A Pilot Study of Immune Checkpoint Inhibition (Durvalumab With or Without Tremelimumab) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer
Phase: PHASE1
Conditions: Pancreatic Neoplasms, Pancreatic Cancer, Cancer of Pancreas, Cancer of the Pancreas, Pancreas Cancer
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
Version Date: 08/24/2018
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Abbreviated Title: antiPDL1, antiCTLA4 & Radiation
CC Protocol: 15-C-0027 I
Version Date: 08/24/2018
NCT number: NCT02311361
Title: A Pilot Study of Immune Checkpoint Inhibition (Durvalumab with or without
Tremelimumab) in Combination with Radiation Therapy in Patients with Unresectable 
Pancreatic Cancer.
NCI Principal Investigator:
Tim Greten, MD
Thoracic & GI Malignancies Branch
Center for Cancer Research
National Cancer Institute
Building 10, Room 3B43
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-760-6114
E-mail:tim.greten@nih.gov
Investigational Agents:    
Drug Name:
Tremelimumab 
Durvalumab (MEDI4736)
IND Number:
123518
123518
Sponsor:
Center for Cancer Research, National 
Cancer Institute
Center for Cancer Research, National 
Cancer Institute
Manufacturer:
MedImmune, Inc.
MedImmune, Inc.

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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PRÉCIS
Background: 
x
Tremelimumab is a monoclonal antibody against CTLA4. Anti-CTLA4 therapy has been 
shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of 
cytotoxic T cells. 
x
Durvalumab is a human monoclonal antibody directed against PD-L1. Blockage of ligation 
between PD-L1 and PD1 induces local immune activation and prevent anergy and exhaustion 
of effectors T-cells. 
x
Several studies have documented an increase in peripheral antitumor immunity following 
radiation. This effect is evidently too weak to be clinically relevant, but has the potential to 
be boosted by immune modulation.
x
The underlying hypothesis of this study is that the effect of Immune Checkpoint inhibitor 
(Durvalumab with or without Tremelimumab) treatment can be enhanced by radiation in 
patients with advanced pancreatic carcinoma.
Objective:
x
To determine the safety, tolerability and feasibility of immune checkpoint inhibition 
[comprising either Durvalumab alone, or combined Durvalumab and Tremelimumab] in 
combination with stereotactic body radiation therapy (SBRT) in patients with unresectable 
pancreatic cancer.
Eligibility:
x
Histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-
recurrent) with at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible 
for biopsy. There is no limit to the number of prior chemotherapy regimens received.
x
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x
Life expectancy of greater than 3 months.
x
Acceptable organ and bone marrow function.
x
Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery 
within the last 2 weeks prior to entering the study. For recent experimental therapies, a 28 
day period of time must have elapsed before commencing protocol treatment.
x
No active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, 
irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves’ disease; 
rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior to the start of 
treatment. 
x
No active or history of inflammatory bowel disease (colitis, Crohn’s), irritable bowel disease, 
celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. 
No active or history of systemic lupus erythematosus, Wegener’s granulomatosis.

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Design:
x
Subjects will be assigned to 4 arms:

Anti-PDL1 (Durvalumab) in combination with radiation (8 Gy in 1 fraction)

Anti-PDL1 (Durvalumab) in combination with radiation (5 Gy in 5 fractions)

Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with 
radiation (8 Gy in 1 fraction)

Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with 
radiation (5 Gy in 5 fractions).

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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TABLE OF CONTENTS
PRÉCIS........................................................................................................................................... 2 
TABLE OF CONTENTS................................................................................................................ 4 
1 
INTRODUCTION ........................................................................................................ 9 
1.1 
Study Objectives ........................................................................................................... 9 
1.1.1 
Primary...................................................................................................................... 9 
1.1.2 
Secondary.................................................................................................................. 9 
1.1.3 
Exploratory ............................................................................................................... 9 
1.2 
Background and Rationale............................................................................................ 9 
1.2.1 
Pancreatic cancer and the current therapeutic paradigm........................................... 9 
1.2.2 
Radiation treatment in pancreatic cancer:............................................................... 10 
1.2.3 
Recent advances in immune-based approaches in solid tumor malignancies......... 12 
1.2.4 
Immune response following radiation, mechanism and rationale for combination 
with immune checkpoint inhibition:..................................................................................... 13 
1.2.5 
Tremelimumab........................................................................................................ 14 
1.2.6 
Anti-CTLA4 therapy in pancreatic cancer.............................................................. 16 
1.2.7 
Durvalumab............................................................................................................. 16 
1.2.8 
Anti-CTLA4 in combination with anti-PD1/PD-L1............................................... 18 
1.2.9 
Justification for dose and schedule ......................................................................... 20 
1.2.10 Rationale for study population and schedule:......................................................... 23 
1.2.11 Justification for Tumor Biopsies............................................................................. 24 
1.2.12 Justification for accrual increase in Arm C2 with Amendment I ........................... 24 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT............................................. 25 
2.1 
Eligibility Criteria....................................................................................................... 25 
2.1.1 
Inclusion Criteria .................................................................................................... 25 
2.1.2 
Exclusion Criteria ................................................................................................... 26 
2.1.3 
Recruitment Strategies............................................................................................ 28 
2.2 
Screening evaluation................................................................................................... 28 
2.3 
Registration Procedures .............................................................................................. 28 
2.3.1 
Treatment Assignment Procedures: ........................................................................ 29 
2.4 
Baseline Studies.......................................................................................................... 29 
3 
STUDY IMPLEMENTATION .................................................................................. 30 

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3.1 
Study Design............................................................................................................... 30 
3.1.1 
Arms A1 and A2..................................................................................................... 31 
3.1.2 
Arms C1 and C2...................................................................................................... 33 
3.1.3 
Protocol Stopping Rules ......................................................................................... 34 
3.1.4 
Re-treatment............................................................................................................ 34 
3.2 
Dose Limiting Toxicities ............................................................................................ 34 
3.2.1 
Definition of Dose-limiting Toxicities (DLTs): ..................................................... 34 
3.2.2 
Definition of Dose-limiting Toxicities (DLTs) excludes the following conditions:
35 
3.2.3 
Investigational Drug Administration ...................................................................... 35 
3.2.4 
Durvalumab Drug Administration.......................................................................... 36 
3.2.5 
Tremelimumab Dose Administration: .................................................................... 36 
3.2.6 
Monitoring of Dose Administration........................................................................ 36 
3.3 
Dosing Delays............................................................................................................. 37 
3.3.1 
Immune-mediated AEs (imAEs)............................................................................. 37 
3.3.2 
Adverse Events of Special Interest ......................................................................... 37 
3.4 
Specific Procedures for Stereotactic Body Radiation Therapy (SBRT)..................... 38 
3.4.1 
Radiotherapy administration................................................................................... 38 
3.5 
Study Calendar............................................................................................................ 40 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria......................... 44 
3.6.1 
Criteria for removal from protocol therapy ............................................................ 44 
3.6.2 
Criteria for Removal from Study............................................................................ 44 
3.6.3 
Off Protocol Therapy and Off Study Procedure ..................................................... 45 
4 
CONCOMITANT MEDICATIONS/MEASURES.................................................... 45 
4.1 
Prohibited Concomitant Medications ......................................................................... 45 
5 
BIOSPECIMEN COLLECTION................................................................................ 46 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 46 
5.2 
NCI correlative studies ............................................................................................... 48 
5.2.1 
Immune monitoring (all arms)................................................................................ 48 
5.2.2 
Liver autoantibody panel for autoimmune hepatitis (AIH) .................................... 48 
5.2.3 
Mandatory tumor biopsy......................................................................................... 48 
5.2.4 
Details of Planned Tumor Analysis........................................................................ 49 

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5.3 
MedImmune Planned Studies ..................................................................................... 49 
5.3.1 
Pharmacokinetics .................................................................................................... 50 
5.3.2 
Immunogenicity...................................................................................................... 50 
5.3.3 
T CELL Activation/ICOS expression..................................................................... 50 
5.3.4 
Plasma-based assays for circulating receptors/ligands e.g. PDL1.......................... 50 
5.4 
Sample Storage, Tracking and Disposition................................................................. 51 
5.4.1 
Samples Managed by Dr. Figg’s Blood Processing Core (BPC)............................ 51 
5.4.2 
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ....... 52 
5.4.3 
Protocol Completion/Sample Destruction .............................................................. 52 
6 
DATA COLLECTION AND EVALUATION........................................................... 52 
6.1 
Data Collection ........................................................................................................... 52 
6.2 
DATA SHARING PLANS......................................................................................... 53 
6.2.1 
Human Data Sharing Plan....................................................................................... 53 
6.3 
Response Criteria........................................................................................................ 53 
6.3.1 
Definitions............................................................................................................... 54 
6.3.2 
Disease Parameters ................................................................................................. 54 
6.3.3 
Methods for Evaluation of Measurable Disease..................................................... 56 
6.3.4 
Response Criteria.................................................................................................... 57 
6.3.5 
Duration of Response.............................................................................................. 60 
6.4 
Modified immune-related response criteria (irRC)..................................................... 60 
6.4.1 
The modified irRC based on RECIST 1.1:............................................................. 60 
6.5 
Toxicity Criteria.......................................................................................................... 61 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
61 
7.1 
Definitions................................................................................................................... 61 
7.1.1 
Adverse Event......................................................................................................... 61 
7.1.2 
Suspected adverse reaction ..................................................................................... 61 
7.1.3 
Unexpected adverse reaction .................................................................................. 61 
7.1.4 
Serious..................................................................................................................... 62 
7.1.5 
Serious Adverse Event............................................................................................ 62 
7.1.6 
Disability................................................................................................................. 62 
7.1.7 
Life-threatening adverse drug experience............................................................... 62 

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7.1.8 
Protocol Deviation (NIH Definition)...................................................................... 62 
7.1.9 
Non-compliance (NIH Definition).......................................................................... 62 
7.1.10 Unanticipated Problem............................................................................................ 62 
7.2 
NCI-IRB and Clinical Director Reporting.................................................................. 63 
7.2.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
63 
7.2.2 
NCI-IRB Requirements for PI Reporting at Continuing Review........................... 63 
7.2.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 63 
7.3 
IND Sponsor Reporting Criteria................................................................................. 64 
7.3.1 
Reporting Pregnancy............................................................................................... 64 
7.4 
Safety Reporting CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
65 
7.4.1 
Reporting of serious adverse events ....................................................................... 65 
7.4.2 
Overdose ................................................................................................................. 66 
7.4.3 
Hepatic function abnormality ................................................................................. 66 
7.4.4 
Reporting Removal from Protocol Therapy and Off Study.................................... 66 
7.5 
Data and Safety Monitoring Plan................................................................................ 66 
7.5.1 
Principal Investigator/Research Team .................................................................... 66 
7.5.2 
Sponsor Monitoring Plan........................................................................................ 67 
8 
STATISTICAL CONSIDERATIONS........................................................................ 67 
8.1 
Cross-arm comparison ................................................................................................ 68 
8.2 
Duration of radiation................................................................................................... 69 
8.3 
Analysis of Immunogenicity....................................................................................... 69 
8.4 
Analysis of Pharmacokinetics..................................................................................... 69 
9 
COLLABORATIVE AGREEMENTS....................................................................... 70 
9.1 
Agreement Type.......................................................................................................... 70 
10 
HUMAN SUBJECTS PROTECTIONS ..................................................................... 70 
10.1 
Rationale For Subject Selection.................................................................................. 70 
10.2 
Participation of Children............................................................................................. 70 
10.3 
Participation of Subjects Unable to Give Consent...................................................... 70 
10.4 
Evaluation of Benefits and Risks/Discomforts for all participants............................. 70 
10.4.1 Risks of exposure to ionizing radiation .................................................................. 70 
10.4.2 Risk of baseline biopsy........................................................................................... 71 

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10.4.3 Other risks/benefits................................................................................................. 71 
10.5 
Risks/Benefits Analysis .............................................................................................. 71 
10.6 
Consent Process and Documentation.......................................................................... 71 
10.6.1 Reconsent via Telephone........................................................................................ 71 
10.6.2 Informed Consent of non-English Speaking Subjects ............................................ 72 
11 
PHARMACEUTICAL INFORMATION................................................................... 72 
11.1 
Tremelimumab............................................................................................................ 72 
11.1.1 Source ..................................................................................................................... 72 
11.1.2 Formulation and Preparation................................................................................... 72 
11.1.3 Stability and Storage............................................................................................... 73 
11.1.4 Administration procedures...................................................................................... 73 
11.1.5 Dose Calculation..................................................................................................... 73 
11.2 
Durvalumab................................................................................................................. 74 
11.2.1 Source ..................................................................................................................... 74 
11.2.2 Formulation and Preparation................................................................................... 74 
11.2.3 Stability................................................................................................................... 75 
11.2.4 Storage .................................................................................................................... 75 
11.2.5 Administration procedures...................................................................................... 75 
11.2.6 Durvalumab Dose Preparation Steps ...................................................................... 76 
11.3 
Investigational Product Preparation steps................................................................... 77 
11.4 
Investigational Product Inspection.............................................................................. 77 
11.5 
Investigational Product Accountability....................................................................... 77 
11.5.1 Reporting Product Complaints................................................................................ 77 
12 
REFERENCES ........................................................................................................... 79 
13 
APPENDICES ............................................................................................................ 83 
13.1 
Appendix A:  Performance Status Criteria ................................................................. 83 
13.2 
Appendix B: MedImmune Sample Preparation Procedures Serum- SST Tube ......... 84 
13.3 
Appendix C: Modified immune-related response criteria (irRC)............................... 85 
13.4 
Appendix D: Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions 
(MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 1 November 2017 Version ........................................ 87 

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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary
x
To determine the safety, tolerability and feasibility of immune checkpoint inhibition 
comprising either Durvalumab alone or combined Durvalumab and Tremelimumab in 
combination with stereotactic body radiation therapy (SBRT) in patients with 
unresectable pancreatic cancer.
1.1.2
Secondary 
x
To characterize the plasma pharmacokinetic (PK) parameters of immune checkpoint 
inhibition in combination with stereotactic body radiation therapy (SBRT) in patients 
with pancreatic cancer.
x
To evaluate the 6-month overall survival rate and overall survival in patients with 
unresectable pancreatic cancer treated with immune checkpoint inhibition and radiation 
therapy relative to (1) the type of immune checkpoint inhibition and (2) quantity of 
radiation administered.
x
To estimate overall response rate (ORR) and progression free survival (PFS) by modified 
immune-related Response criteria (irRC) and Response evaluation criteria in solid tumors 
RECIST 1.1.
x
To estimate median time to progression as calculated by irRC and RECIST 1.1 in patients 
who progress, and duration of response in patients with unresectable pancreatic cancer 
during and following treatment with immune checkpoint inhibition in combination with 
stereotactic body radiation therapy (SBRT).
x
To evaluate the 6-month, 12 month and overall survival in patients with unresectable
pancreatic cancer treated with immune checkpoint inhibition and 5x5 radiation therapy 
(Arm C2).
1.1.3
Exploratory 
x
To measure changes in immune parameters in the peripheral blood and tumors in patients 
with advanced pancreatic cancer treated with immune checkpoint inhibition and radiation 
therapy relative to (1) the type of immune checkpoint inhibition and (2) quantity of 
radiation administered.
1.2
BACKGROUND AND RATIONALE
1.2.1
Pancreatic cancer and the current therapeutic paradigm 
Gemcitabine was established as a cornerstone drug in pancreatic cancer in 1997 following a 
phase III study which demonstrated an improvement in clinical benefit - a composite measure of 
clinical improvement based on three factors: pain, performance status, and weight change - and 

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survival (a secondary endpoint in the study) compared to 5-fluorouracil (5-FU) in patients with 
advanced untreated pancreatic cancer. More patients treated with gemcitabine had an 
improvement in clinical benefit response compared to those treated with 5-FU (23.8% versus 
4.8%; P = 0.0022). There were also (modest) gains in survival (median survival 5.65 versus 4.41; 
P = 0.0025 and 1-year survival 18% versus 2% in favor of gemcitabine). No confirmed objective 
tumor responses were observed. Once gemcitabine became the drug of choice in this disease,
various agents were combined with it in an attempt to build on its modest efficacy. Cytotoxic 
combinations of gemcitabine with capecitabine and platinum agents do appear to offer a small 
benefit, particularly in patients with good performance status but this benefit has not been shown 
to be statistically significant. 
The first trial to show a survival benefit for any combination therapy in pancreas cancer and 
which led to FDA approval of this combination in the front-line treatment of pancreas cancer in 
2005 was a study by Moore et al., in which 569 patients with untreated locally advanced or 
metastatic pancreas cancer were randomized to receive gemcitabine with either erlotinib or 
placebo[1]. There was a very modest but statistically significant improvement in progression-free 
(HR .77, 95% CI, .64-.92; P=.004), one-year survival (23% v 17%; P=.023) and median overall 
survival (6.24 months v 5.91 months, HR .82, 95% CI, .69-.99; P=.038) favoring the erlotinib 
arm.
In 2011 the standard of care initial management for patients with good performance status 
changed with the publication of a phase III trial comparing gemcitabine with an intensive 
polychemotherapy 
regimen 
combining 
oxaliplatin, 
irinotecan 
and 
5-FU/leucovorin 
(FOLFIRINOX). Although there was increased toxicity with the experimental regimen it was 
associated with an impressive response rate (31.6% v 9.4%) and survival advantage (11.1 v 6.8 
months) compared with gemcitabine. Despite this development there remains an unmet need for 
effective treatments in this disease. 
1.2.2
Radiation treatment in pancreatic cancer:
Traditionally, radiation has been employed in the management of all stages of pancreatic cancer 
– adjuvant, locally advanced (LAPC) and metastatic. The efficacy of radiation in each situation 
is a matter of controversy given an increasing awareness of the systemic biology and the efficacy 
data are summarized below. Nevertheless, issues related to locally recurrent or progressive 
disease are a very common occurrence in pancreatic cancer given its location and an important 
cause of morbidity. Patients who have pain related to the loco-regional extent of their disease, 
derive a definite palliative benefit with the use of chemoradiation[2].
The foothold of chemoradiation for LAPC – perhaps the setting in which it is most commonly 
used – was established on the basis of a number of small clinical trials stretching back to the 
1960’s. Two of these studies demonstrated a survival benefit for (5-fluorouracil based) 
chemoradiation compared to radiotherapy alone[3, 4]. Two other studies from the same era 
compared chemotherapy alone to chemoradiation. In a trial by the GITSG a benefit was 
demonstrated for chemoradiation plus chemotherapy compared to chemotherapy alone[5]. The 
chemotherapy consisted of streptozocin, mitomycin and 5-FU and the 1-year survival benefit 
was 41% compared to 19%. The other trial, by the Eastern Cooperative Oncology Group 
(ECOG), compared 5FU-chemoradiation with chemotherapy alone, failing to demonstrate a 
survival benefit[6]. The value of chemoradiation in LAPC has not been quantified in the modern 

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clinical trial era. In an attempt to address this question in the era of gemcitabine a phase III study 
was performed by the FFCD – SFRO (Fédération Francophone de Cancérologie Digestive -
Société Française de Radiothérapie Oncologique) in France[7, 8]. In this study, the first for 
nearly 20 years to address this question, 119 patients (of a planned 176) were randomized to 
undergo induction chemoradiation (with 5-FU 300 mg/m2/24 h as a continuous infusion, day 1–5
every week and cisplatin, 20 mg/m2/d, day 1–5 at week 1 and 5) followed by gemcitabine, or 
straight to chemotherapy with gemcitabine. The study was stopped prior to its full enrollment 
due to an inferior survival in the chemoradiation group (median survival 8.6 v 13 months, p = 
0.014). Although this study is not a definitive answer to the question of chemoradiation, it does 
add to the growing body of opinion that the benefit of chemoradiation in LAPC is most likely 
confined to a carefully selected subgroup. Recently a similar study was presented comparing 
gemcitabine alone (1,000 mg/m2 weekly x 3 every 4 weeks for 7 cycles) to chemoradiation (RT 
50.4 GY in 28 fractions plus gemcitabine 600 mg/m2 weekly x 6) followed by 5 cycles of 
gemcitabine alone (1,000 mg/m2 weekly x 3 every 4 wks.)[9]. The trial was stopped early due to 
slow accrual (N = 74, out of a planned 316). The median survivals were 9.2 months (95% CI 7.8 
- 11.4) and 11.0 months (95% CI 8.4 - 15.5) for the two arms respectively (p=0.044). 
In an interesting attempt to tease out the benefit of chemoradiation, investigators from the 
Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) performed a retrospective 
analysis of 181 patients with locally advanced PAC who had been entered on prior prospective 
GERCOR studies and who had been offered chemoradiation (at the discretion of the 
investigator), but only if they had remained metastasis-free after a 3-month period[10]. For those 
patients who were metastasis-free after initial chemotherapy, there was a survival advantage if 
they proceeded to chemoradiation compared to those who continued with chemotherapy alone 
(median OS 15.0 and 11.7 months, respectively; P = .0009). These data suggest that radiation 
may offer a survival benefit in selected patients who have disease that is proven to be localized 
after a test of time. This is an attractive concept as it allows patients to be selected for 
chemoradiation whilst receiving systemic therapy for their disease and also gives time for the 
logistics of the chemoradiation to be organized. The underlying principle is that patients who 
progress systemically prior to chemoradiation would in all likelihood not have derived a survival 
benefit from chemoradiation anyway and is in manner analogous to patients who develop disease 
progression during neoadjuvant therapy for resectable disease, who would presumably not have 
benefitted from surgery had it gone ahead. 
The same investigators have performed a prospective phase II study based on the same concept, 
i.e. induction chemotherapy (with gemcitabine and oxaliplatin) for a 2-month period, followed 
by chemoradiation if the patient has remained metastasis-free[11]. In this study fifteen percent of 
patients did not go on to receive chemoradiation, which is lower than the 29% rate described in 
their earlier report. The authors speculate that this may have been due to the shorter period of 
induction (2 v 3 months) and the lower amount of chemotherapy administered. The median 
overall survival achieved in this study was 12.2 months which is in the upper level of the survival 
rate range reported for patients with LAPC. Of course, this attractive concept needs to be 
assessed definitively and a phase III randomized study is currently being performed by the same 
group.
In our proposed study, we are proposing the use of radiation in a patient population who 
(metastatic pancreatic cancer) who may not otherwise receive it. Given the proportion of patients 

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with this disease who go on to develop local symptoms we believe that this alone justifies its 
inclusion as part of the therapeutic regimen. Whilst the traditional RT schedule for this disease 
has been over a prolonged course and in combination with a chemotherapeutic (5FU or 
gemcitabine) as radiosensitizer, modern RT techniques allow for a hypofractionated course 
without chemotherapy. This will minimize the duration of RT and will make it easier to combine 
with anti-CTLA4 treatment. Stereotactic body radiation therapy (SBRT) has been shown to be 
safe and effective in locally-advanced pancreatic cancer[12].
1.2.3
Recent advances in immune-based approaches in solid tumor malignancies
The past two years have seen progress for immune-based approaches in solid tumor 
malignancies, with FDA approvals for these approaches in prostate cancer and melanoma[13-
15]. In melanoma, anti-CTLA4 therapy has been shown to demonstrate a median survival benefit 
in two separate phases 3 studies, both of which were associated with long-term disease control in 
approximately one-fifth of patients. More recently, anti-PD-L1 therapy has demonstrated a 
similar degree of clinical activity not only in melanoma and kidney cancer but also in lung 
cancer, a disease type previously thought to be refractory to an immune approach[16].
Appreciation of the role in developing tumors of immune-evasion has also been evidenced by its 
inclusion as one of the (updated) hallmarks of cancer[17].
Both anti-PD-L1 and anti-CTLA4 therapy enhance anti-tumor immunity by blocking tumor 
induced immune suppression of cytotoxic T cells and therefore exaggerating the immune 
activation that must first occur of its own accord and is thought to be the result of tumor neo-
antigens formed as a tumor progresses. The role of CTLA4 and anti-PD-L1 in inhibiting T-cell 
activation is represented in the schematic in Figure 1 below. 

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Figure 1 CTLA-4 and PD-1/PD-L1 are negative regulators of T cell activity in lymphoid tissues and tumor 
microenvironment respectively. Anti-CTLA-4 antibodies, such as ipilimumab and tremelimumab, block 
CTLA4 and, thereby, results in activation of T-cells. Blockade with antibodies of PD-1 or PD-L1 (e.g., 
nivolumab and Durvalumab) augments immune response in peripheral tissues. (Gelao. Toxins 2014[18])
CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial response to 
antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor 
(TCR)-mediated signaling. After the TCR is triggered by antigen encounter, CTLA4 is 
transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the 
greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 
functions as a signal dampener to maintain a consistent level of T cell activation in the face of 
widely varying concentrations and affinities of ligand for the TCR. The PD-1/PD-L1 inhibitory 
receptor pathway plays an important role in modulating T-cell activity in the tumor 
microenvironment during the effector phase of immune response. PD-1 is a surface receptor 
member of the B7-CD28 superfamily. The ligation of PD-1 with PD-L1 causes the negative 
regulation of T-cells resulting in anergy, exhaustion and death of effector T-cells. Blockade with 
antibodies of PD-1 or PD-L1 (e.g., nivolumab and Durvalumab) results in the continuing 
activation of T-cells and enhances anti-tumor immune activity. 
While these studies demonstrate the potential for anti-CTLA4 or anti PD1/PD-L1 therapy to 
enhance the anti-tumor immune response already in process, it clearly does not work in the 
majority of patients. The question is whether the initial immune activation stage can be 
enhanced. The potential for this was intriguingly demonstrated in a recent publication by Postow 
et al who reported a case of the so-called abscopal effect in a patient with melanoma treated with 
ipilimumab and radiotherapy[19]. Temporal associations were noted between tumor shrinkage 
and antibody responses to the cancer-testis antigen NY-ESO-1 in addition to changes in 
peripheral-blood immune cells, and increases in antibody responses to other antigens after a 
patient being treated with anti-CTLA4 was then treated with external beam radiotherapy. The 
enhanced effect from anti-CTLA4 seen after radiation appears to have been due to a boost effect 
of tumor cell death and immune stimulation following deliverance of a tumor antigen load. It is 
this enhanced effect we wish to study in the context of radiation treatment for pancreatic cancer.
1.2.4
Immune response following radiation, mechanism and rationale for combination with 
immune checkpoint inhibition:
Several studies have documented an increase in peripheral antitumor immunity following 
radiation. It may even be the case that an intact immune system is critical for RT to exert its 
maximal antitumor effect. This was suggested by a mouse model of melanoma in which single-
fraction RT slowed the growth of small tumors in immune-competent but not immune-deficient 
mice[20]. The same authors also showed that in an animal model of breast cancer ablative RT of 
a primary tumor prevented the growth of metastatic tumor colonies in the lung, an effect that was 
dependent on the presence of CD8+ T cells. Other animal models have likewise displayed 
augmentation of systemic antitumor immunity following local RT[21-23].
The underlying mechanism appears to be that RT-induced necrosis results in the exposure of 
tumor antigens, thereby increasing the pool of intracellular peptides for cross-presentation[24].
Radiation has been shown to augment MHC-I expression by tumors, which is critical for antigen 

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recognition by cognate CD8+ TCRs and which is known to be diminished in tumors as one of 
their escape mechanisms[25]. Tumor antigen processing and presentation on MHC-I molecules 
is dependent on expression of a protein called high mobility group box 1 (HMGB-1), a “danger 
signal” which binds toll-like receptor 4 (TLR4) on dendritic cells. In a pivotal study Apetoh et al. 
demonstrated that RT causes dying tumor cells to release HMGB-1[26]. Intriguingly these 
authors also reported that in breast cancer patients undergoing radiation and chemotherapy the 
presence of a polymorphism in TLR4 – and by implication a less immunogenic drug-induced cell 
death – was associated with an inferior prognosis. Similarly, in esophageal cancer patients 
preoperative chemoradiation has been shown to increase cancer-specific T cell responses and 
serum levels of HMGB-1, the latter of which correlated with overall survival[27].
Despite this, only a few cases of spontaneous decrease of metastases following radiation – the 
so-called abscopal effect – have been reported[28-30]. This is presumably because the immune 
response by itself is too weak to be clinically significant. A number of studies have tried to boost 
this anti-tumor immune response following ablation by combining with an immunomodulatory 
agent: 
-
Zeng et al. tested the combination of anti-PD-1 immunotherapy with stereotactic 
radiosurgery in a glioblastoma model. Improved survival was demonstrated with the
combination treatment compared with either modality alone. Long-term survival was 
seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at 
day 180+ after treatment. There was also increased tumor infiltration by cytotoxic T cells 
and decreased regulatory T cells in the combined treatment group compared with the 
single modality arms[31].
-
Dewan et al. evaluated RT in combination with anti-CTLA-4 antibody in two separate 
mouse models of breast and colorectal carcinoma[32]. The authors found that the 
combination of anti-CTLA4 and RT achieved enhanced tumor response at the primary 
site (compared to either modality alone). in addition to an abscopal effect. (Interestingly 
this only occurred in fractionated versus single-dose RT). The frequency of CD8+ T cells 
showing tumor-specific IFN-gamma production was proportional to the abscopal effect. 
-
Demaria et al. tested the combination of RT with CTLA-4 blockade in a breast cancer 
model (4T1) known to be poorly immunogenic[33]. Anti-CTLA4 alone did not have any 
effect on primary tumor growth or survival. RT was able to delay the growth of the 
primary irradiated tumor, but in the absence of anti-CTLA4 survival was similar to that 
of control mice. In contrast, mice treated with RT + anti-CTLA4 had a statistically 
significant survival advantage. The increased survival correlated with inhibition of lung 
metastases formation and required CD8+.
1.2.5
Tremelimumab
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb directed against CTLA-4. Upon T 
cell activation, CTLA-4 expression acts to dampen immune responses by CTLA-4 relocation to 
the cell surface in order to modulate and eventually switch off T cell activation.
Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T cell activation. 
The binding of CTLA-4 to its target ligands (B7.1 [CD80] and B7.2 [CD86]) provides a negative 
regulatory signal, which limits T cell activation. Blockade of B7 binding to CTLA-4 by anti-

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CTLA-4 antibodies also results in markedly enhanced T cell activation and antitumor activity in 
animal models, including killing of established murine solid tumors and induction of protective 
antitumor immunity. Tremelimumab is specific for human CTLA-4, with no cross-reactivity to 
related human proteins.
Anti-CTLA-4 therapy has recently been shown to be a validated approach to cancer treatment by 
the approval of the mAb ipilimumab in 2011 for the treatment of patients with metastatic 
melanoma, based on 2 Phase III studies that demonstrated a significant improvement on OS in 
the first- and second-line settings. In general, tumor response rates to anti-CTLA-4 therapy are 
low; approximately 10%, but the durable response or stable disease seen in a proportion of 
patients can lead to a significant prolongation of OS. In a large, single-arm Phase II
Tremelimumab trial in patients with advanced refractory and/or relapsed melanoma, objective 
responses (primary endpoint) following Tremelimumab 15 mg/kg Q3M were observed in 16 of
241 (6.6%) patients (9&,>@5HVSRQVHVZHUHGXUDEOHSUHVHQWDWPRQWKVIURP
enrollment) in all 16 responders. A Phase III, open-label, randomized study comparing
Tremelimumab 15 mg/kg Q3M (Arm A) to either dacarbazine or temozolomide (Arm B) in 
patients with advanced melanoma was terminated following a pre-specified interim futility 
analysis. At the time of database lock, the median OS (primary endpoint) was 12.58 months in 
Arm A and 10.71 months in Arm B (HR=1.1416, p=0.1272).
The efficacy data for tremelimumab are consistent with those of the related – and FDA-
approved- anti-CTLA-4 antibody ipilimumab: tumor response rates are generally low 
(approximately 10%) but the responses observed are generally durable. The ipilimumab 
melanoma data clearly demonstrate that a small proportion of patients with an objective response 
and a small impact on PFS rates can lead to a significant prolongation of OS, and support 
development of this class of agent in other tumors. Although Phase II and Phase III studies of 
tremelimumab in metastatic melanoma failed to meet the primary endpoints of response rate and 
OS, respectively, the data clearly indicate activity of tremelimumab in melanoma, with response
rates and median OS similar to those observed in the ipilimumab trials.
Tremelimumab has been evaluated in a number of clinical studies – and over 1000 patients – and 
demonstrated manageable toxicities[34, 35]. The efficacy data for Tremelimumab are consistent 
with those of the related anti-CTLA-4 antibody ipilimumab: tumor response rates are generally 
low (approximately 10%) but the responses observed are generally durable. The ipilimumab 
melanoma data clearly demonstrate that a small proportion of patients with an objective response 
and a small impact on PFS rates can lead to a significant prolongation of OS, and support 
development of this class of agent in other tumors. Although Phase II and Phase III studies of 
Tremelimumab in metastatic melanoma failed to meet the primary endpoints of response rate and 
OS, respectively, the data clearly indicate activity of Tremelimumab in melanoma, with response 
rates and median OS similar to those observed in the ipilimumab trials.
The AE profile of Tremelimumab is consistent with that of ipilimumab, and with the 
pharmacology of the target. To date, no tumor type or stage appears to be associated with unique 
AEs (except for vitiligo, which appears to be confined to patients with melanoma). Events 
reported at a frequency RIDQGDVVHVVHGE\WKHLQYHVWLJDWRUDVUHODWHGWRWUHDWPHQWOLVWHGLQ
descending order of frequency) were diarrhea, rash, pruritus, fatigue, nausea, vomiting, anorexia, 
headache, abdominal pain, and colitis.

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1.2.6
Anti-CTLA4 therapy in pancreatic cancer
A small number of studies have evaluated the strategy of anti-CTLA4 treatment in pancreatic 
cancer, though not in combination with radiation. Recently, Le et al evaluated ipilimumab in 
combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in patients 
with previously treated pancreatic cancer[36]. Three patients treated with the combination had 
evidence of prolonged disease stabilization (31, 71, and 81 wk.) and 7 patients experienced 
CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of 
progression. The median overall survival (OS) (3.6 vs. 5.7 mo., hazards ratio: 0.51, P = 0.072) 
and 1 year OS (7 vs. 27%) favored the combination of vaccine plus anti-CTLA4. Similar to prior 
ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. 
Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T 
cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031) all of which suggested that 
checkpoint blockade in combination with GVAX has the potential for clinical benefit.
Investigators within NCI performed a phase II trial evaluating the efficacy of Ipilimumab for 
advanced pancreatic cancer. In that study subjects with locally advanced or metastatic pancreas 
adenocarcinoma with measurable disease, good performance status, and minimal comorbidities 
were treated with Ipilimumab (3.0 mg/kg every 3 wk.; 4 doses/course) for a maximum of 2 
courses. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) 
with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern 
Cooperative Oncology Group performance stDWXV WR7KUHHVXEMHFWVH[SHULHQFHGJUDGH
immune-mediated adverse events (colitis:1, encephalitis:1, hypohysitis:1). There were no 
responders by response evaluation criteria in solid tumors criteria but one subject experienced a 
delayed response after initial progressive disease. In this subject, new metastases after 2 doses of 
Ipilimumab established progressive disease, but continued administration of the agent per 
protocol resulted in significant delayed regression of the primary lesion and 20 hepatic 
metastases. This was reflected in tumor markers normalization, and clinically significant 
improvement in performance status. Overall the experience in this study suggests that while 
single agent Ipilimumab at low, (3 mg/kg) dose was ineffective for the treatment of advanced 
pancreas cancer the activity hinted at in the one patient who experienced a significant delayed 
response suggests that this approach deserved further exploration, for example by increasing 
dose or combining with other immune-stimulatory approaches.
1.2.7
Durvalumab
Durvalumab is a human monoclonal antibRG\ RI WKH LPPXQRJOREXOLQ * NDSSD ,J*ț
subclass. The fragment crystallize (Fc) domain of Durvalumab contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to the complement component 
C1q and the Fc gamma receptors responsible for mediating antibody dependent cell mediated 
cytotoxicity[37]. Durvalumab inhibits binding of programmed cell death ligand 1 (PD-L1) to 
programmed cell death 1 (PD-1) and CD80. Programmed death ligand 1 (PD-L1) is a
transmembrane immunoreceptor which controls peripheral tolerance by inhibiting effector
functions of T lymphocytes trough engagement with PD-1 receptor on antigen presenting cell. 
Anti-PD-L1 antibodies directly target tumor cells and expected to have less adverse events in 
comparison with anti-PD-1 antibodies that target effector T-cells in tumor microenvironment.).

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Blockade of PD-L1 with Durvalumab expected to relieve PD-L1-mediated suppression of human 
T-cell activation within tumors. In a xenograft model, Durvalumab inhibited human tumor 
growth via a T-cell-dependent mechanism. PD-L1 is upregulated in a broad range of cancers 
with a high frequency, with up to 88% expression in some indications. In a pancreatic cancer, the 
tumor cell expression of PD-L1 is associated with reduced survival and an unfavorable 
prognosis. In the preclinical studies effect of Durvalumab on the growth of human pancreatic 
adenocarcinoma tumor cell lines in mice was investigated. Durvalumab significantly inhibited 
growth of the pancreatic adenocarcinoma cell line, HPAC, by up to 74% as compared to the 
isotype-control antibody. 
In the clinical studies to date more than 220 subjects have been enrolled and treated. Currently 
Durvalumab
investigated in
5 ongoing clinical studies
(2 employing Durvalumab
as 
monotherapy and 3 as combination therapy). The majority of the clinical data are from Study 
CD-ON-Durvalumab-1108, which has the greatest number of enrolled subjects. This is a Phase 
1, multicenter study in adult subjects with advanced solid tumors refractory to standard therapy 
(N = 198 subjects). Partial efficacy data available for CD-ON-Durvalumab-1108 based on 
Response Evaluation Criteria in Solid Tumors (RECIST). Of the 177 subjects treated with 
Durvalumab 10 mg/kg Q2W, 77 have had at least one post-baseline disease assessment. Four 
subjects (5.2%) had a best response of PR. In addition, 36 subjects (46.8%) had stable disease.
Of the 177 subjects treated with 10 mg/kg Q2W, 121 subjects (71.8%) had at least 1 treatment-
emergent AE (Table 5.3.1.3-RIFXUUHQW,%HGLWLRQ7KHPRVWIUHTXHQWO\UHSRUWHGRI
subjects) TEAEs (all grades) were fatigue, dyspnea, nausea, constipation, and decreased appetite. 
The majority of these TEAEs were Grades 1 to 2 in severity and manageable by the general 
treatment guidelines as described in the current Durvalumab study protocols. Grade 3 or higher 
TEAEs were noted in 44/177 subjects (24.9%). These events occurring in more than 1 subject 
included dyspnea (9 subjects); dehydration (4 subjects); abdominal pain, fatigue, sepsis, 
increased aspartate aminotransferase, and increased gamma-glutamyltransferase (3 subjects); and 
hyperbilirubinemia, back pain, pulmonary embolism, respiratory failure, and hypotension (2 
subjects each). The Grade 3 or higher TEAEs that were considered by the investigator to be 
related to Durvalumab
were increased aspartate
aminotransferase (2 subjects), and 
hypothyroidism, vomiting, fatigue, infusion-related reaction, troponin, dehydration, and 
arthralgia (1 subject each). Treatment-related, TEAEs were reported for 52/177 subjects (29.4%). 
The most frequently reported (2 or more subjects) treatment-related TEAEs (all grades) were 
fatigue (11.3%); nausea (5.6%); dyspnea (4.0%); diarrhea, vomiting, and pyrexia (3.4% each); 
myalgia (2.8%); hypothyroidism, decreased appetite, dizziness, cough, pruritus, and rash (2.3% 
each), abdominal pain, increased aspartate aminotransferase, and arthralgia (1.7% each); and 
asthenia, influenza-like illness, edema peripheral, increased alanine aminotransferase, headache, 
and dry skin (1.1% each). No DLTs have been reported. The SAEs reported for 3 or more 
subjects were dyspnea, dehydration, abdominal pain, and sepsis. Three subjects had treatment-
related SAEs: arthralgia (1 subject); pleural effusion and pneumonitis (both in the same subject); 
and muscular weakness and “rule out cord compression” (verbatim term) (both in the same 
subject). For the entire study population, none of the deaths or TEAEs resulting in 
discontinuation of Durvalumab in this study were considered related to Durvalumab treatment. 

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1.2.8
Anti-CTLA4 in combination with anti-PD1/PD-L1.
Durvalumab and tremelimumab data: There is a sound rationale for evaluating the combination 
of Durvalumab and tremelimumab for the treatment of advanced malignancies. The mechanisms 
of activation of known activity sites for CTLA-4 and PD-L1 are non-redundant, suggesting that 
targeting both pathways may have additive or synergistic activity[38].
The Combination therapy (dual targeting of PD-L1 and CTLA-4) has been shown in preclinical 
studies with a mouse model to cause tumor regression of colorectal cancer. To date, 2 clinical 
trials employing Durvalumab as combination therapy with tremelimumab in adults with 
advanced non-small cell lung cancer (NSCLC) and advanced solid tumors was initiated with 
preliminary efficacy data for combination still pending. Nivolumab plus ipilimumab clinical 
data: Results of nivolumab administered in combination with ipilimumab for stage III or IV 
measurable, unresectable melanoma have recently been reported. At the maximum tolerated 
combination dose—1mg/kg anti-PD1 plus 3 mg/kg ipilimumab every three weeks administered 
concurrently, 53% of patients had an objective response, all with tumor reduction of 80% or 
more. Adverse effects occurred in 53% of patients and were similar in quality and intensity to 
those observed with ipilimumab monotherapy. Sequential administration resulted in a lower 
response rate and lower toxicity rate. With regard to biomarkers previously associated with 
responses to anti-CTLA4 or anti-PD1, investigators evaluated PD-L1 expression in tumors and 
absolute lymphocyte counts and looked for relationships with response. In patients treated 
concurrently, 6/13 patients with PD-L1+ tumors responded whereas 9/22 patients with PD-L1–
tumors responded (P>0.99 by Fisher’s exact). Interestingly however, in the sequential group, 4/8 
patients whose tumors were PD-L1+ responded 6 whereas only 1/13 who had PD-L1- tumors 
responded. Absolute lymphocyte counts at weeks 5-7 were not associated with response in this 
study.
In the ongoing Tremelimumab + Durvalumab combination study D4190C00006 in advanced
NSCLC patients, preliminary AE data as of 18Feb2014 available for 7 subjects treated with 
Durvalumab (3 or 10 mg/kg) and tremelimumab (1 mg/kg) in this study showed that the only 
TEAE reported for more than 1 subject was fatigue (3 subjects). All TEAEs were Grade 1 or 2 
with the exception of one Grade 3 event of increased aspartate aminotransferase. None were 
considered by the investigator to be related to treatment with the exception of one event of 
increased amylase (Grade 2), one event of increased aspartate aminotransferase (Grade 3), and 
one event of increased alanine aminotransferase (Grade 2), which were all deemed related to 
both Durvalumab and tremelimumab. No DLTs have been reported in this study.
Updated information for combination of durvalumab and tremelimumab:
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or 
every 4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up 
to Week 24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The 
study is ongoing and continues to accrue. 
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK (n = 
26) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following 
durvalumab every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W 

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regimens. An approximately dose-proportional increase in PK exposure (Cmax and area under 
the concentration-time curve from 0 to 28 days [AUC0 28]) of both durvalumab and 
tremelimumab was observed over the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 10
mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated accumulation 
consistent with PK parameters estimated from the first dose. It is to be noted that steady state PK 
parameters are based on limited numbers of subjects. The observed PK exposures of durvalumab 
and tremelimumab following combination were consistent with respective monotherapy data, 
indicating no PK interaction between these 2 agents.
As of February 20, 2015, ADA data were available from 60 subjects for durvalumab and 53 
subjects for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for 
anti durvalumab antibodies post treatment. One of 53 subjects were ADA positive for anti 
tremelimumab antibodies post treatment. There was no clear relationship between ADA and the 
dose of either durvalumab or tremelimumab, and no obvious association between ADA and 
safety or efficacy.
The durvalumab + tremelimumab doses and regimen selected for this study were based on the 
goal of selecting an optimal combination dose of durvalumab and tremelimumab that would 
yield sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an 
acceptable safety profile.
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the durvalumab 
monotherapy data indicated that a similar area under the plasma drug concentration-time curve at
steady state (AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w 
durvalumab. The observed durvalumab PK data from the D4190C00006 study were well in line 
with the predicted monotherapy PK data developed preclinically. This demonstrates similar 
exposure of durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when 
durvalumab and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While the 
median Cmax at steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w 
(approximately 1.5-fold) and median trough concentration at steady state (Ctrough,ss) is 
expected to be higher with 10 mg/kg q2w (approximately 1.25-fold), this is not expected to 
impact the overall safety and efficacy profile, based on existing preclinical and clinical data.
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab monotherapy. There was 
evidence of augmented PDx activity relative to durvalumab monotherapy with combination 
doses containing 1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 
1 mg/kg tremelimumab combinations. 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, 
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 
mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A
similar pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab 
increased above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, 

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20
the SAEs frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly 
seen in cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose 
cohorts. Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg 
appeared to minimize the rate of toxicity when combined with durvalumab. As a result, all 
combination doses utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in 
the final dose selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of 
durvalumab may not impact the safety of the combination as much as the tremelimumab dose.
Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in 
safety events with increasing dose of durvalumab. 
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 
PJNJGXUYDOXPDEPJNJWUHPHOLPXPDEJURXSKDGWKHIHZHVW$(V*UDGH$(V6$(V
and treatment discontinuations due to AEs, but still showed strong evidence of clinical activity.
This cohort had a lower number of treatment-UHODWHG*UDGH$(VRUWUHDWPHQWUHODWHG6$(V
No dose-limiting toxicities were reported.
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab q4w cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 11 
patients in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up. Of these, there were 2 patients (40%) with partial 
response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive 
disease (PD). (The fifth patient had only a single scan, which was conducted outside the window 
for these evaluations.)
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had 
the feweVW $(V *UDGH  $(V 6$(V DQG WUHDWPHQW GLVFRQWLQXDWLRQV GXH WR $(V EXW VWLOO
showed some evidence of clinical activity. Altogether, the data suggested that a 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab dose combination should be selected for further 
development.
1.2.9
Justification for dose and schedule
1.2.9.1
Tremelimumab
The proposed dose and schedule is informed by PK, safety, and efficacy data on tremelimumab. 
In an early small Phase II study (A3671002), 2 dosing regimens of tremelimumab were 
compared in subjects with melanoma: 15 mg/kg Q3M (N=45) and 10 mg/kg QM (N=44). 
Comparable efficacy and overall AE rates were observed in both arms; however, the rate of 
treatment-related CTCAE Grade 3 or 4 AEs was higher in the 10 mg/kg QM arm (27%) 
compared to the 15 mg/kg Q3M arm (13%). Subsequently, 2 pivotal tremelimumab studies 
(Phase II Study A3671008 and Phase III Study A3671009) in patients with melanoma used the 
regimen 15 mg/kg Q3M. Although neither study met its primary endpoint, the observed response 

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rate and OS clearly indicate activity of tremelimumab in melanoma. Retrospective exposure-
survival analyses of these studies suggest better OS in subjects with higher tremelimumab 
exposure. In the Phase III trial, there was no difference LQ WKH LQFLGHQFH RI *UDGH  AEs 
between low and high exposure groups of tremelimumab. Tremelimumab at a concentration of 
 ȝJP/ HQKDQFHG ,/-2 release (in vitro) and showed antitumor activity (in vivo), and was 
consequently identified as the target concentration. PK simulations indicate that following a dose 
of 10 mg/kg QM for 6 months, approximately 90% of patients are expected to be above the 
WDUJHWOHYHORIȝJP/GXULQJWKHLQGXFWLRQSKDVH,QWKH3KDVH,,,PHODQRPDWULDOZLWKOHVV
frequent dosing of 15 mg/kg Q3M, only approximately 50% of the patients treated with 
tremelimumab were above the target concentration, for only half of the dosing interval. 
Tremelimumab at a dose of 10 mg/kg QM for 6 months followed by 10 mg/kg Q3M is expected 
to yield PK exposures similar to those of the related anti-CTLA-4 mAb ipilimumab at a dose of 
10 mg/kg every 3-weeks followed by 10 mg/kg Q3M, the dosing regimen that was tested in the 
pivotal first-line melanoma trial[15]. The ipilimumab data suggest that the long-term benefits of 
anti-CTLA-4 therapy may be sustained with a reduced frequency of dosing in patients who are 
benefiting from therapy. Based on these data, we will use a tremelimumab dose of 10 mg/kg QM 
for 6 months of treatment. Following the first 6 months of dosing, in the absence of confirmed 
disease progression, the interval will be increased to Q3M. Treatment will be continued for up to 
one year as long as the patient continues to derive clinical benefit.
1.2.9.2
Durvalumab
Preclinical toxicities studies with Durvalumab in cynomolgus monkeys, showed that repeated
dosing of Durvalumab was not associated with any adverse effects. Therefore, the NOAEL(no-
observed-adverse-effect) level of Durvalumab in all the general toxicity preclinical studies was 
considered to be 100 mg/kg, the highest dose tested in these studies. The majority of the clinical 
safety data for Durvalumab from Study CD-ON-Durvalumab-1108, Phase 1, first-time-in-human 
(FTIH), multicenter, open-label, dose-escalation, and dose-expansion study to determine the 
maximum tolerated dose (MTD) or optimal biologic dose (OBD), safety, PK, immunogenicity, 
and antitumor activity of Durvalumab in adult subjects with advanced solid tumors. A total of 
198 subjects have been enrolled in Study CD-ON-Durvalumab-1108 and 177 of these subjects 
have received Durvalumab at 10 mg/kg Q2W (either in the dose-escalation or dose-expansion 
phase of the study). No DLTs have been reported. The SAEs reported for 3 or more subjects 
were dyspnea, dehydration, abdominal pain, and sepsis. Durvalumab PK/pharmacodynamic data 
were evaluated for 32 subjects in the FTIH study (4 subjects in each of the 0.1 and 0.3 mg/kg 
groups, 3 subjects in each of the 1 and 3 mg/kg groups, and 18 subjects in the 10 mg/kg group).
Results suggest that Durvalumab exhibits nonlinear PK likely due to saturable target-mediated 
clearance, resulting in faster rate of Durvalumab elimination at lower doses compared with high 
doses. The Michaelis constant (Km) describing half maximum capacity for nonlinear clearance 
ZDVaȝJP/%DVHGRQPHDQ.PYDOXH > 99% target saturation (both soluble and membrane 
ERXQGLVH[SHFWHGDWȝJP/ concentration of Durvalumab. Hence, this concentration was 
identified as target trough concentration during dose selection. Pharmacokinetic simulations 
indicate that following 10 mg/kg Q2W dose of Durvalumab, > 90% of subjects are expected to 
PDLQWDLQ 3. H[SRVXUH   ȝJP/ WKURXJKRXW WKH GRVLQJ interval. Near complete target
saturation, membrane bound and soluble PD-L1 (sPD-L1) is expected at a  3.0 mg/kg Q2W 
dose of Durvalumab. Exposures following multiple doses (currently data available up to a 
maximum of 20 doses) demonstrated accumulation consistent with the half-lives estimated from 

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22
the first dose in each group. Significant target engagement, as measured by sPD-L1 suppression, 
was observed in all individuals following dosing.
Samples from 31 subjects were available for ADA (antidrug antibody) testing. Of these subjects, 
3 (1 subject each in the 0.1, 1.0, and 3.0 mg/kg Q2W cohorts) were ADA positive following 
dosing. Low ADA titers of 2 and 4 were observed in ADA-positive samples in 1 subject from 
both the 0.1 and 1.0 mg/kg Q2W cohorts, respectively, with no obvious impact on either PK or 
pharmacodynamics. In 1 subject in the 3.0 mg/kg Q2W cohort, the ADA titer increased from 128 
to 4096 in sequential ADA positive samples. Lower than expected PK exposure and suppression 
of sPD-L1 were observed in this subject likely as a consequence of this ADA response. 
1.2.9.3
Tremelimumab in combination with Durvalumab
Preliminary safety data as of are available for N=7 subjects treated in the ongoing study 
evaluating the combination of Durvalumab and tremelimumab. Three subjects were enrolled in 
each of the first 2 dose cohorts. Thereafter, dose escalation proceeded simultaneously to 
Durvalumab 15 mg/kg with 1 mg/kg tremelimumab and Durvalumab 10 mg/kg with 3 mg/kg 
tremelimumab, with 1 subject enrolled in the latter cohort as of the cutoff date. The only AE 
reported for more than 1 subject was fatigue (3 subjects). All AEs were Grade 1 or 2 with the 
exception of one Grade 3 event of increased aspartate aminotransferase. One subject in this study 
(Durvalumab 3 mg/kg with 1 mg/kg tremelimumab) was discontinued from treatment because of 
an SAE of disease progression. No DLTs or deaths have been reported in this study.
The safety profile of durvalumab and tremelimumab combination therapy in the 102 subjects 
with advanced NSCLC in Study D4190C00006 is generally consistent with that observed across 
177 subjects treated with durvalumab and tremelimumab combination therapy (not including 
subjects treated with blinded investigational product). As of April 15, 2015, 95 of 102 subjects 
(93.1%) reported at least 1 AE. All subjects in the tremelimumab 3 and 10 mg/kg dose cohorts 
experienced AEs; subjects in the durvalumab 20 mg/kg and tremelimumab 1 mg/kg Q4W cohort 
experienced the lowest AE rate (77.8%). Treatment-related AEs were reported in 74 of 102 
subjects (72.6%), with events occurring in > 10% of subjects being diarrhea (27.5%), fatigue 
(22.5%), increased amylase and pruritus (14.7% each), rash (12.7%), colitis (11.8%), and 
increased lipase (10.8%). Treatment-UHODWHG*UDGH$(VUHSRUWHGLQRIVXEMHFWVZHUH
colitis (8.8%), diarrhea (7.8%), and increased lipase (5.9%). Five subjects reported treatment-
related Grade 4 events (sepsis, increased ALT, and increased AST in 1 subject; increased 
amylase in 2 subjects; myasthenia gravis in 1 subject; and pericardial effusion in 1 subject) and 2 
subjects had treatment-related Grade 5 events (polymyositis and an uncoded event of 
neuromuscular disorder [VT]); the Grade 4 event of myasthenia gravis and Grade 5 polymyositis 
occurred in 1 subject. There were 2 subjects (both in the durvalumab 20 mg/kg + tremelimumab 
3 mg/kg Q4W cohort) with dose-limiting toxicities (DLTs): 1 subject with Grade 3 increased 
AST, and 1 subject with Grade 3 increased amylase and Grade 4 increased lipase. Fifty-six 
subjects (54.9%) reported SAEs, with events occurring in > 5% of subjects being colitis (9.8%) 
and diarrhea (7.8%). Thirty-six subjects (35.3%) experienced treatment-related SAEs. Twenty-
seven subjects (26.5%) permanently discontinued treatment due to AEs. Treatment-related AEs 
UHVXOWLQJLQGLVFRQWLQXDWLRQLQVXEMHFWVZHUHFROLWLVVXEMHFWVSQHXPRQLWLVVXbjects), 
diarrhea (3 subjects), and increased AST (2 subjects). Additional safety results from this study 
are presented in Section 1.2.8 and the durvalumab IB.
1.2.9.4
Fixed Dosing for durvalumab and tremelimumab 

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A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
FRHIILFLHQWRI7KHLPSDFWRIERG\:7-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma)[39].
Population PK model indicated minor impact of body WT on PK of tremelimumab (coefficient 
RI7KH:7-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on median 
body WT of ~75 kg) regimens were compared using predicted PK concentrations (5th, median 
and 95th percentiles) using population PK model in a simulated population of 1000 patients with 
body weight distribution of 40 to 120 kg. Similar to durvalumab, simulations indicated that both 
body WT-based and fixed dosing regimens of tremelimumab yield similar median steady state 
PK concentrations with slightly less between-subject variability with fixed dosing regimen. 
Similar findings have been reported by others[40, 41],[42],[43]. Wang and colleagues 
investigated 12 monoclonal antibodies and found that fixed and body size-based dosing perform 
similarly, with fixed dosing being better for 7 of 12 antibodies. In addition, they investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 18 in 
terms of reducing the between-subject variability in pharmacokinetic/pharmacodynamics 
parameters[42].
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 
mg/kg Q4W) is included in the current study. 
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30kg 
body weight due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule.
1.2.10 Rationale for study population and schedule:
RT is part of the standard treatment for advanced pancreatic cancer both in the locally advanced 
setting and in the context of metastatic disease where patients frequently develop symptoms from 
the primary tumor. The vast majority of patients with pancreatic cancer have a primary or locally 
recurrent tumor in-situ for which RT is an acceptable treatment. This allows for a fairly 
homogenous patient population and radiation schedule. Whilst the traditional RT schedule for 
this disease has been over a prolonged course and in combination with a chemotherapeutic (5FU 
or gemcitabine) as radiosensitizer, modern RT techniques allow for a hypofractionated course 

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without chemotherapy. This will minimize the duration of RT and will make it easier to combine 
with Immune Checkpoint inhibitors (Tremelimumab and Durvalumab) treatment. Stereotactic 
body radiation therapy (SBRT) has been shown to be safe and effective in locally-advanced 
pancreatic cancer[12]. Because it is unclear what the optimal schedule of Tremelimumab and 
Durvalumab treatment with regard to RT is, we intend to employ two separate schedules to 
evaluate this in an exploratory manner.
1.2.11 Justification for Tumor Biopsies
Whilst the preclinical data suggest important immune-regulatory effects of radiation treatment on 
tumors, with potential for amplification with immune checkpoint therapy, the effect on humans 
is really unknown. Given that this is essentially a small pilot study evaluating feasibility and
safety whose next step in development – if safe and feasible as per the primary endpoint – will 
most likely be a larger randomized study, it is scientifically important to obtain as much 
information about the treatment effect. This may lead to altered and improved design of the next 
study. The best strategy for doing this is with tumor biopsies in order to evaluated immune cell 
infiltration (CD4/8 T-cells, MDSC). As pointed out by Deng et al. administration of anti–PD-L1 
enhanced the efficacy of radiation through a cytotoxic T cell–dependent mechanism. 
Concomitant with radiation-mediated tumor regression, they observed that radiation and anti–
PD-L1 synergistically reduced the local accumulation of tumor-infiltrating MDSCs, which 
suppress T cells and alter the tumor immune microenvironment. It would be important to 
replicate this observation – or disprove it – in humans and would be relevant knowledge whether 
the clinical data (response, PFS etc.) was either positive or negative. Given this, the historical 
difficulty with obtaining tissue in stroma-rich pancreatic tumors and the fact that in order for the 
biopsy material from any single patient to be relevant and worthwhile in the context of small 
patient numbers we would really require participation from all or almost all of the patients.
However, if a patient has technically biopsiable disease but the interventional radiologist has 
concerns that pursuing the biopsy increases the risk to above average, or if pursuing the biopsy 
creates additional logistical complications (availability, pre-anesthesia requirements etc.) which 
causes delays or inconvenience to an unreasonable degree, we will forgo at investigator 
discretion.
1.2.11.1 Details of Planned Tumor Analysis
We will attempt to perform immunohistochemically and gene analysis of all tumor biopsies. No 
non-tumor tissue will be analyzed. Analysis will be focused and confined to IHC and RNA 
characterization of specific immune cell populations - T-cell, MDSC, NK cells, macrophages- as 
well as markers of importance in the microenvironment such as PD-L1/2 expression. 
RNA analysis will be performed as follows: RNA will be extracted and sent to Cell Processing 
Section at DTM for microarray analysis using a standard Affymetrix array. Genetic analysis will 
be on tumor tissue only. No germ line analysis is planned or will be performed without study 
amendment and IRB approval.
1.2.12 Justification for accrual increase in Arm C2 with Amendment I
The primary purpose of this amendment is to increase enrollment in treatment Arm C2 as we 
enrolled already 10 patients. There are two patients among 10 patients (20%) treated in Arm C2, 
who had been treated with current protocol over one year and obtained durable partial response 

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(>12 months). This outcome is inspiring given the benefit of available clinical trials involved 
with immune checkpoint inhibitors in pancreatic cancer has been decimal. It will be desirable to 
have additional patients enrolled in Arm C2 to more precisely estimate its efficacy. Thus, with 
Amendment I, we would like to double the accrual number of Arm C2 from 10 to a total of 20 
evaluable patients to provide a more precise estimate of the treatment efficacy in this arm.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histopathological confirmation of pancreatic adenocarcinoma prior 
to entering this study by the Laboratory of Pathology of the NCI prior to entering this 
study
2.1.1.2
Patients must have disease that is not amenable to potentially curative resection.
Either primary in-situ (or locally-recurrent) tumor must be present and, in the opinion 
of radiation oncology, be amenable to radiation therapy as planned in the protocol or 
an extra pancreatic lesion which in the opinion of the radiation oncologist is amenable 
to radiation. Each case will be discussed at GI tumor board with multidisciplinary 
team.
2.1.1.3
Patients must have at least 1 measurable metastatic lesion by RECIST1.1 criteria.
2.1.1.4
There is no limit to the number of prior chemotherapy regimens received. Patients 
must have received at least one line of prior systemic chemotherapy for advanced 
unresectable and/or metastatic disease.
2.1.1.5
Age >18 years 
2.1.1.6
Life expectancy of greater than 3 months.
2.1.1.7
ECOG performance status 0-1 (see Appendix A)
2.1.1.8
Patients must have normal organ and marrow function as defined below:
absolute neutrophil count
> 1,000/μL
Platelets
100,000/μL
total bilirubin
%LOL VKRXOG EH   [ ULN (patients 
with Gilbert's Syndrome must have a 
total bilirubin less than 3.0 mg/dL)
serum albumin 
2.5 g/dL
Patients are eligible with ALT or AST up to 3 x ULN. (up to 5 x
ULN if liver metastases present)
Creatinine
<2X institution upper limit of normal
OR

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creatinine clearance
>45 mL/min/1.73 m2, for patients with 
creatinine levels above institutional 
normal
2.1.1.9
Patients must have recovered from any acute toxicity related to prior therapy, 
including surgery.  Toxicity should be  grade 1 or returned to baseline.
2.1.1.10 Patient must be able to understand and willing to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
Malignant ascites that is clinically detectable by physical examination or is 
symptomatic. Evidence of radiographic ascites that is not clinically significant will not be an 
exclusion criterion.
2.1.2.2
$Q\SULRU*UDGHimAE while receiving immunotherapy, including anti-CTLA4 
treatment, or any unresolved imAE > Grade 1. Note: Active or history of vitiligo will 
not be a basis for exclusion. 
2.1.2.3
Patients must not have had standard of care chemotherapy, radiotherapy, or major 
surgery within the last 2 weeks prior to entering the study. Note: Local surgeries for 
isolated lesions for palliative intent are acceptable. For recent experimental therapies,
a 28-day period of time must have elapsed before commencing protocol treatment. 
2.1.2.4
Patients with known brain metastases will be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse 
events.
2.1.2.5
Uncontrolled intercurrent illness, including, but not limited to, ongoing or active 
infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or 
psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring adverse events from Durvalumab
or tremelimumab, or compromise the ability of the subject to give written informed 
consent.
2.1.2.6
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac 
disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves’ 
disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior 
to the start of treatment. The following are exceptions to this criterion:
x
Subjects with vitiligo or alopecia
x
Requirement for intermittent use of bronchodilators or local steroid injections
x
Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement, or psoriasis not requiring systemic treatment

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2.1.2.7
History of primary immunodeficiency or history of active tuberculosis. Note: Latent 
tuberculosis will not be a basis for exclusion.
2.1.2.8
Diverticulitis (either active or history of) within the past 2 years. Note that 
diverticulosis is permitted. 
2.1.2.9
Dementia or significantly altered mental status that would prohibit the understanding 
or rendering of Information and Consent and compliance with the requirements of the 
protocol.
2.1.2.10 True positive test results for hepatitis A (IgM positive). Subjects with a history of 
hepatitis A with IgG blood test are not excluded. True positive test results hepatitis B, 
or C infection. 
2.1.2.11 Active or history of inflammatory bowel disease (colitis, Crohn’s), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated 
with diarrhea. Active or history of systemic lupus erythematosus or Wegener’s 
granulomatosis.
2.1.2.12 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of Durvalumab and tremelimumab. The following are exceptions to this 
criterion:
x
Intranasal, inhaled, and topical steroids
x
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent
x
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication)
2.1.2.13 History of sarcoidosis syndrome.
2.1.2.14 Patients should not be vaccinated with live attenuated vaccines within 1 month of 
starting Tremelimumab and Durvalumab treatment. Subjects, if enrolled, should not 
receive live vaccine during the study and 180 days after the last dose of both drugs.
2.1.2.15 HIV-positive patients receiving anti-retroviral therapy are excluded from this study 
due to the possibility of pharmacokinetic interactions between antiretroviral 
medications and Tremelimumab or Durvalumab. HIV positive patients not receiving 
antiretroviral therapy are excluded due to the possibility that Tremelimumab or 
Durvalumab may worsen their condition and the likelihood that the underlying 
condition may obscure the attribution of adverse events.
2.1.2.16 History of hypersensitivity reaction to human or mouse antibody products.
2.1.2.17 Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab and 
Durvalumab on the developing human fetus are unknown. Enrolled patients must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, the duration of study participation and 180 days 
(female patients) or 90 days (male patients) after the end of the treatment. In addition,
male patients must refrain from sperm donation for 90 days after the final dose of 
investigational product. Female patients must refrain from egg cell donation for 180 
days after the final dose of investigational product. Should a woman become pregnant 

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or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately.
2.1.2.18 Any condition that, in the opinion of the investigator, would interfere with evaluation 
of the investigational product or interpretation of subject safety or study results.
2.1.3
Recruitment Strategies
The study will be posted on the CCR website and on clinicaltrials.gov.
2.2
SCREENING EVALUATION 
Studies should be done within 28 days prior to enrollment.
x
Labs may be performed outside of NIH. Complete history (including prior hormone use) 
and physical examination (including height, weight, vital signs, EKG, and performance 
status).
x
Laboratory Evaluation
o
Hematological profile: CBC with differential and platelet count, PT, INR, aPTT, 
fibrinogen.
o
Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total and direct 
bilirubin, calcium, phosphorus, albumin, magnesium, uric acid, amylase.
o
Hepatitis A, B, C serological testing.
o
Serum or urine pregnancy test for female participants of childbearing age (in the 
absence of prior hysterectomy).
x
Imaging studies 
o
CT scan of chest, abdomen and pelvis
o
And/or MRI abdomen
x
Histologic confirmation by laboratory of Pathology of the NCI (at any time point prior to 
commencement). A block or unstained slides of primary or metastatic tumor tissue will 
be required from each participant to confirm diagnosis.
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents. Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours.

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2.3.1
Treatment Assignment Procedures:
Cohorts
Number
Name
Description
1
Cohort 1
Subjects with unresectable pancreatic cancer 
Arms
Number
Name
Description
1
A1
Durvalumab +8 Gy in 1 fraction
2
A2
Durvalumab +5 Gy in 5 fractions
3
B1*
Tremelimumab + 8 Gy in 1 fraction
4
B2*
Tremelimumab + 5 Gy in 5 fractions
5
C1
Durvalumab + Tremelimumab + 8 Gy in 1 fraction
6
C2
Durvalumab + Tremelimumab + 5 Gy in 5 fractions
Subjects in Cohort 1 will be directly assigned to Arms A1, A2, C1, C2 as follows:
x
Subjects will initially be enrolled in Arm A1 or A2. Assignment to A1 or A2 is per 
investigator discretion in consultation with multidisciplinary team.
x
Once enrollment to arms A1 and A2 are complete, subjects will be enrolled in Arms C1 
and C2, with assignment to C1 or C2 per investigator discretion in consultation with 
multidisciplinary team.
* With amendment A, the study design was revised, Arms B1 and B2 were removed, no subjects 
were assigned to B1 and B2.
2.4
BASELINE STUDIES
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame.
If laboratory tests done within 72 hours of Cycle 1 Day 1 they do not need to be repeated on Day 
1.
Labs may be performed outside of NIH.
Within 28 days prior to study intervention:
x
EKG 
x
CT scan of chest, abdomen and pelvis and/or MRI

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x
Tumor biopsy
Within 7 days prior to study intervention:
x
Tumor marker profile: CA 19-9
x
Physical exam with vital signs
Within 72 hours prior to study intervention:
x
Hematological profile: CBC with differential and platelet count, PT, INR, aPTT, 
fibrinogen.
x
Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, 
calcium, phosphorus, albumin, magnesium, uric acid, amylase.
x
Thyroid function tests (TSH, T3, T4)
x
ANA, AMA, Liver autoantibody panel (autoimmune hepatitis)
x
Immune monitoring
x
Serum or urine pregnancy test for female participants of childbearing age (in the absence 
of prior hysterectomy).
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
The proposed study is a pilot/phase I study of immune checkpoint inhibition in combination with 
short course radiation therapy in patients with unresectable pancreatic cancer.
For arms A1 and A2: Durvalumab treatment will continue until off treatment criteria are met 
(Section 3.6.1) (Figure 2).
For arms B1 and B2: It was intended for Tremelimumab treatment to continue for a total of 12 
months or until confirmed progressive disease (PD; if PD occurs before completion of the 12-
month treatment period) assessed by irRC criteria. With amendment A, the study design was 
revised and it was decided that we would not assign subjects into these treatment arms.
For arms C1 and C2: Assignment to arms C1 and C2 will only proceed following 1) NCI IRB 
approval of updated safety information of ongoing combination therapy studies evaluating
tremelimumab in combination with Durvalumab and 2) submission to the FDA of a revised 
protocol specifying the selected drug doses and dose schedule.
Patients assigned to arms C1 and C2 will receive 1500 mg durvalumab via IV infusion q4w for 
up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and 
then continue 1500 mg durvalumab q4w until off treatment criteria are met (Section 3.6.1) (see 
Figure 3). Patients with a body weight less than or equal to 30 kg should be dosed using a 
weight-based dosing schedule (i.e. 1mg/kg for tremelimumab and 20mg/kg for durvalumab). Flat 
weight dosing will be used for all other patients including those who are greater than 75Kg e.g.
100-110Kg. Tremelimumab will be administered first. Durvalumab infusion will start 
approximately 1 hour after the end of tremelimumab infusion. The duration will be 
approximately 1 hour for each infusion. A 1 hour observation period is required after the first 
infusion of durvalumab and tremelimumab. If no clinically significant infusion reactions are 

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observed during or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab 
infusion).
Subjects who permanently discontinue treatment will be followed. All subjects will be followed 
for survival. Follow up details are outlined in Section 3.5.
-
The original study design was to have 6 separate treatment arms:
x
Arms A1 and A2: anti-PDL1 (Durvalumab) in combination with radiation
o
Arms B1 and B2: anti-CTLA4 (tremelimumab) in combination with radiation
(never opened)
x
Arms C1 and C2: anti-PDL1 (Durvalumab) and anti-CTLA4 (tremelimumab) in 
combination with radiation.
- Arms differ by the quantity of radiation.
-
Arms A1 and C1: 8Gy in 1 fraction (Total = 8Gy) Day 1.
Arms A2 and C2: 5Gy in 5 fractions (Total = 25Gy) for 5 days which will be 
identified as Day -3, Day -2, Day -1, Day 0, Day 1.
- Patient allocation:
x
No randomization will occur.
x
The subjects will be assigned to arms sequentially i.e. A before C (the latter of 
which will require IRB approval.)
- The radiation schedule the patient receives will be decided through multidisciplinary 
discussion with the radiation oncologist and based on clinical factors rather than dictated 
purely by sequence based on when the patient happens to be seen. The reason for this is 
based on our experience thus far where we commonly encounter one of two specific 
scenarios as follows: A) If a patient has a relatively large pancreatic mass which is 
causing pain we would like the flexibility to administer the 5x5Gy schedule as this 
would at least give a good palliative dose of radiation; B) Some patients have very small 
pancreatic primaries which would be more suited to the lower dose of radiation. 
Mandatory baseline and Day 29 tumor biopsies will be obtained on all patients.
However, if a patient has technically biopsiable disease but the interventional radiologist 
has concerns that pursuing the biopsy increases the risk to above average, or if pursuing 
the biopsy creates additional logistical complications (availability, pre-anesthesia 
requirements, etc.) which causes delays or inconvenience to an unreasonable degree, we 
will forgo at investigator discretion.
- Given that the primary aim of this study is to assess safety and feasibility of immune 
checkpoint inhibition in combination with radiation the DLT evaluation period will 
extend for a total of 6 weeks following completion of radiation.
3.1.1
Arms A1 and A2
Figure 2: Durvalumab in combination with radiation:

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Patients with pancreatic cancer who satisfy the eligibility criteria will receive Durvalumab
10mg/kg as an intravenous infusion until off-treatment criteria are met.
Arm
Checkpoint inhibitor
SBRTa
dose/schedule
N
A1
Durvalumab
10mg/kg/q2w
8Gy x 1#
10
A2
Durvalumab
10mg/kg/q2w 
5Gy x 5#
10
aSBRT= Stereotactic body radiation therapy. 
Timing of checkpoint inhibitor with regard to RT: If RT given for 1 day (Arm A1), 
checkpoint inhibitor given on D1, immediately post RT. If RT given for 5 days (Arm A2), 
checkpoint inhibitor(s) given on the last day of RT immediately post RT and this will be 
identified as D1.
-
Initially N=10 patients will be assigned to Arm A1 as per the table. Patients in Arm A1 will 
undergo external beam radiation to the pancreatic mass comprising 8Gy in a single fraction 
on Day 1.
-
The goal will be to evaluate 10 patients in A1 and then 10 in A2, provided that no more 
than 1 of the first 6 in A1 or A2 has a DLT, and that no more than 3 of 10 patients in either 
A1 or A2 has a DLT. If either of these is exceeded, then no further patients would be 
enrolled in arms A1 and A2.
-
Patients in Arm A2 will undergo external beam radiation to the pancreatic mass comprising 
25Gy in 5 fractions (5Gy per fraction) for 5 days, on Day -3, Day -2, Day -1, and Day 0,
Day 1.

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-
Restaging CT scan (or MR) will be performed every 8 weeks. RECIST 1.1 and modified
Immune-related RECIST criteria will be applied.
3.1.2
Arms C1 and C2 
Figure 3: Durvalumab and Tremelimumab in combination with radiation.
Patients with pancreatic cancer who satisfy the eligibility criteria will receive 1500 mg 
durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w until off-
treatment criteria are met (see graphic above). Tremelimumab will be administered first. 
Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. 
The duration will be approximately 1 hour for each infusion. A 1 hour observation period is 
required after the first infusion of durvalumab and tremelimumab. If no clinically significant 
infusion reactions are observed during or after the first cycle, subsequent infusion observation 
periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion).
Arm
Checkpoint inhibitor
SBRTb
dose/schedule
N
Start date
C1
Durvalumab 1500mg +
Tremelimumab 75mg
8Gy x 1#
10
March
2016
C2
Durvalumab 1500mg +
Tremelimumab 75mg
5Gy x 5#
20
aSBRT= Stereotactic body radiation therapy. 
Timing of checkpoint inhibitor with regard to RT: If RT given for 1 day (Arm C1), checkpoint inhibitor 
given on D1, immediately post RT. If RT given for 5 days (Arm C2), checkpoint inhibitor(s) given on the 
last day of RT immediately post RT and this will be identified as D1.

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34
-
The goal will be to evaluate 10 patients in C1 and then 20 in C2, provided that no more 
than 1 of the first 6 in C1 or C2 has a DLT, and that no more than 3 of first 10 patients in 
either C1 or C2 has a DLT. If either of these is exceeded, then no further patients would be 
enrolled in arms C1 and C2.
-
Patients in Arm C2 will undergo external beam radiation to the pancreatic mass comprising 
25Gy in 5 fractions (5Gy per fraction) for 5 days, on Day -3, Day -2, Day -1, and Day 0,
Day 1.
-
Restaging CT scan (or MR) will be performed every 8 weeks. RECIST 1.1 and Immune-
related RECIST criteria will be applied.
-
The decision on which radiation schedule to be employed will be based on technical and 
clinical factors and after discussion with and at the discretion of the radiation oncologist.
3.1.3
Protocol Stopping Rules
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for grading systemic toxicity. For safety reasons, new subject enrollment will be temporarily 
halted for either of the following events.
x
One occurrence of grade 5 toxicity by the NCI-CTCAE version 4.0 attributable to the 
treatment regimen.
x
Two occurrences of grade 4 toxicity by the NCI-CTCAE version 4.0 attributable to the 
treatment regimen.
Discussions will be had, if applicable, with the NCI IRB and Sponsor regarding necessary 
amendment in order to resume enrollment.
3.1.4
Re-treatment
If patient is taken off treatment for reasons other than disease progression or unacceptable 
toxicity, attributed to Durvalumab, but later, in the opinion of Investigator, can benefit from re-
starting of Durvalumab and meets eligibility criteria, re-treatment with Durvalumab will be 
initiated (q4w). Screening evaluations will be repeated. No research procedures will be done
during re-treatment; however, clinical assessments will be performed per study calendar.
3.2
DOSE LIMITING TOXICITIES 
3.2.1
Definition of Dose-limiting Toxicities (DLTs):
A DLT will be defined as any Grade 3 or higher treatment-related (related to any investigational 
product) toxicity that occurs during the DLT evaluation period, including:
3.2.1.1
Any Grade 4 immune-mediated AE (imAE)
3.2.1.2
Any Grade 3 im$(WKDWGRHVQRWGRZQJUDGHWR*UDGHZLWKLQGD\VDIWHURQVHWRI
the event despite maximal supportive care including systemic corticosteroids or 
GRZQJUDGHWR*UDGHRUEDVHOLQHZLWKLQGD\V
3.2.1.3
Liver transaminase elevation higher than 8 × upper limit of normal (ULN) or total 
bilirubin higher than 5 × ULN

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35
3.2.1.4
$Q\*UDGHSQHXPRQLWLVWKDWGRHVQRWUHVROYHWR*UDGHZLWKLQGD\VRIWKH
initiation of maximal supportive care.
3.2.2
Definition of Dose-limiting Toxicities (DLTs) excludes the following conditions:
x
Grade 3 asymptomatic elevation of pancreatic enzymes which resolve to grade 1 within 
28 days.
x
*UDGHUDVKRUSUXULWXVWKDWGRZQJUDGHVWR*UDGHZLWKLQGD\VDIWHURQVHWRIWKH
event with maximal supportive care including systemic corticosteroids or GRZQJUDGHWR
Grade 1 or baseline (on oral prednisone 10mg/day) within 30 days.
x
Grade 3 endocrinopathy that is asymptomatic, managed with or without corticosteroid 
therapy and/or hormone replacement and which downgrades WR  *UDGH  RU EDVHOLQH
within 30 days. Grade 3 inflammatory reaction attributed to a local antitumor response 
(e.g., inflammatory reaction at sites of metastatic disease, lymph nodes, etc.).
x
Dosing may continue despite concurrent vitiligo and alopecia of any AE grade
x
Grade 3 pyrexia, headache, and chills that are controlled with appropriate supportive 
treatment and do not result in permanent treatment discontinuation 
x
Grade 3 nausea, vomiting, or mucositis/esophagitis that is felt to be related to the 
radiation and that responds to maximal supportive care within 3 days
x
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) 
in the absence of a clear alternative etiology. In the absence of clinical abnormality, 
repeat laboratory testing will be conducted to confirm significant laboratory findings 
prior to designation as a DLT.
3.2.3
Investigational Drug Administration
3.2.3.1
The first day of dosing is considered Day 1. 
3.2.3.2
Tremelimumab IV infusion will be approximately 1 hour in duration Durvalumab will 
be approximately 1 hour in duration; 
3.2.3.3
For Arms C1 and C2: Tremelimumab will be administered first. Durvalumab infusion 
will start approximately 1 hour after the end of tremelimumab infusion.
3.2.3.4
Each dose of investigational product should be administered using the following
guidelines: 
1) Investigational product must be administered at room temperature (25°C) by controlled 
infusion at a rate of 250 mL/hr. via an infusion pump into a peripheral vein. Prior to the 
start of the infusion, ensure that the bag contents are at room temperature to avoid an 
infusion reaction due to the administration of the solution at low temperatures.
2) Investigational product must not be administered via IV push or bolus but as a slow IV 
infusion. The entire content of each IV bag will be infused using an infusion pump. 
3) The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration will QHHGWREHHTXLSSHGZLWKRUȝPLQ-line filters. 

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36
4) If there are no requirements to slow, interrupt, or permanently stop the infusion, the 
anticipated infusion time to deliver each dose (250 mL) is anticipated to be
approximately 60 minutes.
5) For infusion-related reactions: The infusion rate of Durvalumab or tremelimumab may be 
decreased by 50% or temporarily interrupted until resolution of the event. 
Acetaminophen and/or antihistamines may be administered per institutional standard at 
the discretion of the investigator. Consider premedication prior to subsequent doses.
6) When an IV bag is used for the infusion, the IV line will be flushed with a volume of 
normal saline equal to the priming volume of the infusion set used after the contents of 
the IV bag are fully administered (unless prohibited by institutional practice). The 
duration of the investigational product administration will be recorded.
3.2.4
Durvalumab Drug Administration 
Each dose of Durvalumab should be administered using the following guidelines:
1) Durvalumab will be administered as an IV infusion over approximately 60 minutes.
2) When an IV bag is used for the infusion, the IV line will be flushed with a volume of 
normal saline equal to the priming volume of the infusion set used after the contents of 
the IV bag are fully administered (unless prohibited by institutional practice). 
3) Since the compatibility of Durvalumab with other IV medications and solutions, other 
than normal saline (0.9% [w/v] Sodium Chloride for Injection), is not known, the 
Durvalumab solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
4) The duration of the investigational product administration will be recorded.
3.2.5
Tremelimumab Dose Administration:
Tremelimumab will be administered as an IV infusion (250 mL) over approximately 1 hour. 
When an IV bag is used for the infusion, the IV line will be flushed with a volume of normal 
saline equal to the priming volume of the infusion set used after the contents of the IV bag are 
fully administered (unless prohibited by institutional practice).
3.2.6
Monitoring of Dose Administration 
Vital signs will be collected within 30 minutes before and within 30 minutes after investigational 
product infusion only. Patients will need to stay for one hour post the infusion to assess for any 
delayed reactions for the first infusion. For subsequent infusions patient will be required to stay 
for only 30 minutes or at the discretion of the Principal Investigator.
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis, 
as per local institutional guidelines.

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3.3
DOSING DELAYS
The following broad guidelines for dose delivery schedule delays and alternations apply to both 
of the planned dosages of Tremelimumab and Durvalumab and are dependent on the clinical and 
laboratory assessment on the day of dosing. Tremelimumab and Durvalumab can be delivered 
within 72 hours of planned interval to accommodate scheduling issues/logistics.
3.3.1
Immune-mediated AEs (imAEs)
Based on the mechanism of action of Durvalumab and tremelimumab leading to T-cell activation 
and proliferation, there is the possibility of observing immune-mediated AEs (imAEs) during 
the conduct of this study. Potential imAEs may be similar to those seen with the use of 
ipilimumab, BMS-936558 (anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may 
include 
immune-mediated 
enterocolitis, 
dermatitis, 
hepatitis
(hepatotoxicity), 
and 
endocrinopathies[14, 16, 44]. These AEs are inflammatory in nature and can affect any organ. 
With anti-PD-LI and anti-CTLA-4 combination therapy (arms C1 and C2), the occurrence of 
overlapping or increasing cumulative toxicities that include imAEs, could potentially occur at 
higher frequencies than with Durvalumab (arms A1 and A2) monotherapy.
Subjects should be monitored for signs and symptoms of imAEs. In the absence of an alternate 
etiology (e.g., infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy. Dosing modification and 
management guidelines for imAEs specified in Appendix D.
3.3.2
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events 
in order to characterize and understand them in association with the use of this investigational 
product.
x
Liver: Immune Checkpoint inhibitors (Tremelimumab and/or Durvalumab) can result in 
severe and fatal inflammation of the liver most commonly manifested as elevation of 
transaminases and hyperbilirubinemia. Liver enzymes and liver function tests (hepatic 
transaminase and bilirubin levels) will be evaluated and patients assessed for signs and 
symptoms of hepatitis before each dose of Tremelimumab and Durvalumab. Guidelines 
for management of subjects with hepatic function abnormality are outlined in Appendix 
D.
x
Pneumonitis Adverse events of pneumonitis are also of interest, as pneumonitis has been 
observed with anti-PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary 
consultation is highly recommended.
x
Infusion Reactions. Adverse events of infusion reactions (also termed infusion-related 
reactions) are of special interest and are defined, for the purpose of this protocol, as all 
AEs occurring from the start of the study treatment infusion up to 48 hours after the 
infusion start time. 

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38
x
Hypersensitivity Reactions: In case of hypersensitivity reactions, the investigator should 
institute treatment measures deemed medically appropriate per institutional guidelines 
-
Grade 1 = Transient flushing or rash; drug fever < 38°C
-
Grade  5DVKIOXVKLQJXUWLFDULDG\VSQHDGUXJIHYHU&
-
Grade 3 = Symptomatic bronchospasm with or without urticaria; parenteral 
medication(s) indicated; allergy-related edema/angioedema; hypotension; anaphylaxis
-
Grade 4 = Anaphylaxis
-
Grade 5 = Death
3.3.2.1
Autoimmunity
If a subject experience an AE that is thought to be possibly of autoimmune nature (e.g.,
thyroiditis, hepatitis, pancreatitis, thrombocytopenia, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for appropriate autoimmune antibody testing and 
immediate consideration of endocrinology consultation. If specific auto-antibodies are present, 
the blood sample taken for storage at baseline can be tested for the presence of auto antibodies. 
Continuation of investigational product in the presence of immune-mediated events should be 
done by the investigator with consideration to risk-benefit analysis.
3.4
SPECIFIC PROCEDURES FOR STEREOTACTIC BODY RADIATION THERAPY (SBRT)
3.4.1
Radiotherapy administration
3.4.1.1
Modality, Fractionation, and Total Dose
Radiation will be delivered with megavoltage external beam radiation with beam energies of 
6MV or higher. For Arms A1 and C1 treatment will be delivered in 8Gy as a single fraction. For 
Arms A2 and C2 treatment will be delivered in 5Gy fractions for 5 days. The decision on which 
radiation schedule to be employed will be based on technical and clinical factors and after 
discussion with and at the discretion of the radiation oncologist.
3.4.1.2
Simulation
Patients will be simulated supine with the addition of a 4D CT if appropriate. A stereotactic 
immobilization device with abdominal compression will be used. Oral contrast will be delivered 
approximately one hour prior to simulation to allow opacification of small bowel unless 
contraindicated. IV contrast may be delivered for the simulation if deemed necessary by the 
treating radiation oncologist.
3.4.1.3
Volume definitions 
GTV: The gross tumor volume (GTV) will be defined as all gross disease evident on imaging 
and examination at the site of treatment PTV: The planning target volume will be a 3-5 mm 
concentric expansion on the GTV. An additional margin of up to 3 mm may be added as needed 
if 4D CT reveals extensive respiratory motion of the target.
3.4.1.4
Target lesions 

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Target lesions for radiation will be primary or recurrent pancreatic lesions. If there is no 
pancreatic lesion present or in the opinion of the radiation oncologist, there is a more amenable 
lesion outside of the pancreas, this may be designated as a target lesion.
3.4.1.5
Dose specification
The PTV doses should meet the following criteria:
1) >93% of the PTV should receive at least 93% of the prescribed dose.
2) < 5% of the PTV should receive more than 110% of the prescribed dose. Efforts will be 
made to reduce heterogeneity if possible.
Normal Structures The following dose goals will apply for normal tissues:

Kidney: mean dose < 10 Gy (total kidney volume)

Small bowel: maximum 35 Gy, mean <25Gy, V30< 5cc, V35Gy <1cc

Duodenum: maximum 35Gy, mean <25Gy, V30< 5cc, V35Gy <1cc

Stomach: 35 Gy, mean <25Gy, V30< 5cc, V35Gy <1cc

Large bowel: maximum 35Gy, mean <25Gy, V30< 5cc, V35Gy <1cc

Liver: V30<10%

Spinal cord: maximum 20Gy
Daily treatment delivery
Treatment will be delivered at the discretion of the radiation oncologist.
Localization will be verified with pretreatment imaging prior to every fraction. Ideally, this will 
include Tomotherapy localization or cone beam CT, although kV/kV imaging may be used if 
necessary.

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3.5
STUDY CALENDAR
Scree
ning
Basel
ine n
C1
C2
C3
D1 of 
every 
subsequ
ent 
cycle
EOT
j
FU 
k
-3
-2
-1
0
1
8
15
22
1
8
15
22
1
8
15
22
Durvalumab a
X
X
X
X
X
X
X
Tremelimumab b, o
X
X
X
X
SBRT c Arms A1, C1
X
SBRT c Arms A2, C2
X
X
X
X
X
Informed consent 
X
Medical history
X
Concomitant meds
X
X
X
X
X
Formal adverse event 
evaluation 
X
X
X
X
X
X
Physical exam 
X
X
X
X
X
X
X
Vital Signs
X
X
Xi
Xi
Xi
Xi
Xi
Xi
X
X
CBC d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis A, B, C
X
PT, INR, PTT,
fibrinogen d
X
X
X
X
Xp
X
Xp
X
TSH, T3, T4 d
X
X
X
X
Biochemical profile d, e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Scree
ning
Basel
ine n
C1
C2
C3
D1 of 
every 
subsequ
ent 
cycle
EOT
j
FU 
k
-3
-2
-1
0
1
8
15
22
1
8
15
22
1
8
15
22
Uric acid, amylase d
X
X
X
X
p
X
p
X
p
X
X
p
X p
X
p
X
X
p
X
p
X p
X
X
CA 19-9
X
X
X
X
X
EKG
X
X
X
X
X
Restaging radiologic 
Evaluation
X
X
X
X f
Tumor biopsy g, o
X
X
Immune monitoring o
X
X
X
X h
Pharmacokinetic 
studies o
X
X
X
X
X
X h
X
X m
Immunogenicity
(ADA) o
X
X
X h
X
X m
ANA, AMA, Liver 
autoantibody panel 
(autoimmune hepatitis)
o
X
X h
T cell activation/ICOS 
expression/ functional 
analyses /
immunodiversity 
(PBMC) o
X
X
X
X
X
X h
X

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Scree
ning
Basel
ine n
C1
C2
C3
D1 of 
every 
subsequ
ent 
cycle
EOT
j
FU 
k
-3
-2
-1
0
1
8
15
22
1
8
15
22
1
8
15
22
Plasma-based assays 
for circulating 
receptors/ligands e.g.,
PDL1o
X
X
X
X
X
X h
X
X m
Advance Directive l
X
Serum or urine 
pregnancy test
X
X
Histologic confirmation
Xo
a Subjects will receive one dose of Durvalumab on Days 1 and 15 in Arms A1 and A2 and on Day 1 only in Arms C1 and C2 until off-
treatment criteria are met.
b Subjects will receive 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles.
c Hypofractionated radiation will be administered to the pancreatic primary tumor OR a lesion noted outside the pancreas per the 
discretion of the radiation oncologist.
d For all labs a ‘+/- 72 hr.’ window applies, with the exception of those needed to determine proceeding with treatment. Labs may be 
performed outside of NIH.
e Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, calcium, phosphorus, albumin, magnesium.
f Restaging CT /MRI scan every 8 weeks (+/- 1 week) to evaluate TTP in target lesion.
g Mandatory baseline and post-RT tumor biopsies (D29 approx. (+/- 7 days) will be obtained on all patients.
h Refer to section 5 for detailed timing schema
I collected within 30 minutes before and within 30 minutes after investigational product infusion.

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j End Off Treatment Visit: patients will be invited to clinical center approximately 30 days following the last dose of study drug. If 
patents are not able or not willing to come, they will be asked by phone for performance status, any adverse events and new cancer 
treatment. 
k FU Follow Up: all study subjects will be followed for overall survival. Follow-up will be semi-annual telephone contact to assess 
survival status. Every attempt will be made to contact patient/subject including: contacting referring physician, contacting emergency 
contact patient identified on admission, checking SSDI (Social Security Death Index).
l Filling out of the Advance Directive will be offered, but obtaining of it is not required. For details see Section 10.3
m Done at day 90 after last dose of drug, but only if patient is willing to come for a visit to NIH
n Tests done at screening do not need to be repeated on baseline if performed in designated time frame.
O will not be done during re-treatment
p Optional 

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3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to documenting removal from off study, effort must be made to have all subjects complete 
a safety visit approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy
x
Withdrawal of consent from further treatment with investigational product 
x
Unacceptable Toxicity as defined in section 3.2
x
Pregnancy or intent to become pregnant
x
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (e.g., refusal to adhere to scheduled visits)
x
Initiation of alternative anticancer therapy including another investigational agent
x
Progressive Disease as defined in section 6.2.4. NOTE: While RECIST PD will be noted 
and recorded the immune-related RECIST criteria will be applied to determine 
discontinuation of study treatment.
x
Subject who has received any amount of infliximab or other tumor necrosis factor alpha 
inhibitor
x
Intercurrent illness that prevents further administration of treatment
x
Investigator discretion
3.6.2
Criteria for Removal from Study
x
Lost to follow-up
Subjects will be considered lost to follow-up only if no contact has been established by the time 
the study is completed such that there is insufficient information to determine the subject’s status 
at that time. Subjects who refuse continuing participation in the study including telephone 
contact should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing subjects throughout 
the study period. If contact with a missing subject is re-established, the subject should not be 
considered lost to follow-up and any evaluations should resume according to the protocol.
x
Death
x
Patient voluntarily chooses to withdraw from the protocol
x
Investigator discretion
x
PI decision to close the study
x
Completed study follow-up period
Subjects who permanently discontinue treatment may either be considered to have completed the 
study or not to have completed the study. An individual subject will be considered to have 
completed the study if the subject was followed through the last protocol-specified 
visit/assessment (including telephone contact) regardless of the number of doses of 

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investigational product that was received. Subjects will be considered not to have completed the 
study if consent was withdrawn or the subject was lost to follow-up.
3.6.3
Off Protocol Therapy and Off Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed 
and 
sent 
via 
encrypted 
email 
to:
NCI 
Central 
Registration 
Office  
ncicentralregistration-l@mail.nih.gov.
4
CONCOMITANT MEDICATIONS/MEASURES
All routine and appropriate supportive care (including blood products) will be provided during 
this study, as clinically indicated, and in accordance with the standard of care practices. Clinical 
judgment should be utilized in the treatment of any AE experienced by the patient.
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in Section 4.1. Best supportive care 
(including antibiotics, nutritional support, correction of metabolic disorders, optimal symptom 
control and pain management [including palliative radiotherapy, etc.]) should be used when 
necessary for all subjects. Information on all concomitant medications, administered blood 
products, as well as interventions occurring during the study must be recorded on the patient’s 
eCRF.
4.1
PROHIBITED CONCOMITANT MEDICATIONS
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following medications are considered exclusionary during the study. The sponsor must be 
notified if a subject receives any of these during the study.
1. Any investigational anticancer therapy
2. Monoclonal antibodies against CTLA-4, PD-1, or PD-L1 through 90 days post last dose 
during the study
3. Any 
concurrent 
chemotherapy, 
radiotherapy 
(except 
palliative 
radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-Į EORFNHUV 8VH RI LPPXQRVXSSUHVVLYH PHGLFDWLRQV IRU WKH PDQDJHPHQW RI
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled, topical, and intranasal corticosteroids is permitted. Temporary 
uses of corticosteroids for concurrent illnesses (e.g., food allergies, CT contrast 
hypersensitivity, etc.) are acceptable.

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5. Live attenuated vaccines during the study through 180 days after the last dose of both 
investigational products
6. Inactivated vaccinations ± 30 days around any dose of investigational product.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
The correlative studies which we wish to perform are outlined below and summarized in the 
table. All samples will be sent to Dr. Figg’s lab for processing and storage until they are 
distributed to Dr. Greten’s lab or MedImmune for sample analysis as described in the protocol.
A description of each test including a brief statement of rationale and processing information is 
made below.
Test/assay
Volume blood 
(approx.)
Type of 
tube
Collection point (+/-
48hrs)
Location of 
specimen 
analysis
Immune- monitoring
120 mL (for 
PBMC)
EDTA
Baseline on day of biopsy,
C2D1, C3D1, C4D1
Greten Lab
5-10 mL (for 
serum)
EDTA
PK
3 mL
SST
C1D1 (pre- dose and End-
of Infusion (EOI)*) 
C1D8 (local patients only)
C1D15 (local patients 
only)
C2D1 (pre-dose)
C3D1 (pre-dose)
C4D1 (pre-dose)
C7D1 (pre-dose and End-
of Infusion(EOI)*)
C10D1 (pre-dose)
C13D1 (pre-dose)
End-of-treatment (EOT), 
and 
90-days post last dose. 
*End of infusion PK 
samples should be 
collected within 
approximately 15 minutes. 
C1D1 and C7D1: pre-
MedImmune /
Intertek Alta

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Test/assay
Volume blood 
(approx.)
Type of 
tube
Collection point (+/-
48hrs)
Location of 
specimen 
analysis
infusion and immediately 
post infusion.
Immunogenicity
(Antidrug antibody 
monitoring) 
4 mL
SST
Pre-dose: C1D1, C2D1, 
C4D1, C7D1, C10D1,
C13D1
End of treatment
90-day post last dose
Medimmune/PPD
ANA
4 mL
SST
Baseline and C4D1
CC Department 
of Laboratory 
Medicine (DLM)
AMA & 
Liver/kidney 
microsomal antibody
4 mL
SST
Baseline and C4D1
CC DLM will 
send to Mayo 
Labs
T cell 
activation/ICOS 
expression
(PBMC)
12 mL
ACD-B (6 
mL 
collection 
tube)
Pre infusion C1D1, C1D8
(local patients only),
C1D15 (local patients 
only), C2D1, C3D1, 
C5D1, and EOT (end of 
treatment) 
Medimmune/ 
Quintiles
Plasma-based assays 
for circulating 
receptors/ligands e.g. 
PDL1
6 mL
EDTA
C1D1 (pre- dose and End-
of Infusion (EOI)*
C1D8 (local patients only)
C1D15 (local patients 
only)
C2D1 (pre-dose)
C3D1 (pre-dose)
C4D1 (pre-dose)
C7D1 (pre-dose and End-
of Infusion(EOI)*)
C10D1 (pre-dose)
C13D1 (pre-dose)
End-of-treatment (EOT), 
and 
90-days post last dose. 
*End of infusion PK 
Medimmune

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Test/assay
Volume blood 
(approx.)
Type of 
tube
Collection point (+/-
48hrs)
Location of 
specimen 
analysis
samples should be 
collected within 
approximately 15 minutes. 
C1D1 and C7D1: pre-
infusion and immediately 
post infusion.
Mandatory tumor 
biopsy
NA
NA
Baseline + C2D1
Pathology
5.2
NCI CORRELATIVE STUDIES
5.2.1
Immune monitoring (all arms)
We will analyze PBMC for quantitative and functional changes of effector cells as well as 
analyze sera for cytokines and chemokines. The effect on (i) CD4 T cell number and activity, (ii) 
CD8 T cell number and activity, (iii) NK cell number and activity, (iv) Treg number, (vi) 
MDSC: frequency + functional assay, (vii) selected cytokines in serum. 
Patients will undergo blood sampling (c.120mls blood) on the time points outlined in the table 
(+/- 48 hrs.). Blood will initially be sent to the Figg’s Blood Processing Core (BPC) for 
barcoding and processing (Section 5.4.1). On certain occasions, the blood may also be brought to 
the Greten lab for processing and analysis. PBMC will be isolated by Ficoll density 
centrifugation. Aliquots of 1 x 107 PBMC/tube will be individually frozen – after initial handling 
and processing at the Figg laboratory.
5.2.2
Liver autoantibody panel for autoimmune hepatitis (AIH)
The AIH Diagnostic Panel includes tests for actin (smooth muscle) antibody, antinuclear 
antibodies (ANAs), and liver/kidney microsome antibody (LKM-1). ANAs and actin antibody 
are associated with type 1 AIH, the most common form in the United States, while LKM-1
antibody is associated with type 2 AIH, more commonly found in Europe and in some South 
American countries. The panel also includes mitochondrial antibody, which can help 
differentiate AIH from PBC. Given that autoimmune hepatitis is a potential complication of 
immune checkpoint inhibition we will perform this panel of autoimmune antibodies to 
investigate this. Samples will be collected at baseline and on D85 approximately. These antibody
titers are exploratory and will not be used to guide therapy in the absence of clinical correlation.
5.2.3
Mandatory tumor biopsy
An image guided tumor biopsy will be attempted (if feasible) at baseline and (approx.) D29 (+/-
7 days) for analysis of immune infiltration. Tumor Tissue will be processed by the Department of 

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Pathology, NCI, NIH (Dr. David Kleiner). Two core biopsies will be the attempted. For each 
specimen obtained the core will be divided in two parts for Surgical Pathology and frozen 
preservation. If for some reason only one core is able to be obtained, the core will be divided, 
with half submitted to Surgical Pathology and half used for PD studies.
1) Formalin-fixed.
i.
The half fixed in 10% formalin will be submitted to Surgical Pathology, 
CCR/NCI (Bldg. 10, 2N212). 
ii.
The specimens will have routine H&E stains made as well as 5 additional 
unstained sections. 
2) Frozen-preservation
i.
Two 1.5 ml cryogenic vials (obtained from Greten lab) will be labeled with the 
patient’s name, accession number (HP#) and date using a waterproof sharpie. 
ii.
The isotherm flask (Greten lab) will be filled with liquid nitrogen on the morning 
of the procedure and will be available together with the cryogenic vials for pick 
up from there when radiology.
iii.
Once the biopsy is ready, the half-core to be cryopreserved will be transferred into 
an empty 1.5-mL cryogenic vial with the use of sterile, pre-chilled (in dry ice) 
disposable tweezers.
iv.
The vial with specimen will be immediately dropped into liquid nitrogen 
contained in an isotherm flask. 
v.
The frozen half will be transferred in the isotherm flask to the protocol-specified 
location for that particular analysis. 
5.2.4
Details of Planned Tumor Analysis
We will attempt to perform immunohistochemically and gene analysis of all tumor biopsies. IHC 
analysis will include characterization of immune cell populations - T-cell, MDSC, NK cells, 
macrophages- as well as markers of importance in the microenvironment such as PD-L1/2 
expression. 
RNA analysis will be performed as follows: RNA will be extracted and sent to Cell Processing 
Section at DTM for microarray analysis using a standard Affymetrix array. Genetic analysis will 
be on tumor tissue only. No germ line analysis is planned or will be performed without study 
amendment and IRB approval.
5.3
MEDIMMUNE PLANNED STUDIES
All samples will be processed and cryopreserved in the Figg laboratory. Transfer in batch to 
Medimmune/vendor facilities for further analysis will occur at a later date. Please also see
Appendix B.

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5.3.1
Pharmacokinetics
The time points for PK sampling are described in the table in section 5 above. A validated 
enzyme-linked immunosorbent assay (ELISA) will be used for the quantitative determination of 
Tremelimumab and Durvalumab in human serum.
Samples will be collected: Day 1 (pre-dose and End of infusion), Day 8 (pre-dose), Day 15 (pre-
dose in case of q 2weeks regimen), Day 29 (pre-dose), Day 57 (pre-dose), Day 85(pre-dose), 
Day 169 (pre-doe and End of Infusion), Day 253 (pre-dose), Day 337 (pre-dose), End of 
treatment and 90 day post last dose. 
5.3.2
Immunogenicity 
The time points for the assessment of anti-Tremelimumab and anti-Durvalumab antibodies are 
described in the table in section 5 above. A validated electrochemiluminescence assay (ECLA) 
using a Meso Scale Discovery (MSD) platform will be used for the detection of anti-drug 
antibodies against Tremelimumab and Durvalumab in human serum.
Samples will be collected Pre-dose Day 1, Day 29, Day 85, Day 169, Day 253, Day 337. 
Additional samples will be collected End of treatment, 90-day post last dose. 
5.3.3
T CELL Activation/ICOS expression
The number and subsets of T cells as well as other immune cells will be evaluated in PBMC by 
flow cytometry. The activation status of T cells will also be assessed in the same study. Whole 
blood samples will be collected pre-infusion at D1, D8, D15 (in case of q2 regimen), D29, D57,
D113 and EOT. Samples will be processed to PBMC and stored frozen until time of analysis. 
Additionally, absolute lymphocyte counts at baseline and in response to Tremelimumab and 
Durvalumab treatment will be evaluated for any relationship with treatment outcome. Isolated 
PBMCs may be used for additional functional analysis or assessment of the diversity of the 
immune cell repertoire
5.3.4
Plasma-based assays for circulating receptors/ligands e.g. PDL1 
Plasma samples are to be collected at the time points listed directly into plastic 6 ml lavender
vacutainer tube with EDTA as anticoagulant. 2-3 ml of obtained plasma are to be aliquoted (1 ml 
each) and frozen. Samples may be analyzed for circulating levels of soluble factors such as CRP, 
cytokines, and chemokines. They may include but are not limited to soluble CTLA-4, soluble 
PD-L1, soluble B7.1/B7.2, soluble IL-6R, vascular endothelial growth factor, fibroblast growth 
factor, IL-1 IL-2, IL-4, IL-6, IL-8, IL-10, cancer biomarkers (alpha fetoprotein, 
carcinoembryonic antigen, cancer antigen 125, prostate specific antigen, soluble mesothelin-
related protein [SMRP]), granzyme B, IFN, C-X-C motif chemokine 10 (CXCL10), suppressor 
of cytokine signaling 3 (SOCS3), a proliferation inducing ligand, B-cell activating factor, 
insulin-like growth factor (IGF)-1, IGF-2, and autoantibodies to host and tumor antigens and 
explore their association with Tremelimumab and Durvalumab treatment and clinical outcome.
Samples will be collected: Day 1 (pre-dose and End of infusion), Day 8 (pre-dose), Day 15 (pre-
dose in case of q 2weeks regimen), Day 29 (pre-dose), Day 57 (pre-dose), Day 85(pre-dose), 
Day 169 (pre-dose and End of Infusion), Day 253 (pre-dose), Day 337 (pre-dose), End of 
treatment and 90 day post last dose. 

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5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All 
samples will be sent to Dr. Figg’s lab for processing and storage until they are distributed to Dr. 
Greten’s lab or MedImmune for sample analysis as described in the protocol.
5.4.1
Samples Managed by Dr. Figg’s Blood Processing Core (BPC) 
5.4.1.1 BPC contact information 
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044.
5.4.1.2 Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course. 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
5.4.1.3 Sample Storage 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80qC
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.

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5.4.2
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not embedded 
in paraffin is stored in formalin for up to three months, in accordance with College of American 
Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) 
guidelines, and then discarded. Following completion of the diagnostic workup, the slides and 
tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are catalogued 
and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled.
5.4.3
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described in 
Section 5.4.1.3. The study will remain open so long as sample or data analysis continues.
Samples from consenting subjects will be stored until they are no longer of scientific value or if a 
subject withdraws consent for their continued use, at which time they will be destroyed. The PI 
will report any loss or destruction of samples to the NCI IRB as soon as he is made aware of 
such loss. If the patient withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved.
x
The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The NCI investigators will be responsible for the collection, maintenance, and quality control of 
the study data. Clinical data will be entered into the NCI C3D electronic database at least once 
every two weeks when patients are enrolled on the trial. Protocol-specific eCRFs will be 
developed for this trial in C3D. All data will be kept secure. The PI will be responsible for 
overseeing entry of data into an in-house password protected electronic system and ensuring data 
accuracy, consistency and timeliness. The principal investigator, associate investigators/research 
nurses and/or a contracted data manager will assist with the data management efforts. All data 
obtained during the conduct of the protocol will be kept in secure network drives or in approved 
alternative sites that comply with NIH security standards. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
The ICOS/activation PBMC data should be transferred from Quintiles to the Biomarker Data 
Mining System at MedImmune. All analysis done at MedImmune should be shared with NCI.

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All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for at least 30 days, after removal from study treatment or 
until off-study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS and, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
I will share de-identified human data generated in this research for future research 

in a NIH-funded or approved public repository clinicaltrials.gov

in BTRIS

in publication and/or public presentations
at the time of publication or shortly thereafter.
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks following 
initial documentation of objective response.
Before stopping the treatment, progressive disease should be confirmed by imaging preferably 6 
weeks after progression has been diagnosed according to RECIST 1.1. Treatment may be 
continued despite progression according to RECIST 1.1 if modified irRC do not match the 
criteria for progression and there are no new tumor-related symptoms or worsening of existing 
symptoms.
Confirmation of progression will not be done if in the opinion of Investigator patient has better 
option with another treatment.

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Response Evaluation Criteria in Solid Tumors (RECIST): Response and progression will be 
evaluated in this study using the new international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)[45]. Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria. To assess response, the 
tumor burden at baseline will be estimated also and used for comparison with subsequent 
measurements. The treatment may continue immune checkpoint inhibitors (Tremelimumab
and/or Durvalumab) and the Subject may remain on study according to the investigator’s 
decision in case of progressive disease according to RECIST 1.1. For this situation, modified
Immune-Related response criteria (irRC) based on RECIST 1.1 in all subjects without worsening 
of existing symptoms or developing new tumor-related symptoms at the time of progression will 
be used. Modified Immune-related response criteria will be primarily used as guidance for 
further clinical care.
Modified immune-related response criteria (irRC): This new classification is based on the 
recent learning from clinical studies with cancer immunotherapies that even if some new lesions 
appear at the beginning of a treatment or if the total tumor burden does not increase substantially, 
tumor regressions or stabilizations might still occur later. The irRC were created using bi-
dimensional measurements (as previously widely used in the World Health Organization 
criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with 
the modified irRC. 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and
response by imaging at 6 weeks after initial imaging (b) do not necessarily score the appearance 
of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum 
of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable 
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6.3.1
Definitions
6.3.1.1
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Tremelimumab and Durvalumab.
6.3.1.2
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.)
6.3.2
Disease Parameters
Measurable disease:
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as: 
x
By chest x-ray: >20 mm; 

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x
By CT scan: 
o
Scan slice thickness 5 mm or under as >10 mm with CT scan
o
Scan slice thickness >5 mm: double the slice thickness 
x
With calipers on clinical exam: >10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
Non-measurable disease
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological l\PSK QRGHV ZLWK  WR  PP VKRUW D[LV DUH FRQVLGHUHG QRQ-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum of diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum of diameters will be used 
as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease.
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.

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6.3.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
6.3.3.1
Clinical lesions
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and t10 mm diameter as assessed using calipers (e.g., skin nodules).
In the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
6.3.3.2
Chest x-ray
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and
surrounded by aerated lung. However, CT is preferable. 
6.3.3.3
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
6.3.3.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances.

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6.3.3.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised. However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained 
or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint.
6.3.3.6
Cytology, Histology 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
6.3.4
Response Criteria
6.3.4.1
Evaluation of Target Lesions
Revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). NOTE: While RECIST PD will be noted and recorded the immune-
related RECIST criteria will be applied to determine discontinuation of study treatment. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
6.3.4.2
Evaluation of Non-Target Lesions
Revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 

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target lesion status. It must be representative of overall disease status change, not a single lesion 
increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
6.3.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
>4 wks. Confirmation**
CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or 
No
PD
no prior SD, PR or CR
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
*
See RECIST 1.1 manuscript for further details.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target 

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
lesions may be accepted as disease progression.
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.

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For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
6.3.5
Duration of Response
6.3.5.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
6.3.5.2
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
6.4
MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC)
Modified immune-related response criteria (irRC) will also be employed in this study. This new 
classification is based on the recent learning from clinical studies with cancer immunotherapies 
that even if some new lesions appear at the beginning of a treatment or if the total tumor burden 
does not increase substantially, tumor regressions or stabilizations might still occur later. The 
irRC were created using bi-dimensional measurements (as previously widely used in the World 
Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 
1.1 to come up with the modified irRC.
6.4.1
The modified irRC based on RECIST 1.1: 
New non-measurable lesions: Do not define progression but precludes (irCR).
New measurable lesions: Incorporated into tumor burden.
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised

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Overall irCR: Complete disappearance of all lesions (whether measurable or not) and no new 
lesions. All measurable lymph nodes also must have a reduction in short axis to 10 mm.
Overall irPR: Sum of the longest diameters of target and new measurable lesions decreases 

Overall irSD: Sum of the longest diameters of target and new measurable lesions neither irCR, 
irPR, (compared to baseline) or irPD (compared to nadir).
Overall irPD: Sum of the longest diameters of target and new measurable lesions increaseV
(compared to nadir), confirmed by a repeat, consecutive observations at least 4 weeks (normally 
it should be done at 6 weeks) from the date first documented.
Please refer to Appendix C.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).
7
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
7.1
DEFINITIONS
7.1.1
Adverse Event
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.
7.1.2
Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.
7.1.3
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 

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pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
7.1.4
Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
7.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
x
A congenital anomaly/birth defect.
x
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.
7.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
7.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death.
7.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB approved research protocol.
7.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.
7.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to 

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(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggest that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
7.2.1
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:
x
All deaths, except deaths due to progressive disease 
x
All Protocol Deviations
x
All Unanticipated Problems
x
All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.
7.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB:
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
7.2.3
NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB.

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7.3
IND SPONSOR REPORTING CRITERIA 
During the first 30 days after the subject receives investigational agent/intervention, the
investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a
or equivalent, any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event. For serious adverse events that occur 
more than 30 days after the last administration of investigational agent/intervention, only report 
those that have an attribution of at least possibly related to the agent/intervention.
Required timing for reporting per the above guideline:
x
Deaths (except death due to progressive disease) must be reported via email within 24 
hours. A complete report must be submitted within one business day. 
x
Other serious adverse events including deaths due to progressive disease must be reported 
within one business day
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov
and to the CCR PI and study coordinator.
7.3.1
Reporting Pregnancy
7.3.1.1 Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”.
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting 
that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it.
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies.
The same timelines apply when outcome information is available.
7.3.1.2 Paternal exposure

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Male patients should refrain from fathering a child or donating sperm during the study and for 90
after the last dose of investigational drug.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
of investigational drug after the last dose should, if possible, be followed up and documented.
7.4
SAFETY
REPORTING 
CRITERIA
TO
THE
PHARMACEUTICAL
COLLABORATORS
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below.
7.4.1
Reporting of serious adverse events
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose 
of durvalumab, or durvalumab + tremelimumab or until the initiation of alternative anticancer 
therapy. The investigator and/or Sponsor are responsible for informing the Ethics Committee 
and/or the Regulatory Authority of the SAE as per local requirements.
The investigator and/or sponsor must inform the FDA, via a MedWatch or equivalent, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 
21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. 
A copy of the MedWatch report must be send to AstraZeneca at the time the event is reported to
the FDA. It is the responsibility of the sponsor to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement timelines and to 
ensure that these reports are also submitted to AstraZeneca at the above timepoints.
* A cover page should accompany the MedWatch form indicating the following:
•
“Notification from an Investigator Sponsored Study”
•
The investigator IND number assigned by the FDA
•
The investigator’s name and address
•
The trial name/title and AstraZeneca ISS reference number (ESR-16-11987) 
(AstraZeneca only)
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator.
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA.

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7.4.2
Overdose
Any overdose of a study subject with durvalumab or durvalumab + tremelimumab, with or 
without associated AEs/SAEs, is required to be reported within 24 hours of knowledge of the 
event to the sponsor and AstraZeneca/MedImmune Patient Safety or designee using the 
designated Safety e-mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com. If the overdose 
results in an AE, the AE must also be recorded as an AE. Overdose does not automatically make 
an AE serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE. There is 
currently no specific treatment in the event of an overdose of durvalumab or tremelimumab. 
The investigator will use clinical judgment to treat any overdose.
If the overdose results in an AE or SAE, these should be reported as such.
7.4.3
Hepatic function abnormality
Hepatic function abnormality in a study subject, with or without associated clinical 
manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety using the 
designated Safety e-mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com, unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is 
unrelated to investigational product has been confirmed.
If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study subject will be based on the 
clinical judgment of the investigator.
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be initiated 
by the investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune
7.4.4
Reporting Removal from Protocol Therapy and Off Study 
The study drug manufacturer should be notified of any ongoing AE that may delay treatment or 
necessitate permanent discontinuation of treatment.
7.5
DATA AND SAFETY MONITORING PLAN
7.5.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about radiation dose and schedule will be made 
based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS. 

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The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.5.2
Sponsor Monitoring Plan
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on:
x
Informed consent process
x
Eligibility confirmation
x
Drug administration and accountability
x
Adverse events monitoring
x
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
8
STATISTICAL CONSIDERATIONS
The primary objective of this trial is to conduct a pilot study of immune checkpoint inhibition in 
combination with Stereotactic Body Radiation Therapy (SBRT) in patients with advanced 
pancreatic cancer. As such, the main goal is to determine the safety of the proposed 
combinations of checkpoint inhibitors and SBRT as well as to evaluate if there may be any 
evidence of acceptable efficacy for any of the treatment combinations as well as whether one 
approach may be considered preferable over the others for use in future trials.
With an amendment A the decision has been made to not proceed with Arms B1 and B2 and 
move directly from Arms A1 and A2 to Arms C1 and C2. Unfortunately, we have not seen any 
evidence of clinical activity as of yet. At the time of study design we did not have any supportive 
safety data for the combination of tremelimumab and durvalumab and that is why a staggered 
approach was conceived. We now have safety data for the combination of durvalumab and 
tremelimumab and the company has a recommended dose and schedule for the combination of 
these agents which they are moving forward across all their studies. We originally thought that 
Arms B1 and B2 (Tremelimumab 10mg/kg + SBRT) would provide some safety data to inform 
Arms C1 and C2, but this is no longer the case as the recommended dosing of Tremelimumab for 
Arms C1 and C2 is 10mg/kg (i.e., 10% of the dose in Arms B1 and B2).
With amendment I, an additional secondary objective has been added to more precisely estimate 
the survival in patients enrolled in Arm C2.

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Safety will be evaluated as follows: the trial will be conducted in a sequential manner with 
patients enrolled in the following order: A1, A2, C1, and C2. The goal will be to evaluate 10 
patients in A1 and then 10 in A2, provided that no more than 1 of the first 6 in A1 or A2 has a 
DLT, and that no more than 3 of 10 patients in either A1 or A2 has a DLT. If either of these is 
exceeded, then no further patients would be enrolled in that particular arm. The same rules apply 
to C1 and C2, but with all 10 in C1 and the first 10 in C2. Thus, if no safety concerns arise (0-1
of the first 6; 0-3 of 10 have a DLT in each of the 4 arms), then a total of 50 evaluable patients 
will be enrolled. To allow for a moderate number (30-40%) of inevaluable patients – based on 
disease progression – we will set the accrual ceiling at 70 patients.
Among the initial patients enrolled in C2, there were two patients who have survived to 
approximately one year and beyond. It will be desirable to have additional patients enrolled in 
this arm to more precisely estimate its survival. Thus, in amendment I, the accrual to arm C2 will 
be expanded to a total of 20 evaluable patients to provide a more precise estimate of the patients’ 
survival in that arm. The survival of the 20 patients will be determined by a Kaplan-Meier curve 
with 95% two-sided confidence intervals reported primarily at the median, and secondarily at 6 
and 12 months. In addition, as a secondary analysis, the survival of the initial 10 patients treated 
on that arm will be reported separately from that of the second 10 patients treated on that arm, 
and the results will be informally compared to establish the degree of similarity of survival in the 
earlier and later treated patients.
The median survival in second-line studies in this patient population is approximately 4 months. 
An important efficacy endpoint will be reached if a given patient is able to survive for 6 months 
or longer.
The fraction of such patients will also be evaluated in the following manner, for purposes of 
making decisions about future directions, in addition to the new secondary endpoint focusing on 
C2, which demonstrated some survival advantage based on the first 10 patients:
8.1
CROSS-ARM COMPARISON
Evaluation will be performed in combination of arms: A1+A2 and C1+C2. Within each of arm 
combinations A1+A2 and C1+C2, the 20 total patients who are treated in the combination of 
arms (A1+A2) and the total of 30 who are treated in the combination of arms (C1+C2) will be 
evaluated as a single group and the following objective will be evaluated: For the combination of 
A1+A2 (n=20), if 3 or more patients out of 20 are able to survive to 6 months, this would be a 
desirable goal, since the probability of observing 3 or more surviving to 6 months is 7.5% if the 
true underlying probability of surviving 6 months is 5% and the probability is 90.9% if the true 
underlying probability of surviving 6 months is 25%. Thus, 3 or more surviving 6 months or 
longer is a meaningful goal in a combination of arms of 20 patients. For the combination of 
C1+C2 (n=30), if 4 or more patients out of 30 can survive to 6 months, this would be a desirable 
goal, since the probability of observing 4 or more surviving to 6 months is 6.1% if the true 
underlying probability of surviving 6 months is 5% and the probability is 96.3% if the true 
underlying probability of surviving 6 months is 25%. Thus, 4 or more surviving 6 months or 
longer is a meaningful goal in a combination of arms of 30 patients. Given that there are 2
combination of treatment arms to be evaluated (A1+A2 and C1+C2), the one with the greatest 
fraction of 6-month survivors, provided that the surviving number is 3 or more of 20 patients in 
A1+A2 or 4 or more of 30 patients in C1+C2, will be considered for further evaluation. The 

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numbers of patients in each combination of arms who live to or beyond 6 months who receive 1 
day of SBRT or receive 5 days of SBRT will also be reported and compared informally, and will 
help guide future decisions.
8.2
DURATION OF RADIATION
In addition, the 20 patients who receive 1 day of SBRT and the 30 patients who receive 5 days of 
SBRT will be evaluated via a selection design, although with the caveat that lack of 
randomization and uneven numbers of patients should be considered when interpreting the 
results. The 20 or 30-patient SBRT combination of arms with the greatest fraction of survivors to 
6 months would be preferentially chosen for further study. If there are 20-30 patients in the two 
groups and assuming the true rates are 15% and 25% in the two groups, the probability of correct 
selection is at least 78%.. Given that the two groups of 20 or 30 patients each have subsets of 10
(or 20) patients treated homogeneously, this would also need to be explored within the arms.
Secondary endpoints include evaluation of clinical endpoints such as response rate, duration of 
response, progression free survival, and overall survival. These will be estimated using 
confidence intervals for response rates, descriptive statistic for duration of response and Kaplan-
Meier curves for PFS and OS. PK parameters will be obtained and results will be estimated and 
described using standard exploratory and descriptive statistical techniques. Any statistical 
comparisons which may be undertaken will be done using non-parametric tests, without formal 
correction for multiple comparisons, but interpreted in the context of the secondary nature of the 
tests and the number of such tests performed.
8.3
ANALYSIS OF IMMUNOGENICITY
Only subjects who receive at least one dose of both Durvalumab and/or tremelimumab, and
provide the baseline and at least one post-treatment sample, will be evaluated. Immunogenicity 
results will be analyzed descriptively by summarizing the number and percentage of subjects 
who develop detectable anti-Durvalumab or anti-tremelimumab antibodies. The immunogenicity 
titer will be reported for samples confirmed positive for the presence of anti-Durvalumab or anti-
tremelimumab antibodies. The impact of ADAs on PK will also be assessed if data allow. 
Samples confirmed positive for ADAs may also be evaluated for neutralizing antibody activity.
8.4
ANALYSIS OF PHARMACOKINETICS
Only subjects who receive at least one dose of Durvalumab and/or tremelimumab, and provide
the baseline and at least one post-treatment sample, will be evaluated. Individual Durvalumab
and tremelimumab concentrations will be tabulated by dose arm along with descriptive statistics. 
The PK of Durvalumab and tremelimumab will be assessed using parameters including Cmax, 
trough concentration (Cmin), time to peak concentration (Tmax) and AUC after the first dose. 
Durvalumab and tremelimumab steady-state PK parameters including peak concentration 
(Cmax,ss), trough concentration (Cmin,ss), and time to peak concentration (Tmax,ss) will be 
estimated. Accumulation to steady state will be assessed as the ratio of Cmax,ss:Cmax and 
Cmin,ss:Cmin. All PK parameters will be estimated by non-compartmental analysis. Descriptive 
statistics of non-compartmental PK parameters will be provided.

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9
COLLABORATIVE AGREEMENTS 
9.1
AGREEMENT TYPE
A CRADA, 02908, is in place between MedImmune, Inc. and CCR, NCI.
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION
Subjects treated on this study, will be individuals with advanced pancreatic adenocarcinoma,
which is not amenable to potentially curative resection. Individuals of any sex, race or ethnic 
group will be eligible for this study. Eligibility assessment will be based solely on the patient’s 
medical status. Recruitment of patients onto this study will be through standard CCR 
mechanisms. No special recruitment efforts will be conducted.
10.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have pancreatic adenocarcinoma, and because of unknown toxicities in pediatric 
patients.
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH Policy 87-4 and NIH 
HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, 
will be followed.
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS FOR ALL PARTICIPANTS
10.4.1 Risks of exposure to ionizing radiation 
This research study involves exposure to radiation from 2 CT guided biopsies. This radiation 
exposure is not required for medical care and is for research purposes only. The amount of 
radiation received in this study is 1.6 rem which is below the guideline of 5 rem per year allowed 
for research subjects by the NIH Radiation Safety Committee. The average person in the United 
States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, 
outer space, and the earth's air and soil. More information about radiation is available in the 
pamphlet, An Introduction to Radiation for NIH Research Subjects.

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10.4.2 Risk of baseline biopsy 
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent.
10.4.3 Other risks/benefits
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival. Potential risks 
include the possible occurrence of any of a range of side effects which are listed in the Consent 
Document. The procedure for protecting against or minimizing risks will be to medically 
evaluate patients on a regular basis as described.
10.5 RISKS/BENEFITS ANALYSIS
For patients with pancreatic adenocarcinoma cancer, median survival is in the range between 6
and 10 months. It is possible that treatment on this protocol may reduce tumor burden or lessen 
symptoms caused by the cancer. While treatment on this protocol may not individually benefit 
subjects. The knowledge gained from this study may help others in the future who have 
pancreatic adenocarcinoma. Potential risks include the possible occurrence of any of a range of 
side effects listed. If patients suffer any physical injury as a result of the biopsies, immediate 
medical treatment is available at the NIH’s Clinical Center in Bethesda, Maryland. Although no 
compensation is available, any injury will be fully evaluated and treated in keeping with the 
benefits or care to which patients are entitled under applicable regulations.
10.6 CONSENT PROCESS AND DOCUMENTATION
Patients will meet with an associate or principal investigator on the trial in the GI oncology 
Clinic, during the initial evaluation for this study. During that meeting, the investigator will 
inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of 
this trial. The investigator will then provide a copy of the IRB-approved informed consent 
document that is included in this protocol. The patient will be allowed to take as much time as he 
wishes, in deciding whether or not he wishes to participate. If a prolonged period of time expires 
during the decision making process (several weeks, as an example), it may be necessary to 
reassess the patient for protocol eligibility.
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on the study.
10.6.1 Reconsent via Telephone
The informed consent document will be sent to the subject. An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.
The subject will sign and date the informed consent. A witness to the subject’s signature-- -will 
sign and date the consent.
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.
A fully executed copy will be returned via mail for the subject’s records.

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The informed consent process will be documented on a progress note by the consenting
investigator.
10.6.2 Informed Consent of non-English Speaking Subjects
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary 
that will be used is the English version of the extant IRB approved consent document. Signed 
copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible). 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form.
11 PHARMACEUTICAL INFORMATION
11.1 TREMELIMUMAB 
11.1.1 Source
Tremelimumab will be supplied by Medimmune, Inc.
11.1.2 Formulation and Preparation
Tremelimumab is a human IgG2 anti-CTLA-4 mAb.
Investigational Product 
Manufacturer 
Concentration 
and 
Formulation as Supplied 
Tremelimumab 
MedImmune 
Formulated 
at 
a 
nominal 
concentration of 20 mg/mL in 
20 
mM 
histidine/histidine 
hydrochloride, 
222 
mM 
trehalose 
dihydrate, 
0.02% 
(w/v) polysorbate 80, and 0.27
mM disodium edetate dihydrate 
(EDTA), pH 5.5. 
Tremelimumab is supplied as a sterile IV solution, filled in 20 mL clear glass vials with a rubber 
stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL 

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accounting to 400 mg/vial) of Tremelimumab, in an isotonic solution at pH 5.5. Vials containing
Tremelimumab must be stored in the refrigerator at 2-8C. The 20 mg/mL solution will be diluted 
into a saline bag for IV infusion. 
For dose preparation steps, the following ancillary items are required: 
x
IV infusion bags of 0.9% sodium chloride injection (250 mL size). Saline bags must be 
latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g.,
polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free. 
x
IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or 
polyethylene or polyurethane. All DEHP-containing or DEHP-free lines are acceptable. 
/LQHVVKRXOGFRQWDLQDRU  ȝP LQ-line filter. The in-line filter can be made of 
polyethersulfone (PES) or polyvinylidine fluoride DRF (PVDF). Lines containing 
cellulose-based filters should not be used with Tremelimumab. 
x
Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless 
steel and/or PVC components. 
x
Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be 
used with Tremelimumab. 
x
Needles made of stainless steel. 
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
Preparation of Tremelimumab and preparation of the IV bag are to be performed aseptically. 
Total in-use storage time for the prepared final IV bag should not exceed 24 hours at 2-8°C or 4 
hours at room temperature (25°C). However, it is recommended that the prepared final IV bag be 
stored in the dark at 2-8°C until needed. The refrigerated infusion solutions in the prepared final 
IV bag should be equilibrated at room temperature for about 2 hours prior to administration. If 
storage time exceeds these limits, a new dose must be prepared from new vials.
11.1.3 Stability and Storage
Tremelimumab must be stored in the refrigerator at 2-80C. The 20 mg/mL solution will be 
diluted into a saline bag for IV infusion. Vials containing Tremelimumab may be gently inverted 
for mixing, but should not be shaken.
11.1.4 Administration procedures
Tremelimumab will be administered as an IV infusion (250 mL) over approximately 1 hour. 
When an IV bag is used for the infusion, the IV line will be flushed with a volume of normal 
saline equal to the priming volume of the infusion set used after the contents of the IV bag are 
fully administered (unless prohibited by institutional practice).
11.1.5 Dose Calculation 
The subject’s weight (in kilograms) must be measured prior to each dosing for dose calculation. 
Measurements can be taken in street clothes without shoes and a calibrated scale must be used 
for all measurements. 
The dose will be calculated at each dosing visit using the following formula: 

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Tremelimumab: 
The tremelimumab dose will be calculated using the following formula:
Arms A1 and A2 only: By weight: Dose (mL) = [subject weight (kg) × dose (mg/kg)]/ 20 
(mg/mL) where 20 mg/mL is tremelimumab concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle only needed for greater than 10% change in weight.
Each vial contains a small amount of overage and the overage should be utilized as much as 
possible before using another vial. 
Arms C1 and C2: Following amendment B, Tremelimumab will be dosed at a flat dose of 75 mg 
via IV infusion q4w for up to 4 doses/cycles). Flat weight dosing will be used for all other 
patients including those who are greater than 75Kg e.g. 100-110Kg.
11.2 DURVALUMAB
11.2.1 Source
Durvalumab will be supplied by Meddimmune, Inc.
11.2.2 Formulation and Preparation 
Durvalumab is a human monoclonal antibody of the immunoglobulin G1 kappa (Ig*ț
subclass.
Investigational Product 
Manufacturer 
Concentration 
and 
Formulation as Supplied 
Durvalumab
MedImmune
Formulated at 50 mg/mL in 26 
mM 
histidine/histidine-HCl, 
275 mM trehalose
dihydrate, 
0.02% 
(weight/volume 
[w/v]) 
polysorbate 80, pH 6.0.
Durvalumab is supplied is supplied as a white to off-white lyophilized powder in clear 10R glass 
vials closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 200 mg 
(nominal) of active investigational product. 
For dose preparation steps, the following ancillary items are required: 
x
IV infusion bags of 0.9% sodium chloride injection.
x
IV infusion lines. All DEHP-containing or DEHP-free lines are acceptable. 
x
Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless 
steel and/or PVC components.

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11.2.3 Stability
Manufacturer
MedImmune
Expiration/Retest Date
Expiration/retest dates are documented on the Certificate of
Container Description
Type:
Material:
Size:
Formulation
Lyophilized powder containing 200 mg Durvalumab. When
reconstituted with 4 mL of WFI, the solution contains 50
mg/mL Durvalumab, 26 mM histidine/histidine-HCl, 275
mM trehalose dihydrate, 0.02% (weight/volume [w/v])
Active Ingredient Content
Mass/Weight:
Volume:
Concentration:
Storage Conditions
+2°C to +8°C
Stability after reconstitution24h at +2-8°C and 6h at +25°C/ambient
Labeling
Product name, lot number, route of administration, and
storage conditions
If Durvalumab administration has to be delayed, temporally interrupted or the infusion rate 
decreased, the total time between reconstitution and completion of the infusion should not 
exceed 6 hours at room temperature or Total in-use storage time from reconstitution of 
Durvalumab to start of administration should not exceed 4 hours at room temperature or 24 hours 
at 2-8 C. If administration time exceeds these limits, a new dose must be prepared from new 
vials. Durvalumab does not contain preservatives and any unused portion must be discarded.
11.2.4 Storage 
Unopened vials of Durvalumab lyophilized Drug Product must be stored at 2°C to 8°C (36°F to 
46°F).
Protect from light.
11.2.5 Administration procedures
Durvalumab is to be administered as an IV solution of 10 mg/kg over approximately 1 hour.
When an IV bag is used for the infusion, the IV line will be flushed with a volume of normal 
saline equal to the priming volume of the infusion set used after the contents of the IV bag are 
fully administered (unless prohibited by institutional practice).
Since the compatibility of Durvalumab with other IV medications and solutions, other than 
normal saline (0.9% [w/v] sodium chloride for injection), is not known, the Durvalumab solution 
should not be infused through an IV line in which other solutions or medications are being 
administered. The date, start time, interruption, and completion time of Durvalumab
administration must be recorded in the source documents.

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For arms C1 and C2 Durvalumab infusion will start approximately 1 hour after the end of 
tremelimumab infusion.
11.2.5.1 Dose Calculation 
11.2.5.1.1 Arms A1 and A2 only
The subject’s weight (in kilograms) must be measured prior to each dosing for dose calculation. 
Measurements can be taken in street clothes without shoes and a calibrated scale must be used 
for all measurements. 
The dose of MEDI 4736 will be calculated at each dosing visit using the following formula: 
By weight:  Dose (mL) = [subject weight (kg) × dose (mg/kg)]/ 50 (mg/mL) where 50 mg/mL is 
Durvalumab concentration after reconstitution. 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle only needed for greater than 10% change in weight.
Each vial contains a small amount of overage and the overage should be utilized as much as 
possible before using another vial. 
11.2.5.1.2 Arms C1 and C2
Following amendment B, MEDI 4736 (now called Durvalumab) will be dosed at a flat dose of 
1500 mg via IV infusion q4w for up to 4 doses/cycles (in combination with 75 mg tremelimumab 
via IV infusion q4w for up to 4 doses/cycles), and then continue 1500 mg durvalumab q4w (see
Figure 3). Patients with a body weight less than or equal to 30 kg should be dosed using a 
weight-based dosing schedule (i.e. 1mg/kg for tremelimumab and 20mg/kg for durvalumab). Flat 
weight dosing will be used for all other patients including those who are greater than 75Kg e.g.
100-110Kg.
11.2.6 Durvalumab Dose Preparation Steps 
11.2.6.1 Durvalumab is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM 
trehalose dihydrate, 0.02% (w/v) polysorbate 80 and is supplied as a lyophilized 
powder in 10R vials 
11.2.6.2 Durvalumab should be reconstituted using aseptic techniques with 4.0 mL sterile 
water for injection (WFI) with the liquid added gently to the side of the vial to 
minimize product foaming, to give a final concentration of 50 mg/mL. The 
reconstituted solution will be diluted with 0.9% (w/v) saline for IV infusion using 
syringes or bags.
11.2.6.3 In arms C1 and C2 Durvalumab infusion will start approximately 1 hour after the end 
of tremelimumab infusion using a 0.2-ȝPLQ-line filter. 
11.2.6.4 Flush the IV line with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete 
the infusion according to institutional policy to ensure the full dose is administered 
and document if the line was not flushed.

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11.3 INVESTIGATIONAL PRODUCT PREPARATION STEPS
The investigational product manager or qualified personnel will be responsible for preparing the 
IV doses using the following steps: 
1) Select the IXRS-assigned number of vials of investigational product required to prepare 
the subject’s dose. 
2)
All investigational product vials should be equilibrated to room temperature for 30 
minutes prior to dose preparation. 
3) To prepare the IV bag, first, calculate the dose volume of investigational product 
required. Second, remove the volume of 0.9% sodium chloride IV solution equivalent to 
the calculated dose volume of investigational product from the IV bag.
4)
Lastly, add the calculated dose volume of investigational product to the IV bag. Gently 
mix the solution in the bag by inverting up and down. Avoid shaking the IV bag to 
prevent foaming. 
5) Example: A subject weighing 85 kg will require 42.5 mL (3 vials) of investigational 
product. Remove 42.5 mL of saline from the commercial IV bag. Add the 42.5 mL of 
investigational product to the IV bag and gently mix by inverting up and down.
6) Labels will be prepared in accordance with Good Manufacturing Practice (GMP).
11.4 INVESTIGATIONAL PRODUCT INSPECTION 
Each vial selected for dose preparation should be inspected. 
If there are any defects noted with the investigational product, the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section (11.5.1) for further 
instructions. 
During the inspection if the solution is not clear or any turbidity, discoloration or particulates are 
observed, notify your site monitor and store the vial(s) in QUARANTINE at refrigerated (2-8ºC) 
temperature for drug accountability and potential future inspection. 
Notify the IXRS that the unusable vials are damaged. The IXRS will indicate the replacement 
vials. Select appropriate replacement vials for the preparation of the subject’s dose, and perform 
the same inspection on the newly selected vials. For accountability, record the total number of 
vials removed from site inventory. Used vials should be held for accountability purposes at 
ambient storage temperature.
11.5 INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies of 
investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of upon 
authorization by MedImmune.
11.5.1 Reporting Product Complaints 
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 

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Complaint Department. During the investigation of the product complaint, all investigational 
products must be stored at labeled conditions unless otherwise instructed. 
Product defects may be related to component, product, or packaging and labeling issues. The list 
below includes, but is not limited to, descriptions of product complaints that should be reported. 
Component Issue: Defect in container or dosing mechanism of the investigational product. The 
component defect may be damaged, missing, or broken. Component examples include vials, 
stoppers, caps, spray barrels, spray nozzles, or plungers. 
Product Issue: Defect in the product itself. The product appearance has visual imperfections 
such as foreign particles, crystallization, discoloration, turbidity, insufficient volume, or anything 
that does not apply to the product description. 
Packaging/Labeling Issue: Defect in the packaging or labeling of the product. The packaging or 
labeling defects may be damaged or unreadable, or the label may be missing. 
When reporting a product complaint, site staff must be prepared to provide the following 
information: 
1) Customer information: reporter name, address, contact number, and date of complaint 
2) Product information: product name, packaging kit number or lot number, expiry date, and 
clinical protocol number 
3) Complaint information: complaint issue category and description 
MedImmune contact information for reporting product complaints: 
Email: productcomplaints@medimmune.com 
Phone: +1-301-398-2105 +1-877-MEDI-411 (+1-877-633-4411) 
Fax: +1-301-398-8800
Mail: MedImmune, LLC Attn: Product Complaint Department One MedImmune Way, 
Gaithersburg, MD USA 20878

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12 REFERENCES 
1.
Moore, M.J., et al., Erlotinib plus gemcitabine compared with gemcitabine alone in 
patients with advanced pancreatic cancer: a phase III trial of the National Cancer 
Institute of Canada Clinical Trials Group. J Clin Oncol, 2007. 25(15): p. 1960-6.
2.
Reyes-Gibby, C.C., et al., Patterns of self-reported symptoms in pancreatic cancer 
patients receiving chemoradiation. J Pain Symptom Manage, 2007. 34(3): p. 244-52.
3.
Moertel, C.G., et al., Combined 5-fluorouracil and supervoltage radiation therapy of 
locally unresectable gastrointestinal cancer. Lancet, 1969. 2(7626): p. 865-7.
4.
Moertel, C.G., et al., Therapy of locally unresectable pancreatic carcinoma: a 
randomized comparison of high dose (6000 rads) radiation alone, moderate dose 
radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The 
Gastrointestinal Tumor Study Group. Cancer, 1981. 48(8): p. 1705-10.
5.
Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-
modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. 
Gastrointestinal Tumor Study Group. J Natl Cancer Inst, 1988. 80(10): p. 751-5.
6.
Klaassen, D.J., et al., Treatment of locally unresectable cancer of the stomach and 
pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus 
concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group 
study. J Clin Oncol, 1985. 3(3): p. 373-8.
7.
Chauffert, B., et al., Phase III trial comparing intensive induction chemoradiotherapy (60 
Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine 
with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive 
results of the 2000-01 FFCD/SFRO study. Ann Oncol, 2008.
8.
Chauffert, B., et al., Phase III trial comparing initial chemoradiotherapy (intermittent 
cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients 
with locally advanced non metastatic pancreatic cancer: A FFCD-SFRO study. J Clin 
Oncol (Meeting Abstracts), 2006. 24(18_suppl): p. 4008-.
9.
P. J. Loehrer, M.E.P., H. R. Cardenes, L. Wagner, J. M. Brell, R. K. Ramanathan, C. H. 
Crane, S. R. Alberts, A. B. Benson, Eastern Cooperative Oncology Group. A randomized 
phase III study of gemcitabine in combination with radiation therapy versus gemcitabine 
alone in patients with localized, unresectable pancreatic cancer: E4201. in ASCO. 2008. 
Chicago.
10.
Huguet, F., et al., Impact of chemoradiotherapy after disease control with chemotherapy 
in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J
Clin Oncol, 2007. 25(3): p. 326-31.
11.
Moureau-Zabotto, L., et al., Concomitant administration of weekly oxaliplatin, 
fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and 
oxaliplatin induction in patients with locally advanced pancreatic cancer: a Groupe 
Coordinateur Multidisciplinaire en Oncologie phase II study. J Clin Oncol, 2008. 26(7): 
p. 1080-5.

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
Version Date: 08/24/2018
80
12.
Chuong, M.D., et al., Stereotactic body radiation therapy for locally advanced and 
borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol 
Biol Phys, 2013. 86(3): p. 516-22.
13.
Kantoff, P.W., et al., Sipuleucel-T immunotherapy for castration-resistant prostate 
cancer. N Engl J Med, 2010. 363(5): p. 411-22.
14.
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med, 2010. 363(8): p. 711-23.
15.
Robert, C., et al., Ipilimumab plus dacarbazine for previously untreated metastatic 
melanoma. N Engl J Med, 2011. 364(26): p. 2517-26.
16.
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65.
17.
Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 
144(5): p. 646-74.
18.
Gelao, L., et al., Immune checkpoint blockade in cancer treatment: a double-edged sword 
cross-targeting the host as an "innocent bystander". Toxins (Basel), 2014. 6(3): p. 914-
33.
19.
Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with 
melanoma. N Engl J Med. 366(10): p. 925-31.
20.
Lee, Y., et al., Therapeutic effects of ablative radiation on local tumor require CD8+ T 
cells: changing strategies for cancer treatment. Blood, 2009. 114(3): p. 589-95.
21.
Blanquicett, C., et al., Antitumor efficacy of capecitabine and celecoxib in irradiated and 
lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: clinical 
implications of abscopal effects. Clin Cancer Res, 2005. 11(24 Pt 1): p. 8773-81.
22.
Camphausen, K., et al., Radiation abscopal antitumor effect is mediated through p53.
Cancer Res, 2003. 63(8): p. 1990-3.
23.
Demaria, S., et al., Ionizing radiation inhibition of distant untreated tumors (abscopal 
effect) is immune mediated. Int J Radiat Oncol Biol Phys, 2004. 58(3): p. 862-70.
24.
Reits, E.A., et al., Radiation modulates the peptide repertoire, enhances MHC class I 
expression, and induces successful antitumor immunotherapy. J Exp Med, 2006. 203(5): 
p. 1259-71.
25.
Sharma, A., et al., gamma-Radiation promotes immunological recognition of cancer cells 
through increased expression of cancer-testis antigens in vitro and in vivo. PLoS One, 
2011. 6(11): p. e28217.
26.
Apetoh, L., et al., Toll-like receptor 4-dependent contribution of the immune system to 
anticancer chemotherapy and radiotherapy. Nat Med, 2007. 13(9): p. 1050-9.
27.
Suzuki, Y., et al., Immunogenic tumor cell death induced by chemoradiotherapy in 
patients with esophageal squamous cell carcinoma. Cancer Res, 2012. 72(16): p. 3967-
76.

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
Version Date: 08/24/2018
81
28.
Bramhall, R.J., K. Mahady, and A.H. Peach, Spontaneous regression of metastatic 
melanoma - clinical evidence of the abscopal effect. Eur J Surg Oncol, 2014. 40(1): p. 34-
41.
29.
Hiniker, S.M., D.S. Chen, and S.J. Knox, Abscopal effect in a patient with melanoma. N
Engl J Med, 2012. 366(21): p. 2035; author reply 2035-6.
30.
Okuma, K., et al., Abscopal effect of radiation on lung metastases of hepatocellular 
carcinoma: a case report. J Med Case Rep, 2011. 5: p. 111.
31.
Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term survival 
in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys, 2013. 86(2): p. 343-9.
32.
Dewan, M.Z., et al., Fractionated but not single-dose radiotherapy induces an immune-
mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res, 
2009. 15(17): p. 5379-88.
33.
Demaria, S., et al., Immune-mediated inhibition of metastases after treatment with local 
radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res, 
2005. 11(2 Pt 1): p. 728-34.
34.
McNeel, D.G., et al., Phase I trial of tremelimumab in combination with short-term 
androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol 
Immunother, 2012. 61(7): p. 1137-47.
35.
Tarhini, A.A., et al., Safety and efficacy of combination immunotherapy with interferon 
alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol, 2012. 
30(3): p. 322-8.
36.
Le, D.T., et al., Evaluation of ipilimumab in combination with allogeneic pancreatic 
tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J
Immunother, 2013. 36(7): p. 382-9.
37.
Oganesyan, V., et al., Structural characterization of a human Fc fragment engineered for 
lack of effector functions. Acta Crystallographica Section D-Biological Crystallography, 
2008. 64: p. 700-704.
38.
Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer, 2012. 12(4): p. 252-64.
39.
Wang, E., et al., Population pharmacokinetic and pharmacodynamic analysis of 
tremelimumab in patients with metastatic melanoma. J Clin Pharmacol, 2014. 54(10): p. 
1108-16.
40.
Ng, C.M., et al., Rationale for fixed dosing of pertuzumab in cancer patients based on 
population pharmacokinetic analysis. Pharm Res, 2006. 23(6): p. 1275-84.
41.
Wang, D.D., et al., Fixed dosing versus body size-based dosing of monoclonal antibodies 
in adult clinical trials. J Clin Pharmacol, 2009. 49(9): p. 1012-24.
42.
Zhang, S., et al., Fixed dosing versus body size-based dosing of therapeutic peptides and 
proteins in adults. J Clin Pharmacol, 2012. 52(1): p. 18-28.

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82
43.
Narwal, R., L.K. Roskos, and G.J. Robbie, Population pharmacokinetics of sifalimumab, 
an investigational anti-interferon-alpha monoclonal antibody, in systemic lupus 
erythematosus. Clin Pharmacokinet, 2013. 52(11): p. 1017-27.
44.
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54.
45.
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer, 2009. 45(2): p. 228-247.

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13 APPENDICES
13.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
100
Normal, no complaints, no 
evidence of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
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).
80
Normal activity with effort; 
some signs or symptoms of 
disease.
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
50
Requires considerable assistance 
and frequent medical care.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
40
Disabled, requires special care 
and assistance.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
20
Very sick, hospitalization 
indicated. Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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13.2 APPENDIX B: MEDIMMUNE SAMPLE PREPARATION PROCEDURES SERUM- SST TUBE
1. Draw maximum volume of blood into gold top SST tube (s). Record time of collection.
2. Gently invert 5 times.
3. Allow the blood to clot for 30 minutes at room temperature.
4. Centrifuge within 2 hours of collection at 1100 -1300 g for 15 minutes.
5. Transfer serum into labeled cryovials. 
6. Immediately freeze the cryovials upright at -20ºC or colder.
7. Store at -20ºC or colder until shipment on dry ice.
Plasma- K2 EDTA Tube
1.
Draw maximum volume of blood into lavender top K2 EDTA tube(s). Record time of 
collection
2. Gently invert 8 to 10 times.
3. Centrifuge within 2 hours of collection at 1100 -1300 g for 10 minutes.
4. Transfer plasma into labeled cryovials.
5. Immediately freeze the cryovials upright at -20ºC or colder.
6. Store at -20ºC or colder until shipment on dry ice.
Tube Label should include:
1. Patient Identifier 
2. Sample ID (Serum 1, Cycle 1, Day 1etc.)
3. Sample type (plasma, serum)
4. Sample volume 
5. Collection time 
6. Barcode (if this system is available)

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13.3 APPENDIX C: MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC)
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and 
PHDVXUDEOHQHZOHVLRQVGRHVQRWLQFUHDVHE\
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. 
All measurements should be recorded in metric notation. The modified irRC based on RECIST 
1.1 are displayed below. 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions

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13.4 APPENDIX D: DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-MEDIATED, INFUSION-
RELATED, AND NON-IMMUNE–MEDIATED REACTIONS (MEDI4736 MONOTHERAPY OR COMBINATION THERAPY WITH 
TREMELIMUMAB OR TREMELIMUMAB MONOTHERAPY) 1 NOVEMBER 2017 VERSION
General Considerations
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03.
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions:
x
Inability to reduce corticosteroid to a dose RI mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen
x
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing
Grade 1
No dose modification
Grade 2
Hold study drug/study regimen dose until Grade 2 resolution to 
*UDGH
If toxicity worsens, then treat as Grade 3 or Grade 4.
Study drug/study regimen can be resumed once event stabilizes to 
*UDGHDIWHUFRPSOHWLRQRIVWHURLGWDSHU
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement.
3.
'RVHVRISUHGQLVRQHDUHDW mg/day or equivalent.
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table:
í
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines.
í
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow.
í
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events. 
í
For persistent (>3 to 5 days) low-JUDGH*UDGHRUVHYHUH*UDGH
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
í
Some events with high likelihood for morbidity and/or mortality – e.g., myo-
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation.
í
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 

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General Considerations
Dose Modifications
Toxicity Management
Grade 3
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below.
Grade 4
Permanently discontinue study drug/study regimen.
Note: FRU*UDGHDV\PSWRPDWLFDP\ODVHRUOLSDVHOHYHOVKROGVWXG\GUXJVWXG\
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed.
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper).
í
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids.
í
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring.
í
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient.
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth.
Pediatric Considerations
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
í
All recommendations for specialist consultation should occur with a 

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Pediatric Considerations
Dose Modifications
Toxicity Management
well as to permanently discontinue study drug/study regimen if unable to reduce 
FRUWLFRVWHURLG a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen
pediatric specialist in the specialty recommended.
í
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients.
í
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
UHFRPPHQGHGIRUSHGLDWULFSDWLHQWV\HDUVROG)RUGRVLQJLQFKLOGUHQ
younger than 6 years old, consult with a pediatric specialist.
í
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist.
í
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.

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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Pneumonitis/Interstitial 
Lung Disease (ILD)
Any Grade
General Guidance
For Any Grade:
í
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below.
í
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan.
Grade 1
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated)
No dose modifications required. However, 
consider holding study drug/study 
regimen dose as clinically appropriate and 
during diagnostic work-up for other
etiologies.
For Grade 1 (radiographic changes only):
í
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated.
í
Consider Pulmonary and Infectious disease consult.
Grade 2
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL)
Hold study drug/study regimen dose until 
*UDGHUHVROXWLRQWR*UDGH
x
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
x
,IWR[LFLW\LPSURYHVWR*UDGH
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper.
For Grade 2 (mild to moderate new symptoms):
í
Monitor symptoms daily and consider hospitalization.
í
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent).
í
Reimage as clinically indicated.
í
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started
í
If still no improvement within 3 to 5 days despite IV 

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methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRU
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])a
í
Consider pulmonary and infectious disease consult.
í
Consider, as necessary, discussing with study physician.
Grade 3 or 4
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated)
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation])
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening):
í
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
í
Obtain Pulmonary and Infectious disease consult; consider, as 
necessary, discussing with study physician.
í
Hospitalize the patient.
í
Supportive care (e.g., oxygen).
í
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOV
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 

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2B recommendation]).a
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade:
í
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus).
í
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc.
í
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event.
í
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1
(Diarrhea: stool 
frequency of <4 over 
baseline per day)
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only)
No dose modifications.
For Grade 1:
í
Monitor closely for worsening symptoms.
í
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment.
Grade 2
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day) 
(Colitis: abdominal 
pain; mucus or blood in 
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGH
x
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
x
,IWR[LFLW\LPSURYHVWR*UDGH
then study drug/study regimen can be 
For Grade 2:
í
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.
í
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 

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stool)
resumed after completion of steroid 
taper.
equivalent.
í
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started.
í
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab.
í
Consider, as necessary, discussing with study physician if no 
UHVROXWLRQWR*UDGHLQWR days.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea: stool 
IUHTXHQF\RIRYHU
baseline per day;
Grade 4 diarrhea: life 
threatening 
consequences)
(Grade 3 colitis: severe 
abdominal pain, change 
in bowel habits, medi-
cal intervention indi-
cated, peritoneal signs;
Grade 3
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
LPSURYHWR*UDGHZLWKLQ days; 
study drug/study regimen can be resumed 
after completion of steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4:
í
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent.
í
Monitor stool frequency and volume and maintain hydration.
í
Urgent GI consult and imaging and/or colonoscopy as 
appropriate.
í
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 

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Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated)
guidance before using infliximab.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURShylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
Any Grade
General Guidance
For Any Grade:
í
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
í
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications).
Grade 1
(AST or ALT >ULN 
aQGî8/1DQGRU
TB > ULN and  
î8/1
x
No dose modifications.
x
If it worsens, then treat as Grade 2 
event.
For Grade 1:
í
Continue LFT monitoring per protocol.
Grade 2
(AST or 
ALT >3.0×ULN and 
î8/1DQGRU
TB >1.5×ULN and  
î8/1
x
Hold study drug/study regimen dose 
XQWLO*UDGHUHVROXWLRQWR*UDGH
x
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
x
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, resume study drug/study 
regimen after completion of steroid 
taper.
For Grade 2:
í
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved.
í
,IQRUHVROXWLRQWR*UDGHLQWRGD\VFRQVLGHUDV
necessary, discussing with study physician.
í
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
í
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.
í
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
PLEASE SEE 
shaded area 
immediately below
this section to find
guidance for
management of
“Hepatitis (elevated 
LFTS)” in HCC 
patients

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immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(Grade 3: AST or 
ALT >5.0×ULN and 
î8/1DQGRU
TB >3.0×ULN and  
î8/1
(Grade 4: AST or 
ALT >20×ULN and/or 
TB >10×ULN)
For Grade 3:
For elevations in transaminases 
 × ULN, or elevations in bilirubin 
 × ULN:
x
Hold study drug/study regimen dose 
XQWLOUHVROXWLRQWR*UDGHRU
baseline
x
Resume study drug/study regimen if 
HOHYDWLRQVGRZQJUDGHWR*UDGHRU
baseline within 14 days and after 
completion of steroid taper.
x
Permanently discontinue study 
drug/study regimen if the elevations 
GRQRWGRZQJUDGHWR*UDGHRU
baseline within 14 days
For elevations in transaminases >8 × ULN 
or elevations in bilirubin >5 × ULN, 
discontinue study drug/study regimen.
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3 × ULN + 
bilirubin >2 × ULN without initial 
For Grade 3 or 4:
í
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
í
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used.
í
Perform hepatology consult, abdominal workup, and imaging 
as appropriate.
í
Once the patient is improving, gradually taper steroids over
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a

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97
findings of cholestasis (i.e., elevated 
alkaline P04) and in the absence of any 
alternative cause.b
For Grade 4:
Permanently discontinue study drug/study 
regimen.
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
Any Grade
General Guidance
For Any Grade:
í
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
í
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]).
í
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg
í
For HCV+ patients: evaluate quantitative HCV viral load
í
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml
í
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased b\-fold
í
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
THIS shaded area 
is guidance only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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98
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
above
Grade 1
(Isolated AST or ALT 
!8/1DQGî8/1
whether normal or 
elevated at baseline) 
x
No dose modifications.
x
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
Grade 2 event.
For all grades, see instructions at bottom 
of shaded area if transaminase rise is not 
isolated but (at any time) occurs in setting 
of either increasing bilirubin or signs of 
DILI/liver decompensation
Grade 2
(Isolated AST or ALT 
>5.0×ULN and 
î8/1LIQRUPDODW
baseline)
(Isolated AST or ALT 
>2.0×baseline and 
î8/1LIHOHYDWHG
>ULN at baseline)
x
Hold study drug/study regimen dose 
XQWLO*UDGHUHVROXWLRQWR*UDGH
or baseline.
x
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, resume study drug/study 
regimen after completion of steroid taper.
For Grade 2:
í
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) 
until elevations of these are improving or resolved.
í
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion.
í
Consider, as necessary, discussing with study physician.
í
If event is persistent (>3 to 5 days) or worsens, and investigator 
suspects toxicity to be immune-mediated AE, recommend to 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
í
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 2 
to 4 mg/kg/day.
í
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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99
(i.e., mycophenolate mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
NOT be used.
Grade 3
(Isolated AST or ALT 
>8.0×ULN and 
î8/1LIQRUPDO
at baseline)
(Isolated AST or ALT 
>12.5×ULN and 
î8/1LI
elevated >ULN at 
baseline)
x
Hold study drug/study regimen dose 
XQWLOUHVROXWLRQWR*UDGHRU
baseline
x
Resume study drug/study regimen if
HOHYDWLRQVGRZQJUDGHWR*UDGHRU
baseline within 14 days and after 
completion of steroid taper.
x
Permanently discontinue study 
drug/study regimen if the elevations 
GRQRWGRZQJUDGHWR*UDGHRU
baseline within 14 days
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b
For Grade 3:
í
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved.
í
Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment of 
liver perfusion; and consider liver biopsy.
í
Consider, as necessary, discussing with study physician.
í
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
í
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should NOT be used.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 4
(Isolated AST or ALT 
>20×ULN,  whether 
Permanently discontinue study drug/study 
regimen.
For Grade 4:
Same as above 
(except would recommend obtaining liver biopsy early)

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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100
normal or elevated at 
baseline)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing WRWDOGLUHFWELOLUXELQî8/1LIQRUPDODWEDVHOLQHRUîEDVHOLQHLI
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
-
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise
-
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise
-
Grade 3-4: Permanently discontinue study drug/study regimen
Nephritis or renal 
dysfunction
(elevated serum 
creatinine)
Any Grade
General Guidance
For Any Grade:
í
Consult with nephrologist.
í
Monitor for signs and symptoms that may be related to changes 
in renal function (e.g., routine urinalysis, elevated serum BUN 
and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria).
í
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections).
í
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event.
Grade 1
(Serum creatinine > 1
to 1.5 × baseline; > 
ULN to 1.5 × ULN)
No dose modifications.
For Grade 1:
í
Monitor serum creatinine weekly and any accompanying 
symptoms.
x
If creatinine returns to baseline, resume its regular 
monitoring per study protocol.
x
If creatinine worsens, depending on the severity, treat 

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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101
as Grade 2, 3, or 4.
í
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
Grade 2
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN)
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGHRUEDVHOLQH
x
If toxicity worsens, then treat as 
Grade 3 or 4.
x
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, then resume study 
drug/study regimen after completion 
of steroid taper.
For Grade 2:
í
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
í
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted.
í
Consult nephrologist and consider renal biopsy if clinically 
indicated.
í
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
í
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
í
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN;
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4:
í
Carefully monitor serum creatinine on daily basis.
í
Consult nephrologist and consider renal biopsy if clinically 
indicated.
í
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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102
Grade 4: serum 
creatinine >6.0 × ULN)
equivalent.
í
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Rash
(excluding bullous skin 
formations)
Any Grade
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:
í
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
í
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED.
Grade 1
No dose modifications.
For Grade 1:
í
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream).
Grade 2
For persistent (>1 to 2 weeks) Grade 2
events, hold scheduled study drug/study 
UHJLPHQXQWLOUHVROXWLRQWR*UDGHRU
baseline.
x
If toxicity worsens, then treat as 
Grade 3.
x
,IWR[LFLW\LPSURYHVWR*UDGHRU
For Grade 2:
í
Obtain dermatology consult.
í
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream).
í
Consider moderate-strength topical steroid.

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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103
baseline, then resume drug/study 
regimen after completion of steroid 
taper.
í
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
í
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGHRUEDVHOine.
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
*UDGHRUEDVHOLQHZLWKLQ days, then 
permanently discontinue study drug/study 
regimen.
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4:
í
Consult dermatology.
í
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
í
Consider hospitalization.
í
Monitor extent of rash [Rule of Nines].
í
Consider skin biopsy (preferably more than 1) as clinically 
feasible.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
í
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
Any Grade
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
General Guidance
For Any Grade:
í
Consider consulting an endocrinologist for endocrine events.
í
Consider, as necessary, discussing with study physician.
í
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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104
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section)
CTC grade/severity)
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness.
í
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections).
í
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c).
í
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as there 
are no other signs or symptoms of pancreatic inflammation.
í
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 
or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH elevation):
í
Monitor patient with appropriate endocrine function tests.
í
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency).
í
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist.

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105
Grade 2
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable.
x
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
3.
'RVHVRISUHGQLVRQHDUH mg/day 
or equivalent.
For Grade 2 (including those with symptomatic endocrinopathy):
í
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan.
í
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, consider short-term corticosteroids (e.g., 1 
to 2 mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones).
í
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.
í
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids.
í
Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) RYHUGD\VDQGFRQVLGHUSURSK\ODFWLF
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
í
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled. 
For Grade 3 or 4:
í
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended.

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106
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
3.
'RVHVRISUHGQLVRQHDUH mg/day 
or equivalent.
í
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones).
í
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity.
í
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.
í
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids.
í
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
RIHQGRFULQRORJLVWRYHUGD\VDQGFRQVLGHUSURSK\ODFWLF
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre)
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity)
General Guidance
For Any Grade:
í
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications).
í
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
í
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations).

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
Version Date: 08/24/2018
107
í
Perform symptomatic treatment with neurological consult as 
appropriate.
í
Grade 1
No dose modifications.
For Grade 1:
í
See “Any Grade” recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
UHJLPHQGRVHXQWLOUHVROXWLRQWR*UDGH
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
UHJLPHQGRVHXQWLOUHVROXWLRQWR*UDGH
If toxicity worsens, then treat as 
Grade 3 or 4.
Study drug/study regimen can be resumed 
RQFHHYHQWLPSURYHVWR*UDGHDQG
after completion of steroid taper.
For Grade 2:
í
Consider, as necessary, discussing with the study physician.
í
Obtain neurology consult.
í
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
í
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
í
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG).
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
UHVROXWLRQWR*UDGH
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
WR*UDGHZLWKLQGD\V
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4:
í
Consider, as necessary, discussing with study physician.
í
Obtain neurology consult.
í
Consider hospitalization.
í
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
í
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly treat 
with additional immunosuppressants (e.g., IV IG).
í
2QFHVWDEOHJUDGXDOO\WDSHUVWHURLGVRYHUGD\V
Peripheral neuromotor 
Any Grade
General Guidance
For Any Grade:

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
Version Date: 08/24/2018
108
syndromes
(such as Guillain-Barre 
and myasthenia gravis)
í
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability.
í
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult.
í
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
neurology consultation.
í
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive to IV IG.
Grade 1
No dose modifications.
For Grade 1:
í
Consider, as necessary, discussing with the study physician.
í
Care should be taken to monitor patients for sentinel symptoms 

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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109
of a potential decompensation as described above.
í
Obtain a neurology consult.
Grade 2
Hold study drug/study regimen dose until 
UHVROXWLRQWR*UDGH
Permanently discontinue study drug/study 
UHJLPHQLILWGRHVQRWUHVROYHWR*UDGH
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability.
For Grade 2:
í
Consider, as necessary, discussing with the study physician.
í
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above.
í
Obtain a neurology consult
í
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist.
o
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient.
o
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.

Abbreviated Title: antiPDL1, antiCTLA4 & radiation
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110
o
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose until 
reVROXWLRQWR*UDGH
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
WR*UDGHZLWKLQGD\VRULIWKHUHDUH
signs of respiratory insufficiency or 
autonomic instability.
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4 (severe or life-threatening events):
í
Consider, as necessary, discussing with study physician.
í
Recommend hospitalization.
í
Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.
o
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG.
o
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.
o
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG.
Myocarditis
Any Grade
General Guidance
For Any Grade:

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Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis.
í
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
í
Consider, as necessary, discussing with the study physician.
í
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy,
including any other diagnostic procedures.
í
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed.
í
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities)
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0.
For Grade 1 (no definitive findings):
-
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated.
-
Consider using steroids if clinical suspicion is high.
Grade 2, 3 or 4
- If Grade 2 -- Hold study drug/study 
For Grade 2-4:

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(Grade 2: Symptoms 
with mild to moderate 
activity or exertion)
(Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated)
(Grade 4: Life-
threatening 
consequences; urgent
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support))
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen.
If Grade 3-4, permanently discontinue 
study drug/study regimen.
í
Monitor symptoms daily, hospitalize.
í
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy.
í
Supportive care (e.g., oxygen).
í
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDntifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:
í
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up.
í
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 

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procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation.
í
Consider, as necessary, discussing with the study physician.
í
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia.
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections).
Grade 1
(mild pain)
- No dose modifications.
For Grade 1:
í
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated.
í
Consider Neurology consult.
í
Consider, as necessary, discussing with the study physician.
Grade 2
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
Hold study drug/study regimen dose until 
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- Permanently discontinue study 
drug/study regimen if it does not 
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For Grade 2:
í
Monitor symptoms daily and consider hospitalization.
í
Obtain Neurology consult, and initiate evaluation.
í
Consider, as necessary, discussing with the study physician.

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of daily living [ADLs])
if there are signs of respiratory 
insufficiency.
í
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant 
í
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day
í
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRU
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Grade 3 or 4
(pain associated with 
severe weakness; 
limiting self-care 
ADLs)
For Grade 3:
Hold study drug/study regimen dose until 
UHVROXWLRQWR*UDGH
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
WR*UDGHZLWKLQGD\VRULIWKHUHDUH
signs of respiratory insufficiency.
For Grade 4:
- Permanently discontinue study 
For Grade 3 or 4 (severe or life-threatening events):
í
Monitor symptoms closely; recommend hospitalization.
í
Obtain Neurology consult, and complete full evaluation.
í
Consider, as necessary, discussing with the study physician.
í
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant.
í
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 

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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal.
drug/study regimen.
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab.
í
Consider whether patient may require IV IG, plasmapheresis.
í
Once the patient is improving, gradually taper steroids over 
GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRU
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a

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Infusion-Related Reactions
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
í
Manage per institutional standard at the discretion of investigator.
í
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia).
Grade 1 or 2
For Grade 1:
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event.
For Grade 2:
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event.
Subsequent infusions may be given at 50% of the initial 
infusion rate.
For Grade 1 or 2:
í
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator.
í
Consider premedication per institutional standard prior to 
subsequent doses.
í
6WHURLGVVKRXOGQRWEHXVHGIRUURXWLQHSUHPHGLFDWLRQRI*UDGH
infusion reactions.
Grade 3 or 4
For Grade 3 or 4:
Permanently discontinue study drug/study regimen.
For Grade 3 or 4:
í
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid).
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.

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Non–Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant.
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2
+ROGVWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR*UDGHRU
baseline.
Treat accordingly, as per institutional standard.
Grade 3
+ROGVWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR*UDGHRU
baseline.
)RU$(VWKDWGRZQJUDGHWR*UDGHZLWKLQGD\VRUUHVROYHWR
*UDGHRUEDVHOLQHZLWKLQGD\VUHVXPHVWXG\GUXJVWXG\
regimen administration. Otherwise, discontinue study drug/study 
regimen.
Treat accordingly, as per institutional standard.
Grade 4
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.).
Treat accordingly, as per institutional standard.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.”
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.

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