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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 | Center for Cancer Research, National |
| Cancer Institute | Cancer Institute                     |                                      |
| Manufacturer:    | MedImmune, Inc.                      | MedImmune, Inc.                      |  
1
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precis 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.
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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.
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eligibility

x Histologically confirmed metastatic pancreatic cancer with primary in-situ (or locallyrecurrent) 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 3DWLHQWVPXVWEH\HDUVRIDJHDQGKDYHDSHUIRUPDQFHVWDWXV(&2*1 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).
3  
| TABLE OF CONTENTS                                                                                                                                       |                                                                                                                                            |                                                                                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                                                                |                                                                                                                                            |                                                                                                                                                        |
| TABLE OF CONTENTS                                                                                                                                       |                                                                                                                                            |                                                                                                                                                        |
| INTRODUCTION ........................................................................................................................................ 9 |                                                                                                                                            |                                                                                                                                                        |
| 1                                                                                                                                                       | 1.1                                                                                                                                        | Study Objectives ................................................................................................................................... 9 |
| 1.1.1                                                                                                                                                   | Primary .                                                                                                                                  |                                                                                                                                                        |
| 1.1.2                                                                                                                                                   | Secondary                                                                                                                                  |                                                                                                                                                        |
| Exploratory ....................................................................................................................................... 9   |                                                                                                                                            |                                                                                                                                                        |
| 1.1.3                                                                                                                                                   | Background and Rationale ............................................................................................................... 9 |                                                                                                                                                        |
| 1.2                                                                                                                                                     |                                                                                                                                            |                                                                                                                                                        |
| 1.2.1                                                                                                                                                   | Pancreatic cancer and the current therapeutic paradigm................................................ 9                                   |                                                                                                                                                        |
| 1.2.2                                                                                                                                                   | Radiation treatment in pancreatic cancer:                                                                                                  |                                                                                                                                                        |
| Recent advances in immune-based approaches in solid tumor malignancies........ 12                                                                       |                                                                                                                                            |                                                                                                                                                        |
| 1.2.3                                                                                                                                                   |                                                                                                                                            |                                                                                                                                                        |
| 1.2.4                                                                                                                                                   | Immune response following radiation, mechanism and rationale for combination                                                               |                                                                                                                                                        |
| with immune checkpoint inhibition: .                                                                                                                    |                                                                                                                                            |                                                                                                                                                        |
| 1.2.5                                                                                                                                                   | T Tremelimumab .                                                                                                                           |                                                                                                                                                        |
| 1.2.6                                                                                                                                                   | Anti-CTLA4 therapy in pancreatic cancer                                                                                                    |                                                                                                                                                        |
| 1.2.7                                                                                                                                                   | D DURVALUMAB                                                                                                                               |                                                                                                                                                        |
| 1.2.8                                                                                                                                                   | Anti-CTLA4 in combination with anti-PD1/PD-L1.                                                                                             |                                                                                                                                                        |
| 1.2.9                                                                                                                                                   | Justification for dose and schedule                                                                                                        |                                                                                                                                                        |
| 1.2.10                                                                                                                                                  | Rationale for study population and schedule: ....................................................................... 23                    |                                                                                                                                                        |
| 1.2.11                                                                                                                                                  | Justification for Tumor Biopsies                                                                                                           |                                                                                                                                                        |
| 1.2.12                                                                                                                                                  | Justification for accrual increase in Arm C2 with Amendment I ............................. 24                                             |                                                                                                                                                        |
| 2                                                                                                                                                       | ELIGIBILITY ASSESSMENT AND ENROLLMENT                                                                                                      |                                                                                                                                                        |
| 2.1                                                                                                                                                     | Eligibility Criteria .                                                                                                                     |                                                                                                                                                        |
| 2.1.1                                                                                                                                                   | Inclusion Criteria .                                                                                                                       |                                                                                                                                                        |
| 2.1.2                                                                                                                                                   | Exclusion Criteria .                                                                                                                       |                                                                                                                                                        |
| 2.1.3                                                                                                                                                   | Recruitment Strategies .                                                                                                                   |                                                                                                                                                        |
| 2.2                                                                                                                                                     | Screening evaluation                                                                                                                       |                                                                                                                                                        |
| 2.3                                                                                                                                                     | Registration Procedures                                                                                                                    |                                                                                                                                                        |
| 2.3.1                                                                                                                                                   | T Treatment Assignment Procedures: .............................................................................................. 29       |                                                                                                                                                        |
| 2.4                                                                                                                                                     | Baseline Studies .                                                                                                                         |                                                                                                                                                        |
| STUDY IMPLEMENTATION .                                                                                                                                  |                                                                                                                                            |                                                                                                                                                        |
| 3                                                                                                                                                       |                                                                                                                                            |                                                                                                                                                        |  
| 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                                                |  
5.3 5.4 6 6.1 6.2 6.3  
| MedImmune Planned Studies                                                           |                                                                                                                                      |
|-------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| 5.3.1                                                                               | Pharmacokinetics .                                                                                                                   |
| 5.3.2                                                                               | Immunogenicity .                                                                                                                     |
| 5.3.3                                                                               | T CELL Activation/ICOS expression                                                                                                    |
| 5.3.4                                                                               | Plasma-based assays for circulating receptors/ligands e.g. PDL1 ............................ 50                                      |
| Sample Storage, Tracking and Disposition                                            |                                                                                                                                      |
| 5.4.1                                                                               | Samples Managed by Dr. Figg's Blood Processing Core (BPC).................................. 51                                       |
| Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ...... 52 |                                                                                                                                      |
| 5.4.2                                                                               |                                                                                                                                      |
| 5.4.3                                                                               | Protocol Completion/Sample Destruction .                                                                                             |
| DATA COLLECTION AND EVALUATION                                                      |                                                                                                                                      |
| DATA COLLECTION                                                                     |                                                                                                                                      |
| DATA SHARING PLANS .                                                                |                                                                                                                                      |
| 6.2.1                                                                               | Human Data Sharing Plan                                                                                                              |
| Response Criteria                                                                   |                                                                                                                                      |
| Definitions                                                                         |                                                                                                                                      |
| 6.3.1                                                                               | Disease Parameters .                                                                                                                 |
| 6.3.2                                                                               |                                                                                                                                      |
| 6.3.3                                                                               | Methods for Evaluation of Measurable Disease .                                                                                       |
| 6.3.4                                                                               | Response Criteria                                                                                                                    |
| Duration of Response                                                                |                                                                                                                                      |
| 6.3.5                                                                               | Modified immune-related response criteria (irRC) .................................................................. 60               |
| 6.4.1                                                                               | The modified irRC based on RECIST 1.1: .......................................................................................... 60 |
| TOXICITY Criteria                                                                   |                                                                                                                                      |
| SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING                            |                                                                                                                                      |
| 61                                                                                  |                                                                                                                                      |
| Definitions                                                                         |                                                                                                                                      |
| 7.1.1                                                                               | A Adverse Event                                                                                                                      |
| 7.1.2                                                                               | Suspected adverse reaction .                                                                                                         |
| Unexpected adverse reaction                                                         |                                                                                                                                      |
| 7.1.3                                                                               |                                                                                                                                      |
| 7.1.4                                                                               | Serious                                                                                                                              |
| 7.1.5                                                                               | Serious Adverse Event                                                                                                                |
| 7.1.6                                                                               | Disability                                                                                                                           |
| 7.1.7                                                                               | Life-threatening adverse drug experience .                                                                                           |  
6.4 6.5 7 PLAN
7.1  
| 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 717                                                    |  
| 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

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.
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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).
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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.
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1.2 background and rationale 1.2.1

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 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.
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1.2.2 radiation treatment in pancreatic

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 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  
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].
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1.2.3 recent advances in immune-based

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[1315]. 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 neoantigens 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.  
12 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
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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 singlefraction 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 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+.
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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- 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&,>@5HVSRQVHVZHUHGXUDEOHSUHVHQWDWPRQWKVIURP
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 FDAapproved- 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 RIDQGDVVHVVHGE\WKHLQYHVWLJDWRUDVUHODWHGWRWUHDWPHQWOLVWHGLQ 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

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 WR7KUHHVXEMHFWVH[SHULHQFHGJUDGH 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.
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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.). 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 treatmentemergent AE (Table 5.3.1.3-RIFXUUHQW,%HGLWLRQ7KHPRVWIUHTXHQWO\UHSRUWHGRI
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 treatmentrelated 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

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 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, 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 PJNJGXUYDOXPDEPJNJWUHPHOLPXPDEJURXSKDGWKHIHZHVW$(V*UDGH$(V6$(V
and treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This cohort had a lower number of treatment-UHODWHG*UDGH$(VRUWUHDWPHQW UHODWHG6$(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.
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1.2.9 justification for dose and

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 rate and OS clearly indicate activity of tremelimumab in melanoma. Retrospective exposuresurvival 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 ȝJP/ 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 WDUJHWOHYHO RI ȝJP/ GXULQJWKHLQGXFWLRQ SKDVH ,QWKH3KDVH ,,,PHODQRPDWULDOZLWKOHVV 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.
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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(noobserved-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 ZDVaȝJP/%DVHGRQPHDQ.PYDOXH > 99% target saturation (both soluble and membrane ERXQGLVH[SHFWHGDWȝJP/ 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   ȝJP/ 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 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 UHSRUWHGLQ   RI VXEMHFWVZHUH
colitis (8.8%), diarrhea (7.8%), and increased lipase (5.9%). Five subjects reported treatmentrelated 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. Twentyseven subjects (26.5%) permanently discontinued treatment due to AEs. Treatment-related AEs UHVXOWLQJLQ GLVFRQWLQXDWLRQLQ   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 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 FRHIILFLHQWRI7KHLPSDFWRIERG\: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 RI7KH: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.
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1.2.10 rationale for study population

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 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.
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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.
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1.2.11.1 details of planned tumor

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.
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1.2.12 justification for accrual increase

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 (>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.
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2 eligibility assessment and enrollment

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:  
| 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   |
|-----------|---|  
| 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 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)
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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  
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.
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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.
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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. 2.3.1 Treatment Assignment Procedures:  
| Number   | Name   | Description   |
|----------|--------|---------------|  
1 Cohort 1 Subjects with unresectable pancreatic cancer  
Arms Subjects in Cohort 1 will be directly assigned to Arms A1, A2, C1, C2 as follows:  
| 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 |  
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.
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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).
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3 study implementation 3.1 study

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 12month 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 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.
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3.1.1 arms a1 and a2

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    | N   |
|----------------------------------------------|------------------------|----------|-----|
| dose/schedule                                |                        |          |     |
| A1                                           | Durvalumab             | 8Gy x 1# | 10  |
| 10mg/kg/q2w                                  |                        |          |     |
| A2                                           | Durvalumab             | 5Gy x 5# | 10  |
| 10mg/kg/q2w                                  |                        |          |     |
| a SBRT= 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.  
- 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  
  
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 offtreatment 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    | N   | Start date   |
|----------------------------------------------|------------------------|----------|-----|--------------|
| dose/schedule                                |                        |          |     |              |
| C1                                           | Durvalumab 1500mg +    | 8Gy x 1# | 10  | March        |
| Tremelimumab 75mg                            | 2016                   |          |     |              |
| C2                                           | Durvalumab 1500mg +    | 5Gy x 5# | 20  |              |
| Tremelimumab 75mg                            |                        |          |     |              |
| a SBRT= 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.  
- 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 Immunerelated 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.
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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.
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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 restarting 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.
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3.2 dose limiting toxicities 3.2.1

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$(WKDWGRHVQRWGRZQJUDGHWR*UDGHZLWKLQGD\VDIWHURQVHWRI
the event despite maximal supportive care including systemic corticosteroids or GRZQJUDGHWR*UDGHRUEDVHOLQHZLWKLQGD\V
3.2.1.3 Liver transaminase elevation higher than 8 × upper limit of normal (ULN) or total bilirubin higher than 5 × ULN
3.2.1.4 $Q\*UDGHSQHXPRQLWLVWKDWGRHVQRW UHVROYHWR*UDGHZLWKLQGD\VRIWKH
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 SUXULWXVWKDW GRZQJUDGHVWR*UDGH ZLWKLQ GD\VDIWHURQVHWRIWKH
event with maximal supportive care including systemic corticosteroids or GRZQJUDGHWR 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.
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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 QHHGWREHHTXLSSHGZLWKRUȝPLQ-line filters.  
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.
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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.
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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).
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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.
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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**.
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3.3.2 adverse events of special

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.  
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  5DVKIOXVKLQJXUWLFDULDG\VSQHDGUXJIHYHU&
- 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.
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3.4 specific procedures for stereotactic

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.
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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.
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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 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.  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| FU  k EOT j                              | X                      | X X                        | Xi Xi Xi Xi Xi Xi X X   | X XX X X X X X X XX X X X   | X XX X X X X X X XX X X X   |           |                   |                              |
|------------------------------------------|------------------------|----------------------------|-------------------------|-----------------------------|-----------------------------|-----------|-------------------|------------------------------|
| D1 of                                    | every  subsequ ent     | cycle                      |                         |                             |                             |           |                   |                              |
| C3                                       | X X                    | X X X                      | X                       | X X X                       | X X Xp X Xp X               |           |                   |                              |
| -3 -2 -1 0 1 8 15 22 1 8 15 22 1 8 15 22 | X X X X                | X                          | X                       | X X                         |                             |           |                   |                              |
| C2                                       | X                      | X                          | 40                      |                             |                             |           |                   |                              |
| Durvalumab a X                           | Tremelimumab b, o X    | X                          | X X X X X               | X                           | X X                         | X         | TSH, T3, T4 d X X |                              |
| C1                                       | Basel ine n Scree ning | X                          | X                       | X X                         | X X                         | CBC d X X | X X               | Biochemical profile d, e X X |
| X                                        | Hepatitis A, B, C X    | PT, INR, PTT, fibrinogen d |                         |                             |                             |           |                   |                              |
| 3.5 STUDY CALENDAR                       | Formal adverse event   | evaluation                 |                         |                             |                             |           |                   |                              |
| SBRT c Arms A1, C1                       | SBRT c Arms A2, C2     | Concomitant meds           |                         |                             |                             |           |                   |                              |
| Informed consent                         | Medical history        | Physical exam              | Vital Signs             |                             |                             |           |                   |                              |  
| FU  k                                    | X h X X m                                     | X h X X m                |                        |                         |        |                   |                                              |                        |                                                              |
|------------------------------------------|-----------------------------------------------|--------------------------|------------------------|-------------------------|--------|-------------------|----------------------------------------------|------------------------|--------------------------------------------------------------|
| EOT j                                    | X p X X X p X X p X p X p X X p X p X p X X p | X h X                    |                        |                         |        |                   |                                              |                        |                                                              |
| D1 of                                    | every  subsequ ent                            | cycle                    |                        |                         |        |                   |                                              |                        |                                                              |
| C3                                       | X f                                           | X h                      | X h                    |                         |        |                   |                                              |                        |                                                              |
| X                                        | X                                             |                          |                        |                         |        |                   |                                              |                        |                                                              |
| -3 -2 -1 0 1 8 15 22 1 8 15 22 1 8 15 22 | X                                             | X                        | X                      | X                       | X      | X                 |                                              |                        |                                                              |
| C2                                       | X                                             | X                        | Tumor biopsy g, o X X  | Immune monitoring o X X | X XX X | X X               | X XX X                                       |                        |                                                              |
| X                                        |                                               |                          |                        |                         |        |                   |                                              |                        |                                                              |
| C1                                       | Basel ine n Scree ning                        | Uric acid, amylase d X X | X                      | X X                     | X X    | X ANA, AMA, Liver | autoantibody panel  (autoimmune hepatitis) o | T cell activation/ICOS | expression/ functional  analyses / immunodiversity  (PBMC) o |
| Restaging radiologic  Evaluation         | Pharmacokinetic                               | studies o                | Immunogenicity (ADA) o |                         |        |                   |                                              |                        |                                                              |
| CA 19-9                                  | EKG                                           |                          |                        |                         |        |                   |                                              |                        |                                                              |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* 41 Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| FU  k                                                               | X h X X m                                |                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
|---------------------------------------------------------------------|------------------------------------------|-----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| EOT j                                                               | 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 offtreatment 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. |                |
| D1 of                                                               | every  subsequ ent                       | cycle                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
| C3                                                                  | -3 -2 -1 0 1 8 15 22 1 8 15 22 1 8 15 22 | X                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
| C2                                                                  | X XX X                                   |                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
| C1                                                                  | Basel ine n Scree ning                   | Advance Directive l X | Serum or urine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | pregnancy test |
| X X                                                                 |                                          |                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
| Plasma-based assays  for circulating  receptors/ligands e.g., PDL1o |                                          |                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* 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 NIHn 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-treatmentp Optional
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3.6 criteria for removal from

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
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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 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.
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3.6.3 off protocol therapy and

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.
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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.
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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.  
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.
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5 biospecimen collection 5.1 correlative

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.  
| made below. Test/assay   | Volume blood     | Type of   | Collection point (+/-      | Location of               |
|--------------------------|------------------|-----------|----------------------------|---------------------------|
| (approx.)                | tube             | 48hrs)    | specimen  analysis         |                           |
| Immune- monitoring       | 120 mL (for      | EDTA      | Baseline on day of biopsy, | Greten Lab                |
| PBMC)                    | C2D1, C3D1, C4D1 |           |                            |                           |
| 5-10 mL (for             | EDTA             |           |                            |                           |
| serum)                   |                  |           |                            |                           |
| PK                       | 3 mL             | SST       | C1D1 (pre- dose and Endof Infusion (EOI)*)                            | MedImmune / Intertek Alta |
| C1D8 (local patients only) C1D15 (local patients  only) C2D1 (pre-dose) C3D1 (pre-dose) C4D1 (pre-dose) C7D1 (pre-dose and Endof 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                          |                  |           |                            |                           |  
| Test/assay                                                                | Volume blood                           | Type of                         | Collection point (+/-                                                                                                       | Location of                                  |
|---------------------------------------------------------------------------|----------------------------------------|---------------------------------|-----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|
| (approx.)                                                                 | tube                                   | 48hrs)                          | specimen  analysis                                                                                                          |                                              |
| infusion and immediately  post infusion.                                  |                                        |                                 |                                                                                                                             |                                              |
| Immunogenicity                                                            | 4 mL                                   | SST                             | Pre-dose: C1D1, C2D1,  C4D1, C7D1, C10D1, C13D1                                                                             | Medimmune/PPD                                |
| (Antidrug antibody  monitoring)                                           | End of treatment 90-day post last dose |                                 |                                                                                                                             |                                              |
| 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                                       | 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                        |
| (PBMC) Plasma-based assays  for circulating  receptors/ligands e.g.  PDL1 | 6 mL                                   | EDTA                            | C1D1 (pre- dose and Endof Infusion (EOI)*                                                                                                                             | Medimmune                                    |
| C1D8 (local patients only) C1D15 (local patients  only) C2D1 (pre-dose) C3D1 (pre-dose) C4D1 (pre-dose) C7D1 (pre-dose and Endof Infusion(EOI)*) C10D1 (pre-dose) C13D1 (pre-dose) End-of-treatment (EOT),  and  90-days post last dose.  *End of infusion PK                                                                           |                                        |                                 |                                                                                                                             |                                              |
| 47                                                                        |                                        |                                 |                                                                                                                             |                                              |  
| Test/assay      | Volume blood   | Type of   | Collection point (+/-   | Location of   |
|-----------------|----------------|-----------|-------------------------|---------------|
| (approx.)       | tube           | 48hrs)    | specimen  analysis      |               |
| samples should be  collected within  approximately 15 minutes.  C1D1 and C7D1: preinfusion and immediately  post infusion.                 |                |           |                         |               |
| Mandatory tumor | NA             | NA        | Baseline + C2D1         | Pathology     |
| biopsy          |                |           |                         |               |
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5.2 nci correlative studies 5.2.1

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.
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5.2.2 liver autoantibody panel for

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.
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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  
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.
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5.2.4 details of planned tumor

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.
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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 (predose 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.
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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.
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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
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5.3.4 plasma-based assays for circulating

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 mesothelinrelated 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 (predose 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

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. 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.
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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.
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6 data collection and evaluation

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. 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.
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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.
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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. 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 bidimensional 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 QHZOHVLRQVGRHVQRWLQFUHDVHE\
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6.3.1 definitions 6.3.1.1 evaluable for

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.)
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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; 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).
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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.
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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.
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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.
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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

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.
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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.
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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.
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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.
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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.
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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.
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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 immunerelated 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  
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  Non-Target  New  Overall  Best Overall Response when  Lesions Lesions Lesions Response Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR NonCR/Non-PD No PR CR Not  No PR evaluated >4 wks. Confirmation** PR NonCR/NonPD/not  evaluated No PR SD NonCR/NonPD/not  evaluated No SD Documented at least once >4  wks. from baseline** PD Any Yes or  PD No Any PD*** Yes or no prior SD, PR or CR PD No 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   |
|---|  
| Target                                          | Non-Target                                                                                                                                                                                                                                                                                                                    | New     | Overall   | Best Overall Response when   |
|-------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------|------------------------------|
| Lesions                                         | Lesions                                                                                                                                                                                                                                                                                                                       | Lesions | Response  | 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. |         |           |                              |  
| 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 |               |                    |  
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.