Phase I/II Study to Evaluate the Safety and Tolerability of Avelumab in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies
Phase: PHASE1
Conditions: Advanced Malignant Solid Neoplasm, Castration-Resistant Prostate Carcinoma, Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Metastatic Prostate Carcinoma, Prostate Carcinoma Metastatic in the Bone, Refractory Malignant Solid Neoplasm, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

MDACC #: 2017-0014 
Protocol Version 11, 24 Jan 2023 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2017-0014 
Protocol Title 
Phase I/II Study to Evaluate the Safety and Tolerability of 
Avelumab in Combination with Other Anti-Cancer Therapies in 
Patients with Advanced Malignancies 
Protocol Phase 
I/II 
Protocol 
Version 
11 
Version Date 
24 Jan 2023 
Protocol PI 
Aung Naing, MD 
Department 
Investigational Cancer Therapeutics 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
135484 

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TITLE: PHASE I/II STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF 
AVELUMAB IN COMBINATION WITH OTHER ANTI-CANCER THERAPIES IN 
PATIENTS WITH ADVANCED MALIGNANCIES 
 
 
Short title: 
Phase I/II of Avelumab Combination with Other 
Anti-Cancer Therapies 
Sponsor: 
The University of Texas MD Anderson Cancer 
Center (MDACC) 
Supporter: 
Pfizer, Inc. 
Coordinating Investigator: 
Aung Naing, MD 
Compounds: 
Avelumab, 
Utomilumab (PF-05082566 (4-1BB)), 
PF-04518600 (OX40) 

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Protocol Version 11 24 Jan 2023 
 
 
 
CONTACT ADDRESSES 
 
 
 
Supporter and Drug 
Supply: 
Pfizer, Inc. 
235 East 42nd Street 
New York, NY 10017 
Coordinating 
Investigator: 
Aung Naing, MD 
1515 Holcombe Blvd, Unit 455 
Houston, Texas 77030 
Phone: 713-563-0803 
Fax: 713-563-0566 
Email: anaing@mdanderson.org 
Sponsor (IND Holder): 
The University of Texas MD Anderson Cancer Center 
Aman Buzdar, M.D. 
Vice President for Clinical Research Administration 
University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 1636 
Houston, TX 77030 
Investigational New Drug 
(IND) Number: 
135484 
Protocol Committee: 
Dr. Juhee Song (Statistical Consultant) 
Aung Naing, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SYNOPSIS 
 
MDACC Protocol 
Number: 
2017-0014 
Protocol Version (Date): 
Version 11 24 Jan 2023 
Study Design: 
Based on preclinical or clinical evidence of anti-tumor activity 
through PD-1/PD-L1/4-1BB/OX40 in tumor microenvironment and 
recommendations by Pfizer and MD Anderson physicians, as of 
Amendment 09, this is a four arm study (Parts A-D) that includes 
2 treatment categories to evaluate safety, pharmacodynamics, 
and anti-tumor activity of avelumab in combination with other 
cancer immunotherapies in Pfizer pipeline with or without 
radiation (XRT), in patients with metastatic solid tumors. 
• 
Category 1: Checkpoint agonist(s) in combination with 
avelumab; 
• 
Category 2: Checkpoint agonist(s) + XRT in combination with 
avelumab. 
This is an open label, single center Phase I/II combination therapy 
study in metastatic cancers. Patients may be enrolled in this study 
if they have advanced staged cancer either unresponsive or 
relapsed following prior standard therapy or for whom there is no 
known effective therapy. Patients who meet these criteria may in 
some cases have received no prior chemotherapy. 
Total Number of Sites: 
1 
Study Population: 
Patients with metastatic solid tumors 
Primary Objectives: 
• 
For Arm D, to establish the safety, tolerability, and dose- 
limiting toxicities (DLTs) of different treatment combinations of 
avelumab when administered in combination with a 
checkpoint agonist with radiation in patients with metastatic 
solid tumors in order to estimate the maximum tolerated dose 
(MTD) and select the recommended phase 2 dose (RP2D). 
• 
To correlate pre- and post-treatment CD8 expression with 
clinical benefit (complete response [CR], partial response 
[PR], or stable disease [SD] for > 6 months). 
Secondary Objectives: 
• 
To evaluate the efficacy of the different treatment 
combinations in patients with metastatic solid tumors by 
assessing objective response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and 
immune-related RECIST (irRECIST). 
• 
To evaluate the efficacy of the different treatment 
combinations in patients with metastatic solid tumors by 
assessing progression-free survival (PFS), duration of 
response (DOR), and overall survival (OS). 
Exploratory Objectives: 
• 
To understand the mechanism of action of the avelumab plus 
an immune modulator combination, as well as potential 
mechanisms of resistance. 
• 
To characterize the effect of avelumab combinations on 
immune biomarkers in peripheral blood and tumor tissue 
obtained from subjects pre- and post-treatment. 

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• 
To compare the response in irradiated versus non-irradiated 
lesions in Arm D. 
• 
To investigate immune biomarkers that are potentially 
predictive of response and resistance with the combination of 
avelumab and an immune modulator. 
Planned Sample Size: 
Two dose levels may be examined in each combination arm during 
the dose escalation/de-escalation with a standard “3+3” design, 
and a total of 3-6 patients will be enrolled per dose level. After each 
escalation or MTD determination by Pfizer, there will be an MTD 
expansion cohort of up to 14 patients each. As of Amendment 09, 
the planned total maximum accrual in this study will be 128 patients 
(Escalation 36 + MTD Expansions 92). Please refer to Section 9.3 
and Table 12 for the history of amendments impacting the accrual. 
Treatment Scheme: 
There are 4 active arms in this study: 
Arm A: Avelumab + Utomilumab (4-1BB) 
Arm B: Avelumab + PF-04518600 (OX40) 
Arm C: Avelumab + Utomilumab (4-1BB) + PF-04518600 (OX40) 
Arm D: Avelumab + Utomilumab (4-1BB) + XRT 
Treatment will continue until progression of disease (PD) or 
unacceptable toxicity, withdrawal of consent by the patients, or 
non-compliance by the patient with protocol requirements. 
Primary Endpoint: 
• 
Safety and tolerability will be assessed by monitoring the 
frequency, duration, and severity of adverse events (AEs) 
according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. 
• 
Evaluation of CD8 immune biomarkers from tumor and blood 
biospecimens. 
Secondary and 
Exploratory Endpoints: 
• 
Objective response rate determined by radiographic disease 
assessments per RECIST v1.1 and irRECIST. 
• 
Progression-free survival, defined as the time from Cycle 1 
start date until the earliest date of disease progression, as 
determined by investigator assessment of objective 
radiographic disease assessments per RECIST v1.1 and 
irRECIST, or death due to any cause, if occurring sooner than 
progression. 
• 
Duration of response determined by radiographic disease 
assessment, defined as the time from earliest date of disease 
response until the earliest date of disease progression per 
RECIST v1.1 and irRECIST, or death due to any cause, if 
occurring sooner than progression. 
• 
Overall survival determined from the Cycle 1 start date until 
death due to any cause. 
• 
Response data in irradiated and non-irradiated lesions. 
• 
Evaluation of various immune biomarkers from tumor and 
blood biospecimens. 

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Efficacy Assessments: 
Anti-tumor activity will be assessed by radiological tumor 
assessments at 8-week intervals (± 7 days), using RECIST v1.1. 
In the event that partial response (PR), complete response (CR), 
or progressive disease (PD) is observed according to RECIST 
v.1.1 and irRECIST, tumor assessments should be repeated at 
least 4 weeks after initial documentation. 
After 1 year of treatment on the study, tumor assessments will be 
conducted less frequently, at 12-week intervals (± 7 days), 
independent of cycle delays. In addition, radiological tumor 
assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration), and at 
the time of End of Treatment/Withdrawal (if not done in the 
previous 8 weeks). 
If a patient discontinues treatment due to any other reason than 
disease progression/ death/ withdrawal of informed consent, the 
disease evaluations shall continue until disease progression. This 
includes patients who wish to discontinue treatment, but agree 
that further data is captured for the purpose of the study (partial 
withdrawal). 
Safety Assessments: 
All adverse events (AEs), including immune-related adverse 
events (irAEs), occurring during the course of the trial and for up 
to 30 days after the last dose of study medication will be captured, 
documented and reported. Toxicity will be graded according to 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
If multiple toxicities are seen, the presence of DLT shall be based 
on the most severe toxicity experienced. DLTs are defined as 
adverse events (AEs) that are related to study events and occur 
during the first 2 cycles or 8 weeks of treatment. Toxicity must 
have possible, probable, or definite attribution to the study drugs. 
Statistical 
Considerations: 
All enrolled patients are eligible for the analyses of toxicity and 
compliance. All patients who received at least 1 dose of study 
medication are eligible for analysis. 

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SCHEDULE OF ASSESSMENTS FOR ARMS A, B, AND C (NON-RADIATION) 
 
The Schedule of Assessments table provides an overview of the protocol visits and procedures for Arms A-C. Refer to the Section 
7.0- Assessments of the protocol for detailed information on each assessment required for compliance with the protocol. The 
investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the patient. 
 
 
Assessments 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dosing of 
Study Drug 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
Informed Consent 1 
X 
Verify Eligibility Criteria 
X 
X 
Medical History 2 
X 
Tumor History 
X 
Serum or Urine Beta- hCG 3 
X 
X 
X 
X 
X 
Protocol /Safety Evaluation 
Physical Exam and ECOG 4 
X 
X 
X 
X 
X 
X 
X 
X 
Height 5 
X 
Weight5 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 6 
X 
X 
X 
X 

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Assessments 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dosing of 
Study Drug 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
ECHO/MUGA7 
X 
X7 
X 
AE/SAE Assessment 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival Status9 
X9 
Laboratory Evaluation 
Hematology 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function 12 
X 
X12 
X 
Urinalysis 13 
X 
X 
X 
X 
Coagulation Test 14 
X 
X 
X 
X 
Hepatitis B and C Testing (Hepatitis B surface 
antigen and core antibody; anti-hepatitis C anti- 
body) 
X 
Cardiac Monitoring15 
X 
X 
X 
X 
X 
Study Treatment 
Expansion Arms A-C: Avelumab Dosing 16 
X 
X 
X 
X 
X 
Arm A: Utomilumab (4-1BB) Dosing 17 
X 
X 
X 
Arm B: PF-04518600 (OX40) Dosing 18 
X 
X 
X 
X 
X 
X 
Arm C: Utomilumab(4-1BB)19 
X 
X 
X 
Arm C: PF-04518600 (OX40)19 
X 
X 
X 
X 
X 
X 

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Assessments 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dosing of 
Study Drug 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
Tumor Measurement 
CT or MRI or PET-CT 20 
X 
Every 8 Weeks 
for up to 1 year, 
then Every 12 
Weeks thereafter 
Every 12 
Weeks 
Tumor Markers (if applicable) 21 
X 
Every 8 Weeks 
for up to 1 year, 
then Every 12 
Weeks thereafter 
Every 12 
Weeks 
Correlative Studies 
Expansion Arms A-C: Tumor Biopsy 22 
X26 
X 
X 
X 
Expansion Arms A-C: Immune Biomarkers 23 
X 
X 
X 
X 
Escalation Arm C: Tumor Biopsy 24 
X26 
X 
X 
Escalation Arm C: Immune Biomarkers 25 
X 
X 
X 
Footnotes 
1. 
Informed consent must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
2. 
Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, disease progression during or after 
therapy, as well as discontinuations due to intolerability or any other serious illness. 
3. 
For female patients of childbearing potential, who do not fit for the definition of “female patients who are not of childbearing potential” in inclusion criterion, a serum or 
urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on two occasions prior to starting study therapy - once at the start of screening (within 7 
days of first dose of study treatment) and once at the baseline visit, immediately before investigational product administration. Pregnancy tests will also be routinely 
repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if 
required by local regulations 

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4. 
Full physical examination and ECOG will be performed at screening, Days 1 and 15 of each cycle and End of Treatment visit. Physical examinations during the study 
should be symptom directed. 
5. 
Vital signs: temperature, pulse, respiratory, blood pressure, body surface area and body weight will be measured. Weight for the purposes of dose calculation must be 
recorded at Screening and within 7 days pre-dose Day 1 of each cycle and Day 15 of each cycle. At screening, height will be obtained from the electronic medical 
record. 
6. 
12-lead ECG (single) will be performed at screening and predose of Day 1 of Cycle 1. 12-lead ECG (single) will be performed at predose of Day 1 of every 
subsequent cycle. 
7. 
For patients on the PF-04518600 (OX40) Arms (B and C) who have had prior exposure to anthracyclines, echocardiogram (ECHO) or multigated acquisition (MUGA) 
will be performed at screening, every 3 cycles (starting at Cycle 4 Day 1), and End of Treatment (if not performed within 3 months of discontinuation). 
8. 
AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03. Patients must be followed for AEs for 30 days after the last 
treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 30 days should the patient commence another anticancer 
therapy in the meantime. 
9. 
Survival Status: Investigators will collect survival data for patients after progression of disease unless patient fully withdrew consent to participate in the study using 
information from a chart review, patient visit, or telephone call. The telephone call will be less than five minutes to obtain information regarding survival status. 
10. Hematology: White blood cell (WBC) count with differential, Hemoglobin, Platelet count, Red blood cell count, Hematocrit, Mean corpuscular volume (MCV), Mean 
corpuscular hemoglobin concentration (MCHC). No need to repeat on Cycle 1 Day 1 if baseline assessment performed within 2 days prior to that date. Post Cycle 3, 
patients in all study arms will have hematology labs on Day 1 and 15 of each cycle. 
11. Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Blood urea nitrogen (BUN), Creatinine, Glucose (non-fasting), Calcium, Phosphate, Magnesium, Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline Phosphatase, Total Bilirubin, Lactate dehydrogenase (LDH), Total Protein, Albumin, Uric acid, 
Amylase, Lipase and Creatine Kinase. No need to repeat on Cycle 1 Day 1 if baseline assessment performed within 2 days prior to that date. Post Cycle 3, patients in 
all study arms will have chemistry labs on Day 1 and 15 of each cycle. 
12. Thyroid function: (thyroid-stimulating hormone (TSH), free thyroxine (T4), and total triiodothyronine (T3). TSH, free T4, and total T3 for endocrine monitoring will be 
evaluated at screening and every tumor restaging (every 8 weeks). 
13. Urine analysis will include Color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin and microscopy including WBC/high power field (HPF), 
RBC/HPF if clinically indicated. Dipstick is acceptable. Urine analysis will be at screening and Day 1 of every cycle. No need to repeat on Cycle 1 Day 1 if baseline 
assessment performed within 2 days prior to that date. 
14. Coagulation test include prothrombin time (PT), international normalization ratio (INR), and activated partial thromboplastin time (aPTT). Coagulation tests will be 
performed at screening and Day 1 of every Cycle. No need to repeat on Cycle 1 Day 1 if baseline assessment performed within 2 days prior to that date. 

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15. For patients on the PF-04518600 (OX40) Arms (B and C) who have had prior exposure to anthracyclines, cardiac enzyme monitoring will be performed at screening, 
Day 1 of every cycle, and End of Treatment. Troponin T and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) will be evaluated prior to dosing. No 
need to repeat on Cycle 1 Day 1 (C1D1) if the screening assessment is performed within 2 days prior to that date. Assessments performed on Cycle 2 Day 1 and Day 
1 of each subsequent cycle should be performed within 48 hours prior to dosing. Assessments should also be performed when clinically indicated. 
16. For MTD Expansion Arms A-C, avelumab will be administered IV every 2 weeks starting on Cycle 1 Day 15 (and then Days 1 and 15 of Cycle 2 and beyond). 
17. For Arm A, utomilumab (4-1BB) will be administered IV every 4 weeks starting on Cycle 1 Day 1 (Day 1 of every cycle). 
18. For Arm B, PF-04518600 (OX40) will be administered IV every 2 weeks starting on Cycle 1 Day 1 (Days 1 and 15 of every cycle). 
19. For Arm C, utomilumab (4-1BB) will be administered IV every 4 weeks starting on Cycle 1 Day 1 (Day 1 of every cycle). PF-04518600 (OX40) will be administered IV 
every 2 weeks starting on Cycle 1 Day 1 (Days 1 and 15 of every cycle). 
20. CT, MRI, or PET-CT Scans will be performed at screening, then every 2 cycles or 8 weeks +/- 7 days for the first year of treatment. Thereafter tumor assessments will 
be performed every 3 cycles or 12 weeks +/- 7 days during treatment, independent of cycle delays. 
21. Tumor markers (if applicable) will be collected at screening, then every 2 cycles or 8 weeks +/- 7 days for the first year of treatment. Thereafter tumor assessments 
will be performed every 3 cycles or 12 weeks +/- 7 days during treatment, independent of cycle delays. 
22. For MTD Expansion Cohorts in Arms A-C, tumor tissue will be obtained pre- treatment (baseline), between Cycle 1 Day 12-15 (prior to study drug dosing), prior to 
Cycle 3 Day 1 study drug dosing, and at progression (if achieved stable disease ≥6 months, partial response, or complete remission) provided there is technically 
biopsiable tumor, and it is safe for patient to undergo biopsy. 
23. For MTD Expansion Cohorts in Arms A-C, blood samples will be collected at baseline, between Cycle 1 Day 12-15 (prior to study drug dosing), prior to Cycle 3 Day 1 
study drug dosing, and at the time of progression (if patient had an initial response of stable disease ≥6 months, partial response, or complete remission) to evaluate 
biological response or predictive markers in blood, tumor, and tumor environment and their relationships to drug exposure, clinical response, or other biologic 
response markers. Cell free DNA from patient’s blood samples will also be analyzed. 
24. For Escalation Cohorts in Arm C (patients enrolled prior to Version 05), tumor tissue will be obtained pre- treatment (baseline), prior to Cycle 2 Day 1 dosing, and at 
progression (if achieved stable disease ≥6 months, partial response, or complete remission) provided there is technically biopsiable tumor, and it is safe for patient to 
undergo biopsy. 
25. For Escalation Cohorts in Arm C (patients enrolled prior to Version 05), blood samples will be collected at baseline, prior to Cycle 2 Day 1 dosing, and at the time of 
progression (if patient had an initial response of stable disease ≥6 months, partial response, or complete remission) to evaluate biological response or predictive 
markers in blood, tumor, and tumor environment and their relationships to drug exposure, clinical response, or other biologic response markers. Cell free DNA from 
patient’s blood samples will also be analyzed. 
26. Archival tissue may not be utilized for the baseline sample time point. 

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SCHEDULE OF ASSESSMENTS FOR ARM D (RADIATION) 
 
The Schedule of Assessments table provides an overview of the protocol visits and procedures for Arm D. Refer to the Section 7.0- 
Assessments of the protocol for detailed information on each assessment required for compliance with the protocol. The investigator 
may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct evaluations or 
assessments required to protect the wellbeing of the patient. 
 
 
Assessments 
Treatment Period 
Post-Treatment 
Screening 
Radiation 
Lead-in4 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dose of 
Radiation 
First Day of 
Radiation 
(+/- 3 Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
Informed Consent 1 
X 
Verify Eligibility Criteria 
X 
X 
Medical History 2 
X 
Tumor History 
X 
Serum or Urine Beta- hCG 3 
X 
X 
X 
X 
X 
Protocol /Safety Evaluation 
Physical Exam and ECOG 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 6 
X 
Weight6 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 7 
X 
X 
X 
X 

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Assessments 
Treatment Period 
Post-Treatment 
Screening 
Radiation 
Lead-in4 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dose of 
Radiation 
First Day of 
Radiation 
(+/- 3 Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
AE/SAE Assessment 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival Status9 
X9 
Laboratory Evaluation 
Hematology 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function 12 
X 
X12 
X 
Urinalysis 13 
X 
X 
X 
X 
Coagulation Test 14 
X 
X 
X 
X 
Hepatitis B and C Testing (Hepatitis B surface 
antigen and core antibody; anti-hepatitis C anti- 
body) 
X 
Study Treatment 
Arm D: XRT 15 
X 
Arm D: Avelumab Dosing 16 
X 
X 
X 
X 
X 
Arm D: Utomilumab (4-1BB) 17 
X 
X 
X 
Tumor Measurement 
CT or MRI or PET-CT 18 
X 
Every 8 Weeks 
for up to 1 year, 
then Every 12 
Weeks thereafter 
Every 12 
Weeks 

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Assessments 
Treatment Period 
Post-Treatment 
Screening 
Radiation 
Lead-in4 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
</= 28 Days 
prior to 1st 
Dose of 
Radiation 
First Day of 
Radiation 
(+/- 3 Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
Day 1 
(+/- 2 
Days) 
Day 15 
(+/- 2 
Days) 
30 Days after 
Last Dose of 
Study Drug 
(+/- 7 Days) 
Every 12 
Weeks 
(+/- 7 Days) 
Tumor Markers (if applicable) 19 
X 
Every 8 Weeks 
for up to 1 year, 
then Every 12 
Weeks thereafter 
Every 12 
Weeks 
Correlative Studies 
Arm D: Tumor Biopsy 20 
X22 
X 
X 
Arm D: Immune Biomarkers 21 
X 
X 
X 
X 
X 
X 
 
Footnotes 
1. 
Informed consent must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
2. 
Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, disease progression during or after 
therapy, as well as discontinuations due to intolerability or any other serious illness. 
3. 
For female patients of childbearing potential, who do not fit for the definition of “female patients who are not of childbearing potential” in inclusion criterion, a serum or 
urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on two occasions prior to starting study therapy - once at the start of screening (within 7 
days of first dose of radiation) and once in the radiation lead-in prior to initial radiation treatment. Pregnancy tests will also be routinely repeated at every cycle during 
the active treatment period, at the end of study therapy and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected. 
Additional pregnancy tests may also be undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations 
4. 
The radiation lead-in will occur within Days -5 to -1 with a +/- 3 day window. There will be 3 fractions or days of radiation. In all cases, the radiation must initiate and 
end within the radiation lead-time. Cycle 1 Day 1 treatment should be within 3 days of last dose of radiation. 
5. 
Full physical examination and ECOG will be performed at screening, within 3 days of first day of radiation, Days 1 and 15 of each cycle and End of Treatment visit. 
Physical examinations during the study should be symptom directed. 

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6. 
Vital signs: temperature, pulse, respiratory, blood pressure, body surface area and body weight will be measured. Weight for the purposes of dose calculation must be 
recorded at Screening and within 7 days pre-dose Day 1 of each cycle and Day 15 of each cycle. At screening, height will be obtained from the electronic medical 
record. 
7. 
12-lead ECG (single) will be performed at screening and predose of Day 1 of Cycle 1. 12-lead ECG (single) will be performed at predose of Day 1 of every 
subsequent cycle. 
8. 
AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03. Patients must be followed for AEs for 30 days after the last 
treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 30 days should the patient commence another anticancer 
therapy in the meantime. 
9. 
Survival Status: Investigators will collect survival data for patients after progression of disease unless patient fully withdrew consent to participate in the study using 
information from a chart review, patient visit, or telephone call. The telephone call will be less than five minutes to obtain information regarding survival status. 
10. Hematology: White blood cell (WBC) count with differential, Hemoglobin, Platelet count, Red blood cell count, Hematocrit, Mean corpuscular volume (MCV), Mean 
corpuscular hemoglobin concentration (MCHC). Hematology will be performed at screening, within 3 days of first day of radiation, Days 1 and 15 of each cycle, and 
End of Treatment visit. 
11. Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Blood urea nitrogen (BUN), Creatinine, Glucose (non-fasting), Calcium, Phosphate, Magnesium, Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline Phosphatase, Total Bilirubin, Lactate dehydrogenase (LDH), Total Protein, Albumin, Uric acid, 
Amylase, Lipase and Creatine Kinase. Chemistry will be performed at screening, within 3 days of first day of radiation, Days 1 and 15 of each cycle, and End of 
Treatment visit. 
12. Thyroid function: (thyroid-stimulating hormone (TSH), free thyroxine (T4), and total triiodothyronine (T3). TSH, free T4, and total T3 for endocrine monitoring will be 
evaluated at screening and every tumor restaging (every 8 weeks). 
13. Urine analysis will include Color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin and microscopy including WBC/high power field (HPF), 
RBC/HPF if clinically indicated. Dipstick is acceptable. Urine analysis will be at screening, within 3 days of first day of radiation, and Day 1 of Cycle 2 and beyond. 
14. Coagulation test include prothrombin time (PT), international normalization ratio (INR), and activated partial thromboplastin time (aPTT). Coagulation tests will be 
performed at screening, within 3 days of first day of radiation, and Day 1 of Cycle 2 and beyond. 
15. For Arm D, radiation will be given to 1-3 metastatic lesions. Radiation as described in Section 3.2 will be given during the Radiation Lead-in (Days -5 to -1) or 3 
consecutive business days (+/-3 days). Cycle 1 Day 1 treatment should be within 3 days of last dose of radiation. 
16. For Arm D, avelumab will be administered IV every 2 weeks starting on Cycle 1 Day 15 (and then Days 1 and 15 of Cycle 2 and beyond). 
17. For Arm D, utomilumab (4-1BB) will be administered IV every 4 weeks starting on Cycle 1 Day 1 (Day 1 of every cycle). 
18. CT, MRI, or PET-CT Scans will be performed at screening, then every 2 cycles or 8 weeks +/- 7 days for the first year of treatment. Thereafter tumor assessments will 
be performed every 3 cycles or 12 weeks +/- 7 days during treatment, independent of cycle delays. 

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19. Tumor markers (if applicable) will be collected at screening, then every 2 cycles or 8 weeks +/- 7 days for the first year of treatment. Thereafter tumor assessments 
will be performed every 3 cycles or 12 weeks +/- 7 days during treatment, independent of cycle delays. 
20. For De-Escalation and MTD Expansion Cohort in Arm D, tumor tissue will be obtained pre- treatment (baseline), prior to Cycle 3 Day 1 dosing, and at progression (if 
achieved stable disease ≥6 months, partial response, or complete remission) provided there is technically biopsiable tumor, and it is safe for patient to undergo 
biopsy. 
21. For De-Escalation and MTD Expansion Cohort in Arm D, blood samples will be collected at baseline (prior to radiation), prior to Cycle 1 Day 1 dosing, prior to Cycle 1 
Day 15 dosing, prior to Cycle 2 Day 1 dosing, prior to Cycle 3 Day 1 dosing, and at the time of progression (if patient had an initial response of stable disease ≥6 
months, partial response, or complete remission). Cell free DNA from patient’s blood samples will also be analyzed. 
22. Archival tissue may not be utilized for the baseline sample time point. 

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GLOSSARY OF ABBREVIATIONS 
 
β-HCG 
Beta human chorionic gonadotropin 
1L 
First Line Treatment 
2L 
Second Line Treatment 
3L 
Third Line Treatment 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
Blood pressure 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
CDDP 
Cisplatin 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CNB 
Core Needle Biopsy 
CNS 
Central nervous system 
CR 
Complete Response 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CT 
Computer tomography 
CTCAE 
Common terminology criteria for adverse events 
D 
Day 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DRAE 
Drug-related Adverse Events 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMR 
Electronic Medical Record 
EOT 
End of treatment 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FIP 
First-in-Patient 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GEJ 
Gastroesophageal Junction 
GI 
Gastrointestinal 

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GLP 
Good laboratory practice 
Gy 
Gray 
H 
Hour 
HCC 
Hepatocellular carcinoma 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HIF 
Hypoxia-Inducible Factors 
HPV 
Human papillomavirus 
HR 
Hazard ratio 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IIR 
Investigator-Initiated Research 
IMP 
Investigational medicinal product 
IMRT 
Intensity-Modulated Radiation Therapy 
INR 
International normalization ratio 
IR 
Irradiation 
IRB 
Institutional review board 
irAE 
Immune-Related Adverse Event 
irRECIST 
Immune-Related Response Evaluation Criteria in Solid 
Tumors 
ITB 
Institutional Tissue Bank 
IV 
Intravenous 
kg 
Kilogram 
LAFB 
Left anterior fascicular block 
LDH 
Lactate dehydrogenase 
LLN 
Lower Limit of Normal 
m² 
Square metre (body surface area) 
LMW 
Low molecular weight 
mAb 
Monoclonal Antibody 
MCC 
Merkel Cell Carcinoma 
MCL 
Mantle Cell Lymphoma 
mg 
Milligram 
MI 
Myocardial infarction 
min 
Minute 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated Acquisition 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear cells 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Progressive disease 
PDn 
Pharmacodynamics 
PET 
Positron emission tomography 

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PFS 
Progression-free survival 
PI 
Principal Investigator 
PLT 
Platelets 
PPS 
Per protocol set 
PR 
Partial Response 
PRN 
as needed 
PT 
Prothrombin time 
QoL 
Quality of Life 
RBBB 
Right bundle branch block 
RBC 
Red blood cells 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
ROSE 
Rapid on Site Evaluation 
RP2D 
Recommend Phase 2 Dose 
RR 
Response Rate 
RT 
Radiation Therapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SADR 
Serious adverse drug reaction 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
T3 
Total triiodothyronine 
T4 
Free thyroxine 
TEAE 
Treatment-Emergent Adverse Events 
TIL 
Tumor-Infiltrating Lymphocytes 
TNBC 
Triple Negative Breast Cancer 
TSH 
Thyroid-Stimulating Hormone 
TSP 
Tumor suppressor protein 
ULN 
Upper limit of normal 
VMAT 
Volumetric modulated arc therapy 
Vs. 
Versus 
WBC 
White blood cell 
WHO 
World Health Organization 
XRT 
Radiation 

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TABLE OF CONTENTS 
TITLE: PHASE I/II STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF 
AVELUMAB IN COMBINATION WITH OTHER ANTI-CANCER THERAPIES IN 
PATIENTS WITH ADVANCED MALIGNANCIES 
1 
SYNOPSIS 
4 
SCHEDULE OF ASSESSMENTS FOR ARMS A, B, AND C (NON-RADIATION) 
7 
SCHEDULE OF ASSESSMENTS FOR ARM D (RADIATION) 
12 
GLOSSARY OF ABBREVIATIONS 
17 
TABLE OF CONTENTS 
20 
 
1.0 
INTRODUCTION 
26 
1.1 
Indications 
26 
1.2 
Background 
28 
1.2.1 
Avelumab (PF-06834635): Anti-PD-L1 Monoclonal Antibody 
28 
1.2.2 
Utomilumab: Anti-4-1BB Agonist Monoclonal Antibody 
31 
1.2.3 
PF-04518600: Anti-OX40 Agonist Monoclonal Antibody 
33 
1.3 
Rationale for Combinations 
35 
1.3.1 
Combination of Checkpoint Agonist(s) with Avelumab 
35 
1.3.1.1 
Combination of Utomilumab (anti-4-1BB mAb) with Avelumab 
36 
1.3.1.2 
Combination of PF-04518600 (Anti-OX40 mAb) with Avelumab 
39 
1.3.1.3 
Combination of Utomilumab and PF-4518600 with Avelumab 
40 
1.3.2 
Combination of Checkpoint Agonist(s) and Radiotherapy with 
Avelumab 
42 
1.3.2.1 
Combination of PF-5082566 and Radiotherapy with Avelumab 
43 
1.3.2.2 
Combination of PF-04518600 and Radiotherapy with Avelumab 
45 
1.3.2.3 
Combination of Utomilumab, PF-04518600, and Radiotherapy with 
Avelumab 
47 

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1.4 
Potential for Overlapping Toxicities 
47 
1.5 
Protocol Arm Closures 
48 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
49 
2.1 
Objectives 
49 
2.1.1 
Primary Objectives 
49 
2.1.2 
Secondary Objectives 
49 
2.1.3 
Exploratory Objectives 
49 
2.2 
Endpoints 
50 
2.2.1 
Primary Endpoints 
50 
2.2.2 
Secondary and Exploratory Endpoints 
50 
3.0 
STUDY DESIGN 
51 
3.1 
Study Overview 
51 
3.1.1 
Part I: Dose Escalation or Dose De-Escalation (Part D Only) 
51 
3.1.2 
Part II: MTD Expansion 
52 
3.2 
Study Treatment Arms 
53 
3.2.1 
Arm A: Avelumab + Utomilumab (4-1BB) 
54 
3.2.2 
Arm B: Avelumab + PF-04518600 (OX40) 
55 
3.2.3 
Arm C: Avelumab + Utomilumab (4-1BB) + PF-04518600 (OX40) 
56 
3.2.4 
Arm D: Avelumab + Utomilumab (4-1BB) + Radiation 
57 
3.3 
Dose-Limiting Toxicity (DLT) Definition 
59 
3.4 
Maximum Tolerated Dose (MTD) Definition 
61 
3.5 
Dose Escalation and Stopping Rules 
62 
4.0 
PATIENT SELECTION 
64 
4.1 
Inclusion Criteria 
64 
4.2 
Exclusion Criteria 
66 
4.3 
Pregnancy and Contraception 
69 

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5.0 
STUDY TREATMENTS 
70 
5.1 
Allocation to Treatment 
70 
5.2 
Investigational Product Supplies 
70 
5.2.1 
Formulation and Packaging 
70 
5.2.1.1 
Avelumab 
70 
5.2.1.2 
Utomilumab (4-1BB) 
71 
5.2.1.3 
PF-04518600 (OX40) 
71 
 
5.2.2 Preparation and Dispensing 
71 
5.2.2.1 
Avelumab 
71 
5.2.1.2 
Utomilumab (4-1BB) 
72 
5.2.1.3 
PF-04518600 (OX40) 
72 
5.2.3 
Administration, Dose Calculation and Infusion Reactions 
72 
5.2.3.1 
Avelumab 
72 
5.2.3.2 
Utomilumab (4-1BB) 
73 
5.2.3.3 
PF-04518600 (OX40) 
73 
5.2.4 
Recommended Dose Modifications 
74 
5.2.4.1 
Dose Interruptions 
74 
5.2.4.2 
Dose Delays 
75 
5.2.4.3 
Dose Modifications 
77 
5.2.5 
Compliance 
86 
5.3 
Drug Storage and Drug Accountability 
86 
5.4 
Concomitant Medications 
86 
5.4.1 
Other Anticancer or Experimental Drugs 
87 
5.4.2 
Supportive Care 
87 
5.4.3 
Hematopoietic Growth Factors 
87 
5.4.4 
Anti-inflammatory Therapy 
87 
5.4.5 
Corticosteroids 
88 
5.4.6 
Surgery 
88 
5.4.7 
Radiation Therapy 
88 

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5.4.7.1 Radiation Technique 
89 
5.4.7.2 Target Volumes 
90 
5.4.7.3 Daily Treatment Setup 
90 
5.4.7.4 Dose Volume Constraints 
91 
5.4.7.5 Radiation Breaks and Discontinuation 
91 
 
6.0 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
93 
6.1 
Screening Period 
93 
6.2 
Study Treatment Period 
93 
6.3 
End of Treatment Visit 
94 
6.4 
Follow-Up Phase 
94 
6.5 
Patient Withdrawal 
95 
7.0 
ASSESSMENTS 
97 
7.1 
Safety Assessments 
97 
7.1.1 
Pregnancy Testing 
97 
7.1.2 
Adverse Events 
98 
7.1.3 
Laboratory Safety Assessments 
99 
7.1.4 
Vital Signs and Physical Examination 
102 
7.1.5 
ECG Assessments 
103 
7.1.6 
Echocardiogram/ Multigated Acquisition Assessments 
104 
7.1.7 
Cardiac Enzyme Monitoring 
104 
7.2 
Tumor Response Assessments 
104 
7.3 
Biopsy Analyses 
106 
7.4 
Biomarker Analyses 
107 
7.5 
Co-Enrollment on Additional Studies 
110 
8.0 
ADVERSE EVENT REPORTING 
112 
8.1 
Adverse Events 
112 
8.2 
Definition of Adverse Event 
112 

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8.3 
Definition of Serious Adverse Event (SAE) 
113 
8.4 
Reporting to FDA 
114 
8.5 
Investigator Communications with Pfizer 
115 
8.6 
Recording of Adverse Events 
117 
8.6.1 
Laboratory Test Abnormalities 
118 
8.6.2 
Pregnancy 
118 
8.6.2 
Adverse Drug Reactions with Concomitant Medication 
119 
9.0 
DATA ANALYSIS/ STATISTICAL METHODS 
120 
9.1 
Analysis Sets 
120 
9.2 
Statistical Methods and Properties 
121 
9.3 
Sample Size Determination 
122 
9.4 
General Statistical Considerations 
125 
9.4.1 
Demographics and Baseline Characteristics 
126 
9.5 
Efficacy Analysis 
126 
9.5.1 
Efficacy Evaluation 
127 
9.6 
Safety Analysis 
127 
9.6.1 
Safety Evaluation 
127 
9.6.2 
Adverse Events 
127 
9.6.3 
Laboratory Data 
128 
9.6.4 
Vital Signs and Physical Examinations 
128 
9.6.5 
Concomitant Medications 
129 
9.7 
Biomarker Analysis 
129 
9.8 
Final Analysis 
129 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
130 
11.0 
DATA HANDLING AND RECORD KEEPING 
131 
11.1 
Case Report Form/ Electronic Data Record 
131 
11.2 
Record Retention 
131 

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11.3 
Audits and Inspections 
132 
12.0 
DEFINITION OF END OF TRIAL 
133 
13.0 
SPONSOR DISCONTINUATION CRITERIA 
134 
14.0 
APPENDICES 
135 
Appendix 1 – Adverse Event Categories for Determining Relationship 
to Test Drug 
136 
Appendix 2 – ECOG Performance Status 
137 
15.0 
REFERENCES 
138 

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1.0 
INTRODUCTION 
 
1.1 
Indications 
 
There is a broad literature of evidence that infiltration of tumor tissue by T cells is 
associated with improved survival in patients with melanoma, breast, ovarian, lung, 
renal cell, colorectal and bladder carcinoma among other solid tumors (1, 2). 
However, eliciting T cell mediated immune response is a challenge as tumor cells 
frequently develop a host of immunosuppressive defense mechanisms to escape 
immune surveillance through a process called immune tolerance (1). It is therefore 
critical to overcome these barriers to elicit clinical response to therapeutic agents. 
 
Despite the success with checkpoint inhibitors, including cytotoxic T-lymphocyte 
associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or 
programmed death-ligand 1 (PD-L1) blockades, many patients are primarily resistant 
or develop resistance to treatment after an initial response (3). Among several 
mechanistic approaches being investigated in the clinic to overcome primary and 
secondary resistance to the immune checkpoint blockers, there is growing evidence 
that combination therapies are potentially synergistic and are far more effective than 
monotherapies to combat resistance mechanisms as tumors use multiple pathways to 
evade immune elimination (4). Further, few immunologic parameters have been 
identified as early markers of response including intra tumoral CD8+ T cells. (5-7). 
Therefore, this program has been conceived to identify fine-tuned combination 
therapies that would facilitate infiltration of CD8+ T cells into tumor cells and 
demonstrate synergistic anti-tumor activity, allowing the capability to hone in on 
combinations and tumor types of interest. 
 
Based on preclinical or clinical evidence of anti-tumor activity through PD-1, PD-L1, 4- 
1BB, and OX40 in tumor microenvironment, a six-arm study that includes 2 treatment 
categories to evaluate safety, pharmacodynamics, and anti-tumor activity of avelumab 
in combination with other cancer immunotherapies in Pfizer pipeline with or without 
radiation (XRT), in patients with metastatic solid tumors was initially to be conducted. 
• Category 1: Checkpoint agonist(s) in combination with avelumab; 
• Category 2: Checkpoint agonist(s) + XRT in combination with avelumab. 

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As of Amendment 09, the study was re-assessed, and the Joint Steering Committee 
decided that Arms E and F of checkpoint agonist(s) and radiation combined with 
avelumab were to be discontinued. 
 
This study will assess whether checkpoint agonist(s), initially drives CD8+ T cells intra- 
tumorally, which helps avelumab (PD-L1 inhibitor) to augment the response in a limited 
series of indications. Based on emerging preclinical and clinical data, studies to 
evaluate combinations of avelumab with other immune modulators may follow. 
 
Table 1: Treatment Arms of Avelumab in Combination with Other Cancer 
Immunotherapies with or without Radiation. 
Categories 
Treatment 
Arm 
Treatment 
Projected 
Phase I 
Enrollment 
I. Avelumab + 
Checkpoint 
Agonist(s) 
A 
Avelumab + 
Utomilumab (4-1BB) 
*Max. 14 
B 
Avelumab + 
PF-04518600 (OX40) 
*Max. 14 
C 
Avelumab + 
Utomilumab (4-1BB) + 
PF-04518600 (OX40) 
**Max. 18 
II. Avelumab + 
Checkpoint 
Agonist(s) + 
XRT 
D 
Avelumab + 
Utomilumab (4-1BB) + 
XRT 
***Max. 32 
*In Arm A, B and C, the MTD will be provided by Pfizer. The projected number of 
patients to be enrolled in Phase I is for MTD expansion cohorts only. This number 
does not include patients enrolled on the previous avelumab dosing schedule (prior 
to Version 05). 
** The projected number of patients to be enrolled in Phase I includes dose 
escalation and MTD expansion cohort. 
***In Arm D, the projected number does not include patients enrolled on the previous 
avelumab and radiation dosing schedule (prior to Version 08 and Version 09). 
Please refere to Section 9.3 for Sample Size Determination. 

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1.2 
Background 
 
Immune cells in the tumor microenvironment express a diverse array of co-stimulatory 
and co-inhibitory receptors, the immune checkpoints, which are potential targets in the 
immune system that could be exploited to augment/sustain the anti-tumor response 
(8). Agents that block the co-inhibitory receptors and “release the brakes” on the 
immune system (checkpoint inhibitors) and those that enhance the co-stimulatory 
response (checkpoint agonist) have demonstrated broad anti-tumor effects in clinic, 
representing a new chapter in cancer immunotherapy (9). 
 
1.2.1 
Avelumab (PF-06834635): Anti-PD-L1 Monoclonal Antibody 
Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody (mAb). PD-L1 is the 
binding partner for the PD-1 receptor and serves as a brake, or checkpoint, on the 
immune response. PD-1/PD-L1 checkpoint inhibitors “release the brakes” on the 
immune system, allowing it to fight the cancer (10). Targeting PD-L1 is also expected 
to have fewer immune-related adverse events (irAE) than CTLA-4 blockade due to the 
distinct biologic features of the two pathways (10, 11). Avelumab is currently in clinical 
development with ongoing phase I studies in patients with solid tumors, phase II 
studies in patients with Merkel cell carcinoma, and Phase III studies in patients with 
NSCLC, gastric, and ovarian cancer. In a phase I trial with PD-L1 antibody, among 
patients with evaluable response, an objective response was observed in 9 of 52 
patients with melanoma, 2 of 17 with renal cell cancer, 5 of 49 with non-small cell lung 
cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 
16 patients with at least 1 year of follow-up (10). 
 
In a Phase I Trial EMR 100070-001 in solid tumors, treatment-emergent adverse 
events (TEAEs) occurred in all 53 subjects (100.0%) participating in the dose 
escalation cohort, of which 43 subjects (81.1%) reported treatment-related TEAEs. 
The most frequently observed treatment related TEAE was fatigue reported in 21 
subjects (39.6%), followed by influenza-like illness in 11 subjects (20.8%), and pyrexia 
in 8 subjects (15.1%). Nine of the 53 subjects (17.0%) in the dose escalation cohort 
experienced at least 1 Grade ≥ 3 treatment-related TEAE. These included event terms 
of autoimmune disorder (3 subjects; 5.7%), aspartate aminotransferase (AST) 
increased and blood creatine phosphokinase (CPK) increased (each in 2 subjects; 

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3.8%), and fatigue, abdominal pain lower, lipase increased, amylase increased, 
alanine aminotransferase (ALT) increased, blood alkaline phosphatase increased, and 
lymphocyte count decreased (each in 1 subject; 1.9%). Of the 9 subjects (17.0%) who 
had Grade ≥ 3 treatment-related TEAEs, 7 (13.2%) had Grade 3 events, 2 (3.8%) had 
Grade 4 events (blood CPK increased and autoimmune disorder), and no Grade 5 
treatment-related TEAEs were observed. Overall, the TEAE profile was similar across 
different dose escalation cohorts and the incidences of TEAEs by TEAE category did 
not increase with increasing dose. In the 1300 subjects comprising the pooled 
expansion cohort including subjects from 16 tumor expansion cohorts, the most 
frequently reported TEAEs were fatigue (27.4%), followed by nausea (21.2%), 
infusion-related reaction (16.2%), diarrhea (15.8%), and constipation (15.7%) (12). 
 
The safety data analysis for the Japanese Phase I Trial EMR 100070-002 consists of 
data from 17 subjects treated in the dose escalation phase (5, 6, and 6 subjects with 
solid tumor treated with 3.0, 10.0, and 20.0 mg/kg of avelumab, respectively) and 35 
subjects with gastric cancer treated with 10 mg/kg of avelumab once every 2 weeks in 
the treatment expansion phase. Nineteen serious TEAEs were reported in 15 
subjects. Fourteen serious TEAEs were reported as ≥ Grade 3 (including 10 Grade 3 
events and 4 Grade 5 events; none were reported as Grade 4). Seventeen serious 
TEAEs in 14 subjects were assessed as not related to treatment. Three subjects 
experienced serious TEAEs resulting in a fatal outcome. Two serious TEAEs, in one 
subject, resulted in a fatal outcome and were considered as treatment-related: acute 
kidney injury (Grade 5) and tumor lysis syndrome (Grade 5). One subject died due to 
disease progression and the other subject due to myocardial infarction, both serious 
TEAEs were not considered to be treatment-related. In this trial, three cases in 2 
subjects with potential immune related AEs (irAEs) were identified, including 
hyperthyroidism (Grade 1), hypothyroidism (Grade 2), and colitis (Grade 2). All 3 irAEs 
were regarded as non-serious events and considered as related to treatment. Thirteen 
cases of infusion-related reactions in 11 subjects were identified, including 12 non- 
serious events of infusion-related reaction (Grade 1 or 2; all treatment-related) and a 
single serious event of drug hypersensitivity (Grade 2; assessed as not related to 
treatment, as it was caused by subsequent chemotherapy with oxaliplatin after trial 
discontinuation) (12). 

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The safety data analysis for the Phase II Trial EMR 100070-003 consists of data from 
88 subjects treated with 10.0 mg/kg avelumab for MCC once every 2 weeks. A total 
of 78 serious TEAEs were reported in 35 subjects. Fifty-seven serious TEAEs were 
reported as ≥ Grade 3 (including 39 Grade 3 events, 7 Grade 4 events, and 11 Grade 
5 events). The majority of serious TEAEs (70/78) were assessed as not related to 
treatment. Eight serious TEAEs in 6 subjects were considered as treatment-related: 
chondrocalcinosis (2 events; both Grade 2), enterocolitis (Grade 2), synovitis (Grade 
2), transaminases increased (Grade 3), tubulointerstitial nephritis (Grade 2), infusion- 
related reaction (Grade 2), and hypothyroidism (Grade 2). In this trial, 2 cases in 2 
subjects with potential irAEs were identified including a serious event of 
encephalopathy (Grade 2; assessed as not related to treatment) and a serious event 
of hypothyroidism (Grade 2; treatment-related) (12). 
 
The clinical efficacy information summarized in the Investigator’s Brochure includes 
data from the NSCLC and ovarian cancer expansion cohorts of the ongoing Phase I 
Trial EMR 100070-001, and for 20 subjects in the gastric cancer expansion cohort of 
the ongoing Phase I Trial EMR 100070-002. The NSCLC expansion cohort in the 
ongoing Phase I Trial EMR 100070-001 had a cutoff date of 15 January 2015, 6 
months after start of avelumab treatment of the last subject in this expansion cohort 
(a total of 184 treated subjects). The objective response rate (ORR) based on 
confirmed and unconfirmed responses for subjects treated in the NSCLC expansion 
cohort was 14.1% (26 of 184 NSCLC subjects). Progression free survival (PFS) and 
overall survival (OS) were all evaluated for all NSCLC subjects treated in the 
expansion phase. As of 15 January 2015, the median PFS and OS for the NSCLC 
treatment expansion cohort were 11.6 weeks and 8.4 months, respectively. The 
clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 expression 
status in the NSCLC expansion cohort. An objective response was observed in 20 of 
122 subjects (16.4%) who were PD-L1 positive (defined as having at least 1% PD-L1 
positive tumor cells) compared with 2 of 20 subjects (10.0%) who were considered 
PD-L1 negative (defined as having less than 1% PD-L1 positive tumor cells). A longer 
median PFS (12.0 vs 5.9 weeks) and OS (8.9 vs 4.6 months) were both observed in 
PD-L1 positive compared with PD-L1 negative subjects. The ovarian cancer 

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expansion cohort had a data cutoff of 13 February 2015, approximately 13 weeks after 
the start of avelumab treatment on the last subject who was included in this pre- 
planned interim analysis on this expansion cohort. The ORR based on confirmed and 
unconfirmed responses for subjects treated in the ovarian cancer expansion cohort 
was 10.7% (8 of 75 subjects). The median PFS for the ovarian cancer expansion 
cohort was 11.4 weeks (95% confidence interval (CI): 6.3 to 12.0 weeks). The 
preliminary efficacy data for the ongoing Phase I Trial EMR 100070-002 are based on 
a data cutoff of 11 March 2015. As of the data cutoff, 3 of 20 subjects responded to 
trial treatment (all responses were partial responses [PRs] and all responses were 
confirmed responses), and the best overall response (BOR) was 15.0% (95% CI: 3.2% 
to 37.9%). The median PFS of this group was 11.9 weeks (95% CI: 6.0 to 12.3 weeks) 
(12). 
 
Currently avelumab has received FDA approval for metastatic Merkel cell carcinoma 
and metastatic urothelial carcinoma indications (13, 14) 
 
 
1.2.2 
Utomilumab: Anti-4-1BB Agonist Monoclonal Antibody 
Utomilumab or PF-05082566 is a fully humanized monoclonal antibody that stimulates 
signaling through the co-stimulatory receptor 4-1BB (CD-137), a member of the tumor 
necrosis factor receptor superfamily. 4-1BB is an activation dependent protein 
expressed in many immune cells (8). Co-stimulation through 4-1BB activates multiple 
signaling cascades within the T cell, which enhances the anti-tumor immune function 
and promotes formation of immunological memory. However, there are conflicting 
reports on the impact of 4-1BB stimulation on Treg expansion and suppressive 
capacity (8). Paradoxically, 4-1BB agonist antibodies also alleviate auto immune 
diseases, suggesting that it may reduce the clinical signs of autoimmune response 
associated with its anti-cancer activity (15). This dual activity of 4-1BB to provide anti- 
tumor activity while dampening irAEs usually associated with immunotherapy 
approaches makes it an attractive target (8). Further 4-1BB agonists alter the 
phenotype of T cells, favoring a potent tumoricidal ThEO T cell phenotype over Th17 
phenotype (16). This may be critical in the treatment of colon cancer, in which the 
Th17 polarized T cells play important roles in tumor formation (8). 4-1BB targeted 

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immunotherapy has demonstrated durable anti-tumor response in wide range of 
murine tumors including floor of mouth squamous cell cancer, lymphoma, 
hepatocellular carcinoma, melanoma and colon cancer (8). 
 
Utolimumab has been administered in a total of 110 patients: as a single agent to 47 
(Study B1641001 Portion A) patients with advanced cancer at dose levels between 
0.006 and 10.0 mg/kg and in 40 (Study B1641001 Portion B) patients at dose levels 
between 0.03 and10.0 mg in combination with rituximab, and in 23 (Study B1641003) 
patients at dose levels between 0.45mg/kg and 5.0 mg/kg in combination with 
pembrolizumab (17). 
 
In B1641001 Portion A, a total of 19 (40.4%) patients out of 47 experienced treatment- 
related AEs, and the most frequently reported treatment-related AE was pyrexia (5 
patients, 10.6%), which was generally mild, followed by fatigue (4 patients, 8.5%), 
which was mild except for one patient treated at 10 mg/kg, which was the highest PF- 
05082566 dose studied. This case was considered as a Grade 3, non-serious AE. 
For B1641001 Portion B of this study, a total of 18 out of 40 treated patients (45%) 
experienced treatment-related AEs, with the most common AE being fatigue (22.5% 
of patients). AEs were mild to moderate with the exception of one case of Grade 3 
thrombocytopenia (platelet count decreased) which lasted less than 7 days, and was 
not considered as a serious adverse event (SAE). No Grade 4 or Grade 5 treatment- 
related AEs were observed in either study portion (17). 
 
For the anti-tumor activity of B1641001 Portion A single agent PF-05082566, best 
clinical responses observed have been one complete response (CR) and one partial 
response (PR) in Merkel cell carcinoma (MCC) patients who were treated at 0.24 
mg/kg and 0.6 mg/kg respectively. In Portion B patients treated with a combination of 
PF-05082566 and rituximab, 2 patients both with FL and treated at 0.03 and 0.12 
mg/kg respectively, achieved a CR and 2 additional FL patients, treated at 0.18, 
achieved PRs. Two FL patients at 1.2 mg/kg and a patient with CD20 + Hodgkin’s 
lymphoma treated at 1.2 mg/kg achieved a PR. A patient with Mantle Cell Lymphoma 
(MCL) treated at 2.4 mg/kg achieved a PR. No PR or CR was observed at doses above 
2.4 mg/kg as of the data cutoff (17). 

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In the B1641003 Study, 14 of the 23 (60.9%) patients dosed experienced at least one 
treatment related AE. Fatigue was the most common treatment-related AE reported 
in 8 (34.8%) patients, (maximum Grade 2) which was followed by rash maculo-papular 
in 6 (26.1%) patients (maximum Grade 1). There were no Grade 3 or higher treatment 
related AEs reported and all treatment-related AEs were mild to moderate in severity 
(Grade 1/2). Summary data indicate that there were several system organ class 
categories with an incidence of very common (>/=10%) AEs that were treatment- 
related; gastrointestinal disorders (nausea), general disorders and administration site 
conditions (fatigue and pyrexia), metabolism and nutrition disorders (decreased 
appetite), skin and subcutaneous tissue disorders (rash maculopapular and pruritus) 
(17). 
 
For the anti-tumor activity of PF-05082566 in combination with pembrolizumab in 
patients with advanced solid tumors in Study B1641003, all patients evaluated for 
tumor responses have been in dose-escalation cohorts. Of the 5 patients treated in 
Cohort 1 (0.45 mg/kg) two patients achieved a best response of PR, one patient with 
RCC and the other patient with NSCLC. Three patients discontinued due to 
progression. There were no responses reported for the 3 patients treated in Cohort 2 
(0.90 mg/kg). One of patients discontinued treatment due to progression, one withdrew 
consent and the third discontinued due to a non-treatment related AE of pain 
management. Of the 3 patients treated in Cohort 3 (1.8 mg/kg) one patient with RCC 
achieved a PR. One patient in this cohort had not achieved a response to date and 
the third patient progressed. Of the 3 patients treated in Cohort 4 (3.6 mg/kg) one 
patient with anaplastic thyroid disease achieved a PR. The other two patients in the 
cohort have discontinued due to progression. Of the 9 patients treated at the MTD in 
Cohort 5 (5.0 mg/kg) response information on 6 of these patients are available as of 
the data cut-off date. Of those 6 patients, 3 patients have discontinued due to 
progression, and three patients have not achieved a response to date (17). 
 
1.2.3 
PF-04518600: Anti-OX40 Agonist Monoclonal Antibody 
PF-04518600 is an agonistic antibody that recognizes the co-stimulatory receptor 
OX40, a member of the tumor necrosis factor receptor superfamily expressed by 

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activated effector T cells and Treg cells (18). OX40 mAb selectively binds with OX40 
receptors and augments T cell differentiation and cytolytic function while counteracting 
the immunosuppressive effects of Tregs (19, 20), and generates long term memory 
(20) leading to enhanced anti-tumor immunity against a variety of tumors. However, 
there are conflicting reports that these agonists may promote or diminish Treg cell 
responses depending upon the context of stimulation and the cytokine milieu (21). 
Administration of soluble OX40L or OX40 agonist antibody enhanced anti-tumor 
responses and led to tumor free survival in mouse models of melanoma, sarcoma, 
colon cancer, breast cancer (22, 23), thymoma and glioma (18, 21, 24). 
 
Agonist antibodies to OX40 are currently in phase I clinical trials for cancer (3, 21). 
Thirty patients with metastatic solid malignancies refractory to conventional therapy 
were enrolled in a phase I study using the 9B12 murin agonistic anti-human OX40 
mAb (25). A single cycle of anti-OX40 mAb was administered on days 1, 3, and 5. 
mild to moderate side effects included a brief period of lymphopenia, fatigue, 
fever/chills, and mild rashes. Twelve out of the 30 patients had regression of at least 
1 metastatic lesion with only 1 cycle of treatment. Regression and stable disease were 
observed in patients with melanoma, renal cancer, squamous cell carcinoma of the 
urethra, prostate cancer, and cholangiocarcinoma. The longest interval of stable 
disease lasted 470 days in a patient with renal cancer, who received no other therapy 
during that time. Patients receiving the OX40 agonist had an expansion of CD4 (non- 
Treg cells) and CD8 T cells following drug infusion with concomitant expression of 
activation markers CD38 and HLA-DR (21). 
 
In the first-in-patient study (FIP), Protocol B0601002, PF-04518600 monotherapy 
(Part A) is being studied in cancers that are considered to be amendable to 
immunotherapy, including advanced or metastatic hepatocellular carcinoma (HCC), 
melanoma, clear cell renal cell carcinoma (RCC), and head and neck squamous cell 
carcinoma (HNSCC) (26). 
PF-04518600 was administered intravenously at increasing doses (0.01 – 3 mg/kg) 
every 2 weeks until disease progression or unacceptable toxicity. Additional biomarker 
cohorts (opened at each dose level except 0.01 mg/kg) enrolled patients who 
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immunohistochemistry and RNA sequencing. As of 09 March 2016, 31 patients have 
enrolled in the dose-escalation phase of PF-04518600 study: 0.01 mg/kg (2 patients), 
0.1 mg/kg (10 patients), 0.3 mg/kg (8 patients), 1.5 mg/kg (7 patients) and 3 mg/kg (4 
patients). There were 25.8% of patients that had previously received ≥ 4 prior 
therapies for advanced disease. There were no dose limiting toxicities, and no drug- 
related or immune related grade 3-5 adverse events (AEs) were observed. Drug- 
related AEs (DRAEs) were all grade 1/2 events and occurred in 21 patients (67.7%). 
The most common DRAEs were fatigue (29.0%) and decreased appetite (9.7%). Out 
of 25 patients evaluable for response, 1 patient experienced partial response (PR, - 
50%, confirmed), and 15 patients experienced stable disease (SD). Eleven patients 
remain on treatment, and 5 patients continued treatment for >13 weeks. Assessments 
of peripheral blood lymphocyte indicated full OX40 receptor occupancy at ≥0.3 mg/kg, 
and maximal memory T cell proliferation at 0.1 and 0.3 mg/kg. These preliminary 
results demonstrate that PF-8600 is safe up to 3 mg/kg (27). 
 
PF-04518600 will also be studied in combination with utomilumab (PF-05082566 anti- 
4-1BB mAb) in Protocol B0601002 Part B in patients with advanced or metastatic 
melanoma, HNSCC, non-small cell lung cancer (NSCLC), bladder, gastric or cervical 
cancers, who are unresponsive to existing therapies, for whom no standard treatment 
is available, or who have declined standard therapy (26). 
 
 
1.3 
Rationale for Combinations 
 
1.3.1 
Combination of Checkpoint Agonist(s) with Avelumab 
Checkpoint inhibitors have attracted much attention following the approval of 
ipilimumab for treating patients with Stage III metastatic melanoma. Nivolumab has 
also been approved for treating metastatic melanoma, metastatic non-small cell lung 
cancer, and metastatic renal cell cancer in patients who have already tried an 
angiogenesis inhibitor; whereas pembrolizumab has been approved for treating 
patients with metastatic melanoma, and metastatic non-small cell lung cancer whose 
tumors express the protein PD-L1 on a companion diagnostic test. Recently, the 
combination of ipilimumab and nivolumab was approved for metastatic melanoma. 
However, generating a robust therapeutic immune response requires not only release 

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of “brakes” on T cells, but also stepping on the “gas”. T cell co-stimulation through 
receptors, like OX40 or 4-1BB, provides a potent “go” signal that actively promotes the 
optimal “killer” CD8 T cell responses (21). 
 
1.3.1.1 
Combination of Utomilumab (anti-4-1BB mAb) with Avelumab 
The activation of 4-1BB signaling usually results in production of a large amount of 
IFN-γ, robust proliferation of T cells with enhanced effector function and memory 
potential (28). However, the enhanced T cell effector function is counterbalanced by 
upregulation of PD-L1 (29, 30). Expression of PD-L1 in tumors is inversely correlated 
with survival of patients (31), implying a need for a combination to counteract the 
negative immunoregulatory elements of signaling through 4-1BB. Further, in a 
syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8), PD-L1 blockade 
resulted in tumor rejection in 60% (7/12) of the mice, indicating that PD-1/PD-L1 
pathway is highly relevant, and is active very early in the process of establishment of 
ovarian tumors. Co-administration of a PD-L1 antagonist with α4-1BB and a cellular 
vaccine expressing GM-CSF (GVAX) triggered rejection of ID8 tumors and was 
associated with increase in proliferation of CD8+ T cell with a concomitant decrease 
in regulatory T cells (32). 
 
In another preclinical study, mice transplanted with ID8 ovarian cancer cells was 
treated with control, mAb against 4-1BB (two different clones of mAb against CD137), 
or PD-1, or CD137+PD-1. Synergistic anti-tumor effect was observed with anti- 
CD137+PD-1 mAbs compared to control, mAb against 4-1BB or PD-1 (33). Overall 
survival (OS) was prolonged in mice treated with a combination of anti-PD-1 mAb with 
either anti-CD137 mAb as opposed to monotherapy, with the mean survival time being 
doubled (p<0.05 compared with control and single mAb groups) (Figure 1). 

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Figure 1: Survival in mice (8-9/group) transplanted intraperitoneal with ID8 cells. 
They were injected intraperitoneal twice at 4 days interval with 0.5 mg of control, anti- 
PD-1, anti-CD137 and anti-PD-1/CD137 mAb and their survival was recorded. *P < 
0.05, **P < 0.01, compared with control mAb treated mice (28). 
 
Presence of significantly increased CD8+ effector T cells and decreased 
immunosuppressive cells with anti-CD137/PD-1 mAbs suggests a systemic immune 
response (Figure 2). 
Figure 2: Analysis of lymphocyte components in spleens from mice treated with 
mAb combinations: The percentages and numbers of CD3+, CD4+, CD8+, CD19+, 
FoxP3+/CD4 and GR-1+CD11b+ cells in spleens (28). 

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Likewise, a robust anti-tumor effect of the anti–4-1BB/anti–PD-1 combination was 
observed in the 4-1BB agonist antibody resistant MC38 colon cancer model (Figure 3) 
(34). At the end of the study (Day 21 after tumor implant), tumor growth inhibition for 
the combination treatment was 63% relative to the control (P < 0.0001). The 
suppression was also significant when compared with the single agent alone (P < 0.05 
versus (vs.) anti–4-1BB alone and P < 0.001 vs. anti–PD-1 alone). Anti-tumor efficacy 
of the combination was also evaluated in B16F10 melanoma model. Consistent with 
the above-mentioned results, pronounced tumor inhibition was reported when anti– 
PD-1 and anti–4-1BB were administered concomitantly. There was an 85% tumor 
growth inhibition compared to control (p<0.0001), and the response was dependent 
on IFNγ and CD8+ T cells (34). The combination treatment significantly increased 
both the central memory and effector memory CD8+ T cells in the spleen in both the 
models (34). 
 
Figure 3: 4-1BB activation and PD-1 blockade synergistically amplify the 
antitumor effects in B16F10 melanoma and MC38 colon carcinoma models. 
C57BL/6 mice were inoculated subcutaneous (day 0) with 1 106 B16F10 or 1 106 
MC38 cells. Animals were administered intraperitoneal rat IgG2a (isotype control, 10 
mg/kg), anti–4-1BB (1 mg/kg), anti–PD-1 (10 mg/kg), or anti–LAG-3 (10 mg/kg) mAbs 
in a volume of 200 mL, alone or in combinations as indicated in the figure, on days 9 
and 14 (indicated by arrows). Statistics were generated using two-way ANOVA, , P < 

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0.05; , P < 0.01; , P < 0.001; and , P < 0.0001, when comparing groups as indicated 
by the vertical lines (29). 
 
Similar results were observed in mice inoculated with H22 hepatocellular carcinoma 
cells or B16 melanoma cells, where 4-1BBL in combination with soluble PD-1 to inhibit 
the PD-L1/PD-1 pathway produced synergistic immune response compared to 
monotherapy with either agent (29). 
 
Based on preclinical data, a theoretical risk for the anti-4-1BB mAb class is that 
treatment causes liver inflammation (8); however, significant liver toxicity has not been 
noted with utomilumab (17). In a preclinical study, Melero et al. (35) injected small 
doses of the antibody intratumorally as CD137 expression is strongly favored in tumor- 
infiltrating lymphocytes (TILs) as a result of a hypoxia-inducible factor (HIF)-1α– 
dependent response to hypoxia. Combined treatments of minute doses of anti-CD137 
mAb given intratumorally and anti-B7-H1 mAb given systemically achieved complete 
regressions in 10 of 12 CT26-bearing BALB/c mice. These cured mice were immune 
to a rechallenge with CT26 cells 3 months later as a result of systemic immune 
memory. This method of administration of the agents also helped to avoid liver 
inflammation (35). Limitation of such liver side effects while keeping therapeutic 
efficacy would be a remarkable advantage. 
 
1.3.1.2 
Combination of PF-04518600 (Anti-OX40 mAb) with Avelumab 
Despite the remarkable responses that have been reported in certain murine models 
treated with either anti-PD-1 or OX40 mAb, monotherapies are generally ineffective 
against poorly immunogenic tumors like ID8 ovarian cancer, signifying a need for 
combination therapies (36). Further, OX40 ligation enhances IFN-γ production by T 
cells, which induces PD-L1 expression by the cancerous cells (21). Taken together, 
blockade of PD-1/PD-L1 pathway is likely to compliment the therapeutic efficacy of 
OX40-driven effector lymphocytes within the tumor microenvironment. Existing body 
of evidence suggests that blockade of PD-1/PD-L1 may synergize with OX40 agonists 
and may be well suited for tumors that express high levels of PD-L1. 
 
In a recent report, Guo and colleagues observed that combined anti-PD-1/OX40 mAb 
treatment markedly inhibited tumor outgrowth in a murine ID8 ovarian cancer model 

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(Figure 4) and significantly increased progression-free survival (PFS) of mice with 60% 
of mice tumor free 90 days after tumor inoculation (p,0.001, combined mAb compared 
to single or control mAb) (37). Combined anti-PD-1/OX40 mAb treatment fostered a 
local immunostimulatory microenvironment and tumor protection was associated with 
a systemic immune response with memory and antigen specificity and required CD4+ 
cells and CD8+ T cells. The anti-PD-1/OX40 mAb treatment increased CD4+ and 
CD8+ cells and decreased immunosuppressive regulatory T cells and myeloid 
suppressor cells (37). The combined treatment induced a specific and long-lasting 
anti-tumor immune response in treated mice as they were resistant to a subsequent 
rechallenge intraperitoneal or subcutaneously. with the same cell line (37). 
 
Figure 4: Treatment of combined anti-PD-1/OX40 mAb induced tumor-specific 
immunity against ID8 ovarian cancer. (A) Mice (10 mice per group) transplanted 
intraperitoneal with 16106 ID8 cells 10 day before were treated thrice with 200 mg of 
control, anti-PD-1, anti-OX40 and anti-PD-1/OX40 mAb at 4 days interval and overall 
survival of mice was recorded. (B) Mean survival time of mice with tumor growth was 
calculated. (C) The peritoneal tumor masses was weighed when mice were 
euthanized with each dot representing each mouse. ***P,0.001, combined mAb vs 
control or single mAb treated mice (32). 
 
Though the combination is likely to produce increased toxicity and irAEs, synergy 
between anti-OX40 therapy and checkpoint blockade may yield objective responses 
at lower dosages than are required when each drug is used as a monotherapy (21). 
 
1.3.1.3 
Combination of Utomilumab and PF-4518600 with Avelumab 
Multiple complimentary interventions enhances the possibility of effective anti-tumor 
immunity. One possibility is the triple combination of utomilumab (4-1BB mAb), PF- 
4518600 (OX40 mAb) with avelumab as all three antibodies have demonstrated signs 
of efficacy when administered as monotherapies (10, 21, 38) or as doublets (33, 37). 
Further, simultaneous dual costimulation through 4-1BB and OX40 synergistically 

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induced specific CD8 T cell clonal expansion in several in vivo models, contributing to 
effective tumor control in a fibrosarcoma model (39). The anti-tumor activity of this 
dual combination was due to enhanced effector T cell accumulation that was 
independent of the presence of CD4 Tcells (39), suggesting the possibility of 
development of an efficacious treatment under immunocompromised conditions. 
 
In a preclinical study (40), autochthonous hepatocellular carcinoma in c-myc 
transgenic mice that are highly resistant to immunotherapy approaches was used to 
evaluate the efficacy of the combination of these 3 antibodies. Synergistic anti-tumor 
activity and statistically significant prolonged survival was observed in mice treated 
with the triple combination than any of the drugs as monotherapy (Figure 5). The mice 
were also selectively depleted of CD8β+ T lymphocytes or CD4+ T cells at the time of 
therapy instigation. It was observed that only CD8+ cells were absolutely required to 
prolong survival (40). Higher content of CD8+ and CD4+ T lymphocytes with brighter 
surface expression of CD137, OX40, and PD-1 were observed in the cell suspension 
from the livers of the mice treated with Combo 3. Though Tregs were also upregulated, 
CD8+/Treg ratios were clearly increased upon Combo3 treatment (Figure 6). 
Figure 5. The triple combination is efficacious and dependent on CD8+ 
lymphocytes. (A) 100 mg of individual antibodies were dosed to the indicated 
groups. (B) Mice were depleted with anti-CD8b or anti-CD4 mAbs. Fractions of 
surviving mice at day 250 (A) and 150 (B) in the indicated groups are provided in the 
legend. P (log rank test) ns, non-significant; *P <0.05; ***, P <0.001) (34). 

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Figure 6: Combo3 treatment induces infiltrates of blastic T lymphocytes and 
increases the CD8/Treg ratio. (A) Absolute numbers of retrieved CD8+ and CD4+ 
lymphocytes for the indicated treatment groups and the number of blastic cells gated. 
(B) Absolute numbers of Foxp3+ CD4+ lymphocytes and the ratio of the absolute 
numbers of CD8+ lymphocytes to Foxp3+ CD4+ regulatory T cells. #, absolute 
number of cells. *, P < 0.05; **, P < 0.01 (34). 
 
1.3.2 
Combination of Checkpoint Agonist(s) and Radiotherapy with 
Avelumab 
Therapies that target 4-1BB, OX40, and PD-1/PD-L1 pathway , either as single agent 
(10, 21, 38), doublet (33, 37, 39), or triplet (40), have exhibited anti-tumor activity in a 
number of model systems. Likewise, radiotherapy is known to awaken and augment 
dormant tumor responses (8) in non-immunogenic and weakly immunogenic tumors 
as radiation-induced cell death dramatically increases antigen presentation and T-cell 
priming in draining lymphoid tissues, leading to reduction/eradication of the primary 
tumor or distant metastasis in a CD8+ T cell-dependent fashion (41). But, the 
abscopal 
effect 
may 
be 
dampened 
by 
radiation-induced 
activation 
of 
immunesuppressive signals through upregulation of PD-L1 in the tumor 
microenvironment (42). 
 
Nevertheless, the abscopal effect of radiation has been restored by effective 
suppression of immune suppresive signals through PD-L1 blockade (42). Together, 
immunotherapy and radiation therapy complement each other. Checkpoint agonist 
promotes expansion of T cells; while radiation improves antigen presentation, and 
primes an immune response; and, PD-L1 blockade reverses T-cell exhaustion to 

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alleviate depression in the CD8/Treg ratio (43). Further, radiation and immunotherapy 
have fundamentally different mechanisms of action, different cellular targets and non- 
overlapping toxicities (44). These findings support the concept that combining 
radiation and immunotherapy can lead to significant improvements in treatment 
outcomes. 
 
1.3.2.1 
Combination of PF-5082566 and Radiotherapy with Avelumab 
In a preclinical study, the therapeutic efficacy of anti- 4-1BB mAbs in combination with 
radiation therapy was evaluated in murine lung (M109) and breast (EMT6) carcinoma 
models (45). 4-1BB mAbs caused modest regression of murine lung tumors, but 
significantly delayed the growth of breast tumors (Figure 7). However, when combined 
with irradiation, enhanced anti-tumor activity was observed in lung models, albeit only 
at the highest evaluated radiation dose. On the contrary, enhanced anti-tumor activity 
was observed in breast models at all radiation doses. 
 
 
Figure 7: Median tumor response curves of EMT6 tumors exposed to 4-1BB 
antibodies, fractionated radiotherapy, or the combination of both treatments (39). 
 
Though combined treatment with checkpoint agonist(s) and radiotherapy improved 
treatment outcomes in murine models and clinical trials (43), resistance to therapy was 
frequently reported as radiation-induced upregulation of PD-L1 expression in the 
tumor microenvironment, promotes T cell exhaustion resulting in tumor relapse after 
radiotherapy (46). Addition of an anti-PD-L1 was found to inhibit resistance to 
radiotherapy, conferring long term immunity. In a preclinical study, irradiation was 
combined with anti-PD-L1 antibody to treat 2 allograft tumor models, TUBO breast 

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cancer and MC38 colon cancer (Figure 8) (47). The combination treatment not only 
produced synergistic anti- tumor immunity, but also induced an abscopal effect in both 
tumor models, suggesting that the combination of irradiation and anti-PD-L1 antibody 
can potentially control both local and distal tumors. 
 
 
Figure 8: Irradiation (IR) and PD-L1 blockade synergistically amplify the 
antitumor effect. (A) Combination of anti–PD-L1 (αPD-L1) and IR significantly 
enhanced the inhibition of TUBO tumor growth. **P< 0.01; ***P< 0.001. (B) 
Combination therapy greatly delayed MC38 tumor growth compared with single 
treatments. *P< 0.05; ***P< 0.001. (C) Systemic effect of combination treatment 
greatly reduced the growth of secondary tumors (41). 
 
Similarly, 4-1BB combined with radiation therapy exhibited anti-tumor activity in 
orthotopic AT-3 triple-negative mammary tumor models (Figure 9) (48). However, 
enhanced growth inhibition was not possible due to PD-L1 expression by these 
tumors, which were largely unaffected by radiation. 
Figure 9: Rejection of established subcutaneous AT-3 tumors with radiotherapy 
and α-CD137/α-PD-1 mAbs. Mean tumor sizes in each group at day 28 post-tumor 
inoculation. *, P < 0.05; **, P < 0.01; and ***,P< 0.001 (42). 
 
Surprisingly, all mice bearing established orthotopic AT-3 mammary tumors were 
cured when antagonistic α-PD-1 mAb was added to the combination of radiotherapy 
and anti-4-1BB mAb treatment (48). 

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Also, equally robust anti-tumor responses was reported in some of the most malignant 
tumor models treated with triple combination that included 4-1BB activation, CTLA-4 
blockade, and focal radiation therapy (49). For example, survival significantly 
improved from 24 days when treated with focal radiation therapy to 67 days (p,0.05 
vs. all other treatment modalities) with the triple combination in an orthotopic mouse 
model of glioma (Figure 10) by a CD4+ T cell dependent mechanism, with long-term 
survival in at least 50% of the mice (49). 
 
Figure 10. Kaplan Meier survival curves for double immunotherapy and triple 
therapy (n = 18/group). Treatment with triple therapy was superior to double 
immunotherapy with anti-4-1BB and anti-CTLA-4 antibodies (p,0.05), focal RT alone 
(p,0.01) and untreated mice (p,0.001) (43). 
 
Together, these results forms the basis for the rational design of the combination of 
utomilumab (4-1BB), radiation, and avelumab. 
 
1.3.2.2 
Combination of PF-04518600 and Radiotherapy with Avelumab 
In a mouse model of using lung cancer cell line 3LL (50), treatment with radiation 
therapy increased the median survival significantly in a CD8 dependent manner (21 
day vs. 47 day P<0.001). Following CD8 depletion, though the median survival 
decreased, it was significantly better than no treatment (P<0.005). In order to improve 
the efficacy of radiation therapy, mice bearing 3LL tumors were treated with focal 
radiation and a single dose of OX40 or control antibody 1 day after the first radiation 
dose. It was reported that the combination of radiation and OX40 significantly 

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increased survival compared with either agent alone (Figure 11) and a significant 
proportion of mice were tumor free and resistant to rechallenge (50). 
 
 
Figure 11: Response to combination of radiation and OX40 mAb in 3LL tumors. 
Graph shows mean leg thickness and survival of tumor-bearing mice (44). 
 
In another murine lung cancer model, combination of anti-OX40 mAb and radiotherapy 
induced antigen specific cytotoxicity independent of CD4+ T cells, resulting in a high 
rate of CD8+ T cell-dependent complete cure rate (in 6 of 8 mice vs none) and 
prolonged survival compared to those treated with either radiotherapy or anti-OX40 
mAb (Figure 12) (51). Irradiation enhanced the amount of OX40+ CD8+ Tcells in the 
draining lymph node. Further, mice treated with anti-OX40 mAb in combination with 
radiotherapy resisted tumor rechallenge due to development of immunological 
memory. 
 
Though radiation therapy may upregulate expression of PD-L1 in tumors (46), 
concomitant blockade of the PD-1/PD-L1 pathway can complement treatment with 
OX40 mAb and radiotherapy as remarkable response has been reported with this 
combination in orthotopic AT-3 mammary tumors (48). 

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Figure 12: Anti-OX40 monoclonal antibody (mAb) in combination with 
radiotherapy (RT) (A) Tumor volume in mice treated with control IgG, or local 
radiotherapy (20 Gray (Gy)) with control IgG, anti-OX40 mAb, or radiotherapy (20 Gy) 
with intratumoral injection of anti-OX40 mAb. (B) The survival of mice following various 
protocols is shown. *P=0.001 versus the anti-OX40 mAb alone group, and P<0.001 
versus the RT+IgG group (45). 
 
1.3.2.3 
Combination of Utomilumab, PF-04518600, and Radiotherapy with 
Avelumab 
Collectively, existing data from preclinical studies discussed above indicate that 
concomitant targeting of immunostimulatory and immunoinhibitory checkpoints with 
immunomodulatory antibodies can enhance the tumor control potential of 
radiotherapy. This forms the basis for the rational design of the combination of 
utomilumab (4-1BB), PF-04518600 (OX40), radiotherapy, and avelumab. 
 
1.4 
Potential for Overlapping Toxicities 
 
 
The combination drugs used in this protocol have associated toxicities that may 
overlap with those of checkpoint agonists. The adverse events associated with each 
study drug are detailed in the respective Investigator’s Brochure. 
 
For patients in the radiation arms, radiation treatment in abdomen that could result in 
bowel radiation could aggravate colitis (52). 

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1.5 
Protocol Arm Closures 
 
 
In Protocol Version 07, Arm G of avelumab, radiation and cisplatin was closed due to 
the inability to enroll patients. Closure of Arm G was decided in the September 2018 
Joint Steering Committee meeting. The protocol was revised at that time to remove all 
language regarding Arm G. 
 
In Protocol Version 09, Arm E of avelumab, PF-04518600 (OX40), and radiation; and 
Arm F of avelumab, utomilumab (4-1BB), PF-04518600 (OX40), and radiation were 
closed due to emerging data, which does not support combination of two T cell 
agonists. Closure of Arm F was decided in the November 2019 Joint Steering 
Committee meeting. Closure of Arm E was decided in the January 2020 meeting 
between Pfizer and the PI. The protocol was revised at that time to remove all 
language regarding Arms E and F. 

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2.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 
Primary Objectives 
• For Arm D, to establish the safety, tolerability, and dose-limiting toxicities (DLTs) 
of different treatment combinations of avelumab when administered in 
combination with a checkpoint agonist with radiation in patients with metastatic 
solid tumors in order to estimate the maximum tolerated dose (MTD) and select 
the recommended phase 2 dose (RP2D). 
• To correlate pre- and post-treatment CD8 expression with clinical benefit 
(complete response [CR], partial response [PR], or stable disease [SD] for > 6 
months). 
 
2.1.2 
Secondary Objectives 
• To evaluate the efficacy of the different treatment combinations in patients with 
metastatic solid tumors by assessing objective response rate (ORR) per 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and immune- 
related RECIST (irRECIST)(53). 
• To evaluate the efficacy of the different treatment combinations in patients with 
metastatic solid tumors by assessing progression-free survival (PFS), duration of 
response (DOR), and overall survival (OS). 
 
2.1.3 
Exploratory Objectives 
• To understand the mechanism of action of the avelumab plus an immune 
modulator combination, as well as potential mechanisms of resistance. 
• To characterize the effect of avelumab combinations on immune biomarkers in 
peripheral blood and tumor tissue obtained from subjects pre- and post-treatment. 
• To compare the response in irradiated versus non-irradiated lesions in Arm D. 
• To investigate immune biomarkers that are potentially predictive of response and 
resistance with the combination of avelumab and an immune modulator. 

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2.2 
Endpoints 
 
2.2.1 
Primary Endpoints 
• Safety and tolerability will be assessed by monitoring the frequency, duration, 
and severity of adverse events (AEs) according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
• Evaluation of CD8 biomarkers from tumor and blood biospecimens. 
 
2.2.2 
Secondary and Exploratory Endpoints 
• Objective response rate determined by radiographic disease assessments per 
RECIST v1.1 and irRECIST. 
• Progression-free survival, defined as the time from Cycle 1 start date until the 
earliest date of disease progression, as determined by investigator assessment 
of objective radiographic disease assessments per RECIST v1.1 and irRECIST, 
or death due to any cause, if occurring sooner than progression. 
• Duration of response determined by radiographic disease assessment, defined 
as the time from earliest date of disease response until the earliest date of 
disease progression per RECIST v1.1 and irRECIST, or death due to any cause, 
if occurring sooner than progression. 
• Overall survival determined from the Cycle 1 start date until death due to any 
cause. 
• Response data in irradiated and non-irradiated lesions. 
• Evaluation of various immune biomarkers from tumor and blood biospecimens. 

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3.0 
STUDY DESIGN 
 
3.1 
Study Overview 
 
Currently, this is a single-center, open-label, four-arm Phase I/II study of avelumab in 
combination with additional therapy. In Arms A, B, and C, avelumab will be 
administered in combination with a checkpoint agonist(s) in patients with advanced or 
metastatic solid tumors. In Arm D, avelumab will be administered in combination with 
a checkpoint agonist with radiation in patients with advanced or metastatic solid 
tumors. 
 
As of Amendment Version 09, there are 4 treatment arms in this study: 
• Arm A: Avelumab + Utomilumab (4-1BB) 
• Arm B: Avelumab + PF-04518600 (OX40) 
• Arm C: Avelumab + Utomilumab (4-1BB) + PF-04518600 (OX40) 
• Arm D: Avelumab + Utomilumab (4-1BB) + XRT. 
 
Arm D will have two phases: 1) Dose De-Escalation Phase; and, 2) Maximum- 
Tolerated Dose (MTD) Expansion Phase. In Arm A: Avelumab + Utomilumab (4-1BB) 
and Arm B: Avelumab + PF-04518600 (OX40), and Arm C: Avelumab + Utomilumab 
(4-1BB) + PF-04518600 (OX40), the known MTDs from the ongoing studies enrolling 
patients for treatment with utomilumab (4-1BB) and avelumab and PF-04518600 
(OX40) and avelumab will be provided by Pfizer. Therefore, patients in Arms A-C will 
be enrolled on MTD expansion cohorts only in Phase I part of the study. 
 
All study treatment arms will undergo a 28-day study cycle. 
 
 
3.1.1 
Part I: Dose Escalation or Dose De-Escalation (Part D Only) 
A standard “3+3” study design will be used for this study. Patients enrolled at each 
dose level in Arm D will be evaluated for dose-limiting toxicity (DLT) for the purpose of 
determining the MTD. For Arm D, dose de-escalation will occur at the planned dose 
levels until the MTD is determined. The MTD is defined as the highest dose level with 
less than 2 patients with DLT out of at least six patients in the cohort. Management 

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and dose modifications associated with adverse events are outlined in subsequent 
protocol sections. 
 
Two dose levels may be examined during the dose de-escalation with a standard “3+3” 
design, and a total of 3-6 patients will be enrolled per dose level. The de-escalation 
will be conducted as shown in Table 2 to evaluate the safety, tolerability, and MTD in 
patients with or metastatic solid tumors. 
 
Table 2: Dosing Pattern of Avelumab in Combination with Other Cancer 
Immunotherapies with or without XRT. 
Categories 
Treatment 
Arm 
Treatment 
De-Escalation 
Fixed Dose 
I. Avelumab 
+ 
Checkpoint 
Agonist(s) 
A 
Avelumab + 
Utomilumab 
(4-1BB) 
MTD from Pfizer 
B 
Avelumab + 
PF-04518600 
(OX40) 
MTD from Pfizer 
C 
Avelumab + 
Utomilumab 
(4-1BB) + 
PF-04518600 
(OX40) 
MTD from Pfizer 
II. 
Avelumab + 
Checkpoint 
Agonist(s) + 
XRT 
D 
Avelumab + 
Utomilumab 
(4-1BB) + XRT 
XRT** 
Utomilumab (4- 
1BB) + 
Avelumab 
**Dose de-escalation 
 
Arm D will have de-escalation of radiation schedules. 
 
 
3.1.2 
Part II: MTD Expansion 
Once the MTD is determined, an additional 14 patients will be enrolled on the MTD 
expansion cohort for additional characterization of safety and response, and for 
correlative studies to establish the recommended phase 2 dose (RP2D) for each 
combination. 

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For patients enrolled in the MTD expansions of Arms A-C, biopsies, blood samples 
will be collected at baseline, between Cycle 1 Day 12-15 (prior to study drug dosing), 
prior to Cycle 3 Day 1 study drug dosing, and at the time of progression (if patient had 
an initial response of stable disease ≥6 months, partial response, or complete 
remission) to evaluate biological response or predictive markers in blood, tumor, and 
tumor environment and their relationships to drug exposure, clinical response, or other 
biologic response markers. 
 
For patients enrolled in the MTD expansion of Arm D, biopsies will be collected at 
baseline, prior to Cycle 3 Day 1 dosing, and at the time of progression (if patient had 
an initial response of stable disease ≥6 months, partial response, or complete 
remission). For patients enrolled in the MTD expansion of Arm D, blood samples will 
be collected at baseline, prior to Cycle 1 Day 1 dosing, prior to Cycle 1 Day 15 dosing, 
prior to Cycle 2 Day 1 dosing, prior to Cycle 3 Day 1, and at the time of progression (if 
patient had an initial response of stable disease ≥6 months, partial response, or 
complete remission). We will also evaluate mutation burden and immune scoring. Cell 
free DNA from patient’s blood samples will also be analyzed. 
 
Once the pharmacodynamic, toxicity, and efficacy data is available, the Investigational 
Cancer Therapeutics team will collaborate with Pfizer and disease-specific experts in 
each department to a) identify the most effective combination dose for these tumor 
types, as well as other tumor types of interest, based on toxicity, biology, and target 
interaction, and b) evaluate the most appropriate methods for determining 
progression-free survival and other clinical variables that may vary across tumor types. 
 
3.2 
Study Treatment Arms 
 
All study treatment arms will have a 28 day cycle. Study drug administration may be 
delayed for toxicity according to protocol Section 5.2.4. 

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Figure 13: Study Treatment Arms 
 
 
3.2.1 
Arm A: Avelumab + Utomilumab (4-1BB) 
In Arm A of avelumab and utomilumab, there will be no dose escalation. The escalation 
of avelumab and utomilumab will be performed under a previously conducted Pfizer 
protocol. 
 
The Arm A MTD expansion will enroll up to 14 patients at the established safe dose 
for additional safety and correlative studies to establish the RP2D for this combination. 
 
Utomilumab will be administered at the fixed flat dose of 100 milligrams (mg) 
intravenously (IV) on Day 1 of each 28-day cycle or every 4 weeks. Avelumab will be 
administered at the fixed dose of 10 mg/kg IV on Day 15 of Cycle 1 and Days 1 and 
Day 15 of subsequent cycles. Premedications will be administered per institutional 
standard. 
 
On days when both avelumab and utomilumab are administered, avelumab will be 
administered first. 
 
Patients will be restaged at the end of every two cycles and tumor response evaluation 
will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and 
immune-related RECIST (irRECIST). Patients may be allowed to continue treatment 

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after two cycles of avelumab combinations if there is continued clinical response or 
disease stabilization and patients do not have significant toxicities. A patient may 
continue treatment on this combination therapy until the patient experiences confirmed 
disease progression, unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, and/or treatment is discontinued following 
investigator’s decision to withdraw the patient, pregnancy, patient withdraws consent, 
noncompliance with trial treatment or procedure requirements, or administrative 
reasons. 
 
Table 3: Dosing for Arm A: Avelumab + Utomilumab (4-1BB) 
Dose Level 
Utomilumab (4-1BB) IV 
Every 4 Weeks 
Starting Cycle 1 Day 1 
Avelumab IV 
Every 2 Weeks 
Starting Cycle 1 Day 15 
MTD/RP2D 
Determined by 
Pfizer 
100 mg 
10 mg/kg 
As of Amendment Version 06, the avelumab dosing for Arm A was revised; therefore, 
a new cohort of 14 patients was enrolled. 
 
3.2.2 
Arm B: Avelumab + PF-04518600 (OX40) 
In Arm B of avelumab and PF-04518600 (OX40), there will be no dose escalation. The 
escalation of avelumab and PF-04518600 will be performed under a previously 
conducted Pfizer protocol. 
 
The Arm B MTD expansion will enroll up to 14 patients at the established safe dose 
for additional safety and correlative studies to establish the RP2D for this combination. 
 
PF-04518600 (OX40) will be administered at the fixed dose of 0.3 mg/kg IV on Days 
1 and 15 of each 28-day cycle or every 2 weeks. Avelumab will be administered at 
the fixed dose of 10 mg/kg IV on Day 15 of Cycle 1 and Days 1 and 15 of subsequent 
cycles. Premedications will be administered per institutional standard. 
 
On days when both avelumab and PF-04518600 are administered, avelumab will be 
administered first. 

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Patients will be restaged at the end of every two cycles and tumor response evaluation 
will be based on RECIST 1.1 and irRECIST. Patients may be allowed to continue 
treatment after two cycles of avelumab combinations if there is continued clinical 
response or disease stabilization and patients do not have significant toxicities. A 
patient may continue treatment on this combination therapy until the patient 
experiences confirmed disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, and/or treatment 
is discontinued following investigator’s decision to withdraw the patient, pregnancy, 
patient withdraws consent, noncompliance with trial treatment or procedure 
requirements, or administrative reasons. 
 
Table 4: Dosing for Arm B: Avelumab + PF-04518600 (OX40) 
Dose Level 
PF-04518600 (OX40) IV 
Every 2 Weeks 
Starting Cycle 1 Day 1 
Avelumab IV 
Every 2 Weeks 
Starting Cycle 1 Day 15 
MTD/RP2D 
Determined by 
Pfizer 
0.3 mg/kg 
10 mg/kg 
As of Amendment Version 06, the avelumab dosing for Arm B was revised; therefore, 
a new cohort of 14 patients was enrolled. 
 
3.2.3 
Arm C: Avelumab + Utomilumab (4-1BB) + PF-04518600 (OX40) 
 
 
As of Amendment Version 05, in Arm C of avelumab, utomilumab (4-1BB), and PF- 
04518600 (OX40), there will be no dose escalation. The escalation of PF-04518600 
(OX40) in combination with fixed doses of avelumab and utomilumab (4-1BB) was 
performed under a previously conducted Pfizer protocol. 
 
The Arm C MTD expansion will enroll up to 14 patients at the established safe dose 
for additional safety and correlative studies to establish the RP2D for this combination. 
 
PF-04518600 (OX40) will be administered at the fixed dose of 0.3 mg/kg by IV on Days 
1 and 15 of each 28-day cycle or every 2 weeks. Utomilumab (4-1BB) will be 
administered at the fixed flat dose of 20 mg IV on Day 1 of each 28-day cycle or every 
4 weeks. Avelumab will be administered at the fixed dose of 10 mg/kg IV on Day 15 of 

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Cycle 1 and Days 1 and 15 of subsequent cycles. Premedications will be administered 
per institutional standard. 
 
On days when avelumab, utomilumab, and PF-04518600 are administered, avelumab 
will be administered first followed by utomilumab then PF-04518600. 
 
Patients will be restaged at the end of every two cycles and tumor response evaluation 
will be based on RECIST 1.1 and irRECIST. Patients may be allowed to continue 
treatment after two cycles of avelumab combinations if there is continued clinical 
response or disease stabilization and patients do not have significant toxicities. A 
patient may continue treatment on this combination therapy until the patient 
experiences confirmed disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, and/or treatment 
is discontinued following investigator’s decision to withdraw the patient, pregnancy, 
patient withdraws consent, noncompliance with trial treatment or procedure 
requirements, or administrative reasons. 
 
Table 5: Dosing for Arm C: Avelumab + Utomilumab (4-1BB) + PF-04518600 
(OX40) 
Dose 
Level 
PF-04518600 (OX40) 
IV Every 2 Weeks 
Starting Cycle 1 Day 
1 
Utomilumab (4-1BB) 
IV Every 4 Weeks 
Starting Cycle 1 Day 1 
Avelumab IV 
Every 2 Weeks 
Starting Cycle 1 
Day 15 
MTD/RP2D 
Determined 
by Pfizer 
0.3 mg/kg 
20 mg 
10 mg/kg 
As of Amendment Version 06, the avelumab dosing for Arm C was revised; therefore, 
a new cohort of 14 patients was enrolled. 
 
 
 
3.2.4 
Arm D: Avelumab + Utomilumab (4-1BB) + Radiation 
In the dose escalation phase, the dose of radiation will be de-escalated in combination 
with fixed doses of utomilumab (4-1BB) and avelumab to evaluate the safety, 
tolerability, and MTD in patients with advanced solid tumors. 

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Once the MTD or RP2D is determined, the Arm D MTD expansion will enroll up to 14 
patients at the previously established safe dose for additional safety and correlative 
studies to establish the RP2D for this combination. 
 
Radiation will be administered to 1-3 metastatic sites. This will be de-escalated from 
a total of 24 Gy to 21 Gy. The technique will be stereotactic radiation via intensity- 
modulated radiation therapy (IMRT) or Volumetric modulated arc therapy (VMAT). 
The radiation lead-in will occur within Days -5 to -1 with a +/- 3 day window. There 
will be 3 fractions or days of radiation. In all cases, the radiation must initiate and end 
within the radiation lead-time. Cycle 1 Day 1 study drug treatment should begin 
within 3 days of last dose of radiation. 
 
Utomilumab (4-1BB) will be administered at the fixed flat dose of 100 mg IV on Day 1 
of each 28-day cycle or every 4 weeks. Avelumab will be administered at the fixed 
dose of 10 mg/kg IV on Day 15 of Cycle 1 and Days 1 and 15 of each subsequent 28- 
day cycle or every 2 weeks. Premedications will be administered per institutional 
standard. 
 
On days when both avelumab and utomilumab are administered, avelumab will be 
administered first. 
 
Patients will be restaged at the end of every two cycles and tumor response evaluation 
will be based on RECIST 1.1 and irRECIST. Patients may be allowed to continue 
treatment after two cycles of avelumab combinations if there is continued clinical 
response or disease stabilization and patients do not have significant toxicities. 
Following radiation, a patient may continue treatment on this combination therapy until 
the patient experiences confirmed disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of treatment, and/or 
treatment is discontinued following investigator’s decision to withdraw the patient, 
pregnancy, patient withdraws consent, noncompliance with trial treatment or 
procedure requirements, or administrative reasons. 
 
Table 6: Dosing for Arm D: Avelumab + Utomilumab (4-1BB) + Radiation 

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Dose 
Level 
Radiation 
Days -5 to -1 
Utomilumab (4-1BB) 
IV Every 4 Weeks 
Starting Cycle 1 Day 1 
Avelumab IV 
Every 2 Weeks 
Starting Cycle 1 
Day 15 
1 (Start) 
24 Gy in 8 Gy / 
fraction for 3 fractions 
100 mg 
10 mg/kg 
-1 
21 Gy in 7 Gy/ 
fraction for 3 fractions 
100 mg 
10 mg/kg 
As of Amendment Version 09, the avelumab and radiation dosing for Arm D was 
revised; therefore, the dose de-escalation was re-started. 
 
 
 
 
 
 
3.3 
Dose-Limiting Toxicity (DLT) Definition 
 
Severity of adverse events will be graded according to CTCAE version 4.03. For the 
purpose of dose de-escalation, a DLT is defined as any of the following adverse events 
occurring in the first 56 days following Cycle 1 Day 1 (dosing of PF-04518600 (OX40) 
and/ or Utomilumab (4-1BB)) of study participation during the dose de-escalation, 
unless there is a clear alternative explanation (eg, related to underlying disease/ 
progression): 
• Discontinuation of a patient due a toxicity that is at least possibly study drug(s) 
and/or radiation related before completing DLT period. 
• Delay by more than 4 weeks (28 days) in receiving the next scheduled cycle due 
to persisting toxicities attributable to the study drug(s) and/or radiation. 
• Non Hematologic (all will be graded according to CTCAEv4.03 criteria): 
• Grade >/= 3 nausea/vomiting or diarrhea lasting >/= 72 hours while taking 
optimal supportive medications; 
• Grade >/= 3 fatigue lasting >/=7 days; 
• Grade >/= 2 pneumonitis lasting >/= 7 days despite treatment with 
corticosteroids; 
• Grade >/=3 rash lasting >/= 7 days despite treatment; 
• Grade >/= 3 immune related toxicities lasting >/= 7 days despite treatment 
with corticosteroids; 

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• Any other Grade >/=3 non-hematological toxicity (except for electrolytes 
abnormalities that are reversible and asymptomatic or hair loss which is not 
dose-limiting); 
• Grade >/= 3 AST, ALT, or total bilirubin elevation lasting >/= 7 days. 
• Hematologic: 
• Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] lasting 
>/=7 days; 
• Febrile neutropenia (ANC<1000/mm3 with a single temperature >/= 38.3ºC 
or sustained temperature of >38°C for over 1 hour); 
• Grade >/=3 thrombocytopenia associated with bleeding, or grade 4 
thrombocytopenia; 
• Grade 4 anemia. 
 
Elevation of amylase and/or lipase without clinical and/or radiographic evidence of 
pancreatitis are not considered DLT, and the patient can resume treatment at any 
grade at the discretion of the treating physician in consultation with the PI. 
 
During the dose de-escalation portion (Arm D) of the study, patients who missed any 
doses during the DLT period for reasons unrelated to study drug are not evaluable for 
DLT and will be replaced. 
For both de-escalation (up to 4 cycles) and expansion (up to 6 cycles) phases of the 
study, if a patient comes off study unrelated to toxicity or progression of disease (such 
as intercurrent disease or social reasons), the patient for that cohort will be replaced. 
 
The expansion cohort for each arm will be stopped early if the aggregate DLT rate > 
33% for that particular arm. The aggregate DLT rate for each arm will include patients 
that were treated at the same dose level in the dose escalation or de-escalation phase. 
 
In rare instances, an event may fall within the definition of a DLT as defined above but 
the event may be considered not a DLT (eg: not clinically meaningful/significant). If 
this occurs, the PI will thoroughly review the event and supporting data and the 
reasons for not considering the event a DLT will be clearly documented with supporting 

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rationale. In addition, other events may occur which do not meet the definition of a 
DLT but are concerning to the PI, may be then considered to be DLTs. 
 
In the event that a DLT is at least possibly related to the study drug(s) occurs, patients 
will halt treatment with the combination until symptoms resolve to the grade outlined 
in Section 5.2.4. Study drug(s) may be restarted as described in Section 5.2.4. 
 
 
 
 
3.4 
Maximum Tolerated Dose (MTD) Definition 
 
In the Dose De-Escalation cohorts, patients will be assigned sequentially into cohorts 
of up to six patients in each cohort. Three to six patients will initially be enrolled in 
each cohort for DLT observation. A total of six patients will be enrolled in a cohort in 
the event that a DLT is observed in one of the first three patients and/or additional 
safety data are needed. 
 
The MTD is defined as the highest dose level with less than 2 patients with DLT out of 
at least six patients in the cohort. Management and dose modifications associated with 
adverse events are outlined in subsequent protocol sections. 
 
For all Arms, the DLT assessment window is 56 days (from Cycle 1 Day 1). In the 
absence of DLTs, patients continue consecutive treatment. For patients who 
experience a DLT, they may continue treatment with modifications if the toxicity 
resolves and at discretion of the attending physician and PI. In the absence of clinical 
deterioration and if the investigator believes that the patient continues to receive 
benefit from the treatment, patients may continue to receive study drug combinations 
after the first indication of progressive disease until a confirmation scan is obtained. 
 
To understand and safeguard against potential cumulative toxicities the study team 
will continue to monitor the occurrence of study drug related SAEs and AEs throughout 
the treatment period and during potential treatment extensions to allow for dose 
correction in the event of cumulative immune-mediated toxicities. 

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Delayed onset of significant toxicity at the discretion of the investigator will be 
evaluated on a case-by-case basis upon consultation between the IND Office, Pfizer, 
and the principal investigator. At minimum, a review and discussion of potential 
delayed onset of significant toxicity will take place at each cohort review prior to a dose 
escalation decision. 
 
 
3.5 
Dose Escalation and Stopping Rules 
 
The decision to proceed to the next dose level will be made after the first three patients 
in a cohort have completed 56 days (2 cycles) of dosing (from Cycle 1 Day 1). Prior 
to advancing/changing dose levels, a cohort summary will be completed and submitted 
to the IND Medical Monitor for review and approval. 
 
Dose de-escalation decisions will be made in accordance with a standard “3+3” study 
design using the rules below: 
Table 7. 
 
Number of Patients with DLT* at 
a Given Dose Level (assessed 
independent for each of arm) 
De-Escalation Decision Rule 
0 out of 3 
Enter 3 more patients at this dose level 
>2 
Dose de-escalation will occur. This dose 
level will be declared the maximally 
administered dose (highest dose 
administered). Three additional patients 
will be entered at the next lowest dose 
level. 
1 out of 3 
Enter at least 3 more patients at this dose 
level. 
If 0 of these 3 patients experience DLT, 
then this is the maximum tolerated dose 
(MTD). 
If 1 or more of this group suffer DLT, then 
dose de-escalation will occur. Three 
additional patients will be entered at the 
next lowest dose level. 
MTD: The highest dose at which no more than 1 of 6 evaluable patients has 
had a DLT. Six patients should be treated before the dose is declared the 
MTD. 

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Dose de-escalation will occur at the planned dose levels until the MTD is determined. 
The MTD is defined as the highest dose level with less than 2 patients with DLT out of 
at least six patients in the cohort. The recommended Phase 2 dose (RP2D) will be 
based on safety and preliminary efficacy data from the dose escalation and dose 
expansion cohorts. 
 
All patients will be treated at the highest current dose level. All enrolled participants 
will be considered in the DLT analysis. If a DLT occurs in a cohort with 3 patients 
within first 56 days (from Cycle 1 Day 1), 3 additional patients will be enrolled in that 
cohort. If at any time more than or equal to one third (33%) of the participants at a 
dose level experience DLT, the MTD will be reassessed and the next lowest dose level 
for the combination therapy will be considered the MTD. 

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4.0 
PATIENT SELECTION 
 
This study can fulfill its objectives only if appropriate patients are enrolled. The 
following eligibility criteria are designed to select patients for whom protocol treatment 
is considered appropriate. All relevant medical and non- medical conditions should be 
taken into consideration when deciding whether this protocol is suitable for a particular 
patient. 
 
Patient eligibility should be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria and none of the exclusion 
criteria to be eligible for enrollment into the study: 
 
The baseline tumor assessment must have taken place within 28 days prior to start of 
treatment. Under no circumstances are patients, who were once enrolled and treated 
in this study, permitted to be re-enrolled into the same study. If patients screenfail prior 
to receiving treatment, the patient may be re-enrolled if eligible. 
 
4.1 
Inclusion Criteria 
 
To be eligible for this trial, subjects must fulfill the following criteria: 
 
 
1. Subjects must be refractory to, or intolerant of, established therapy known to 
provide clinical benefit for their conditions, or where subjects refuse existing 
therapies. 
2. Subjects must have measurable disease (RECIST v1.1) or patients may have 
bone metastatic disease evaluable by Prostate Cancer Working Group 2 
(PCWG2) for subjects with metastatic castration-resistant prostate cancer 
(CRPC) or according to tumor evaluation criteria best suitable and accepted for 
the tumor type evaluated. 
3. Age >/= 18 years. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
5. Adequate hematologic function defined as: 

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• Platelets >/= 100 x 109/L (For patients with hepatocellular carcinoma, 
Platelets >/= 70 x 109/L); 
• Hemoglobin >/= 9 g/dL; 
• Absolute Neutrophil Count (ANC) >/=1.5 x 109/L; 
• White Blood Cell (WBC) >/= 3 x 109/L. 
6. Adequate liver function defined as: 
• Alanine transaminase (ALT) </= 2.5 x upper normal limit (ULN) (</=5 x 
ULN for subjects with documented metastatic disease to the liver); 
• Aspartate aminotransferase (AST) </= 2.5 x ULN (</=5 x ULN for 
subjects with documented metastatic disease to the liver); 
• Alkaline phosphatase < 4 x ULN; 
• Total Bilirubin </= 1.5 x ULN (In the expansion cohort, subjects with 
Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must 
have a total bilirubin of </= 3 x ULN); 
• Albumin >/=3 g/dL. 
7. Renal function defined serum creatinine </=2 x upper limit of normal (ULN) or 
estimated creatinine clearance >/=30 ml/min as calculated using the Cockroft- 
Gault formula. 
8. Subject has recovered to Grade </= 1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03)14 
from the effects of recent surgery, radiotherapy, chemotherapy, hormonal 
therapy, or other targeted therapies, with the exception of alopecia. The 
exceptions for such effects are allowed lab values of </= Grade 2 specified 
elsewhere in these inclusion criteria. 
9. Life expectancy of at least 12 weeks. 
10. Negative serum pregnancy test in women of childbearing potential within 7 days 
of first dose of treatment and patients of child-bearing potential must agree to 
use effective contraception during and after 90 days post dose. A woman of 
childbearing potential is defined as a premenopausal female capable of 
becoming pregnant. This includes women on oral, injectable or mechanical 
contraception; women who are single and women whose male sexual partners 
have been vasectomized or whose male sexual partners have received or are 
utilizing mechanical contraceptive devices. 

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11. Subjects must have biopsiable disease. For Arms A, B, and C, subjects must 
have at least two lesions amenable to biopsy and response evaluation. For Arm 
D subjects should have at least three lesions amenable to biopsy, response 
evaluation, and radiation. Tumor lesions used for biopsy should not be lesions 
used as RECIST target lesions. However, if patients in Arm D do not have three 
separate lesions, patients will be eligible if there are two lesions, in which one 
is > 2 centimeters (short axis) and can be used for both biopsy and response 
evaluation. 
12. Subjects must give informed consent according to the rules and regulations of 
the individual participating sites. 
 
 
4.2 
Exclusion Criteria 
 
Subjects with any of the following will not be eligible for the study: 
 
1. Subjects with primary central nervous system (CNS) tumor or CNS tumor 
involvement. However, subjects with metastatic CNS tumors may participate 
in this study if the subject is: 
• >4 weeks from prior therapy completion (including radiation and/or surgery) 
• Clinically stable with respect to the CNS tumor at the time of study entry 
• Not receiving steroid therapy in treating CNS tumor or CNS tumor 
involvement 
• Not receiving anti-convulsive medications (that were started for brain 
metastases). 
2. Major surgery, radiation therapy or systemic anti-cancer therapy within 4 weeks 
of study drug administration (6 weeks for mitomycin C or nitrosoureas). 
Palliative radiotherapy to a limited field is allowed after consultation with the 
medical monitor at any time during study participation, including during 
screening, unless it’s clearly indicative of disease progression. 
3. Subjects with prior anti-PD-1, anti-PD-L1 treatment. For Arms A and D, subjects 
may not have had prior 4-1BB treatment. For Arm B, subjects may not have 
had prior OX40 treatment. For Arm C, subjects may not have had prior 4-1BB 
or OX40 treatment. 

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4. Diagnosis or recurrence of invasive cancer other than the present cancer within 
3 years (except basal or squamous cell carcinoma of the skin that has been 
definitively treated). 
5. Clinically significant (i.e., 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 Classification Class II), or serious cardiac arrhythmia 
requiring medication. 
6. Active infection requiring systemic therapy. 
7. Treatment with an investigational anti-cancer study drug within 4 weeks prior to 
study drug administration date. 
8. Concurrent therapy with approved or investigational anticancer therapeutics. 
9. Known prior severe hypersensitivity to investigational product(s) or any 
component in its formulations, including known severe hypersensitivity 
reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade >/= 3). 
10. Current use of immunosuppressive medication, EXCEPT for the following: a. 
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. Systemic corticosteroids at physiologic doses </= 10 mg/day of 
prednisone or equivalent; c. Steroids as premedication for hypersensitivity 
reactions (e.g., CT scan premedication). 
11. Active autoimmune disease that might deteriorate when receiving an immuno- 
stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or 
hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 
12. Prior organ transplantation including allogenic stem-cell transplantation. 
13. Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
14. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening 
(positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test 
positive) 
15. Vaccination (live attenuated virus) within 4 weeks of the first dose of avelumab 
and while on trials is prohibited except for administration of inactivated 
vaccines. 

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16. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); 
however, alopecia, sensory neuropathy Grade </= 2, or other Grade </= 2 not 
constituting a safety risk based on investigator’s judgment are acceptable. 
17. Other severe acute or chronic medical conditions including colitis, inflammatory 
bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormalities that may increase the risk associated with study 
participation or study treatment 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. 
18. Medical, psychological or social conditions that may interfere with the patient's 
participation in the study or evaluation of the study results. 
19. Pregnancy or lactation. 
20. Men whose partner is a woman of child-bearing potential, (i.e. biologically able 
to conceive), and who is not employing two forms of highly effective 
contraception. Highly effective contraception (e.g. male condom with 
spermicide, diaphragm with spermicide, intra-uterine device) must be used by 
both sexes during the study and must be continued for 90 days after the end of 
study treatment. Women of child-bearing potential is defined as sexually mature 
women who are not surgically sterile or who have not been naturally 
postmenopausal for at least 12 consecutive months (e.g., who has had menses 
any time in the preceding 12 consecutive months). 
21. A diagnosis of active scleroderma, lupus, or other rheumatologic disease which 
in the opinion of the treating radiation oncologist precludes safe radiation 
therapy. 
22. Has had prior radiation therapy within the past 3 months where the high dose 
area of the prior radiation would overlap with the high dose area of the intended 
radiation based on the judgement of the treatment oncologist. 

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4.3 
Pregnancy and Contraception 
 
In this study, patients of childbearing potential will receive study drug(s), for which the 
teratogenic risks are currently unknown. Patients should not become pregnant or 
father a child while on this study because the drugs in this study can affect an unborn 
baby. Women should not breastfeed a baby while on this study. It is important patients 
understand the need to use birth control while on this study. Female patients of child- 
bearing potential must have a negative serum pregnancy test at screening and agree 
to use reliable methods of contraception for 90 days after their last dose of medication. 
 
 
Two (2) methods of highly effective contraception must be used throughout the study 
and continued for at least 90 days after the last dose. The investigator, in consultation 
with the patient, will select two appropriate methods of contraception for the individual 
patient from the permitted list of contraception methods, and instruct the patient in their 
consistent and correct use. The investigator, at each study visit, will discuss with the 
patient the need to use highly effective contraception consistently and correctly and 
document such conversation in the patient chart. In addition, the investigator will 
instruct the patient to call immediately if a selected birth control method is discontinued 
or if pregnancy is known or suspected. 
 
Highly effective methods of contraception are those that, alone or in combination, 
result in a failure rate of less than 1% per year when used consistently and correctly 
(ie, perfect use) and include: 
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for 
an adequate period of time to ensure effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, suppository). 
4. Male sterilization with appropriately confirmed absence of sperm in the post- 
vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy. 

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5.0 
STUDY TREATMENTS 
 
5.1 
Allocation to Treatment 
 
Eligible patients will be enrolled to receive one of the study drug combinations in an 
open-labeled, unblinded manner. Patients will be registered and successively 
assigned to the next available treatment slot at a dose level decided on after the 
previous cohort’s safety evaluation and ongoing observations of earlier enrolled 
patients. 
 
Dose level allocation will be performed after patients have given their written informed 
consent and have completed the necessary baseline assessments. 
 
5.2 
Investigational Product Supplies 
 
Avelumab, utomilumab (4-1BB), and PF-04518600 (OX40) will be supplied for the 
study by Pfizer. 
 
The Investigational Pharmacy will receive a supply of study drug(s) prior to activation 
with instructions on how to confirm drug receipt. Resupplies will be made during the 
course of the study based on need. 
 
5.2.1 
Formulation and Packaging 
 
 
5.2.1.1 
Avelumab 
The active pharmaceutical ingredient in avelumab drug product is a fully human 
antibody (calculated molecular weight of 143832 Dalton) of the immunoglobulin G 
(IgG) 1 isotype that specifically targets and blocks PD-L1, the ligand for PD-1. 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution 
intended for intravenous (IV) infusion. The drug is presented at a concentration of 20 
mg/mL in single-use glass vial containing 200 mg of avelumab. 

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Avelumab drug product must be stored at 2°C to 8°C until use, and it must not be 
frozen. Rough shaking of avelumab product must be avoided. Avelumab drug product 
must be diluted with 0.9% saline solution; alternatively a 0.45% saline solution can be 
used if needed. It is recommended that the diluted avelumab solution is used 
immediately. 
 
5.2.1.2 
Utomilumab (4-1BB) 
Utomilumab is provided as a 10 mg/mL sterile solution for injection, in a 20 mM 
histidine buffered solution at pH 5.5. The drug product is supplied in 2 mL Type 1 clear 
glass vial sealed with a coated serum stopper and aluminum seal (nominal fill volume 
of 2.0 mL or 10.0 mL). The labeled storage conditions for utomilumab, Injection, 10 
mg/mL is 2–8°C, and it should not be frozen. 
 
5.2.1.3      PF-04518600 (OX40) 
PF-04518600 drug product, 10 mg/mL is presented as an aqueous solution 
compounded in histidine buffer with excipients at pH 5.5. The drug product is supplied 
in sterilized 10 mL Type 1 clear glass vials with 20 mm serum stoppers and 20 mm 
aluminum flip-off seals, with a nominal fill volume of 10 mL. The drug product should 
be stored refrigerated (2-8 °C) and protected from light. 
 
5.2.2 Preparation and Dispensing 
5.2.2.1 
Avelumab 
For administration in clinical trials, avelumab drug product must be diluted with 0.9% 
saline solution (sodium chloride injection) supplied in an infusion bag; alternatively a 
0.45% saline solution can be used if needed. Detailed information on infusion bags 
and medical devices to be used for the preparation of the dilutions and subsequent 
administration will be provided in the manual of preparation. 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by 
adequate trained personnel under a laminar flow box using aseptic techniques. 
 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to 
room temperature. Use a disposable syringe equipped with a needle of suitable size 

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to remove a volume of sodium chloride solution to be replaced by avelumab from the 
infusion bag and discard the removed solution. Use a new disposable syringe 
equipped with a needle of suitable size to inject a volume of avelumab drug product 
identical to the discarded volume of sodium chloride solution into the infusion bag. 
Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid 
foaming or excessive shearing of the protein solution. The preparation must be 
carefully inspected as it should result in a homogeneous looking clear solution, free of 
visible particles. 
 
5.2.1.2 
Utomilumab (4-1BB) 
Refrigerated utomilumab drug product will be equilibrated to ambient temperature 
before preparation and administration. 
 
5.2.1.3      PF-04518600 (OX40) 
PF-04518600 10 mg/mL injection is presented as a sterile solution for intravenous 
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 (2-8°C) that are monitored 
with temperature control monitoring devices. 
 
5.2.3 
Administration, Dose Calculation and Infusion Reactions 
 
 
5.2.3.1 
Avelumab 
Avelumab will be administered as a 1-hour (+/- 30 minutes) infusion dose of 10 mg/kg 
body weight administered IV once every 2 weeks starting on Cycle 1 Day 15. 
 
Subjects are at risk of developing infusion-related reactions including drug 
hypersensitivity reactions, mainly mild to moderate, but which may also be life- 
threatening. 
Premedication 
with 
an 
antihistamine 
and 
with 
paracetamol 
(acetaminophen) (e.g., 25-50 mg diphenhydramine and 500-650 mg paracetamol 
[acetaminophen] IV or oral equivalent) is mandatory prior to each dose of avelumab. 

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Avelumab 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. 
 
Following avelumab infusions, patients must be observed for 2 hours post-infusion for 
potential infusion-related reactions 
 
5.2.3.2 
Utomilumab (4-1BB) 
Patients will receive doses of utomilumab IV once every four weeks (one cycle). A 
cycle is defined as the time from day 1 dose to the next day 1 dose. If there are no 
treatment delays, a cycle will be four weeks in duration. 
 
Pre-medication is recommended for all patients, and may include an antihistamine, 
anti-inflammatory agent or pain reliever. 
 
The duration of infusion is 1 hour (+/- 30 minutes). The infusion rate should be reduced 
or interrupted in the case of symptoms of infusion reaction, and symptomatic 
treatment administered. The infusion may be continued at one-half the previous rate 
upon improvement of symptoms. If symptoms persist or worsen, the infusion should 
be discontinued. 
 
5.2.3.3      PF-04518600 (OX40) 
PF-04518600 will be administered as an intravenous infusion over 1 hour (+/- 5 
minutes) on Days 1 and 15 of each 28-day cycle. In previous studies, the starting dose 
for the monotherapy portion of the study was 0.01 mg/kg IV with escalation to 
subsequent dosages of 0.1, 0.3, 1.5, and 3.0 mg/kg after review of the results. The 
starting dose for PF-04518600 in combination with utomilumab will be 0.1 mg/kg, 
escalating to 0.3 mg/kg. On cycles whereby both PF-04518600 and utomilumab are 
to be administered on the same day, PF-04518600 will be administered after, but no 

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sooner than 30 minutes after completion of the utomilumab infusion in absence of 
infusion reaction. 
 
5.2.4 
Recommended Dose Modifications 
Every effort should be made to administer the study drugs on the planned dose and 
schedule. 
 
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below. Toxicity will be graded according to NCI CTCAE, version 4.03. In the event of 
multiple toxicities, dose modification should be based on the worst toxicity observed. 
Patients are to be instructed to notify Investigators at the first occurrence of any 
adverse symptom. 
 
Dose modifications may occur: 
• Within a cycle: dosing interruption until adequate recovery and dosing 
reduction, if required, during a given treatment cycle; 
Between cycles: next cycle administration may be delayed due to persisting 
toxicity when a new cycle is due to start. 
 
5.2.4.1 Dose Interruptions 
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. Criteria required before treatment can resume are 
described in section Dose Delays (Section 5.2.4.2). 
 
Doses may be held as needed until toxicity resolution. Depending on when the AE 
resolved, a treatment interruption may lead to the patient missing all subsequent 
planned doses within that same cycle or even to delay the initiation of the subsequent 
cycle. 
 
If the AE that led to the treatment interruption recovers within the same cycle, then re- 
dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the 
same cycle. The need for a dose reduction at the time of treatment resumption should 
be based on the criteria defined in Dose Modifications (Section 5.2.4.3), unless 

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expressly agreed otherwise following discussion between the Investigator and the 
MDACC IND Office. 
 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting >28 days, treatment resumption will be decided in 
consultation with the MDACC IND Office. 
 
5.2.4.2 Dose Delays 
Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable 
Grade 
2 
toxicity 
despite 
supportive 
care 
should 
have 
their 
treatment 
interrupted/delayed. Appropriate follow-up assessments should be done until 
adequate recovery (or until deemed irreversible) occurs as assessed by the 
Investigator. A treatment delay of more than 4 weeks due to lack of recovery will result 
in discontinuation of the patient from the treatment, unless continuation (with dose 
reduction) upon subsequent recovery is considered in the patient’s best interest by the 
investigator (eg, proven clinical benefit). 
 
A new cycle of treatment (or Day 15 of any cycle subject to treatment) may begin only 
if: 
• ANC >/= 1,000/µL; 
• Platelet count >/= 50,000/µL; 
• Hemoglobin >/= 8 g/dL; 
• Non-hematologic toxicities have returned to baseline or Grade </=1 severity (or, 
at the investigator discretion, Grade </=2 if not considered a safety risk for the 
patient). 
 
Withhold scheduled dose for grade >/=3 clinically significant lab abnormality attributed 
to the treatment. Resume the treatment once the lab abnormality returns to grade 
</=1. In cases of potential liver injury, consultation with a hepatologist should be 
considered in the decision to initiate treatment with anti-inflammatory medications. 
 
If these conditions are not met, treatment must be delayed by 1 week. If, after a 1- 
week delay, all toxicities have recovered within the limits described above, treatment 

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with study drugs, can be resumed. Both study drugs should be delayed 
simultaneously if applicable. If the patient has not recovered after 1 week of delay, 
treatment may be delayed by 1 more week. However, initiation of the next cycle can 
only be delayed by a maximum of 4 weeks (28 days). Therefore, if persisting toxicity 
does not allow for the resumption of treatment, the patient will be permanently 
discontinued. 
 
For all ≥ Grade 3 hematological or non-hematological AEs that are NOT study drug- 
related, at the discretion of the treating physician, study drug dosing may be 
continued. 
 
Elevation of amylase and/or lipase without clinical and/or radiographic evidence of 
pancreatitis are not considered DLT, and the patient can resume treatment at any 
grade at the discretion of the treating physician in consultation with the PI. 
 
For Arm D, patients who experience: 
• Grade 1 and 2 diarrhea related to radiation therapy and chemotherapy occurs 
in majority of patients starting around the end of the 3rd week of radiation 
therapy. Diarrhea prior to the 3rd week of radiation therapy is not usually 
associated with chemotherapy and radiation therapy and other causes need to 
be ruled out including C. Diff. This diarrhea lasts through the 5th week of 
radiation therapy and up to a week after the external beam radiation therapy is 
completed. This diarrhea is usually controlled with Imodium AD but sometimes 
Lomotil is used to control it. Grade 3 or higher diarrhea – not controlled with 
Imodium or Lomotil is rare – usually less than 2-3% in patients in patients 
receiving chemotherapy and radiation therapy. 
• Grade 1 and 2 diarrhea related to radiation may continue avelumab or 
utomilumab (4-1BB) at the discretion of the physician, 
• Grade 3 and 4 diarrhea related to radiation will hold avelumab or utomilumab 
(4-1BB). At the physician’s discretion, avelumab or utomilumab (4-1BB) may 
continue at same dose if diarrhea improves to </= Grade 1. 
• In case the event of diarrhea is suspected to be immune-related and/or in the 
case the event of diarrhea does not respond to the measures applied for 

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radiotherapy-induced diarrhea and has an increase in severity, follow the 
toxicity management described for diarrhea/colitis in the immune-related 
adverse event toxicity management (Table 10). 
 
Patients continuing on protocol after more than a 28 days delay in treatment can 
continue on a case by case basis after discussion with the Medical Monitor and at the 
discretion of the treating physician. 
 
 
Each dose modification or treatment delay has to be documented in the eCRF, 
including the respective reason. 
 
5.2.4.3 Dose Modifications 
In the event that a DLT that is at least possibly related to one of the study drugs occurs, 
patients will halt treatment with study drugs until symptoms resolve to the grade 
outlined in Section 5.2.4.2, and then treatment can be restarted. After the first two 
cycles reduction in the frequency of dosing in study drug(s) may be required based on 
the worst toxicity experienced in the previous cycle. 
 
No specific dose adjustments are recommended for Grade 1/2 treatment-related 
toxicity. However, investigators should always manage their patients according to their 
medical judgment based on the particular clinical circumstances. 
 
During dose escalation cohorts, patients experiencing recurrent and intolerable Grade 
2 toxicity may resume dosing at the next lower dose level or at a decreased frequency 
once recovery to >/=Grade 1 or baseline is achieved. Patients enrolled in the 
expansion cohorts may resume dosing, once recovery to </= Grade 1 or baseline is 
achieved after experiencing recurrent and intolerable >/= Grade 2. If a dose or 
frequency reduction is required due to the treatment related toxicity, this may be 
allowed as an alternative to discontinuation of treatment, upon agreement with the 
MDACC IND Office. 

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Once a patient has a dose reduction or reduction in the frequency in the dosing for a 
drug-related toxicity, the dose will not be re-escalated. Patient requiring more than two 
dose reductions will be withdrawn from treatment unless otherwise agreed between 
the investigator and the MDACC IND Office. 
 
Adverse events (both non-serious and serious) associated with study drug(s) 
exposure may represent an immunologic etiology. These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. 
Immunotherapy study drugs (avelumab, utomilumab, and PF-04518600) must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per Table 8- 
10 below. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. The dose modification guidelines are intended to be 
applied when the physician determines the events to be related to one or more of the 
immunotherapy study drugs (avelumab, utomilumab, and PF-04518600). 
 
For subjects whose dose was withheld due to toxicity, subjects may resume 
immunotherapy study drug(s) (avelumab, utomilumab, and PF-04518600) upon 
resolution of toxicity to Grade 0-1 or baseline. 

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Table 
8. 
Adverse 
Drug 
Reactions 
Requiring 
Immunotherapy 
Agent 
Discontinuation or Modification 
In the following table, immunotherapy study drugs or agents refer to avelumab, 
utomilumab, or PF-04518600. 
Any Grade 4 Adverse Drug Reactions (ADRs) require treatment discontinuation with 
immunotherapy agents (avelumab, utomilumab, or PF-04518600) except for single laboratory 
values out of normal range that are unlikely related to study treatment as assessed by the 
Investigator, do not have any clinical correlate, and resolve within 7 days with adequate medical 
management 
Any Grade 3 ADRs require treatment discontinuation with immunotherapy agents except for 
any of the following: 
• 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
• 
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤ 1 
• 
Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) 
that are unlikely related to study treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management 
• 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 
• 
Change in ECOG PS to ≥ 3 that does not resolve to ≤ 2 within 14 days (infusions should not be 
given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
Any Grade 2 ADR should be managed as follows: 
• 
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
• 
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle. If at the end of the following cycle the event has not 
resolved to Grade 1, the subject should permanently discontinue treatment with an 
immunotherapy agent ADR (except for hormone insufficiencies, that can be managed by 
replacement therapy; for these hormone insufficiencies, up to 2 subsequent doses may be 
omitted). 
• 
Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with immunotherapy 
agents has to be permanently discontinued. 

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Table 9. Treatment Modification for Symptoms of Infusion-Related Reactions 
In the following table, immunotherapy study drugs or agents refer to avelumab, utomilumab, or PF-04518600. 
 
NCI-CTCAE Grade 
Treatment Modification for Study Drug 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the study drug infusion rate by 50% and 
monitor closely for any worsening. 
The total infusion time for study drug should not 
exceed 120 minutes. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for ≤ 24 
h. 
Stop study drug infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, 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 study drug infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study drug treatment and must not receive any 
further study drug treatment. 
- Once the immunotherapy agents infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions. 
- If the subject has a second infusion-related reaction Grade ≥ 2 on the slower infusion rate, the 
infusion should be stopped and the subject should be removed from study treatment. 
- If hypersensitivity reaction occurs, the subject must be treated according to the best available medical 
practice. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 

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Table 10. Management of Immune-mediated Adverse Reactions 
In the following table, immunotherapy study drugs or agents refer to avelumab, 
utomilumab, or PF-04518600. 
 
 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur. 
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring 
Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4: treat with high dose corticosteroids 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic and endocrine irAEs should follow 
guidelines set forth in the table. 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic 
Continue immunotherapy 
agent therapy 
Symptomatic treatment 
(for example, loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3/4 
Grade 2 
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool 
Delay immunotherapy 
agent therapy 
Symptomatic treatment 
If improves to Grade 1: 
Resume immunotherapy agent therapy 
If persists > 5 to 7 days or recur: 
0.5 to 1.0 mg/kg/day methylprednisolone 
or equivalent 
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
immunotherapy agent therapy per 
protocol. 
If worsens or persists > 3 to 5 days with 
oral steroids: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 hrs.; 
interfering with ADL 
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4: life-threatening, 
perforation 
Discontinue 
immunotherapy agent 
therapy per protocol 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade 1, then 
taper over at least 1 month 
If persists > 3 to 5 days, or recurs after 
improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should 
not be used in cases of perforation or 
sepsis 

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Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2 
Covering ≤ 30% body surface 
area 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
Continue immunotherapy 
agent therapy 
If persists > 1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay immunotherapy agent therapy 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral equivalent. 
Once improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume immunotherapy agent 
therapy 
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences 
Delay or discontinue 
immunotherapy agent 
therapy 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections 
Resume immunotherapy agent therapy 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only 
Consider delay of 
immunotherapy agent 
therapy 
Monitor for symptoms 
every 2 to 3 days 
Consider Pulmonary and 
Infectious Disease 
consults 
Re-image at least every 3 weeks 
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2 
Mild to moderate new symptoms 
Delay immunotherapy 
agent therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization 
1.0 mg/kg/day methyl- 
prednisolone IV or oral 
equivalent 
Consider bronchoscopy, 
lung biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near Baseline, 
taper steroids over at least 1 month and 
then resume immunotherapy agent 
therapy and consider prophylactic 
antibiotics 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Severe new symptoms; New / 
worsening hypoxia; life- 
threatening 
Discontinue 
immunotherapy agent 
therapy 
Hospitalize 
If improves to Baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or 
worsening: 

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Pulmonary and Infectious 
Disease consults 
2 to 4 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, 
lung biopsy 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil) 
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN to 
3.0 x ULN and / or total bilirubin 
> ULN to 1.5 x ULN 
Continue immunotherapy 
agent 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 
Delay immunotherapy 
agent therapy 
Increase frequency of 
monitoring to every 3 days 
If returns to Baseline: 
Resume routine monitoring, resume 
immunotherapy agent therapy 
If elevations persist > 5 to 7 days or 
worsen: 
0.5 to 1 mg/kg/day methylprednisolone 
or oral equivalent and when LFT returns 
to Grade 1 or Baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume immunotherapy 
agent therapy 
Grade 3 to 4 
AST or ALT > 5 x ULN and / or 
total bilirubin > 3 x ULN 
Discontinue 
immunotherapy agent 
therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
Add prophylactic 
antibiotics for opportunistic 
infections 
Consult gastroenterologist 
Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted 
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily 
If no response within an additional 3 to 5 
days, consider other 
immunosuppressants per local 
guidelines 
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH abnormality 
Continue immunotherapy agent therapy 

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If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 
2 subsequent measurements: include T4 at subsequent cycles as 
clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine 
function 
Consider pituitary scan 
Symptomatic with 
abnormal lab / pituitary 
scan: 
Delay immunotherapy 
agent therapy 
1 to 2 mg/kg/day 
methylprednisolone IV or 
by mouth equivalent 
Initiate appropriate 
hormone therapy 
No abnormal lab / pituitary 
MRI scan but symptoms 
persist: 
Repeat labs in 1 to 3 
weeks / MRI in 1 month 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month and 
consider prophylactic antibiotics for 
opportunistic infections 
Resume immunotherapy agent therapy 
Subjects with adrenal insufficiency may 
need to continue steroids with 
mineralocorticoid component 
Suspicion of adrenal crisis (for 
example, severe dehydration, 
hypotension, shock out of 
proportion to current illness) 
Delay or discontinue immunotherapy agent therapy 
Rule out sepsis 
Stress dose of IV steroids with mineralocorticoid activity 
IV fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 
Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis. 
Withhold immunotherapy 
agent 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- 
mediated myocarditis. 
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start 
immunotherapy agent 
therapy. 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
immunotherapy agent. 
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Methylprednisolone 1-2 
mg/kg/day. 
Once improving, taper steroids 
over at least 1 month and add 
prophylactic antibiotics for 
opportunistic infections. 
If no improvement or 
worsening, consider additional 
immunosuppressions (e.g. 
azathioprine, cyclosporine A) 

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ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CT = computed tomography; irAE = immune-related adverse event; IV=intravenous; LFT = liver 
function test; LLN = lower limit of normal; MRI = magnetic resonance imaging; NCI-CTCAE = National 
Cancer Institute-Common Terminology Criteria for Adverse Event; T4 = free thyroxine; TSH = thyroid- 
stimulating hormone; ULN = upper limit of normal. 
*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website: 
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t= 
1001 

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5.2.5 
Compliance 
The Investigational Pharmacy site will complete required accountability and dosage 
preparation logs to be monitored by the MDACC IND Office. The existing clinical site's 
documentation system will capture all pertinent /required information on the 
preparation and administration of the dose. 
 
 
5.3 
Drug Storage and Drug Accountability 
 
The study drugs will be shipped and stored at a temperature between 2° and 8 °C. 
The storage conditions stated in the investigator brochure may be superseded by the 
label storage. 
 
The storage conditions and temperatures will be recorded on the Investigational 
Pharmacy temperature logs. 
 
The Investigator or an approved representative (eg, pharmacist) will ensure that all 
investigational product is stored in a strictly controlled, secure area, at appropriate 
temperatures and in accordance with applicable regulatory requirements. 
 
The Investigator or designated personnel must maintain adequate records 
documenting the receipt, use, loss or other disposition of the investigational 
product(s). Accountability Logs will be maintained by the Investigational Pharmacy. 
The forms must identify the investigational product, including batch or code 
numbers, and account for its disposition on a patient by patient basis, including 
specific dates and quantities. 
 
Destruction of investigational product will be performed per the MDACC policy. 
 
 
5.4 
Concomitant Medications 
 
Concomitant treatment considered necessary for the patient’s well-being may be given 
at discretion of the treating physician. 

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All concomitant medications, blood products, as well as interventions (eg, 
paracentesis, etc.) received by patients from screening until the end of study visit will 
be recorded in the electronic medical record (EMR). 
 
5.4.1 
Other Anticancer or Experimental Drugs 
No additional anticancer therapy will be permitted while patients are receiving one of 
the study drug combinations. 
 
Additionally, the concurrent use of vitamins or herbal supplements should be 
considered with caution. 
 
Palliative and supportive care for disease related symptoms may be administered at 
the Investigator’s discretion. 
 
5.4.2 
Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at 
the Investigator’s discretion and according to any available American Society of 
Clinical Oncology (ASCO) guidelines. 
 
5.4.3 
Hematopoietic Growth Factors 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted 
during the first two cycles of treatment but they may be used to treat treatment 
emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines (J Clin Oncol, 2006. 24(19): p. 3187-3205). 
 
Erythropoietin may be used at the investigator’s discretion for the supportive treatment 
of anemia. 
 
5.4.4 
Anti-inflammatory Therapy 
Anti-inflammatory or narcotic analgesic may be offered as needed. Systemic anti- 
inflammatory therapies may be used to treat SAEs potentially related to the study 
drug(s). However, in such cases it is suggested that Investigators consult with a 
specialist based on the involved organ systems before instituting treatment. 

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5.4.5 
Corticosteroids 
Chronic, systemic corticosteroid (more than 10 mg/ day of prednisone equivalent) use 
for palliative or supportive purpose is not permitted. Use of corticosteroids as 
symptomatic treatment may be allowed on individual basis and upon discussion with 
the MDACC IND Office. Steroids for replacement therapy (physiologic replacement) 
are allowed. Acute emergency administration, topical applications, inhaled sprays, eye 
drops or local injections of corticosteroids are allowed. 
 
5.4.6 
Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. 
The appropriate interval of time between surgery and the study drug(s) required to 
minimize the risk of impaired wound healing and bleeding has not been determined. 
Stopping study drug(s) is recommended at least 14 days prior to surgery. 
 
Postoperatively, the decision to reinitiate study drug(s) treatment should be based on 
a clinical assessment of satisfactory wound healing and recovery from surgery. 
 
5.4.7 
Radiation Therapy 
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician. All attempts should be made to rule out disease 
progression in the event of increased localized pain. If palliative radiotherapy is 
needed to control bone pain, the sites of bone disease should be present at baseline, 
otherwise, bone pain requiring radiotherapy will be considered as a sign of disease 
progression. 
 
The technique of radiation will be VMAT/IMRT for all arms. For Arm D, the treatment 
dose will be prescribed to the planning target volume (PTV) for all treatment groups. 
It is required that the prescribed isodose line should cover 100% of the internal gross 
tumor volume (IGTV) and more than 95% of the PTV. For central lung or liver lesion 
close to critical structures, compromised PTV coverage is allowed in order to meet 
normal tissue dose constraints, pending clinical judgments regarding optimal target 
coverage and normal tissues sparing by the treating physician. 

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There is no or little aperture margin recommended. The external border of the PTV will 
be covered by a lower isodose surface than usually used in conventional radiotherapy 
planning, which typically ranges from 70-95%. However, higher isodoses (hotspots) 
must be manipulated to occur within the target and not in adjacent normal tissue. 
Heterogeneity correction should be applied for planning. 
 
5.4.7.1 Radiation Technique 
Patients will be evaluated for regularity of breathing, responsiveness to feedback 
guidance, breath-hold capability. Based on this evaluation, a treatment delivery 
technique will be selected among the following: 
1. Breath-hold (with or without feedback guidance). 
2. Gated treatment. 
3. Free-breathing (with or without feedback guidance). 
4. Abdominal compression. 
5. A combination of the above techniques. 
 
 
A CT scan obtained using the same method of respiratory management as intended 
for treatment will be required for treatment planning purposes. This includes 4- 
dimensional CT (4DCT) for free-breathing, gated or abdominal compression 
techniques or repeated breath-hold CTs for breath hold techniques. Feedback 
guidance, including visual and/or audio techniques, will be used for all patients who 
would both benefit from and respond to training with such devices. 
 
4DCT is a fast CT scan that capable of imaging tumor position during the entire breath 
cycle. A CT scan is obtained with the patient in each couch position for a whole breath 
cycle (usually lasting 5 to 6 seconds in each position) followed by repositioning to the 
next couch position. Following a scan, the computer resorts all images and 
reconstructs the tumor positions for an entire breath cycle, i.e., a movie file is created 
which captures organ movement throughout the breath cycle. Radiotherapy will be 
designed based on the path of organ motion captured by 4DCT. 

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5.4.7.2 Target Volumes 
1. Gross Target Volume (GTV): Gross tumor as observed on a non-contrast CT 
should be delineated on lung (for lung tumors) or abdominal (for liver or adrenal 
tumors) windows from either 4DCT or repeated breath-hold CTs (see IGTV below). 
 
2. Internal Gross Target Volume (IGTV): IGTV is the volume containing the GTV 
throughout its motion during respiration or positional variability during repeated breath 
holds. The motion during free breathing (with or without abdominal compression) will 
be determined from 4DCT, the variability of tumor location during breath hold will be 
determined by repeated breath hold CTs obtained on the same day. One method to 
combine the data from the multiple CT datasets is to create a maximal intensity 
projection (MIP) that is used as an aid to contour the IGTV. All CT datasets will be 
transferred to the treatment planning system for reference. 
 
3. Clinical Target Volume (CTV) + Planning Target Volume (PTV): GTV plus 5-10 
mm margin (based on physician discretion). Due to tight PTV margin, CTV margin is 
not recommended to be edited except when normal tissue toxicity is concerning based 
on treating physician’s judgment. The prescribed dose of radiation (either 50 Gy or 60 
Gy) will be dosed to the PTV, we recommend 95% coverage if possible. 
 
5.4.7.3 Daily Treatment Setup 
The appropriate immobilization will be chosen for each patient. Most patients will be 
immobilized with arms up using a commercially available vacuum immobilization bag 
that extends from the patient’s head to their pelvis combined with a wing board. 
 
On-board imaging: Daily on-board imaging such as CT on-rails, cone beam CT, or 4- 
D cone beam CT will be conducted prior to each radiation fraction. Position adjustment 
and target coverage confirmation will be performed daily based on imaging study. The 
setup uncertainty will be kept to less than a 3 mm (2 s) variation. This value is based 
on the uncertainties of the couch readouts added in quadurature with ½ the voxel size 
of the CT. Adjustment of patient position is needed if target coverage is judged by the 
treating physician to be inadequate and/or critical normal tissues toxicity is concerning. 

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Repeated on-board CT after position adjustment is recommended if more than 5 mm 
shift is conducted. 
 
5.4.7.4 Dose Volume Constraints 
 
 
60 Gy in 10 fractions dose constraints (54-58): 
• Spinal Cord: 40 Gy ≤1 cc 
• Lung: V20 ≤20%, V10<30%, V5<50% 
• Esophagus: 60 Gy ≤1 cc, 40 Gy ≤10 cc 
• Trachea: 70 Gy ≤1 cc, 60 Gy ≤10 cc 
• Main bronchus: 70 Gy ≤1 cc, 60 Gy ≤10 cc 
• Heart: 70 Gy ≤5 cc, 50 Gy ≤10 cc 
• Brachial plexus: 50 Gy ≤1 cc, 40 Gy ≤10 cc 
• Major vessels: 70 Gy ≤5 cc, 60 Gy ≤10 cc 
• Skin (defined as outer 0.5 cm of body surface): 60 Gy ≤1 cc, 50 Gy ≤10 cc 
• Kidney: V50 ≤33% 
 
 
Please note that patients on Arm D will have radiation as part of the study treatment 
regimen combination. 
 
5.4.7.5 Radiation Breaks and Discontinuation 
Radiation breaks will occur for radiation-related Grade ≥ 3 toxicities uncontrolled by 
symptom management and medications pending judgment of the treating radiation 
oncologist. Continual re-evaluation will occur daily while a patient is on a radiation 
break until which time the treating radiation oncologist re-initiates the patient on 
radiation or discontinues treatment. Patients will be considered evaluable on the study 
if the planned radiation fractions were administered with < 5 days of unplanned 
treatment breaks. Patients will be considered evaluable on the study if patients 
received 75% of radiation dose. 
 
For Arm D, patients who experience: 

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• Grade 1 and 2 diarrhea related to radiation therapy and chemotherapy occurs 
in majority of patients starting around the end of the 3rd week of radiation 
therapy. Diarrhea prior to the 3rd week of radiation therapy is not usually 
associated with chemotherapy and radiation therapy and other causes need to 
be ruled out including C. Diff. This diarrhea lasts through the 5th week of 
radiation therapy and up to a week after the external beam radiation therapy is 
completed. This diarrhea is usually controlled with Imodium AD but sometimes 
Lomotil is used to control it. Grade 3 or higher diarrhea – not controlled with 
Imodium or Lomotil is rare – usually less than 2-3% in patients in patients 
receiving chemotherapy and radiation therapy. 
• Grade 1 and 2 diarrhea related to radiation may continue avelumab or 
utomilumab (4-1BB) at the discretion of the physician, 
• Grade 3 and 4 diarrhea related to radiation will hold avelumab or utomilumab 
(4-1BB). At the physician’s discretion, avelumab or utomilumab (4-1BB) may 
continue at same dose if diarrhea improves to </= Grade 1. 
• In case the event of diarrhea is suspected to be immune-related and/or in the 
case the event of diarrhea does not respond to the measures applied for 
radiotherapy-induced diarrhea and has an increase in severity, follow the 
toxicity management described for diarrhea/colitis in the immune-related 
adverse event toxicity management (Table 10). 

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6.0 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
 
For screening, treatment period and follow-up procedures, see Schedule of 
Assessments. 
 
For the treatment period discussed below, where multiple procedures are scheduled 
at the same nominal time point(s) relative to dosing, the following prioritization of 
events should be adhered to, where possible, in order of the most important to the 
least important: 
 
• 
Clinical safety lab tests – obtain prior to study drug administration. 
• 
Blood pressure/ pulse rate – may be obtained prior to or after ECG collection 
but must be obtained prior to study drug administration. 
• 
ECGs – obtain within 30 minutes of drug administration. 
• 
Other procedures – All other procedures should be obtained as close as 
possible to the scheduled time, but may be obtained before or after blood 
specimen collection, unless sampling is determined by the study personnel 
to potentially impact the results. 
 
6.1 
Screening Period 
 
All patients will be screened and screening procedures performed within 28 days prior 
to the start of induction treatment. 
 
The required screening assessments and laboratory tests are summarized in the 
Schedule of Assessments and Section 7.0 Assessments. Following completion of the 
screening assessments and confirmation of eligibility, patients may be initiate study 
treatment. 
 
6.2 
Study Treatment Period 
 
Treatment will continue until progression of disease (PD) or unacceptable toxicity, 
withdrawal of consent by the patient, or non-compliance by the patient with protocol 

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requirements. Safety assessments will be performed as illustrated in the Schedule of 
Assessments. 
 
Per the physician’s discretion, a patient may continue treatment even if there is 
progression of disease after avelumab is added as long as the patient remains 
clinically stable and/or pseudoprogression is assumed. 
 
Clinical and radiological examinations for disease status are performed every 2 cycles 
or 8 weeks (± 7 days) for up to 1 year. After completion of 1 year, tumor assessments 
will be performed every 3 cycles or 12 weeks (± 7 days) during treatment, independent 
of cycle delays. 
 
If a patient discontinues treatment due to any other reason than disease progression/ 
death/ withdrawal of informed consent, the disease evaluations shall continue until 
disease progression. This includes patients who wish to discontinue treatment, but 
agree that further data is captured for the purpose of the study (partial withdrawal). 
 
6.3 
End of Treatment Visit 
 
Patients that discontinue from treatment will undergo an end of treatment (EOT) visit, 
regardless of the reason of discontinuation, 30 days (+/-7 days) after the last dose of 
study medication. 
 
In the event a patient is unable to return to the clinic for the follow-up visit, telephone 
contact with the patient to assess adverse events and concomitant medications and 
treatment is expected. If laboratory assessments are needed to follow-up unresolved 
adverse events, retrieval of assessments performed at an institution local to the 
patient is acceptable. 
 
 
6.4 
Follow-Up Phase 
 
Patients who discontinue treatment for reasons other than progression of disease (and 
withdrawal of consent for participation in the trial) will continue to visit the clinic for 
evaluation of their disease by CT/MRI scan approximately every 12 weeks until 

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progression of disease is determined or patient receives additional anti-neoplastic 
medication. 
 
Of note, a patient may decide to discontinue study treatment. This is not the same as 
full withdrawal of consent to participate in the trial and these patients should be 
encouraged to continue to be followed up as for other patients until progression of 
disease. If a patient chooses to have no further interaction regarding the study (fully 
withdrawal of consent), the investigator must provide written documentation of the 
patient’s decision to fully withdraw from the study. 
 
Investigators will collect survival data for patients after progression of disease unless 
patient fully withdrew consent to participate in the study by using information from a 
chart review, patient visit, or telephone call. The telephone call will be less than five 
minutes to obtain information regarding survival status. 
 
6.5 
Patient Withdrawal 
 
Patients will be free to discontinue treatment or withdraw from the study at any time, 
for any reason, or they may be withdrawn/ removed if necessary in order to protect 
their health (see reasons for withdrawal below). It is understood by all concerned that 
an excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. Patients who are withdrawn 
from the study outside of the DLT period will not be replaced. 
 
Patients will be removed from further treatment for the following reasons: 
• Disease progression; 
• Non-compliance; 
• Need of treatment with medications not allowed by the study protocol; 
• Patient no longer consents to participate in the study; 
• Intercurrent illness that interferes with study assessments; 
• Incidence or severity of AEs in this study indicates a potential health hazard to 
the patient; 
• Investigator discretion; 

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• Pregnancy; 
• Termination of the study. 
 
 
Reasons for withdrawal from study follow-up may include: 
• Completed study follow-up; 
• Study terminated by Sponsor; 
• Lost to follow-up; 
• Refusal for further follow-up for survival; 
• Death. 
 
If there is a medical reason for withdrawal of treatment, the patient will remain under 
the supervision of the investigator until the AEs have been resolved or declined to 
baseline values. 
 
If a patient has failed to attend scheduled assessments in the study, the investigator 
must determine the reasons and circumstances as completely and accurately as 
possible. 
 
In case of premature discontinuation of the study treatment, the investigations 
scheduled for the EOT and the follow-up visits should be performed, if possible. The 
reason for discontinuation has to be documented in the eCRF in all cases. Should a 
patient decide to withdraw, every effort will be made to complete and report the 
observations as thoroughly as possible. The investigator should contact the patient to 
determine as completely as possible the reason for the withdrawal. A complete final 
evaluation at the time of the patient’s withdrawal should be made, with an explanation 
of why the patient is withdrawing from the study. If the reason for removal of a patient 
from the study is an adverse event or an abnormal laboratory test result, the principal 
specific event or test will be recorded on the case report form. 
 
 
If a patient withdraws consent for further study treatment, the patient should still be 
followed for progression and survival. If a patient withdraws consent for further 
participation in the study, follow-up assessments will be discontinued. 

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7.0 
ASSESSMENTS 
 
Every effort should be made to ensure that the protocol required tests and procedures 
are completed as described. However, it is anticipated that from time to time there 
may be circumstances, outside of the control of the investigator, which may make it 
unfeasible to perform the test. In these cases, the investigator will take all steps 
necessary to ensure the safety and well-being of the patient. When a protocol required 
test cannot be performed the investigator will document the reason for this and any 
corrective and preventive actions which he/she has taken to ensure that normal 
processes are adhered to as soon as possible. The study team will be informed of 
these incidents in a timely fashion. 
 
All procedures should be followed within the allowed flexibility windows as outlined in 
the Schedule of Assessments. 
 
7.1 
Safety Assessments 
 
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, ECG (12 lead), laboratory assessments, including pregnancy tests and 
verification of concurrent medications. 
 
7.1.1 
Pregnancy Testing 
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting 
study therapy-once at the start of screening and once at the baseline visit (prior to 
initiating study drugs (Arms A-C) or radiation (Arm D), immediately before 
investigational product administration. 
 
Following a negative pregnancy result at screening, appropriate contraception must 
be commenced and a further negative pregnancy result will then be required at the 
baseline visit before the patient may receive the investigational product. Pregnancy 
tests will also be routinely repeated at every cycle during the active treatment period, 
at the end of study therapy, and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected. In the case of a positive hCG test 

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and confirmed pregnancy, the patient will be withdrawn from the study medication and 
will be withdrawn from the study. Additional pregnancy tests may also be undertaken 
if requested by Institutional Review Board (IRB)/ Independent Ethics Committee 
(IECs) or if required by local regulations. 
 
7.1.2 
Adverse Events 
An adverse event (AE) is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if the event 
is not considered to be related to study drug. Medical conditions/diseases present 
before starting study drug are only considered adverse events if they worsen after 
starting study drug. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
 
Assessment of AEs will include the type, incidence, severity (graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03) timing, seriousness, and relatedness. 
 
AEs that occur during the study, including baseline signs and symptoms, will be 
recorded on the AEs CRF page. The active reporting period begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 30 calendar days after the last 
administration of the investigational product. 
 
The investigator (or physician designee) is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for all 
adverse events for subjects enrolled. 
 
Table 11: Recommended Adverse Event Recording Guidelines 
Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

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Unrelated 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Possible 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Probable 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II 
Phase III 
 
 
 
7.1.3 
Laboratory Safety Assessments 
Hematology, serum chemistry, and thyroid function labs will be drawn at the time 
points described in the Schedule of Assessments and analyzed at local laboratories. 
All laboratory safety assessments conducted on Cycle 1 Day 1 (C1D1) for Arms A-C 
or prior to radiation for Arm D must be completed prior to dosing; hematology and 
chemistry results must be reviewed by an advance practice provider or a physician 
prior to dosing. 
 
Assessments performed on dosing days in each subsequent cycle should be 
performed within 48 hours prior to dosing. Investigators may have additional blood 
tests performed for the purpose of planning treatment administration, dose 
modification, or following AEs. 
 
For Arms A-C, there is no need to repeat C1D1 laboratory assessments if baseline 
assessment is performed within 2 days prior to that date. For Arm D, there is no need 
to repeat initial laboratory assessments if baseline assessment is performed within 3 
days prior to initiation of radiation. 

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Hematology 
Chemistry 
Endocrine 
Monitoring 
Coagulation Urinalysis 
Pregnancy Test 
Hepatitis 
Screening 
Cardiac Enzyme 
Monitoring 
Hemoglobin 
ALT 
TSH 
PT or INR 
Urine dipstick for 
urine protein: If 
positive( ≥ 2+), 
collect 24-hr 
urine or collect 
spot urine) and 
microscopic 
(Reflex Testing) 
For female 
patients 
of childbearing 
potential, 
serum or urine 
Hepatitis B surface 
antigen and core 
antibody; anti- 
hepatitis C 
antibody. 
Troponin T and NT- 
proBNP 
Platelets 
AST 
Free T4 
PTT 
WBC 
Alkaline 
Phosphatase 
Total T3 
Absolute Neutrophils 
Sodium 
Potassium 
Absolute Monocytes 
Magnesium 
Urine dipstick for 
urine blood: If 
positive and 
clinically 
indicated collect 
a microscopic 
(Reflex Testing) 
Absolute Eosinophils 
Chloride 
Absolute Basophils 
Total Calcium 
Total Bilirubin 
Direct Bilirubin 
Indirect Bilirubin 
Blood urea 
nitrogen (BUN) or 
Urea 
Creatinine 
Uric Acid 
Glucose (non- 
fasted) 
Albumin 

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Hematology 
Chemistry 
Endocrine 
Monitoring 
Coagulation Urinalysis 
Pregnancy Test 
Hepatitis 
Screening 
Cardiac Enzyme 
Monitoring 
Phosphorous or 
Phosphate 
Total protein 
Amylase 
Lipase 
Creatine kinase 
Lactate 
dehydrogenase 
(LDH) 
Bicarbonate 

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7.1.4 
Vital Signs and Physical Examination 
Patients will have a physical exam to include weight, vital signs, assessment of ECOG 
status and height. 
 
A complete physical examination (PE) will be performed at Screening, Days 1 and 15 
of each cycle, and the End of Treatment visit for each patient and will include the 
measurement of body weight, vital signs and assessment of ECOG performance 
status. Findings of all physical examinations should be recorded in the source 
documents, and any change from baseline considered by the investigator to be 
clinically significant should be recorded as an adverse event in the CRF. At screening 
only, height will be obtained from the electronic medical record. 
 
Abbreviated PEs should be performed as appropriate at each visit where complete 
physical exams are not required, with special attention to skin and mucosa, and on an 
as needed basis for assessment of adverse events. Abbreviated exams should be 
targeted to specific symptoms or complaints and be consistent with local standard of 
care. 
 
Patient’s body weight will be measured at Day 1 of each dosing cycle, and it will be 
used to calculate the patient’s dose of study treatment for that cycle. 
 
Vital signs will include measurements of blood pressure, pulse rate and temperature 
(oral, tympanic, temporal or axillary). Sitting blood pressure (BP) will be measured with 
the patient’s arm supported at the level of the heart and recorded to the nearest mmHg 
after approximately 5 minutes of rest. On Day 1 of each cycle, vital signs should be 
measured prior to infusion start (pre-dose) of first study drug (if more than one study 
drug is given) and 1 hour after the start of the infusion of last study drug (if more than 
one study drug is given). The same arm (preferably the dominant arm) will be used 
throughout the trial. The blood pressure cuff, which has been properly sized and 
calibrated, should be used to measure blood pressure. The use of automated devices 
for measuring BP and pulse rate is acceptable. 

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7.1.5 
ECG Assessments 
Electrocardiogram (ECG): Single 12-lead (with a 10-second rhythm strip) tracing in the 
supine position will be used for all ECGs. It is preferable that the machine used has a 
capacity to calculate the standard intervals automatically. Single ECGs will be 
performed Day 1 of every cycle. 
 
If the QTc is prolonged (>500 msec by any correction method, ie, CTCAE Grade 3), 
then the ECG should be re-evaluated by a qualified person at the site for confirmation 
as soon as the finding is made, including verification that the machine reading is 
accurate. If manual reading verifies a QTcF of >500 msec, immediate correction for 
reversible causes (including electrolyte abnormalities, hypoxia and concomitant 
medications for drugs with the potential to prolong the QTc interval) should be 
performed. In addition, repeat ECG should be immediately performed hourly for at 
least 3 hours until the QTc interval resolves to Grade 1 or less. 
 
If QTc interval reverts to less than 500 msec, and in the judgment of Investigator(s) 
and the MDACC IND Office is determined to be due to cause(s) other than study drug, 
treatment may be continued with regular ECG monitoring. If in that timeframe the QTc 
intervals rise above 500 msec the study drug will be held until the QTc interval 
decreases to Grade 1 or less. Patients will then re-start the study drug at the next 
lowest dose level. If the QTc interval has still not decreased to <500 msec after 2 
weeks, or if at any time a patient has a QTc interval >515 msec or becomes 
symptomatic, the patient will be removed from the study. Additional triplicate ECGs 
may be performed as clinically indicated. 
 
Prior to concluding that an episode of prolongation of the QTc interval is due to study 
drug, thorough consideration should be given to potential precipitating factors (eg, 
change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist. 
 
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event. 

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7.1.6 
Echocardiogram/ Multigated Acquisition Assessments 
For patients with prior history of anthracycline treatment that are enrolled on the PF- 
04518600 (OX40) Arms B or C, an echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan will be performed at screening, every 3 cycles (starting at Cycle 4 Day 
1), and End of Treatment (if not performed within 3 months of discontinuation). 
 
7.1.7 
Cardiac Enzyme Monitoring 
For patients with prior history of anthracycline treatment that are enrolled on the PF- 
04518600 (OX40) Arms B or C, cardiac ezyme monitoring will be performed at 
screening, Day 1 of every cycle, and End of Treatment. 
 
Troponin T and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) 
will be evaluated in patients with previous history of anthracycline treatment. 
Assessments must be performed prior to dosing. No need to repeat on Cycle 1 Day 1 
(C1D1) if the screening assessment is performed within 2 days prior to that date. 
Assessments performed on Cycle 2 Day 1 and Day 1 of each subsequent cycle should 
be performed within 48 hours prior to dosing. Assessments should also be performed 
when clinically indicated. 
 
 
7.2 
Tumor Response Assessments 
 
Objective response will be evaluated based on RECIST criteria Version 1.1 and 
irRECIST using CT scan or MRI scan or PET-CT scan. For patients with multiple 
measurable lesions, up to 5 lesions in total and 2 lesions per organ should be 
identified. 
 
For Arm D (radiation), radiated target lesions will be evaluated with a modified 
version of the international criteria proposed by the RECIST Committee, version 1.1. 
 
The exact technique used for measurement of lesions (i.e., either CT or MRI or PET- 
CT scan) will be left to the discretion of the investigator, however, for each patient the 
same technique must be used throughout the study, assessed whenever possible by 

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the same individual. The CT/ MRI abdomen must include the pelvis. A PET/CT is 
allowed, but ultrasound and x-ray of thorax is not allowed. 
 
In cases where there is suspicion of progression before the next scheduled 
assessment, an unscheduled tumor assessment should be performed. In case a 
detected increase in tumor size is below the resolution limit of the CT/ MRI scanner, it 
is accepted to continue with treatment until a second assessment at a later time point 
unequivocally confirms progressive disease. Partial response requires confirmation 
with a follow-up scan at least 4 weeks apart. 
 
If the increase in tumor burden is >/= 20% relative to nadir, then in the absence of 
rapid clinical deterioration, confirmation by a repeat, consecutive assessment no less 
than 4 weeks from the date first documented is recommended. Patients will continue 
with study drug until confirmation scan is obtained. 
 
The following are defined as non-target lesions: bone lesions, leptomeningeal disease, 
pleural/pericardial effusion, ascites, inflammatory breast disease, lymphangitis, cystic 
lesions and lesions not measurable by CT or MRI. All non-target lesions are described 
over time and need not be measured. 
 
The first evaluation of disease status by imaging will be done after 2 cycles or 8 weeks 
(± 7 days) of treatment and every 2 cycles or 8 weeks (± 7 days) thereafter at the 
physician’s discretion. After completion of 1 year of treatment, tumor assessments will 
be performed every 3 cycles or 12 weeks (± 7 days) during treatment, independent of 
cycle delays. 
 
Patients will also be eligible for the study if their disease is evaluable outside irradiated 
field on CT/ MRI. 
 
In case palliative radiation becomes necessary during the treatment within the study, 
there must be at least two target lesions left outside the irradiated filed for continuous 
assessment for response. 

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7.3 
Biopsy Analyses 
 
For patients in the MTD expansion cohorts of Arms A-C, tumor tissue will be obtained 
pre- treatment (baseline), between Cycle 1 Day 12-15 (prior to study drug dosing), 
prior to Cycle 3 Day 1 study drug dosing, and at progression (if achieved stable 
disease ≥6 months, partial response, or complete remission) provided there is 
technically biopsiable tumor, and it is safe for patient to undergo biopsy. 
 
For patients in the escalation cohorts of Arm C (patients enrolled prior to Version 05), 
tumor tissue will be obtained pre- treatment (baseline), prior to Cycle 2 Day 1 dosing, 
and at progression (if achieved stable disease ≥6 months, partial response, or 
complete remission) provided there is technically biopsiable tumor, and it is safe for 
patient to undergo biopsy. 
 
For patients in the de-escalation and MTD Expansion cohort of Arm D, tumor tissue 
will be obtained pre- treatment (baseline), prior to Cycle 3 Day 1 dosing, and at 
progression (if achieved stable disease ≥6 months, partial response, or complete 
remission) provided there is technically biopsiable tumor, and it is safe for patient to 
undergo biopsy. 
 
Correlative studies for biomarker analyses will be performed during this study. 
 
 
A fresh core needle biopsy (CNB) will be obtained solely with the purpose of research 
studies (pre-treatment samples) and sent to the Institutional Tissue Bank (ITB) 
immediately after collection. Up to 5 cores will be obtained from the CNB procedure. 
The number of cores obtained will be affected by the patient clinical condition at the 
time of biopsy and determined by the radiologist who is performing the procedure. It 
is important to note that in some of these trials, the biopsy sample will also be required 
for clinical diagnosis. In such case, the first specimen will be prioritized for clinical 
specimen processing. In most instances, a rapid on site evaluation (ROSE) is available 
locally to evaluate the adequacy of clinical sample, thus additional biopsies may be 
procured for this research project. Nevertheless, the amount tissue available for 
correlative studies can be variable. Core biopsy is typically performed using 21-18 
gauge needle and with condition permitting, up to 5 cores should be collected. 

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For Arms A, B, and C, subjects must have at least two lesions amenable to biopsy and 
response evaluation. Tumor lesions used for biopsy should not be lesions used as 
RECIST target lesions. Every effort will be made to biopsy the same lesion at each 
time point. 
 
For Arm D, subjects should have at least three lesions amenable to biopsy, response 
evaluation, and radiation. Tumor lesions used for biopsy should not be lesions used 
as RECIST target lesions. Every effort will be made to biopsy the same lesion at each 
time point. In addition, the radiated lesion will also be biopsied at each time point. 
However, if patients in Arm D do not have three separate lesions, patients will be 
eligible if there are two lesions, in which one is > 2 centimeters (short axis) and can 
be used for both biopsy and response evaluation. 
 
 
 
 
7.4 
Biomarker Analyses 
 
Biomarker analyses will be performed to investigate biomarkers that are potentially 
predictive of response with the combination of avelumab and an immune modulator. 
In addition, biomarker studies of tumor and blood biospecimens will be carried out to 
help further understand the mechanism of action of the avelumab plus the study 
treatments, as well as potential mechanisms of resistance. 
 
For the MTD Expansion cohorts of Arms A-C, blood samples will be collected at 
baseline, between Cycle 1 Day 12-15 (prior to study drug dosing), prior to Cycle 3 Day 
1 study drug dosing, and at the time of progression (if patient had an initial response 
of stable disease ≥6 months, partial response, or complete remission) to evaluate 
biological response or predictive markers in blood, tumor, and tumor environment and 
their relationships to drug exposure, clinical response, or other biologic response 
markers. Cell free DNA from patient’s blood samples will also be analyzed. 

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For the escalation cohorts of Arm C (patients enrolled prior to Version 05), blood 
samples will be collected at baseline, prior to Cycle 2 Day 1 dosing, and at the time of 
progression (if patient had an initial response of stable disease ≥6 months, partial 
response, or complete remission) to evaluate biological response or predictive 
markers in blood, tumor, and tumor environment and their relationships to drug 
exposure, clinical response, or other biologic response markers. Cell free DNA from 
patient’s blood samples will also be analyzed. 
 
For the de-escalation and MTD Expansion cohort of Arm D, blood samples will be 
collected at baseline, prior to Cycle 1 Day 1, prior to Cycle 1 Day 15, prior to Cycle 2 
Day 1 dosing, prior to Cycle 3 Day 1 dosing, and at the time of progression (if patient 
had an initial response of stable disease ≥6 months, partial response, or complete 
remission). Cell free DNA from patient’s blood samples will also be analyzed. 
 
 
The plan for biomarker analyses in Arms A-D is the following: 
Immunohistochemistry (IHC): The samples collected will be analyzed by IHC 
analysis of tumors for markers that may include, but are not limited to, PD-L1, CD3, 
CD4, Foxp3, CD25, CD8, CD68, CD56, CD20, CD45RO and granzyme B. We may 
also include PD-L2, B7-H3, B7-x/H4, galectin 9, HVEM and CD48 to measure in 
tumors and PD-1, 2B4, LAG-3, Tim-3 and BTLA in TILs. 
 
Multiplex IF Analysis: Up to 10 immune markers, 2 panels may be utilized. Currently, 
there are 2 Vectra panels optimized: Panel#1, CD3, CD8, CD68, PD-L1, PD-1 pan- 
cytokeratin and DAPI; Panel #2, CD20, CD45RO, FOXP3, Granzyme B, CD57, pan- 
cytokeratin and DAPI. For multiplex IF analysis, we will use the Opal chemistry and 
multispectral microscopy Vectra system (Perkin-Elmer) which includes the Nuance 
software; analysis will be performed using the InForm software. Additional markers 
will be selected according the results of the gene expression analysis and may include 
other immunotherapy targets (e.g., OX-40, Vista, GITR, TIM-3, LAG-3, NKp46/CD16, 
etc.) and proliferation markers (e.g., Ki67). 

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Molecular Analyses (in Tissue and Blood): Using FFPE tumor tissues and blood 
samples, Immuno-oncology (IO) gene panels will be examined using the Nanostring 
technology (nCounter). This assay will be used to measure expression levels of drug 
targets, tumor infiltrate composition, and total immune cell composition using a single 
section of FFPE tumor tissue. Next Generation Sequencing (NGS) analysis: To study 
tumor molecular abnormalities, fresh, and alternatively, FFPE tumor tissues and blood 
samples before and after treatment will be examined for targeted gene panel NGS 
(analysis of mutations, copy number, indels, and translocations), whole exome 
sequencing (WES) and RNA sequencing (Illumina Hi-seq platform). 
 
Flow Cytometry of Blood: Collected blood will be analyzed by flow cytometry for 
lymphocyte subsets in PBMCs. This flow cytometry panel includes: (1) FACS 
phenotyping for CD4+ and CD8+ naïve (TN), central memory (TCM), effector-memory 
(TEM) and terminally differentiated effector (TTDE) cells; (2) Staining for suppressor 
cells such as CD4+ T-regulatory cell and myeloid derived suppressor cells (MDSC) 
subsets; (3) Phenotyping of NK cells and (4) Identification of APC subsets (pDC, mDC, 
B cells, macrophages). To detect and enumerate these populations we have 
developed FACS cell surface and intracellular staining panels on samples that are 
analyzed using a FACScanto II flow cytometer (BD Biosciences). These staining 
panels include antibodies against pan-leukocytes (CD45), T cells (CD4, CD8, CD25, 
CD27, CD28, CD45RA, CD45RO, CD62L, CD69, OX40, 41BB, CCR7, GB, PFN), 
CD4+ T-reg cells (CD4, CD25, Foxp3, CD127, CD27, CD62L, CTLA-4, GARP, ICOS, 
CD39, and LAP), B cells (CD19 CD20), pDC and mDC (CD11c, CD11b, BDCA2, 
CD123, CD86, CD80, CD83, HLA class II), monocyte/macrophages (CD14, CD11b, 
CD13), MDSCs (CD33, CD11b, CD14, CD15, HLA-DR, S100A9) and NK cells (CD16, 
CD56, CD69, NKG2D). 
 
Flow cytometry of freshly disaggregated tumor tissue: Fresh tissue will be 
available for flow cytometry analysis on larger tumor samples only using Core 3. This 
will include assessment of the proportion of various immune cells by gating on the pan 
immune marker CD45 and sub-gating on cell specific markers defining T cell, MDSC, 
macrophage, DC or NK cell subsets. The expression of checkpoints or their ligands 
can be explored on each of those cell subsets. In addition, for tissue samples, live 

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cells can be sub-gated on the CD45-negative fraction to exclude immune cells. 
EPCAM will be used as a marker of tumor cells and CD90 as a fibroblast marker. The 
expression of CD80, CD86, GITR-L, ICOS-L, MIC A/B, B7-H3, B7-H4, CD73, PD-L2 
and OX40L can all be assessed. 
 
 
Serum Cytokine Analyses: Cytokines (IFN-γ, IL-1α, IL-2, IL-4, IL-5, IL-8, IL-10, IL- 
12p70, IL-13, and TNF-α) will be measured in the serum using the Meso Scale 
Discovery Platform (Rockville, MD). This technology allows for the detection of up to 
40 analytes per well and uses a very low sample volume. This method has a sensitivity 
up to 1000 fold higher than traditional ELISA assays with a large linear range of 3-4 
logs. The instrument performs immunoassays utilizing electrochemiluminescense to 
detect the signal in a 96 well plate format. This technology can be utilized for either 
single agent detection or in multiplex format. A wide menu of validated single or 
multiplex kits for the detection of 1 to 40 analytes are available from the manufacturer 
and can be customized. 
 
Liquid Biopsy Analyses: For cfDNA, both ultra-deep next-generation sequencing 
(NGS) mutation analysis of a panel of 50 genes (CMS50) (Ion Torrent PGM and Ion 
Proton), as well as uniplex or multiplex digital droplet PCR (ddPCR, BioRad and 
Raindance) are available using 40-50 ng of DNA extracted from 4-5 ml of plasma 
(blood, purple top). 
 
 
7.5 
Co-Enrollment on Additional Studies 
 
Patients enrolled on this study will be approached for co-enrollment on PA15-0315 
prospective study to assess immune-related adverse events when receiving 
immunotherapy at the University of Texas MD Anderson Cancer Center (Aung 
Naing, MD). All samples and scans will be collected using procedures characterized 
in this protocol, and all patients will be consented for procedures done under this 
protocol separately. 
 
Patients enrolled on this study will be approached for co-enrollment on the 2014- 
0938, APOLLO (Adaptive Patient-Oriented Longitudinal Learning and Optimization) 

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protocol, which is an MD Anderson Moon Shot platform. All samples will be 
collected using procedures characterized in this protocol, and all patients will be 
consented for procedures done under this protocol separately. 

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8.0 
ADVERSE EVENT REPORTING 
 
8.1 
Adverse Events 
 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the 
following sections. 
 
For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a serious adverse event (SAE) requiring immediate notification to 
Pfizer or its designated representative. For all AEs, sufficient information should be 
obtained by the investigator to determine the causality of the AE. The investigator is 
required to assess causality. Follow-up by the investigator may be required until the 
event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
the MDACC IND Office concurs with that assessment. 
 
As part of ongoing safety reviews conducted by the MDACC IND Office, any non- 
serious AE that is determined by the MDACC IND Office to be serious will be reported 
by the MDACC IRB as an SAE per MDACC institutional policy. 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. 
 
The active reporting period begins from the time that the patient provides informed 
consent through 30 calendar days after the last administration of the investigational 
product. 
 
 
8.2 
Definition of Adverse Event 
 
An adverse event is defined in the International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient 
or clinical investigation subject administered a pharmaceutical product and that does 
not necessarily have a causal relationship with this treatment” (ICH E6:1.2). 

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An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated 
with the use of a medicinal product, whether or not it is considered related to the 
medicinal product. 
 
8.3 
Definition of Serious Adverse Event (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 

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• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB. 
• Serious adverse events will be captured from the time of the first protocol- 
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
 
8.4 
Reporting to FDA 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 

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8.5 
Investigator Communications with Pfizer 
 
For SAEs, the active reporting period to Pfizer or its designated representative begins 
from the time that the patient provides informed consent through 30 calendar days 
after the last administration of the investigational product. SAEs occurring to a patient 
after the active reporting period has ended should be reported to Pfizer if the 
investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to investigational 
product are to be reported to Pfizer. 
 
AEs (serious and non-serious) should be recorded on the case report form (CRF) from 
the time the patient has taken at least one dose of investigational product through the 
patient’s last visit. 
 
If a patient begins a new anticancer therapy, the AE reporting period for non-serious 
AEs ends at the time the new treatment is started. Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment. 
 
The investigator primary responsibilities in the safety reporting are to identify and 
follow-up on Serious Adverse Events (SAEs) experienced by participants in the study 
and to forward the information to IRB, IND Office, and Pfizer, as required by local 
regulations (for regulatory reporting) and Investigator-Initiated Research (IIR) 
agreement (for reporting to Pfizer). 
 
The following reportable events must be submitted to Pfizer within 24 hours (or 
immediately for death or life-threatening events) using the MDACC SAE form with the 
Pfizer Reportable Events Fax Cover Sheet with each SAE submission. 
 
• Serious Adverse Events 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an 
adverse event) 
• Occupational exposure (even if not associated with an adverse event) 

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• Potential drug-induced liver injury (Hy’s Law cases): 
These events are 
considered important medical events and should be reported as SAEs. 
 
 
 
Contact information for submission of reportable events to Pfizer: 
• Fax: Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322. 
Or 
• E-mail: USA.AEReporting@pfizer.com , specifying: 
PROTOCOL: 
SUBJECT: 
SITE/PI: 
SAE/ONSET: 
 
 
 
The MDACC SAE form will be submitted to Pfizer. The following detailed information 
must be recorded for each serious adverse event in the SAE report form: 
• A description of the AE in medical terms according to NCI-CTC Version 4.03, 
not as reported by the subject. 
• The severity grade as assessed by the investigator according to the definitions 
in NCI-CTC Version 4.03. 
• The date of becoming serious and the date of becoming known (if different). 
• The reason for seriousness. 
• The outcome of the SAE at the time of the report. 
• Information on administration of the study drug and chemotherapy and any 
action taken. 
• Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history. 
 
If in any one subject the same SAE occurs on several occasions, then the SAE in 
question must be documented and assessed anew each time. The investigator is 
required to submit SAE Follow-up reports until the SAE has resolved or stabilized and 
all queries have been answered. 

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8.6 
Recording of Adverse Events 
 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by subjects are properly recorded in the subjects’ medical 
records and the electronic case report form. 
 
The following adverse event attributes must be assigned by the investigator: 
• Adverse event term according to the NCI-CTC criteria Version 4.03; 
• Severity grade according to the NCI-CTC criteria Version 4.03; 
• Start date and stop date (or date of last assessment); 
• Outcome; 
• Causality to study drug and chemotherapy (to be assessed as either related or 
unrelated); 
• Any action taken. 
 
Adverse events will be followed until they resolve to baseline or considered stable. It 
will be left to the investigator’s clinical judgment to determine whether an adverse 
event is related and of sufficient severity to require the subject’s removal from 
treatment or from the study. A subject may also voluntarily withdraw from treatment 
due to what he or she perceives as an intolerable adverse event. If either of these 
situations arises, the subject should be strongly encouraged to undergo an end-of- 
study assessment and be under medical supervision until symptoms cease or the 
condition becomes stable. 
 
Pre-existing diseases, when worsening during study therapy, have to be considered 
as adverse events. They can lead to serious adverse events, if the meet the criteria 
described in Section 8.3. 
 
Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. If an adverse event 
occurs which is not described in the CTCAE version 4.03, the four-point scale below 
will be used. 

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• Mild: Discomfort noticed but no disruption of normal daily activity. 
• Moderate: 
Discomfort sufficient to reduce or affect daily activity. 
• Severe: 
Inability to work or perform normal daily activity. 
• Life-threatening: 
Represents an immediate threat to life. 
 
8.6.1 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the eCRF. 
In the event of unexplained abnormal laboratory test values, the tests should be 
repeated immediately and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. 
 
Laboratory test value abnormalities as such should not be reported on the AE page of 
the eCRF as adverse events unless they are treatment-emergent and they satisfy one 
or more of the following conditions for clinical significance: 
1) Accompanied by clinical symptoms; 
2) Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation); 
3) Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
 
Please note: Any laboratory result abnormality fulfilling the criteria for a serious 
adverse event (SAE) should be reported as such, in addition to being recorded as an 
adverse event in the eCRF. 
 
8.6.2 
Pregnancy 
Pregnancy per se is not considered an AE. A medical occurrence observed in the 
mother or fetus/newborn would be an AE. 
 
Female patients must be instructed to immediately inform the investigator if they 
become pregnant during the study. The study treatment must immediately be stopped 
and the patient must be withdrawn from the study. Pregnancies occurring up to 6 
months after the completion of the last treatment cycle must also be reported to the 

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investigator. The investigator must report all pregnancies within 24 hours of 
knowledge to Pfizer. The investigator should counsel the patient; discuss the risks of 
continuing the pregnancy and the possible effects on the fetus. The patient should be 
monitored until the conclusion of the pregnancy. 
 
Pregnancy occurring in the partner of a patient participating in the study should also 
be reported to the investigator, MDACC IND Office, and Pfizer. The partner should be 
counseled and followed as described above. 
 
8.6.2        Adverse Drug Reactions with Concomitant Medication 
The investigators must be aware that for all concomitant medications the regulations 
of post-marketing reporting for suspected adverse drug reactions apply, i.e. reporting 
to the marketing authorization holder or the local regulatory bodies. 

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9.0 
DATA ANALYSIS/ STATISTICAL METHODS 
 
Dr. Juhee Song (Department of Biostatistics at MD Anderson) will perform all 
statistical analyses. Detailed methodology for summary and statistical analyses of 
the data collected in this trial will be documented below. 
 
9.1 
Analysis Sets 
 
1) Safety Analysis Set 
The safety analysis set includes all enrolled patients who receive at least one dose of 
each study medication in the assigned treatment combination. Patients in Arms A and 
D must receive at least one dose of avelumab and utomilumab each. Patients in Arm 
B must receive at least one dose of avelumab and PF-04518600 (OX40) each. Patients 
in Arm C must receive at least one dose of avelumab, utomilumab, and PF-04518600 
(OX40) each. Subjects who have not received at least one dose of each study 
medication in the assigned treatment combination will be replaced. 
 
2) Full Analysis Set 
The full analysis set includes all enrolled patients. 
 
 
3) Per Protocol Analysis Set 
All enrolled patients who are eligible, receive study treatment and who either 
experience DLT during the first 56 days (following Cycle 1 Day 1) of study treatment 
or complete the 56-day treatment without DLT will be included. Patients who are lost 
to follow-up due to reasons unrelated to treatment related AEs are not evaluable for 
DLT. 
 
The per-protocol population will consist of all patients who are compliant with study 
assessments and who have no major protocol violations that would compromise the 
assessment of efficacy. Major violations will be determined independently of 
knowledge of response to therapy. This population will be used for primary inferences 
concerning efficacy, however, if there are major differences between the results in this 
population and those obtained in the treated population, this will be taken into 
consideration in the decision to continue to later phase studies, or in the design of 

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further studies. 
 
 
4) Response Analysis Set 
All enrolled patients who are eligible, receive study treatment, have baseline 
assessments and at least 1 on-study tumor assessment will be considered evaluable 
for response. Patients who are treated and removed from study prior to on-study 
tumor assessment because of disease progression will be considered evaluable for 
efficacy and counted as failures. 
 
 
9.2 
Statistical Methods and Properties 
 
As of Amendment Version 09, this study will be conducted in 4 arms. Arms A, B, and 
C will each enroll an MTD expansion cohort. Arm D will have a dose de-escalation and 
MTD. 
 
In Arm D, standard 3 +3 dose de-escalation and MTD will be applied for dose level 1 
and -1 with standard MTD and DLTs rule. We will use CTCAE criteria to capture 
adverse events related to the study drugs. If cohort 1 is not tolerable, there will be de- 
escalation to cohort -1. 
 
Each study treatment arm will have an MTD expansion cohort of up to 14 patients 
each. The expansion cohort for each arm will be stopped early if the aggregate DLT 
rate > 33% for that particular arm. The aggregate DLT rate for each arm will include 
patients that were treated at the same dose level in the dose escalation or de- 
escalation phase. If the trial does not stop early, we will estimate the disease control 
rate and the response rate separately for each cohort with appropriate 95% confidence 
intervals. We will also estimate the progression free survival (PFS) and overall survival 
(OS) distributions using the Kaplan-Meier product limit method and report summary 
measures such as the median value and probabilities at selected times (again with 
appropriate 95% confidence intervals). 

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9.3 
Sample Size Determination 
 
During the course of the study, two to three dose levels were to be examined in each 
combination arm during the dose escalation/de-escalation with a standard “3+3” 
design, and a total of 3-6 patients will be enrolled per dose level. After each escalation 
or MTD determination by Pfizer, there will be an MTD expansion cohort of up to 14 
patients each. 
Prior to Amendment Version 05, Arm C was designed to have an escalation and 4 
patients were enrolled; however, Pfizer provided recommendations for the MTD and 
requested that the MTD expansion commence. As of Amendment Version 06, the 
avelumab dosing for Arms A-C was revised; therefore, a new cohort of 14 patients 
each are expected to be enrolled for the MTD expansions of Arms A-C. As of 
Amendment Version 07, the original Arm G escalation and expansion (N= 32 total 
patients) cohorts have been removed from the study due to inability to accrue patients. 
Prior to Amendment Version 06, there was a total of 31 patients treated in the MTD 
expansions on the previous avelumab dosing schedule (Arm A: 8; Arm B: 12; Arm C: 
11). 
As of Amendment Version 08, the dosing schedules for Arms D-F were revised; 
therefore, Arms D, E, and F were re-initiated with the new schedule. Prior to 
Amendment Version 08, there were 11 patients enrolled on Arms D-F (Arm D: 4; Arm 
E: 3; Arm D: 4). 
 
As of Amendment Version 09, the dosing schedule for Arm D was revised; therefore, 
Arm D dose de-escalation was to be re-initiated with the new schedule (2 dose levels 
of up to 6 patients each, or up to 12 patients total). Arms E and F were discontinued. 
Prior to Amendment Version 09, there were 20 patients enrolled on Arms D-F (Arm D 
prior to Amendment Version 08: 4 and Arm D on Version 08: 3; Arm E prior to 
Amendment Version 08: 3 and Arm E on Version 08: 3; and Arm F prior to Amendment 
Version 08: 4 and Arm F on Version 08: 3). 
 
Thus, the planned maximum number of patients for the dose escalation/ de-escalation 
phase is 36 patients as indicated in Table 12. The planned maximum number of 
patients for the MTD expansion phase is 92 as indicated in Table 12. Therefore, the 
planned total maximum accrual in this study will be 128 patients (Escalation 36 + MTD 

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Expansions 92). Due to screen failures and replacement of inevaluable patients, up 
to 250 patients may be consented to this trial. 
 
For the objective of describing the toxicity profile, descriptive statistics will be provided 
on the grade and type of toxicity by dose level. Clinical efficacy will be measured by 
objective tumor response per RECIST criteria. The clinical response is defined as a 
CR or PR or at least 6 months SD. A 95% confidence interval of response rate will be 
estimated based on a binomial distribution. 
Table 12: Total Planned Accrual for Each Treatment Arm 
 
Treatment Arm 
Dose 
Escalation 
MTD 
Expansion 
Total 
Enrollment 
Arm A: Avelumab + 
Utomilumab (4-1BB) 
NA (Escalation 
at Pfizer) 
N=8 (Prior to 
Amendment 
Version 06) 
24 
N=16 (As of 
Amendment 
Version 06) 
Arm B: Avelumab + 
PF-04518600 (OX40) 
NA (Escalation 
at Pfizer) 
N=12 (Prior to 
Amendment 
Version 06) 
28 
N=14 (As of 
Amendment 
Version 06) 
*Treated 16 
after replacing 
2 patients with 
IND Office 
Approval 
Arm C: Avelumab + 
Utomilumab (4-1BB) + 
PF-04518600 (OX40) 
N=4 
NA (Escalation 
at Pfizer) 
N=11 (Prior to 
Amendment 
Version 06) 
32 
N=14 (As of 
Amendment 
Version 06) 
*Treated 17 
after replacing 
3 patients with 
IND Office 
Approval 
Arm D: Avelumab + 
Utomilumab (4-1BB) + 
XRT 
N=4 (Prior to 
Amendment 
Version 08) 
N=14 
33 
N=3 (On 
Amendment 
08) 

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Treatment Arm 
Dose 
Escalation 
MTD 
Expansion 
Total 
Enrollment 
N=12 (As of 
Amendment 
09) 
Arm E: Avelumab + 
PF-04518600 (OX40) 
+ XRT 
N=3 (Prior to 
Amendment 
Version 08) 
Closed per 
Amendment 
Version 09 
6 
N=3 (On 
Amendment 
08) 
Arm F: Avelumab + 
Utomilumab (4-1BB) + 
PF-04518600 (OX40) 
+ XRT 
N=4 (Prior to 
Amendment 
Version 08) 
Closed per 
Amendment 
Version 09 
7 
N=3 (On 
Amendment 
08) 
Total 
36 
92 
128 
 
MDACC Investigational New Drug (IND) Office, Medical Affairs and Safety Group will 
review safety and efficacy data with Principal Investigator (and statistician if needed), 
at a predetermined interval as indicated next: 
 
PHASE I 
The first analysis will occur after the first 3 evaluable subjects per arm (Arm D), are 
treated for 56 days from Cycle 1 Day 1 and prior to advancing/changing dose levels; 
and every 3 evaluable subjects thereafter. 
 
PHASE II 
Efficacy/toxicity analysis will occur every 7 evaluable subjects per arm when treated 
for 6 months after the first study therapy dose. Assess toxicity at the end of the first 
56 days following Cycle 1 Day 1, and response after 6 months of treatment. On 
every report submission, the information from previous reported patients will need to 
be updated for response. 

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A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder 
under “sponsor correspondence”. 
 
Evaluation of toxicity based on the duration of radiation therapy: 
if after 7 patients, 3 or more have a duration of radiation therapy greater than 8 weeks 
then the treatment should be considered excessively toxic in this cohort. 
This will allow for identification of toxicity causing a delay in radiation which will 
translate to worse outcomes. Let p = true probability of duration of radiation therapy 
being > 8 weeks. Let q = probability of seeing 3 or more patients with excessive 
radiation duration out of 7 patients. Table 13 is a table of p and q. 
 
Table 13: Probability 
 
p 
q 
0.2 
3% 
0.3 
13% 
0.4 
29% 
0.5 
50% 
0.6 
71% 
0.7 
87% 
0.8 
97% 
 
 
 
 
9.4 
General Statistical Considerations 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy and 
safety parameters. For categorical variables, summary tabulations of the number and 
percentage of subjects within each category (with a category for missing data) of the 
parameter will be presented, as well as two-sided 95% confidence intervals, unless 
otherwise stated. For continuous variables, the number of subjects, mean, median, 
standard deviation (SD), minimum, and maximum values will be presented. Time-to- 
event data will be summarized using Kaplan-Meier methodology using 25th, 50th 

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(median), and 75th percentiles with associated 2-sided 95% confidence intervals, as 
well as percentage of censored observations. 
 
No imputation of missing efficacy data is planned. For time to event analyses, patients 
who have no efficacy evaluations for disease recurrence will be considered censored 
at time 0. 
 
For adverse events (AEs), missing dates will not be imputed, however, if partial dates 
are available, they will be used to assess if the AE occurred during the treatment 
period. Missing severities of AEs will not be imputed and will be considered missing 
in any tabulations of AE severity. If an AE is missing a response to the question 
regarding relationship to treatment, the event will be considered to be related. 
 
9.4.1 
Demographics and Baseline Characteristics 
The demographic characteristics to be summarized will include gender, race, ethnicity 
(Hispanic origin), and age at time of consent. For gender, race, and Hispanic origin, 
the summary statistics will be the number and percentage of patients within each 
group or the total sample. The categories for race will be those recorded in the 
database. For age at time of consent, the mean, median, minimum, maximum, and 
standard deviation will be provided for each group and the total sample. 
 
Baseline characteristics include: Performance Status; duration from initial diagnosis; 
response to previous therapy (Y/N). 
 
9.5 
Efficacy Analysis 
 
The treated population will consist of all patients who receive at least one dose of each 
study medication and have post-baseline efficacy follow-up information. This 
population will be used for primary analyses of efficacy. 

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9.5.1 
Efficacy Evaluation 
Clinical efficacy will be measured by objective tumor response per RECIST 1.1 criteria. 
The clinical response is defined as a CR or PR or SD. A 95% confidence interval of 
response rate will be estimated based on a binomial distribution. 
 
 
9.6 
Safety Analysis 
 
The safety population will consist of all patients who have received any amount of 
study medication. 
 
9.6.1 
Safety Evaluation 
Safety analyses will be conducted using the Safety Population. For the objective of 
describing the toxicity profile, descriptive statistics will be provided on the grade and 
type of toxicity by dose level. 
 
9.6.2 
Adverse Events 
Adverse Events (AEs) will be coded using the NCI-CTCAE (4.03) dictionary and 
displayed for all study patients combined. Analyses of AEs will be performed for those 
events that are considered treatment emergent, where treatment-emergent is defined 
as any AE with onset or worsening of a pre-existing condition on or after the first 
administration of study medication through 30 days following last dose or any event 
considered drug-related by the investigator through the end of the study. AEs with 
partial dates will be assessed using the available date information to determine if 
treatment-emergent; AEs with completely missing dates will be assumed to be 
treatment-emergent. 
 
AEs will be summarized by patient incidence rates, therefore, in any tabulation, a 
patient contributes only once to the count for a given AE preferred term. The number 
and percentage of patients with any treatment-emergent AE will be summarized for all 
study patients combined. The number and percentage of patients with treatment- 
emergent AEs assessed by the Investigator as at least possibly related to treatment 
will also be tabulated. The number and percentage of patients with any grade ≥ 3 
treatment-emergent AE will be tabulated in the same manner. In the event a patient 

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experiences repeated episodes of the same AE, then the event with the highest 
severity and/or strongest causal relationship to study treatment will be used for 
purposes of tabulations. 
 
Serious AEs will also be tabulated. 
 
 
No formal hypothesis-testing analysis of AE incidence rates will be performed. All 
AEs (treatment emergent and post-treatment) will be listed in patient data listings. By- 
patient listings will be provided for the following: patient deaths; serious AEs; and AEs 
leading to withdrawal. 
 
9.6.3 
Laboratory Data 
The actual value and change from baseline to each on study evaluation will be 
summarized for each clinical laboratory parameter, including hematology and clinical 
chemistry, for all study patients combined. In the event of repeat values, the last non- 
missing value per study day/time will be used. 
 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g. 
those measures that have a corresponding CTCAE grade classification). Labs with 
CTCAE grades greater than or equal to 3 will be presented in a data listing. Shift tables 
that present changes from baseline to worst on-study values relative to CTCAE 
classification ranges will be produced. 
 
9.6.4 
Vital Signs and Physical Examinations 
The actual value and change from baseline to each on study evaluation will be 
summarized for vital signs for all study patients combined. By-patient listings of vital 
sign measurements will be presented in data listings. 
 
Physical examination results at screening will be summarized; all other abnormal 
physical examination data were to be recorded on the AE eCRF. All examination 
findings will be presented in a data listing. 

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9.6.5 
Concomitant Medications 
The use of concomitant medications will be included in by-patient data listings. 
 
 
9.7 
Biomarker Analysis 
 
For the primary objective, we will analyze changes in CD8 expression before and after 
treatment using a paired t-test if the data are Normally distributed, and a Wilcoxon 
signed rank test if not. With 14 patients in each cohort, we will have 90% power 
(assuming 2-sided 5% alpha) to detect a 0.94*s mean difference where “s” is the 
standard deviation of the differences. With all 7 cohorts combined, we will have 98 
patients, which yields 90% power to detect a 0.33*s mean difference. We will correlate 
CD8 expression with clinical benefit (CR/PR/SD>6m) using ROC curve analysis. With 
98 patients, we would have 90% power to detect and area under the ROC curve of 
0.69 (vs. 0.5 which is the null value) assuming 5% alpha and half the patients showing 
clinical benefit. 
 
For the exploratory objective, we will conduct similar analyses on additional 
unspecified biomarkers. 
 
9.8 
Final Analysis 
 
The final analysis for each study treatment arm will take place after the MTD expansion 
had been completed. Additional data summarization may take place after all available 
survival data are collected, or after investigator decision, as appropriate. 

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10.0 QUALITY CONTROL AND QUALITY ASSURANCE 
 
This study will be monitored by the MD Anderson IND Office and a protocol-specific 
monitoring plan will be followed. 

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11.0 DATA HANDLING AND RECORD KEEPING 
 
11.1 Case Report Form/ Electronic Data Record 
 
All patients who meet eligibility criteria and are enrolled in this trial will be registered in 
Clinical Oncology Research Database (CORe) at the University of Texas MD 
Anderson Cancer Center at Houston. Data will be collected and stored in the 
Investigational Cancer Therapeutics database, Molecular and Clinical Data Integrated 
Platform (MOCLIP). 
 
 
11.2 Record Retention 
 
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
These documents should be classified into two separate categories: investigator’s 
study file and subject/ patient data. 
 
The investigator’s study file will contain all essential documents such as the protocol/ 
amendments, case report and query forms, patient information and informed consent 
form, ethics committee and regulatory authority approval, notification of the federal 
regulatory authority and competent regional authorities (if applicable), drug records, 
staff 
curriculum 
vitae 
and 
authorisation 
forms, 
and 
other 
appropriate 
documents/correspondence, etc. 
 
Patient data includes patient hospital/clinic records (e.g. medical reports, surgery 
reports appointment book, medical records, pathology and laboratory reports, ECG, 
etc.), signed informed consent forms and patient screening and eligibility screening 
forms. 
 
The investigator must keep these two categories of documents on file for at least 15 
years (or longer, as legally required) after completion or discontinuation of the study. 
The documents must be archived in a secure place and treated as confidential 
material. 

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11.3 Audits and Inspections 
 
This study may be audited by the IND sponsor, any person authorized by the IND 
sponsor, or the competent health authority in order to determine the authenticity of the 
recorded data and compliance with the study protocol. 
 
The investigator must be aware that source documents for this trial should be made 
available to appropriately qualified personnel working on behalf of the authority 
inspectors after appropriate notification for the purposes of source data verification 
and proper review of the study progress. The verification of the case report form data 
must be done via direct inspection of the source documents. The investigator agrees 
to comply with the IND sponsor and regulatory authority requirements regarding the 
auditing of the study. 
 
All materials used in clinical studies are subjected to quality control. 

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12.0 DEFINITION OF END OF TRIAL 
 
End of Trial is defined as the time at which it is deemed that sufficient patients have 
been recruited and completed the study as stated in the regulatory application (ie, 
Clinical Study Application (CTA)). Poor recruitment (recruiting less than the 
anticipated number in the CTA) is not a reason for premature termination but is 
considered a normal conclusion. 
 
End of Trial is defined as Last Patient Last Visit. 

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13.0 SPONSOR DISCONTINUATION CRITERIA 
 
Premature termination of this study may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion 
of the MDACC IND Office. In addition, Pfizer retains the right to discontinue 
development of avelumab, utomilumab, PF-04518600 at any time. 
 
If a study is prematurely terminated or discontinued, Pfizer or the MDACC IND Office 
will promptly notify the investigator. As directed by Pfizer, all study materials must be 
collected and all CRFs completed to the greatest extent possible. 

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14.0 APPENDICES 
 
Appendix 1: 
Adverse Event Categories for Determining Relationship to Test 
Drug 
Appendix 2: 
ECOG Performance Status 

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Appendix 1 – Adverse Event Categories for Determining Relationship to Test 
Drug 
 
 
(a) Related (must have one of them) 
This category applies to those adverse events that are considered to be related to the 
test drug. An adverse event may be considered related if: 
1. It follows a reasonable temporal sequence from administration of the drug 
2. It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors or other modes of therapy administered 
to the subject 
3. It disappears or decreases on cessation or reduction in dose. (There are important 
exceptions when an adverse event does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists: e.g. (1) bone marrow depression, (2) 
tardive dyskinesias.) 
4. It follows a known pattern of response to the suspected drug 
5. It reappears upon rechallenge 
 
 
(b) Unrelated 
This category is applicable to those adverse events which are judged to be clearly 
and incontrovertibly due only to extraneous causes (disease, environment, etc.) and 
do not meet the criteria for drug relationship listed under related. 

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Appendix 2 – ECOG Performance Status 
 
GRAD 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work 
2 
Ambulatory and capable of all self-care, but unable to carry out work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to 
bed or chair. 
5 
Dead 

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15.0 REFERENCES 
 
1. 
Hadrup S, Donia M, Thor Straten P. Effector CD4 and CD8 T cells and their 
role in the tumor microenvironment. Cancer microenvironment : official journal of the 
International Cancer Microenvironment Society. 2013 Aug;6(2):123-33. 
 
2. 
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani 
G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. 
The New England journal of medicine. 2003 Jan 16;348(3):203-13. 
 
3. 
Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle 
A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016 Jan;52:50- 
66. 
 
4. 
Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2011 Dec 20;29(36):4828-36. 
 
5. 
Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, et al. 
Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical 
benefit in advanced melanoma patients treated with ipilimumab. Proceedings of the 
National Academy of Sciences of the United States of America. 2011 Oct 
4;108(40):16723-8. 
 
6. 
Di Giacomo AM, Calabro L, Danielli R, Fonsatti E, Bertocci E, Pesce I, et al. 
Long-term survival and immunological parameters in metastatic melanoma patients 
who responded to ipilimumab 10 mg/kg within an expanded access programme. 
Cancer Immunol Immun. 2013 Jun;62(6):1021-8. 
 
7. 
Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic 
influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta- 
analysis. British journal of cancer. 2011 Jun 28;105(1):93-103. 
 
8. 
Bartkowiak T, Curran MA. 4-1BB Agonists: Multi-Potent Potentiators of Tumor 
Immunity. Front Oncol. 2015;5:117. 
 
9. 
Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune 
Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting 
the Host as an "Innocent Bystander". Toxins. 2014 Mar;6(3):914-33. 
 
10. 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. 
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The 
New England journal of medicine. 2012 Jun 28;366(26):2455-65. 

Page 139/143 
Page 139/143 
 
 
11. 
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. 
Colocalization of inflammatory response with B7-h1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune escape. 
Sci Transl Med. 2012 Mar 28;4(127):127ra37. 
 
12. 
Pfizer. Avelumab (MSB0010718C). Investigator's Brochure. 2016;5. 
 
13. 
Beatty S, O’Neill L. FDA Accepts the Biologics License Application for 
Avelumab for the Treatment of Metastatic Urothelial Carcinoma for Priority Review. 
2017. 
 
14. 
Beatty S, O’Neill L. FDA Grants Approval for BAVENCIO®(avelumab), the 
First Immunotherapy Approved for Metastatic Merkel Cell Carcinoma. 2017. 
 
15. 
Lynch DH. The promise of 4-1BB (CD137)-mediated immunomodulation and 
the immunotherapy of cancer. Immunological reviews. 2008 Apr;222:277-86. 
 
16. 
Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL, Al-Shamkhani A, et al. 
Systemic 4-1BB activation induces a novel T cell phenotype driven by high 
expression of Eomesodermin. The Journal of experimental medicine. 2013 Apr 
8;210(4):743-55. 
 
17. 
Pfizer. PF-05082566. Investigator's Brochure, 2015. 
 
18. 
Croft M. Control of Immunity by the TNFR-Related Molecule OX40 (CD134). 
Annual Review of Immunology, Vol 28. 2010;28:57-78. 
 
19. 
Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, et al. OX40 
costimulation turns off Foxp3+ Tregs. Blood. 2007 Oct 1;110(7):2501-10. 
 
20. 
Weinberg AD, Morris NP, Kovacsovics-Bankowski M, Urba WJ, Curti BD. 
Science gone translational: the OX40 agonist story. Immunological reviews. 2011 
Nov;244(1):218-31. 
 
21. 
Linch SN, McNamara MJ, Redmond WL. OX40 Agonists and Combination 
Immunotherapy: Putting the Pedal to the Metal. Front Oncol. 2015;5:34. 
 
22. 
Weinberg AD, Rivera MM, Prell R, Morris A, Ramstad T, Vetto JT, et al. 
Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 
2000 Feb 15;164(4):2160-9. 
 
23. 
Morris A, Vetto JT, Ramstad T, Funatake CJ, Choolun E, Entwisle C, et al. 
Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. 
Breast cancer research and treatment. 2001 May;67(1):71-80. 

Page 140/143 
Page 140/143 
 
 
24. 
Goulding J, Tahiliani V, Salek-Ardakani S. OX40:OX40L axis: emerging 
targets for improving poxvirus-based CD8(+) T-cell vaccines against respiratory 
viruses. Immunological reviews. 2011 Nov;244(1):149-68. 
 
25. 
Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd 
K, et al. OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients. 
Cancer research. 2013 Dec 15;73(24):7189-98. 
 
26. 
Pfizer. PF-04518600. Investigator's Brochure. 2016. 
 
27. 
Diab A, El-Khoueiry A, Eskens F, Ros W, Thompson J, Konto C, et al. A first- 
in-human (FIH) study of PF-04518600 (PF-8600) OX40 agonist in adult patients (pts) 
with select advanced malignancies. Annals of Oncology. 2016;27(suppl 6):1053PD. 
 
28. 
Wang C, Lin GH, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 
4-1BBL: complexities and challenges. Immunological reviews. 2009 May;229(1):192- 
215. 
 
29. 
Xiao H, Huang B, Yuan Y, Li D, Han LF, Liu Y, et al. Soluble PD-1 facilitates 
4-1BBL-triggered antitumor immunity against murine H22 hepatocarcinoma in vivo. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2007 Mar 15;13(6):1823-30. 
 
30. 
Ai M, Curran MA. Immune checkpoint combinations from mouse to man. 
Cancer Immunol Immunother. 2015 Jul;64(7):885-92. 
 
31. 
Zhang Y, Kang S, Shen J, He J, Jiang L, Wang W, et al. Prognostic 
significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression 
in epithelial-originated cancer: a meta-analysis. Medicine (Baltimore). 2015 
Feb;94(6):e515. 
 
32. 
Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade 
augments with other modalities of immunotherapy T-cell function to prevent immune 
decline in ovarian cancer. Cancer research. 2013 Dec 1;73(23):6900-12. 
 
33. 
Wei HF, Zhao LK, Li W, Fan KX, Qian WZ, Hou S, et al. Combinatorial PD-1 
Blockade and CD137 Activation Has Therapeutic Efficacy in Murine Cancer Models 
and Synergizes with Cisplatin. PloS one. 2013 Dec 19;8(12). 
 
34. 
Chen S, Lee LF, Fisher TS, Jessen B, Elliott M, Evering W, et al. Combination 
of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T 
cells in a poorly immunogenic tumor model. Cancer immunology research. 2015 
Feb;3(2):149-60. 
 
35. 
Palazon A, Martinez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, 
Sanmamed MF, et al. The HIF-1alpha hypoxia response in tumor-infiltrating T 

Page 141/143 
Page 141/143 
 
 
lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov. 
2012 Jul;2(7):608-23. 
 
36. 
Dai M, Wei H, Yip YY, Feng Q, He K, Popov V, et al. Long-lasting complete 
regression of established mouse tumors by counteracting Th2 inflammation. J 
Immunother. 2013 May;36(4):248-57. 
 
37. 
Guo ZQ, Wang X, Cheng DL, Xia ZJ, Luan M, Zhang SL. PD-1 Blockade and 
OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of 
Ovarian Cancer. PloS one. 2014 Feb 27;9(2). 
 
38. 
Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I. Clinical experiences with 
anti-CD137 and anti-PD1 therapeutic antibodies. Seminars in oncology. 2010 
Oct;37(5):508-16. 
 
39. 
Lee SJ, Myers L, Muralimohan G, Dai J, Qiao Y, Li Z, et al. 4-1BB and OX40 
dual costimulation synergistically stimulate primary specific CD8 T cells for robust 
effector function. J Immunol. 2004 Sep 1;173(5):3002-12. 
 
40. 
Morales-Kastresana A, Sanmamed MF, Rodriguez I, Palazon A, Martinez- 
Forero I, Labiano S, et al. Combined Immunostimulatory Monoclonal Antibodies 
Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse 
Model. Clinical Cancer Research. 2013 Nov 15;19(22):6151-62. 
 
41. 
Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, et al. Therapeutic 
effects of ablative radiation on local tumor require CD8+ T cells: changing strategies 
for cancer treatment. Blood. 2009 Jul 16;114(3):589-95. 
 
42. 
Seyedin SN, Schoenhals JE, Lee DA, Cortez MA, Wang X, Niknam S, et al. 
Strategies for combining immunotherapy with radiation for anticancer therapy. 
Immunotherapy. 2015;7(9):967-80. 
 
43. 
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati 
E, et al. Radiation and dual checkpoint blockade activate non-redundant immune 
mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. 
 
44. 
Koski GK, Czerniecki BJ. Combining innate immunity with radiation therapy 
for cancer treatment. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2005 Jan 1;11(1):7-11. 
 
45. 
Shi W, Siemann DW. Augmented antitumor effects of radiation therapy by 4- 
1BB antibody (BMS-469492) treatment. Anticancer research. 2006 Sep- 
Oct;26(5A):3445-53. 

Page 142/143 
Page 142/143 
 
 
46. 
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. 
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in 
mice. The Journal of clinical investigation. 2014 Feb;124(2):687-95. 
 
47. 
Deng L, Liang H, Burnette B, Weicheslbaum RR, Fu YX. Radiation and anti- 
PD-L1 antibody combinatorial therapy induces T cell-mediated depletion of myeloid- 
derived suppressor cells and tumor regression. Oncoimmunology. 2014;3:e28499. 
 
48. 
Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, et 
al. Radiotherapy increases the permissiveness of established mammary tumors to 
rejection by immunomodulatory antibodies. Cancer research. 2012 Jul 
1;72(13):3163-74. 
 
49. 
Belcaid Z, Phallen JA, Zeng J, See AP, Mathios D, Gottschalk C, et al. Focal 
radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long- 
term survival and a protective antigen-specific memory response in a murine glioma 
model. PloS one. 2014;9(7):e101764. 
 
50. 
Gough MJ, Crittenden MR, Sarff M, Pang P, Seung SK, Vetto JT, et al. 
Adjuvant Therapy With Agonistic Antibodies to CD134 (OX40) Increases Local 
Control After Surgical or Radiation Therapy of Cancer in Mice. Journal of 
Immunotherapy. 2010 Oct;33(8):798-809. 
 
51. 
Yokouchi H, Yamazaki K, Chamoto K, Kikuchi E, Shinagawa N, Oizumi S, et 
al. Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results 
in therapeutic antitumor immunity to murine lung cancer. Cancer science. 2008 
Feb;99(2):361-7. 
 
52. 
Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, et al. The 15- 
Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear 
Industry: estimates of radiation-related cancer risks. Radiation research. 
2007;167(4):396-416. 
 
53. 
Bohnsack O, Hoos A, Ludajic K. Adaptation and modification of the immune 
related response criteria (IRRC): IrRECIST. American Society of Clinical Oncology, 
2014. 
 
54. 
Chang JY, Balter PA, Dong L, Yang Q, Liao Z, Jeter M, et al. Stereotactic 
body radiation therapy in centrally and superiorly located stage I or isolated recurrent 
non–small-cell lung cancer. International Journal of Radiation Oncology* Biology* 
Physics. 2008;72(4):967-71. 
 
55. 
Kelly P, Balter PA, Rebueno N, Sharp HJ, Liao Z, Komaki R, et al. 
Stereotactic body radiation therapy for patients with lung cancer previously treated 
with thoracic radiation. International Journal of Radiation Oncology* Biology* 
Physics. 2010;78(5):1387-93. 

Page 143/143 
Page 143/143 
 
 
56. 
Welsh J, Thomas J, Shah D, Allen PK, Wei X, Mitchell K, et al. Obesity 
increases the risk of chest wall pain from thoracic stereotactic body radiation 
therapy. International Journal of Radiation Oncology* Biology* Physics. 
2011;81(1):91-6. 
 
57. 
Chang JY, Liu H, Balter P, Komaki R, Liao Z, Welsh J, et al. Clinical outcome 
and predictors of survival and pneumonitis after stereotactic ablative radiotherapy for 
stage I non-small cell lung cancer. Radiation Oncology. 2012;7(1):152. 
 
58. 
Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg 
SJ, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for 
liver metastases. Journal of Clinical Oncology. 2009;27(10):1572-8.