pembrolizumab monotherapy was observed.  Adverse events 
associated with SD-101 were transient, mainly mild to moderate injection-site reactions and 
flu-like symptoms that were manageable with over-the-counter medications.  The 
combination therapy demonstrated promising efficacy in patients with SCCHN (Prior 
anti-PD-1/PD-L1 naïve), with an ORR of 27%.  Responses were observed in both SD-101 
injected and non-injected lesions and in both PD-L1 negative and positive tumors.  The study 
provides preliminary evidence of safety and therapeutic activity of intratumoral TLR agonist 
and check point inhibitor combination in SCCHN treatment.75
Combination of avelumab plus CMP-001 and utomilumab or PF-04518600 
T cell activation by antigen-presenting cells, anticipated to occur in tumor-draining lymph 
nodes, results in upregulation of 4-1BB76 and OX40.77 It is thought that in most cancer 
patients, 4-1BB and OX40 are not significantly induced in the absence of activation of these 
antigen presenting cells.  Therefore, it is reasonable to predict that TLR9-activated pDCs will
induce 4-1BB and/or OX40 in patients and thus increase expression of targets for 
utomilumab and PF-04518600, respectively.  As noted in Section 1.2.5.2, this prediction is 
supported by tumor growth control and increased survival following combination of 
CMP-001, OX40 agonist, and PD-1 antagonist in the CT26 colon tumor model.66 In this 
study, combining 4-1BB and OX40 agonists with PD-1 blockade and IT treatment with
TLR9 agonists led to at least additive tumor growth inhibition in a mouse melanoma model, 
supporting the clinical evaluation of the hypothesis.78  Whether 4-1BB and/or OX40 is 


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induced on T cells may depend on the specific tumor antigens presented to T cells by the 
pDCs.  At this time, the specific tumor antigens recognized by T cells from patients with 
SCCHN are unknown, justifying separate study arms to evaluate these agonist mAbs in 
combination with CMP-001 and avelumab.  
1.2.7. Rationale for the Tumor Types to be Evaluated
The tumor types were selected based one or more of the following in settings of unmet 
medical need: (a) an agent of the same class has shown clinical activity in the tumor type of 
interest, (b) clinical response to the study compounds, either as single agents or in 
combination with compounds having related mechanisms of action, (c) expression of the 
target(s) in the tumor by immunohistochemistry and/or gene expression profiling (eg, TCGA 
analysis), (d) correlation of target expression with expression of genes related to anti-tumor 
immunity, such as IFN-.  For all tumor types, settings were chosen where the study 
treatments would not unreasonably delay any available survival-benefiting therapy.  Other 
tumor types may be added based on emerging data.
1.2.7.1. Combination A (Avelumab plus Utomilumab)
The tumor types selected for this combination (NSCLC, melanoma, SCCHN, TNBC) have 
shown clinical response to single-agent avelumab and expression of the 4-1BB target in the 
tumor.  Based on clinical data showing a CR in SCLC with the combination of utomilumab 
and pembrolizumab,58 and the observation that a subset of these tumors may be 
immuno-responsive,61,62 the combination of avelumab plus utomilumab may also be 
evaluated in patients with SCLC. 
1.2.7.1.1. Rationale for Inclusion of First-Line Patients with Advanced Non-Small Cell 
Lung Cancer in Combination A
PD-1/PD-L1 blockade was first shown to result in an improved response rate, as well as 
longer survival in patients with advanced NSCLC in a second-line setting compared with 
docetaxel, which led the regulatory approval of two PD-1 blocking mAbs in this 
setting.65,80,81
More recently, interim results of a Phase 1b study of avelumab as a first-line treatment for 
patients with advanced NSCLC were presented (Study EMR 100070-0001).83  In accord with 
the enrollment criteria for Combination A in the current B9991004 Javelin Medley study, 
patients with metastatic or recurrent NSCLC negative for epidermal growth factor receptor 
(EGFR) mutation or anaplastic lymphoma kinase (ALK) translocations who had not received 
prior treatment for metastatic or recurrent disease were eligible for treatment.  Patients were 
required to have tumor material available for biopsy but were not pre-selected based on 
tumor PD-L1 expression, and received continued treatment with 10 mg/kg avelumab Q2W as 
a single agent until confirmed disease progression, unacceptable toxicity, or other withdrawal 
criteria were met.  The primary objective was safety and tolerability of avelumab and 
secondary objectives included best overall response, progression-free survival (PFS), and 
overall survival (OS), as well as an evaluation of the association between PD-L1 expression 
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As of 23 October 2015, among 75 of 145 (51.7%) patients who were treated with avelumab 
as a first-line therapy for advanced NSCLC who had at least a 13-week follow–up period for 
responses by RECIST, the objective response rate (ORR) was 18.7% (14/75), with 1 CR and 
13 PRs, and the disease control rate (DCR) was 64% based on 14 responses and 34 patients 
with stable disease.  Patients with PD-L1 expression in tumor cells with a threshold of 1% 
had an ORR of 20.0% (7/35) and patients with PD-L1 negative tumors did not respond 
(0/10).  Median duration of response had not been reached at the time of the data analysis and 
85.7% of responses (12/14), including 1 CR, were ongoing.  The PFS rate at 6 months in all 
patients was 35.6% and the median PFS was 11.6 weeks.  OS data were not yet mature.  
Safety-related data on all 145 patients with advanced NSCLC treated in this setting indicated 
that avelumab was well tolerated as a single agent, with 2.8% (4/145) of patients 
experiencing treatment associated immune-related AEs of Grades 1 or 2 at maximum 
intensity.
As stated in Section 1.2.2.3, animal modeling suggests that there will be a synergy in 
anti-tumor activity in combining avelumab (PD-L1 inhibition) with utomilumab (4-1BB 
agonism).  Importantly, this increased activity was not associated with increased toxicity and 
is supported by preliminary data from Combination A Phase 1b of this study.  As of 
30 September 2016, no DLTs have been reported at any of the doses of utomilumab (20 mg, 
100 mg, or 500 mg) every 4 weeks (Q4W) combined with avelumab 10 mg/kg Q2W in 
patients with advanced NSCLC who had received at least one prior therapy.  As the study has 
continued to expand the number of advanced NSCLC patients treated in Phase 2 with this 
combination, the combination continues to be well tolerated, with a low frequency of 
Grade 3 events and no apparent increase in treatment-associated immune-related AEs 
 
and no study drug-related deaths.  In addition, preliminary data from the Combination A 
Phase 2 cohort have emerged which suggests that advanced NSCLC patients who were either 
previously untreated or had not received prior chemotherapy had rapid tumor responses 
(noted by the first on-treatment assessment), including in one case, a CR on brain lesions.  
These data are preliminary and patients remain under treatment, along with a continued 
assessment for tumor responses.  In the context of these data, the potential risk/benefit 
supports the continued exploration of the combination of utomilumab with avelumab in 
previously untreated patients with advanced NSCLC (see Enrollment Criteria in Section 4.1) 
to obtain additional safety and clinical activity information.
1.2.7.1.2. Rationale for Evaluation of Sequenced Administration of Avelumab and 
Utomilumab (Cohorts A9 and A10)
Emerging preclinical evidence indicates that the order in which immune cells are exposed to 
activating stimuli can influence the potency of the immune response.  For instance, exposure 
of dendritic cells to tumor antigen plus interleukin-2 (IL-2) followed by IFN-α elicits more 
effective anti-tumor immunity than simultaneous exposure to all three components.90  
Removal of tumor-infiltrating lymphocytes (TIL) from the tumor microenvironment and 
re-exposure to cognate antigen in vitro leads to upregulation of 4-1BB,91 suggesting that 
release of TIL from microenvironmental inhibition can prepare them for activation by 4-1BB 
agonists such as utomilumab.  On the other hand, 4-1BB signaling can protect chimeric 
CCI


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antigen receptor (CAR)-T cells from exhaustion induced by tonic receptor signaling,92 which 
suggests that utomilumab may be best administered prior to re-initiation of TCR signaling by 
avelumab.  
Limited early data from Cohorts A1, A2, and A3 of this study suggest that patients with 
previously untreated advanced NSCLC may benefit from the concurrent administration of 
utomilumab and avelumab.  To potentially optimize the clinical benefit of this combination 
in this clinical setting, Cohorts A9 and A10 introduce the sequenced administration of 
avelumab and utomilumab into this study (see Combination A Schedule of Activities).
1.2.7.2. Combination B (Avelumab plus PF-04518600)
Tumor types selected for this combination may include advanced NSCLC, melanoma, and 
SCCHN, which have shown clinical response to single-agent avelumab and expression of the 
OX40 target in the tumor.  One melanoma patient achieved a PR on PF-04518600 
monotherapy treatment after anti-PD-1 and anti-CTLA-4 therapy had failed.82  In Protocol 
Amendment 6, advanced/metastatic CRC has been removed as a tumor type for this
combination for strategic reasons after critical review of emerging biomarker data from both 
internal and published reports, which suggest that OX40 agonists might not be effective as 
doublets with PD-1/PD-L1 pathway inhibitors for the treatment of patients with CRC. 
1.2.7.3. Combination C (Avelumab plus PD 0360324)
Tumor types selected for this combination may include advanced ovarian cancer, SCCHN, 
and NSCLC, which have shown clinical response to single-agent avelumab as well as M-CSF 
and PD-1-IFNsignature correlations and/or association of higher TAM density with 
negative prognosis.  Gastric cancer may be added to the expansion phase if activity is
observed during the dose escalation phase.  Patients with Tenosynovial giant cell 
tumor/pigmented villonodular synovitis (TGCT/PVNS) are allowed during Phase 1b.  These 
tumors often express CSF-1 and shown to be responsive to inhibition of signaling between 
CSF-1 and CSF-1R.96,97
1.2.7.4. Combination D (Avelumab plus Utomilumab plus PF-04518600)
Tumor types selected for this combination may include advanced NSCLC, melanoma, 
SCCHN, bladder cancer, which have shown response to single-agent avelumab and 
expression of the 4-1BB and OX40 targets in the tumor.  Tumor types will be further 
prioritized based on the clinical activity observed for the respective doublets evaluated in this 
study in Combinations A and B.  Other tumor types may be considered based on emerging 
data from the study across all combinations, as applicable. 
1.2.7.5. Combination F1 (Avelumab plus CMP-001); F2 (Avelumab plus CMP-001 and 
utomilumab); F3 (Avelumab plus CMP-001 and PF-04518600)
SCCHN has been selected for these combinations for the following reasons.  Firstly, as noted 
in previous sections, SCCHN is expected to respond to avelumab. Secondly, 
TLR9-responsive pDCs have been observed in SCCHN98 and a combination of TLR9 agonist
and checkpoint inhibitor has demonstrated safety and preliminary signs of clinical activity in 




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1.2.8.3. PF-04518600
Doses of PF-04518600 proposed for the Phase 1b dose escalation cohorts include 0.3, 1.0, 
and 3.0 mg/kg Q2W, with 0.1 mg/kg as the starting dose for Combination D.  This lower 
dose is two dose levels below the Combination B dose level of 1.0 mg/kg that will be 
evaluated for DLTs before initiating Combination D.  Safety information observed for 
PF-04518600 monotherapy includes completed safety evaluation of 5 dose levels
(0.01, 0.1, 0.3, 1.5, and 3.0 mg/kg, see Section 1.2.3.4).  To date, all treatment-related AEs 
have been mild or moderate (Grade 1 and 2) in severity.  One treatment-related SAE, 
Grade 2 congestive heart failure occurring in a patient with pre-existing risk factors to 
atherosclerosis and cardiac disease and prior cardiotoxic cytotoxic therapy (doxorubicine) 
55 days following first PF-04518600 treatment, has been reported.  In addition, peripheral 
blood receptor occupancy has indicated full receptor occupancy in peripheral blood at the 
0.3 mg/kg dose.  For Combination B, the starting dose is 0.3 mg/kg PF-04518600 with the 
option to de-escalate to a dose of 0.1 mg/kg in the event of unacceptable toxicity at the 
0.3 mg/kg dose. 
1.2.8.3.1. PF-04518600 Dose for Combination F
In a monotherapy setting, the activity of PF-04518600 was observed at the 0.3 mg/kg dose 
level and full receptor occupancy was achieved for all patients at doses ≥0.3 mg/kg.  In the 
current study, PF-04518600 at 0.3 mg/kg, 1 mg/kg, and 3 mg/kg given Q2W was tested in 
combination with 10 mg/kg Q2W avelumab.  No DLTs were observed and no dose-response 
relationship was observed for safety or efficacy endpoints.  Based on the collective 
monotherapy and combination data, the lowest dose level (0.3 mg/kg Q2W) was chosen for 
further evaluation.
1.2.8.4. PD 0360324
Doses of PD 0360324 to be used for the Phase 1b dose escalation part of Combination C of 
this study are 50 mg, 100 mg, and 150 mg Q2W.  Although clinical efficacy has not been 
demonstrated, PD 0360324 appears to be well tolerated.  Across the 4 clinical studies of 
PD 0360324 in autoimmune indications (Section 1.2.4.3), no DLTs were observed for 
patients treated up to 150 mg Q2W.  PD 0360324 appeared to maximally inhibit circulating 
CD14+ CD16+ monocytes at doses 30 mg, and dose/exposure-dependent periorbital edema 
was observed in previous clinical studies with Q2W dosing up to 150 mg.  Therefore, based 
on a wide safety margin of 2 dose levels and the anticipated pharmacodynamic activity 
range, a 50 mg dose administered Q2W has been selected as the starting dose of PD 0360324 
in combination with avelumab.
1.2.8.5. CMP-001
1.2.8.5.1. Rationale for CMP-001 Dose Selected 
The 1, 3, 5, 7.5 and 10 mg CMP-001 IT doses at two different concentrations (1 mg/mL and 
6 mg/mL) in combination with the standard dose of IV pembrolizumab have been evaluated 
in the Dose Escalation Phase of the Checkmate CMP-001-001 study.  Durable responses 
have been seen at the 3 mg, 5 mg, 7.5 mg, and 10 mg dose levels. Analysis of 
pharmacodynamic, toxicity and clinical response does not indicate a dose-response 


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relationship.  Therefore, the highest dose tested of 10 mg has been chosen for further 
evaluation for Combination F. 
1.2.8.5.2. Rationale for CMP-001 Route of Administration
Tumors recruit immature, inactivated pDC.  The highest concentrations of pDC are believed 
to reside within tumors.  Therefore, the administration of one or more doses of CMP-001 
directly into the tumor, is believed to deliver a local concentration of drug that is effective in 
activating the highest numbers of tumor-antigen-bearing pDC.  The rationale, for using a 
hybrid route of administration that begins with SC dosing and switching to IT dosing, is to 
provide a dosing regimen whereby the initial SC doses of CMP-001 induce the production of 
anti-Qb antibodies (the Qb component of the VLP capsid protein), and upon IT dosing, the 
induced anti-Qb antibodies will opsonize the VLP and direct its uptake into the pDC 
endosomal compartment through a specific FcR, FcγRII.  In the absence of the anti-Qb 
antibodies, the VLP is not efficiently taken up by the pDC, nor does it effectively activate the 
pDC.  Following endosomal uptake, the G10 (the CpG component of CMP-001) activates 
TLR9, stimulating the pDC to switch from the immature state to a mature, fully activated 
state.  Activated pDC then traffic to tumor-draining lymph nodes where presentation of
tumor antigens to T cells occurs, thus inducing the anti-tumor T cell response.  The hybrid 
route of administration that begins with SC dosing followed by IT dosing is currently the 
recommended dosing regimen for CMP-001 and PDx combination studies.  The SC dosing, 
if administered peritumorally, may also induce pDC activation, although this is expected to 
be less efficient compared with IT administration and limited data are available to support 
this route of administration. 
Both the SC and IT routes of administration (ROA) have been evaluated in ongoing studies 
with CMP-001.  Both ROAs have demonstrated an acceptable safety profile and durable 
clinical responses.  This protocol allows the investigator to switch to a SC route after initial 
IT injections.  It is acknowledged that this may create a degree of dosing variability.  
However, continued IT injections may not be feasible for patients that either have limited 
accessible tumors, or who are not tolerating the IT injections.  The recommended schedule 
and ROA of IT and SC route for CMP-001 ensures that the sufficient level of TLR9 
activation will occur in these patients enabling the chance for clinical activity.
1.3. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of the trial.  
Avelumab demonstrated clinical activity in patients with advanced solid tumors in an 
expansion cohort of an ongoing Phase 1 study.  The clinical safety data available to date, 
with single-agent avelumab in patients with advanced solid tumors, suggest an acceptable 
safety profile of the compound.  Most of the observed events were either in line with those 
expected in patients with advanced solid tumors or with similar class effects of mAbs 
blocking the PD-1/PD-L1 axis.  Infusion-related reactions including hypersensitivity and 
immune-related adverse events (irAEs)/autoimmune disorders have been identified as 


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important risks for avelumab.  Respective risk mitigation measures have been implemented 
in all ongoing clinical studies with avelumab, including this clinical trial protocol.  These 
include guidelines for treatment interruption and discontinuation in case of irAEs, as well as 
mandatory pre-treatment with a H1 blocker and acetaminophen.
The 4-1BB mAb, utomilumab, has also demonstrated clinical activity as monotherapy in 
patients with advanced solid tumors and in combination with rituximab in patients with NHL 
in an ongoing Phase 1 study.  The clinical safety profile of utomilumab supports its use as 
both a single agent and in combination with rituximab.  Treatment-related AEs were 
generally mild or moderate with only two Grade 3 AEs (hyponatremia and fatigue) related to 
utolimumab monotherapy. No AEs Grade ≥3 AEs related to utolimumab have been reported 
among patients receiving utomilumab in combination with rituximab.  
The OX40 mAb, PF-04518600, is being evaluated as a single agent or in combination with 
utolimumab in an ongoing Phase 1 dose escalation study in patients with advanced or 
metastatic cancer (Study B0601002).60  As of 27 October 2016, DLTs were not observed in 
patients treated up to 3.0 mg/kg.  The safety profile of PF-04518600 supports its use as a 
single agent, and a dose escalation approach is being taken in this study in combination with 
avelumab. Combination B and Combination D will start with 0.3 mg/kg and 0.1 mg/kg 
PF-04518600, 2 and 3 dose levels below the highest safe single agent dose level tested thus 
far, respectively, in the ongoing Study B0601002.  In order to mitigate safety risks with the 
triplet Combination D, at least 6 patients will be evaluated for DLTs in Combination B at the 
1 mg/kg PF-04518600 and 10 mg/kg avelumab dose level before Combination D Cohort D11 
(0.1 mg/kg PF-04518600 plus 20 mg utomilumab plus 10 mg/kg avelumab) can be initiated.
As of June 2017, multiple doses of single-agent PD 0360324 have been administered to a 
total of 68 patients with autoimmune diseases at doses ranging from 20 to 150 mg.  The 
observed safety events in these studies appear to be acceptable in developing PD 0360324 for 
an oncology indication.  There have been no deaths or SAEs with PD 0360324.  For 
Combination C, the starting dose of PD 0360324 is 50 mg (2 dose levels under the MTD of 
150 mg), with possible escalation to 100 and 150 mg.
CMP-001 administered IT to patients with melanoma, either as a single agent or in 
combination with pembrolizumab (anti-PD-1), has shown a clinically manageable safety 
profile in a study of escalating CMP-001 IT doses up to 10 mg (see Section 1.2.5.3).  
According to the information in the CMP-001 IB, AEs typically present on or after the third 
CMP-001 dose and generally resolve within a few hours with standard supportive care.  
Clinical activity was observed for the combination of CMP-001 and pembrolizumab in 
patients with melanoma in Study CMP-001-001. In addition, a combination of another IT 
administered TLR9 agonist, SD-101, and another PD-L1/PD-1 checkpoint inhibitor, 
pembrolizumab, showed a favorable safety and clinical activity profile in SCCHN patients.75  
As detailed in Sections 1.2.2.4 and 1.2.3.4, the doublets of avelumab plus utomilumab and 
avelumab plus PF-04518600, have shown a favorable safety profile, clinical activity, and 
signs of pharmacodynamic activity.  


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Combination F will test combinations of avelumab plus CMP-001, avelumab plus CMP-001 
and utomilumab, and avelumab plus CMP-001 and PF-04518600, with concurrent enrollment 
using 1:1:1 randomization.  In these combinations, CMP-001 will first be administered SC in 
two weekly doses, followed by IT administration of CMP-001.  The decision of concurrent 
enrollment is based in part on the data generated in this study for the doublets of avelumab 
plus utomilumab and avelumab plus PF-04518600, which did not show evidence of any 
additional safety risk as compared to single agent use of these study drugs.  In addition, 
concurrent enrollment can also be justified by the previous finding in the clinic that AEs 
associated with CMP-001 were clinically manageable and were not likely to be associated 
with the first dose.  Therefore, the above triplet combinations are not expected to confer 
significant additional toxicity as compared to avelumab as single agent or avelumab in 
combination with CMP-001. The proposed 4-week DLT observation period is based on the 
observed acute safety profile of CMP-001, when administered intratumorally, and the 
observation in this study that DLTs were not observed for the avelumab plus utomilumab and 
avelumab plus PF-04518600 doublets.
Based on the nonclinical and Phase 1 data available to date for avelumab, utomilumab, 
PF-04518600, PD 0360324, and CMP-001, the conduct of the trial is considered justifiable 
using the dose and frequency of administration of avelumab and the dose, frequency and 
mode of administration of these other immune modulators as specified in this clinical trial 
protocol.  As the clinical safety profiles for PF-04518600, and PD 0360324 are less well 
understood compared with utomilumab and CMP-001, a dose-escalation approach has been 
planned during Phase 1b evaluation for Combinations B, C, and D.
Combination D will be initiated only after the respective doublets in Combinations A and B 
are observed to provide a safety margin of at least 2 dose levels (no more than 1 DLT out of 
6 patients at the respective 500 mg utomilumab [A1] or 1 mg/kg PF-04518600 [B13] 
Phase 1b dose levels) above the starting doses in Combination D. Of note, no DLTs have 
been observed in the Phase 1b cohorts for Combination A, meeting the criterion for that 
combination, and no DLTs have been observed at the 0.3 mg/kg (B12) and 1 mg/kg (B13) 
PF-04518600 dose levels of Combination B.  Six (6) patients will be enrolled at 1 mg/kg 
PF-04518600 during Phase 1b of Combination B and evaluated for safety prior to initiating 
Combination D. 
Any combination in this study shall be discontinued in the event of any new findings that 
indicate a significant deterioration of the risk-benefit relationship that would render 
continuation of the combination unjustifiable.
While clinically significant irAEs have not been observed with utomilumab, 
PF-04518600, or PD 0360324, risk mitigation measures have been implemented in ongoing 
clinical studies for each of these investigational products, which are also included in this 
clinical trial protocol.  These include guidelines for treatment interruption and 
discontinuation in case of treatment-related irAEs.  Avelumab has been approved in the US 
for the treatment of metastatic Merkel cell carcinoma.  In addition, avelumab has 
demonstrated anti-tumor activity in various tumor types (eg, NSCLC, urothelial cancers, 
mesothelioma, ovarian cancer, and gastric cancer). It is expected that various 


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mechanistically complementary immunotherapy combination partners will enhance the 
efficacy of avelumab.
Thus, the projected benefit/risk of avelumab given in combination with utomilumab 
(Combination A), PF-04518600 (Combination B), PD 0360324 (Combination C), 
utomilumab plus PF-04518600 (Combination D), and CMP-001 (Combination F) is 
anticipated to be favorable for investigation in this population of patients with advanced solid 
tumors.
1.4. Biomarker Rationale
This study intends to characterize the ability of various immunomodulators to increase the 
clinical benefit seen with single-agent avelumab.  As the immunomodulators may vary with 
respect to targets engaged, target modulation needed for optimal activity, potential for the 
combination of avelumab and a given immunomodulator to generate unexpected 
pharmacological outcomes, and amount of prior clinical experience with each 
immunomodulator, some customization of the biomarker strategy will be needed for each 
combination tested.  The following represents an overview of the planned strategy, followed 
by comments specific to each combination.
The success of the combinations will be contingent on selection of active doses for each 
agent, and these doses may be different in the setting of the combination relative to each 
single agent.  For this reason, a given combination may incorporate measurements of target 
engagement on immune cells in peripheral blood, levels of circulating soluble target, and 
other biomarkers in blood and tumor.  Such assessments may be discontinued if the sponsor 
considers sufficient data has been obtained to recommend a given dose for further 
development.
The success of the combinations will also be contingent on identifying the specific tumor 
types most likely to respond to the combination, which in turn will be shaped at the start of 
therapy by the number, type, and activation state of the tumor infiltrating lymphocytes, the 
level of target expression by the appropriate cell types, and the presence of immune 
inhibitory mechanisms that are may continue to suppress the effect of the combination.  The 
collection of pre-treatment biopsies, archival and/or de novo, is mandatory in order to enable 
such assessments.  These parameters will be assessed by multiple methods that may include 
but not be limited to assessment of target expression by tumor and/or immune cell types in
the tumor using immunohistochemistry, relative expression of genes representative of 
immune activation versus suppression by gene expression profiling, and the number and 
diversity of TCR sequences by DNA sequencing.
Evaluation of target modulation in the tumor may be needed to confirm synergistic PD 
effects of the combinations tested.  In the event that clinical benefit is not observed or is 
transient, assessment of reasons for lack of benefit may help guide patient selection for future 
development of the combinations.  For these reasons, biopsies on treatment and at end of 
treatment in the event of discontinuation due to disease progression are requested from 
patients with specified tumor types unless clinically contraindicated.  Collection of these 


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biopsies may be discontinued if the sponsor considers sufficient data has been obtained to 
confirm the PD behavior of the combination or possible causes for lack of clinical benefit.
1.4.1. Specific Features of Combination A: Avelumab plus Utomilumab
As summarized in Section 1.2.2.4, prior clinical experience with utomilumab has indicated 
that clinical activity may be observed across a broad dose range without notable safety or 
tolerability concerns at any dose level.  The biomarker strategy for this combination is 
therefore to confirm PD activity at 3 doses of PF-050592566 considered active based on this 
experience, and test hypotheses regarding which patients are most likely to benefit. 
1.4.2. Specific Features of Combination B: Avelumab plus PF-04518600
The aim of biomarker collections and analyses for Combination B is to provide evidence of 
differentiated, PD and immune-modulatory activity for the combination of avelumab and 
PF-04518600.  In the peripheral blood, PD measures that will be used to test for 
enhancement of PD activites observed in single agent studies include the expression of 
proliferation and activation markers (Ki67 and HLA-DR/CD38, respectively) on T cell 
subsets in peripheral blood and the quantity and phenotype of TIL infiltration by 
immunohistochemistry (IHC).  These and other biomarker assessments will contribute to the 
broad objectives of characterizing the degree and nature of enhanced PD activity, its 
relationship to tumor responses to better understand the most relevant mechanisms and the 
identification of patient immunophenotypes more likely to benefit from this combination 
therapy. 
1.4.3. Specific Features of Combination C: Avelumab plus PD 0340324
An objective of the biomarker plan unique to Combination C is the measurement of PD 
effects on the numbers and distribution of tumor associated macrophages in tumor tissue.  
Targets selected for analysis by flow cytometry, immunoassay, and IHC may include those 
associated with both T cells and mononocytes/macrophages.  Examples of these may include, 
but not be limited to, soluble M-CSF by immunoassay and CD68+ macrophages by IHC.  
Furthermore, the effect of PD 0340324 on the macrophage content of tumor-associated 
ascites fluid will be measured in tumor types such as ovarian cancer, when samples are 
available. 
1.4.4. Specific Features of Combination D: Avelumab plus Utomilumab plus 
PF-04518600
The biomarker collections in Combination D will be used to characterize combinatorial 
agonistic activity of utomilumab and PF-04518600 in the presence of checkpoint blockade 
mediated by avelumab.  To this end, assessment of T cell proliferation markers such as 
Ki-67 and T cell activation such as HLA-DR may be assessed via peripheral blood flow 
cytometry.  Other biomarkers of particular importance will be the quantity and phenotype of 
tumor-infiltrating lymphocyte (TIL) infiltration by IHC and potential effects on T cell 
diversity by TCR sequencing.  Plasma samples will be collected and may be used to confirm 
or further characterize clinical events of interest, such as cytokine release syndrome (CRS).






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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, clinical activity, PK, and 
PD study of avelumab in combination with other immune modulators in adult patients with 
locally advanced or metastatic solid tumors (eg, NSCLC, melanoma, SCCHN, TNBC, gastric 
cancer, ovarian cancer, bladder cancer, or SCLC).  In Phase 1b and Phase 2, enrollment 
criteria vary by tumor type and are described in detail in Section 4.1.  Incorporation of the 
other immune modulators into this study is based on preclinical and clinical data supportive 
of single-agent tolerability and potential clinical benefit, as well as non-clinical data 
suggesting safety, tolerability, and clinical benefit of agent(s) in combination with avelumab.  
Combinations of avelumab plus other immune modulator(s) to be evaluated are as follows:

Combination A: Avelumab plus utomilumab (4-1BB agonist mAb);

Combination B: Avelumab plus PF-04518600 (OX40 agonist mAb);

Combination C: Avelumab plus PD 0360324 (M-CSF mAb);

Combination D: Avelumab plus utomilumab plus PF-04518600.

Combination F: avelumab plus CMP-001 (TLR9 agonist) and utomilumab or 
PF-04518600:

Cohort F1: avelumab plus CMP-001;

Cohort F2: avelumab plus CMP-001 and utomilumab; 

Cohort F3: avelumab plus CMP-001 and PF-04518600.
For Phase 1b dose escalation and Phase 2 expansion cohorts, patients may be enrolled into 
different combinations in parallel.  In non-randomized cohorts, slot assignments will be 
managed by the study team and sites will be notified in advance of cohort initiations.  
Patients are not allowed to crossover between the different combinations evaluated in this 
study.
Each combination will be studied individually in 2 study parts: 1) a Phase 1b lead-in part to 
evaluate safety, and determine the maximum tolerated dose (MTD) or maximum 
administered dose (MAD) and RP2D (if applicable), of the combination, and 2) a Phase 2 
part to evaluate efficacy and further evaluate safety of the selected dose from the Phase 1b 
portion in prespecified patient populations.  Enrollment of patients in different combinations 
may be staged in order of combination alphabetical order and by tumor type.  Therefore, for 
Phase 1b dose escalation cohorts and Phase 2 expansion cohorts, staging of patient 
recruitment will be communicated to clinical sites in advance of the opening of new cohorts.  
Study design details for each combination are provided Section 3.2.


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Additional combinations of avelumab with other immune modulators may be added to this 
protocol based on emerging preclinical and clinical data. 
For all combinations, treatment with investigational products will continue until disease 
progression is confirmed by the Investigator, patient refusal, unacceptable toxicity, or until 
the study is terminated by the Sponsor, whichever occurs first.  See Section 5.3.5.3 for details 
of treatment after initial determination of radiological disease progression. 
Patients who stop avelumab or the other immune modulator(s) may continue on treatment 
with the investigational product(s) that is/are not considered to be responsible for any severe 
AE in consultation with the Sponsor’s Medical Monitor. 
It is recommended that patients who have experienced a confirmed complete response (CR) 
should continue to be treated with investigational products at the discretion of the 
Investigator after discussion with the Sponsor. 
Patients who stop treatment and experience radiologic disease progression shortly thereafter 
will be eligible for re-treatment with either avelumab and/or the other immune modulator(s) 
at the discretion of the Investigator and after discussion with the Sponsor.
3.1.1. Tumor Assessments
Anti-tumor activity will be assessed by radiological tumor assessments at 8-week intervals, 
using RECIST version 1.1.  In case partial response (PR), CR, or PD is observed according to 
RECIST v.1.1, tumor assessments should be repeated at least 4 weeks after initial 
documentation.  After 1 year from randomization in the study (randomized cohorts) or the
first dose (non-randomized cohorts), tumor assessments will be conducted less frequently, ie, 
at 12-week (after 1 year) and 16-week (after 2 years) intervals, respectively.  In addition, 
radiological tumor assessments will also be conducted whenever disease progression is 
suspected (eg, symptomatic deterioration), and at the End of Treatment/Withdrawal (if not 
done in the previous 4 weeks and prior response is other than confirmed PD).  Details of the 
treatment after initial evidence of radiological disease progression are provided in 
Section 5.3.5.3. 
Further specific guidance on tumor imaging is provided in Section 7.6.
3.1.2. Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as reported in the Schedule of Activities and described in Section 7.1. 
The results of safety assessments on dosing days that potentially require dose modifications
must be reviewed prior to dosing as specified in Section 7.1.4.
3.1.3. Pharmacokinetic/Immunogenicity Assessments
PK/immunogenicity blood sampling will be collected as described in the Schedule of 
Activities for each combination and described in Section 7.2.


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The proposed doses, schedule(s), and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data. 
3.1.4. Biomarker Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate biomarkers that are potentially predictive of treatment benefit with the 
combination of avelumab and other immune modulator(s).  In addition, biomarker studies of 
tumor and blood biospecimens will be carried out to help further understand the mechanism 
of action of the combination of avelumab plus other immune modulator(s), as well as 
potential mechanisms of resistance. Biomarkers that correlate with pharmacodynamics 
effects may be considered when prioritizing dose levels for further exploration.  Biomarker 
assessments are described in Section 7.4.
3.1.5. Modified Toxicity Probability Interval Dose Escalation Design (Combinations B, 
C, and D)
In Phase 1b for Combinations B, C, and D, the escalation/de-escalation rules for the immune 
modulator(s) tested in combination with avelumab will follow the modified toxicity 
probability interval (mTPI) method (overview provided here and described in greater detail 
in (Section 9.2.2).  Briefly, the mTPI method relies upon a statistical probability algorithm, 
calculated using all patients treated in prior and current cohorts at the same dose level (DL) 
to determine whether future cohorts should involve dose re-escalation, no change in dose, or 
dose de-escalation.  The detailed dose finding rules based on the mTPI are illustrated in 
Table 13.


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Table 13.
Detailed Dose Escalation/De Escalation Scheme
Number of patients treated at current dose
3
4
5
6
7
8
9
10
11
12
Number of dose limiting toxicities (DLTs)
0
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
S
E
E
E
E
E
2
D
D
S
S
S
S
S
S
S
S
3
DU
DU
DU
D
S
S
S
S
S
S
4
DU
DU
DU
DU
DU
D
S
S
S
5
DU
DU
DU
DU
DU
DU
D
S
6
DU
DU
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
E = Escalate to the next higher dose
S = Stay at the current dose.
D = De-escalate to the next lower dose level.
U = The current dose is unacceptably toxic.
Targeted DLT rate at MTD =25%.
As an example, if the total number of patients treated at DL0 is 3, then the following dosing 
rules are to be applied:

0 DLT escalate to DL1;

1 DLT remain at the same DL (DL0);

2 DLTs de-escalate to DL-1 and allow for possible re-escalation back to 
DL0;

3 DLTs de-escalate to DL-1 as DL0 is intolerable.
Rules for dose finding using the mTPI method include the following:

The target enrollment cohort size is 3-6 patients. 

The next cohort will be enrolled, if necessary, when at least 3 patients evaluable for 
DLT at the current dose cohort have been evaluated (each patient completes the initial 
2 cycles [ie, the 8-week DLT observation period] or experiences a DLT, whichever 
comes first). The next cohort will receive the DL as assigned by mTPI approach even 
if a dose modification is required at the current dose level.


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
If a patient does not receive the protocol-specified administrations of avelumab and 
the other immune modulator(s) (at least 75% of planned doses) within the DLT 
observation period (2 cycles = 8 weeks) for reasons other than study drug-related 
toxicity, another patient will be enrolled to replace that patient at the current dose 
level.
Phase 2 can be initiated if not more than 3 in 10 (Combination C) or 12 (Combinations B, 
and D) DLT-evaluable patients have experienced a DLT at the recommended Phase 2 dose 
level (see Section 9.2.2).
For Combinations B, C, and D once the MTD or MAD is identified in Phase 1b, Phase 2 will 
begin with enrollment into tumor type specific cohorts. 
3.2. Study Designs for Each Combination 
For the purpose of this study, a cycle is defined as the time from the Day 1 dose to the next 
Day 1 dose of avelumab.  The planned treatment cycle duration is 4 weeks (28 days). 
Each combination will be administered in cycles according to avelumab dosing.  The DLT 
observation period for evaluation of each dose level during Phase 1b (Combination A, B, C, 
and D) is the first 2 cycles (8 weeks) of treatment.  The DLT observation period during Phase 
1b of Combination F is the first treatment cycle (4 weeks). 
3.2.1. Combination A (Avelumab plus Utomilumab)
Combination A includes a Phase 1b lead-in part and a Phase 2 part.  During Phase 1b, up to 
18 NSCLC patients will be randomized 1:1:1 to 1 of 3 cohorts (6 patients each) to receive 
utomilumab at 500 mg (Cohort A1), 100 mg (Cohort A2), or 20 mg (Cohort A3) 
administered intravenously (IV) every 4 weeks (Q4W) in combination with 10 mg/kg of 
avelumab administered IV every 2 weeks (Q2W) for 2 cycles (ie, 8 weeks).  If a DLT is 
observed in at least 2 of 6 DLT-evaluable patients treated within a cohort, further evaluation 
of the cohort will be stopped (DLT definitions are provided in Section 3.3).  Patients treated 
in Phase 1b who are not considered DLT evaluable (as defined in Section 9.1) will be 
replaced for the assessment of the DLT rate in the cohort to which they were randomized.  
The study treatments to be evaluated in patients with NSCLC during Phase 1b are presented 
in Table 14.
Table 14.
Combination A (Avelumab Plus Utomilumab) Phase 1b Study Treatments –
NSCLC Only
Treatment Groupa
Utomilumab Dose
Avelumab Dose
A1
500 mg IV Q4W
10 mg/kg IV Q2W
A2
100 mg IV Q4W
10 mg/kg IV Q2W
A3
20 mg IV Q4W
10 mg/kg IV Q2W
a.
Parallel evaluation of utomilumab treatment groups in combination with avelumab.


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For each PF-05082566 dose level that is tolerated (ie, not meeting the DLT criteria) in the 
Phase 1b lead-in, the corresponding dose level cohort(s) will continue enrollment for 
Phase 2 with up to 22 additional patients each.  Therefore, all 3 cohorts could potentially 
enroll additional patients. 
Figure 15. Combination A Phase 1b and Phase 2 Study Design Schema - NSCLC Only 
(Cohorts A1, A2, A3)
In addition to potential expansion of enrollment of patients with NSCLC to
Cohorts A1, A2, or A3, Phase 2 will also enroll patients with melanoma (Cohort A4; N=28), 
SCCHN (Cohort A5; N=35), TNBC (Cohort A6; N=20), SCLC (Cohort A7; N=20), and 
first-line advanced NSCLC (Cohort A8; N=20, up to 26 patients will be enrolled to achieve a 
minimum of 20 PD-L1-positive patients (Figure 16).  Enrollment into Cohorts A7 and 
A8 may be staged based on activity observed during the Phase 1b portion of the combination 
(ie, new cohorts may be opened based on activity data emerging from the randomized dose 
level cohorts of Combination A). 
For Cohorts A4 through A8, the projected utomilumab dose to be used in each of these 
cohorts is 100 mg which may be modified based upon emerging safety data for 
utomilumab from randomized dose cohorts of Combination A.  In the event that the 
utomilumab dose is modified after the initiation of Cohorts A4 through A8, additional
patients will be enrolled to achieve the target number of patients treated at the modified dose.


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Figure 16. Combination A Phase 2 Study Design Schema - Melanoma (Cohort A4), 
SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort A7), and 
First-Line NSCLC (Cohort A8)
* Utomilumab dose = 100 mg (may be modified based on emerging data)
Sequenced (single agent administration for 1 cycle followed by combination therapy) 
administration of single agent avelumab or utomilumab for 1 cycle followed by 
administration of combination (avelumab plus utomilumab) will be evaluated in 2 additional 
cohorts.  Both cohorts will enroll 20 patients each with PD-L1 positive, 1L advanced 
NSCLC.  Cohort A9 will evaluate utomilumab single-agent administration, one month prior 
to initiation of combination treatment on Cycle 2 Day 1 (28 days after start of the 
single-agent treatment).  Cohort A10 will evaluate avelumab single-agent administration, one 
month prior to initiation of combination treatment on Cycle 2 Day 1 (28 days after start of 
the single-agent treatment).  Patients will be randomized 1:1 to Cohorts A9 and A10.  
Figure 17. Combination A Phase 2 Study Design Schema – Sequenced Administration 
in Patients with First-Line NSCLC (Cohort A9 and Cohort A10)
In Phase 2, efficacy and safety will be assessed separately for each cohort of 
utomilumab plus avelumab in the NSCLC Cohorts A1, A2, and A3, as well as for Cohorts 
A4 (melanoma), A5 (SCCHN), A6 (TNBC), A7 (SCLC), and A8-A10 (first-line NSCLC). 


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Additional details on the study design for Combination A are provided in Section 9.2.1 and 
the Statistical Analysis Plan (SAP). 
Originally, approximately 253 patients with solid tumors were planned to be enrolled in 
Combination A across all cohorts.  Enrollment of patients into Cohorts A1 to A6 and A8 
were completed as planned.  In Cohort A7, 10 SCLC patients were enrolled.  However, the 
level of clinical activity observed in Cohort A7 does not support further clinical development 
and further enrollment in this cohort is not planned.  In addition, due to recent improvements 
in the standard of care for 1L NSCLC patients, the level of clinical activity observed in 
Cohort A10 does not support further development.  Given that Cohort A9 and A10 use 1:1 
randomization for enrollment, further enrollment in Cohort A9 alone would not conform with 
the study design.  Therefore, further enrollment in Cohorts A7, A9, and A10 is not planned.
3.2.2. Combination B (Avelumab plus PF-04518600)
Combination B includes a Phase 1b dose-escalation part and Phase 2 part.  In the Phase 1b 
part for Combination B, patients with locally advanced or metastatic solid tumors as defined 
in Section 4.1 will be evaluated to identify the MTD or MAD of avelumab plus
PF-04518600 using the mTPI design described in Section 3.1.5.  Patients will receive 
PF-04518600 Q2W in combination with 10 mg/kg avelumab Q2W for 2 cycles (8 weeks).  
The study treatments to be evaluated during Phase 1b of Combination B are presented in 
Table 15. 
Table 15.
Combination B Phase 1b Study Treatments (Avelumab plus PF-04518600)
Treatment Groupa
PF-04518600 Dose
Avelumab Dose
B14
3 mg/ kg IV Q2W
10 mg/kg IV Q2W
B13
1 mg/kg IV Q2W
10 mg/kg IV Q2W
B12
0.3 mg/kg IV Q2W
10 mg/kg IV Q2W
B11
0.1 mg/kg IV Q2W
10 mg/kg IV Q2W
a.
Sequential evaluation of PF-04518600 doses starting with B12. 
The starting dose level (B12) for Combination B is 0.3 mg/kg PF-04518600 Q2W plus 
10 mg/kg avelumab Q2W.  Initially 3 patients will be enrolled, treated, and monitored during 
the 8-week DLT period.  If recommended by the mTPI design, the dose level can be 
a) expanded in cohorts of up to 3 patients and then up to an additional 6 patients, b) escalated 
to the next dose level, or c) de-escalated to a lower dose level.  A total of 12 patients will be 
treated at the RP2D.  If at any point the mTPI requires a de-escalation, the next 3 patients 
will be enrolled at the lower dose level according to Section 3.1.5.  Dose escalation will be 
allowed as long as the next highest dose level has not been determined to have exceeded the 
MTD. 
Following the 8-week DLT observation period, if no patients experience DLTs, the next
higher dose cohort may be initiated.  Initially 3 patients will be assigned to a new open dose 
level.  Up to 3 patients can be added at the same dose level if no DLTs are observed after 
4 weeks of observation.  After the first 3 patients enrolled in a dose escalation cohort have 


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completed the 8-week DLT period, additional cohorts of up to 6 patients each may be 
enrolled into any dose level that has been deemed safe (if recommended by the mTPI design) 
for a total of 12 patients to obtain additional safety and PD data.  See the subsection for all 
combination in Inclusion Criterion 1 (Section 4.1) for biopsy requirements.
Once the Phase 1b part is completed and the MTD or MAD is determined, the Phase 2 
portion of Combination B will be initiated.  During Phase 2, patients with NSCLC, 
melanoma, or SCCHN will be enrolled into 3 separate cohorts of 25 patients each to evaluate 
safety and efficacy at the RP2D determined during Phase 1b for those tumor types.  Each 
cohort will provide preliminary estimates for objective response rate (ORR) to help inform 
future trials.  The study design for Combination B is illustrated in Figure 18.
Figure 18. Combination B Phase 1b and Phase 2 Study Design Schema
Originally, approximately 105 patients were planned to be enrolled in Combination B.  
Enrollment in Phase 1 was completed and enrollment in the Phase 2 SCCHN cohort was also 
completed. The safety profile on this combination was acceptable and there was evidence of 
pharmacodynamic activity. However, the observed clinical activity does not support further 
development.  Therefore, the completion of patient enrollment into the Phase 2 NSCLC 
cohort and the initiation of enrollment into the Phase 2 melanoma cohort are not planned.  
3.2.3. Combination C (Avelumab plus PD 0360324)
Combination C includes a Phase 1b sequential dose-escalation lead-in part and Phase 2 part.  
In the Phase 1b lead-in part for Combination C, patients with locally advanced or metastatic 
solid tumors as defined in Section 4.1 will be evaluated to identify the MTD or MAD of 
avelumab plus PD 0360324 using the mTPI design described in Section 3.1.5.  Patients will 
receive PD 0360324 Q2W in combination with 10 mg/kg avelumab Q2W for 2 cycles
(8 weeks).  The study treatments to be evaluated the Phase 1b portion of Combination C are 
presented in Table 16. 


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Table 16.
Combination C Phase 1b Study Treatments (Avelumab Plus PD 0360324)
Treatment Groupa
PD 0360324 Dose
Avelumab Dose
C13
150 mg IV Q2W
10 mg/kg IV Q2W
C12
100 mg IV Q2W
10 mg/kg IV Q2W
C11
50 mg IV Q2W
10 mg/kg IV Q2W
a.
Sequential evaluation of PD 0360324 doses starting with C11.
If recommended by the mTPI design, a dose level may be a) expanded in cohorts of up to 
3 patients and then up to an additional 4 patients, b) escalated to the next dose level, or 
c) de-escalated to a lower dose level. 
The starting dose level (C11) of Combination C is 50 mg PD 0360324 Q2W plus 10 mg/kg 
avelumab Q2W.  Starting with dose level C11, 3 patients will be enrolled, treated, and 
monitored during the 8-week DLT period.  Fresh biopsies will not be required for the first 
3 patients enrolled in each dose level.  If at any point the mTPI requires a de-escalation, the 
next 3 patients will be enrolled at the lower dose level according to Section 3.1.5. Dose 
escalation will be allowed as long as the next highest dose level has not been determined to 
have exceeded the MTD. 
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is re-confirmed per mTPI design. 
During Phase 1b, if allowed by the mTPI design, a cohort may be expanded to approximately 
10 patients total to collect additional safety, clinical activity, and biomarker related data. 
Once the Phase 1b is completed and the MTD or MAD is determined, the Phase 2 portion of 
Combination C will be initiated to evaluate safety and efficacy at the RP2D determined 
during Phase 1b. Up to 2 tumor types among the following will be selected for evaluation: 
ovarian cancer, SCCHN, NSCLC, gastric cancer.  
The study design for Combination C is illustrated in Figure 19.


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Figure 19. Combination C Phase 1b and Phase 2 Study Design Schema
Originally, approximately 80 patients were planned to be enrolled in Combination C.  
However, the level of clinical activity observed in cohorts C11, C12, and C13, did not 
support development beyond Phase 1b.  Therefore, Phase 2 is not planned. 
3.2.4. Combination D (Avelumab plus Utomilumab plus PF-04518600)
Combination D includes a Phase 1b sequential dose escalation part and a Phase 2 part.  In the 
Phase 1b part for Combination D, patients with locally advanced or metastatic solid tumors 
as defined in Section 4.1 will be evaluated to identify the MTD or MAD of avelumab plus 
utomilumab plus PF-04518600 using the mTPI design described in Section 3.1.5.  Patients 
will receive utomilumab plus PF-04518600 in combination with avelumab Q2W for 2 cycles 
(8 weeks) and will be evaluated for DLT.  The study treatments to be evaluated during the 
Phase 1b portion of Combination D are presented in Table 17. 
Table 17.
Combination D (Utomilumab Plus PF-04518600 Plus Avelumab) Phase 1b 
Study Treatments
Treatment Group
Utomilumab Dose
PF-04518600 Dose
Avelumab Dose
D11a
20 mg IV Q4W
0.1 mg/kg IV Q2W
10 mg/kg IV Q2W
D21b
20 mg IV Q4W
0.3 mg/kg IV Q2W
10 mg/kg IV Q2W
D12b
50 mg IV Q4W
0.1 mg/kg IV Q2W
10 mg/kg IV Q2W
D22c
50 mg IV Q4W
0.3 mg/kg IV Q2W
10 mg/kg IV Q2W
D31d
20 mg IV Q4W
1.0 mg/kg IV Q2W
10 mg/kg IV Q2W
D32e
50 mg IV Q4W
1.0 mg/kg IV Q2W
10 mg/kg IV Q2W
a.
Sequential evaluation of utomilumab and PF-04518600 doses starting with D11.
b.
D21 and D12 to be evaluated in parallel if D11 is safe. 
c.
D22 to be evaluated only if D21 and D12 are safe.
d.
D31 can be evaluated if D21 is safe.
e.
D32 to be evaluated only if D22 and D31 are safe.
The starting dose level (D11) for Combination D is 20 mg utomilumab Q4W plus 0.1 mg/kg 
PF-04518600 Q2W plus 10 mg/kg avelumab Q2W.  The initiation of patient recruitment at 


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D11 is dependent upon the observation of no more than 1 DLT out of 6 patients treated in 
Phase 1b Combinations A and B at 500 mg utomilumab and 1 mg/kg PF-04518600, 
respectively.  As of 30 September 2016, this study has completed the Phase 1b part of 
Combination A with no DLTs observed and, for the Phase 1b part of Combination B, no 
DLTs have been observed at the starting dose level of 0.3 mg/kg PF-04518600 (B12) with 
evaluation of the 1 mg/kg PF-04158600 dose level ongoing.  Since no DLTs were observed 
during Phase 1b of Combination A, Combination D will be initiated once the safety of the 
1 mg/kg PF-04518600 dose level of Combination B is confirmed (eg, dose is acceptable per 
mTPI design following treatment of at least 6 patients treated at that dose or higher). 
If recommended by the mTPI design, a dose level can be a) expanded in cohorts of up to 
3 patients and then up to an additional 6 patients, b) escalated to the next dose level, or c) 
de-escalated to a lower dose level. 
Starting with dose level D11, 3 patients will be enrolled, treated, and monitored during the 
8-week DLT period.  Fresh biopsies will not be required for the first 3 patients enrolled in 
each dose level.  If at any point the mTPI requires de-escalation, the next 3 patients will be 
enrolled at the lower dose level according to Section 3.1.5.  Dose escalation will be allowed 
as the dose level satisfies the mTPI criteria.
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is re-confirmed per mTPI design.
During Phase 1b, if allowed by the mTPI design, a cohort maybe expanded to approximately 
12 patients total to collect additional safety, clinical activity, and biomarker related data. 
Once the Phase 1b lead-in is completed and the MTD or MAD is determined, the 
Phase 2 portion of Combination D may be initiated to evaluate the safety and efficacy at the 
RP2D (one or more dose levels) determined during Phase 1b, if the safety and clinical 
activity are supportive of further development.  Up to 2 tumor types among the following 
may be selected for evaluation: NSCLC, melanoma, SCCHN, or bladder cancer.  
The study design for Combination D is illustrated in Figure 20.


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Figure 20. Combination D Phase 1b and Phase 2 Study Design Schema*
* A solid arrow to a dose level implies that only the dose level from which the arrow is originating needs to be 
safe (escalate per mTPI design) for that dose level to be opened.  For example, D21 can be opened if D11 is safe 
and D31 can be opened if D21 is safe.  A dashed arrow to a dose level implies that more than 1 dose level is 
required to be safe (escalate per mTPI design for more than 1 dose level) for that dose level to be opened.  For 
example, D12 and D21 both need to be safe (escalate per mTPI design for both) for D22 to be opened, and 
D31 and D22 both need to be safe for D32 to be opened.  Cohorts D12 and D21 and Cohorts D22 and D31 may 
be opened and enroll patients in parallel since only either utomilumab or PF-04518600 is escalated at a time. 
Originally, approximately 122 patients were planned to be enrolled in Combination D.  
However, the level of clinical activity observed in cohorts D11 to D32, did not support 
development beyond Phase 1b.  Therefore, Phase 2 is not planned. Overall 71 patients were 
enrolled for Combination D treatment.
3.2.5. Combination F (Avelumab plus CMP-001 and Utomilumab or PF-04518600) 
Combination F includes a Phase 1b safety lead-in part and a Phase 2 part.  Eligible patients 
will have recurrent or metastatic SCCHN, will have been previously treated with an 
anti-PD-1 or anti-PD-L1 containing therapy, and will have experienced disease progression 
prior to study entry (see Inclusion Criteria in Section 4.1).  
In the Phase 1b safety lead-in part, patients will initially be randomized 1:1:1 into each of 
Cohorts F1, F2, and F3.  Six DLT evaluable patients are needed to assess safety in each 
cohort.  Patients who are not evaluable for DLTs, might be replaced by enrolling patients
without randomization.
Up to 12 patients will be randomized into each cohort in the Phase 1b safety lead-in part and 
evaluated for DLT during the first treatment cycle (4 weeks) as follows:

If 1 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
14 additional patients in the Phase 2 cohort expansion;


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
If 2 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
6 additional DLT-evaluable patients in the Phase 1b lead-in part of the study:

If 3 of 12 patients experience DLT, the cohort will be expanded to enroll up to 
8 additional patients in the Phase 2 cohort expansion;

If 4 of up to 12 patients experience DLT, enrollment in the specific cohort will 
be discontinued. 

If 3 of up to 6 patients experience DLT, enrollment in the specific cohort will be 
discontinued.
If one cohort is discontinued, patients will be randomized to the remaining cohorts in a 1:1 
ratio. Therefore, the total number of possible enrolled patients per cohort may be 
approximately 20 patients for cohorts that do not meet the stopping criteria and the total 
number of patients enrolled for this combination may be approximately 60 patients. 
In addition to the rules for the continuation of a cohort based on DLTs, the Sponsor will 
monitor DLTs across the cohorts and may elect to pause or discontinue patient enrollment at 
any time based on emerging safety and efficacy data from the current study or other studies 
with CMP-001.
The following 3 cohorts will be evaluated (see Figure 21):

Cohort F1: avelumab plus CMP-001;

Cohort F2: avelumab plus CMP-001 and utomilumab;

Cohort F3: avelumab plus CMP-001 and PF-04518600.
Figure 21. Combination F Phase 1b and Phase 2 Study Design Schema
The dose levels of the study treatments to be evaluated during the Combination F are 
presented in Table 18. 


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Table 18.
Combination F (Avelumab Plus CMP-001 Plus Utomilumab or 
PF-04518600) Study Treatments
Cohort
CMP-001 
(SC and IT)a
Utomilumab Dose
PF-04518600 Dose 
(IV)
Avelumab Dose 
(IV)
F1
10 mg
NA
NA
10 mg/kg Q2W
F2
10 mg
100 mg Q4W
NA
10 mg/kg Q2W
F3
10 mg
NA
0.3 mg/kg Q2W
10 mg/kg Q2W
IV=intravenous; SC=subcutaneous; NA = not applicable; IT= intratumoral. 
a.
CMP-001 will be administered initially as 2 weekly SC doses, followed by IT dosing at weekly intervals 
for 5 additional doses (Q2W) (all cohorts).  From C2D1, if IT administration is no longer feasible, then 
CMP-001 should be administered in peritumoral region. If peritumoral administration is not feasible, then SC 
administration in an area of the draining lymph node where primary disease exists should be implemented.  If 
any of the above is not feasible, then SC (either arm, thigh or anterior abdominal wall) administration should be 
implemented (see Section 5.3.5 and guidance in Appendix 4). 
3.3. Dose-Limiting Toxicity Definition
Severity of AEs will be graded according to CTCAE v.4.03.  For the purpose of the 
Phase 1b lead-in, any of the following AEs occurring during the DLT observation period (the 
first 2 cycles of treatment [8 weeks] for combinations A to D, and the first treatment cycle 
[4 weeks] for combination F) which are attributable to one or more of the investigational 
products in the combination 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 ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (>101 degrees F) or a sustained temperature of 38 degrees C 
(100.4 degrees F) for more than 1 hour; 

Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection);

Grade 3 thrombocytopenia (platelet count <50,000 - 25,000/mm3 or <50.0 – 25.0 x 
109/L) with bleeding;

Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L);

Grade 4 anemia.
Non-Hematologic (Non-Laboratory):

Any Grade 3 toxicity, except for any of the following:

Transient (24 hours) Grade 3 fatigue, local reactions, or headache that resolves 
to Grade 1;


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
Grade 3-4 nausea and vomiting controlled by optimal medical therapy within 
72 hours;

Grade 3 hypertension controlled by medical therapy;

Grade 3 diarrhea that improves to Grade 2 within 72 hrs after medical 
management has been initiated; 

Grade 3 skin toxicity that resolves to Grade 1 in less than 7 days after medical 
management (eg, immunosuppressant treatment) has been initiated;

Any Grade 3 amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis;

Grade 3 endocrinopathies controlled with medical therapy;

Tumors flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor.

Grade 4 CRS or Grade 3 CRS lasting >24 hours despite optimal treatment.
Important for Combination F: CMP-001 activates pDCs through agonism of TLR9.  Upon 
activation by CMP-001, pDCs will induce large amounts of IFNα and Th1-promoting 
cytokines.  Therefore, it is expected that toxicities associated with CMP-001 dosing may 
resemble interferon-related toxicities and symptoms associated with cytokine release, such as 
fever, flu-like symptoms, tachypnea, headache, tachycardia, hypotension, rash, and hypoxia 
which may present hours after CMP-001 injection.  Therefore, AEs such as headache, fever, 
flu-like symptoms and/or hypotension that are ≤Grade 3 AND resolved to ≤Grade 1 within 
24 hours with standard supportive care will not be considered as DLTs.  

Non-hematologic Grade 3 laboratory abnormality if medical intervention is required 
to treat the patient or the abnormality leads to hospitalization. 

Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the Investigator, do not have any clinical correlate, and 
resolve to Grade 1 within 7 days with adequate medical management are not to 
be considered DLTs;

ALT or AST >3 x upper limit of normal (ULN) (if normal at baseline) or >3 x 
ULN and doubling the baseline (if > ULN at baseline) associated with bilirubin 
>2 x ULN. 
Non-Adherence to Treatment Schedule:

Delay of ≥3 weeks in receiving the next scheduled administration due to persisting 
treatment-related toxicities;


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
Failure to receive at least 75% of the planned doses each of the investigational 
products during the DLT observation period due to treatment-related toxicities.
In the absence of associated clinical abnormalities, abnormal laboratory tests should be 
repeated to confirm relevance. 
While the rules for adjudicating DLTs in the context of the dose determination phase 
(Phase 1b) are specified above, an AE not listed above, or an AE meeting the DLT criteria 
above but occurring outside of the DLT observation period may be defined as a DLT after 
consultation between Sponsor and Investigator, based on the emerging safety profile.
3.4. Maximum Tolerated Dose Definitions
The MTD estimate is the highest dose level of an immune modulator being tested in 
combination with 10 mg/kg of avelumab associated with a DLT rate of <33% among the 
patients treated at that dose level provided that a higher dose level of the immune 
modulator in combination with 10 mg/kg of avelumab was tested and had an associated DLT 
rate 33%. 
For Combinations B and C, there can be only 1 MTD.  For Combination D, there can be 
1 (eg, D32) or 2 (eg, D31 and D22) MTDs.
3.5. Maximum Administered Dose Definitions
The MAD is the highest dose of the other immune modulator administered in combination 
with 10 mg/kg avelumab.
3.6. Recommended Phase 2 Dose Definition
The RP2D or doses 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, and PK/PD relationships observed at doses 
lower than the MTD or MAD will also be factors considered when choosing 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 non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
Eligibility criteria specific to each unique combination of avelumab and the other immune 
modulator(s) are highlighted. 
Study entry is defined as randomization date for randomized cohorts and first dose date for 
non-randomized cohorts. 


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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histological or cytological diagnosis of advanced/metastatic solid tumor as follows

For all combinations: 

Measurable disease by RECIST v1.1 with at least 1 measurable lesion that 
has not previously been irradiated.

Availability of tumor specimens: For Phase 1b: Archival formalin-fixed 
paraffin-embedded (FFPE) tissue is required if available for the first 
3 patients enrolled in a cohort, including replacement patients.  For additional 
patients enrolled in each Phase 1b cohort and Phase 2, FFPE tissue must be 
available from the most recent primary or metastatic tumor biopsy or 
resection prior to start of study therapy, taken within 1 year prior to study 
entry, with no intervening systemic anti-cancer therapy.  This tissue may be 
prepared from a de novo biopsy obtained prior to study entry.  Core needle or 
excision biopsies are preferred.

The following baseline data should be available for each respective tumor 
type: human papilloma virus (HPV) status based on locally approved testing 
for patients with SCCHN, EGFR, ALK and ROS-1 status for non-squamous 
NSCLC and PD-L1 status based on locally approved testing for first-line 
NSCLC patients.

Unless specified, the prior therapy requirements apply to anti-cancer drug 
treatment in advanced stage/metastatic disease.  If patient relapses within 
1 year of adjuvant/neoadjuvant treatment, the respective therapy must be 
counted as treatment in advanced disease/metastatic setting.

Combination A:

Phase 1b: NSCLC that has progressed on standard therapy or for which no 
standard therapy is available.


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
Phase 2: 

Cohorts A1 – A5: NSCLC, melanoma, or SCCHN in any line of therapy; 
NSCLC patients with tumor anaplastic lymphoma kinase (ALK) 
translocations or epidermal growth factor receptor (EGFR) mutations must 
have received, or been refractory/intolerant to standard therapy. 

Cohort A6: TNBC that has progressed after 1 line of therapy or is 
ineligible for/intolerant to SOC; or

Cohort A7: SCLC that has progressed after up to 1 line of prior therapy in 
advanced metastatic setting or is ineligible for/intolerant to standard of 
care (SOC).  No prior PD-1/PD-L1 therapy allowed.

Cohorts A8, A9, and A10: 

NSCLC first-line Stage IV (per 7th International Association for the 
Study of Lung Cancer [IASLC] classification) or recurrent NSCLC 
that is histologically proven and is demonstrated to express PD-L1 
(Tumor Proportion Score [TPS] ≥1%) as determined by a 
bioanalytically validated test (eg. Dako 22C3 or Ventana SP263).   
Patients must not have received treatment for their metastatic or 
recurrent disease.  Neither activating EGFR mutation nor ALK or 
ROS1 translocation/rearrangement are permitted (non-squamous cell 
histologies require testing if status is unknown). 
Patients could have received adjuvant chemotherapy or locoregional 
treatment that included chemotherapy for locally advanced disease as 
long as disease treatment occurred at least 6 months prior to study 
entry.  No prior PD-1/PD-L1 therapy allowed.

Combination B: 

Phase 1b: 

NSCLC, melanoma, or SCCHN that has progressed after at least 1 line of 
standard therapy or is ineligible for/intolerant to SOC; No prior PD-1/
PD-L1 therapy allowed.


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
Phase 2: 

NSCLC: Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed.  No prior PD-1/PD-L1 therapy allowed. Neither 
activating EGFR mutation nor ALK or ROS1 translocation/rearrangement 
are permitted (non-squamous cell histologies require testing if status is 
unknown).  

Cutaneous or mucosal metastatic melanoma: Up to 2 lines of prior therapy 
in advanced/metastatic disease settings allowed.  No prior PD-1/PD-L1 
therapy allowed. 

SCCHN: Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed.  No prior PD-1/PD-L1 therapy allowed.

Combination C: 

Phase 1b:

NSCLC: Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed.  No prior PD-1/PD-L1 therapy allowed.  Neither 
activating EGFR mutation nor ALK or ROS1 translocation/rearrangement 
are permitted (non-squamous cell histologies require testing if status is 
unknown).  

SCCHN:  Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed.  No prior PD-1/PD-L1 therapy allowed.

Gastric cancer that has progressed after at least 1 line or is ineligible 
for/intolerant to SOC and not more than 2 lines of standard therapy in 
advanced/metastatic disease settings or is ineligible for/intolerant to SOC.  
No prior PD-1/PD-L1 therapy allowed.

Platinum resistant ovarian cancer that has not received more than 2 lines 
of standard therapy in the platinum resistant setting or is ineligible 
for/intolerant to SOC.  No prior PD-1/PD-L1 therapy allowed.  Platinum 
resistant is defined as progression of disease within 6 months of last dose 
of platinum based treatment.

Progressing Tenosynovial giant cell tumor/pigmented villonodular 
synovitis (TGCT/PVNS) that is either inoperable or requires extensive 
surgery for resection, as determined by a qualified surgeon or 
multi-disciplinary tumor board.  Prior treatment with agents targeting 
CSF-1 or CSF-1R is not allowed.


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
Phase 2: Up to 2 of the tumor types included in Phase 1b will be selected and 
communicated to the sites by protocol administrative change letter.

Combination D: 

Phase 1b: 

NSCLC: Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed.  No prior PD-1/PD-L1 therapy allowed. Neither 
activating EGFR mutation nor ALK or ROS1 translocation/rearrangement 
are permitted (non-squamous cell histologies require testing if status is 
unknown).   

Cutaneous or mucosal metastatic melanoma: Up to 2 lines of prior therapy 
in advanced/metastatic disease settings allowed.  No prior PD-1/PD-L1 
therapy allowed.

SCCHN: Up to 2 lines of prior therapy in advanced/metastatic disease 
settings allowed. No prior PD-1/PD-L1 therapy allowed.

Bladder cancer (transitional cell carcinoma of the urothelium): Up to 
2 lines of prior therapy in advanced/metastatic disease settings allowed.  
No prior PD-1/PD-L1 therapy allowed.  Other urothelial transitional cell 
tumor types may be considered upon consultation with the Sponsor.

Phase 2: Up to 2 of the tumor types included in Phase 1b will be selected and 
communicated to the sites by protocol administrative change letter.

Combination F:

Recurrent or metastatic SCCHN.

One to three prior lines of systemic therapy for advanced (can be locally 
recurrent not amenable to local treatment) or metastatic disease.

Patients must have received anti-PD-1/PD-L1-containing therapy (requires at 
least two doses of PD-1/PD-L1 agent). Disease progression no earlier than 
6 weeks from the initiation of the latest anticancer therapy.  Study entry 
requires evidence of radiographic progression.

Patient must be a candidate for intralesional administration with at least one 
tumor lesion which can be injected safely. The criteria for lesion selection 
are described in Appendix 4.


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
Patient must not have received previous OX-40 agonists or 4-1BB agonists 
or IT anticancer treatment including, talimogene laherparepvec, other 
oncolytic virus therapies, or other TLR agonists. 
2. Age 18 years (20 years where applicable according to local regulation). 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
4. Estimated life expectancy of at least 3 months. 
5. Adequate bone marrow function, defined as:
a.
ANC 1.5 x 109/L (1,500/L);
b. Platelets 100 x 109/L (100,000/L); 
c.
Hemoglobin 9 g/dL (>5.6 mmol/L).
Patients must be transfusion independent (ie, no blood product transfusions for a 
period of at least 14 days prior to study entry).
6. Adequate renal function, including estimated creatinine clearance 50 mL/min 
(Phase 1b) or 30 mL/min (Phase 2) as calculated using the Cockcroft-Gault (CG) 
equation. 
7. Adequate liver function, including:
a.
Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert
syndrome;
b. AST and ALT 2.5 x ULN.
8. Resolved acute effects of any prior therapy to baseline severity or NCI CTCAE 
v.4.03 Grade 1 (except alopecia and Grade 2 sensory neuropathy are acceptable).
9. Negative serum/urine pregnancy test (for females of childbearing potential) at 
screening.
10. Sexually active male patients able to father children and female patients of 
childbearing potential and at risk for pregnancy must agree to use at least one highly 
effective method of contraception as detailed in Section 4.3, throughout the study and 
for at least 90 days after the last dose of assigned treatment or longer as required by 
local regulations. 


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Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range 
for postmenopausal women. 
11. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
12. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study: 
1. Monoclonal antibody based anti-cancer therapy within 28 days prior to study entry or 
small-molecule based anti-cancer therapy (targeted therapy or chemotherapy) within 
14 days prior to study entry.  For Combination F: PD-1/PD-L1 agents within 14 days 
prior to study entry.
2. Current use of immunosuppressive medication at time of study entry.  The following 
are exceptions to this exclusion criterion: intranasal, inhaled, topical steroids, or local 
steroid injections (eg, intra-articular injection); systemic corticosteroids at
physiologic doses not to exceed 10 mg/day of prednisone or equivalent; steroids as 
premedication for hypersensitivity reactions (eg, CT scan premedication). 
3. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Exceptions include: patients with controlled diabetes type 
1, controlled hypo- or hyperthyroidism, resolved childhood asthma/atopy, vitiligo, or 
psoriasis not requiring immunosuppressive treatment.
4. Known prior or suspected hypersensitivity to investigational products or any 
component in their formulations, including known severe hypersensitivity reactions to 
mAbs (NCI CTCAE v.4.03 Grade 3).


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5. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry.  
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been 
completed at least 48 hours prior to study entry and there is at least 1 measurable 
lesion that has not been irradiated. Patients must have recovered from any of the 
acute adverse effects of radiation.
6. Patients with known symptomatic brain metastases requiring steroids.  Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery
prior to study entry, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks prior to study entry, and are neurologically stable.
7. Previous high-dose chemotherapy requiring stem cell rescue. 
8. Prior allogeneic stem cell transplant or organ graft. 
9. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months 
prior to enrollment), unstable angina, congestive heart failure (New York Heart
Association Class II), or serious cardiac arrhythmia requiring medication.
10. Symptomatic pulmonary embolism within 6 months prior to study entry.
11. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) related illness.
12. Combination C only: Existing periorbital edema.
13. Combination C only: Hypocalcemia (serum albumin adjusted calcium <7.5 mg/dL), 
clinically significant bone disease that may affect safe study participation at the 
discretion of the investigator, or recent bone fracture (within 12 weeks prior to study 
entry). 
14. Active infection requiring systemic therapy.
15. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening tests positive).
16. Vaccination within 4 weeks of the first dose of investigational product and while on 
trial is prohibited except for administration of inactivated vaccines (for example,
inactivated influenza vaccines).
17. Diagnosis of any other malignancy within 2 years prior to study entry, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix, or low-grade (Gleason 6) prostate cancer on surveillance 
with no plans for treatment intervention (eg, surgery, radiation or castration).


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18. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
19. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry and/or during study participation. 
20. Persisting toxicity related to prior therapy NCI CTCAE v.4.03 Grade >1 (alopecia 
and Grade 2 sensory neuropathy, or other Grade 2 AEs not constituting a safety 
risk based on Investigator judgment are acceptable); previous Grade 3 irAE within 
3 months prior to study entry; or unresolved irAEs prior to study entry. 
21. Other severe acute or chronic medical conditions, psychiatric conditions 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 products 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.
22. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant; male patients able to father children and female patients of 
childbearing potential who are unwilling or unable to use at least 1 highly effective 
method of contraception, as outlined in this protocol for the duration of the study and 
for at least 90 days after the last dose of investigational product or longer as required 
by local regulations. 
4.3. Lifestyle Guidelines
Patients enrolled in this study will receive avelumab in combination with other
investigational products (ie, utomilumab, PF-04518600, PD 0360324, or CMP-001) for 
which the teratogenic risk is currently unknown.  Male patients who are able to father 
children and female patients who are of childbearing potential, if sexually active and at risk 
for pregnancy with their partner(s), will need to affirm that they meet the criteria for correct 
use of the selected method of contraception throughout the study and continue for at least 
90 days after the last dose or longer as required by local regulations.  The investigator or his 
or her designee, in consultation with the patient, will select an appropriate method of 
contraception for the individual patient and his/her partner from the list of permitted 
contraception methods (see below) and instruct the patient in its consistent and correct use.  
Patients need to affirm that they meet the criteria for correct use of the selected method of 
contraception.  The investigator or his or her designee will discuss with the patient the need 
to use at least 1 highly effective contraception method, preferably with low user dependency 
consistently and correctly according to the Schedule of Activities and document such 
conversation in the patient’s chart.  In addition, the investigator or his or her designee will 
instruct the patient to call immediately if selected contraception method is discontinued or if 
pregnancy is known or suspected in the patient or the patient’s partner. 


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Highly Effective Methods That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days.
Highly Effective Methods That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.

Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.

Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.


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1. Female patients of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum FSH level within
the laboratory’s reference range for postmenopausal women.
All other female patients (including females with tubal ligations) will be 
considered to be of childbearing potential.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33). This is a study of 
avelumab in combination with other immune modulators.  The investigational products to be 
evaluated in this study are described in Table 19.


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Table 19.
Study B9991004 Investigational Products
Investigational Product
Dose(s)
Regimen
Combination(s)
Avelumab
10 mg/kg
1-hr IV Q2W
All 
Utomilumab (4-1BB agonist mAb)
20, 100, 500 mg 
1-hr IV Q4W
A
20, 50 mg
1-hr IV Q4W
D
100 mg
1-hr IV Q4W
F
PF-04518600 (OX40 agonist mAb)
0.1, 0.3, 1, 3 mg/kg
1-hr IV Q2W
B
0.1, 0.3, 1 mg/kg
1-hr IV Q2W
D
0.3 mg/kg
1-hr IV Q2W
F
PD 0360324 (M-CSF mAb)
50, 100, 150 mg 
30-min IV Q2W
C
CMP-001
10 mg
SC/IT
F
IT = intratumoral; mAb = monoclonal antibody; M-CSF = macrophage colony stimulating factor; SC = subcutaneous.
5.1. Allocation to Treatment
Each combination will be evaluated in 2 study parts, Phase 1b and Phase 2.  During Phase 1b 
and Phase 2 for all combinations, allocation of patients to specific dose levels or cohorts will 
be performed by an interactive response technology (IRT) system after patients have given 
their written informed consent and have completed the necessary baseline assessments. 
The IRT system will also be used to assign a patient identification number, which will be
used on all Case Report Form (CRF) pages and other study-related documentation or 
correspondence referencing that patient. 
No patient shall receive study treatments 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 cohort for that patient, and

Permission to proceed with dosing the patient.
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will
inform study sites about the next possible enrollment date. 
Study treatment in randomized cohorts must be initiated preferably on the day of 
randomization, but no later than 7 days after randomization.   


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5.2. Patient Compliance
5.2.1. Parenterally Administered Investigational Products
For avelumab, utomilumab, PF-04518600, PD 0360324, and CMP-001, the site will 
complete required dosage Preparation Record located in the Investigational Product Manual.  
The use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent /required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor. 
5.3. Investigational Product Supplies
5.3.1. Avelumab (MSB0010718C)
Avelumab (MSB0010718C) will be supplied for the study by Pfizer Global Clinical Supply, 
Worldwide Research and Development.  Drug supplies will be shipped to the study sites with 
a Drug Shipment and Proof of Receipt form.  This form will be completed, filed, and the 
shipment confirmed as directed on the bottom of the Drug Shipment and Proof of Receipt 
form.  The Investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and usage 
of investigational products in accordance with the protocol and any applicable laws and 
regulations.
5.3.2. Other Immune Modulators 
PF-05092566, PF-04518600, PD 0360324 and CMP-001 investigational products and 
CMP-001 diluent will be supplied for the study by Pfizer Global Clinical Supply, Worldwide 
Research and Development.  See details above for avelumab (Section 5.3.1).
5.3.3. Formulation/Dosage Forms and Packaging
5.3.3.1. Avelumab (MSB0010718C)
Avelumab (MSB0010718C) is a sterile, clear, and colorless solution intended for IV 
administration.  It is presented with a nominal volume of 10 mL at a concentration of 
20 mg/mL in single-use glass vials closed with a rubber stopper and sealed with an aluminum
polypropylene flip off seal.  The vial is intended for single use only. 
Avelumab will be shipped under refrigerated conditions (2C to 8C) that are monitored with 
temperature control monitoring devices.
5.3.3.2. Other Investigational Products
5.3.3.2.1. Utomilumab (Combinations A, D and F)
Utomilumab is a sterile, colorless solution intended for IV administration.  It is presented at a 
concentration of 10 mg/mL with a nominal volume of 10 mL in glass vials closed with a 
rubber stopper and sealed with an aluminum overseal.  The vial is intended for single use 
only. 


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Utomilumab will be shipped under refrigerated conditions (2C to 8C) that are monitored 
with temperature control monitoring devices.
5.3.3.2.2. PF-04518600 (Combinations B, D and F)
PF-04518600 10 mg/mL injection is presented as a sterile solution for IV administration.  
Each vial has a nominal volume of 10 mL, is sealed with a coated stopper and an overseal, 
and labeled according to local regulatory requirements.  The vial is intended for single use 
only.
PF-04518600 will be shipped under refrigerated conditions (2C to 8C) that are monitored 
with temperature control monitoring devices.
5.3.3.2.3. PD 0360324 Combination C
PD 0360324 is provided 75 mg/vial as a powder for solution for injection for IV 
administration.  The drug product is supplied in a clear glass vial with an appropriate stopper 
and an aluminum overseal.  The formulation consists of the active drug substance containing 
the precedented excipients.  The vial is intended for single use only.
PD 0360324 will be shipped under refrigerated conditions (2C to 8C) that are monitored 
with temperature monitoring devices.
5.3.3.2.4. CMP-001 Combination F
The CMP-001 drug product will be supplied at a concentration of 5 mg/mL.  CMP-001 is a 
colorless to pale yellow/brown opalescent liquid.  Each single-use vial contains an 
extractable volume of 1 mL (with an overfill of 0.1 mL).  Please refer to the Pharmacy 
Manual for dose preparation. CMP-001 will be shipped under refrigerated conditions (2C to 
8C) that will be monitored with temperature monitoring devices.
5.3.3.2.5. CMP-001 Diluent
The CMP-001 diluent product will also be supplied by Pfizer Inc. CMP-001 diluent is a 
colorless to pale yellow/brown opalescent liquid. Each single-use vial contains an 
extractable volume of 10 mL. Please refer to the dosage and administration (DAI) section of 
the Investigational Product (IP) manual for dose preparation. CMP-001 diluent will be 
shipped under refrigerated conditions (2C to 8C) that are monitored with temperature 
monitoring devices.
5.3.4. Preparation and Dispensing
Investigational products must not be used for any purpose other than the trial.  
5.3.4.1. Parenterally Administered Investigational Products
For avelumab, utomilumab, PF-04518600, PD 0360324, and CMP-001, please see the dosage
and administration instructions (DAI) section of the Investigational Product (IP) Manual for 
instructions on how to prepare the investigational products for administration.  The IV 
investigational products should be prepared and dispensed by an appropriately qualified and 


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experienced member of the study staff (eg, physician, nurse, physician’s assistant, 
practitioner, pharmacist, or medical assistant) as allowed by local, state, and institutional 
guidance. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
hazardous agents.
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
Detailed information on infusion bags and medical devices to be used for the preparation of 
the dilutions and subsequent administration(s) for each investigational product will be 
provided in the DAI section of the IP Manual. 
5.3.5. Administration
5.3.5.1. Parenterally Administered Investigational Products
Avelumab, utomilumab, PF-04518600, and PD 0360324 investigational products will be 
administered IV at the investigational site on an outpatient basis.  After Cycle 1, IV 
investigational products may be administered up to 2 days before or after the scheduled 
treatment day of each cycle for administrative reasons.  However, if the IV administration is 
given 2 days before or after the scheduled treatment day, and multiple IV investigational 
products are to be administered, all scheduled IV investigational products should be given on 
the same day.  Patients will be observed in the clinic for at least 2 hours after the last infusion
of investigational product.  If, following the 4th infusion of avelumab, no infusion reaction is 
observed, the post-infusion observation period may be discontinued thereafter.
Avelumab (all combinations) will be administered at 10 mg/kg as a 1-hour IV infusion Q2W 
on Day 1 and Day 15 of each cycle.  Note: for all patients except those in Cohort A9, 
avelumab administration will start on Cycle 1 Day 1.  For patients randomized to Cohort A9, 
avelumab administration will begin on Cycle 2 Day 1.  
Utomilumab (Combination A, Combination D and Combination F) will be administered as a 
1-hour IV infusion Q4W on Day 1 of each cycle.  Note: for all patients except those in
Cohort A10, utomilumab administration will start on Cycle 1 Day 1. For patients 
randomized to Cohort A10, utomilumab administration will begin on Cycle 2 Day 1.  
PF-04518600 (Combination B, Combination D and Combination F) will be administered as a 
1-hour IV infusion, Q2W on Day 1 and Day 15 of each cycle. 
PD 0360324 (Combination C) will be administered as a 30-minute IV infusion Q2W on 
Day 1 and Day 15 of each cycle.


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Avelumab, utomilumab, and PF-04518600 are to be administered as a 1-hour IV infusions; 
PD 0360324 is to be administered as a 30-minute IV infusion.  Sites should make every 
effort to target infusion timing to be as close to the duration specified for the investigational 
product as possible.  However, the 1–hour infusion(s) administered over 50-80 minutes will 
be considered protocol compliant.  The accepted window for a 30 min infusion is 
10 minutes.  The exact duration of infusion should be recorded in both source documents 
and CRFs.  Dose reduction for toxicity management for any of the investigational products is 
not permitted, however next cycle administration may be omitted due to persisting toxicity as 
described in Table 21 and Section 5.3.7.2.
The dose amount required to prepare the dose for weight-based infusion solutions 
(ie, avelumab and PF-04518600) will be based on the patient’s weight in kilograms (kg).  All 
patients should be weighed within 3 days prior to dosing for every cycle.  If the patient 
experienced either a weight loss or gain >10% compared to the weight used to calculate the 
prior dose, the amount of investigational product required for preparation and administration 
for the current cycle must be recalculated using this most recent weight obtained.  If weight 
change is 10% compared to the weight used to calculate the prior dose, dose recalculation is 
optional and the site should follow their standard practice.
CMP-001 will be administered initially as 2 weekly SC doses followed by IT dosing at 
weekly intervals for 5 additional doses. After the first 7 doses, CMP-001 will be 
administered IT every 2 weeks (Q2W) (all cohorts). From C2D1, if IT administration is not 
feasible then CMP-001 should be administered in the peritumoral region. If peritumoral 
administration is not feasible, then SC administration in an area of the draining lymph node 
where primary disease exists should be implemented.  If any of the above is not feasible, then 
SC (either arm, thigh, or anterior abdominal wall) administration should be implemented.  
CMP-001 administration and requirements are summarized in Table 20.
Table 20.
CMP-001 Administration and Requirements
Visit/Dose
CMP-001 Administrationa
Premedications
Post injection 
Observation Period
C1D1 and C1D8
SC (either arm, 
thigh or 
anterior 
abdominal 
wall)
Weekly
Mandated
Required (4 hrs)
C1D15, C1D22, 
C2D1, C2D8
ITb
Weekly
Mandated
Required (4 hrs)
C2D15 onwards
ITb
Every 2 weeks
Recommended
Required (can be reduced 
up to 1 hr based on 
reactions to prior 
injections and clinical 
judgement).
C=cycle; D=day; hr=hour; IT=intratumoral; SC=subcutaneous.
a. CMP-001 will be administered initially as 2 weekly SC doses, followed by IT dosing at weekly intervals for 5
additional doses.  After the first 7 doses, CMP-001 will be administered IT every 2 weeks (Q2W) (all cohorts).
b. From C2D1, if IT is not feasible then CMP-001 should be administered in peritumoral region. If peritumoral 
administration is not feasible, then SC administration in an area of the draining lymph node where primary 
disease exists should be implemented.  If any of the above is not feasible, then SC (either arm, thigh or anterior 
abdominal wall) should be implemented.


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Detailed instructions for CMP-001 administration, including tumor lesion selection and dose 
splitting, are provided in Appendix 4 and in the Injection Manual. 
5.3.5.2. Timing of Investigational Product Administration
For Combinations A, B, and C, the avelumab infusion is to be administered at least 
30 minutes (+20-minute time window, if needed) after the end of the infusion of the other 
investigational product. 
For Combination D, on days when three investigational products are to be administered, 
utomilumab will be administered first, followed at least 30 minutes (+20-minute time 
window, if needed) later by the PF-04518600 infusion (second), followed at least 30 minutes 
(+20-minute time window, if needed) later by the avelumab infusion (third).  On days when 
only avelumab and PF-04518600 are administered, PF-04518600 will be administered first 
followed by the avelumab infusion at least 30 minutes (+20-minute time window, if needed) 
after the end of the PF-04518600 infusion.
For Combination F, on days when two investigational products are to be administered 
(CMP-001 and avelumab), avelumab will be administered first followed by CMP-001.  On 
days when three investigational products are to be administered, either utomilumab (Cohort 
F2) or PF-04518600 (Cohort F3) will be administered first, followed by avelumab and then 
followed by CMP-001.  A 30 to 50 minute window is recommended between administration 
of the individual drugs to conduct end of infusion/injection procedures (eg, sample 
collections) and accommodate any logistical arrangements (eg, drug preparation, moving 
patient from one location to another for treatment administration etc.).  The drug 
administration visits can be spread over two consecutive days eg, avelumab alone or 
avelumab and utomilumab or avelumab and PF-04518600 to be administered on 1 day (eg, 
C1D1) and CMP-001 to be administered on the next day (eg, C1D2).
For Combination F, during the Phase 2 part of the study, the order of drug administration can 
be changed for individual patients to address any logistical issues to accommodate IT 
injections. Such changes should be discussed with the medical monitor of the study before 
implementation.
On days when PK samples are taken, samples will be taken relative to dosing as described in 
the Schedule of Activity tables.  
Premedication for avelumab in Combinations A, B, C, D, and F:
Avelumab premedication: in order to mitigate infusion-related reactions, patients must be 
premedicated with an antihistamine and with paracetamol (acetaminophen) prior to the first 
four infusions of avelumab.  Premedication should be administered for subsequent avelumab 
doses based upon clinical judgment and presence and severity of prior infusion reactions.  In 
Combinations A, B, C, and D, when two or three investigational products are to be 
administered on the same day, premedication should be given prior to the first investigational 


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product administration.  This may be modified based on local treatment standards and 
guidelines. 
Premedication in Combination F:
To reduce the severity of symptoms associated with CMP-001 induced cytokines,
prophylaxis is mandated prior to the initial two SC (C1D1 and C1D8) and four IT (C1D15, 
C1D22, C2D1, C2D8) doses.
The following premedication regimen is mandated in prevention of CMP-001 induced 
reactions unless clinically contraindicated: 

Fluids (ie, 1000 mL IV normal saline);

NSAIDS (ie, 1000 mg acetaminophen and 50 mg indomethacin);

Anti-emetics (ie, 8 mg Zofran orally [per os (PO)]).  
It is also highly recommended to continue to administer additional fluids immediately
following the CMP-001 injection, rather than waiting to initiate fluids when hypotension is 
detected.  
If some of these premedications are administered prior to avelumab infusion, they may not 
need to be repeated before CMP-001 administration. If the drug administration visit is 
spread over two consecutive days, appropriate premedication should be administered on both 
days, according to the study drug being administered on each day. Premedication for 
subsequent CMP-001 doses (C2D15 onwards) is recommended and should be administered 
based upon clinical judgment and presence and severity of prior infusion reactions.  The 
CMP-001 premedication requirements are summarized in Table 20.
Stress Dose Steroids 
Prophylaxis with stress dose steroids is recommended for patients who have experienced 
CMP-001-related Grade 3 CRS lasting ≤24 hours (ie, a minimum dose of corticosteroids of 
25 mg prednisone or equivalent [eg, hydrocortisone, methylprednisone, and dexamethasone]) 
for subsequent CMP-001 doses.  The selection and dose of corticosteroid should be 
determined by the Investigator based on clinical parameters.
Patients with a history of adrenal insufficiency are at increased risk for moderate to severe 
AEs such as hypotension which may occur with 1 to 4 hours after injection.  It is strongly 
recommended that these patients receive stress dose steroids (eg, 50 to 100 mg 
hydrocortisone administered orally [PO] every 8 hours [Q8]) prior to and for 24 to 48 hours 
following CMP-001 injection. 


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Post Administration Observation Period
Combinations A, B, C, D
Patients will be observed in the clinic for at least 2 hours after the last infusion of 
investigational product.  If, following the fourth infusion of avelumab, no infusion reaction is 
observed, the post-infusion observation period may be discontinued thereafter.
Combination F
CMP-001 post-injection observation period: the observation period is mandated after the 
initial two SC (C1D1 and C1D8) and four IT (C1D15, C1D22, C2D1, and C2D8) doses.  
Patients must be observed for a period of at least 4 hours following each of the CMP-001 
injections for signs and symptoms of reactions to the injection and other AEs.  Vital signs 
including measurement of blood pressure (systolic and diastolic blood pressure [mmHg]), 
respiratory rate, heart rate (bpm), and body temperature (°C) are to be collected prior to 
CMP-001 injection, and at 30 (±15) minute intervals during the post-infusion observation 
period.  Starting on C2D15, the observation period can be reduced to 1 hour based on the 
investigators assessment of AE profile associated with prior injections.  
5.3.5.3. Treatment after Initial Evidence of Radiological Disease Progression
Immunotherapeutic agents such as avelumab and the other immune modulators to be 
evaluated in this study may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses.  The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and can 
manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  
If radiologic imaging shows disease progression, tumor assessment should be repeated 
4 weeks later in order to confirm the observation.  Assigned study treatments may be 
continued at the Investigator’s discretion while awaiting radiologic confirmation of disease 
progression. 
Patients may receive study treatments while waiting for confirmation of PD if they are
clinically stable as defined by the following criteria: 

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression. 

No decline in ECOG performance status. 

Absence of rapid progression of disease by radiographic imaging. 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.


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If repeat imaging no longer shows PD but rather CR, PR or SD compared to the initial scan, 
treatment may be continued/resumed.  In determining whether or not the tumor burden has 
increased or decreased, Investigators should consider all target as well as non-target lesions 
(refer to the Study Manual).  Before continuation of treatment after initial PD, the patient 
must be re-consented via an informed consent addendum and informed that by continuing to 
receive investigational products, the patient may be foregoing available therapy with possible 
clinical benefit(s).
If repeat imaging does not confirm PD, treatment with investigational products may be 
continued.  
If the repeat imaging confirms PD, patients should be considered for discontinuation from all 
investigational products.  However, according to the Investigator’s clinical judgment and 
after discussion between the Investigator and the Sponsor, if a patient with evidence of PD is 
still experiencing clinical benefit, the patient may be eligible for continued treatment with the 
investigational products.  The Investigator’s judgment should be based on the overall
benefit-risk assessment and the patient’s clinical condition, including performance status, 
clinical symptoms, adverse events, and laboratory data.  
Patients who stop treatment for reasons other than toxicity with any of the investigational 
products and then experience radiologic disease progression shortly thereafter will be eligible 
for re-treatment with the investigational products at the discretion of the Investigator and 
after discussion with the Sponsor. 
5.3.5.4. Treatment after Confirmed Complete Response
Patients who have experienced a confirmed CR may continue treatment under the discretion 
of the investigator and upon agreement with the Sponsor for up to 2 years from the first dose 
of investigational product (Cycle 1 Day 1). 
5.3.6. Food Requirements
The IV, SC, and IT investigational products may be administered without regard to food. 
5.3.7. Recommended Dose Modifications
Every effort should be made to administer each of the investigational products at the planned 
dose and schedule.  No dose modifications are permitted in this study, but the next 
administration of investigational product may be omitted based on persisting toxicity, as 
outlined in the next sections.
5.3.7.1. Dose Delays
In the event of significant toxicity, dosing for investigational products may be delayed as
described below.  In the event of multiple toxicities, dose delays should be based on the 
worst toxicity observed.  Patients are to be instructed to notify Investigators at the first 
occurrence of any adverse symptom.  In addition to dose delays, investigators are encouraged 
to employ best supportive care according to local institutional clinical practices and 
according to the guidance for selected adverse events provided below.


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5.3.7.2. Study Treatment Modifications for Investigational Products Drug-Related 
Toxicity
Recommended treatment modifications for the investigational product attributable to 
drug-related toxicity are shown in Table 21.  
Table 21.
Avelumab, Utomilumab, PF-04518600, PD 0360324, and CMP-001 
Treatment Modifications for Drug-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Treatment Modification
Drug-related adverse 
reactions
(excluding infusion-related 
reaction/hypersensitivity 
and immune-related AEs)
Grade 1
Continue per schedule.
Grade 2
Continue per schedule.
Consider withholding treatment for intolerable adverse reaction 
based on medical judgment.
Grade 3
Withhold until recovery to Grade 1 or better. 
If toxicity does not resolve to Grade 1 or better within 12 weeks 
of last administration or if based on medical judgment the event 
is considered critical, consider permanent discontinuation after 
consultation with the sponsor.
Upon the second occurrence of the same Grade 3 toxicity that 
does not resolve to Grade 1 by the next administration, 
treatment must be permanently discontinued.
Exceptions are: 
Laboratory values out of normal range that do not have any 
clinical correlation.
Grade 4
Permanent discontinuation.
Exceptions are: 
Laboratory values out of normal range that do not have any 
clinical correlation. 
Infusion-related Reaction 
Grade 1-4
See Section 5.3.7.3.1 and Table 22.
Hypersensitivity reactions
Grade 3-4
See Section 5.3.7.3.2.
Immune-related AE (irAE)
Grade 1-4
See Section 5.3.7.3.4 and Table 25.
5.3.7.3. Special Precautions for Avelumab, Utomilumab, PF-04518600, PD 0360324, and 
CMP-001 Administration
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Investigational products (biologics) should be administered in a setting 
that allows for immediate access to an intensive care unit or equivalent environment and 
administration of therapy for anaphylaxis, such as the ability to implement immediate 
resuscitation measures.  Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), 
allergy medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should 
be available for immediate access.
Premedications to mitigate infusion-related reactions associated with investigational product 
administration are described in Section 5.3.5.
Treatment recommendations for the management of infusion-related reactions, severe 
hypersensitivity reactions, and CRS are outlined in Section 5.3.7.3.1, Section 5.3.7.3.2 and 
Section 5.3.7.3.3, respectively.


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Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at the earliest after weeks of treatment.  Such events may consist of persistent rash, 
diarrhea and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or 
uveitis and other inflammatory eye conditions.  The spectrum of hypothetical irAEs also 
includes formation of auto-antibodies like antinuclear antibodies (ANAs) or antineutrophil 
cytoplasmic antibodies (ANCAs).  Treatment recommendations for the management of irAEs 
are outlined in Section 5.3.7.3.4.
5.3.7.3.1. Management of Infusion-Related Reactions 
Since some of the investigational products (mAbs) are administered IV, infusion-related 
reactions may occur (with symptoms such as fever, chills, rigors, diaphoresis, and headache).  
Treatment of the infusion-related reaction and modifications of the infusion(s) are mainly 
dependent upon severity, as indicated in Table 22.
Table 22.
Treatment Modification for Symptoms of Infusion-Related Reactions
NCI CTCAE Grade 
Treatment Modifications
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the investigational product infusion rate 
by 50% and monitor closely for any worsening.a
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for 24 hours.
Stop investigational product infusion.
Resume infusion at 50% of previous rate as soon as 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any recurrence or worsening.a
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the investigational product infusion 
immediately and disconnect bag infusion tubing 
from the patient.
Investigational product treatment must be 
permanently discontinued.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
a.
The total infusion time for each investigational product should not exceed 120 minutes.
Once the investigational product infusion rate has been decreased by 50% due to an
infusion-related reaction, it must remain so for the next scheduled infusion. If no infusion 
reaction is observed at the next scheduled infusion, the infusion rate may be returned to 
baseline at subsequent infusions.
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: In the 
event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 22 (including reducing the infusion 
rate by 50%), the Investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that infusion.  At the next infusion, the Investigator may consider 


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the addition of H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, or 
ibuprofen to the mandatory premedication.  Prophylactic steroids are NOT permitted. 
5.3.7.3.2. Management of Investigational Product-related Severe Hypersensitivity 
Reactions and Flu-like Symptoms 
Many mAb therapies can induce flu-like symptoms and hypersensitivity reactions, including 
impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, hypotension, 
pale/clammy skin, and cyanosis.  In addition, given the CMP-001 mechanism of action 
resulting in secretion of large amounts of type 1 intereferons, flu-like symptoms similar to 
that seen after administration of interferons (eg, fever, rigors, nausea, and vomiting) may be 
associated with IT injection of CMP-001.  
Investigational products (mAbs) should be administered in a setting that allows for 
immediate access to an intensive care unit or equivalent environment if required.  Patient 
should be placed on monitor immediately and epinephrine injection and dexamethasone 
infusion should be available for immediate access.
For prophylaxis of flu-like symptoms, and for patients treated with CMP-001, 25 mg 
indomethacin or comparable nonsteroidal anti- inflammatory drugs (NSAID) dose (eg, 
ibuprofen 600 mg, naproxen sodium 500 mg) may be administered at Investigator discretion 
2 hours before and 8 hours after the start of each dose of investigational product(s) thought to
be related to symptoms.  Alternative treatments for fever (eg, paracetamol or ibuprofen) and 
rigors (eg, meperidine) may be given to patients at the discretion of the Investigator.
5.3.7.3.3. Management of Symptoms Associated with Cytokine Release 
CMP-001 is designed to specifically bind to TLR9 expressed in the endosomes of pDCs.  
Upon activation through TLR9, pDCs will secrete large amounts of type 1 interferons and 
associated Th1-promoting cytokines. Therefore it is expected that symptoms associated with 
IFN-inducible chemokines and cytokines release, such as chills/rigors, fever, 
nausea/vomiting and hypotension, may occur within hours of a CMP-001 IT injection.
The recommended algorithm for the treatment of symptoms associated with cytokine release 
below has been adapted for the treatment of CRS resulting from other immunotherapies such 
as CAR-T cell therapy.101  Its effectiveness in treating symptoms associated with cytokine 
release resulting from CMP-001 has not been previously studied.  The first line of treatment 
for hypotension unresponsive to supportive care such as fluids, is stress dose steroids as 
outlined below.  Additional treatment measures include the use of drugs targeting specific 
cytokines believed to be involved in the development of CRS-induced hypotension. 






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Table 25.
Management of Immune-Related Adverse Events 
Gastrointestinal irAEs
Diarrhea / Colitis
(NCI CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
baseline;
Colitis: asymptomatic 
Continue investigational product 
therapy.
Symptomatic treatment 
(eg, loperamide).
Close monitoring for worsening symptoms.
Educate patient to report worsening
immediately.
If worsens:
Treat as Grade 2 or ¾.
Grade 2
Diarrhea: 4 to 6 stools per day over 
baseline; IV fluids indicated 
<24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold investigational product 
therapy.
Symptomatic treatment.
If improves to Grade 1: 
Resume investigational product therapy.
If persists >5-7 days or recur:
Treat as Grade 3 to 4.
Grade 3 to 4
Diarrhea (Grade 3): 7 stools per day 
over baseline; incontinence; IV fluids 
24 hrs.; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold investigational product 
for Grade 3.
Permanently discontinue 
investigational product for Grade 4 
or recurrent Grade 3.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider lower endoscopy.
If improves: 
Continue steroids until Grade ≤1, then taper 
over at least 1 month; resume investigational 
product following steroids taper (for initial 
Grade 3).
If persists >3 to 5 days, or recur after 
improvement:
Add infliximab 5 mg/kg (if no 
contraindication). Note: Infliximab should 
not be used in cases of perforation or sepsis.
Dermatological irAEs
Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2
Covering 30% body surface area 
Symptomatic therapy 
(eg, antihistamines, topical 
steroids).
Continue investigational product 
therapy.
If Grade 2 persists >1 to 2 weeks or recurs: 
Consider skin biopsy.
Withhold investigational product therapy.
Consider 0.5 to 1.0 mg/kg/day prednisone or 
equivalent.  Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and
resume investigational product therapy 
following steroids taper.
If worsens: 


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Table 25.
Management of Immune-Related Adverse Events 
Treat as Grade 3 to 4.
Grade 3 to 4
Covering >30% body surface area; 
life threatening consequences 
Withhold investigational product 
for Grade 3.
Permanently discontinue for Grade 
4 or recurrent Grade 3.
Consider skin biopsy.
Dermatology consult.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
If improves to Grade ≤1: 
Taper steroids over at least 1 month.
Resume investigational product therapy 
following steroids taper (for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding of 
investigational product therapy.
Monitor for symptoms every 2 to 
3 days.
Consider Pulmonary and 
Infectious Disease consults.
Re-assess at least every 3 weeks.
If worsens: 
Treat as Grade 2 or Grade 3 to 4.
Grade 2
Mild to moderate new symptoms
Withhold investigational product 
therapy.
Pulmonary and Infectious Disease 
consults.
Monitor symptoms daily, consider 
hospitalization.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider bronchoscopy, lung 
Re-assess every 1 to 3 days.
If improves: 
When symptoms return to near baseline, 
taper steroids over at least 1 month.
Resume investigational product therapy.
If not improving after 2 weeks or worsening 
or for recurrent Grade 2: 
Treat as Grade 3 to 4.


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Table 25.
Management of Immune-Related Adverse Events 
biopsy 
Grade 3 to 4
Severe new symptoms; 
New/worsening hypoxia; 
life-threatening 
Permanently discontinue 
investigational product therapy.
Hospitalize.
Pulmonary and Infectious Disease 
consults.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider bronchoscopy, lung 
biopsy.
If improves to baseline: 
Taper steroids over at least 6 weeks.
If not improving after 48 hours or worsening: 
Add additional immunosuppression (eg, 
infliximab, cyclophosphamide, intravenous 
immunoglobulin, or mycophenolate 
mofetil).
Hepatic irAEs
Liver Function Tests (LFT) 
Increase
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue investigational product 
therapy.
Continue liver function monitoring.
If worsens: 
Treat as Grade 2 or 3 to 4.
Grade 2
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to
3 x ULN 
Withhold investigational product 
therapy.
Increase frequency of monitoring to 
every 3 days.
If returns to baseline: 
Resume routine monitoring, resume 
investigational product therapy.
If elevations persist >5 to 7 days or worsen: 
Treat as Grade 3 or Grade 4.
Grade 3 to 4
AST or ALT >5 x ULN and /or 
total bilirubin >3 x ULN 
Permanently discontinue 
investigational product therapy.
Increase frequency of monitoring to 
every 1 to 2 days.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consult 
gastroenterologist/hepatologist.
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted.
If returns to Grade ≤1: 
Taper steroids over at least 1 month.
If does not improve in >3 to 5 days, worsens 
or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily.
If no response within an additional 3 to 
5 days, consider other immunosuppressants
per local guidelines.


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Table 25.
Management of Immune-Related Adverse Events 
Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN–1.5 x 
ULN
Continue investigational product 
therapy.
Continue renal function monitoring.
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased > 1.5 – 6 x 
ULN
Withhold investigational product 
therapy.
Increase frequency of monitoring to 
every 3 days.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
If returns to Grade ≤1:
Taper steroids over at least 1 month and 
resume investigational product therapy 
following steroids taper.
If worsens:
Treat as Grade 4.
Grade 4
Creatinine increased > 6 x ULN
Permanently discontinue 
investigational product therapy.
Monitor creatinine daily.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
Nephrology consult.
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (eg, 
troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis.
Withhold investigational product 
therapy.
Hospitalize.
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management.
Cardiology consult to establish 
etiology and rule-out immune-related 
myocarditis. 
If symptoms improve and immune-related 
etiology is ruled out, re-start investigational 
product therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-related 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-related 
myocarditis


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Table 25.
Management of Immune-Related Adverse Events 
Guideline based supportive treatment 
as per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology 
consult.
Immune-related myocarditis
Permanently discontinue 
investigational product therapy.
Guideline based supportive treatment 
as appropriate as per cardiology 
consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Once improving, taper steroids over at least 
1 month and add prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, consider 
additional immunosuppressants (eg, 
azathioprine, cyclosporine A).
*Local guidelines, or eg, European Society of Cardiology or American Heart Association guidelines.
European Society of Cardiology guidelines website:  
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
American Heart Association guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Grade 1 or Grade 2 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue investigational product 
therapy.
Endocrinology consult if needed.
Start thyroid hormone replacement 
therapy (for hypothyroidism), anti-
thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency), or insulin 
(for type I diabetes mellitus) as 
appropriate.  
Rule-out secondary endocrinopathies 
(eg, hypopituitarism/hypophysitis).
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold investigational product 
therapy.
Consider hospitalization.
Endocrinology consult.
Start thyroid hormone replacement 
therapy (for hypothyroidism), anti-
thyroid treatment (for 
Resume investigational product once 
symptoms and/or laboratory tests improve to 
Grade ≤1 (with or without hormone 
replacement/suppression).
Continue hormone replacement/ suppression 
and monitoring of endocrine function as 
appropriate.


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Table 25.
Management of Immune-Related Adverse Events 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency), or insulin 
(for type I diabetes mellitus) as 
appropriate.  
Rule-out secondary endocrinopathies 
(eg, hypopituitarism/hypophysitis).
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (eg,
subnormal serum thyroxine with 
inappropriately low 
thyroid-stimulating hormone and/or 
low serum cortisol with 
inappropriately low 
adrenocorticotropic hormone):

Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens 
in women).

Hormone replacement/ 
suppressive therapy as 
appropriate.

Perform pituitary MRI and 
visual field examination as 
indicated.
If hypophysitis confirmed:

Continue investigational 
product if mild or moderate
symptoms with normal MRI. 
Repeat the MRI in 1 month.

Withhold investigational 
product if severe symptoms or 
life-threatening symptoms of 
hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate high-dose 
corticosteroids (1 to 
2 mg/kg/day 
methylprednisolone IV or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month.

Add prophylactic antibiotics for 
opportunistic infections.
Resume investigational product once 
symptoms and hormone tests improve (with or 
without hormone replacement).
In addition, for hypophysitis with abnormal 
MRI, resume investigational product only once 
shrinkage of the pituitary gland on MRI scan is
documented. 
Continue hormone replacement/ suppression 
therapy as appropriate.


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Table 25.
Management of Immune-Related Adverse Events 
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a
potential irAE
Withhold investigational product 
therapy pending clinical 
investigation.
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider 
resuming investigational product therapy.
If irAE is confirmed, treated as Grade 2 or 
3 irAE.
Grade 2 irAE or first occurrence of 
Grade 3 irAE
Withhold investigational product 
therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Specialty consult as appropriate.
If improves to Grade ≤1:
Taper steroids over at least 1 month and 
resume investigational product therapy 
following steroids taper.
Recurrence of same Grade 3 irAE 
Permanently discontinue 
investigational product therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Specialty consult as appropriate.
If improves to Grade ≤1:
Taper steroids over at least 1 month.
Grade 4 irAE
Permanently discontinue 
investigational product therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressants as needed.
Add prophylactic antibiotics for 
opportunistic infections.
Specialty consult.
If improves to Grade ≤1:
Taper steroids over at least 1 month.
Requirement for 10 mg 
prednisone per day or equivalent 
for more than 12 weeks for 
reasons other than hormonal 
replacement for adrenal 
insufficiency 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks 
Permanently discontinue 
investigational product therapy.
Specialty consult as appropriate.
ALT=alanine aminotransferase, AST=aspartate aminotransferase, irAE=immune-related adverse event, IV=intravenous, 
MRI=magnetic resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse 
Events, TSH=thyroid-stimulating hormone, ULN=upper limit of normal.


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5.4. Investigational Product Storage
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the Sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to Sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
5.5. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all investigational product supplies.  
5.5.1. Destruction of Investigational Product Supplies
The Sponsor or designee will provide guidance on the destruction of unused investigational 
products (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.6. Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period, except for administration of the inactivated 
influenza vaccine.  Because multiple novel combinations will be explored during this study, 
live vaccines are not allowed during the active treatment period and for 90 days after the last 
dose of study treatment.


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If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor, and the patient.
Concomitant treatment considered necessary for the patient’s wellbeing may be given at 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatments and up to 90 days after the last dose of 
study treatment.  All concomitant medications should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).  
Concomitant treatments will not be collected for patients who initiate subsequent anticancer 
therapy.
Concurrent anticancer therapy with agents other than study treatments is not allowed.  
Medications intended solely for supportive care (eg, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat infusion-related reactions, hypersensitivity reactions and 
flu-like symptoms, tumor lysis syndrome and immune-related events are reported in 
Section 5.3.7.3.1, Section 5.3.7.3.2, Section 5.3.7.3.3, and Section 5.3.7.3.4, respectively.
5.6.1. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
Cycle 1 of treatment, but they may be used to treat treatment emergent neutropenia as 
indicated by the current American Society of Clinical Oncology (ASCO) guidelines.22
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Patients who enter the study on stable doses 
of erythropoietin or darbepoietin may continue this treatment, and patients may start either 
drug during the study at the discretion of the treating physician. 
5.6.2. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and administration of investigational products
required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  In case of a surgical procedure, investigational products should be delayed.  
Postoperatively, the decision to reinitiate investigational products should be discussed with 
the Sponsor. 


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5.6.3. Concomitant Radiotherapy
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.  Study 
treatment should be withheld for the entire duration of palliative radiotherapy and can be 
restarted upon recovery from any radiotherapy-related toxicities, but no sooner than 48 hours 
after radiotherapy completion.   
5.6.4. Other Prohibited Concomitant Medicines and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol. 

Investigational agents other than investigational products. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.6.3).

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see 
Table 25. below Clarification Regarding Steroid Use).

Other experimental pharmaceutical products.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines (eg, influenza vaccine).

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).
Combination F:

Agents known to have TLR9 antagonist activity are prohibited throughout the study. 
The known antagonists are chloroquine, hydroxychloroquine, and quinacrine. 
Clarifications Regarding Steroid Use: Data indicate that corticosteroids have an adverse 
effect on T-cell function and that they inhibit and damage lymphocytes.23,24  Furthermore, as 
with all immunotherapies intended to augment T-cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit.  
However, studies with anti-CTLA-4 compounds indicate that short term use of steroids can 
be employed without compromising clinical outcomes.25  Therefore, the use of steroids 
during this trial is restricted as follows:


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
Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs, steroids are permitted according to the modalities indicated in 
Table 25.

Therapeutic use for treatment of CRS as specified in Section 5.3.7.3.3 is permitted. 

Stress dose steroids to prevent severe CRS in patients enrolled in Combination F as 
specified in Section 5.3.5.2.

Physiologic use: replacement for adrenal insufficiency at doses equivalent to ≤10 mg 
prednisone daily are acceptable.  Higher doses of corticosteroids may be allowed for 
patients with a previous diagnosis of adrenal insufficiency.  Sponsor consultation is 
required prior to enrollment to Combination F of a patient with adrenal insufficiency. 

Prophylactic use: prophylactic use, eg, for the prevention of acute infusion-related 
reactions, constitutes concomitant use and is prohibited except stress steroids to 
prevent severe CRS reactions in patients enrolled into Combination F as specified in 
Section 5.3.5.2.

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) are permitted.  

There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7. Rescue Medications and Supportive Care
5.7.1. Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 25.

Anti-inflammatory or narcotic analgesics may be offered as needed. 


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
Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the Schedule of Activities and Assessments section
(Section 7).
6.1.1. Tumor Biospecimens
6.1.1.1. Combination A, B, C and D 
For Phase 1b: Archival formalin-fixed paraffin-embedded (FFPE) tissue is required if 
available for the first 3 patients enrolled in a cohort, including replacement patients.  For 
additional patients enrolled in each Phase 1b cohort and Phase 2, FFPE tissue must be 
available from the most recent primary or metastatic tumor biopsy or resection prior to start
of study therapy, taken within 1 year prior to enrollment/randomization, with no intervening 
systemic anti-cancer therapy.  This tissue may be obtained from a de novo biopsy performed 
prior to study entry.
A biopsy is required between Cycle 1 Day 21 (4 days) and Cycle 2 Day 1 (prior to dosing) 
and then as clinically indicated during treatment.  These on-treatment biopsies are required 
except in instances where the procedure poses unacceptable risks per investigator 
documentation. 
A de novo tumor sample at End of Treatment if a patient discontinues due to disease 
progression is required except in instances where the procedure poses unacceptable risks per 
investigator documentation.  The de novo tumor sample collected at the End of Treatment 
should be performed BEFORE initiation of subsequent anticancer therapy, preferably no later 
than 7 days after the End of Treatment visit. 
6.1.1.2. Combination F 
Baseline biopsy samples are required for all patients in Combination F.
1. Archival: Required for all patients when available.
2. De novo before first SC dose on C1D1.  This is not required if an archival specimen 
is available from the most recent primary or metastatic tumor biopsy or resection
prior to start of study therapy, with no intervening systemic anticancer therapy. 
Tissue is also required to be provided if tumor biopsies are taken during the study period as 
standard of care.  If possible, the following tissues are preferable (a) at initial diagnosis, 
(b) between second SC dose (C1D8) and first IT dose on C1D15, (c) between C1D22 and 


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C2D1 before the IT dose on C2D1, and (d) within 30 days of disease progression 
confirmation and before initiation of subsequent anticancer therapy.
In rare circumstances, if a patient is motivated to participate and the investigator judges that 
the risk associated with the baseline biopsy is not appropriate for a research setting, after 
consultation with the Sponsor’s medical monitor, the patient may be allowed on study 
without a biopsy prior to start of therapy. 
6.1.1.3. Sample Processing and Submission Requirements 
The biopsy sample(s) should be FFPE per routine pathology practice, and the resulting FFPE 
tissue should be submitted to the central laboratory.  FFPE tissue blocks should be provided 
if available and permitted by local laws and policies.  If blocks cannot be provided for these 
reasons, then sections must be freshly cut (cut no more than 30 days prior to shipment to the 
central laboratory), 5 µm thick, and mounted on positively-charged microscope slides 
(SuperFrost Plus glass slides are recommended).  A minimum of 15 (preferably 25) slides 
should be provided.  Core needle, excisional biopsies, or resection specimens are strongly 
preferred since intact tumor architecture is required for adequate assessment of CD8 and 
PD-L1 proximity.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) should only be submitted for patients for whom 
excisional or core needle biopsy methods are contraindicated.  Additional information on 
tumor biospecimen collection procedures is included in the study laboratory manual. 
Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet 
material), should only be submitted for patients for whom excisional or core needle biopsy 
methods are contraindicated.  
6.1.1.4. Selection of Lesion for Biopsy 
For each biopsy, a suitable tumor lesion will be designated for biopsy by the investigator.  
This designation will take into account: 1) the likelihood that the lesion is representative of 
the tumor, 2) the likelihood that the biopsy can be accessed safely, and 3) the lesion is 
distinct from the target lesions being followed for measurable disease.  First preference is 
superficial (skin, subcutaneous, lymph node), palpable lesions.  For other non-superficial 
locations, image guided biopsies are highly preferred.  Second preference is abdominal 
lesions.  Intrathoracic lesions should not be biopsied unless the potential for pneumothorax is 
judged to be minimal. Biopsies from bone lesions should not be submitted.   
6.2. Treatment Period
For treatment period procedures, see the Schedule of Activities and Assessments section 
(Section 7).  For all combinations, 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 
drugs.  After 2 years of treatment, patients without other options for treatment may continue 
on treatment with the combination to which they have been assigned or single agent 
avelumab upon agreement with the Sponsor.


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For the treatment period, 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:

Pharmacokinetic blood specimens – obtain at the scheduled time. When multiple 
investigational products are administered on the same day, the pre-dose PK samples 
for all investigational products may be obtained at any time BEFORE an infusion of 
the first investigational product on the given infusion day. The acceptable window 
for the post-dose sample(s) is 10 minutes of an infusion completion. 

Electrocardiograms (ECGs) – obtain as close as possible to the scheduled time, but 
prior to blood specimen collection (eg, PK).  In exceptional circumstances when 
blood sampling is not feasible before ECG measurement, the ECG measurement may 
be performed after the blood draws.  The pre-dose ECG may be obtained any time 
before investigational product infusion.  The acceptable window for the post-dose 
ECG is +30 minutes of an infusion completion. 

Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must 
be obtained prior to blood specimen collection.  The pre-dose blood pressure/pulse 
rate may be obtained any time before infusion of the first investigational product.

Clinical safety laboratory 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.
6.3. Follow-up
For follow-up procedures see the Schedule of Activities and Assessments section (Section 7).
Patients should be evaluated up to 90 days (30 days, 60 days, and 90 days) after last dose of 
investigational product(s) for safety.  Patients continuing to experience toxicity following 
discontinuation of investigational products will continue to be followed at least every 
4 weeks regardless of initiation of new anticancer treatment until resolution or determination, 
in the clinical judgment of the Investigator, that no further improvement is expected.  
Follow-up beyond 30 days after last dose of investigational products product(s) may be 
performed either via a clinic visit or by remote contact (eg, telephone), with subsequent clinic 
visits requested if any concerns are noted during the telephone call.
Physical examination, ECOG status, vital signs, and safety laboratory measurements are not 
required for patients who initiate new anticancer treatment, unless the patient continues to 
experience toxicity following discontinuation of the investigational products.  Contraception 
check and serum/urine pregnancy tests are required for all patients who enter Follow-up 
regardless of initiation of subsequent anticancer therapy.  Patients whose disease has not 
progressed at the time of treatment discontinuation will enter into disease follow-up (for 
tumor assessment).    


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Patients will be followed for survival, independently of time of disease progression or 
initiation of subsequent anticancer therapy, for at least 2 years after randomization of the last 
patient in the randomized cohorts and for at least 2 years after first dose of the last patient for 
the non-randomized cohorts unless lost to follow-up, consent withdrawal, or study 
discontinued by the Sponsor.  Patients will be contacted every 3 months for survival status 
and subsequent anticancer treatment. 
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the Investigator or Sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression by RECIST v1.1 assessment.  However, patients with 
disease progression who are continuing to derive clinical benefit from the study 
treatment will be eligible to continue study treatment, provided that the treating 
physician has determined that the benefit/risk for doing so is favorable (See 
Section 5.3.5.3 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to 1 or more of the
investigational products, the Investigator (in discussion with the Sponsor) may 
discontinue only the causal investigational product(s) and continue treatment with the 
other investigational product(s);

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;


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
Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessments
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs 
and physical examination, ECG (12-lead), laboratory assessments, including pregnancy tests 
and verification of concomitant treatments.  The results of safety assessments potentially 
requiring dose modifications must be reviewed prior to dosing as specified in Section 7.1.4. 
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatments; once at the start of screening and once at the 
baseline visit, immediately before study drugs administration.  Following a negative 
pregnancy test result at screening, appropriate contraception must be commenced and another 
negative pregnancy test result will then be required at the baseline visit before the patient 
may receive the investigational products.  Additional pregnancy tests (serum or urine) will 
also be routinely repeated at every cycle, prior to dosing, during the active treatment period, 
at the end of treatment, during follow-up (up to 90 days after last study treatment), and 


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additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive human chorionic gonadotropin (hCG) test, the patient 
will be withdrawn from study drugs but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by institutional review 
boards/ethics committees (IRB/ECs) or if required by local regulations.
7.1.2. Contraceptive Check
Male patients who are able to father children and female patients who are of childbearing 
potential, if sexually active and at risk for pregnancy with their partner(s), will need to affirm 
that they meet the criteria for correct use of the selected method of contraception.  The 
investigator or his or her designee will discuss with the patient the need to use at least 
1 highly effective contraception method consistently and correctly and document such 
conversation in the patient’s chart.  In addition, the investigator or his or her designee will 
instruct the patient to call immediately if selected contraception method is discontinued, or if 
pregnancy is known or suspected in the patient or the patient’s partner.
7.1.3. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study will be recorded on the adverse events CRF page.
7.1.4. Laboratory Safety Assessments
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  They may also be performed when clinically 
indicated. The hematology, blood chemistry, and pregnancy test (if applicable) results must 
be available and reviewed by the treating physician prior to study treatment administration.  
Further details are presented in Section 5.3.7. The required laboratory tests are listed in 
Table 26.
Table 26.
Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy 
Test
Other 
Hemoglobin
ALT
INR
Urine dipstick for 
urine protein: If 
positive collect 
24-hr and 
microscopic 
(Reflex Testing)
For female 
patients of 
childbearing 
potential, 
serum or 
urine (to be 
specified in 
the 
protocol)
HBV surface 
antigen
Anti-HCV 
antibody
If Anti-HCV 
antibody 
positive, then 
HCV RNA 
testing
Platelets
AST
aPTT
WBC
Alk Phos
Absolute 
Neutrophils
Sodium
Absolute 
Lymphocytes
Potassium
Absolute 
Monocytes
Magnesium
Urine dipstick for
urine blood: If 
positive collect a 
microscopic 
Absolute 
Eosinophils
Chloride


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Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy 
Test
Other 
Absolute 
Basophils
Total Calcium
(Reflex Testing)
Total Bilirubina
Thyroid 
Function 
Tests: TSH, 
free T4
BUN or Urea
Creatinine
Other Tests: 
ACTH
Glucose 
(non-fasted)
Morning, 
cortisolb
Albumin
Corticotropin 
(ACTH) 
stimulation 
test c
Phosphorous or 
Phosphate
Amylase
Gamma glutamyl 
transferase
Creatine kinase
Lipase
Note:
a. For potential Hy's Law cases, In addition to repeating measurements of AST and ALT and total bilirubin, laboratory tests 
should include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma glutamyl transferase (GGT), prothrombin 
time (PT)/international normalized ratio (INR), total bile acids, alkaline phosphatase and acetaminophen drug and/or protein 
adduct levels.
b. Morning, cortisol required at Screening and when clinically indicated (adrenal insufficiency suspected) for Combination F 
patients.  Blood sample should be drawn with ACTH.
c. Serum cortisol response to acute ACTH stimulation with a 250 μg dose should be performed to establish the diagnosis of 
adrenal insufficiency if basal morning ACTH and cortisol results are suggestive of adrenal insufficiency (eg, cortisol level is 
low) at Screening and when clinically indicated for Combination F patients.  Institutional standards should apply.
Abbreviations: ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT = activated partial 
thromboplastin time; AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, HBV= hepatitis 
B Virus, HCV= hepatitis C Virus, INR=international normalized ratio, LDH=lactate dehydrogenase, PT=prothrombin time; 
TSH=thyroid-stimulating hormone, WBC=white blood cell.
7.1.5. Vital Signs and Physical Examination
Patients will have a physical examination to include major body systems, supine or sitting 
blood pressure, pulse rate, assessment of ECOG performance status, and height (height will 
be measured at screening only) at the time points described in the Schedule of Activities. 
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle.  Weight will not be collected at End of Treatment. 
7.1.6. (12-Lead) Electrocardiogram
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs. 
All patients require a single ECG measurement at screening and End of Treatment (EoT) 
visit.  On-treatment ECGs will be performed on Day 1 of Cycles 1 and 2, before and at the 
end of study treatment administration.  At each time point, three (3) consecutive 12-lead 
ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc 
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assessment should be performed prior to blood sample collection, such that the blood sample 
is collected at the nominal time.  If patient experiences a cardiac or neurologic AE 
(specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at 
time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be 
re-evaluated by a qualified person at the institution for confirmation and repeated as 
clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
Clinically significant findings seen on follow-up ECGs should be recorded as adverse events. 
To ensure safety, if there is finding of QTc >500 msec (ie, > CTCAE Grade 2), ECG must be 
reviewed by qualified personnel at the site as soon as the finding is made, including verifying 
that the machine reading is accurate and that the Fridericia correction formula is applied.  If 
manual reading verifies a rate corrected QTc of >500 msec, repeat ECG should be
immediately performed at least two times approximately 2 to 4 minutes apart. 
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc interval is due to study treatment, 
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 QTc interval reverts to less than 500 msec, and in the 
judgment of investigator and sponsor is determined to be due to a cause other than study 
treatment, then treatment may be continued with regular ECG monitoring. 
7.2. Pharmacokinetics Assessments
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the post-dose samples obtained within 10 min window relative to the end 
of infusion (eg, between 50-70 min of infusion start for 60 minute sample) will be considered 
Protocol compliant.  The exact time of the sample collection is noted on the source document 
and data collection tool (eg, CRF).  The pre-dose samples can be taken at any time before 
infusion start.  When multiple investigational products are administered on the same day, the 
pre-dose PK samples for all investigational products may be obtained at any time BEFORE 
the infusion of first investigational product on the given infusion day.  If the infusion of 
avelumab is interrupted due to AE, the PK sample associated with that dose is not required.  
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.
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided to the investigator site prior to initiation of the trial.  Samples will be analyzed 
using a validated analytical method in compliance with Pfizer standard operating procedures.  
The samples must be processed and shipped as indicated to maintain sample integrity.  Any 
deviations from the processing steps (eg, sample collection and processing steps, interim 
storage or shipping conditions), including any actions taken, must be documented and 
reported to the sponsor.  On a case by case basis, the sponsor may make a determination as to 
whether sample integrity has been compromised.  Any deviation from the specified sample 
handling procedure resulted in compromised sample integrity, will be considered a protocol 
deviation.  
 
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7.3.6. Combination F: Immunogenicity Assessment of CMP-001, Utomilumab and 
PF-04518600
Blood samples (3.5 mL whole blood for utomilumab and 5.0 mL whole blood for 
PF-04518600 at each time point) for evaluation of immunogenicity (ADAs) of utomilumab 
(Cohort F2) and PF-04518600 (Cohort F3) will be collected at each sampling point from all 
patients as outlined in the Schedule of Activities. 
Blood samples (5.0 mL whole blood for Anti-Qb10 at each time point) for evaluation of 
immunogenic response will be collected at each sampling point from all patients as outlined 
in the Schedule of Activities.
7.4. Biomarker and Pharmacodynamic Assessments
Information about tumor biomarkers of known prognostic significance will be collected at 
Screening.  These include but are not limited to:

NSCLC: EGFR, ALK, ROS1 (required for non-squamous NSCLC); PD-L1 (required 
for 1st line NSCLC); KRAS (if available);  

SSCHN: HPV(required); EBV, PD-L1 (if available);

Melanoma: BRAF, NRAS, KIT, PD-L1 (if available);

TNBC: estrogen receptor, progesterone receptor, HER2, BRCA1, BRCA2, PD-L1 (if 
available);

Ovarian cancer: BRAF, BRACA, KRAS, PD-L1 (if available);

Gastric cancer: HER 2, PD-L1 (if available).
Availability of PD-L1 status is required for NSCLC patients in Cohorts A8, A9, A10.  
Biospecimens may be used to analyze candidate cellular, DNA, RNA, protein, or metabolic 
biomarkers, or relevant signatures of biomarkers, for (a) confirming appropriate target 
engagement, (b) determining pharmacodynamic effects of the study combinations and 
(c) identifying those patients who are most likely to benefit from treatment.  Biospecimens 
collected at the End of Treatment visit may also help understand potential mechanisms of 
resistance.
As noted earlier, avelumab is expected to increase the effectiveness of anti-tumor T cells by 
preventing inhibition of T cell activation by PD-L1.  This effect is expected to be enhanced 
by agents that promote anti-tumor immunity by complementary mechanisms such as 
extension of T cell survival or removal of other inhibitory factors such as myeloid cell 
activity.  In order to test this hypothesis consistently across combinations in this study, 
PD-L1 expression and presence of CD8+ lymphocytes will be evaluated in tumors of all 
patients.  Both PD-L1 and CD8 have been considered biomarkers of tumor responsiveness to 
immunotherapy.  Levels of these biomarkers at baseline and on therapy will be correlated 


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with clinical endpoints in order to understand better the proportion of patients that respond to 
the combinations as well as the robustness of response.  Further correlations between other 
biomarkers such as IFN-associated genes and TCR sequence diversity will be conducted as 
enabled by specimen availability.
Additional biomarker assessments may be performed to address questions related to specific 
combinations.  Examples of biomarker specimen collections and analyses are described in 
Table 27.  Details of biospecimen collections and potential analyses are included in the 
Schedule of Activities for each combination.
These analyses will be conducted using technical platforms that the Sponsor has confirmed to 
be fit for purpose.  Examples are cited in Table 27.  To enable these analyses, whole blood, 
serum, plasma, and tissue biospecimens will be retained in the central laboratory during 
study conduct until transfer to a qualified assay laboratory under Sponsor oversight.  
Biospecimens remaining at the close of the study may be transferred to long-term storage 
under Sponsor oversight and be assessed in accordance with the uses set forth in the 
informed consent document, unless prohibited by local regulation or by decision of the IRB 
or EC.  Biospecimens not transferred to long-term storage will be destroyed. 
Table 27.
Examples of Biomarker Analyses and Intended Uses
Intended Use
Sample Type
Analysis (example of technical 
platform)
Confirm adequate target coverage 
at selected doses of study drug
Whole Blood
Target occupancy (flow cytometry)
Identify and/or confirm candidate 
biomarkers associated with 
pharmacodynamic effect and/or 
patient response
Tissue (FFPE)
Immune cell phenotype and location 
(immunohistochemistry and/or 
immunofluorescence)
Gene expression profiling 
(next-generation sequencing or 
nanostring)
T Cell Receptor profiling 
(next-generation sequencing)
Mutation analysis (next generation 
sequencing)
Whole Blood
Immune cell phenotyping (flow 
cytometry)
Gene expression profiling
(next-generation sequencing)
T Cell Receptor profiling 
(next-generation sequencing)
Serum and Plasma
Soluble factors associated with 
immune activation and regulation 
(using methods such as next-
generation sequencing, immunoassay 
and mass spectrophotometry)
Ascitic fluid (ovarian cancer 
only)
Immune cell phenotyping (flow 
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Table 27.
Examples of Biomarker Analyses and Intended Uses
Intended Use
Sample Type
Analysis (example of technical 
platform)
Soluble factors associated with 
immune activation and regulation 
(immunoassay or mass 
spectrophotometry)
7.4.1. Combination A: Avelumab plus Utomilumab (4-1BB/CD136 Agonist mAb)\
Additional biomarkers to be assessed include 4-1BB expression by tumor-infiltrating 
lymphocytes, distribution of 4-1BB+ lymphocytes within the tumor, and association of 
4-1BB with biomarkers linked to T cell exhaustion such as PD-1. 
7.4.2. Combination B: Avelumab plus PF-04518600 (OX40/CD134 Agonist mAb)
Additional biomarkers to be assessed include expression of Ki67 and HLA-DR/CD38 on 
peripheral blood T cell subsets, OX40 expression by tumor-infiltrating lymphocytes, and 
distribution of OX40+ lymphocytes within the tumor.
7.4.3. Combination C: Avelumab plus PD 0360324 (Anti-M-CSF)
Additional biomarkers to be assessed include levels of CD14+ monocytes and CD68+ 
macrophages at baseline and on treatment. 
7.4.4. Combination D: Avelumab plus Utomilumab plus PF-04518600 
Additional biomarkers to be assessed include levels of OX40 and 4-1BB on
tumor-infiltrating lymphocytes with specific attention given to differences between the triple 
combination and the double Combinations A and B respecting the baseline target expression 
needed for clinical benefit.
7.4.5. Combination F: Avelumab and CMP-001 with Utomilumab or PF-04518600 
Serum will be collected for assessment of soluble proteins such as IP-10 that are expected to 
be released by pDCs after treatment with CMP-001.  Lineage markers of the pDCs that are 
expected to respond to CMP-001 may be assessed in tissue.
7.4.6. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Tumor biospecimens from archived tissue samples and metastatic lesions and de novo
biopsies (see Section 6.1.1) will be used to analyze candidate DNA, RNA, or protein 
markers, or relevant signatures of markers for their ability to identify those patients who are 
most likely to benefit from treatment with the study drugs.  Markers that may be analyzed 
include, but may not necessarily be limited to, PD-L1 expression, tumor-infiltrating CD8+ T 
lymphocytes, and interferon-gamma-regulated genes.  In addition, the quantity, target 
expression (eg, OX40, 4-1BB), phenotype and tissue localization of tumor associated 
macrophages (TAMs) may be evaluated.  Optional tumor biopsies obtained upon disease 
progression may be used to investigate acquired mechanisms of resistance, such as the 




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required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians, nor will 
they be recorded in the patient’s medical record. There is no intention to contact patients 
after completion of the clinical study.
A 4 mL blood sample (K2 edetic acid [ethylenediaminetetraacetic acid (EDTA)] whole blood 
collection optimized for DNA analysis) will be collected at the Cycle 1 Day 1 visit prior to 
dosing to be retained for potential pharmacogenomic/biomarker analyses related to drug 
response, unless prohibited by local regulations or by decision of the institutional review 
board or ethics committee.  For example, putative safety biomarkers, drug-metabolizing
enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined. 
The banked biospecimens will be collected from all patients unless prohibited by local 
regulations or ethics committee decision. Detailed collection, processing, storage, and 
shipment instructions are provided in the laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.5.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, patients will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Patients need not provide additional biospecimens for the uses described in this section; the
biospecimens specified in the Markers of Drug Response Section will be used.  Patients may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section. 
7.6. Tumor Response Assessments
The decision for body areas to be scanned will depend on disease under study and extent of 
disease.  Tumor assessments must include all known or suspected disease sites.  Imaging may 
include chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan for patients with 
known or suspected brain metastases. If stable brain metastases are present at baseline, brain 
imaging should be repeated at each tumor assessment.  Bone imaging using bone scan (bone 
scintigraphy) or 18-fluorodeoxyglucose positron emission tomography (18F- FDG-PET) or 


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CT or MRI is required at baseline only if bone metastases are known or suspected outside the 
body areas scanned using other techniques, then every 16 weeks only if bone metastases are 
present at baseline.  Otherwise, bone imaging is required only if new bone metastases are 
suspected.  Bone imaging is also required at the time of confirmation of CR for patients who
have bone metastases.  The minimum recommended body areas to be scanned depending 
upon malignancy are detailed in the Imaging Manual. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, every 8 weeks during treatment, at end of treatment, and until disease progression, 
as specified in the Schedule of Activities.  Baseline tumor assessment must be performed 
within 28 days prior randomization (for randomized cohorts) or first dose (non-randomized 
cohorts).  On treatment tumor assessments should be performed every 8 weeks (7 days) 
starting from randomization (randomized cohorts) or first dose (non-randomized cohorts).  In 
addition, radiological tumor assessments will be conducted whenever disease progression is 
suspected (eg, symptomatic deterioration), and at the time of withdrawal from treatment (if 
not done in the previous 4 weeks and prior response is other than confirmed PD).  In case PR, 
CR, or PD is observed according to RECIST v1.1, tumor assessments should be confirmed 
on repeated imaging at least 4 weeks after initial documentation. After 1 year from 
randomization in the study (randomized cohorts) or first dose (non-randomized cohorts), 
tumor assessments will be conducted less frequently, ie, at 12-week (after 1 year) and 
16-week (after 2 years) intervals, respectively.  See the Schedule of Activities and
Section 5.3.5.3 for treatment after initial evidence of disease progression.
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy.
Assessment of response will be made using RECIST version 1.1 (Appendix 1).  
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 


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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.
8.1.1. Avelumab Adverse Events of Special Interest
Any AE that is suspected to be a potential immune-related AE (irAE) will be considered an 
AE of special interest (AESI).  Specific guidance for the management of immune-related 
AEs is provided in Section 5.3.7.3.4.  AESIs are reported according to the general AE 
reporting rules specified in this section (Section 8).
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of the study treatment.
SAEs occurring to a subject 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 treatment 
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 subject has taken at least 1 dose of study treatment through 90 calendar days after 
the last administration of the study treatment. 
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 and SAE must be reported if it occurs 
during the SAE reporting period after the last dose of study treatment, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;


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
Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the study drugs;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page. 
The guidance on reporting of medication errors also applies to the reporting of overdose. 
In this study, overdose of avelumab is defined as any dose 5% over the calculated dose for 
that particular administration as described in this protocol.  For utomilumab and for 
PF-04518600, overdose is defined as any dose exceeding the prescribed dose by 20% over 
the prescribed dose for the dosing cohort under study. 
Medication errors should be reported to the sponsor within 24 hours on a SAE Report Form 
only when associated with an SAE.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;


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
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death
must be recorded as an AE and as an SAE with CTCAE Grade 5 (see Section 8.8 on 
Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
(DILI) 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 (Tbili) baseline values within the 
normal range who subsequently present with AST or ALT values 3 times the upper 
limit of normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no 
evidence of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above;


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
For patients with preexisting AST or ALT baseline values above the normal range,
AST or ALT value 2 times the baseline values and 3 × ULN, or 8 × ULN 
(whichever is smaller).
Concurrent with:

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
Rises in AST/ALT and total bilirubin separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it
represents a potential Hy’s law case should be reviewed with the sponsor.
This evaluation should include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over the counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 


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however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE. Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.8. Severity Assessment
AEs will be reported using concise medical terminology (verbatim) as well as the Common 
Terminology Criteria (CTC) term for Adverse Events (Version 4.03, Publish Date: 
June 14, 2010, http://ctep.cancer.gov/reporting/ctc.html) listed in the Cancer Therapy 
Evaluation Program.
The investigator may use the following definitions of Severity in accordance with CTCAE 
Version 4.03 to describe the maximum intensity of the adverse event. 
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements.  If the 
investigator's causality assessment is “unknown but not related to investigational product,” 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.


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For combination treatments, causality assessment will be performed for each of the 
individual drugs included in the combination.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product(s); or the female becomes or is found to be pregnant after discontinuing 
and/or being exposed to the investigational product(s);
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product(s) 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(s), the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form. This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational products.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See also Section 6.4 on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
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.
This section describes the data analysis and statistical methods for each of the combinations 
of avelumab evaluated in this study. 


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9.1. Analysis Sets 
9.1.1. Full Analysis Set
For Combination A, the full analysis set includes all randomized patients for Cohorts A1, 
A2, A3, A9, and A10 and all enrolled patients for Cohorts A4, A5, A6, A7, and A8 who 
receive at least 1 dose of study treatment.  For the randomized cohorts, patients will be 
assigned to the randomized treatment assigned at randomization regardless of the treatment 
received.
For Combination B, the full analysis set includes all enrolled patients who receive at least 
1 dose of study treatment.
For Combination C, the full analysis set includes all enrolled patients who receive at least
1 dose of study treatment.
For Combination D, the full analysis set includes all enrolled patients who receive at least 
1 dose of study treatment. 
For Combination F, the full analysis set includes all randomized patients.  Patients will be 
assigned to the randomized treatment assigned at randomization regardless of the treatment 
received. 
9.1.2. Safety Analysis Set 
The safety analysis set includes all patients who receive at least 1 dose of study treatment.  
Patients will be classified according to the treatment assigned at randomization (for the
randomized cohorts) unless the incorrect treatment(s) was/were received throughout the 
dosing period in which case patients will be classified according to the first treatment 
received.
9.1.3. Evaluable for DLT Analysis Set
This is the primary analysis set for the Phase 1 lead-in parts for all Combinations and 
includes all enrolled patients in Phase 1b who are eligible for the study, receive at least 
1 dose of study treatment, and either experience DLT during the DLT observation period, or
complete the DLT observation period. For Combinations A, B, C, and D, the DLT 
observation period is the first 2 cycles (8 weeks) of treatment.  For Combination F, the DLT 
observation period will be 4 weeks including the first two weekly SC injections and the
subsequent two weekly IT administrations.
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the prescribed doses for all investigational products in the combination for reasons other than 
treatment-related toxicity (eg, missed appointments or development of rapidly progressing 
disease) are not evaluable for DLT.


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9.1.4. PK/Immunogenicity Analysis Sets
The PK/ADA concentration population is a subset of the safety analysis set including all 
patients who have at least one post-dose concentration measurement of either avelumab or
other study drugs.
9.1.5. Biomarker Analysis Set
For all combinations, the biomarker analysis set is a subset of the safety analysis set 
including all patients who have at least one screening biomarker assessment.  Analysis sets 
will be defined separately for blood-based and tumor tissue-based biomarkers.
If mutational profiling is performed on samples derived from the biomarker analysis set, the 
analysis may be limited to screening samples only.
9.2. Statistical Methods and Properties
9.2.1. Combination A
Phase 1b: Before expanding NSCLC Cohorts A1, A2, and/or A3 after the lead-in phase, the 
safety must be confirmed in the first 6 patients evaluable for DLT in those cohorts.  The dose 
level is considered as safe and a cohort can be expanded when there are not more than 1 of
6 patients with DLTs within the first 2 cycles of treatment.
Table 28. shows the probability of confirming the safety in the first 6 patients for a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
greater than 89% probability of confirming safety and expanding the corresponding cohort.  
Conversely, for a DLT that occurs with a rate of 60%, the probability of expanding is 4%. 
Table 28.
Combination A: Probability of Expanding Dose Level
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of expanding dose level
0.89
0.66
0.42
0.23
0.11
0.04
0.01
<0.01
<0.01
9.2.2. Combinations B, C, and D
Phase 1b: Dose escalation to identify a safe dose and RP2D of the other immune 
modulator(s) used in combination with avelumab (all solid tumor types): 
A safe dose will be determined using the adaptive mTPI design.  The mTPI design is flexible
and allows dose reduction to doses in between the planned doses.
The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of 3 dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target probability (pT) rate 
(pT=0.25).  If the toxicity rate of the currently used dose level is far smaller than pT, the 
mTPI will recommend escalating the dose level; if it is close to pT, the mTPI will
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level.  These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 


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probabilities calculated under a coherent probability model.  As shown by Ji and Wang, 
mTPI design is more efficient and safer thanthe 3+3 design.49  They considered 42 scenarios 
to cover a wide range of practical dose-response shapes, and concluded that the 3 + 3 design 
was more likely to treat patients at toxic doses above the MTD and less likely to identify the 
true MTD than the mTPI design.  For example, the 3 + 3 design exhibited a lower overall 
toxicity percentage than the mTPI design in only 1 of 42 scenarios.
Being a model-based design, mTPI automatically and appropriately tailors dose re-escalation 
and de-escalation decisions for different studies with different toxicity parameters. More 
importantly, all the dose re-escalation/de-escalation decisions for a given study can be 
pre-calculated under the mTPI design and presented in a 2-way table.  Thus, compared to 
other advanced model-based designs published in the literature, the mTPI design is 
logistically less complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0, pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of PF-04518600, and PD 0360324, and avelumab, e1 is selected as 0.09, and 
e2 is selected as 0.08.  Therefore, the target interval for the DLT rate is (0.16, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
underdosing interval corresponds to a dose re-escalation (RE), overdosing corresponds to
dose de-escalation (D), and proper dosing corresponds to staying at the current dose (S).  
Given a dosing interval and a probability distribution, the UPM of that dosing interval is 
defined as the probability of a patient belonging to that dosing interval divided by the length 
of the dosing interval.  The mTPI design calculates the UPMs for the 3 dosing intervals, and 
the one with the largest UPM informs the corresponding dose-finding decision, which is the 
dose level to be used for future patients.  For example, if the underdosing interval has the 
largest UPM, the decision will be to escalate, and the next cohort of patients will be treated at 
the next higher dose level.  Simulations have demonstrated that the decision based on UPM is 
optimal in that it minimizes a posterior expected loss (ie, minimizes the chance of making a 
wrong dosing decision).
Phase 2 can be initiated if not more than 3 in 10 (Combination C which has a maximum 
sample size of 10 patients for a dose level) or 12 (Combinations B, and D which have a 
maximum sample size of 12 patients for a dose level) DLT-evaluable patients have 
experienced a DLT at the recommended Phase 2 dose level since it meets the criterion 
associated with the target interval for the DLT rate of (0.16, 0.33) as described above.
For each of Combinations B, and C, it is estimated that up to approximately 30 to 
36 DLT-evaluable patients will need to be enrolled to estimate MTD for the combinations 
under evaluation.  For Combination D, it is estimated that approximately 72 DLT-evaluable 
patients will need to be enrolled to estimate the MTD for the utomilumab plus PF-04518600 
plus avelumab combination.


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9.2.3. Combination F
Phase 1b: Before expanding cohorts F1, F2, and F3 into the Phase 2 cohort expansion, the 
safety of the combination in that cohort must be confirmed in DLT-evaluable patients in the 
Phase 1b lead-in.
Up to 12 patients will be randomized into each cohort in the Phase 1b lead-in and evaluated 
for DLT during the first treatment cycle (4 weeks) as follows:

If 1 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
14 additional patients in the Phase 2 cohort expansion.

If 2 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
6 additional DLT-evaluable patients in the Phase 1b lead-in part of the study:

If 3 of 12 patients experience DLT, the cohort will be expanded to enroll up to 
8 additional patients in the Phase 2 cohort expansion;

If 4 of up to 12 patients experience DLT, enrollment in the specific cohort will 
be discontinued.

If 3 of up to 6 patients experience DLT, enrollment in the specific cohort will be 
discontinued.
Table 29 shows the probability of expanding enrollment of a cohort into Phase 2 based on the 
DLT rates observed for 6 or 12 DLT-evaluable patients in Phase 1b and a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
97% probability of confirming safety and expanding the corresponding cohort.
Table 29.
Combination F: Probability of Expanding Dose Level
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of expanding 
dose level
0.97
0.82
0.56
0.31
0.14
0.05
0.01
0.002
<0.0001
DLT = dose limiting toxicity.
9.3. Sample Size Determination
9.3.1. Combination A
The number of patients to be enrolled in Combination A may depend upon the observed 
safety profile, which will determine the number of patients at each dose level and the number 
of dose levels explored.  The total number of patients treated in Combination A (Phase 1b 
and Phase 2 combined) is expected to be approximately 253.


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9.3.1.1. Sample Size Determination for Utomilumab and Avelumab for NSCLC 
Cohorts A1, A2, and A3 
There will be up to 3 dose level cohorts of patients with NSCLC that will be assessed for 
efficacy independently.  The null hypothesis that the objective response rate does not exceed 
15% (H0: ORR15%) will be tested against the alternative (H1: ORR>15%) for each cohort 
using the binomial distribution at one-sided level of significance =0.05.  For each cohort, 
data from the Phase 1b lead-in and Phase 2 will be combined for this assessment.
Within each cohort, 28 patients will provide at least 80% power to reject the null hypothesis 
if the true ORR is at least 35% (ORR35%).
At the end of the study, if there are 7 objective responders of 28 patients treated in a given 
cohort (6 +22 patients), then it will be declared that for that cohort, the null hypothesis cannot 
be rejected, or that clinically meaningful activity has not been demonstrated.  If there are 
8 objective responders of 28 patients treated in a given cohort, the null hypothesis will be 
rejected for that cohort and clinically meaningful activity has been demonstrated.
9.3.1.2. Sample Size Determination for Utomilumab and Avelumab for Melanoma 
Cohort A4 
The primary objective for Cohort A4 is to test null hypothesis that the ORR in melanoma 
patients treated with combination of utomilumab and avelumab does not exceed 15% 
(H0: ORR15%).  The null hypothesis will be tested against the alternative (H1: ORR>15%) 
at one-sided level of significance α=0.05 using the binomial distribution. 
Twenty-eight patients will provide at least 80% power to reject the null hypothesis if the true 
ORR is at least 35% (ORR35%).
At the end of the study, if there are 7 objective responders of 28 patients in this cohort, then 
it will be declared that the null hypothesis cannot be rejected, or that clinically meaningful 
activity has not been demonstrated.  If there are 8 objective responders of 28 patients treated 
in the cohort, the null hypothesis will be rejected and clinically meaningful activity has been 
demonstrated. 
9.3.1.3. Sample Size Determination for Utomilumab and Avelumab for SCCHN 
Cohort A5 
The primary objective for Cohort A5 is to test null hypothesis that the ORR in SCCHN 
patients treated with combination of utomilumab and avelumab does not exceed 20% 
(H0: ORR20%).  The null hypothesis will be tested against the alternative (H1: ORR>20%) 
at one-sided level of significance =0.05 using the binomial distribution. 
Thirty-five patients will provide at least 80% power to reject the null hypothesis if the true 
objective response rate is at least 40% (ORR40%). 


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At the end of the study, if there are 11 objective responders of 35 patients in this cohort, 
then it will be declared that the null hypothesis cannot be rejected, or that clinically 
meaningful activity has not been demonstrated.  If there are 12 objective responders of 
35 patients treated in the cohort, the null hypothesis will be rejected and clinically 
meaningful activity has been demonstrated.
9.3.1.4. Sample Size Determination for Utomilumab and Avelumab for TNBC 
Cohort A6, SCLC Cohort A7, and First-Line NSCLC Cohorts A8, A9 and A10
Based on the emerging data, PD-L1 expression status shows prognostic significance for 
NSCLC patients.  Thus, inclusion criteria for Cohort A8 are updated to add the requirement 
of having positive PD-L1 expression status.  To reflect this change, at least 20 PD-L1 
positive patients will be enrolled in the Cohort A8. Overall sample size for Cohort A8 may 
be larger (N= up to 26, based primarily on internal data that 6 patients [~30%] will need 
replacement) and can include PD-L1 negative patients that were enrolled prior to Protocol 
Amendment #6. 
Twenty (20) patients each will be enrolled in Cohorts A6, A7, A9 and A10.
With 20 patients in each of the TNBC, SCLC cohorts, and 20 PD-L1 positive patients in 
first-line (1L) NSCLC cohorts, ORR can be estimated with a maximum standard error of 
11.2%.  Table 30. provides the exact binomial 90% confidence intervals for ORR based on 
different observed responses in a cohort. 
Table 30.
Sample Size and Exact 90% CI for ORR in Combination A, 
Cohort A6-A10. 
N per cohort
Number of responses
Observed ORR
90% CI for ORR
20
1
5%
(0.3% - 21.6%)
2
10%
(1.8% - 28.3%)
3
15%
(4.2% - 34.4%)
4
20%
(7.1% - 40.1%)
5
25%
(10.4% - 45.6%)
6
30%
(14.0% - 50.8%)
7
35%
(17.7% - 55.8%)
8
40%
(21.7% - 60.6%)
9
45%
(25.9% - 65.3%)
10
50%
(30.2% - 69.8%)
11
55%
(34.7% -74.1%)
12
60%
(39.4% -78.3%)
13
65%
(44.2% -82.3%)
14
70%
(49.2% - 86.0%)
15
75%
(54.4% - 89.6%)
9.3.2. Combination B: Sample Size Determination for PF-04518600 and Avelumab 
Up to 105 patients (Phase 1b and Phase 2 combined) may be enrolled for Combination B 
treatment.


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For Phase 1b of Combination B, due to the dynamic nature of the Bayesian allocation 
procedure, the exact sample size of the “Up-and-Down” matrix design using the mTPI 
approach cannot be determined in advance.  It is expected that up to 30 patients will need to 
be enrolled in Phase 1b using the mTPI approach.
For Phase 2 of this combination, 25 patients will be enrolled from each of 3 tumor types: 
NSCLC, melanoma, and SCCHN.  Thus up to 75 patients will be enrolled in Phase 2 for 
Combination B.
With 25 patients, ORR can be estimated with a maximum standard error of 10%.
Table 31 provides the exact binomial 90% confidence intervals for ORR based on different 
observed responses in a cohort.
Table 31
Sample Size and Exact 90% CI for ORR in Combinations B, C, and D 
N per cohort
Number of responses
Observed ORR
90% CI for ORR
25
1
4%
(0.2% - 17.6%)
2
8%
(1.4% - 23.1%)
3
12%
(3.4% – 28.2%)
4
16%
(5.7% – 33.0%)
5
20%
(8.2% – 37.5%)
6
24%
(11.0% – 42.0%)
7
28%
(13.9% – 46.2%)
8
32%
(17.0% – 50.4%)
9
36%
(20.2% – 54.4%)
10
40%
(23.6% – 58.3%)
11
44%
(27.0% – 62.1%)
12
48%
(30.5% – 65.9%)
13
52%
(34.1% – 69.5%)
14
56%
(37.9% – 73.0%)
15
60%
(41.7% – 76.4%)
20
80%
(62.5% - 91.8%)
9.3.3. Combination C: Sample Size Determination for PD 0360324 and Avelumab 
Up to 80 patients (Phase 1b and Phase 2 combined) may be enrolled for Combination C 
treatment.  For the Phase 1b part of Combination C, due to the dynamic nature of the 
Bayesian allocation procedure, the exact sample size of the “Up-and-Down” matrix design 
using the mTPI approach cannot be determined in advance.  It is expected that up to 
30 patients will need to be enrolled in the Phase 1b part using the mTPI approach and 
backfill.
For the Phase 2 part of this combination, 2 tumor-specific cohorts of 25 patients each with 
the selected tumor types chosen for evaluation will be enrolled.  The selected tumor types 
will be selected following completion of Phase 1b for the combination. 


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With 25 patients in each cohort, ORR can be estimated with a maximum standard error of 
10%.  Table 31 provides the exact binomial 90% confidence intervals for ORR based on 
different observed responses in a cohort.
9.3.4. Combination D: Sample Size Determination for Utomilumab and
PF-04518600 and Avelumab 
Up to 122 patients (Phase 1b and Phase 2 combined) may be enrolled for Combination D 
treatment. 
For the Phase 1b part of Combination D, due to the dynamic nature of the Bayesian 
allocation procedure, the exact sample size of the “Up-and-Down” matrix design using the 
mTPI approach cannot be determined in advance.  It is expected up to 72 patients may be 
enrolled in the Phase 1b part using the mTPI approach and backfill.
For the Phase 2 part of this combination, 2 tumor-specific cohorts of 25 patients each with 
the selected tumor types chosen for evaluation may be enrolled.  The selected tumor types
will be selected following completion of Phase 1b for the combination. 
The level of clinical activity observed in the Phase 1b part of Combination D, did not support 
further development.  Therefore, Phase 2 is not planned.
With 25 patients in each cohort, ORR can be estimated with a maximum standard error of
10% within each tumor-specific cohort.  Table 31 provides the exact binomial 90% 
confidence intervals for ORR based on different observed responses in a cohort. 
9.3.5. Combination F: Sample Size Determination for CMP-001 and Avelumab and 
Utomilumab or PF-04518600 
Up to 20 patients will be randomized in each of the Cohorts F1, F2 and F3 at the selected 
dose level.
With 20 patients in each cohort, ORR can be estimated with a maximum standard error of 
0.112.  The exact binomial 90% CIs for ORR based on different observed responses for each 
of the cohorts F1, F2 and F3 are as presented in Table 32. 


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Table 32
Sample Size and Exact 90% Confidence Intervals for Objective Response 
Rate in Combination F (Cohorts F1 to F3)
Number per cohort
Number of responses
Observed ORR
90% CI for ORR
20
1
5%
(0.3% - 21.6%)
2
10%
(1.8% - 28.3%)
3
15%
(4.2% - 34.4%)
4
20%
(7.1% - 40.1%)
5
25%
(10.4% - 45.6%)
6
30%
(14.0% - 50.8%)
7
35%
(17.7% - 55.8%)
8
40%
(21.7% - 60.6%)
9
45%
(25.9% - 65.3%)
10
50%
(30.2% - 69.8%)
11
55%
(34.7% -74.1%)
12
60%
(39.4% -78.3%)
13
65%
(44.2% -82.3%)
14
70%
(49.2% - 86.0%)
15
75%
(54.4% - 89.6%)
CI=confidence interval; ORR=objective response rate.
9.4. Efficacy Analysis
All efficacy analyses will be performed for each cohort and combination separately including 
Phase 1b lead-in and Phase 2 patients in the full analysis set. 
In the definitions below, start date refers to the date of randomization for the NSCLC cohorts 
in Combination A, for all the cohorts in Combination F, and to the date of first dose of study 
treatment for all other cohorts in the other Combinations.  For Cohort A8, A9 and A10, 
analysis will be performed for PD-L1 positive patients as assessed by central lab.
OR is defined as a CR or PR per RECIST v1.1 from the start date until disease progression or 
death due to any cause.  Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.  Objective 
response rate (ORR) is defined as the proportion of patients with a confirmed CR or PR per 
Investigator’s assessment according to RECIST v.1.1.  Confirmed responses are those that 
persist on repeat tumor assessments for at least 4 weeks after initial documentation or 
response.  Otherwise, the patient will be counted as a non-responder in the assessment of 
ORR.  Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no follow up assessments) will be considered as non-responders in the 
assessment of ORR.  The two-sided exact 90% CIs for ORR will be calculated.
Progression-Free Survival (PFS) is defined as the time from the start date to the date of 
disease progression by RECIST v1.1 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), for patients who start new anti-cancer treatment prior to an 
event, or for patients with an event after 2 or more missing tumor assessments.  Patients who 
do not have a baseline tumor assessment or who do not have any post-baseline tumor


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assessments will be censored on the start date unless death occurred on or before the time of 
the second planned tumor assessment in which case the death will be considered an event.
Time to Tumor Response (TTR) is defined for patients with confirmed objective response 
(CR or PR) as the time from the start date to the first documentation of objective tumor
response.
Duration of Response (DR) is defined for patients with confirmed objective response (CR or 
PR) as the time from the first documentation of objective tumor response to the first
documentation of objective tumor progression or to death due to any cause, whichever occurs 
first. 
Overall Survival (OS) is defined as the time from the start date to the date of death.  Patients 
without an event (death) will be censored at the date of last contact.
TTR will be summarized using simple descriptive statistics (eg median and range).  DR, PFS, 
and OS will be analyzed using Kaplan-Meier methods and descriptive statistics.  Point 
estimates will be presented with their 90% and 95% confidence intervals.  In addition, 
progression date, death date, date of first response, and last tumor assessment date will be 
listed, together with best overall response (BOR), TTR, DR, and PFS.
9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics of Study Drugs 
Ctrough and Cmax for avelumab (all Combinations), utomilumab (Combination A and 
Combination D), PF-04518600 (Combination B and Combination D), and PD 0360324 
(Combination C) will be summarized descriptively (n, mean, SD, coefficient of variation 
(CV), median, minimum, maximum, geometric mean, its associated CV, and 95% confidence 
interval) by dose, cycle, and day. 
Dose normalized parameters (eg, CDN- Cmax, CDN- Ctrough) will be reported as appropriate.  
The trough concentrations for avelumab, utomilumab, PF-04518600 and PD 0360324 will be 
plotted for each dose using a box whisker plot by cycle and day in order to assess the 
attainment of steady state.  These plots will be used to help understand the relationship 
between PK parameters and dose.
The observed accumulation ratio and the linearity will be summarized descriptively.  Each 
will be analyzed after natural log transformation using a one-way analysis of variance with a 
single term for dose.  The means and 90% confidence intervals (CIs) obtained from the 
model will be back-transformed to provide means and 90% CIs for the accumulation and 
linearity ratios for each dose.  Individual and median profiles will be presented on both 
linear-linear and log-linear scales.
9.5.2. Analysis of Biomarker Endpoints
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.  


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Appropriate change from baseline measurements will be provided.  For discrete measurement 
biomarkers, frequencies and percentages of categorical biomarker measures will be 
determined at baseline and on-treatment/post-treatment time points, as appropriate; shift 
tables may also be provided. 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Wilcoxon signed-rank test, Wilcoxon rank-sum test, correlation/linear 
regression, box-and-whisker plots, etc.  The statistical approaches will examine correlations 
of biomarker results with pharmacokinetic parameters and measures of efficacy, such as 
tumor response and progression free survival.
9.5.3. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
Modeling
PK and PD 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 avelumab plus 
utomilumab (Combination A), avelumab and PF-04518600 (Combination B), avelumab plus 
PD 0360324 (Combination C), or avelumab plus utomilumab plus PF-04518600 
(Combination D), exposure and biomarkers or significant safety endpoints.  The results of 
these analyses, if performed, may be reported separately.
9.5.4. Analysis of Immunogenicity Data of Avelumab and Other Study Drugs
ADA/neutralizing antibody (Nab) data will be listed and summarized for each dosing interval 
for avelumab (all Combinations), utomilumab (Combination A, Combination D, and 
Combination F), PF-04518600 (Combination B, Combination D, and Combination F), 
PD 0360324 (Combination C), and Anti-Qb10 (Combination F).  The percentage of patients 
with positive ADA and Nabs each 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 on avelumab, utomilumab, PF-04518600, and 
PD 0360324 concentrations will be evaluated if data permit.
9.6. Safety Analysis
9.6.1. Analysis of the Primary Endpoint in the Phase 1b Lead-in
DLT is the primary endpoint of the Phase 1b lead-in part of the study for all Combinations 
evaluated. 
Analyses of DLT are based on the DLT-evaluable set.  The occurrence of DLTs and AEs 
constituting DLTs will be summarized and listed per cohort for patients in the Phase 1b 
lead-in (Combination A and Combination F) and summarized and listed for all patients in the 
Phase 1b lead-in (Combinations B, C, and D).
9.6.2. Analysis of Secondary Safety Endpoints
The Safety Analysis Set will be the primary population for safety evaluations.  Summaries of 
AEs and other safety parameters will be performed for each cohort and combination 
separately including Phase 1b lead-in and Phase 2 patients.


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9.6.2.1. Adverse Events
AEs will be graded by the investigator according to the CTCAE v.4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on TEAE, those with initial onset or increasing in severity after the first dose of study 
treatment.  The number and percentage of patients who experienced any AE, 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).
9.6.2.2. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v.4.03 severity grade 
whenever applicable.  The number and percentage of patients who experienced laboratory 
test abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test. 
The analyses will summarize laboratory test results both on the entire study period and by 
cycle (Cycle 1 and Cycles >1). 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
Shift tables will be provided to examine the distribution of laboratory toxicities.
9.6.2.3. Electrocardiograms
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post baseline corrected QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically relevant morphological ECG changes will be summarized (including 
frequency and percentage).


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The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
9.7. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate. 
9.8. Data Safety Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for the study.  For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases.  Procedures include:
Surveillance for serious adverse events (SAEs) according to regulatory guidelines;
Discussions between the investigators and the sponsor of AEs and laboratory tests alterations 
seen at each dose level will be performed in an ongoing manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if further 
enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, address, birth date and other identifiable data will be replaced by a numerical code 
consisting of a numbering system provided by Pfizer in order to de identify the study patient.  
The study site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patient personal data 
consistent with applicable privacy laws.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be
reviewed and approved by the sponsor, approved by the IRB/Independent Ethics Committee 
(IEC) before use, and available for inspection.


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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 document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and Investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study drugs, 
Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.  
13.2. End of Trial in All Other Participating Countries
End of Trial in all other participating countries is defined as Last Subject 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/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab or other immune modulators at any time.


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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 1 month.  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.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the pre-specified protocol or was terminated.
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.


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15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines
Adapted from E.A. Eisenhauer, et al.  New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.35  
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 <15 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.  

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should
not be recorded either as target or non-target disease. Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment/Randomization 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 post-baseline. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
the lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a 
lesion is determined to be present but too small to measure, the lesion status will 
indicate “too small to measure and judged to be less than 10 mm” and 5 mm will be 
used in the calculation of the sum of the diameters.
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 (ie, Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED.  Multiple non-target lesions in one organ may 
be recorded as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
should be discussed with the radiologist and the Sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are not evaluable.  
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.  All target lesions must be assessed.  

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), 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.  

Not evaluable (NE): Progression has not been documented, and 

one or more target 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 
(if being followed).  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 (if 
being followed) 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.  

Not evaluable (NE): Progression has not been determined, and:

one or more non-target lesion sites have not been assessed; or

assessment methods used were inconsistent with those used at baseline; or

one or more non-target lesions cannot be assessed (eg, poorly visible or unclear 
images); or

one or more non-target lesions were excised or irradiated and have not reappeared 
or increased.
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 PD even after discontinuation of study 
treatment.  


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Determination of Tumor Response by RECIST
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in the 
following table.
Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or not all evaluated
No
PR
PR
Non-PD* or not all evaluated
No
PR
SD
Non-PD* or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes**
PD
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment/randomization until disease progression/recurrence (taking as reference for PD the
smallest sum on study).  For CR and PR, the patient’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria.  CR and PR must be 
confirmed by 2 measurements at least 4 weeks apart.  In the case of SD, follow up 
measurements must have met the SD criteria at least once after start of the 
treatment/randomization at a minimum interval of 6 weeks. 


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Appendix 2. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead
From: Oken MM, Creech RH, Tormey DC et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol. 1982; 5: 649–655.


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Appendix 3. Abbreviations and Definitions of Terms
1L
First-line 
4-1BBL
4-1BB Ligand
ACTH
Adrenocorticotropic Hormone
ADA
Anti-Drug Antibody
ADCC
Antibody-Dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIDS 
Acquired Immune Deficiency Syndrome
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine Aminotransferase
ANA
AntinuclearAntibody
ANC
Absolute Neutrophil Count
ANCA
Antineutrophil Cytoplasmic Antibody
APC
Antigen Presenting Cell
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BA
Biomarker Analysis
BID
Twice-Daily
BMDC
Bone marrow-derived dendritic cell
BOR
Best Overall Response
BP
Blood Pressure
BUN 
Blood Urea Nitrogen
CAR 
Chimeric Antigen Receptor
CEA
Carcinoembryonic Antigen
CG
Cockroft-Gault
CI
Confidence Interval
CK-MB
Creatine Kinase – Muscle and Brain Subunits
CL
Clearance
CLE
Cutaneous Lupus Erythematosus
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease 
CPK
Creatine Phosphokinase
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CRS
Cytokine Release Syndrome
CSA
Clinical Study Agreement
CSF-1
Colony-Stimulating Factor-1
CSF-1R
Colony-Stimulating Factor-1 Receptor
CT
Computerized Tomography
CTA
Clinical Trial Application
CTCAE 
Common Terminology Criteria for Adverse Events (US NCI)


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CTL
Cytotoxic T cell
CTLA-4
Cytotoxic T Lymphocyte Associated Protein
CV
Coefficient of Variation
D
De-escalation
DAI
Dosage and Administration Instructions
DC
Dendritic Cell
DILI
Drug-Induced Liver Injury
DL
Dose Level
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
EC
Ethics Committee 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
EDTA
Ethylene Diamene Tetra-acetic Acid
EGFR
Epidermal Growth Factor Receptor
EOT
End of Treatment
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FcR
Fragment Crystallizable gamma Receptor
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin Fixed, Paraffin Embedded
FL
Follicular Lymphoma
FSH
Follicle Stimulating Hormone
GCP 
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GITR
Glucocorticoid Induced TNF Receptor
GLP
Good Laboratory Practices
GVHD
Graft versus Host Disease
HA
Hyaluronic Acid
HBV
Hepatitis B Virus
HCC
Hepatocellular Carcinoma
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDPE
High-Density Polyethylene 
HIV 
Human Immunodeficiency Virus
HPV
Human Papilloma Virus
NIB
Investigator’s Brochure
IASLC
International Association for the Study of Lung Cancer
IB
Investigator’s Brochure
ICH
International Committee Harmonization
ID
Identification
IDO1
Indoleamine 2, 3-dioxygenase 
IEC 
Independent Ethics Committee


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IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL-2
Interleukin-2
IL-12
Interleukin-12
IND
Investigational New Drug
INN
International Nonproprietary Name
INR 
International Normalized Ratio
IP
Investigational Product
irAE
Immune-Related Adverse Event
IRB 
Institutional Review Board
IRR
Infusion-Related Reaction
irRECIST
Immune Related RECIST
irSD
Immune-Related Stable Disease
IRT
Interactive Response Technology
IT
Intra Tumoral
IUD
Intra-Uterine Device
IUS
Intrauterine System
IV
Intravenous
KD
Dissociation Constant
LFT
Liver Function Test
LLOQ
Lower Limit of Quantification
mAb
Monoclonal Antibody
MAD
Maximum Administered Dose
MAP
Mitogen Activated Protein
MCC
Merkel Cell Carcinoma
MCL
Mantle Cell Lymphoma
M-CSF
Macrophage-Colony Stimulating Factor
M-CSFR
Macrophage-Colony Stimulating Factor Receptor
MD
Multiple Dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI 
Magnetic Resonance Imaging
MSI
Microsatellite Instability
MSIhigh
Microsatellite Instability High
MSS
Microsatellite Stable
MTD
Maximum Tolerated Dose
mTPI
Modified Toxicity Probability Interval
NA
North America
Nab
Neutralizing Antibody
NCI 
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
NK
Natural Killer
NKT
Natural Killer T-cell
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
ODN
Oligodeoxynucleotide 


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OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamic
PD
Progressive Disease 
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
pDC
Plasmocytoid Dendritic Cell
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
PO
Per os (orally)
PR
Partial Response
PS
Performance Status
PT
Preferred Term
PT
Prothrombin Time
PVNS 
Pigmented Villonodular Synovitis
Q3D
Every 3 Days
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
Q4W
Every 4 Weeks
QD
Once Daily
R
Rituximab
RA
Rheumatoid Arthritis
RCC
Renal Cell Carcinoma
RE
Re-escalation
RECIST
Response Evaluation Criteria in Solid Tumors
RES
Reticuloendothelial System
RF
Rheumatoid Factor
RNA
Ribonucleic Acid
ROA
Route of administration
RP2D
Recommended Phase 2 Dose
S
Stay (at current dose)
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCCHN
Squamous cell carcinoma of the head and neck
SCLC
Squamous cell lung cancer
SD
Stable Disease
SD
Standard Deviation
SoD
Sum of Diameter
SEM
Standard Error of the Mean
SIB
Suicidal Ideation and Behavior
SOC
Standard of Care


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SOC
System Organ Class
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
Plasma elimination half life
TAM
Tumor Associated Macrophage
TBili
Total Bilirubin
TCGA
The Cancer Genome Atlas
TCR
T-cell Receptor
TE
Target Engagement
TEAE
Treatment Emergent Adverse Event
TGCT
Tenosynovial Giant Cell Tumor
TGI
Tumor Growth Inhibition
Th1
T helper cell type 1
TID
Three-Times-Daily
TIL
Tumor Infiltrating Lymphocytes 
TKI
Tyrosine Kinase Inhibitor
TLS
Tumor-Lysis Syndrome
TLR9
Toll- like receptor 9
Tmax
Time to Maximum Plasma Concentration
TNBC
Triple Negative Breast Cancer
TNF
Tumor Necrosis Factor
TNFRSF
Tumor Necrosis Factor Receptor Superfamily
TO
Target Occupancy
TPS
Tumor Proportion Score
TRAF
TNF Receptor Associated Factor
TSH
Thyroid Stimulating Hormone
TTR
Time to Tumor Response
UK
United Kingdom
ULN 
Upper Limit of Normal
UPM
Unit Probability Mass
US
United States
VLP
Virus Like Particle
Vss
Volume of Distribution
WBC 
White Blood Cell
WHO
World Health Organization


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Appendix 4. CMP-001 Administration
Tumor Selection 
It is recommended that the tumors selected at baseline for CMP-001 intratumoral injection be 
at least 1 cm in diameter and may be cutaneous, subcutaneous, and/or nodal or visceral 
tumors that are visible, palpable, or detectable by appropriate imagining guidance. The 
lesion must be safe to inject. The assessment for safety should consider following aspects:

Proximity to major blood vessels: lesions in the vicinity of large vessels with a risk of 
vessel blow out (eg, the common, internal or external carotid arteries or their 
branches), or other situations with a risk of vascular catastrophe such as tumor-
encased large vessels should be excluded. Special caution should be taken in patients 
with neck lesions that have been re-irradiated, especially if the second course of 
radiation was given at radical doses with curative intent and in whom the disease is 
ulcerated and/or connects to a skin or mucosal surface. Also, patients with tumor 
lesions with macroscopic intravascular tumor invasion (eg, liver lesions with tumor 
infiltration into the main portal vein, hepatic vein or vena cava) should not receive
intratumoral therapy.103

Potential for airway obstruction: lesions in close proximity to airway and potential to 
obstruct airway with slight increase in size should be avoided eg, hypopharynx, 
larynx, trachea.
The most preferred of these to be selected for injection is the most aggressively progressing 
tumor in the judgment of the Investigator. The tumor selected for injection does not need to 
be the largest lesion. 
CMP-001 can be injected into target or non-target lesions, although target lesions are 
preferred.  Preferably single large lesions should be injected with the entire dose of 10 mg.  If 
the total dose of CMP-001 is to be split across lesions, a minimum of approximately 5 mg 
should be injected into each lesion.  The same tumor(s) should be injected each week during 
therapy, if possible, except as outlined below to involuting tumors.  If the full volume cannot 
be administered into the tumor, peritumoral injection of any remaining volume is acceptable.
If over time an injected tumor is clearly responding to therapy (regresses below the minimum 
size that can readily be injected with the required volume), or if in the judgment of the 
Investigator, the patient cannot tolerate continued injections in that lesion because of a local 
injection site reaction or other issues, then the injection may instead be administered 
intratumorally into a different progressing tumor lesion, or peritumorally at the original site 
or into a new tumor lesion site. 
For patients who have a documented Complete Response (CR), the investigator has the 
option to continue study treatment given subcutaneously in an area of the draining lymph 
node where primary disease exists if this is determined to be in the best interest of the patient 
by the Investigator; or study therapy may be discontinued and the patient can continue in 
safety and long term survival follow up.  Therapy for patients taken off-treatment for a 


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confirmed CR may be continued upon subsequent relapse, if there is no intervening 
anticancer therapy and if the relapse occurs within the maximum treatment period specified 
for the study.
Table 33.
CMP-001 Injection Volumes
Dose
Size of lesion to 
be injected in
greatest 
dimension (cm)
Volume of 
injection
Concentration
Of Injection
10 mg
<5 cm
2 mL
5 mg/mL
10 mg
≥5 cm
5 mL
2 mg/mL
The CMP-001 drug product will be supplied at a concentration of 5 mg/mL. Detailed information regarding 
dilutions and injected volumes for multiple lesions can be found in the Pharmacy Manual.
Table 34.
CMP-001 Administration and Requirements
Visit/Dose
CMP-001 Administrationa
Premedications
Post injection 
Observation Period
C1D1 and C1D8
SC (either 
arm, thigh 
or anterior 
abdominal 
wall)
Weekly
Mandated
Required (4 hrs.)
C1D15, C1D22, 
C2D1, C2D8
ITb
Weekly
Mandated
Required (4 hrs.)
C2D15 onwards
ITb
Every 2 weeks
Recommended
Required (can be reduced 
up to 1 hr. based on 
reactions to prior 
injections and clinical 
judgement).
C=cycle; D=day; hr=hour; IT=intratumoral; SC=subcutaneous.
a. CMP-001 will be administered initially as 2 weekly SC doses, followed by IT dosing at weekly intervals for 5 
additional doses.  After the first 7 doses, CMP-001 will be administered IT every 2 weeks (Q2W) (all cohorts).
b. From C2D1, if IT is not feasible then CMP-001 should be administered in peritumoral region. If peritumoral 
administration is not feasible, then SC administration in an area of the draining lymph node where primary 
disease exists should be implemented.  If any of the above is not feasible, then SC (either arm, thigh or anterior 
abdominal wall) should be implemented.
Method of CMP-001 Subcutaneous Administration 
CMP-001 should be injected using aseptic technique. Use of topical and/or local anesthetic 
is permitted. The injection may be given into any SC site in the body. Using standard 
aseptic technique, the needle is inserted into the SC tissue. After using gentle backward 


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pressure on the syringe plunger to confirm extravascular location of the needle tip, the 
desired volume of CMP-001 is injected and the needle is withdrawn.
Initial 2 SC injections (C1D1 and C1D8) can be administered at any suitable subcutaneous 
site (arm, thigh, anterior abdominal wall etc.) as a single injection.
For SC injections following initial IT injections, in order to maximize the distribution and 
exposure to CMP-001, the full volume from a single dose should be distributed to as many 
SC sites as is practical. It is recommended that equal amounts of drug be injected at each SC 
site. Preferred sites of subcutaneous injection include: within the area of lymphatic drainage 
corresponding to the site of metastatic disease. For example, in a patient with a muscle or 
bone metastasis in the lower leg, preferred SC injection sites would be in the same leg, with 
the expectation that at least some of the CMP-001 will drain to lymph nodes that also contain 
tumor antigens. Likewise, in a patient with metastases in an upper lobe of the lung, a 
preferred SC injection site would be in the ipsilateral supraclavicular fossa, where the 
injection may activate pDC in the supraclavicular lymph nodes that also can drain the upper 
lung. Unsuitable sites for injection would include, for example, the palm of the hand or the 
sole of the foot.
Method of CMP-001 Intratumoral Administration
Topical, local, or general anesthesia may be given as appropriate in the Investigators’ 
judgment.  Using standard aseptic technique, the needle is inserted near the tumor periphery 
(Figure 23 left panel) and is advanced into the tumor to the desired depth (usually to the
needle hub, if the tumor size permits) while maintaining gentle backward pressure on the 
syringe plunger to confirm extravascular location of the needle tip.  The syringe and needle 
are then slowly withdrawn to within a few millimeters of the skin or tumor surface while 
maintaining gentle downward pressure on the plunger to inject the desired volume of 
CMP-001 along the needle track (Figure 23, middle panel).  With the tip of the needle still 
within the skin, the syringe is then rotated by approximately 20 to 40o and the process of 
insertion and injection during needle withdrawal is repeated (Figure 23, right panel).  Using 
this process, CMP-001 is injected along multiple tracks through a single insertion point as far 
as the radial reach of the needle allows within the tumor; two insertion points can be used if
the tumor is larger than the radial reach of the needle and the intended CMP-001 volume 
cannot be delivered from a single insertion point.  If gentle injection pressure along five 
needle tracks within the tumor has not succeeded in delivering the desired volume, then the 
remainder of the CMP-001 may be injected in the area of tumor location, around the same 
lesion. 


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Figure 23. Method for CMP-001 Intratumoral Injection
Essentially the same process is performed for subcutaneous, nodal and visceral injections, but 
for deeper injections, the tip of the needle may be kept within the tumor and a longer needle 
may be used.  
For detailed guidance on tumor selection and method of CMP-001 administration refer to the 
Injection Manual.

SAP_001.pdf: 
Avelumab 
B9991004 (MSB0010718C, PF-05082566, PF-04518600, PD 0360324, CMP-001) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 1 
 
JAVELIN MEDLEY 
A PHASE 1B/2 OPEN-LABEL STUDY TO EVALUATE SAFETY, CLINICAL 
ACTIVITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF 
AVELUMAB (MSB0010718C) IN COMBINATION WITH OTHER CANCER 
IMMUNOTHERAPIES IN PATIENTS WITH ADVANCED MALIGNANCIES 
 
STATISTICAL ANALYSIS PLAN – B9991004 
 
Compounds:  
MSB0010718C 
PF-05082566 
PF-04518600 
PD 0360324 
CMP-001 
 
Compound Name: 
Avelumab (MSB0010718C) 
Utomilumab (PF-05082566) 
 
Version: 
Version 6 
Date: 
22-Feb-2022 
 
 
 
 
 
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 


Avelumab 
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Page 2 
TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................5 
LIST OF FIGURES ...................................................................................................................6 
APPENDICES ...........................................................................................................................7 
1. VERSION HISTORY ............................................................................................................8 
2. INTRODUCTION ...............................................................................................................13 
2.1. Study Objectives .....................................................................................................13 
2.2. Study Design ...........................................................................................................14 
2.2.1. Combination A............................................................................................15 
2.2.2. Combination B ............................................................................................17 
2.2.3. Combination C ............................................................................................18 
2.2.4. Combination D............................................................................................20 
2.2.5. Combination F ............................................................................................21 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................22 
3.1. Primary Endpoints ...................................................................................................22 
3.2. Secondary Endpoints ...............................................................................................24 
3.2.1. Safety endpoints ..........................................................................................24 
3.2.2. Pharmacokinetic endpoints .........................................................................24 
3.2.3. Immunogenicity endpoints .........................................................................25 
3.2.4. Efficacy endpoints ......................................................................................25 
3.2.5. Biomarker endpoints ...................................................................................25 
 
3.4. Baseline Variables ...................................................................................................26 
3.4.1. Study drug, study treatment and baseline definitions .................................26 
3.4.2. Baseline characteristics ...............................................................................29 
3.5. Safety Endpoints .....................................................................................................30 
3.5.1. Adverse events ............................................................................................30 
4. ANALYSIS SETS ...............................................................................................................30 
4.1. Full Analysis Set .....................................................................................................30 
4.2. Safety Analysis Set ..................................................................................................30 
4.3. Other Analysis Set ...................................................................................................31 
4.3.1. DLT-evaluable set ......................................................................................31 
CCI


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4.3.2. PK analysis set ............................................................................................31 
4.3.3. Biomarker analysis sets ..............................................................................31 
4.3.4. Immunogenicity analysis sets .....................................................................31 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................32 
5.1. Hypotheses and Decision Rules ..............................................................................32 
5.1.1. Hypotheses and sample size determination ................................................32 
5.1.2. Decision rules .............................................................................................37 
5.2. General Methods .....................................................................................................40 
5.2.1. Data handling after the cut-off date ............................................................41 
5.2.2. Pooling of centers .......................................................................................41 
5.2.3. Presentation of continuous and qualitative variables ..................................41 
5.2.4. Definition of study day ...............................................................................41 
5.2.5. Definition of start of new anti-cancer drug therapy ....................................41 
5.2.6. Definition of start of new anti-cancer therapy ............................................42 
5.2.7. Definition of on-treatment period ...............................................................42 
5.2.8. Standard derivations and reporting conventions .........................................42 
5.2.9. Unscheduled visits ......................................................................................43 
5.2.10. Adequate baseline tumor assessment ........................................................43 
5.2.11. Adequate post-baseline tumor assessment................................................43 
5.3. Methods to Manage Missing Data ..........................................................................43 
5.3.1. Missing data ................................................................................................43 
5.3.1.1. Pharmacokinetic concentrations ................................................44 
5.3.1.2. Pharmacokinetic parameters .....................................................44 
5.3.2. Handling of incomplete dates .....................................................................45 
5.3.2.1. Disease history ..........................................................................45 
5.3.2.2. Adverse events ..........................................................................45 
5.3.2.3. Prior and concomitant medications ...........................................45 
5.3.2.4. Exposure ....................................................................................46 
5.3.3. Imputation rules for date of last contact and efficacy assessments ............46 
5.3.3.1. Date of last contact ....................................................................46 
5.3.3.2. Death date ..................................................................................47 
5.3.3.3. Tumor assessments ....................................................................47 
5.3.3.4. Date of start of new anti-cancer therapy ...................................47 


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6. ANALYSES AND SUMMARIES ......................................................................................49 
6.1. Primary Endpoints ...................................................................................................49 
6.1.1. DLT for Phase 1b lead-in ...........................................................................49 
6.1.1.1. Primary analysis ........................................................................49 
6.1.2. Confirmed OR as assessed by the Investigator per RECIST v1.1 for 
Phase 2 .............................................................................................................50 
6.1.2.1. Primary analysis ........................................................................50 
6.2. Secondary Endpoint(s) ............................................................................................51 
6.2.1. Safety endpoints ..........................................................................................51 
6.2.2. Efficacy endpoints ......................................................................................52 
6.2.2.1. Tumor shrinkage from baseline .................................................52 
6.2.2.2. Disease control ..........................................................................52 
6.2.2.3. Duration of response .................................................................52 
6.2.2.4. Time to response .......................................................................54 
6.2.2.5. Progression-free survival ...........................................................54 
6.2.2.6. Overall Survival ........................................................................56 
6.2.3. Pharmacokinetic endpoints .........................................................................57 
6.2.4. Population pharmacokinetic endpoints .......................................................58 
6.2.5. Biomarker Endpoints ..................................................................................58 
6.2.6. Endpoints for immunogenicity data of avelumab and other study 
drugs .................................................................................................................59 
6.2.6.1. Time to and Duration of ADA response ...................................60 
6.2.6.2. ADA titer ...................................................................................60 
6.2.6.3. Analysis of PK by immunogenicity status ................................61 
 
 
6.4. Subset Analyses .......................................................................................................61 
6.5. Baseline and Other Summaries and Analyses .........................................................62 
6.5.1. Baseline summaries ....................................................................................62 
6.5.1.1. Demographic characteristics .....................................................62 
6.5.1.2. Medical history ..........................................................................63 
6.5.1.3. Disease characteristics ...............................................................64 
6.5.1.4. Prior anti-Cancer therapies ........................................................64 
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6.5.2. Study conduct and patient disposition ........................................................65 
6.5.2.1. Patient disposition .....................................................................65 
6.5.2.2. Protocol deviations ....................................................................67 
6.5.3. Study treatment compliance and exposure .................................................67 
6.5.3.1. Exposure to avelumab ...............................................................68 
6.5.3.2. Exposure to utomilumab ...........................................................69 
6.5.3.3. Exposure to PF-04518600 .........................................................70 
6.5.3.4. Exposure to PD 0360324 ...........................................................70 
6.5.3.5. Exposure to CMP-001 ...............................................................71 
6.5.3.6. Dose reductions .........................................................................72 
6.5.4. Concomitant medications and non-drug treatments ...................................72 
6.5.5. Subsequent anti-cancer therapies ................................................................72 
6.6. Safety Summaries and Analyses .............................................................................73 
6.6.1. Adverse events ............................................................................................73 
6.6.1.1. All adverse events .....................................................................74 
6.6.1.2. Adverse events leading to interruption of study treatment .......75 
6.6.1.3. Adverse events leading to discontinuation of study 
treatment ............................................................................................76 
6.6.2. Deaths .........................................................................................................77 
6.6.3. Serious adverse events ................................................................................77 
6.6.4. Other significant adverse events .................................................................77 
6.6.5. Laboratory data ...........................................................................................78 
6.6.5.1. Hematology and chemistry parameters .....................................78 
6.6.5.2. Other laboratory parameters ......................................................81 
6.6.6. Vital signs ...................................................................................................81 
6.6.7. Electrocardiogram .......................................................................................81 
7. INTERIM ANALYSES .......................................................................................................82 
8. REFERENCES ....................................................................................................................83 
9. APPENDICES .....................................................................................................................84 
 
LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ....................................8 


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Table 2. 
PK Parameters to be Determined for Avelumab, Utomilumab, PF-
04518600 and PD 0360324 ......................................................................24 
Table 3. 
Biomarker Definition and Determination .................................................25 
Table 4. 
Sample Size and Exact 90% CI for ORR in Combination A ...................33 
Table 5. 
Sample Size and Exact 90% CI for ORR in Combinations B, C, and 
D ...............................................................................................................34 
Table 6. 
Sample Size and Exact 90% Confidence Intervals for Objective 
Response Rate in Combination F (Cohorts F1, F2 and F3) ......................37 
Table 7.  
Probability of Expanding Dose .................................................................37 
Table 8. 
Combination F: Probability of Expanding Dose Level ............................40 
Table 9. 
Outcome and Event Dates for DR Analyses .............................................53 
Table 10.  
DR Censoring Reasons and Hierarchy .....................................................54 
Table 11. 
Outcome and Event Dates for PFS Analyses ...........................................55 
Table 12. 
PFS Censoring Reasons and Hierarchy ....................................................56 
Table 13. 
OS Censoring Reasons and Hierarchy ......................................................57 
Table 14.  
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................59 
Table 15. 
Case Definition for irAEs .........................................................................84 
Table 16. 
Case Definition for IRRs – IV Study Drugs Administered Alone Or 
In Combination With Non-IV Study Drugs..............................................86 
Table 17. 
Case Definition for IRRs – IV Study Drugs Administered in 
Combination (eg, Doublets or Triplets) ....................................................87 
 
LIST OF FIGURES 
Figure 1. 
Combination A Phase 1b and Phase 2 Study Design 
Schema - NSCLC Only (Cohorts A1, A2, A3) ........................................15 
Figure 2. 
Combination A Phase 2 Study Design Schema - Melanoma (Cohort 
A4), SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort 
A7), and First-Line NSCLC (Cohort A8) .................................................15 
Figure 3. 
Combination A Phase 2 Study Design Schema – Sequenced 
Administration in Patients with First-Line NSCLC (Cohort A9 and 
Cohort A10) ..............................................................................................16 
Figure 4. 
Combination B Phase 1b and Phase 2 Study Design Schema ..................17 
Figure 5.  
Combination C Phase 1b and Phase 2 Study Design Schema ..................18 
Figure 6. 
Combination D Phase 1b and Phase 2 Study Design Schema* ................20 
Figure 7.  
Combination F Phases 1b and Phase 2 Study Design Schema .................21 


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APPENDICES 
Appendix 1. Immune-Related Adverse Events ........................................................................84 
Appendix 2. Infusion Related Reactions .................................................................................86 


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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study B9991004 is based on the protocol amendment 
8 dated 27-Feb-2019.  
Table 1. 
Summary of Major Changes in SAP Amendments 
Version 
Version Date 
Summary of Changes 
6 
22-Feb-2022 
Section 2 “Introduction” - this section was modified to indicate that the primary 
analysis will occur after last subject last visit across all tumor types and 
combinations. 
Section 6.4 “Subset Analyses” - relapse and resistant categories for prior 
checkpoint inhibitor status are now combined. 
Section 6.2.6.1 “Time to and Duration of ADA” - removed text regarding 
assessments after discontinuation for censoring. 
Section 6.2.2.6 “Overall Survival” -  added the following text “OS analysis will 
be conducted for patients up to LSLV of the study”. 
Minor editorial and consistency changes throughout the document. 
5 
17-Dec-2020 
Section 3.4.2 “Baseline characteristics” - removed “physical measurements”. 
Section 6.2.2.3 “Duration of response” - removed listing for DR. 
Section 6.2.2.5 “Progression-free survival” - removed time of follow-up for 
PFS. 
Section 6.2.2.6 “Overall survival” - removed time of follow-up for OS. 
Section 6.2.3 “Pharmacokinetic endpoints” - removed linear-linear and log-
linear PK plots. 
Section 6.2.6.3 “Analysis of PK by immunogenicity status”- removed data 
listing for immunogenicity and relevant PK and safety data; removed “safety” 
from header. 
Section 6.2.6.3 “Analysis of PK by immunogenicity status” - removed safety 
and immunogenicity summaries; removed log-linear plots. 
Section 6.4 “Subset Analyses” - combined subset of prior PD-1 and PD-L1 into 
PD-1/PD-L1; added in PD-L1 subset analysis and CD8 descriptive analysis by 
OR. 
Section 6.5.1 “Baseline summaries” - updated listing to Prior anti-cancer drug 
therapies. 
Section 6.5.1.1 “Demographic characteristics” - removed reference to “physical 
measurements”, and to height, weight, BMI and BSA. 
Section 6.5.4 “Concomitant medications and non-drug treatments” - removed 
prior medication summaries and listings; removed anti- cancer treatment 
listings. 
Section 6.6.1.1 “All adverse events” - removed summary of TEAE leading to 
interruption of individual study drugs and included any study drug; Removed 
redundant summary for TEAE; removed summaries for TEAEs by SOC and PT 
related to each study drug; added TEAEs related to any study drug by SOC and 
PT and grade. 
Section 6.6.1.2 “Adverse events leading to interruption of study treatment” - 
removed summary of TEAE leading to interruption of CMP. 
Section 6.6.5.1 “Hematology and chemistry parameters” - removed summary of 
laboratory parameters by CTCAE grade table. 
Section 6.6.4 “Other significant adverse events” - removed summary of irAE 
(and IRR) leading to discontinuation of a study drugs (except Avelumab); 
removed summary of irAE (and IRR) by death and grade >=3.  
Section 6.6.5.2 “Other laboratory parameters” - removed listing of abnormal 
values for hematology, chemistry, urinalysis, and coagulation. 
Section 6.6.6 “Vital signs” - removed vital signs summaries. 


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Section 6.6.7 “Electrocardiogram” - removed ECG listings and ECG summaries 
by timepoint. 
Table 15 “Case Definition for irAEs” - added in “Steps 3 and 4 will be checked 
concurrently. Step 5 will be checked if the criteria in Step 4 is met, irrespective 
of whether the Criteria in Step 3 is met”.  
4 
10-Jun-2019 
Updated study objectives (Section 2.1), endpoints (Section 3.1, Section 3.3, 
Section 6.3), study design (Section 2.2), study treatments (Section 3.4.1), 
definition of DLT-evaluable set (Section 4.3.1), sample size (Section 5.1.1), 
decision rules (Section 5.1.2) and associated statistical considerations (Section 6 
and subsections) as per revisions in Protocol Amendments 6 through 8. 
In addition, the following updates were made to the SAP. 
Sections 3.2.2 and 6.2.3 “Pharmacokinetic endpoints” – aligned content of 
Table 2 and associated analyses to the protocol-specified endpoints. 
Section 3.2.3 “Immunogenicity endpoints”, Section 4.3.4 “Immunogenicity 
analysis set”, Section 6.2.6 “Endpoints for immunogenicity data of avelumab 
and other study drugs” – deleted reference to neutralizing antibodies (nAb) 
since not specified in the protocol. 
Section 3.4.1 “Study drug, study treatment and baseline definitions” – added 
definition of baseline for immunogenicity analyses. 
Section 3.5 “Adverse Events” - the definition of Treatment-emergent adverse 
events (TEAEs) was modified to include all AEs with onset date during the on-
treatment period.  Cytokine Release Syndrome was added as an AE of special 
interest for Combination F. 
Section 5.2.10 “Adequate baseline tumor assessment” - the criteria were 
updated to include only criteria that can be derived programmatically.  
Section 5.3.3.1 “Date of last contact” – added withdrawal of consent date in the 
derivation of date of last contact. 
Section 5.3.3.4 “Date of start of new anti-cancer therapy” – revised to include 
additional details of imputation rules for incomplete dates for start date of new 
anti-cancer therapy. 
Section 6.2.2.3 “Duration of response” – added details regarding censoring for 
duration of response since “no adequate baseline assessment” which is used in 
censoring for PFS analyses is not applicable to analyses of duration of response 
for patients with objective response.  Updated the time points for derivation of 
DR rates to be aligned with the schedule of tumor assessments. 
Section 6.2.2.5 “Progression-free survival” - updated the time points for 
derivation of PFS rates to be aligned with the schedule of tumor assessments; 
added further details for summary of time of follow-up for PFS. 
Section 6.2.2.6 “Overall survival” – updated the time points for derivation of 
OS rates; added further details for summary of time of follow-up for OS. 
Section 6.2.5 “Biomarker endpoints” – simplified analyses to include only 
descriptive summaries. 
Section 6.2.6 “Endpoints for immunogenicity data of avelumab and other study 
drugs”- added details for the analyses of ADA. 
Section 6.5.1.3 “Disease characteristics” – simplified summaries for smoking 
history. 
Section 6.5.1.4 “Prior anti-cancer therapies” – aligned with data collected in 
eCRF. 
Section 6.5.2.1 “Patient disposition” – deleted references to randomization 
stratification factors since not applicable to the study. 
Section 6.5.3 “Study treatment compliance and exposure” – added derivations 
for CMP-001 as per Protocol Amendment 8; deleted by-cycle summaries; 
deleted summaries for dose omissions, dose delays, infusion rate reductions and 


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infusion interruptions since such changes are captured in the overall derivation 
of relative dose intensity. 
Section 6.6.1 “Adverse events” and subsections – updated definition of 
treatment-emergent adverse event; added summaries of AEs leading to 
interruption of study drug; added summaries for cykotine release syndrome 
(Combination F only); given the nature of immune-related AEs (irAEs) and 
infusion related reactions (IRRs), removed the summaries of treatment-related 
irAEs and treatment-related IRRs; removed the requirement that all summaries 
by SOC and PT will be replicated by PT only.   
Section 6.6.2 “Death” – deleted references to primary reason for death since not 
collected in the eCRF. 
Section 6.6.5 “Laboratory data” and subsections –added summary for patients 
with newly occurring or worsening laboratory abnormities; updated lab 
parameters as per protocol; deleted summaries of laboratory data by time point 
since the data can adequately be characterized and interpreted based on CTCAE 
grade and shift tables to low, normal and high for parameters that are not graded 
per CTCAE. 
Section 6.6.7 “Electrocardiogram” – deleted QTcP since the number of patients 
enrolled in each cohort is small.  
Section for “Physical Examination” was removed as data not collected in the 
eCRF (abnormal findings are reported as AEs). 
Section 8 ”References” – references updated. 
Appendix 1 “Immune-related Adverse Events” – updated the ATC codes for 
concomitant medications in Step 4 of the case definition for irAEs and added a 
statement regarding medical review if needed to refine the programmatic 
derivation. 
Minor editorial and consistency changes throughout the document. 
3 
06-Dec-2016 
Updated objectives, endpoints, study design, sample size and other statistical 
considerations as per revisions in Protocol Amendment 5, namely as it pertains 
to the addition of the SCLC and 1L NSCLC cohorts in Phase 2 of Combination 
A, addition of Combinations C and D.  Additional changes and updates 
described below. 
Section 2 “Introduction” – changed the cut-off date for the primary CSR from 
12 to 18 months after last patient first treatment to allow for efficacy data to 
mature and to have longer follow-up for safety.   
Section 3.4.1 “Study drug, study treatment and baseline definitions” – added 
definition of end date of study treatment; referred to RR instead of heart rate in 
ECG baseline derivations since the CRF collects RR rather than heart rate. 
Start of new anti-cancer drug therapy and start of new anti-cancer therapy are 
added in Sections 5.2.5 and 5.2.6, respectively.  
Section 5.2.10 “Adequate baseline tumor assessment” and 5.2.11 “Adequate 
post-baseline tumor assessment” were added 
Section 5.3.3.4 “Date of start of new anti-cancer therapy” was added to provide 
details of imputation rules for incomplete dates for start date of new anti-cancer 
therapy (drug therapy, radiation, surgery). 
Section 6.1.2.1 “Primary analysis” of OR by investigator assessment – added an 
additional reason for BOR of NE associated with inadequate or missing 
baseline assessment; included an additional reason for NE associated with death 
prior to first post-baseline tumor assessment; added definition of BOR of non-
CR/non-PD for patients without measurable disease at baseline. 
Section 6.2.2.2 “Disease control” –corrected the definition of DC to include 
BOR of non-CR/non-PD to take into account patients without measurable 
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Section 6.2.2.5 “Progression-free survival”– provided more details and 
hierarchy associated with the derivation of reasons for censoring. 
Section 6.2.2.6 “Overall survival” – provided more details and hierarchy 
associated with the derivation of reasons for censoring. 
Section 6.3.1 “irRECIST endpoints” – added irNE as a category for irBOR and 
provided more details for outcome and event dates for irPFS and irDR as was 
done for PFS and DR. 
Section 6.4 “Subset Analyses” – added subcategories to prior checkpoint 
inhibitor status (now includes relapsed, refractory, resistant, naïve). 
Section 6.5.1.1 “Demographic characteristics” – added Middle East as another 
possible geographic region and changed the geographic region Australia to 
Australasia. 
Section 6.5.1.3 “Disease characteristics” – added time since diagnosis of 
local/regional recurrence of disease. 
Section 6.5.1.4 “Prior anti-cancer therapies” – clarified that prior anti-cancer 
therapies will be listed together with concomitant and follow-up therapies but 
with a flag to identify them as prior therapies. Removed the summary of prior 
anti-cancer drug therapies and radiotherapy due to the first-line setting of the 
study.  
Section 6.5.2.1 “Patient disposition” –clarified the summary descriptions to 
match the CRF data collection and descriptors 
Section 6.5.3 “Study treatment compliance and exposure” – provided details 
regarding cycle derivations  
Section 6.5.3.6 “Dose omissions” and Section 6.5.3.9 “Infusion interruptions” 
were added. 
Section 6.5.3.7 “Dose delays” – provided further derivation details. 
Section 6.5.3.8 “Infusion rate reductions” – added further derivation details. 
Section 6.5.4 “Concomitant medications and non-drug therapies” – non-drug 
treatments will be listed but not summarized 
Section 6.5.5 “Subsequent anti-cancer therapies” – deleted the summary of 
BOR across all anti-cancer drug therapies since not meaningful from a clinical 
standpoint. 
Section 6.6.1 “Adverse events” and subsections – corrected details associated 
with irAE and IRR based on FDA feedback. 
Section 6.6.5 “Laboratory data” and subsections –corrected the descriptor of the 
eDISH plot; changed the formula for corrected calcium to be expressed in SI 
units; clarified that the denominator to calculate percentages for each laboratory 
parameter is the number of patients evaluable for the particular summary. 
Section 6.6.7 “Electrocardiogram” – clarified that the denominator to calculate 
percentages for each category is the number of patients evaluable for the 
particular summary.  Deleted the summary for patients with ECG abnormalities 
based on morphology since collected in a free text field. 
Section 9 “Appendices” – added appendices with the irAE and IRR derivation 
rules; deleted the tabulation of cycle derivations since included with more 
details in the exposure section. 
Minor editorial and consistency changes throughout the document. 
2 
01-Apr-2016 
Changed objectives, endpoints, and other statistical considerations as per 
revisions in Protocol Amendment 2 
Phase 2 study design for Combination A updated to include TNBC cohort.  
Phase 1b dose-escalation lead-in and Phase 2 for Combination B added to study 
design.  
Analysis sets updated to include those for Combination B.  


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Added statistical methods and decision rules for Combination B. 
Updated to include sample size determination for the TNBC cohort for 
Combination A and sample size determination for Combination B.  
Updated to include Combination B in efficacy analysis. 
Updated document throughout to include specific details for Combination B. 
1 
03-Sep-2015 
Original SAP 
 


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2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991004. 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, 
biopsy data from the central laboratory and pharmacokinetic (PK) data).  
The primary analysis will occur after the last subject last visit (LSLV) has been achieved 
across all tumor types and combinations.  
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. 
2.1. Study Objectives 
Primary Objectives 
• Phase 1b lead-in: To assess safety and tolerability of a single dose level of avelumab in 
combination with increasing dose levels of other immune modulators in patients with 
locally advanced or metastatic solid tumors in order to select the recommended Phase 2 
dose(s) [RP2D(s)]/schedule for the combination.  
• Phase 2: To assess objective response (OR) of avelumab in combination with other 
immune modulators in patients with locally advanced or metastatic solid tumors. 
Secondary Objectives 
• To assess the overall safety and tolerability of avelumab and other immune modulators 
when given in combination;  
• To characterize the PK of avelumab and other immune modulators when given in 
combination; 
• To evaluate the immunogenicity of avelumab and other immune modulators when given 
in combination; 
• To assess the antitumor activity of avelumab and other immune modulators when given 
in combination in patients with locally advanced or metastatic solid tumors;  
• To assess the correlation of antitumor activity of avelumab and other immune modulators 
with immune biomarkers in baseline tumor tissue. 


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• 
 
 
 
 
• 
 
 
2.2. Study Design 
This is a Phase 1b/2, open-label, multi-center, multiple-dose, safety, clinical activity, PK, and 
PD study of avelumab in combination with other immune modulators in adult patients with 
locally advanced or metastatic solid tumors (eg, NSCLC, melanoma, SCCHN, TNBC, gastric 
cancer, ovarian cancer, bladder cancer, or SCLC).  Combinations of avelumab plus other 
immune modulator(s) to be evaluated are as follows: 
• Combination A: Avelumab plus utomilumab (4-1BB agonist mAb); 
• Combination B: Avelumab plus PF-04518600 (OX40 agonist mAb); 
• Combination C: Avelumab plus PD 0360324 (M-CSF mAb); 
• Combination D: Avelumab plus utomilumab plus PF-04518600; 
• Combination F: avelumab plus CMP-001 (TLR9 agonist) and utomilumab or 
PF-04518600;  
- Cohort F1: avelumab plus CMP-001; 
- Cohort F2: avelumab plus CMP-001 and utomilumab;  
- Cohort F3: avelumab plus CMP-001 and PF-04518600. 
Patients are not allowed to crossover between the different combinations evaluated in this 
study. 
Each combination will be studied individually in 2 study parts:  
1) a Phase 1b lead-in to evaluate safety, and determine the maximum tolerated dose (MTD) 
or maximum administered dose (MAD) and RP2D (if applicable), of the combination, 
and  
2) a Phase 2 to evaluate efficacy and further evaluate safety of the selected dose from the 
Phase 1b part in prespecified patient populations.   
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2.2.1. Combination A 
Figure 1. Combination A Phase 1b and Phase 2 Study Design Schema - NSCLC Only 
(Cohorts A1, A2, A3) 
 
Figure 2. Combination A Phase 2 Study Design Schema - Melanoma (Cohort A4), 
SCCHN (Cohort A5), TNBC (Cohort A6), SCLC (Cohort A7), and 
First-Line NSCLC (Cohort A8) 
 
* Utomilumab dose = 100 mg (may be modified based on emerging data) 


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Figure 3. Combination A Phase 2 Study Design Schema – Sequenced Administration 
in Patients with First-Line NSCLC (Cohort A9 and Cohort A10) 
 
 
Phase 1b lead-in 
During Phase 1b, up to 18 NSCLC patients will be randomized 1:1:1 to 1 of 3 cohorts 
(6 patients each) to receive utomilumab at 500 mg (Cohort A1), 100 mg (Cohort A2), or 
20 mg (Cohort A3) administered intravenously (IV) every 4 weeks (Q4W) in combination 
with 10 mg/kg of avelumab administered IV every 2 weeks (Q2W) for 2 cycles (ie, 8 weeks).  
If a dose-limiting toxicity (DLT) is observed in at least 2 of 6 DLT-evaluable patients treated 
within a cohort, further evaluation of the cohort will be stopped. Patients treated in Phase 1b 
who are not considered DLT evaluable (as defined in Section 3.1) will be replaced for the 
assessment of the DLT rate in the cohort to which they were randomized. 
Phase 2 
For each utomilumab dose level that is tolerated (ie, not meeting the DLT criteria) in the 
Phase 1b lead-in, the corresponding dose level cohort(s) will continue enrollment for 
Phase 2 with up to 22 additional patients each.  Therefore, all 3 cohorts could potentially 
enroll additional patients. 
In addition to potential expansion of enrollment of patients with NSCLC to 
Cohorts A1, A2, or A3, Phase 2 will also enroll patients with melanoma (Cohort A4; N=28), 
SCCHN (Cohort A5; N=35), TNBC (Cohort A6; N=20), SCLC (Cohort A7; N=20), and 
first-line advanced NSCLC (Cohort A8; N=20, up to 26 patients will be enrolled to achieve a 
minimum of 20 PD-L1-positive patients).  Enrollment into Cohorts A7 and A8 may be staged 
based on activity observed during the Phase 1b part of the combination (ie, new cohorts may 
be opened based on activity data emerging from the randomized dose level cohorts of 
Combination A).  
For Cohorts A4 through A8, the projected utomilumab dose to be used in each of these cohorts 
is 100 mg which may be modified based upon emerging safety data for utomilumab from 
randomized dose cohorts of Combination A.  In the event that the utomilumab dose is modified 
after the initiation of Cohorts A4 through A8, additional patients will be enrolled to achieve 
the target number of patients treated at the modified dose. 
Sequenced (single agent administration for 1 cycle followed by combination therapy) 
administration of single agent avelumab or utomilumab for 1 cycle followed by administration 
of combination (avelumab plus utomilumab) will be evaluated in 2 additional cohorts.  Both 
cohorts will enroll 20 patients each with PD-L1 positive, 1L advanced NSCLC.  Cohort A9 


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will evaluate utomilumab single-agent administration, one month prior to initiation of 
combination treatment on Cycle 2 Day 1 (28 days after start of the single-agent treatment).  
Cohort A10 will evaluate avelumab single-agent administration, one month prior to initiation 
of combination treatment on Cycle 2 Day 1 (28 days after start of the single-agent treatment).  
Patients will be randomized 1:1 to Cohorts A9 and A10. 
Originally, approximately 253 patients with solid tumors were planned to be enrolled in 
Combination A across all cohorts.  Enrollment of patients into Cohorts A1 to A6 and A8 
were completed as planned.  In Cohort A7, 10 SCLC patients were enrolled.  However, the 
level of clinical activity observed in Cohort A7 does not support further clinical development 
and further enrollment in this cohort is not planned.  In addition, due to recent improvements 
in the standard of care for 1L NSCLC patients, the level of clinical activity observed in 
Cohort A10 does not support further development.  Given that Cohort A9 and A10 use 1:1 
randomization for enrollment, further enrollment in Cohort A9 alone would not conform with 
the study design.  Therefore, further enrollment in Cohorts A7, A9, and A10 is not planned. 
2.2.2. Combination B  
Figure 4. Combination B Phase 1b and Phase 2 Study Design Schema 
 
Phase 1b lead-in 
In the Phase 1b part for Combination B, patients with locally advanced or metastatic solid 
tumors will be evaluated to identify the MTD or MAD of avelumab plus PF-04518600 using 
the modified toxicity probability index (mTPI) design as described in Section 5.1.2.  Patients 
will receive PF-04518600 Q2W in combination with 10 mg/kg avelumab Q2W for 2 cycles 
(8 weeks).   
The starting dose level (B12) for Combination B is 0.3 mg/kg PF-04518600 Q2W plus 
10 mg/kg avelumab Q2W.  Initially 3 patients will be enrolled, treated, and monitored during 
the 8-week DLT period.  If recommended by the mTPI design, the dose level can be 
a) expanded in cohorts of up to 3 patients and then up to an additional 6 patients, b) escalated 
to the next dose level, or c) de-escalated to a lower dose level.  A total of 12 patients will be 


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treated at the RP2D.  If at any point the mTPI requires a de-escalation, the next 3 patients 
will be enrolled at the lower dose level as described in Section 5.1.2.  Dose escalation will be 
allowed as long as the next highest dose level has not been determined to have exceeded the 
MTD.  
Following the 8-week DLT observation period, if no patients experience DLTs, the next 
higher dose cohort may be initiated.  Initially 3 patients will be assigned to a new open dose 
level.  Up to 3 patients can be added at the same dose level if no DLTs are observed after 
4 weeks of observation.  After the first 3 patients enrolled in a dose escalation cohort have 
completed the 8-week DLT period, additional cohorts of up to 6 patients each may be 
enrolled into any dose level that has been deemed safe (if recommended by the mTPI design) 
for a total of 12 patients to obtain additional safety and PD data.   
Phase 2 
Once the Phase 1b part is completed and the MTD or MAD is determined, the Phase 2 part of 
Combination B will be initiated.  During Phase 2, patients with NSCLC, melanoma, or 
SCCHN will be enrolled into 3 separate cohorts of 25 patients each to evaluate safety and 
efficacy at the RP2D determined during Phase 1b for those tumor types. 
Originally, approximately 105 patients were planned to be enrolled in Combination B.  
Enrollment in Phase 1 was completed and enrollment in the Phase 2 SCCHN cohort was also 
completed. The safety profile on this combination was acceptable and there was evidence of 
pharmacodynamic activity. However, the observed clinical activity does not support further 
development.  Therefore, the completion of patient enrollment into the Phase 2 NSCLC 
cohort and the initiation of enrollment into the Phase 2 melanoma cohort are not planned. 
2.2.3. Combination C  
Figure 5.  Combination C Phase 1b and Phase 2 Study Design Schema  
 
Phase 1b lead-in 
In the Phase 1b lead-in for Combination C, patients with locally advanced or metastatic solid 
tumors will be evaluated to identify the MTD or MAD of avelumab plus PD 0360324 using 


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the mTPI design described in Section 5.1.2.  Patients will receive PD 0360324 Q2W in 
combination with 10 mg/kg avelumab Q2W for 2 cycles (8 weeks).   
If recommended by the mTPI design, a dose level may be a) expanded in cohorts of up to 
3 patients and then up to an additional 4 patients, b) escalated to the next dose level, or 
c) de-escalated to a lower dose level.  
The starting dose level (C11) of Combination C is 50 mg PD 0360324 Q2W plus 10 mg/kg 
avelumab Q2W.  Starting with dose level C11, 3 patients will be enrolled, treated, and 
monitored during the 8-week DLT period.  If at any point the mTPI requires a de-escalation, 
the next 3 patients will be enrolled at the lower dose level as described in Section 5.1.2.  
Dose escalation will be allowed as long as the next highest dose level has not been 
determined to have exceeded the MTD.  
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is re-confirmed per mTPI design.  
During Phase 1b, if allowed by the mTPI design, a cohort may be expanded to approximately 
10 patients total to collect additional safety, clinical activity, and biomarker related data.  
Phase 2 
Once the Phase 1b is completed and the MTD or MAD is determined, the Phase 2 part of 
Combination C will be initiated to evaluate safety and efficacy at the RP2D determined 
during Phase 1b. Up to 2 tumor types among the following will be selected for evaluation: 
ovarian cancer, SCCHN, NSCLC, gastric cancer.   
Originally, approximately 80 patients were planned to be enrolled in Combination C.  
However, the level of clinical activity observed in cohorts C11, C12, and C13, did not 
support development beyond Phase 1b.  Therefore, Phase 2 is not planned. 


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2.2.4. Combination D 
Figure 6. Combination D Phase 1b and Phase 2 Study Design Schema*  
* A solid arrow to a dose level implies that only the dose level from which the arrow is originating needs to be 
safe (escalate per mTPI design) for that dose level to be opened.  For example, D21 can be opened if D11 is safe 
and D31 can be opened if D21 is safe.  A dashed arrow to a dose level implies that more than 1 dose level is 
required to be safe (escalate per mTPI design for more than 1 dose level) for that dose level to be opened.  For 
example, D12 and D21 both need to be safe (escalate per mTPI design for both) for D22 to be opened, and D31 
and D22 both need to be safe for D32 to be opened.  Cohorts D12 and D21 and Cohorts D22 and D31 may be 
opened and enroll patients in parallel since only either utomilumab or PF 04518600 is escalated at a time. 
Phase 1b lead-in 
In the Phase 1b part for Combination D, patients with locally advanced or metastatic solid 
tumors will be evaluated to identify the MTD or MAD of avelumab plus utomilumab plus 
PF-04518600 using the mTPI design described in Section 5.1.2.  Patients will receive 
utomilumab plus PF-04518600 in combination with avelumab Q2W for 2 cycles (8 weeks) 
and will be evaluated for DLT. 
The starting dose level (D11) for Combination D is 20 mg utomilumab Q4W plus 0.1 mg/kg 
PF-04518600 Q2W plus 10 mg/kg avelumab Q2W.  The initiation of patient recruitment at 
D11 is dependent upon the observation of no more than 1 DLT out of 6 patients treated in 
Phase 1b Combinations A and B at 500 mg utomilumab and 1 mg/kg PF-04518600, 
respectively.  As of 30 September 2016, this study has completed the Phase 1b part of 
Combination A with no DLTs observed and, for the Phase 1b part of Combination B, no 
DLTs have been observed at the starting dose level of 0.3 mg/kg PF-04518600 (B12) with 
evaluation of the 1 mg/kg PF-04158600 dose level ongoing.  Since no DLTs were observed 
during Phase 1b of Combination A, Combination D will be initiated once the safety of the 
1 mg/kg PF-04518600 dose level of Combination B is confirmed (eg, dose is acceptable per 
mTPI design following treatment of at least 6 patients treated at that dose or higher).  
If recommended by the mTPI design, a dose level can be a) expanded in cohorts of up to 
3 patients and then up to an additional 6 patients, b) escalated to the next dose level, or c) 
de-escalated to a lower dose level.  


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Starting with dose level D11, 3 patients will be enrolled, treated, and monitored during the 
8-week DLT period.  If at any point the mTPI requires de-escalation, the next 3 patients will 
be enrolled at the lower dose level as described in Section 5.1.2.  Dose escalation will be 
allowed as the dose level satisfies the mTPI criteria. 
In addition, if a DLT is observed in a lower dose level previously determined to be safe per 
mTPI, enrollment of additional patients in the higher dose levels will be delayed until the 
safety of the lower dose is re-confirmed per mTPI design. 
During Phase 1b, if allowed by the mTPI design, a cohort maybe expanded to approximately 
12 patients total to collect additional safety, clinical activity, and biomarker related data.  
Phase 2 
Once the Phase 1b lead-in is completed and the MTD or MAD is determined, the 
Phase 2 part of Combination D may be initiated to evaluate the safety and efficacy at the 
RP2D (one or more dose levels) determined during Phase 1b, if the safety and clinical 
activity are supportive of further development.  Up to 2 tumor types among the following 
may be selected for evaluation: NSCLC, melanoma, SCCHN, or bladder cancer.   
Up to approximately 122 patients will be enrolled for Combination D treatment.     
2.2.5. Combination F 
Figure 7.  Combination F Phases 1b and Phase 2 Study Design Schema 
 
Phase 1b lead-in and Phase 2 
In the Phase 1b safety lead-in, patients will initially be randomized 1:1:1 into each of Cohorts 
F1, F2, and F3.  Six DLT evaluable patients are needed to assess safety in each cohort.  
Patients who are not evaluable for DLTs, might be replaced by enrolling patients without 
randomization. 
Up to 12 patients will be randomized into each cohort in the Phase 1b lead-in and evaluated 
for DLT during the first treatment cycle (4 weeks) as described in Section 5.1.1. 


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If one cohort is discontinued, patients will be randomized to the remaining cohorts in a 1:1 
ratio.  Therefore, the total number of possible enrolled patients per cohort may be 
approximately 20 patients for cohorts that do not meet the stopping criteria and the total 
number of patients enrolled for this combination may be approximately 60 patients.  
In addition to the rules for the continuation of a cohort based on DLTs, the Sponsor will 
monitor DLTs across the cohorts and may elect to pause or discontinue patient enrollment at 
any time based on emerging safety and efficacy data from the current study or other studies 
with CMP-001. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
• Phase 1b lead-in:  
- First 2 Cycles DLT(s) for Combinations A, B, C and D; 
- First Cycle DLT(s) for Combination F only.  
Severity of adverse events (AEs) will be graded according to Common Terminology 
Criteria for Adverse Events [CTCAE] v.4.03.  For the purpose of the Phase 1b lead-in, 
any of the following AEs occurring during the DLT observation period (the first 2 cycles 
of treatment [8 weeks] for combinations A to D, and the first treatment cycle [4 weeks] 
for combination F) which are attributable to one or more of the investigational products 
in the combination 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 ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (>101 degrees F) or a sustained temperature of 38 degrees C 
(100.4 degrees F) for more than 1 hour;  
• Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection); 
• Grade 3 thrombocytopenia (platelet count <50,000 - 25,000/mm3 or <50.0 – 25.0 x 
109/L) with bleeding; 
• Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L); 
• Grade 4 anemia. 
Non-Hematologic (Non-Laboratory): 
• Any Grade 3 toxicity, except for any of the following: 


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• Transient (24 hours) Grade 3 fatigue, local reactions, or headache that resolves 
to Grade 1; 
• Grade 3-4 nausea and vomiting controlled by optimal medical therapy within 
72 hours; 
• Grade 3 hypertension controlled by medical therapy; 
• Grade 3 diarrhea that improves to Grade 2 within 72 hrs after medical 
management has been initiated;  
• Grade 3 skin toxicity that resolves to Grade 1 in less than 7 days after medical 
management (eg, immunosuppressant treatment) has been initiated; 
• Any Grade 3 amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis; 
• Grade 3 endocrinopathies controlled with medical therapy; 
• Tumors flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor. 
• Grade 4 CRS or Grade 3 CRS lasting >24 hours despite optimal treatment. 
Important for Combination F: CMP-001 activates pDCs through agonism of TLR9.  
Upon activation by CMP-001, pDCs will induce large amounts of IFNα and Th1-
promoting cytokines.  Therefore, it is expected that toxicities associated with CMP-001 
dosing may resemble interferon-related toxicities and symptoms associated with cytokine 
release, such as fever, flu-like symptoms, tachypnea, headache, tachycardia, hypotension, 
rash, and hypoxia which may present hours after CMP-001 injection.  Therefore, AEs 
such as headache, fever, flu-like symptoms and/or hypotension that are ≤ Grade 3 AND 
resolved to ≤ Grade 1 within 24 hours with standard supportive care will not be 
considered as DLTs.   
• Non-hematologic Grade 3 laboratory abnormality if medical intervention is required 
to treat the patient or the abnormality leads to hospitalization.  
- Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the Investigator, do not have any clinical correlate, and resolve 
to Grade 1 within 7 days with adequate medical management are not to be 
considered DLTs; 
- ALT or AST >3 x upper limit of normal (ULN) (if normal at baseline) or >3 x ULN 
and doubling the baseline (if > ULN at baseline) associated with bilirubin >2 x ULN.  


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Non-Adherence to Treatment Schedule: 
• Delay of ≥3 weeks in receiving the next scheduled administration due to persisting 
treatment-related toxicities; 
• Failure to receive at least 75% of the planned doses each of the investigational 
products during the DLT observation period due to treatment-related toxicities. 
In the absence of associated clinical abnormalities, abnormal laboratory tests should be 
repeated to confirm relevance.  
While the rules for adjudicating DLTs in the context of the dose determination phase 
(Phase 1b) are specified above, an AE not listed above, or an AE meeting the DLT 
criteria above but occurring outside of the DLT observation period may be defined as a 
DLT after consultation between Sponsor and Investigator, based on the emerging safety 
profile. 
• Phase 2: Confirmed objective response (OR), as assessed by the Investigator using 
RECIST v1.1. 
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the ‘start date’ until the date of the first documentation of progressive disease 
(PD). Both CR and PR must be confirmed by repeat assessments performed no less than 
4 weeks after the criteria for response are first met. 
3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
• AEs as characterized by type, severity (as graded by National Cancer Institute [NCI] 
CTCAE v.4.03), timing, seriousness, and relationship to study treatments; 
AEs will be graded by the investigator according to the CTCAE v.4.03 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) 
• Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03) and timing. 
3.2.2. Pharmacokinetic endpoints 
• PK parameters (Cmax and Ctrough).  
Table 2. 
PK Parameters to be Determined for Avelumab, Utomilumab, PF-
04518600 and PD 0360324 
Parameter 
Definition 
Method of Determination 
Cmax 
Maximum observed plasma concentration  
Observed directly from data 
Ctrough 
Predose concentration during multiple dosing 
Observed directly from data 
Cmax(dn) 
Dose normalized Cmax 
Cmax / Dose 
a If data permit 


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3.2.3. Immunogenicity endpoints 
• Anti-drug antibody (ADA) levels. 
ADA titers for avelumab and utomilumab (Combination A) or for avelumab and PF-
04518600 (Combination B) or for avelumab and PD 0360324 (Combination C) or for 
avelumab, utomilumab and PF-04518600 (Combination D) or for Avelumab and CMP-
001 and utomilumab or PF-04518600 (Combination F).  
3.2.4. Efficacy endpoints 
• Time-to-event endpoints including Time to Tumor Response (TTR), Duration of 
Response (DR), Progression-free survival (PFS) as assessed by the investigator using 
RECIST v1.1, and Overall Survival (OS);  
TTR is defined, for patients with an OR, as the time from the ‘start date’ to the first 
documentation of objective response (CR or PR) which is subsequently confirmed.  
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.   
PFS is defined as the time from the ‘start date’ to the date of the first documentation of 
PD or death due to any cause, whichever occurs first. 
OS is defined as the time from the ‘start date’ to the date of death due to any cause. 
• Confirmed OR during Phase 1b, as assessed by the investigator using RECIST v1.1. 
OR is defined as in the primary endpoint section. 
3.2.5. Biomarker endpoints 
• Biomarkers such as PD-L1 expression and tumor infiltrating CD8+ T lymphocytes in 
baseline tumor tissue. 
Table 3. 
Biomarker Definition and Determination 
Parameter 
Definition 
Method of Determination 
PD-L1 expression 
The percent of counted cells scored as PD-L1+ 
and qualitative assessment of PD-L1 staining on 
tumor and inflammatory cells as defined by cell 
morphology in regions of interest 
Pathologist, assisted by 
image analysis 
Tumor infiltrating 
CD8+ lymphocytes 
The percent of counted cells that are scored as 
CD8+ 
Pathologist, assisted by 
image analysis 
 
 
• 
 
 
 
 
 
CCI
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• 
 
 
3.4. Baseline Variables 
3.4.1. Study drug, study treatment and baseline definitions 
In this study ‘study drug’ refers to avelumab, utomilumab, PF-04518600, PD 0360324 or 
CMP-001 and ‘study treatment’ (or ‘treatment group’) refers to one of the following. 
Assignment to cohorts A1, A2 or A3, assignment to cohorts A9 or A10, and assignment to 
cohorts F1, F2 or F3 will be done via randomization.  Assignment to all other cohorts is not 
randomized as described in Section 2.2. 
Combination A 
• Cohort A1 (Phase 1b/Phase 2 NSCLC):  avelumab 10 mg/kg IV Q2W in combination 
with 500 mg utomilumab IV Q4W 
• Cohort A2 (Phase 1b/Phase 2 NSCLC):  avelumab 10 mg/kg IV Q2W in combination 
with 100 mg utomilumab IV Q4W 
• Cohort A3 (Phase 1b/Phase 2 NSCLC):  avelumab 10 mg/kg IV Q2W in combination 
with 20 mg utomilumab IV Q4W 
• Cohort A4 (Phase 2 Melanoma):  avelumab 10 mg/kg IV Q2W in combination with 100 
mg utomilumab IV Q4W  
• Cohort A5 (Phase 2 SCCHN):  avelumab 10 mg/kg IV Q2W in combination with 100 mg 
utomilumab IV Q4W 
• Cohort A6 (Phase 2 TNBC):  avelumab 10 mg/kg IV Q2W in combination with 100 mg 
utomilumab IV Q4W 
• Cohort A7 (Phase 2 SCLC):  avelumab 10 mg/kg IV Q2W in combination with 100 mg 
utomilumab IV Q4W 
• Cohort A8 (Phase 2 1L NSCLC):  avelumab 10 mg/kg IV Q2W in combination with 100 
mg utomilumab IV Q4W 
• Cohort A9 (Phase 2 1L NSCLC): utomilumab 100 mg IV Q4W followed by utomilumab 
100 mg IV Q4W in combination with avelumab 10 mg/kg IV Q2W 
• Cohort A10 (Phase 2 1L NSCLC): avelumab 10 mg/kg IV Q2W followed by utomilumab 
100 mg IV Q4W in combination with avelumab 10 mg/kg IV Q2W  
For Cohorts A4 through A10, the projected utomilumab dose to be used is 100 mg which 
may be modified based upon emerging safety data for utomilumab from randomized dose 
cohorts of Combination A. 
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Combination B 
• Cohort B11 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 0.1 mg/kg PF-
04518600 IV Q2W 
• Cohort B12 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 0.3 mg/kg PF-
04518600 IV Q2W 
• Cohort B13 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 1 mg/kg PF-
04518600 IV Q2W 
• Cohort B14 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 3 mg/kg PF-
04518600 IV Q2W 
• Cohort B21 (Phase 2 NSCLC):  avelumab 10 mg/kg IV Q2W in combination with PF-
04518600 dose selected at the end of Phase 1b 
• Cohort B22 (Phase 2 Melanoma):  avelumab 10 mg/kg IV Q2W in combination with PF-
04518600 dose selected at the end of Phase 1b (no patients will be enrolled) 
• Cohort B23 (Phase 2 SCCHN):  avelumab 10 mg/kg IV Q2W in combination with PF-
04518600 dose selected at the end of Phase 1b 
Combination C 
• Cohort C11 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 50 mg PD 
0360324 IV Q2W 
• Cohort C12 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 100 mg PD 
0360324 IV Q2W 
• Cohort C13 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 150 mg PD 
0360324 IV Q2W 
• Cohort C21 (Phase 2 tumor type to be decided among ovarian cancer, SCCHN, NSCLC, 
gastric cancer):  avelumab 10 mg/kg IV Q2W in combination with PD 0360324 dose 
selected based on Phase 1b (no patients will be enrolled) 
• Cohort C22 (Phase 2 tumor type to be decided among ovarian cancer, SCCHN, NSCLC, 
gastric cancer):  avelumab 10 mg/kg IV Q2W in combination with PD 0360324 dose 
selected based on Phase 1b (no patients will be enrolled) 
Combination D 
• Cohort D11 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 20 mg 
utomilumab IV Q4W and 0.1 mg/kg PF-04518600 IV Q2W 
• Cohort D12 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 50 mg 
utomilumab IV Q4W and 0.1 mg/kg PF-04518600 IV Q2W 


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• Cohort D21 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 20 mg 
utomilumab IV Q4W and 0.3 mg/kg PF-04518600 IV Q2W 
• Cohort D22 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 50 mg 
utomilumab IV Q4W and 0.3 mg/kg PF-04518600 IV Q2W 
• Cohort D31 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 20 mg 
utomilumab IV Q4W and 1 mg/kg PF-04518600 IV Q2W 
• Cohort D32 (Phase1b):  avelumab 10 mg/kg IV Q2W in combination with 50 mg 
utomilumab IV Q4W and 1 mg/kg PF-04518600 IV Q2W 
• Cohort D-1 (Phase 2 tumor type to be decided among NSCLC, melanoma, SCCHN, or 
bladder cancer): avelumab 10 mg/kg IV Q2W in combination with utomilumab and PF-
04518600 doses selected based on Phase 1b 
• Cohort D-2 (Phase 2 tumor type to be decided among NSCLC, melanoma, SCCHN, or 
bladder cancer):  avelumab 10 mg/kg IV Q2W in combination with utomilumab and PF-
04518600 doses selected based on Phase 1b 
Combination F 
• Cohort F1 (Phase 1b/Phase 2 SCCHN): avelumab 10 mg/kg IV Q2W in combination 
with 10 mg CMP-001  
• Cohort F2 (phase 1b/ Phase 2 SCCHN): avelumab 10 mg/kg IV Q2W in combination 
with 10 mg CMP-001 and 100 mg utomilumab IV Q4W 
• Cohort F3 (Phase 1b/ Phase 2 SCCHN):  avelumab 10 mg/kg IV Q2W in combination 
with 10 mg CMP-001 and 0.3 mg/kg PF-04518600 IV Q2W 
CMP-001 will be administered initially as 2 weekly subcutaneous (SC) doses followed by 
intra tumoral (IT) dosing at weekly intervals for 5 additional doses.  After the first 7 doses, 
CMP-001 will be administered IT every 2 weeks (Q2W) (all cohorts). 
Start and end dates of study treatment: 
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination.  
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination. 
Definition of baseline:  
Definition of baseline for efficacy analyses in randomized cohorts 
The last measurement prior to the ‘start date’ 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 
assessments data where the baseline assessment would be considered as missing.  


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Definition of baseline for immunogenicity analyses 
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing. 
Definition of baseline for efficacy analyses in non-randomized cohorts 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 and efficacy (for non-randomized cohorts) analyses.  
If an assessment is planned to be performed prior to the first dose of study treatment in the 
protocol and the assessment is performed on the same day as the first dose of study 
treatment, it will be assumed that it was performed prior to study treatment administration, if 
assessment time point is not collected or is missing. If assessment time points are collected, 
the observed time point will be used to determine pre-dose on study day 1 for baseline 
calculation. Unscheduled assessments will be used in the determination of baseline. 
However, if time is missing, an unscheduled assessment on study day 1 will be considered to 
have been obtained after study treatment administration. 
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR 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 RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point. 
3.4.2. Baseline characteristics 
Baseline characteristics (including demographics, 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.   


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3.5. Safety Endpoints 
3.5.1. Adverse events 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period.  
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. 
Adverse Events of Special Interest (AESIs) 
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  For 
Combination F, AESIs also include Cytokine Release Syndrome. The criteria for 
classification of an AE as an irAE or IRR are described in Appendix 1 and Appendix 2, 
respectively. 
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 study treatment assigned at randomization.  
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 study 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 study 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 


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classified according to the first study treatment received. For the non-randomized cohorts, the 
FAS and the safety analysis set are identical.  
4.3. Other Analysis Set 
4.3.1. DLT-evaluable set 
This is the primary analysis set for the Phase 1 lead-in for all Combinations and includes all 
enrolled patients in Phase 1b who are eligible for the study, receive at least 1 dose of study 
treatment, and either experience DLT during the DLT observation period, or complete the 
DLT observation period.   
• For Combinations A, B, C, and D, the DLT observation period is the first 2 cycles (8 
weeks) of treatment.   
• For Combination F, the DLT observation period will be 4 weeks including the first two 
weekly SC injections and the subsequent two weekly IT administrations. 
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the prescribed doses for all study drugs in the combination for reasons other than 
treatment-related toxicity (eg, missed appointments or development of rapidly progressing 
disease) are not evaluable for DLT.  
4.3.2. PK analysis set 
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for at least one of the study drugs in the combination.  
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for at least one of the study drugs in 
the combination. 
4.3.3. Biomarker analysis sets  
The baseline biomarker analysis set is a subset of the safety analysis set and will include 
patients who have at least one screening biomarker assessment.  
The paired biomarker analysis set is a subset of the safety analysis set and will include 
patients who have at least one pre-treatment biomarker assessment and one on-treatment 
assessment of the same biomarker.   
Analysis sets will be defined separately for blood-based and tumor tissue-based biomarkers. 
4.3.4. Immunogenicity analysis sets 
The immunogenicity analysis sets will be per study drug in a combination. The analyses sets 
are subsets of the safety analysis set and will include patients who have at least one ADA 
sample collected for each study drug in the combination. 


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5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and sample size determination 
Combination A 
The number of patients to be enrolled in Combination A may depend upon the observed 
safety profile, which will determine the number of patients at each dose level and the number 
of dose levels explored.  The total number of patients treated in Combination A (Phase 1b 
and Phase 2 combined) is expected to be approximately 253. 
Phase 1b lead-in  
There is no formal hypothesis testing in this phase. However, before expanding NSCLC 
Cohorts A1, A2, and/or A3 after the lead-in phase, the safety must be confirmed in the first 6 
patients evaluable for DLT in those treatment groups. The dose level is considered as safe 
and a treatment group can be expanded when there are not more than 1 of 6 patients with 
DLTs within the first 2 cycles of treatment. 
Phase 2  
Hypotheses will be tested separately for each treatment group based on OR rate (ORR, 
proportion of patients with OR) using the data from the combined Phases 1b and 2 (Cohorts 
A1, A2, A3) and the data from Phase 2 (Cohorts A4, A5). There is no formal hypothesis 
testing for Cohorts A6, A7, A8, A9, and A10. These cohorts use an estimation approach. 
Cohorts A1, A2, A3 (NSCLC) 
The null hypothesis will be tested against the alternative hypothesis at the one-sided 
significance level α=0.05 using an exact binomial test   
H0: ORR≤15% vs H1: ORR>15%. 
Within each treatment group, 28 patients will provide at least 80% power to reject the null 
hypothesis if the true ORR is ≥35%.  
Cohort A4 (melanoma) 
The null hypothesis will be tested against the alternative hypothesis at the one-sided 
significance level α=0.05 using an exact binomial test  
H0: ORR≤15% vs H1: ORR>15%. 
Twenty-eight (28) patients will provide at least 80% power to reject the null hypothesis if the 
true ORR is ≥35%. 


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Cohort A5 (SCCHN) 
The null hypothesis will be tested against the alternative hypothesis at the one-sided 
significance level α=0.05 using an exact binomial test  
H0: ORR≤20% vs H1: ORR>20%. 
Thirty-five (35) patients will provide at least 80% power to reject the null hypothesis if the 
true ORR is ≥40%. 
Cohort A6 (TNBC), Cohort A7 (SCLC), Cohorts A8, A9, and A10 (1L NSCLC) 
Twenty (20) patients each will be enrolled in Cohorts A6, A7, A9 and A10. Overall sample 
size for Cohort A8 may be larger (up to 26 patients) and can include PD-L1 negative patients 
that were enrolled prior to Protocol Amendment 6. 
With 20 patients in each of the TNBC, SCLC cohorts, and 20 PD-L1 positive patients in 1L 
NSCLC cohorts, ORR can be estimated with a maximum standard error of 0.112. Table 4 
provides the exact binomial 90% confidence intervals (CIs) for ORR based on different 
possible observed responses in a cohort.    
Table 4. 
Sample Size and Exact 90% CI for ORR in Combination A 
 
N per cohort 
Number of 
responders 
Observed ORR 
90% CI for ORR 
20 
1 
5% 
(0.3, 21.6) 
2 
10% 
(1.8, 28.3) 
3 
15% 
(4.2, 34.4) 
4 
20% 
(7.1, 40.1) 
5 
25% 
(10.4, 45.6) 
6 
30% 
(14.0, 50.8) 
7 
35% 
(17.7, 55.8) 
8 
40% 
(21.7, 60.6) 
9 
45% 
(25.9, 65.3) 
10 
50% 
(30.2, 69.8) 
15 
75% 
(54.4, 89.6) 
CI=confidence interval; ORR=objective response rate. 
 
Combination B 
Up to 105 patients (Phase 1b and Phase 2 combined) may be enrolled for Combination B 
treatment. 


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Phase 1b lead-in  
For Phase 1b of this combination, due to the dynamic nature of the Bayesian allocation 
procedure, the exact sample size of the “Up-and-Down” matrix design using the mTPI 
approach cannot be determined in advance.  It is expected that up to 30 patients will need to 
be enrolled in Phase 1b using the mTPI approach.     
Phase 2  
For Phase 2 of this combination, 25 patients will be enrolled from each of 3 tumor types: 
NSCLC, melanoma, and SCCHN.  Thus up to 75 patients will be enrolled in Phase 2 for 
Combination B. 
With 25 patients, ORR can be estimated with a maximum standard error of 0.10.  Table 5 
provides the exact binomial 90% CIs for ORR based on different possible observed 
responses in a cohort.   
Table 5. 
Sample Size and Exact 90% CI for ORR in Combinations B, C, and D  
N per cohort 
Number of 
responses 
Observed ORR 
90% CI for ORR 
25 
1 
4% 
(0.2, 17.6%) 
2 
8% 
(1.4, 23.1%) 
3 
12% 
(3.4, 28.2%) 
4 
16% 
(5.7, 33.0%) 
5 
20% 
(8.2, 37.5%) 
6 
24% 
(11.0, 42.0%) 
7 
28% 
(13.9, 46.2%) 
8 
32% 
(17.0, 50.4%) 
9 
36% 
(20.2, 54.4%) 
10 
40% 
(23.6, 58.3%) 
11 
44% 
(27.0, 62.1%) 
12 
48% 
(30.5, 65.9%) 
13 
52% 
(34.1, 69.5%) 
14 
56% 
(37.9,73.0%) 
15 
60% 
(41.7, 76.4%) 
20 
80% 
(62.5, 91.8%) 
CI=confidence interval; ORR=objective response rate. 
 


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Combination C 
Up to 80 patients (Phase 1b and Phase 2 combined) may be enrolled for Combination C 
treatment.   
Phase 1b lead-in  
For Phase 1b of this combination, due to the dynamic nature of the Bayesian allocation 
procedure, the exact sample size of the “Up-and-Down” matrix design using the mTPI 
approach cannot be determined in advance.  It is expected that up to 30 patients will need to 
be enrolled in the Phase 1b part using the mTPI approach and backfill.   
Phase 2  
For Phase 2 of this combination, 2 tumor-specific cohorts of 25 patients each with the 
selected tumor types chosen for evaluation will be enrolled.  The selected tumor types will be 
selected following completion of Phase 1b for the combination.  
With 25 patients in each cohort, ORR can be estimated with a maximum standard error of 
10%.  Table 5 provides the exact binomial 90% CIs for ORR based on different observed 
responses in a cohort. 
Combination D 
Phase 1b lead-in  
For Phase 1b of this combination, due to the dynamic nature of the Bayesian allocation 
procedure, the exact sample size of the “Up-and-Down” matrix design using the mTPI 
approach cannot be determined in advance.  It is expected up to 72 patients may be enrolled 
in the Phase 1b part using the mTPI approach and backfill. 
Phase 2  
For Phase 2 of this combination, 2 tumor-specific cohorts of 25 patients each with the 
selected tumor types chosen for evaluation will be enrolled.  The selected tumor types will be 
selected following completion of Phase 1b for the combination.   
With 25 patients in each cohort, ORR can be estimated with a maximum standard error of 
10% within each tumor-specific cohort. Table 5 provides the exact binomial 90% CIs for 
ORR based on different possible observed responses in a cohort. 
Combination F 
Up to 20 patients will be randomized in each of the Cohorts F1, F2 and F3 at the selected 
dose level. 


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Phase 1b lead-in  
There is no formal hypothesis testing in this phase. Before expanding cohorts F1, F2, and F3 
into the Phase 2 cohort expansion, the safety of the combination in that cohort must be 
confirmed in DLT-evaluable patients in the Phase 1b lead-in.  
Up to 12 patients will be randomized into each cohort in the Phase 1b lead-in and evaluated 
for DLT during the first treatment cycle (4 weeks) as follows. 
• If 1 of 6 patients experience DLT, the cohort will be expanded to enroll up to 
14 additional patients in the Phase 2 cohort expansion; 
• If 2 of 6 patients experience DLT, the cohort will be expanded to enroll up to 6 additional 
DLT-evaluable patients in the Phase 1b lead-in of the study; 
- If 3 of 12 patients experience DLT, the cohort will be expanded to enroll up to 
8 additional patients in the Phase 2 cohort expansion; 
- If 4 of up to 12 patients experience DLT, enrollment in the specific cohort will be 
discontinued.  
• If 3 of up to 6 patients experience DLT, enrollment in the specific cohort will be 
discontinued. 
Phase 2 
With 20 patients in each cohort (Phase 1b and 2 combined), ORR can be estimated with a 
maximum standard error of 0.112.  The exact binomial 90% CIs for ORR based on different 
observed responses for each of the cohorts are as presented in Table 6.  


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Table 6. 
Sample Size and Exact 90% Confidence Intervals for Objective Response 
Rate in Combination F (Cohorts F1, F2 and F3) 
Number per cohort 
Number of responses 
Observed ORR 
90% CI for ORR 
20 
1 
5% 
(0.3, 21.6) 
2 
10% 
(1.8, 28.3) 
3 
15% 
(4.2, 34.4) 
4 
20% 
(7.1, 40.1) 
5 
25% 
(10.4, 45.6) 
6 
30% 
(14.0, 50.8) 
7 
35% 
(17.7, 55.8) 
8 
40% 
(21.7, 60.6) 
9 
45% 
(25.9, 65.3) 
10 
50% 
(30.2, 69.8) 
11 
55% 
(34.7, 74.1) 
12 
60% 
(39.4, 78.3) 
13 
65% 
(44.2, 82.3) 
14 
70% 
(49.2, 86.0) 
15 
75% 
(54.4, 89.6) 
CI=confidence interval; ORR=objective response rate. 
 
5.1.2. Decision rules 
Combination A 
Phase 1b lead-in 
Table 7 shows the probability of confirming the safety in the first 6 patients for a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
greater than 89% probability of confirming safety and expanding the corresponding treatment 
group.  Conversely, for a DLT that occurs with a rate of 60%, the probability of expanding is 
4%.   
Table 7.  
Probability of Expanding Dose 
True underlying DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of expanding dose 
0.89 
0.66 
0.42 
0.23 
0.11 
0.04 
0.01 
<0.01 
<0.01 
 


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Phase 2 
Cohorts A1, A2, A3 (NSCLC) 
Within each treatment group using the combined data from the Phase 1b and Phase 2, at the 
time of the analysis cut-off: 
• if there are ≤7 objective responders of 28 patients treated in a given cohort (6+22 
patients), then it will be declared that the null hypothesis cannot be rejected, or that 
clinically meaningful activity has not been demonstrated.   
• if there are ≥8 objective responders of 28 patients treated in a given cohort, the null 
hypothesis will be rejected and clinically meaningful activity has been demonstrated. 
Cohort A4 (melanoma) 
At the time of the analysis cut-off: 
• if there are ≤7 objective responders out of 28 patients treated in this cohort, then it will be 
declared that the null hypothesis cannot be rejected, or that clinically meaningful activity 
has not been demonstrated.   
• if there are ≥8 objective responders out of 28 patients treated in the cohort, the null 
hypothesis will be rejected and clinically meaningful activity has been demonstrated. 
Cohort A5 (SCCHN) 
At the time of the analysis cut-off: 
• if there are ≤11 objective responders of 35 patients treated in this cohort, then it will be 
declared that the null hypothesis cannot be rejected, or that clinically meaningful activity 
has not been demonstrated.   
• if there are ≥12 objective responders of 35 patients treated in the cohort, the null 
hypothesis will be rejected and clinically meaningful activity has been demonstrated. 
Cohort A6 (TNBC), Cohort A7(SCLC), Cohorts A8, A9, and A10 (1L NSCLC) 
There are no formal decision rules.  
Combinations B, C and D 
Phase 1b lead-in  
Dose escalation to identify a safe dose and RP2D of the other immune modulators to be used 
in combination with avelumab (all tumor types).  
A safe dose will be determined using the adaptive mTPI design.  The mTPI design is flexible 
and allows dose reduction to doses in between the planned doses. 


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The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of 3 dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target probability (pT) rate 
(pT=0.25).  If the toxicity rate of the currently used dose level is far smaller than pT, the 
mTPI will recommend escalating the dose level; if it is close to pT, the mTPI will 
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level.  These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model.  As shown by Ji and Wang 
(2013)3, mTPI design is more efficient and safer than the 3+3 design.  They considered 
42 scenarios to cover a wide range of practical dose-response shapes, and concluded that the 
3 + 3 design was more likely to treat patients at toxic doses above the MTD and less likely to 
identify the true MTD than the mTPI design.  For example, the 3 + 3 design exhibited a 
lower overall toxicity percentage than the mTPI design in only 1 of 42 scenarios. 
Being a model-based design, mTPI automatically and appropriately tailors dose re-escalation 
and de-escalation decisions for different studies with different toxicity parameters.  More 
importantly, all the dose re-escalation/de-escalation decisions for a given study can be 
pre-calculated under the mTPI design and presented in a 2-way table.  Thus, compared to 
other advanced model-based designs published in the literature, the mTPI design is 
logistically less complicated and easier to implement.  
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0, pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of PF-04518600, and PD 0360324, and avelumab, e1 is selected as 0.09, and 
e2 is selected as 0.08.  Therefore, the target interval for the DLT rate is (0.16, 0.33). 
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
underdosing interval corresponds to a dose re-escalation (RE), overdosing corresponds to 
dose de-escalation (D), and proper dosing corresponds to staying at the current dose (S).  
Given a dosing interval and a probability distribution, the UPM of that dosing interval is 
defined as the probability of a patient belonging to that dosing interval divided by the length 
of the dosing interval.  The mTPI design calculates the UPMs for the 3 dosing intervals, and 
the one with the largest UPM informs the corresponding dose-finding decision, which is the 
dose level to be used for future patients.  For example, if the underdosing interval has the 
largest UPM, the decision will be to escalate, and the next cohort of patients will be treated at 
the next higher dose level.  Simulations have demonstrated that the decision based on UPM is 
optimal in that it minimizes a posterior expected loss (ie, minimizes the chance of making a 
wrong dosing decision). 
Phase 2 can be initiated if not more than 3 in 10 (Combination C which has a maximum 
sample size of 10 patients for a dose level) or 12 (Combinations B, and D which have a 
maximum sample size of 12 patients for a dose level) DLT-evaluable patients have 
experienced a DLT at the recommended Phase 2 dose level since it meets the criterion 
associated with the target interval for the DLT rate of (0.16, 0.33) as described above.   


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Combination F 
Phase 1b lead-in  
Table 8  shows the probability of expanding enrollment of a cohort into Phase 2 based on the 
DLT rates observed for 6 or 12 DLT-evaluable patients in Phase 1b and a range of 
underlying true DLT rates.  For example, for a DLT that occurs in 10% of patients, there is a 
97% probability of confirming safety and expanding the corresponding cohort. 
Table 8. 
Combination F: Probability of Expanding Dose Level 
True underlying DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of expanding 
dose level 
0.97 
0.82 
0.56 
0.31 
0.14 
0.05 
0.01 
0.002 
<0.0001 
DLT = dose limiting toxicity. 
 
Phase 2  
There are no formal decision rules for the phase 2 of Combinations B, C, D or F. 
5.2. General Methods 
In this study ‘treatment group’ refers to one of the cohorts described in Section 3.4.1.  
Unless otherwise noted the analyses and summaries will be performed as outlined below 
Combinations A and F: combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, 
F2 and F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10).  
Combinations B, C and D: Phase1b and from Phase 2 separately and for each combination.       
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group as noted above.  
DLTs will be summarized based on the DLT-evaluable set by treatment group from Phase 1b 
only. Other safety data, exposure data, concomitant medications and non-drug treatments will 
be summarized based on the safety analysis set by treatment group as noted above.  
PK data will be summarized based on the PK analysis set by treatment group as noted above. 
Biomarker data will be summarized based on the biomarker analysis sets by treatment group 
as noted above.  
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group as noted above. 


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5.2.1. Data handling after the cut-off date 
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations. 
5.2.2. Pooling of centers 
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients 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. 
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 Cancer 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, 


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the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer 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 ‘start date’ amongst the 
following: 
• Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages 
• Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’  
• Surgery date recorded in ‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages 
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 Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘Concomitant Surgery’, 
and ‘Follow-up 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. 
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) 


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- 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. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
• All baseline assessments must be within 28 days prior to and including ‘start date’. 
• All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions). 
5.2.11. Adequate post-baseline tumor assessment 
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.2.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date. 
5.3. Methods to Manage Missing Data 
5.3.1. Missing data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 


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


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5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
• If the day is missing, it will be imputed to the 15th day of the month.  
• If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st. 
• If both day and month are missing and the year is same as the year of the first study 
treatment, 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 the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment. 
• If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. 
• If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014. 
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the 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, then the medication date will be replaced by 
the start of study treatment. 
• If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015.  


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• If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/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 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• 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.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
• If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date 
• If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)  
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases. 
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’) 
• Study drug start and end dates 
• Randomization date 


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• Withdrawal of consent date 
• 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 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as the day after the date of last contact  
• If the day or both day and 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. 
5.3.3.4. Date of start of new anti-cancer therapy 
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. 


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• The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is 
o completely missing then it will be ignored in the imputations below 
o partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 
o 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 
• For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below.  
• 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 derived as follows: 
o Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy] 
o Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = 01JANYYYY 
o Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available 
IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 


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MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]); 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = 01 MMM YYYY. 
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 for Phase 1b lead-in 
6.1.1.1. Primary analysis 
The following analyses will be based on the DLT-evaluable set for patients in the Phase 1b 
for all combinations.  DLTs will be listed and summarized by treatment group for Phase 1b 
cohorts. 


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6.1.2. Confirmed OR as assessed by the Investigator per RECIST v1.1 for Phase 2 
6.1.2.1. Primary analysis 
Combinations A and F 
The following analyses will be based on the FAS by treatment group using the data from the 
combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, F3) and the data from 
Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10).    
Combinations B, C and D  
The following analyses will be based on the FAS by treatment group using the data from 
Phase 2 Cohorts for each combination.   
Assessment of response will be made as per investigator using RECIST v1.1. 
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the ‘start date’ until the first documentation of PD, 
according to the following rules. Only tumor assessments performed on or before the start 
date of any further anti-cancer therapies will be considered in the assessment of BOR.  
Clinical deterioration will not be considered as documentation of disease progression. 
BOR Based on Confirmed Responses:  
• CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD  
• PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR)  
• SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the ‘start date’ and before first documentation of 
PD (and not qualifying for CR or PR)  
• Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the ‘start date’ and 
before first documentation of PD (and not qualifying for CR or PR). 
• PD = first documentation of PD ≤ 12 weeks after the ‘start date’ (and not qualifying for 
CR, PR, SD or non-CR/non-PD) 
• 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. 


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Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1. 
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set. 
A formal test of hypothesis for each treatment group (Cohorts A1, A2, A3, A4, and A5 only) 
in Combination A will be performed at the 1-sided significance level α=0.05 based on the 
exact binomial test as described in Section 5.1.1.  
ORR by treatment group will also be calculated along with the 2-sided 90% CI using the 
Clopper-Pearson method 2 (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option). Two-sided 95% CIs will also be calculated and 
reported. 
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD, and NE will be tabulated. Patients with confirmed 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 of insufficient duration (<6 weeks after the ‘start date’ without further evaluable 
tumor assessments) 
• PD too late (>12 weeks after the ‘start date’) 
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD of early’ (ie, SD of insufficient duration). 
6.2. Secondary Endpoint(s) 
6.2.1. Safety endpoints 
Refer to Section 6.6. 


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6.2.2. Efficacy endpoints 
Combinations A and F 
The following analyses will be based on the FAS by treatment group using the data from the 
combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2 and F3) and the data 
from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10).  
Combinations B, C and D 
The following analyses will be based on the FAS by treatment group using the data from 
Phase1b and from Phase 2 separately and for each combination.       
Tumor-related endpoints will be analyzed based on investigator assessment using RECIST 
v1.1.  In addition to what is described below, the objective response (OR) will also be 
analyzed similar to that described in Section 6.1.2.1 for each of the Phase 1b cohorts of 
Combinations B, C and D. 
6.2.2.1. Tumor shrinkage from baseline 
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as: 
• ((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100 
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as: 
• Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100 
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameters 
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment. 
6.2.2.2. Disease control 
Disease Control (DC) is defined as BOR of CR, PR, non-CR/non-PD or SD.  DC rate (DCR) 
is the proportion of patients with DC.     
DCR will be summarized by frequency counts and percentages. 
6.2.2.3. Duration of response 
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 


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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 described in Table 9. 
 
DR (months) = [date of event or censoring– first date of OR +1]/30.4375 
Table 9. 
Outcome and Event Dates for DR Analyses 
Scenario 
Date of event/censoring 
Outcome 
PD or death  
- 
After at most one missing or inadequate 
post-baseline tumor assessment, OR 
- 
≤ 16 weeks after the ‘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 a 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 a 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 nti-cancer therapy given  
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
a  If there are no adequate post-baseline assessments prior to 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 DR time with 2-sided 
95% CIs.  In particular, the DR rates at 2, 4, 6, 8, 10 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 (1982)1 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 (2002)4 (conftype=loglog default option in SAS Proc LIFETEST) 
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula. 
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided. 


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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 10 following the hierarchy shown. 
Table 10.  DR Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
Start of new anti-cancer therapy    
Start of new anti-cancer therapy 
2  
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization 
Event after 2 or more missing 
assessments a 
3 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
4 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
5 
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 
6  
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.     
 
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) which is subsequently confirmed.  
 
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 the ‘start date’ to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.    
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.  Patients who do not have an adequate baseline tumor assessment or who do not 
have an adequate post-baseline tumor assessment will be censored on the ‘start date’ unless 
death occurred on or before the time of the second planned tumor assessment (ie ≤ 16 weeks 
after the ‘start date’) in which case the death will be considered an event.  
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 8 weeks (±7 days) until PD regardless of initiation of 
subsequent anti-cancer therapy.  After 1 year from the ‘start date’, tumor assessments will be 


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conducted at 12-week (±7 days) intervals and after 2 years from the ‘start date’, tumor 
assessments will be conducted at 16-week (±7 days) intervals. 
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 11.   
 
PFS (months) = [date of event or censoring– ‘start date’ +1]/30.4375 
Table 11. Outcome and Event Dates for PFS 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 the ‘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 the ‘start date’ the death is an event with date on death date 
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the ‘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 2, 4, 6, 8, 10, 12 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 (1982)1 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 (2002)4 (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 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 12 following the hierarchy shown. 
Table 12. PFS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy  
Start of new anti-cancer therapy 
3  
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’ 
Event after missing assessments a 
4 
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Patient 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. 
6.2.2.6. Overall Survival 
Overall survival (OS) is defined as the time from the ‘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 2, 4, 6, 8, 10, 12, 18 and 24 months will be estimated 
with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 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 (2002)4 (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 an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 13 following the hierarchy shown. 


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Table 13. OS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Patient refused further follow-up]  
Withdrawal of consent 
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. 
OS analysis will be conducted for patients up to LSLV of the study. 
 
6.2.3. Pharmacokinetic endpoints 
Combinations A and F 
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group using the data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts 
F1, F2, F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D 
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group using the data from Phase 1b and from Phase 2 separately and for each combination.  
Ctrough and Cmax for avelumab for all combinations, utomilumab (for Combination A and D), 
PF-04518600 (for Combinations B and D), and PD 0360324 (for Combination C) will be 
summarized descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean, 
its associated CV, and 95% CI) by treatment group, cycle, and day. Dose normalized 
parameters (eg, CDN- Cmax, CDN- Ctrough) will be reported as appropriate. The trough 
concentrations for avelumab, utomilumab, PF-04518600 and PD 0360324 will be plotted for 
each dose using a box whisker plot by cycle and day in order to assess the attainment of 
steady state 
Pharmacokinetic parameters for avelumab, utomilumab, PF-04518600 and PD 0360324 will 
be taken from observed values or derived from plasma concentration-time data as described 
in Section 3.2.2. 
Presentation of pharmacokinetic data will include: 
• Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of plasma 
concentrations will be presented in tabular form by treatment group, dose level, cycle, 
day and nominal time. Additionally, similar descriptive statistics will also be generated 


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for dose-normalized utomilumab (Combination A and D), PF-04518600 (Combination B 
and D), PD 0360324 (Combination C) pharmacokinetic parameters, if appropriate. 
• Pharmacokinetic parameters for avelumab, utomilumab, PF-04518600, and PD 0360324 
will be listed and summarized by treatment group/dose level, cycle and study day using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean 
and its associated %CV, and 95% CI). For Tmax, the range (min, max) will also be 
provided. PK parameters with zero values will be excluded from the calculation of 
geometric means and its associated %CV. If an intrapatient dose escalation or reduction 
occurs, dose-dependent PK parameters (Cmax) for that patient may be dose-normalized 
when it is known that the drug exhibits linear PK within the dose range and other PK 
parameters will be reported as estimated; or may only be included in descriptive statistics 
and summary plots up to the time of the dose change. In addition, dose-normalized Cmax 
and Ctrough parameters will be summarized (as described above) using data pooled across 
treatment groups in which different utomilumab doses, PF-04518600 doses or PD 
0360324 doses were administered, if appropriate. 
6.2.4. Population pharmacokinetic endpoints 
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 avelumab and utomilumab (Combination A), avelumab and PF-
04518600 (Combination B), avelumab and PD 0360324 (Combination C) or avelumab, 
utomilumab and PF-04518600 (Combination D) or Avelumab (Combination F) exposure and 
biomarkers or significant safety/efficacy endpoints. The results of these analyses, if 
performed, may be reported separately. 
6.2.5. Biomarker Endpoints 
Combinations A and F 
The following biomarker analyses will be based on the biomarker analysis sets by treatment 
group using the data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts 
F1, F2, F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
 Combinations B, C and D 
The following biomarker analyses will be based on the biomarker analysis sets by treatment 
group using the data from Phase 1b and from Phase 2 separately and for each combination.  
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate. 
Appropriate change from baseline measurements will be provided. For discrete measurement 
biomarkers, frequencies and percentages of categorical biomarker measures will be 
determined at baseline and on-treatment/post-treatment time points, as appropriate; shift 
tables may also be provided.   


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6.2.6. Endpoints for immunogenicity data of avelumab and other study drugs 
Combinations A and F 
The following analyses of immunogenicity data will be based on the Immunogenicity 
analysis set by treatment group using the data from the combined Phases 1b and 2 (Cohorts 
A1, A2, A3 and Cohorts F1, F2, F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, 
A9, A10). 
Combinations B, C and D  
The following analyses of immunogenicity data will be based on the Immunogenicity 
analysis set by treatment group using the data from Phase 1b and from Phase 2 separately and 
for each combination.  
Blood samples for avelumab and other study drug immunogenicity testing will be collected 
as outlined in the “Schedule for Pharmacokinetic Sample Collection” table of the Schedule of 
Assessments section of the protocol.  
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 14.   
Table 14.  Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category 
Definition 
Patients at Risk (Denominator for 
Incidence) 
ADA never-positive  
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
ADA ever-positive  
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
Baseline ADA 
positive 
A positive ADA result at baseline 
Number of patients with valid baseline 
ADA result 
Treatment-boosted 
ADA 
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab 
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result 
Treatment-induced 
ADA 
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Transient ADA 
response 
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive. 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Persistent ADA 
response 
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
ADA: anti-drug antibody, NR = not reportable. 


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The number and percentage of patients in each ADA category will be summarized.  
6.2.6.1. Time to and Duration of ADA response  
The ADA analyses described below will include patients with treatment-induced ADA.   
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).   
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
• the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or 
• the last ADA assessment is positive AND patient discontinued treatment with avelumab. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982)1 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)4 (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. 
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
6.2.6.2. ADA titer 
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory.  
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored.  


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6.2.6.3. Analysis of PK by immunogenicity status 
The following ADA status will be used for the analyses described below. 
ADA  
• ADA ever-positive versus ADA never-positive  
• ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 
PK parameters and immunogenicity status 
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.  Blood samples for avelumab, utomilumab, PF-04518600, and PD 
0360324  PK will be collected as outlined in the “Schedule for Pharmacokinetic Sample 
Collection” table of the Schedule of Assessments section of the protocol. 
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear plots of mean and median for Ctrough and Cmax over nominal time and by 
ADA status will be presented.  
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
Ctrough and Cmax have any changes before and after the first positive ADA assessment. To be 
included in this analysis, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as: 
(PK assessment nominal day) – (first positive ADA assessment nominal day). 
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -28. Linear-linear plots of mean and 
median for Ctrough and Cmax over relative PK day will be presented.  
 
 
 
6.4. Subset Analyses 
ORR and DR (if meaningful) will be summarized in the following subsets within each 
treatment group: 
• general prior anti-cancer immuno-therapy (Yes, No)  
• Checkpoint inhibitors 
- prior PD-1/PD-L1 therapy (Yes, No) 
CCI
CCI
CCI


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- prior anti-CTLA4 therapy (Yes, No) 
- prior checkpoint inhibitor status (relapsed/resistant, refractory, naïve) 
▪ naïve: has not previously received a checkpoint inhibitor 
▪ resistant/relapse: progressed after SD or better  
▪ refractory: BOR of PD 
• HPV status (positive, negative) for SCCHN patients 
• PD-L1 status (positive, negative, unknown) at baseline 
  
For CD8, descriptive statistics will be provided by objective response category. 
 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
Combinations A and F 
The following analyses will be based on the FAS overall and separately by treatment group 
using the data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, 
F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D 
The following analyses will be based on the FAS overall and separately by treatment group 
using the data from Phase1b and from Phase 2 separately and for each combination.  
6.5.1.1. Demographic characteristics 
Demographic characteristics 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 or Latino  
▪ Not Hispanic or Latino 
- 
Age (years): summary statistics  
- 
Age categories:  
▪ < 65 years, ≥ 65 years  


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▪ < 65, 65-<75, 75-<85, ≥ 85 years 
- 
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/treated 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  
• Baseline disease status 
- 
HPV status (positive, negative) for SCCHN patients  
Center 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, and ECOG 
performance status. 
6.5.1.2.  Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’ 
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 


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6.5.1.3.  Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized overall and by treatment group. Summary statistics will be 
presented for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
• 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 
• 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 eCRF page: 
• Measurable disease (lesions) at baseline (Yes, No) 
• Involved tumor sites at baseline 
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ eCRF pages) and derived variables as above. 
6.5.1.4.  Prior anti-Cancer therapies 
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages. 
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated: 
• Patients with at least one type of prior anti-cancer 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 for metastatic 
disease 


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• Prior anti-cancer immune therapy (including PD-1, PD-L1, anti-CTLA4, others) 
• Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced / Metastatic, Locoregional 
disease /Recurrence 
• Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from 
the last treatment regimen. 
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. 
Prior anti-cancer drug therapies 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 anti-cancer drug therapies  
6.5.2. Study conduct and patient disposition 
Combinations A and F 
The following analyses will be performed based on the FAS overall and separately by 
treatment group using the data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and 
Cohorts F1, F2, F3) and the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combination B, C and D 
The following analyses will be performed based on the FAS overall and separately by 
treatment group using the data from Phase 1b and Phase 2 separately and for each 
combination. 
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) 


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• 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 follow-up overall and by the main 
reason for discontinuation 
• Number and percentage of patients who entered long-term follow-up 
• Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation 
The results of the randomization algorithm 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 vs. patients treated (Cohorts A1, A2 and A3, Cohorts 
A9 and A10, and Cohorts F1, F2 and F3) 
 
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 follow-up overall and by the main 
reason for discontinuation 
• Number and percentage of patients who entered long-term follow-up 


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• Number and percentage of patients who discontinued long-term follow-up 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 
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 
Combinations A and F 
The following analyses will be based on the safety analysis set by treatment group using the 
data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, F3) and 
the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D  
The following analyses will be based on the safety analysis set by treatment group using the 
data from Phase1b and from Phase 2 separately and for each combination. 
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.   


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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 – 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 derivations below are provided for the following. 
• Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 2 weeks 
in 4-week cycles  
• Utomilumab administered as a 1-hour IV infusion at a dose of 20 mg, 100 mg, or 500 mg 
once every 4 weeks in 4-week cycles  
• PF-04518600 administered as a 1-hour IV infusion at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 
mg/kg or 3 mg/kg once every 2 weeks in 4-week cycles  
• PD 0360324 administered as a 30-min IV infusion at a dose of 50 mg, 100 mg, or 150 mg 
once every 2 weeks in 4-week cycles  
• CMP-001 administered initially as 2 weekly 10 mg SC doses followed by IT dosing at 
weekly intervals for 5 additional doses of 10 mg.  After the first 7 doses, CMP-001 will be 
administered as 10 mg IT every 2 weeks (Q2W) 
 
6.5.3.1. Exposure to avelumab  
The dose level for avelumab 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. 


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Intended duration of treatment with avelumab (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab – first dose date of avelumab + 14)/7   
Cumulative dose is the sum of the actual doses of avelumab received overall.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (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] = [20 (mg/kg)] / [1 (4-week cycle)] = 20 (mg/kg/4-week 
cycle) 
• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [20 (mg/kg/4-week cycle)]  
6.5.3.2. Exposure to utomilumab  
The dose level for utomilumab is calculated as actual dose administered (mg).  
Intended duration of treatment with utomilumab (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to utomilumab (weeks) =  
(last dose date of utomilumab – first dose date of utomilumab + 28)/7   
Cumulative dose is the sum of the actual doses of utomilumab received overall.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with utomilumab (weeks)/4]  
Relative Dose Intensity (RDI)   
• Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [d (mg)] / [1 (4-week cycle)] = d (mg/4-week cycle) 


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• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [d (mg/4-week cycle)]  
where d=20, 100 or 500. 
6.5.3.3. Exposure to PF-04518600  
The dose level for PF-04518600 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-04518600 (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to PF-04518600 (weeks) =  
(last dose date of PF-04518600 – first dose date of PF-04518600 + 14)/7   
Cumulative dose is the sum of the actual doses of PF-04518600 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-04518600 (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] = [2×d (mg/kg)] / [1 (4-week cycle)] = 2×d (mg/kg/4-
week cycle) 
• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [2×d (mg/kg/4-week cycle)]  
where d=0.1, 0.3, 1 or 3. 
6.5.3.4. Exposure to PD 0360324  
The dose level for PD 0360324 is calculated as actual dose administered (mg).  
Intended duration of treatment with PD 0360324 (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to PD 0360324 (weeks) =  
(last dose date of PD 0360324 – first dose date of PD 0360324 + 14)/7   
Cumulative dose is the sum of the actual doses of PD 0360324 received overall.   


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Actual Dose Intensity (DI)  
• Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with PD 0360324 (weeks)/4].   
Relative Dose Intensity (RDI)   
• Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [2×d (mg)] / [1 (4-week cycle)] = 2×d (mg/4-week 
cycle) 
• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [2×d (mg/4-week cycle)]  
where d=50, 100 or 150. 
6.5.3.5. Exposure to CMP-001  
The dose level for CMP-001 is calculated as actual dose administered (mg).  
Intended duration of treatment with CMP-001 (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1 
Duration of exposure to CMP-001 (weeks) =  
(last dose date of CMP-001 – first dose date of CMP-001 + d)/7, 
where d=7 if last dose date of CMP-001 – first dose date of CMP-001 ≤39 (corresponding to 
the study day after the first 6 weekly doses of CMP-001, before dosing schedule changes to 
Q2W, plus window), or d=14 otherwise.   
Cumulative dose is the sum of the actual doses of CMP-001 received overall.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with CMP-001 (weeks)/4]   
Relative Dose Intensity (RDI)   
• Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [d (mg)] / [1 (4-week cycle)] = d (mg/4-week cycle) 
• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [d (mg/4-week cycle)]  
where  
o d=40 if last dose date of CMP-001 – first dose date of CMP-001 ≤25 (corresponding 
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o d=30 if 26 ≤last dose date of CMP-001 – first dose date of CMP-001 ≤50 
(corresponding to Cycle 2 dosing), else  
o d=20 
6.5.3.6. Dose reductions  
Applicable only to avelumab, utomilumab, PF-04518600, PD 0360324, and CMP-001. 
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 dose 
reductions (1, 2, 3, ≥4) will be summarized.  
6.5.4. Concomitant medications and non-drug treatments 
Combinations A and F 
The following analyses will be based on the safety analysis set by treatment group using the 
data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, F3) and 
the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D  
The following analyses will be based on the safety analysis set by treatment group using the 
data from Phase1b and from Phase 2 separately and for each combination. 
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period.  
Concomitant medications will be summarized from the ‘General Concomitant Medications’ 
eCRF page.  
Summary of 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 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.  
6.5.5. Subsequent anti-cancer therapies 
Combinations A and F 


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The following analyses will be based on the safety analysis set by treatment group using the 
data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, F3) and 
the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D  
The following analyses will be based on the safety analysis set by treatment group using the 
data from Phase1b and from Phase 2 separately and for each combination. 
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 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages.  
6.6. Safety Summaries and Analyses 
The Safety Analysis Set will be the primary population for safety evaluations.  
Combinations A and F 
The following analyses will be based on the safety analysis set by treatment group using the 
data from the combined Phases 1b and 2 (Cohorts A1, A2, A3 and Cohorts F1, F2, F3) and 
the data from Phase 2 (Cohorts A4, A5, A6, A7, A8, A9, A10). 
Combinations B, C and D  
The following analyses will be based on the safety analysis set by treatment group using the 
data from Phase1b and from Phase 2 separately and for each combination. 
6.6.1. Adverse events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period as defined in Section 3.5.1. 
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings. 
• Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (ie, no answer to the question ‘Relationship 
with study treatment’).  Related AEs are those related to any study drug (ie, at least one of 
the study drugs).  
• Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes). 
• Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 


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both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion. 
• Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).   
• Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
• Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan (SRP) and finalized for analysis of the current study 
data prior to DB lock) 
• Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
SRP and finalized for analysis of the current study data prior to DB lock. 
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 based on the frequencies observed.  
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity. 
6.6.1.1. All adverse events 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category.  
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed.  
The following tables will be created:  
• The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group: 
- TEAEs 
- TEAEs, Grade ≥ 3 
- Related TEAEs 
- Related TEAEs, Grade ≥ 3 
- TEAEs leading to interruption of any study drug 
- TEAEs leading to discontinuation of avelumab 


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- TEAEs leading to discontinuation of utomilumab 
- TEAEs leading to discontinuation of PF-04518600 
- TEAEs leading to discontinuation of PD 0360324 
- TEAEs leading to discontinuation of CMP-001 
- TEAEs leading to discontinuation of any study drug 
- Related TEAEs leading to discontinuation of avelumab 
- Related TEAEs leading to discontinuation of utomilumab 
- Related TEAEs leading to discontinuation of PF-04518600 
- Related TEAEs leading to discontinuation of PD 0360324 
- Related TEAEs leading to discontinuation of CMP-001 
- Related TEAEs leading to discontinuation of any study drug 
- Serious TEAEs 
- Related Serious TEAEs  
- TEAEs leading to death 
- Related TEAEs leading to death 
- irAEs 
- IRRs  
- Cytokine Release Syndrome (Combination F only) 
• TEAEs by SOC and PT and worst grade 
• TEAEs related to any study drug by SOC and PT and worst grade 
• TEAEs leading to death by SOC and PT 
• Related TEAEs leading to death by SOC and PT 
 
6.6.1.2. Adverse events leading to interruption of study treatment 
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay).  
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding  


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• IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.6). These IRRs will be considered as IRRs leading to 
interruption of infusion. 
• IRRs occurring on the day after infusion and subsequent dose administration had no delay 
(as defined in Section 6.5.3.6). 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group: 
• TEAEs leading to interruption of avelumab by SOC and PT 
• TEAEs leading to interruption of utomilumab by SOC and PT 
• TEAEs leading to interruption of PF-04518600 by SOC and PT 
• TEAEs leading to interruption of PD 0360324 by SOC and PT 
 
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
6.6.1.3. Adverse events leading to discontinuation of study treatment 
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 avelumab by SOC and PT 
• TEAEs leading to discontinuation of utomilumab by SOC and PT 
• TEAEs leading to discontinuation of PF-04518600 by SOC and PT 
• TEAEs leading to discontinuation of PD 0360324 by SOC and PT 
• TEAEs leading to discontinuation of CMP-001 by SOC and PT 
• TEAEs leading to discontinuation of any study drug by SOC and PT 
• Related TEAEs leading to discontinuation of avelumab by SOC and PT 
• Related TEAEs leading to discontinuation of utomilumab by SOC and PT 
• Related TEAEs leading to discontinuation of PF-04518600 by SOC and PT 
• Related TEAEs leading to discontinuation of PD 0360324 by SOC and PT 
• Related TEAEs leading to discontinuation of CMP-001 by SOC and PT 
• Related TEAEs leading to discontinuation of any study drug by SOC and PT 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  


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6.6.2. Deaths 
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the 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 
• Reason for Death  
- Disease progression 
- Study treatment toxicity 
- AE not related to study treatment 
- Unknown 
- Other. 
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information: 
• AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5),  
• Flag for death within 30 days of last dose of study treatment.  
6.6.3. Serious adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group: 
• SAEs by SOC and PT 
•  Related SAEs by SOC and PT 
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period. 
6.6.4. Other significant adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group: 
•  irAEs, by Cluster, PT, and maximum CTCAE Grade 
•  irAEs leading to discontinuation of avelumab, by Cluster and PT  
• irAEs leading to discontinuation of any study drug by Cluster and PT 
• Serious irAEs, by Cluster and PT  


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The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group and for each study drug: 
• IRRs, by PT and maximum CTCAE grade 
• IRRs leading to discontinuation of avelumab, by PT  
• IRRs leading to discontinuation of any study drug, by PT  
• Serious IRRs, by PT 
• Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later).  
For IV study drugs administered in combination the infusion numbers are those associated 
with the regimen, rather than the individual study drugs. 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
For Combination F only (Cohorts F1, F2 and F3) Cytokine Release Syndrome (as defined in 
the SRP) may be summarized and listed as described above for irAEs by Cluster and PT or 
by PT only, as applicable. 
6.6.5. Laboratory data 
6.6.5.1. Hematology and chemistry parameters 
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges).  
Abnormalities classified according to NCI-CTCAE toxicity grading v.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) 


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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 
- % 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 ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5×ULN, 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. 


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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 
• 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 concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) 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 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 number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)). 
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). 
•  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, 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). 


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Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with:  
• shifts from baseline normal to at least one result above normal during on-treatment period  
• shifts from baseline normal to at least one result below normal during on-treatment period 
In this study, these apply to the following parameters:  
• Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils 
• Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH) 
 
6.6.5.2. Other laboratory parameters 
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.   
6.6.6. Vital signs 
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Height will be measured at screening only. 
6.6.7. Electrocardiogram 
ECG summaries will include all ECG assessments from the on-treatment period.  QTcB and 
QTcF will be derived based on RR 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  


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3 RR
QT
QTcF =
 , 
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.   
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. Data will be 
summarized using QTcF and QTcB.   
ECG Summaries 
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category. 
• Pearson correlation between QT and HR, QTc (QTcB and QTcF) and HR using individual 
(non-averaged) baseline assessments  
• 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  
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. 
7. INTERIM ANALYSES 
There is no formal interim analysis planned for this study.   


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8. REFERENCES 
1. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982. 
2. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413. 
3. 
Ji Y and Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol 
2013;31(14):1785-1791. 
4. 
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.   
5. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958. 


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 15.  
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.   
Table 15. Case Definition for irAEs 
Step 
Selection Criteria 
Additional Notes 
1 
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list, then it is in for the next 
step 
 
2 
AE onset during 1st study drug 
administration or anytime thereafter through 
90 days after last dose of study treatment. 
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications 
3 
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’ 
 Steps 3 and 4 will be checked concurrently. Step 5 
will be checked if the criteria in Step 4 is met, 
irrespective of whether the Criteria in Step 3 is met.  
 
4 
AE treated with corticosteroids or other 
immunosuppressant therapy.   
For endocrinopathies only: AE required 
hormone replacement 
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) OR C) below are met then the AE is in 
for the next step 
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB, 
L04AC, L04AD, L04AX, A07EA) and AE PT 
is in any of the irAE clusters. 
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated 
with “Immune-mediated endocrinopathies” 
C) conmed ATC code is A10A and AE PT is in 
the irAE cluster associated with “Immune-
mediated endocrinopathies: Type I Diabetes 
Mellitus” 


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5 
A) No clear etiology (other than immune 
mediated etiology) 
 
 
 
 
 
 
 
B) Histopathology / biopsy consistent with 
immune-mediated event 
 
 
 
 
 
 
 
 
 
Event is in if  
[Answer to 5B1 and 5B2 is YES (regardless 
of answer to 5A)] 
OR 
[Answer to 5B1 is YES AND answer to 
5B2 is NO AND answer to 5A is NO]  
OR 
[Answer to 5B1 is NO AND answer to 5A 
is NO] 
A) From the AE eCRF page. 
Is the AE clearly related to an etiology other 
than immune-mediated etiology?    Yes / No 
If answer is Yes, check all that apply: 
• Underlying malignancy / progressive disease. 
• Other medical conditions.  
• Prior or concomitant medications / 
procedures.   
• Other.  Specify. 
 
B) From the AE eCRF page. 
B1) Was there a pathology /histology 
evaluation performed to investigate the AE?  
Y/N 
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N 
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text) 
 
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses. 
 


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Appendix 2. Infusion Related Reactions 
For defining an AE as IRR, the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered.  
• All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset.  
• All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of resolution date). 
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab.  
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 16 
or Table 17 and will be identified for IV drugs only.      
Table 16. Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs 
Conditio
n 
Selection criterion 
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)] then AE is classified as an IRR 
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug (‘DURING’, ‘AFTER’) AND  
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date ≤2  
3 
PT is included in the ‘IRRs CORE’ list  
4A 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug in (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion 
 


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Table 17. Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) 
Conditio
n 
Selection criterion 
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in 
combination.  Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  The 
IV study drug or drugs associated with the IRR need to be identified in the analysis data set to enable 
subsequent analysis. 
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ from 
one or more of I, II, III, IV, V below: 
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ 
that meets the 2A1 criterion  
II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ 
and associated with DJ+1 that meets the 2A2 criterion  
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all DJ 
that meet the 4B criterion. 
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ 
that meets the 4A1 criterion  
V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ  
and associated with DJ+1 that meets the 4A2 criterion  
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1]AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date ≤2  
2A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date ≤2  
3 
PT is included in the ‘IRRs CORE’ list  
4A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1] 
4A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion of study drug D J