A Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC
Phase: PHASE2
Conditions: Metastatic Colorectal Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Stage IV Colorectal Cancer AJCC v7, Stage IV Lung Non-Small Cell Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

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Local Protocol #: 17-719 
 
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Incorporated CIMAC biomarker network for biomarker 
analyses  
 
 

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For Protocol Amendment # to: 
 
NCI Protocol #: 
10021 
 
Local Protocol #: 
17-719 
 
ClinicalTrials.gov Identifier:  NCT02888743 
 
TITLE: A Phase 2 Study of MEDI4736(durvalumab) and Tremelimumab Alone or in 
Combination with High or Low-Dose Radiation in Metastatic Colorectal and NSCLC  
 
Study disease:  
1. Non-small cell lung cancer 10029514 
2.  Colorectal cancer 10010029 
 
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Principal Investigator: 
Jonathan Schoenfeld 
Dana-Farber Cancer Institute 
450 Brookline Ave. DA L257 
Boston, MA 02115 
Phone: 617-632-3591 
Fax: 617-632-4247 
jdschoenfeld@partners.org 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
  
 

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Statistician: 
 
Study Coordinator: 
 
Anita Giobbie-Hurder 
Amanda Stroiney  Dana-Farber Cancer 
Institute 
Dana Farber Cancer Institute 
 
450 Brookline Ave (CLSB 11007) 
450 Brookline Ave.  
 
Boston, MA 02215 
Boston, MA 02215 
 
p617-632-2193 
p617-632-3289 
 
f617-632-5444 
f617-632-7227 
 
agiohur@jimmy.harvard.edu                        
amanda_stroinry@dfci.harvard.edu 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Rose Baylies, R.N. 
Amanda Stroiney 
 
Dana-Farber Cancer Institute 
Dana Farber Cancer Institute 
 
450 Brookline Ave  
450 Brookline Ave. 
 
Boston, MA 02215 
Boston, MA 02215 
 
p617-632-6278 
p617-632-3289 
 
f617-632-6949 
f617-632-7227 
 
RosemarieKristinaM_baylieskelley@dfci.harvard.edu 
 
janiceamanda_stroineyrussell@dfci.harvard.edu  
 
 
NCI-Supplied Agent(s):   
MEDI4736(NSC 778709) 
Tremelimumab (NSC 744483) 
 
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
[Revised / Version #11 /August 30, 2019] 
 
 
 

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SCHEMA 
 
 
8Gy x 3 +  
durvalumab/ 
tremelimumab 
Low-dose RT*+  
durvalumab/ 
tremelimumab 
Continue 
durvalumab to 
progression 
Metastatic NSCLC that 
failed to respond to 
prior PD-1 or PD-L1 
inhibitor 
durvalumab/ 
tremelimumab 
NSCLC Cohort- Cohort 1 
Arm A 
Arm B 
Arm C 
8Gy x 3 +  
durvalumab/ 
tremelimumab 
Colorectal Cohort- Cohort 2 
Low-dose RT*+  
durvalumab/ 
tremelimumab 
*0.5 Gy BID x2 days repeated q4weeks with durvalumab / tremelimumab 
Continue 
durvalumab to 
progression 
Metastatic CRC, 
progressive on >=1 
chemotherapy regimens 
(exclude MSI tumors)  
Arm A 
Arm B 

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TABLE OF CONTENTS 
 
SCHEMA .......................................................................................................................................14 
1. OBJECTIVES .........................................................................................................................17 
1.1 Primary Objectives ....................................................................................................17 
1.2 Secondary Objectives ................................................................................................17 
2. BACKGROUND ....................................................................................................................18 
2.1 Study Disease(s) ........................................................................................................18 
2.2 CTEP Agent(s) ..........................................................................................................18 
2.3 Other Agent(s) - Radiotherapy ..................................................................................24 
2.4 Rationale ...................................................................................................................29 
2.5 Correlative Studies Background ...............................................................................30 
            2.6     Exploratory Patient Reported Outcomes                                                                 33 
3. PATIENT SELECTION .........................................................................................................33 
3.1 Eligibility Criteria ....................................................................................................33 
3.2 Exclusion Criteria .....................................................................................................38 
3.3 Inclusion of Women and Minorities .........................................................................42 
4. REGISTRATION PROCEDURES ........................................................................................43 
4.1 Investigator and Research Associate Registration with CTEP .................................43 
4.2 Site Registration ........................................................................................................44 
4.3 Patient Registration ...................................................................................................47 
4.4 General Guidelines ....................................................................................................49 
5. TREATMENT PLAN .............................................................................................................49 
5.1 Agent Administration ................................................................................................49 
5.2 Definition of Dose-Limiting Toxicity .......................................................................65 
5.3 General Concomitant Medication and Supportive Care Guidelines .........................67 
5.4 Duration of Therapy ..................................................................................................69 
5.5 Duration of Follow Up ..............................................................................................69 
5.6 Criteria for Removal from Study ..............................................................................70 
5.7 Criteria to Resume Treatment ...................................................................................70 
5.8 Treatment Beyond Progression .................................................................................70 
5.9 Discontinuation of Treatment Following Complete Response .................................71 
6. DOSING DELAYS/DOSE MODIFICATIONS.....................................................................72 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ...............................102 
7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ................102 
7.2 Adverse Events of Special Interest                                                                    110 
7.3    Adverse Event Characteristics ................................................................................111 
7.4 Expedited Adverse Event Reporting .......................................................................111 
7.5 Routine Adverse Event Reporting ..........................................................................114 

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7.6 Secondary Malignancy ............................................................................................114 
7.7 Second Malignancy .................................................................................................115 
8. PHARMACEUTICAL INFORMATION .............................................................................115 
8.1 CTEP IND Agent(s) ................................................................................................115 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...........................................120 
9.1 Integrated Correlative Studies .................................................................................129 
9.2 Exploratory/Ancillary Correlative Studies .............................................................131 
10. STUDY CALENDAR ........................................................................................................135 
11. MEASUREMENT OF EFFECT.........................................................................................140 
11.1 Antitumor Effect – Solid Tumors .........................................................................140 
            11.2 Antitumor Effect–Hematologic Tumors ...............................................................147 
            11.3 Other Response Parameters ..................................................................................147 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................151 
12.1 Study Oversight ....................................................................................................151 
12.2 Data Reporting ......................................................................................................152 
12.3 CTEP Multicenter Guidelines ...............................................................................154 
12.4 Collaborative Agreements Language ....................................................................154 
13. STATISTICAL CONSIDERATIONS................................................................................157 
13.1 StudyDesign/Endpoints.........................................................................................157 
13.2 Endpoint Definitions .............................................................................................157 
13.3 Randomization ......................................................................................................158 
13.4 Sample Size/Accrual .............................................................................................158 
13.5 Accrual ..................................................................................................................159 
13.6 Interim Safety Analysis.........................................................................................160 
13.7 Analysis of Primary Endpoints .............................................................................161 
13.8 Analysis of Secondary Endpoints .........................................................................161 
13.9 Reporting and Exclusions .....................................................................................163 
REFERENCES ............................................................................................................................165 
APPENDIX A PERFORMANCE STATUS CRITERIA .........................................................169  
APPENDIX B 
DRUG INFORMATION  AND CONTACT SHEET  .....................................170 
APPENDIX C    Guidance Document for Research Blood Samples & Tissue Collection……172 
APPENDIX D    RECIST 1.1 Guidelines……………………………………………………   178 
APPENDIX E:  PRO-CTCAE Items for collection                                                                     178 
APPENDIX F: Medidata Patient Cloud Registration                                                                  180 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
NSCLC Cohort:  
1. To assess safety and tolerability of combined checkpoint blockade with 
MEDI4736(durvalumab) and tremelimumab alone or with high or low-dose radiation in 
NSCLC 
2.  To compare the overall response (excluding the irradiated lesion(s)) between combined 
checkpoint blockade with MEDI4736 and tremelimumab alone or combined checkpoint 
blockade with low or high dose radiation.  
 
Colorectal Cohort:  
1. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 and 
tremelimumab with high or low-dose radiation 
2.  To determine the overall response rate (excluding the irradiated lesion(s)) with combined 
checkpoint blockade with MEDI473 6and tremelimumab with either low or high dose 
radiation.  
 
1.2 
Secondary Objectives 
 
NSCLC Cohort   
x To estimate median progression-free survival and overall survival  
x To determine local control within the irradiated field(s) and abscopal response rates  
x To evaluate associations between PD-L1 expression as well as levels of infiltrating 
CD3+, CD8+ T-cells and overall response 
x To explore changes in changes in PD-L1 expression, circulating T-cell populations, T-
cell infiltration, RNA expression, spatial relationship of immune markers, and mutational 
burden as a result of low or high dose radiation 
 
Colorectal Cohort   
x To estimate median progression-free survival and overall survival  
x To determine local control within the irradiated field and abscopal response rates  
x To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+ 
CD8+ T-cells and overall response 
x To evaluate changes between PD-L1 expression as well as levels of infiltrating CD3+, 
CD8+ T-cells induced by targeted low or high dose radiation  
x To explore changes in changes in circulating T-cell populations, T-cell infiltration, RNA 
expression, spatial relationship of immune markers, and mutational burden as a result of 
low or high dose radiation 
1.3. Exploratory Endpoints 
        1.  To explore the inclusion of patient reported symptomatic adverse events 
 
 
2. BACKGROUND 
 

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2.1 
Study Disease(s) 
 
Metastatic non-small cell lung cancer 
 
Over 225,000 people are diagnosed per year with non-small cell lung cancer in the United States, 
and this disease is responsible for over 150,000 deaths per year, making it the leading cause of 
cancer deaths and representing a clear unmet need [1].  In patients without a targetable driver 
mutation, first-line chemotherapy with two cytotoxic agents is generally superior to single agent 
therapy and is associated with an approximate 25% response rate and 1-year survival between 30 
and 40%[2]. Responses to additional lines of chemotherapy following progression are 
significantly reduced and generally less than 10%, with median survival of approximately 6 
months in this setting[3].  In comparison, PD-1 checkpoint blockade has been associated with an 
approximate 20% response rate and improved survival as compared to chemotherapy in the 
second line setting in both squamous and non-squamous cancers[4, 5].  For these reasons, PD-1 
inhibition is actively being investigated in the first line setting, with promising initial results [6].  
CTLA-4 therapy alone has not demonstrated impressive response rates[7]; however, an 
intriguing case report demonstrated the combination of CTLA-4 and radiation led to a complete 
radiologic response[8]. The combination of CTLA-4 and PD-1 inhibition is also being 
investigated in this disease; however, preliminary reports suggest that the majority of metastatic 
non-small cell lung cancer patients may not respond to the combination of these two agents 
alone[9].  Therefore, we propose to evaluate whether low or high dose radiation will increase 
response rates as compared to combined checkpoint blockade of CTLA-4 and PD-L1 alone in 
patients that have previously failed to respond to either PD-1 or PD-L1 inhibitors.  
 
Metastatic colorectal cancer 
 
Approximately 130,000 people are diagnosed with colorectal cancer annually in the United 
States, and this disease is responsible for over 45,000 deaths per year[10]. First-line 
chemotherapy with multi-agent regimens can have response rates approaching 50%[11, 12].  In 
the second line setting, there is a significantly decreased response rate that is generally less than 
20%, and many patients are not candidates for many of the potential second-line regimens 
because of prior treatment and/or concerns regarding toxicity and quality of life[13].   
 
Previous studies have suggested that treatment with immune checkpoint blockade alone does not 
generally lead to response in most colorectal cancer patients, except for patients with 
microsatellite instable tumors[14]. Therefore, we propose to attempt to induce a significant 
number of responding patients in microsatellite stable patients by combining either low or high 
dose radiation with CTLA-4 and PD-1 blockade in patients that have progressed after first line 
chemotherapy.  
 
2.2 
CTEP Agent(s) 
 
2.2.1 MEDI4736(durvalumab) 
 
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 

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attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells. PD-L1 is one such protein, and is upregulated in a broad range of 
cancers with a high frequency, with up to 88% expression in some indications. In a number of 
these cancers, including lung[15], renal [16-18], pancreatic [19-21], and ovarian cancer [22], 
tumor cell expression of PD-L1 is associated with reduced survival and an unfavorable 
prognosis. For example, in ovarian cancer, the 5-year survival rate in patients with low 
expression of PD-L1 was 80.2% compared to 52.6% in patients with high expression levels of 
PD-L1 [22]. In lung cancer, only 20% of patients with tumors expressing PD-L1 survived more 
than 3 years compared to 49% of patients with tumors lacking PD-L1 expression[15]. Along 
with PD-L1 expression data generated internally, these data suggest that an antibody targeting 
PD-L1 has the potential to affect multiple solid tumor types. PD-L1 is part of a complex system 
of receptors and ligands that are involved in controlling T-cell activation. PD-L1 acts at multiple 
sites in the body to help regulate normal immune responses and is utilized by tumors to help 
evade detection and elimination by the host immune system tumor response. In the lymph nodes, 
PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an 
inhibitory signal to the T cell [23, 24]. This results in reduced T-cell activation and fewer 
activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells 
binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers an inhibitory 
signal to those T cells, preventing them from killing target cancer cells and protecting the tumor 
from immune elimination[25]. Based on in vitro studies, an antibody that blocks the interaction 
between PD-L1 and its receptors can relieve PD-L1-dependent immunosuppressive effects and 
enhance the cytotoxic activity of antitumor T cells [26]. The levels of tumor-infiltrating 
lymphocytes, and more specifically cytotoxic T cells, have been correlated with improved 
prognosis in a number of cancers including colorectal, melanoma, and lung [27], suggesting that 
an antitumor immune response is beneficial to patients. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients with 
cancer. Results of several preclinical studies using mouse tumor models support this hypothesis 
[28-30]. In these studies, antibodies directed against PD-L1 or its receptor, PD-1, demonstrated 
antitumor activity. 
 
MEDI4736is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that inhibits 
binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the treatment 
of cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.) The 
proposed mechanism of action for MEDI4736 is interference of the interaction of PD-L1, 
expressed on cancer cells and a subset of leukocytes, with the PD-1 (cluster of differentiation 
[CD] 279) and B7-1 (CD80) molecules on antigen-presenting cells and T-cells. By binding to 
PD-L1 on tumor cells, the mechanism of action of MEDI4736 includes stimulation of the 
patient’s antitumor immune response. 
 
The non-clinical experience is fully described in the current version of the 
MEDI4736Investigator’s Brochure. In vitro studies demonstrate that MEDI4736 antagonizes the 
inhibitory effect of PD-L1 on primary human T cells, resulting in their restored proliferation and 
release of interferon gamma (IFN-γ). Additionally, MEDI4736 demonstrated a lack of antibody-
dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in 

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cell-based functional assays. In vivo studies show that MEDI4736 inhibits tumor growth in a 
xenograft model via a T-lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse 
(m)PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when given as 
monotherapy.  
 
To date MEDI4736has been given to more than 6000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents.  Details on the safety profile of 
MEDI4736monotherapy are summarized below.  Refer to the current MEDI4736Investigator’s 
Brochure for a complete summary of non-clinical and clinical information including safety, 
efficacy and pharmacokinetics.   
 
The majority of the safety data currently available for MEDI4736 are based on the first-time-in-
human, single-agent study (Study CD-ON-MEDI4736-1108; hereafter referred to as Study 1108) 
and are summarized in the IB. Based on available PK/pharmacodynamic data from ongoing 
Study 1108 with doses ranging from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab 
exhibited non-linear (dose̻dependent) PK consistent with target-mediated drug disposition.  The 
PK approached linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation 
(membrane-bound and sPD-L1), and further shows that the durvalumab dosing frequency can be 
adapted to a particular regimen given the linearity seen at doses higher than 3 mg/kg.   The 
expected half̻life with doses ≥3 mg/kg Q2W is approximately 21 days.  A dose-dependent 
suppression in peripheral sPD-L1 was observed over the dose range studied, consistent with 
engagement of durvalumab with PD-L1.  A low level of immunogenicity has been observed.  No 
patients have experienced immune-complex disease following exposure to durvalumab (For 
further information on immunogenicity, please see the current IB).  1 
 
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab Q4W or Q2W.  (For 
further information on PK observations in Study 006, please see the current IB).   
 
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.   
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other tissues. 
 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune mediated mechanism and which may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These risks can include gastrointestinal AEs such as colitis and 
diarrhoea, pancreatitis, pneumonitis/interstitial lung disease (ILD), renal AEs such as nephritis 
and increases in creatinine, hepatic AEs such as hepatitis and liver enzyme elevations, skin 
events such as rash and dermatitis, endocrinopathies such as hypo- and hyper-thyroidism, 

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hyophysitis,adrenal insufficiency, diabetes mellitus type I and diabetes insipidus, and 
neurotoxicities such as myasthenia gravis and Guillain-Barre syndrome. 
 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus,  
hypophysitis and adrenal insufficiency) hepatitisincreases in transaminases,  nephritis/increases 
in creatinine, pancreatitis increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, 
myositis/polymyositis,  other rare or less frequent inflammatory events including neurotoxicities, 
infusion-related reactions, hypersensitivity  reactions, and infections/serious infections.  
Further information on all  identified and potential risks with durvalumab please always refer to 
the  current version of the durvalumab IB. 
 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, asthenia,  anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see the Dosing Modification and Toxicity 
Management Guidelines in Section 6). 
 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB. 
 
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is being 
studies in a number of other ongoing clinical trials in a number of different indications, and has 
to date shown a manageable safety and tolerability profile.   
 
The potential risks with the combination of durvalumab + tremelimumab are similar to those for 
durvalumab and tremelimumab monotherapy. Emerging data from study 006, other studies 
evaluating the combination,  and from combinations of other agents in the same class indicate an 
increased frequency and/or severity of some of these potential immune-mediated toxicities. 
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are fatigue, 
diarrhoea,nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, constipation, cough, 
abdominal pain, pyrexia, back pain, hyponatraemia and rash.  
 
Approximately 13% of patients experienced an AE that resulted in permanent discontinuation of 
study drug and approximately 13% of patients experienced an SAE that was considered to be 
related to durvalumab and tremelimumab by the study investigator. 
 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 

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current version of the durvalumab IB. 
 
Information on durvalumab efficacy data can be found in the current version of the durvalumab 
IB 
 
 
 
2.2.2 Tremelimumab 
 
Tremelimumab, a CTLA-4 mAb of the IgG 2 kappa isotype, is an immunomodulatory therapy 
(IMT) that is being developed by AstraZeneca for use in the treatment of cancer. Tremelimumab 
is a human IgG2 mAb directed against CTLA-4. CTLA-4 is a critical regulatory signal for T-cell 
expansion and activation following an immune response, and it serves as a natural braking 
mechanism that maintains T-cell homeostasis. During T-cell activation, T cells upregulate 
CTLA-4, which binds to B7 ligands on antigen-presenting cells, sending an inhibitory signal that 
limits T-cell activation. Tremelimumab blocks the inhibitory signal resulting from CTLA-4 
binding to B7, leading to indirect prolongation and enhancement of T-cell activation and 
expansion. An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules. Refer to the 
tremelimumab IB for a complete summary of non-clinical and clinical information; see 
Section 5.3 for guidance on management of tremelimumab-related toxicities. 
 
To date tremelimumab has been given to more than 1500 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of tremelimumab monotherapy are summarized in this Section. A detailed summary 
tremelimumab exposure data can be found in the current version of the tremelimumab IB. 
 
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following IV infusion. 
The estimate of clearance (CL), volume of distribution at steady state (Vss), and terminal-phase 
half-life is 0.132 mL/h/kg, 81.2 mL/kg and 22.1 days, respectively. These values are consistent 
with those of natural IgG2.  
 
Risks with tremelimumab monotherapy include, but are not limited to,  GI effects (colitis, 
diarrhoea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, other gastrointestinal 
events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic events including 
hepatitis, and liver enzyme elevations; pneumonitis and ILD; nervous system events including 
encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle 
weakness; cytopenias including thrombocytopenia, anemia and neutropenia; infusion-related 
reactions, anaphylaxis, and allergic reactions; renal events including renal failure, acute kidney 
injury, nephritis, nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such 
as hypokalemia; autoimmune diseases including autoimmune arthritis, Sjogren's syndrome and 
giant cell temporal arteritis; hyperglycemia and diabetes mellitus; and pyrexia.  
 

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Further information on the identified and potential risks with tremelimumab please always refer 
to the current version of the tremelimumab IB. 
 
Using pooled data from monotherapy clinical studies AEs (all grades) reported very commonly 
(≥ 10% of patients)  were diarrhea, nausea, fatigue, pruritus, decreased appetite, rash,  vomiting, 
dyspnoea, constipation, cough, pyrexia, abdominal pain, decreased weight, headache, asthenia, 
and anaemia. Approximately 16% of patients experienced an AE that resulted in permanent 
discontinuation of tremelimumab and approximately 45% of patients experienced an SAE. 
 
A detailed summary of tremelimumab monotherapy AE data can be found in the current version 
of the tremelimumab IB.  
 
Please also refer to the tremelimumab IB for a complete summary of non-clinical and clinical 
information; see Section 5.3  for guidance on management of tremelimumab-related toxicities. 
Information about safety of combined tremelimumab / MEDI4736is provided in section 2.1, 
below, and also the MEDI4736IB.  
 
2.2.2.1 
MEDI4736/ tremelimumab combination 
 
A population PK model was developed for durvalumab using monotherapy data from the Phase 1 
study, CD-ON-MEDI4736-1108 (N = 292; doses of 0.1 to 10 mg/kg Q2W or15 mg/kg Q3W; 
solid tumors). Population PK analysis indicated only minor impact of body weight on PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body weight-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 weight of ~75 kg). A 
total of 1000 subjects were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight- 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 of 0.01 to 15 mg/kg Q4W or every 90 days; 
metastatic melanoma; Wang et al, 2014). The population PK model indicated minor impact of 
body weight on PK of tremelimumab (coefficient of ≤ 0.5). The weight-based (1 mg/kg Q4W) 
and fixed dosing (75 mg/kg Q4W; based on median body weight of ~75 kg) regimens were 
compared using predicted PK concentrations (5th, median and 95th percentiles) using population 
PK model in a simulated population of 1,000 subjects with body weight distribution of 40 to 120 
kg. Similar to durvalumab, simulations indicated that both body weight-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 (Ng et al, 2006; Wang et al, 2009; Zhang et al, 2012; Narwal et al, 2013). Wang and 
colleagues investigated 12 mAbs and found that fixed and body size-based dosing perform 
similarly, with fixed dosing being better for 7 of 12 antibodies (Wang et al, 2009). 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 PK/pharmacodynamics 
parameters (Zhang et al, 2012).  
 

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A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, we considered 
it feasible to switch to fixed dosing regimens. Based on an average body weight of 75 kg, a fixed 
dose of 750 mg Q2W durvalumab is equivalent to 10 mg/kg Q2W, 1500 mg Q4W durvalumab is 
equivalent to 20 mg/kg Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W.  
 
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is being 
studied in a number of other ongoing clinical trials, in a number of different indications, and has 
to date shown a manageable safety and tolerability profile.   
The types of risks with the combination of durvalumab + tremelimumab (based on an equivalent 
durvalumab dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to those for 
durvalumab and tremelimumab monotherapy. Emerging data from study 006, other studies 
evaluating the combination,  and from combinations of other agents in the same class indicate an 
increased frequency and/or severity of some of these immune-mediated toxicities. 
For information on all identified and potential risks with the durvalumab+tremelimumab 
combination please always refer to the current version of the durvalumab IB 
In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are fatigue, 
diarrhoea,nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, constipation, cough, 
abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, oedema peripheral, 
weight, decreased hyponatraemia and rash.  
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation of 
study drug and approximately 15% of patients experienced an SAE that was considered to be 
related to durvalumab and tremelimumab by the study investigator. 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB. 
  
 
2.3 
Other Agent(s) - Radiotherapy 
 
Radiotherapy is a mainstay of cancer management, with approximately 50% of cancer patients 
receiving radiation during their course of illness[31]. Advances in technology have allowed for 
more precise radiation treatments delivered with such techniques as intensity modulated 
radiotherapy (IMRT) or stereotactic radiosurgery (SRS). These targeted forms of radiation 
therapy have become more widely adapted over recent years[32]. Although large field radiation 
has historically been appreciated for its immunosuppressive ability, targeted radiation can induce 
substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke 
innate and adaptive immune responses.    
 
Radiation directly damages DNA or more commonly indirectly induces the formation of free 
radicals that cause tumor cell apoptosis[33]. Following DNA damage, mechanisms of radiation-
mediated tumor cell death include apoptosis, necrosis, mitotic catastrophe, or autophagy[31]. It is 

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now increasingly appreciated that under the proper circumstances these mechanisms of cellular 
damage and death induced by focal radiation can enhance anti-tumor immune responses, 
although inhibitory effects may also be present[34]. More specifically, previous studies have 
highlighted radiation-induced changes in costimulatory immune signals, proinflammatory 
cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune 
receptors on tumor cells. Some of these changes in localized and systemic immune mediators 
have been linked to expansion of tumor-reactive T cells, as well as improved clinical responses 
in preclinical models[35]. 
 
The potential immunologic effects of radiation therapy include radiation-induced increases in 
epitope diversity, antigen presentation, and T-cell trafficking [36, 37] that may compliment the 
immune effects of both CTLA-4 and PD-1 pathway inhibition [38].  Indeed, preclinical studies 
have demonstrated synergies with both classes of agents[36] in terms of improved local and 
distant control, including “abscopal” regression of established tumors outside of the radiation 
treatment field. Preclinical results of radiation combined with PD-1 inhibitors have been 
particularly impressive in recent studies summarized below in table 1. Of note, the combination 
of radiation, CTLA-4 and PD-1 inhibition led to 60-80% response rates across tumor 
models[38], significantly greater than any single component or the combination of dual 
checkpoint blockade without radiation.  
 
Table 1 – Studies demonstrating synergy between radiation and PD-1 pathway inhibition[38-42] 
 
 
There is mixed evidence about the most appropriate dose of radiation to use in combination with 
immune therapy.  For a variety of reasons, extrapolation of radiation dose effects from animal to 
human studies is not straightforward[43], not the least of which being the absolute differences in 
numbers of irradiated cells. However, these limitations notwithstanding, various animal studies 
have demonstrated potential synergy with hypofractionated and high dose radiation[36].  
Specifically, 8 Gy x 3 was compared with other fractionated and single fraction regimens in 
combination with CTLA-4 inhibition and provided the most enhanced response of primary and 
abscopal lesions[36].  8 Gy fractions administered to a total dose of 16 or 24Gy have also been 
specifically tested in combination with CTLA-4 [38].  In this study, increased numbers of 
circulating PD1+ CD8+ T-cells were associated with poor responders, suggesting a potential 
benefit to the addition of PD1 pathway inhibition to the 8 Gy per fraction / CTLA-4 blockade 

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combination.  Finally the feasibility of delivering 8 Gy fractions for palliative benefit at sites 
throughout the body has been confirmed by a study conducting in patients with oligometastatic 
disease [44]. 
 
There are also animal models that suggest that low dose per fraction radiation may be more 
effective at recruiting T-cells to the tumor microenvironment than higher doses [45].  
Specifically, in a preclinical study performed by Klug et al., a dose of 0.5 Gy was the most 
significant inducer of T-cell infiltration into tumor deposits 7 days following the receipt of 
treatment (Figure 1)[45]. Given increased T-cell infiltration has been associated with improved 
response to immune checkpoint blockade, this may indicate potential synergy.  
  
Figure 1 – Adapted from Klug et al.  
 
 
Low dose fractionated radiotherapy (LDFRT) is particularly appealing as a potential treatment 
strategy given potential immune effects, tolerability and favorable side effect profile, as well as 
the phenomenon of low dose hyper-radiosensitivity whereby cell killing is more effective than 
might be expected extrapolating from higher dose effects[46, 47]. Indeed, previous data suggests 
that LDFRT causes clonogenic inhibition with corresponding in vitro response data in addition to 
in vivo response data.  Specifically, LDFRT was shown to potentiate the effects of cisplatin 
independent of the hyper-radiation sensitivity in human lung cancer cells [48]. In this study, to 
improve the understanding of HRS in a setting of low dose fractions versus clinically relevant 
dose fractionation settings, the cells were subjected to 12 fractions of 0.5 Gy or 6 fractions of 1 
Gy or 3 fractions of 2 Gy. The decrease in surviving fractions was directly proportional to the 
number of fractions in all the cell lines for all fractionating schemes and the differences were 
statistically significant.  Overall, all the fractionation schemes were statistically significant and 2 
Gy dose per fraction had the highest surviving fraction in both H-157 and UKY-29 lines except 
at a total dose of 4 Gy and 6 Gy for UKY-29. For UKY-29, the mean estimates (of surviving 
fractions) at a total dose of 4 Gy for 0.5 Gy, 1 Gy and 2 Gy dose per fraction were very close to 
each other and resulted in no statistically significant difference at all possible pairwise 
comparisons (p-values ranges from 0.0331 to 0.5561). However, at a total dose of 6 Gy, the 
mean differences between all possible pairwise comparisons were statistically significant (p-

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value<0.0003, see table and figure pasted below).   
 
 
Figure 2 – Adapted from Gupta et al.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2 – Adapted from Gupta et al. The following hypothesis was tested for surviving fraction 
as an outcome of measure for two cell lines at a given specific dose level. Hypothesis: There are 
no differences in means surviving fractions among different fractionations at a given cell line.
* Note that only 0Gy, 2Gy, 4Gy, 6Gy dose levels are common to all different fractionation groups i.e. 0.5Gy, 1Gy 
and 2Gy dose per fraction. Therefore, the analysis was restricted only to 0Gy, 2Gy, 4Gy, 6Gy dose levels. Since 
there is no variation in surviving fraction at dose=0Gy (i.e. SF=1 for all fractionation schemes) no test can be done.
** Estimate, its standard error and p-value for a given cell and the dose level were calculated from fitting one-way 
analysis of variance (one-way ANOVA) to surviving fractions with different fractionation schemes
¥ Type-I error was set to 5%. The p-values for pairwise group comparisons i.e. 0.5Gy vs. 1Gy dose per fraction, 
0.5Gy vs. 2Gy dose per fraction and 1Gy vs. 2Gy dose per fraction should be compared to 1.66% due to Bonferroni 
correction to multiple comparison. Bold p-values are the one that are NOT statistically significant.
***Overall, all the fractionation schemes were statistically significant and 2Gy dose per fraction scheme had the 
higher surviving fraction in both cells for all doses but not for UKY-29 at a total dose of 4Gy and 6Gy. Notice that 
the mean estimate for UKY-29 at a total dose of 4Gy for 2Gy dose per fraction and at dose=0.5Gy were very close 
to each other. There were statistically significant differences between different fractionation schemes when we 
performed pairwise comparisons such as 0.5Gy vs. 1Gy dose per fraction, 0.5Gy vs. 2Gy dose per fraction and 1Gy 
vs. 2Gy dose per fraction at a given dose level for each of the cell lines. The bold p-values listed in the table are the 
ones that are NOT statistically significant i.e. there is no significant differences between the mean surviving fraction 
for given two groups for that particular cell line and the dose level.
In addition to this study, a number of other preclinical studies have demonstrated potential 
efficacy and immunologic effects of LDFRT [46].  Additionally, in systematic human studies of 
patients treated with radiation and ipilimumab, two studies have interestingly found that systemic 
responses tended to improve most following lower fractional doses of radiation[49, 50]. In 
addition, Golden et al. recently report a promising 28% abscopal response rate in patients treated 
with fractionated radiation at a dose of 3.5 Gy per fraction in combination with systemic GM-

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CSF[51]. Clinically, the use of LDFRT has been explored as a palliative treatment option in prior 
and ongoing clinical trials [52, 53].  Twice a day radiation regimens have a proven track record 
of feasibility and efficacy in squamous cell carcinoma of the head and neck as well as small cell 
lung cancer and have been investigated in non small cell lung cancer and [54-56], as does the use 
of palliative radiation regimens administered at set intervals that can be tailored to response and 
toxicities, such as the QUAD-SHOT regimen [57, 58].  
 
2.4 
Rationale 
 
Clinical and nonclinical data suggest that combining immunotherapy agents that target 
2 non-overlapping pathways such as MEDI4736 and tremelimumab may result in improved 
response rates relative to monotherapy with either agent alone [59]. Support for this is seen in 
mouse syngeneic models of transplantable solid tumors demonstrating superior anticancer 
activity of the combination therapy compared with monotherapy. Refer to the MEDI4736 IB for 
a full description of these results. Furthermore, clinical data from the combination of CTLA-4 
and PD-1 blockades in melanoma have resulted in higher 1-year survival and an ORR of 40% 
compared to either agent alone, with rapid, deep and durable responses [59]. The combination of 
these agents has also demonstrated improved response as compared to single agent immune 
checkpoint blockade in a randomized controlled trial [60]. Additional support has been observed 
in sponsored studies with the preliminary efficacy and safety data available for Study 
D4190C00006 (see above). 
 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics, and preliminary antitumor activity of MEDI4736 + tremelimumab 
combination therapy in patients with advanced NSCLC. The dosing schedule utilized is 
MEDI4736 (every 4 weeks [q4w]) up to Week 48 (12 months), combined with tremelimumab 
q4w up to Week 24 for 7 doses, then tremelimumab every 12 weeks (q12w) for 2 additional 
doses for up to 12 months. Preliminary efficacy, safety and clinical data summarized above 
demonstrate that the combination can be safely combined with evidence of clinical activity. 
 
Despite the improved response rates seen with the combination of CTLA-4 and PD-L1 inhibitors 
across multiple disease types, there is still a need to improve response rates further to increase 
the potential for long term clinical benefit.  In lung cancer, preliminary data indicate that there 
will be an increasing population of patients who have failed to respond to PD-1 directed 
therapies.  Although response rates may be increased with combined checkpoint blockade, the 
majority of patients will likely not respond.  In patients with microsatellite stable colorectal 
cancer, few responses have been observed with single or combination checkpoint blockade. 
These data highlight the need for further potentiation of the immune system.  
 
Specifically, by increasing antigen presentation, anti-tumor immune responses, and immune 
infiltration, targeted radiation has the potential to increase response rates to combined checkpoint 
blockade in these diseases, as evidenced by preclinical studies that have elucidated mechanisms 
of synergy that extend across multiple disease types [38]. This immune potentiating effect of 
radiation will be evaluated in the context of this trial.  We further explore whether LDFRT may 
serve as an efficient means of immune potentiation in the setting of combined checkpoint 
blockade.The use of LDFRT in this study will allow for repeated cycles of radiation to be 

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delivered with checkpoint blockade, which is not usually feasible with higher dose regimens and 
may have additional immune stimulating effects extrapolating from the preclinical data that 
demonstrated superiority of multiple fraction radiation regiments as compared to single dose 
regimens [61]. Similar to vaccination in infectious disease, repeated administration of radiation 
could potentially help generate a more robust and durable anti-tumor immune response.  
 
Specifically, this trial will enroll two cohorts of patients.  The first cohort will include patients 
with non-small cell lung cancer that have previously progressed on prior PD-1pathway directed 
therapy. This randomized phase 2 cohort will test the hypothesis that either low or high dose 
radiation will improve response rates in this setting. The second cohort will include patients with 
metastatic colorectal cancer (excluding patients with known microsatellite instability), in which 
checkpoint blockade alone is expected to have little effect.  Here, a two-stage Simon design will 
evaluate whether the addition of low or high dose radiation to this regimen will result in 
promising response rates.  The combination of radiation and concurrent immune checkpoint 
blockade is relatively novel; therefore, we will also carefully monitor safety and toxicity on this 
protocol.  The potential overlapping toxicity should be limited to the local effects of radiation 
including pneumonitis, skin inflammation and swelling, lymphopenia and general symptoms 
such as fatigue. However, initial analyses conducted by our group and others have not suggested 
significant increases in toxicity with the combination of radiation and immune checkpoint 
blockade [62, 63], including aptients whom received combined concurrent CTLA-4/PD-1 
blockade [64].  Of note, several of these patients received radiation dose to the lung or colon, 
without any evidence of grade-3 or higher pneumonitis or colitis within the radiation treatment 
field, a reasuring deature that was also observed in our recently published multicenter analysis 
[65].  These are two potential theoretic concerns with the combination of radiation and immune 
checkpoint blockade, although the risk of these radiation induced side effects are likely reduced 
with the use of targeted radiation fields mandated in this protocol.  
 
2.5 
Correlative Studies Background  
 
We plan a series of in-depth correlative studies to help identify the mechanism of action of 
combined checkpoint blockade in combination with radiation, identify biomarkers of response, 
and explain the mechanisms governing treatment response or failure. This study incorporates 
serial tissues samples pre- treatment, during therapy and at progression. These studies will also 
help us evaluate the immunomodulatory effects of different doses of radiotherapy in combination 
with dual checkpoint blockade of PD-1 and CTLA-4.  Finally, by incorporating a tumor type in 
which anti-tumor activity with PD-1 and combined PD-1 plus CTLA-4 inhibition has been 
demonstrated (NSCLC) [4, 5, 9] and a cohort in which response is unproven (MSS CRC) we can 
evaluate for varying mechanisms of treatment resistance. 
 
Integrated biomarkers - PD-L1 expression, CD3+, CD8+ T-cell infiltration 
 
Data from ongoing studies with MEDI4736 and other agents targeting the PD-1/PD-L1 pathway 
suggest, as shown in a number of tumor types (e.g., NSCLC, renal cell carcinoma, and 
melanoma), that monotherapy may be more efficacious for tumors with PD-L1-expression. 
For example, data presented by Roche at the Annual Meeting of the American Society of 
Clinical Oncology 2013 [66] suggested that PD-L1 expression in NSCLC, melanoma, and renal 

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cell carcinoma patient cohorts is associated with greater clinical benefit from anti-PD-L1 
treatment. Using a proprietary assay for PD-L1 immunohistochemistry 
(IHC), a 36% ORR was observed in patients who had PD-L1-positive tumors, 33% with PR and 
50% with SD. In contrast, in patients with PD-L1-negative tumors, only a 13% ORR was 
observed, 33% with PR and 28% with SD. Similarly, in data presented by Bristol-Myers 
Squibb at the Annual Meeting of the American Society of Clinical Oncology 2013 [67], PD-L1 
staining, when assessed using a different method and scoring algorithm, appeared to be 
associated with greater clinical benefit in patients treated with nivolumab (anti-PD-1). A 44% 
ORR was observed in patients with PD-L1–positive tumors versus a 17% ORR in patients with 
PD-L1–negative tumors, with patients with PD-L1–positive tumors having a higher PFS (9.1 
versus 2.0 months) and OS than patients with PD-L1-negative tumors (21 versus 12 months). 
Similar patterns were seen in a data set presented by Merck & Co at the World Conference on 
Lung Cancer [68] and in a prospective trial evaluating PD-L1 expression in patients treated with 
pembrolizumab [68].  Therefore, it appears that the selection of patients based on PD-L1 
expression levels within the tumor microenvironment may improve the probability and/or quality 
of responses to PD-1 pathway-targeting agents and may have merit as a patient enrichment tool. 
 
Response to dual blockade of the PD-1 and CTLA-4 checkpoint may be less dependent on PD-
L1 expression[60].  Pre-clinical data suggest that radiotherapy may upregulate intratumoral PD-
L1 expression[40] but little is known about the dose response of these effects.  Additionally little 
is known about how the pattern of expression (i.e., tumor cells vs. infiltrating immune cells) 
affects response.  According to a recent publication[69] roughly 50% of NSCLCs express PD-L1 
in tumor cells and 50% in tumor infiltrating immune cells.  About 15% of CRCs express PD-L1 
in tumor cells but about 50% in tumor infiltrating immune cells.  Data presented at ASCO and 
SITC indicate that MEDI4736monotherapy response rates in NSCLC are 27% in PD-L1 positive 
tumors and 5% in PD-L1 negative tumors.  In patients with dual checkpoint blockade 
(MEDI4736+ tremelimumab) the response rate was 35% in PD-L1 positive tumors and 22% in 
PD-L1 negative tumors; however, preliminary data suggests that PD-L1 expression could 
potentially serve as a predictive biomarker in this setting (Hellman et al. ASCO 2016).  
 
In this study, we will examine PD-1 expression as a predictor of response in all patient cohorts 
and treatment arms, investigating if PD-L1 expression as a biomarker of response in patients 
treated with dual checkpoint inhibition in NSCLC or colorectal cancer in the setting of low or 
high dose radiation.  Additionally, sequential biopsies, when feasible, will allow us to evaluate 
the impact of radiotherapy + dual checkpoint inhibition on PD-L1 expression. When available, 
we will also collect data in regards to prior PD-L1 testing performed (date, type of testing, 
result).  
 
In addition to PD-L1 expression, increased numbers of tumor infiltrating lymphocytes have also 
been associated with benefit following treatment with PD-1 pathway blockade. CD8+ T-cells 
present at the invasive front margin between tumor and stroma was associated with favorable 
response in patients with metastatic melanoma treated with the PD-1 inhibitor pembrolizumab 
[70]. Similarly, in patients with mismatch repair deficient tumors, CD8+ T-cells, particularly at 
the invasive front margins, were associated with a trend towards response or stable disease [14].  
Radiation has also been demonstrated to impact levels of tumor infiltrating T-cells in animal 
models and clinical series [71, 72].  Interestingly, this effect may extend outside of the radiation 

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treatment field in patients treated with checkpoint blockade [8].  Therefore, we will also evaluate 
T cell infiltration in the tumor microenvironment as a predictor of outcome and also determine 
changes in this parameter induced by low and high dose radiation.  
 
Multiplex Immunofluorescence – Spatial Analysis of the Immunologic Tumor 
Microenvironment  
As mentioned above, TILs and a T-cell inflamed phenotype have been linked with response to 
CTLA-4 checkpoint blockade in melanoma[73, 74].  Exclusion of T-cells in the tumor 
microenvironment has also been linked with lack of response to checkpoint inhibition[75] with 
down-regulation of CCL4 mediated dendritic cell recruitment as one potential mechanism[75].  
RT has been demonstrated to induce TILs[45] and may potentially overcome this mechanism of 
resistance to checkpoint blockade. Our unpublished data suggests that RT can induce CCL4 
expression and increase TILs. These studies will examine the density and subtype of TILs using 
markers such as CD3, CD4, CD8, CD56, FoxP3, and PD-1 and integrate spatial proximity data 
to determine whether a combined analyses of features of the tumor microenvironment such as 
PD-L1 expressing tumor cells in proximity to CD8+, PD-1 expressing T-cells is a better 
predictor of response to combined checkpoint blockade than single markers in isolation. We will 
also examine changes in the tumor microenvironment that occur as a result of if high or low dose 
radiotherapy in combination with dual checkpoint blockade. 
 
Mutational Burden 
Mutational burden and antigenic load are thought to represent a surrogate for tumor antigenicity 
and have been linked with response to checkpoint blockade in NSCLC[76].  The purpose of 
these studies is to perform whole exome sequencing to examine mutational load as a biomarker 
of response to radiotherapy + dual checkpoint inhibition in patients with NSCLC and to define 
potential tumor antigens. 
 
RNA seq 
The purpose of these studies will be to examine the intratumoral and peripheral gene signatures 
and correlate with treatment outcomes in a hypothesis generating manner.  Genes examined will 
include cytokines, chemokines, markers of T-cell exhaustion, and canonical pathways of immune 
activation or suppression including indolamine 2,3 dioxygenase. RNAseq will be used to identify 
infiltrating immune cell populations using deconvolution techniques and also confirm expression 
of predicted neoantigens. 
 
CyTOF 
The purpose of these studies will be a detailed examination of immune cell subsets and 
functionality in the periphery and in the tumor and to correlate these readouts with treatment 
response in a hypothesis-generating manner.  
 
Luminex 
The purpose of these studies will be to examine systemic cytokine and chemokine signatures pre- 
therapy and during therapy and to correlate these readouts with treatment response in a 
hypothesis generating manner.   
 

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2.6 
Exploratory Patient Reported Outcomes 
 
The Patient-Reported Outcomes version of the CTCAE was designed for patients to report their 
symptomatic AEs in a complementary manner to clinician graded CTCAE AE items. 
https://healthcaredelivery.cancer.gov/pro-ctcae ) While the measurement system has been 
validated, the current use of PRO-CTCAE in clinical trials remains exploratory. Clinician 
reported AE items remains the safety standard.  There is no real-time review of the patients’ 
responses. Patients are encouraged to report their concerning symptoms to their physicians 
and/or nurses. 
 
In this study, the Comprehensive Adverse Event and Potential Risk list (CAEPR) has identified 
multiple symptomatic AEs to be monitored through clinician reporting. These symptomatic AE 
items can be reported by patients through the PRO-CTCAE.  Patients will be asked to respond to 
24 questions that represent 13 AE items (diarrhea, nausea, abdominal pain, vomiting, fatigue, 
decreased appetite, headache, shortness of breath, fever, night sweats, general pain, cough, 
itching and rash). For each AE item, the patient may be asked 1-3 questions for the presence, 
frequency, severity and level of interference (see Appendix C). Patients will score their 
responses 0 to 5 at baseline and every 2 weeks for the first two cycles (8 weeks) and the once 
every 4 weeks at the beginning of each subsequent cycle for a total of 8 cycles.  
 
The patient scores do not correspond to clinician grading, particularly as clinicians use medical 
judgement to grade based upon a safety concern. Patients are providing their assessment of the 
severity, frequency and level of interference. The collection of both patient and clinician offers 
the opportunity to explore levels of severity and interference that correspond with protocol 
specific events. PRO-CTCAE scores are not to be used for protocol specific dose modifications. 
Patients are to be instructed to contact their clinical team for any concerning symptoms. 
 
The PRO-CTCAE data will be evaluated for data quality, to characterize baseline symptom 
status of patients on study, to explore the development of symptomatic AEs and their change 
over time. Feasibility of the electronic collection as well compliance of patients with the 
reporting will be captured. In addition, patient reported symptomatic AE scores will be analyzed 
in an exploratory way with other relevant clinical information including, but not limited to, 
collections of symptomatic AEs, clinician graded AEs, and laboratory information. 
 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed non-small cell lung cancer 
(cohort 1) or colorectal cancer (cohort 2) 
 

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3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1.5 cm) with spiral CT scan, MRI, or calipers by clinical 
exam.  See Section 11 for the evaluation of measurable disease. See also 3.1.7 as all 
measurable/target lesions must not be located with in the planned radiation field.  
 
3.1.3 Patients in both cohorts must have progressive disease following prior therapy. 
Specifically: 
 
- 
Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical disease 
progression during previous treatment with systemic PD-1 directed therapy and/or 
have been deemed not to derive clinical benefit from PD-1 directed treatment. This 
includes patients who demonstrated an initial response and subsequent progression. 
No prior treatment with chemotherapy or targeted agents are required. Intervening 
therapy is allowed between previous PD-1 directed treatment and there is no required 
interval from prior PD-1 treatment required.  PD-1 directed treatment includes 
treatment with antibodies targeting the PD-1 receptor such as pembrolizumab or 
nivolumab, as well as PD-L1 targeted antibodies such as MEDI4736(durvalumab), 
atezolizumab and avelumab.  These agents may have been administered as part of a 
clinical trial.  
- 
Cohort 2 (Colorectal cancer): Patients must have progressed on ≥ one -line 
chemotherapy. 
 
At least 21 days must have elapsed from prior systemic therapy(chemotherapy or 
radiation).  
 
3.1.4 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of MEDI4736in combination with tremelimumab and radiation in patients <18 years 
of age, children are excluded from this study, but will be eligible for future pediatric 
trials. 
 
3.1.5 ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A) and life expectancy 
greater than 6 months. Furthermore, enrollment of patients with greater than 10 
measurable lesions is discouraged.  
 
3.1.6 Patients must have normal organ and marrow function independent of transfusion for at 
least 7 days prior to screening and independent of growth factor support for at least 14 
days prior to screening as defined below: 
 
 
Hgb  
>=9g/dl 
 
absolute neutrophil count 
≥1,500/mcL 
 
platelets 
≥100,000/mcL 
 
total bilirubin 
<=1.5 x normal institutional limits. This will not apply  
 
 
 
 
to patients with confirmed Gilbert’s syndrome 
 
 
 
 
(persistent or recurrent 

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hyperbilirubinemia[predominantly unconjugated 
 
 
 
 
bilirubin] in the absence of evidence of hemolysis or  
 
 
 
 
hepatic pathology), who will be allowed in consultation  
 
 
 
 
with their physician. 
 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal; for patients  
 
 
 
 
 
 
 
with hepatic metastases, ALT and AST <=5x ULT 
 
creatinine clearance 
Measured creatinine clearance (CL) >40 mL/min 
 
OR 
 Calculated creatinine clearance (CL) >40 mL/min as 
determined by Cockcroft-Gault (using actual body 
weight) 
 
Males: 
Creatinine CL =  Weight (kg) × (140 - Age) 
(mL/min) 72 × serum creatinine (mg/dL) 
 
Females: 
Creatinine CL =  Weight (kg) × (140 - Age)  
 × 0.85 
(mL/min) 72 × serum creatinine (mg/dL) 
 
3.1.7 Patients must have at least one lesion that has not previously been irradiated (and is not 
within a previously radiated field) and for which palliative radiation is potentially 
indicated and could be safely delivered at the radiation doses specified in this protocol. 
This lesion must not be the only measurable lesion (as defined in 3.1.2) so that it is still 
possible to determine the response rate outside of the radiation treatment field. This 
lesion must not be within the CNS (brain or spinal cord) or requiring urgent or emergent 
palliative radiation given the timing of radiation specified on this protocol. Furthermore, 
this lesion:  
- 
For cohort 1 (NSCLC cohort) – the lesion to be irradiated must be in the lung, lymph 
nodes, adrenal gland or liver  
- 
For cohort 2 (colorectal cohort) – the lesion to be irradiated must be in the liver 
 
3.1.8 The effects of MEDI4736and tremelimumab on the developing human fetus are 
unknown.  For this reason and because radiation is known to be teratogenic, evidence of 
post-menopausal status or negative urinary or serum pregnancy test for female pre-
menopausal patients is required. Women will be considered post-menopausal if they have 
been amenorrheic for 12 months without an alternative medical cause. The following 
age-specific requirements apply: 
- 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
- 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced oophorectomy with last menses >1 year ago, had 

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chemotherapy-induced menopause with >1 year interval since last menses, or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy). 
 
Female patient of child-bearing potential 
 
Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception (see 
table) from the time of screening and must agree to continue using such 
precautions for 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy. 
Non-sterilised male partners of a female patient must use male condom plus 
spermicide throughout this period. Cessation of birth control after this point 
should be discussed with a responsible physician.  Not engaging in sexual activity 
for the total duration of the drug treatment and the drug washout period is an 
acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control.  Female patients 
should also refrain from breastfeeding throughout this period. 
Male patients with a female partner of childbearing potential 
 
Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 
180 days after receipt of the final dose of durvalumab + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab 
monotherapy.  Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  Male patients should refrain from sperm 
donation throughout this period. 
 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (see table).   
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described inthe tab;e 
below.  Note that some contraception methods are not considered highly effective (e.g. 
male or female condom with or without spermicide; female cap, diaphragm, or sponge 
with or without spermicide; non-copper containing intrauterine device; progestogen-only 
oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode 
of action [excluding Cerazette/desogestrel which is considered highly effective]; and 
triphasic combined oral contraceptive pills). 
 

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Highly Effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
x 
Copper T intrauterine device 
x 
Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)a 
 
x 
Implants: Etonogestrel-releasing 
implants: e.g. Implanon® or Norplan®  
x 
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing®   
x 
Injection: Medroxyprogesterone 
injection: e.g. Depo-Provera®   
x 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
x 
Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. Ortho 
Evra®    
x 
Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill 
a 
This is also considered a hormonal method 
 
 
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.   
 
3.1.9 Ability of a patient or a Legally Authorized Representative (LAR) to understand and the 
willingness to sign a written informed consent document. 
 
3.1.10 Body weight > 30 kg. 
3.1.11 Must have a life expectancy of at least 12 weeks  
 
 
3.1.12 Cohort specific eligibility requirements:  
 

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3.1.12.1 
Cohort 1 (NSCLC cohort)  
3.1.12.1.1. Ability to undergo a fresh tumor biopsy for the purpose of screening 
for this clinical trial (including able and willing to give valid written 
consent) to ability or to provide an available archival tumor sample 
taken less than 3 months prior to study enrollment (and not obtained 
prior to progression on a PD-1/PD-L1 inhibitor) if a fresh tumor 
biopsy is not feasible with an acceptable clinical risk. Tumor lesions 
used for fresh biopsies should be the same lesions to be irradiated 
when possible and should not be the same lesions used as RECIST 
target lesions, unless there are no other lesions accessible. 
Additional, optional archival tumor tissue is also requested from 
before the prior PD-1 directed therapy.  
 
3.1.12.2 
Cohort 2 (Colorectal cohort)  
3.1.12.2.1. Ability to undergo a fresh tumor biopsy for the purpose of screening 
for this clinical trial (including able and willing to give valid written 
consent) to ability or to provide an available archival tumor sample 
taken less than 3 months prior to study enrollment if a fresh tumor 
biopsy is not feasible with an acceptable clinical risk. Tumor lesions 
used for fresh biopsies should be the same lesions to be irradiated 
when possible and should not be the same lesions used as RECIST 
target lesions, unless there are no other lesions accessible.  
3.1.12.2.2. MSS tumor as documented by either:  
- IHC testing that does not suggest loss of MLH-1, MSH-2, PMS2 or 
MSH6.  
- PCR testing that does not suggest MSI 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had systemic(chemotherapy, biologic therapy or radiotherapy) within 
3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study 
 
3.2.2 Receipt of prior radiotherapy or condition for any reason that would contribute radiation 
dose that would exceed tolerance of normal tissues, at the discretion of the treating 
physician. 
 
3.2.3 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1)   
 
3.2.4 Patients who are receiving any other investigational agents. 
 

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3.2.5 Patients with untreated brain metastases, spinal cord compression, or leptomeningeal 
carcinomatosis should be excluded from this clinical trial because of their poor prognosis, 
because of symptoms that may arise from inflammatory reactions, and because they often 
develop progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. Patients whose brain metastases have been treated 
may participate provided they show radiographic stability (defined as 2 brain images, 
both of which are obtained after treatment to the brain metastases. These imaging scans 
should both be obtained at least four weeks apart and show no evidence of intracranial 
progression). In addition, any neurologic symptoms that developed either as a result of 
the brain metastases or their treatment must have resolved or be stable either, without the 
use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its 
equivalent <<and anti-convulsants>> for at least 14 days prior to the start of treatment 
 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to tremelimumab and MEDI4736or previous toxicity attributed to 
MEDI4736or other PD-1 or PD-L1 directed therapy that led to drug discontinuation. 
 
3.2.7 Prior exposure to immune-mediated therapy, including durvalumab and tremelimumab, 
except for anti-PD-1 or anti_PD-L1 therapy (including durvalumab) in NSCLC patients. 
This includes anti-CTLA-4 agents (prior treatment with these agents is NOT allowed in 
either cohort) and, excludes therapeutic anticancer vaccines. Exposure to other 
investigational agents may be permitted after discussion with the Study PI.  
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
uncontrolled hypertension, pneumonitis,  interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea or psychiatric illness/social situations 
that would limit compliance with study requirements. 
 
3.2.9 Pregnant women are excluded from this study because MEDI4736(durvalumab), 
tremelimumab are immune checkpoint inhibitors with the potential for teratogenic or 
abortifacient effects, as is radiation therapy.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with 
MEDI4736(durvalumab), tremelimumab and radiation, breastfeeding should be 
discontinued if the mother is treated with MEDI4736(durvalumab), tremelimumab and 
radiation. 
 
3.2.10 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the 
last dose of durvalumab + tremelimumab combination therapy, whichever is later. 
 

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3.2.11 HIV-positive patients are ineligible due to the risks associated with immune checkpoint 
blockade.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
3.2.12 Any concurrent chemotherapy, immune therapy, biologic, hormonal therapy for cancer 
treatment. 
 
3.2.13 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of their assigned IP. The following are exceptions to this criterion: 
- 
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) 
- 
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent  
- 
Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-
medication) 
 
3.2.14 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  Note: Local surgery of isolated lesions for palliative intent is acceptable. 
 
3.2.15 History of allogeneic organ transplantation 
 
3.2.16 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease, diverticulitis (with the exception of diverticulosis). 
sarcoidosis syndrome, or other serious GI chronic conditions associated with diarrhea; 
systemic lupus erythematosus; Wegener syndrome[granulomatosis with polyangiitis]; 
Graves’ disease; rheumatoid arthritis; hypophysitis; uveitis; sarcoidosis syndrome, etc.) 
within the past 3 years prior to the start of treatment. The following are exceptions to this 
criterion:  
- 
Patients with vitiligo or alopecia 
- 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone 
replacement or psoriasis not requiring systemic treatment 
- 
Any chronic skin condition that does not require systemic therapy 
- 
Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
- 
Patients with celiac disease controlled by diet alone 
 
3.2.17 History of another primary malignancy except for  
- 
Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of study drug and of low potential risk for recurrence   
- 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease  
- 
Adequately treated carcinoma in situ without evidence of disease (eg, cervical cancer 
in situ)  
 

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3.2.18 Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from  
electrocardiograms (ECGs) using Fridericia’s Correction. Abnormal ECGs should be 
repeated.  
 
3.2.19 History of active primary immunodeficiency  
 
3.2.20 Known history of previous clinical diagnosis of tuberculosis  
 
3.2.21 Active infection including hepatitis B (known positive HBV surface antigen (HBsAg) 
result or, hepatitis C.  Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.  
Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. Negative serologies documented over the past year 
are sufficient evidence of this.  
 
3.2.22 Receipt of live, attenuated vaccine within 30 days prior to the first dose of investigational 
treatment. Note: Patients, if enrolled, should not receive live vaccine during the study and 
up to 30 days after the last dose of investigational treatment.  
 
3.2.23 Any condition that, in the opinion of the Investigator, would interfere with evaluation of 
the investigational treatment or interpretation of patient safety or study results 
3.2.24 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria                                                                                                                                                             
                           -Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician.   Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with 
the Study Physician. 
3.2.25 Cohort specific exclusion criteria:  
 

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3.2.25.1 
Cohort 1 (NSCLC cohort)  
3.2.25.1.1. In regards to administration of prior anti-PD-1 or  anti PD-L1 
antibodies, a patients: 
Must not have experienced a toxicity that led to permanent 
discontinuation of prior immunotherapy.  
 
All AEs while receiving prior immunotherapy must have 
completely resolved or resolved to baseline prior to screening 
for this study. 
 
Must not have experienced a ≥ Grade 3 immune related AE or 
an immune related neurologic or ocular AE of any grade while 
receiving prior immunotherapy. NOTE: Subjects with 
endocrine AE of ≤ Grade 2 are permitted to enroll if they are 
stably maintained on appropriate replacement therapy and are 
asymptomatic. 
 
Must not have required the use of additional 
immunosuppression other than corticosteroids for the 
management of an AE, not have experienced recurrence of an 
AE if re-challenged, and not currently require maintenance 
doses of > 10 mg prednisone or equivalent per day. 
 
 
3.2.25.1.2. Eligibility for FDA-approved agents targeting the EGFR, ROS1 or 
ALK pathway, which should be evaluated as per standard of care.  
Exceptions to this requirement may be considered on a case-by-case 
basis by the principal investigator if the patient was previously 
treated with another targeted agent.  
 
 
 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  

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Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if applicable) 
D 
CV (optional) 
D 
D 
D 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
x Added to a site roster 
x Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x Act as the site-protocol PI on the IRB approval.    
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 

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4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
x An active Federal Wide Assurance (FWA) number 
x An active roster affiliation with the Lead Network or a participating organization 
x A valid IRB approval 
x Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
x Active registration status 
x The IRB number of the site IRB of record listed on their Form FDA 1572 
An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10021 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
x Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 

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x Click on the Protocols tab in the upper left of your screen.  
x Either enter the protocol # in the search field at the top of the protocol tree, or 
x Click on the By Lead Organization folder to expand, then select LAO-MA036 
and protocol #10021. 
x Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 10021 Site Registration: 
 
x  
x IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 4.2.3 Requirements for Protocol #10021 Site Registration for Sites Participating in the Medidata 
Patient Cloud ePRO to collect PRO-CTCAE Items 
 
a. Medidata Patient Cloud ePRO 
This study includes the use of Medidata Patient Cloud ePRO (electronic patient-reported 
outcomes).  After the patient is registered to the trial via OPEN, and if the patient is willing 
to participate in electronic data collection, the site staff will then complete a registration for 
the patient to the Patient Cloud ePRO through iMedidata. Note: Site staff must have already 
completed required eLearning for the Patient Cloud ePRO application to register a patient 
and information about the training is in the ePRO Appendix. The registration to the Patient 
Cloud ePRO will create a unique patient registration code that the site staff will provide to 
the patient. The patient (with assistance from the site staff) should be instructed to 
download the Patient Cloud ePRO app onto his/her own device (IOS, Android, phone or 
tablet) and use the unique patient registration code to create an account. Once the patient's 
account is set up, the patient will be able to complete the submission of patient reported 
outcomes electronically for the trial.  
 
For sites providing a shared institutional device for use by multiple patients on site:  
x The site staff should assist the patient with access and registration to the Patient 
Cloud ePRO app, and the patient can then complete the electronic data 
submission independently.  Site staff may need to assist patients with logging on 
to the device at each visit.  
 
b. CRA Patient Registration Instructions for ePRO 
Please visit the Medidata Learning Tool for reference information on Patient Cloud ePRO for 
CRAs.  
i. The subject registration process starts in iMedidata.  Begin by selecting 
the Patient Cloud ePRO Registration link for your study 

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ii. The patient management app will display, select your STUDY and SITE 
from the drop downs and click Launch. 
iii. Now you can register your first patient. Create a subject ID and select a 
Country / Language from the drop down, (these are the only required data 
fields). The subject initials are optional, but are helpful in identifying 
which subject ID maps with which activation code. When finished, click 
Add. 
iv. The subject added and will include the date the patient was added, the 
subject ID, subject initials, (if included) and a unique auto-generated 
activation code. The activation code is unique for each patient and linked 
to the subject ID, it is not interchangeable. In addition, there is a status 
section, which indicates if the patient has registered. When the patient has 
registered the status will change from "invited" to "registered". 
 
REMINDER- SITE STAFF MUST HAVE ALREADY COMPLETED THE MEDIDATA PATIENT CLOUD 
TRAINING IN ORDER TO REGISTER STUDY PARTICIPANTS .PLEASE VISIT THE MEDIDATA LEARNING 
TOOL FOR REFERENCE INFORMATION ON PATIENT CLOUD EPRO FOR 
CRAS. HTTPS://LEARN.MDSOL.COM/PATIENT-CLOUD/EN/VIDEO-LIBRARY-FOR-PROVIDERS-
102101952.HTML 
 
4.2.4 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) Æ Regulatory Tab ÆRegulatory 
Submission  
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
 
4.2.5 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
x Go to https://www.ctsu.org and log in to the members’ area using your CTEP-

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IAM username and password 
x Click on the Regulatory tab at the top of your screen 
x Click on the Site Registration tab 
x Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks.. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type.   
 To approve slot reservations or access cohort management:  Be identified 
to Theradex as the “Client Admin” for the studySlot enrollment will be 
used for the first 10 patients in each arm for the colorectal cancer cohort to 
allow for the parallel Simon two-stage designs.  For the NSCLC cohorts, 
slot enrollment will be used for the first 20 patient in each arm to allow for 
an early safety look after 10 patients per arm, and for an interim evaluation 
of efficacy at 20 patients per arm. 
x Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.   
x If applicable, all patients have signed an appropriate consent form and HIPAA 

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authorization form. 
 
4.3.3 Patient Enrollment Instructions   
 
Patients within the NSCLC cohort will be randomly assigned in a 1:1:1 allocation to 
MEDI4736(durvalumab)/tremelimumab alone 
 or to  
MEDI4736(durvalumab)/tremelimumab with either high- or low-dose radiation.    
 
Patients enrolled to the colorectal cancer cohort will be randomized in a 1:1 allocation to 
MEDI4736(durvalumab)/tremelimumab with either high- or low-dose radiation.   
 
The randomization schemes will be developed and conducted separately.   
Within each cohort, the randomization will be based on the permuted block method.   
 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
 
4.3.5 Digital RT Submission Using Triad 
Patients will have their treatment plans submitted to IROC Rhode Island via TRIAD.  See section 5.1 
Radiation therapy 9) Compliance criteria for details of the data to be submitted. 
TRIAD is the American College of Radiology’s (ACR) image exchange application. TRIAD 
provides sites participating in clinical trials a secure method to transmit DICOM,  DICOM RT and 
other objects. TRIAD anonymizes and validates images as they are transferred. 
TRIAD Access Requirements 
Site radiation therapy staff who will submit data images through TRIAD will need to be registered 
with the Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity 
and Access Management (IAM) account, and be registered as an AP, NPIVR or IVR.  Please refer 
to the CTEP Registration Procedures section for instructions on how to request a CTEP-IAM 
account and complete registration in RCR.  
To submit data via TRIAD, the site  user must be on the site’s roster and be assigned the 'TRIAD 
site user' role in RSS.. Users should contact their site’s CTSU Administrator or Data Administrator 
to request assignment of the TRIAD site user role. 
TRIAD Installations 
When a user applies for a CTEP-IAM account with the proper user role, he/she will need 
to have the TRIAD application installed on his/her workstation to be able to submit data. 
TRIAD 
installation 
documentation 
can 
be 
found 
by 
following 
this 
link 
https://triadinstall.acr.org/triadclient/   

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This process can be done in parallel with obtaining your CTEP-IAM account username and 
password. 
If you have any questions regarding this information, please send an e-mail to the TRIAD Support 
mailbox at TRIAD-Support@acr.org. 
 
4.3.6 Patient Registration for ePRO (Medidata Patient Cloud) 
 
This study includes the use of Medidata Patient Cloud ePRO, (electronic patient-reported 
outcomes). After the patient is registered to the trial, the CRA (Clinical Research Associate) will 
complete a second registration to the Patient Cloud ePRO. The CRA will create a unique patient 
registration code by accessing the Patient Cloud ePRO through iMedidata. Patients (with 
assistance from CRAs) will need to download the Patient Cloud ePRO app onto their own device 
and use the unique registration code given by the CRA to create an account. Once completed, the 
patient will be able to complete the submission of patient reported outcomes electronically.  
 
If sites intend to use a shared institutional device, the CRA can assist the patient with access and 
registration to the Patient Cloud ePRO app, with the patient completing the electronic data 
submission independently. Detailed instructions are included in Appendix D. If patients will be 
using devices supplied by the institution, CRAs will need to help the patient log into the device 
registration to the Patient Cloud are included in Appendix D.  
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. All weight-based dosing will be 
calculated according to the treating institution’s standard dosing policy. Reported adverse events 
and potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
Radiation therapy:  
In addition to providing palliative benefit, this study attempts to use radiation to engender a 
systemic immune response in the context of combined checkpoint inhibition.  Prior to radiation 
simulation, initial staging scans will be analyzed in detail. Lesions will be prioritized for 
treatment as follows (in order of priority): 1) Lesions must be safe to irradiate at the dose 
prescribed by the protocol as deemed by the treating radiation oncologist and able to meet 
standardly accepted radiation dose constraints and as specified below; 2) Lesions must be 

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irradiated for potential palliative benefit as determined by the treating physicians but must not 
require urgent palliation (e.g. cord compression, pain crisis).  Additionally, the following cohort 
specific rules will be applied when choosing a radiation target.  
 
Cohort 1 (NSCLC patients): Irradiation of 1-2 lesions within the lung, lymph nodes, liver or 
adrenal glands are allowed. In order of priority, irradiation of: 1) lesions progressing on prior 
PD-1 directed therapy; 2) liver > lung > adrenals > lymph nodes;  and 3) the largest feasibly 
treated lesion that may provide palliative benefit, is preferred.  
 
Cohort 2 (Colorectal patients): Only irradiation of 1-2 lesions within the liver / porta hepatis are 
allowed.  Irradiation of the largest feasibly treated lesion within the liver complex that may 
provide palliative benefit is preferred.  
 
The radiation treatment and planning process will proceed as follows:  
 
1) Localization, Simulation and Immobilization: 
a. Immobilization 
i. Patients will be positioned in a stable and comfortable position allowing 
accurate reproducibility of the target position from treatment to treatment. 
ii. A variety of immobilization systems may be used, including full-body 
stereotactic frames that surround the patient on three sides and/or full-
body, patient-customized rigid pillows (conforming to patients’ external 
contours) . Patient immobilization must be reliable enough to insure that 
the gross tumor volume (GTV) does not deviate beyond the confines of 
the planning treatment volume (PTV) with any significant probability (i.e., 
< 5%). 
 
b. Radiation CT simulation 
i. The treatment planning process will include CT based simulation with 
axial imaging every 1.25- 2.5-mm to cover the area(s) of interest. 
ii. Intravenous (i.v.) contrast during the planning CT is optional, but 
recommended for tumors adjacent to blood vessels and for liver tumors. 
iii. Average phase CT (from 4D CT) is recommended as the baseline CT for radiation 
therapy planning, but free-breathing and exhale breath-hold CT may also be used. 
 
c. Internal Motion Management 
i. Internal tumor and organ motion (e.g. due to breathing) must be accounted 
for during the simulation and planning process. 
ii. Deep inspiration or expiration breath hold is not allowed for initial tumor 
motion assessment as such assessment generally overestimates free 
breathing tumor motion. Options for motion assessment included real time 
fluoroscopy, 4-D CT scanning, 
iii. For targets (e.g. lung, liver, adrenal and thoracic/upper abdominal lymph 
node targets), that have significant motion 4D-CT planning is mandatory 
for patients randomized to receive 24 Gy in 3 fractions, and other motion 
management gating/compression systems may be used.   
iv. In some tumor locations, the assessed tumor motion measurement 

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indicates that tumor motion (e.g. > 1 cm) would increase the likelihood of 
resulting in marginal miss or excessive volume of irradiation unless a 
motion management strategy is employed. 
v. Acceptable motion management include reliable abdominal compression, 
linear accelerator beam gating with the respiratory cycle, tumor tracking, 
and active breath-holding techniques. Internal organ management 
maneuvers must be reliable enough to insure that the GTV does not 
deviate beyond the confines of the PTV with any significant probability 
(i.e., < 5%). 
d. Daily Target Localization 
i. Image-guided raidaiton therapy (IGRT) is mandatory for patients 
randomized to receive 24 Gy in 3 fractions. 
ii. Isocenter or reference point port localization images should be obtained on 
the treatment unit immediately before each treatment to ensure proper 
alignment of the geometric center (i.e., isocenter) of the simulated fields. 
These IGRT images can be obtained with planar kV imaging devices, an 
in-room helical CT device, tomotherapy helical CT, cone-beam CT 
equipment, of standard EPID imaging. 
For SBRT treatments, all IGRT systems must be checked daily to 
guarantee coincidence between the imaging coordinate system and the 
treatment coordinate system. This test is required by the AAPM Task 
Group 142 report and is described in detail in both the ASTRO/ACR 
practice guideline on SBRT available 
at:http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guid
elines/ro/stereo_body_radiation and the ACR Technical Standard on IGRT 
available 
at:http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guid
elines/med_phys/monitor_IGRT. 
This test is particularly important when the treatment equipment is not 
equipped with any device that allows direct visualization of anatomical 
structures using the treatment beam. For example, this test must be 
performed routinely for the CyberKnife, Tomotherapy units as well as any 
BrainLab equipment that does not include an electronic portal imaging 
device (EPID) that intercepts the treatment beam. 
iii. Fiducial markers may be placed for localization of soft tissue targets 
depending on institutional practice, but should be considered for targets in 
the liver and adrenal for participants on Arm A.  
 
2) Contours: Tumor contours will be defined by the physician and radiation oncology staff: 
 
- 
Gross tumor volume (GTV): These volumes include gross disease and further details 
regarding contouring technique are shown in the Table below.  Elective irradiation to 
other areas is not permitted.  For targets that have significant motion (e.g. lung or 
liver targets), 4D-CT planning with is mandatory for patients randomized to receive 
24 Gy in 3 fractions, and other motion management (e.g. gating/compression 
systems) may be used.  Delineation of an internal target volume (ITV) in these cases 

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is mandatory using the 4D-CT data set or maximum intensity projections (MIP) for 
lung tumors and minimum intensity projection (MinIP) for liver metastases as 
appropriate. Sites should be aware that the (MIP/MinIP) should be used with caution 
because the MIP reconstruction for lung or MinIP reconstruction for liver may 
erroneously define an ITV in cases of significant irregular breathing or when tumors 
abut soft tissue structures (e.g., the diaphragm for MIP) or fat (for the MinIP).  The 
exact margins are patient- specific.  Additional imaging modalities (e.g. PET, MRI, 
diagnostic CT with contrast) may be fused with the planning CT to guide GTV-
delineation. 
 
- 
CTV: Clinical tumor volume. An optional 0-1 cm margin on GTV is allowed when 
determining the CTVs at the treating radiation oncologist’s discretion to account for 
any uncertainty or microscopic disease. This margin may be expanded based on 
clinical judgment with permission of the principal investigator.  
- 
PTV: A 5mm planning tumor volume (PTV) margin will be uniformly added to the 
CTV will also be included to account for set up variation, as appropriate to each 
individual lesion.  
 
Planning  
Parameter  
Lung  
 
Liver  
Adrenals 
Mediastinal/  
Cervical Lymph 
Nodes  
CT 
window/level  
Pulmonary/  
mediastinal  
Hepatic  
Soft Tissue 
Pulmonary/  
mediastinal  
Additional 
Optional 
Studies  
PET/CT  
PET/CT  
MRI  
PET/CT 
PET/CT  
 
 
 
 
 
Anatomy of 
focus for 
multi  
modality 
fusion  
Bony 
Anatomy  
Liver  
Bony 
Anatomy 
Bony anatomy  
4DCT 
Mandatory 
Mandatory 
Mandatory 
Mandatory for 
mediastinal LN 
OARs 
Spinal Cord 
Brachial 
Plexus 
Chest 
Wall/Rib 
Esophagus 
Great 
Vessels 
Heart 
Lung 
Skin 
Trachea/Bron
chial Tree 
 
Spinal 
Cord 
Chest 
Wall/Rib 
Dudoenu
m 
Esophagu
s 
Jejunum/Il
eum 
Large 
Bowel 
Heart 
Kidneys 
Liver 
Great 
Vessels 
(IVC) 
Lungs 
Stomach 
Skin 
 
Spinal Cord 
Chest 
Wall/Rib 
Dudoenum 
Esophagus 
Jejunum/Ileu
m 
Large Bowel 
Kidneys 
Liver 
Great Vessels  
Renal 
Hilum/vascula
r trunk 
Stomach 
Skin 
 
Spinal Cord 
Brachial Plexus 
Esophagus 
Great Vessels 
Heart 
Lung 
Skin 
Trachea/Bronchi
al Tree 

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- 
Several contours of the organs at risk will be defined by the physician and/or 
treatment planner if visible within the axial slices covered by the PTV using existing 
guidelines as described below. These contours should be labeled according Standard 
Naming Conventions listed below in parentheses as per  
o Spinal cord (SpinalCord) 
 The spinal cord will be contoured based on the bony limits of the 
spinal canal. The spinal cord should be contoured starting at least 10 
cm above the superior extent of the PTV and continuing on every CT 
slice to at least 10 below the inferior extent of the PTV. 
o Brachial plexus (BrachialPlex_L and BrachialPlex_R) 
 The defined ipsilateral brachial plexus originates from the spinal 
nerves exiting the neuroforamina on the involved side from around C5 
to T2. However, for the purposes of this protocol, only the major 
trunks of the brachial plexus will be contoured using the subclavian 
and axillary vessels as a surrogate for identifying the location of the 
brachial plexus. This neurovascular complex will be contoured starting 
proximally at the bifurcation of the brachiocephalic trunk into the 
jugular/subclavian veins (or carotid/subclavian arteries) and following 
along the route of the subclavian vein to the axillary vein ending after 
the neurovascular structures cross the second rib. 
o Esophagus (Esophagus) 
 The esophagus will be contoured using mediastinal windowing on CT 
to correspond to the mucosal, submucosa, and all muscular layers out 
to the fatty adventitia. The esophagus should be contoured starting at 
least 10 cm above the superior extent of the PTV and continuing on 
every CT slice to at least 10 below the inferior extent of the PTV and 
ideally from the post-cricoid space to the GE junction. 
o Great Vessels (GreatVes) 
 The great vessels (aorta and vena cava, not the pulmonary artery or 
vein) will be contoured  using mediastinal windowing on CT to 
correspond to the vascular wall and all muscular  layers out to the fatty 
adventitia. The great vessel should be contoured starting at least 10  
cm above the superior extent of the PTV and continuing on every CT 
slice to at least 10 cm below the inferior extent of the PTV. For right 
sided tumors, the vena cava will be  
contoured, and for left sided tumors, the aorta will be contoured 
o Heart/pericardium (Heart) 
 The heart will be contoured along with the pericardial sac. The 
superior aspect (or base) for 
 purposes of contouring will begin at the level of the inferior aspect of 
the aortic arch (aortopulmonary 
 window) and extend inferiorly to the apex of the heart. 
o Trachea and proximal bronchial tree (Trachea, Bronchus) 
 The trachea and proximal bronchial tree including the mainstem and 

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lobar bronchi including trachea, the carina, the right and left mainstem 
bronchi, the right and left upper lobe bronchi, the intermedius 
bronchus, the right middle lobe bronchus, the lingular bronchus, 
 and the right and left lower lobe bronchito the bifurcation of the first 
segmental airways will be contoured  using mediastinal windows on 
CT to correspond to the mucosal, submucosa and cartilage rings and 
airway channels associated with these structures.  
o Skin (Skin) 
 The skin will be defined as the outer 0.5 cm of the body surface. As 
such it is a rind of uniform thickness (0.5 cm) which envelopes the 
entire body in the axial planes. The cranial and caudal surface of the 
superior and inferior limits of the planning CT should not be contoured 
as skin unless skin is actually present in these locations (e.g., the scalp 
on the top of the head). 
o Stomach (Stomach) 
 The entire stomach and its contents should be contoured as a single 
structure as a continuation of the esophagus and ending at the first part 
of the duodenum. 
o Duodenum (Duodenum) 
 The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum 
will be contoured as one structure beginning where the stomach ends 
and finishing as the superior mesenteric artery crosses over the third 
part of the duodenum 
o Jejunum/ilieum (Bowel small) 
 Small bowel from end of duodenum to the ileocecal area. 
o Large Bowel (Bowel large) 
 From the ileocecal area to include the ascending, transverse, 
descending and sigmoid colon as one structure. 
o Renal hilum/vascular trunk (Kidney Hilums) 
 The renal artery and vein from the renal cortex to the great vessels. 
o Liver (Liver) 
 The entire live minus the GTV 
o Kidneys (Kidney_L and Kidney_R) 
 
Both the right and left kidney, excluding renal pelvis/collecting system, should be 
contoured in their entirety (the renal cortex) 
o Lung (Lungs) 
 Both the right and left lungs should be contoured as one structure. 
Contouring should be carried out using pulmonary windows. All 
inflated and collapsed lung should be contoured; however, gross tumor 
(GTV) and trachea/ipsilateral bronchus as defined above should not be 
included in this structure. 
 
3) Prescriptions: Patients randomized to higher dose radiation arm (Arm A) will be 
prescribed a total dose of 24 Gy in 3 fractions.  Patients randomized to the lower dose 
radiation (Arm B) will be prescribed a total dose of 2 Gy in 4 fractions to be repeated 
with each of the first 4 cycles (total overall dose 8 Gy).  In cohort 1 (NSCLC), patients 
randomized to the no radiation arm (Arm C) will not receive any radiation.  Please also 

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refer to schema below:  
 
 
 
Only photons treatments are allowed, and volumetric treatment planning is mandated. 
Planning may be 3D conformal, IMRT or SBRT, as appropriate to each individual case / 
lesion to achieve coverage of the PTV target and maintain normal tissue tolerance. The 
percentage PTV covered to 100% of the prescription dose will be reported along with the 
maximum hotspot; reasonable effort should be made to keep this greater than 95% while 
maintaining normal tissue dose constraints as indicated below. Bolus may be used as 
appropriate.  Note that for patients prescribed 24 Gy in 3 fractions, maximum hotspot 
should not exceed 115% in any case. 
 
4)  Timing of radiation treatment:   
- 
Arm A: Higher dose radiation. Radiation will start on week 2. Three treatments of 8 
Gy will generally be delivered every other day. They must not be delivered on 
consecutive calendar days and more than one fraction may not be delivered on the 
same day. The total treatment time must not extend over more than 10 calendar days.  
Shorter treatment courses (approximately 5 days) are favored, but no specific 
8Gy x 3 +  
durvalumab/ 
tremelimumab 
Low-dose RT*+  
durvalumab/ 
tremelimumab 
Continue 
durvalumab to 
progression 
Metastatic NSCLC that 
failed to respond to 
prior PD-1 or PD-L1 
inhibitor 
durvalumab/ 
tremelimumab 
NSCLC Cohort- Cohort 1 
Arm A 
Arm B 
Arm C 
8Gy x 3 +  
durvalumab/ 
tremelimumab 
Colorectal Cohort- Cohort 2 
Low-dose RT*+  
durvalumab/ 
tremelimumab 
*0.5 Gy BID x2 days repeated q4weeks with durvalumab / tremelimumab 
Continue 
durvalumab to 
progression 
Metastatic CRC, 
progressive on >=1 
chemotherapy regimens 
(exclude MSI tumors)  
Arm A 
Arm B 

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treatment schedule is mandated to account for weekends, holidays, machine 
maintenance, etc.  
- 
Arm B: Lower dose radiation: Radiation will start on week 2. Four treatments of 0.5 
Gy will be delivered no more frequently than every 6 hours and will be scheduled to 
occur twice per day over a period of two days. Although treatment is allowed to 
extend over three calendar days in the case of machine maintenance or patient illness, 
this is strongly discouraged.  
o Note:  Patients enrolled on Arm B should continue to receive lower dose 
radiation (2 Gy delivered in 4 fractions) with each of the first 4 cycles of 
treatment (weeks 2, 6, 10, 14).  The radiation target and treatment plan need 
not change between treatment courses; however, if there is clinical or 
radiographic evidence of complete resolution of the irradiated lesion, this 
lesion should not be treated with additional radiation.  If this occurs and there 
is another lesion appropriate for palliative radiation that satisfies the above 
criteria, additional lower dose radiation may be considered after discussion 
with the study PI.  This irradiation of a new lesion will not be counted as 
tumor progression.  
 
5) Dosimetry: 
a. Only photons treatments are allowed, and volumetric treatment planning is 
mandated.  
b. Planning may include 3D conformal, IMRT or SBRT, as appropriate to each 
individual case / lesion to achieve coverage of the PTV target and maintain 
normal tissue tolerance. IROC credentialing is required for the most complex 
modality (IMRT>3D) used by each center as well as for IGRT (see section 4.2.2). 
c. PTV coverage should ideally be 95% of PTV conformally covered by the 
prescription isodose surface (D95=100%), , while maintaining normal tissue dose 
constraints as indicated below. Bolus may be used as appropriate 
d. The percentage PTV covered to 100% of the prescription dose will be reported 
along with the maximum hotspot;.   
e. Doses higher than the prescription isodose (i.e., hotspots) should be manipulated 
to occur within the planning target volume. 
f. Note:For patients prescribed 24 Gy in 3 fractions, maximum hotspot should not 
exceed 115% in any case. 
g. For purposes of dose planning and calculation of monitor units for actual 
treatment, this protocol requires tissue density heterogeneity corrections approved 
by IROC. Examples of appropriate tissue density heterogeneity correction 
algorithms include properly commissioned superposition/convolution (collapsed 
cone), AAA, and Monte Carlo. Simple pencil beam and Clarkson algorithms that 
account for attenuation but not scatter will not be allowed.  
h. For 3D conformal cases, coplanar or non-coplanar beam arrangements will be 
custom designed for each case to deliver conformal prescription dose 
distributions. 
i. For IMRT cases, the treatment dose plan may be made up of multiple static beams 
or arcs, and the apertures are determined by inverse treatment planning 
j. For SBRT cases, either conformal or IMRT techniques are allowed. 

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i. 3D-conformal SBRT: Three-dimensional coplanar or non-coplanar beam 
arrangements will be custom designed for each case to deliver highly 
conformal prescription dose distributions. Non-opposing, non-coplanar 
beams are preferable. Typically, ≥ 10 beams of radiation will be used with 
roughly equal weighting. Generally, more beams are used for larger lesion 
sizes. When static beams are used, a minimum of seven non-opposing 
beams should be used. For arc rotation techniques, a minimum of 340 
degrees (cumulative for all beams) should be utilized. For this protocol, 
when using a gantry mounted linear accelerator, the isocenter is defined as 
the common point of gantry and couch rotation for the treatment unit. For 
other types of treatment units (e.g., tomotherapy or CyberKnife), a 
reference point in space that is typically positioned at the center of the 
target is used instead of a mechanical isocenter. For non-IMRT or dose 
painting techniques, the conformal field aperture size and shape should 
correspond nearly identically to the projection of the PTV along a beam‟s 
eye view (i.e., no additional “margin” for dose buildup at the edges of the 
blocks or MLC jaws beyond the PTV). The only exception will be when 
observing the minimum field dimension of 3 cm when treating small 
lesions (see above). As such, prescription lines covering the PTV will 
typically be the 60-90% line (rather than 95-100% as is common with 
conventional radiotherapy); however, higher isodoses (hotspots) must be 
manipulated to occur within the target and  limited to 115% per protocol 
and should not be in normal tissue. The stereotactic reference point 
(corresponding to the mechanical isocenter for gantry mounted treatment 
units) will be determined from system fiducials (or directly from the 
tumor) and translated to the treatment record.  
ii. IMRT SBRT: The treatment dose plan will be made up of multiple static 
beams or arcs and , the apertures are determined by inverse treatment 
planning. 
6) Organs at risk (OAR).  Treating radiation oncologists will abide by accepted radiation 
dose constraints, especially in regards to 24 Gy delivered in 3 fractions.  For patients in 
Arm B, a cumulative dose calculation is also recommended to record dose delivered to 
OAR. Additionally, for patients prescribed 24 Gy in 3 fractions, maximum hotspot 
should not exceed 115% in any case.  
 
The following table lists maximum dose limits to a maximum point or to a critical 
volume for critical organs at risk.  Except for the rib, these are absolute limits, and 
treatment delivery that exceeds these limits will constitute a protocol violation). The dose 
is listed as total delivered. PTV coverage may be compromised to ensure an acceptable 
plan. Please use the indicated planning system names for the structures in your treatment 
planning system. 
 
Note: Maximum point dose will be defined as the maximum dose to a 0.035 cc volume. 
 
Table 5.1: Critical Organ Dose-Volume Limits for Arm A. 
 

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Structure 
Description 
Planning 
System 
Name 
Volume 
(cc) 
Volume Max 
(Gy)  
Max Point 
Dose (Gy) 
Volumetric 
Constraint 
Avoidance 
Endpoint 
Spinal cord 
SpinalCord 
<0.25 
18 
19.5 
 
Myelitis 
Brachial 
plexus  
BrachialPle
xs = 
BrachialPle
x_L + 
BrachialPle
x_R 
<3 
22.5 
24 
 
Plexopathy  
 
Cauda 
equina 
CaudaEquin
a 
<5 
21.9 
24 
 
Neuritis 
Esophagus 
Esophagus 
<5 
21 
27 
 
Stenosis/Fist
ula 
Great 
Vessels 
GreatVes 
-<5 
-21 
25.2 (105% of 
Rx dose) 
 
 
Heart/perica
rdium 
Heart 
<15- 
24- 
25.2 (105% of 
Rx dose)  
 
Pericarditis 
Trachea and 
ipsilateral 
bronchus 
Trachea, 
Bronchus 
<4 
15 
25.2 (105% of 
Rx dose)  
 
Stenosis/Fist
ula 
Sacral 
Plexus 
SacralPlex 
<5 
22.5 
24 
 
Plexopathy 
Skin s 
Skin  
<10 
22.5 
24 
 
Ulceration 
Stomach 
Stomach 
<10 
21 
24 
 
Ulceration/Fi
stula 
Duodenum 
Duodenum 
<5 
15 
24 
 
Ulceration/Fi
stula 
Jejunum/ilie
um 
Bowel_Sma
ll 
<5 
16.2 
25.2 (105% of 
Rx dose)  
 
Ulceration/Fi
stula 
Large 
Bowel 
Bowel_Larg
e 
<20 
24 
25.2 (105% of 
Rx dose) 
 
Ulceration/Fi
stula 
Renal 
Hilum 
Kidney_Hil
ums 
<15 
19.5 
-25.2 (105% 
of Rx dose) 
 
Malignant 
hypertension 
Liver  
Liver  
700cc 
spared 
from 
volume 
max   
17.1 
- 
 
 
Kidneys 
Kidneys = 
Kidney_L + 
Kidney_R 
200cc 
spared 
from 
volume 
max   
14.4 
 
 
 
Lung (left 
and right)  
Lungs 
1000mL 
spared 
from 
volume 
max 
11.4 
 
V20<10% 
 
Lung (left 
and right)  
Lungs 
1500mL 
spared 
10.5 
 
V20<10% 
 

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Rib/Chest wall Dose Constraints  
Recent studies have shown that the rib and chest wall in proximity to the treated lesion may 
represent an organ at risk for complication such as chest wall pain and rib fracture. While target 
coverage should not be compromised to limit dose to the rib/chest wall, every effort should be 
made to minimize dose and hostpots to this OAR. 
 
7) Planning Priorities 
a. Successful treatment planning goals are listed above. In general, attempts should 
be made to successfully satisfy all of the goals without deviation. In some 
circumstances, improvements can be made to the dosimetry plan beyond simply 
meeting the specified goals. In other circumstances, clinicians are faced with the 
prospect of not ideally meeting one or more of the goals (i.e., accepting an 
acceptable deviation). In this section, we provide priorities in which a most ideal 
plan for protocol purposes is realized. Suggested priority of planning goals in 
order of importance is: 
 
i. Respect spinal cord dose constraints.  
ii.  Meet organ constraints other than spinal cord.  
iii. Achieve PTV coverage 
 
 
 
8) Technical Factors: 
a. Physical Factors: 
i. 
Only photon (x-ray) beams produced by linear accelerators,with photon 
energies of at least 6MVwill be allowed.  
ii. 
Cobalt-60 and charged particle beams (including electrons, protons, and 
heavier ions) are not allowed.  
iii. 
For lung tumor cases,  > 10 MV may be used but not > 15 MV, and 
should be used sparingly only for a limited number (≤ 2) beams that 
must travel more than a cumulative distance of 10 cm through soft tissue 
from 
volume 
max 
Lung (left 
and right) 
 
1500mL 
spared 
from 
volume 
max 
10.5 
 
 
 

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(not lung) to reach the target . 
b. Treatment Platforms 
i. 
The trial allows most commercially available photon producing 
treatment units except the exclusion of units described above (e.g., 
cobalt units and charge particle accelerators). As such, conventional 
linear accelerators, specialized linear accelerators with image guidance 
(e.g., TrueBeam, Agility, Novalis, Trilogy, Synergy, Artiste) are 
allowed. These units can be used with conformal dose delivery or IMRT. 
Other specialized accelerators (e.g., the CyberKnife® or Tomotherapy) 
are allowed as long as they meet the technical specifications of the 
protocol 
c. Minimum Field Size 
i. 
For SBRT treatments, because of uncertainties in beam commissioning 
resulting from electronic disequilibrium within small beam apertures, an 
equivalent square field dimension of 3.0 cm is required for any field 
used for treatment delivery for sites using standard 3-D conformal 
techniques where nearly all of the PTV is encompassed for each beam. 
d. Dose Verification at Treatment  
i. 
Personal dosimeter measurements (e.g., diode, TLD) are not required, 
but may be obtained for surface dose verification for accessible beams as 
per institutional preference. 
e. Use of Intensity Modulated Radiation Therapy (IMRT) Using Multileaf 
Collimation 
i. 
The protocol allows for IMRT, but caution should be utilized when 
tumor motion is significant since IMRT can result in dosimetric 
inaccuracies especially in circumstances where tumor motion is either 
unknown or not properly accounted. Thus, IMRT should only be utilized 
if tumor motion is less than 5 mm, OR if motion management inherently 
diminishes motion effects (e.g., gating, breath hold, or tracking). 
9) Compliance Criteria 
a. Digital RT Data Submission Requirements 
Submission of treatment plans in digital format as DICOM RT is required. Digital data must include 
CT scans, structures, plan, and dose files. This study uses TRIAD for RT data submission. Use of 
TRIAD requires several preliminary steps. See section 4.3.5 for details.  Additional information can 
be found at https://www.irocqa.org/Resources/TRIAD for guidelines regarding digital submission 
using TRIAD. Use of SFTP will also be accepted as an alternate method of data submission on this 
study. See the instructions for submission of data via SFTP on the IROC Rhode Island website 
(www.irocri.qarc.org) under Digital Data. 
Any items on the list below that are not part of the digital submission may be included with the 
transmission of the digital RT data. 
 
On-treatment review is NOT required for this study. Within one week of the 
completion of radiation therapy, detailed treatment data shall be submitted 
as follows:  
 
 
 
i. 
Treatment Planning System Output 

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a. RT treatment plans including CT, structures, dose and plan files. These items are 
included in the digital plan. 
b. Dose volume histograms (DVH) for the composite treatment plan for all target 
volumes and required organs at risk. For all IMRT plans, a DVH shall be 
submitted for a category of tissue called “unspecified tissue.” This is defined as 
tissue contained within the skin, but which is not otherwise identified by 
containment within any other structure. DVHs are included in the digital plan. 
c. Digitally reconstructed radiographs (DRR) for each treatment field, showing the 
collimator and beam aperture. Submission of DRR's is not required for IMRT. 
d. Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest 
dose statistics. 
i. 
Supportive data 
a. All diagnostic imaging used to plan the target volume. This includes CT, 
MRI and/or PET. Digital format is required.  
b. If the recommended doses to the organs at risk are exceeded, an 
explanation should be included for review by the IROC and the radiation 
oncology reviewers.   
ii. 
Forms 
a. RT-1 Dosimetry Summary Form 
b. Motion Management Reporting Form (if applicable) 
c. The RT-2 Radiotherapy Total Dose Record Form 
d. A copy of the patient's radiotherapy record including the prescription, and the 
daily and cumulative doses to all required areas. 
 
Supportive data and forms may be included with the transmission of the digital RT 
data or submitted separately via e-mail (DataSubmission@qarc.org) or mailed to: 
IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: 
(401) 753-7600 
Fax: 
(401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
Protocol Dosimetrist 
IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: 
(401) 753-7600 

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Fax: 
(401) 753-7601 
b. Dosimetry Compliance 
 
Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Prescription 
Dose 
Delivered daily or total 
dose to the PTV is 
within 5% of the 
protocol dose.  
Delivered  daily or total 
dose to the PTV differs 
from the protocol 
specified dose by 6-10%  
Delivered daily or total 
dose to the PTV differs 
from the 
protocol  specified 
dose by >10% 
Dose 
Uniformity 
More than 95% of the 
PTV receives the 
prescribed dose. 
95% of the PTV receives 
between 95 and 100% of 
the prescribed dose 
95% of the PTV 
receives <95% of the 
prescribed dose. For 
Arm A maximum dose 
>115% of the 
prescribed dose. 
Volume 
Volumes follow protocol 
guidelines 
CTV or PTV margins 
are less than the protocol 
specified margins or 
excessively large 
GTV does not 
encompass gross 
disease resulting in 
inadequate tumor 
coverage. 
Organs at 
Risk 
Dose to all OAR’s meets 
the  criteria in Table 5.1 
for Arm A.  
For Arm A dose to any 
OAR (except spinal cord 
and brachial plexus) 
exceeds the maximum 
point dose limits in 
Table 5.1 by more than 
2.5%. 
For Arm A dose to any 
OAR (except spinal 
cord and brachial 
plexus) exceeds the 
maximum point dose 
limits in Table 5.1 by 
more than 5%. 
Dose to spinal cord or 
brachial plexus may 
not exceed the limits 
in Table 5.1. 
Interruptions Treatment is completed 
within 10 calendar days 
for Arm A and 2 
calendar days for Arm 
B. 
Treatment is completed 
within 3 calendar days 
for Arm B. 
Treatment is 
completed in >10 
calendar days for Arm 
A and >3 calendar 
days for Arm B. 
 
 
 
5.1.1 Tremelimumab and MEDI4736(durvalumab) 
 
 
1.1.1.1 Regimen Description 
Agent 
Premedication; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Tremelimumab 
Mot routinely 
75mg  
IV over 1 hour before 
Day 1  
28 days 

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necessary 
unless prior 
infusion 
reaction 
 
Max of 
4 doses 
MEDI4736/durvalumab; 
refer to section 8.1.2 for 
compatible infusion set 
materials  
(4 
weeks) 
MEDI4736(durvalumab) 
Not routinely 
necessary 
unless prior 
infusion 
reaction 
1500mg  
 
Max of 
13 doses 
IV over 1 hour; refer to 
section 8.1.1 for 
compatible infusion set 
materials  
Day 1 
Patients will receive tremelimumab 75 mg q4w for 4 doses in combination with MEDI4736, 1500 mg 
for 4 doses, followed by MEDI4736monotherapy 1500 mg q4w initiated 4 weeks after the last combined 
dose and administered for up to 9 additional doses. Observation period for post MEDI4736 will be 60 
minutes. 
 
MEDI4736 infusion will start approximately 1 hour after the end of tremelimumab infusion for the first 
infusion only.  Infusions may be administered consecutively at subsequent infusions at the Investigator’s 
discretion. 
A window of +/-10 minutes is allowed for infusion of study treatment.  
A window of +/- 2 days is allowed between cycles. 
 
 
 
 
 
5.1.2 Radiation therapy 
 
The individual medical / radiation oncologist may deliver supportive care as indicated. 
The use of prophylactic steroids before or after the radiation treatments is not allowed.  In 
patients who receive radiation twice per day, at least 6 hours must elapse between 
treatments.  
 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
Although there is significant safety data for the MEDI4736/ tremelimumab treatment and 
palliative radiation, the combination is relatively untested, although emerging safety data 
suggests the combination of the two treatments (specifically in regards to limited palliative 
radiation treatment fields) do not increase the rates of irAE or radiation toxicity [64]. Although 
this retrospective data compares favorably to previous studies testing combined checkpoint 
inhibition, to provide greater confidence in the safety of radiation and combined checkpoint 
inhibition, DLT’s will be monitored in a step-wise fashion and over time.  As part of the safety 
assessment for the NSCLC cohort, complete review of the adverse event data for the first 10 
patients assigned to MEDI4736(durvalumab)/tremelimumab/high-dose RT and for the first 10 
patients assigned to treatment with MEDI4736(durvalumab)/tremelimumab/low-dose RT will 
occur after completion of two cycles of therapy. If three of more patients within a therapy arm 
experience one or more pre-specified dose-limiting toxicities the addition of RT will be 
considered too toxic and enrollment to that arm will stop. If this occurs in the high-dose radiation 
arm,  all safety data from that arm will be reviewed and a protocol amendment may be 
considered. 
 

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Concurrent with the end of the first stage of each Simon design for the colorectal cohort, a 
complete safety review of adverse event data will be conducted for each treatment.  If three of 
more patients within a therapy experience one or more pre-specified dose-limiting toxicities, 
enrollment to that arm will stop.   
 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). Although we will continue to monitor 
toxicity over time, the DLT period in this study refers to toxicities experienced during the first 4 
weeks of treatment.  
 
DLTs will be graded according to the National Cancer Institute’s CTCAE v5.0 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
(http://ctep.cancer.gov/forms/CTCAEv45.pdf).  
A DLT will be defined as any <<Grade 3 or higher>> toxicity that occurs during the DLT 
evaluation period. Toxicity that is clearly and directly related to the primary disease or to another 
etiology is excluded from this definition. The following will be DLTs: 
x Any Grade 4 irAE 
x Any ≥ Grade 3 colitis 
x Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
x Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation 
of maximal supportive care 
x Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days 
x Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN 
x Any grade 3 or 4 febrile neutropenia 
x Any grade 3 or 4 thrombocytopenia with significant bleeding 
x Any ≥ Grade 3 non-irAE, except for the exclusions listed below 
The definition excludes the following conditions:  
x Grade 3 fatigue lasting ≤ 7 days 
x Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 
x Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
x Concurrent vitiligo or alopecia of any AE grade 

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x Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
x Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be 
a DLT regardless of duration or reversibility 
x Grade 3 or 4 lymphopenia 
x Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days 
x Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days 
x Grade 3 fever lasting ≤ 24 hours with or without medical therapy and is not considered an 
SAE 
Immune-related AEs (irAEs) 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. 
 
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as a DLT after consultation with the sponsor and Investigators, based 
on the emerging safety profiles of MEDI4736and tremelimumab.  Likewise, subjects who become 
not evaluable for DLT because they discontinued or interrupted treatment due to toxicities other 
than DLTs will be counted as DLT subjects using the same criteria as other DLTs (Grade 3 or 
higher toxicity that occurs during the DLT evaluation period and excluding toxicity that is clearly 
and directly related to the primary disease or to another etiology.)  
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
CTEP. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician; however, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the Investigator, CTEP, and 
the patient. 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 

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fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs. 
 
Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
- 
Anti-cancer systemic chemotherapy or biological therapy or any other investigational 
cancer therapy other than those being investigated in this study. 
- 
Immunotherapy not specified in this protocol. 
- 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial until 30 days after last dose of study drug. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
- 
 Glucocorticoids for any purpose other than to modulate symptoms from an event of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor. 
- 
Additional radiation therapy non-specified in the protocol.    
o Note:  If the patient develops indication for urgent palliative radiation such as 
brain metastases or spinal cord compression (either within the previously 
irradiated field or outside), the patient will be considered to have progressed 
(see below) and will be removed from the trial.   
- 
Drugs with laxative properties and herbal or natural remedies for constipation should 
be used with caution through to 90 days after the last dose of tremelimumab during 
the study 
- 
Sunitinib should not be given concomitantly or through 90 days after the last dose of 
tremelimumab (acute renal failure has been reported with combination therapy of 
tremelimumab and sunitinib) 
- 
EGFR tyrosine kinase inhibitors should not be given concomitantly, and should be 
used with caution in the 90 days post last dose of durvalumab. Increased incidences 
of pneumonitis (with third generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR TKIs) has been reported when 
durvalumab has been given concomitantly. 
- 
Herbal and natural remedies which may have immune-modulating effects should not 
be given concomitantly unless agreed by the sponsor 
 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Patients may receive other 
medications that the investigator deems to be medically necessary. 
 

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The Exclusion Criteria describe other medications that are prohibited in this trial. There are no 
prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 12 months 
or until one of the following criteria applies which would prompt permanent discontinuation of 
study treatment: 
 
x 
Disease progression 
 
x 
Intercurrent illness that prevents further administration of treatment 
 
x 
Unacceptable adverse event(s), as defined in Section 6.  
 
x 
Patient decides to withdraw from the study 
 
x 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
x 
Patient non-compliance 
 
x 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
x 
Termination of the study by sponsor 
 
x 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.5 
Duration of Follow Up 
 
Patients will be followed for at least 12 weeks after removal from study treatment or until death, 
whichever occurs first. Patients removed from study treatment for unacceptable adverse event(s) 
will be followed until progression. All patients will be followed for at least a year from the time 
of initiation of treatment.  
 

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5.6 
Criteria for Removal from Study  
 
When study treatment is terminated per the criteria in Section 5.4 patients will remain on study 
follow-up.Study follow-up will be terminated at death or for at least one year from the time of 
treatment initiation and at least 12 weeks afer removal from study treatment, whichever occurs 
first.  Patients removed from study treatment for unacceptable adverse event(s) will continue on 
study follow-up until the preceeding criteria are met or disease progression, whichever occurs 
later. The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
5.7 
Criteria to Resume Treatment  
 
For non-autoimmune or inflammatory events, patients may resume treatment with study drug 
according to section 6. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the treatment should resume at the earliest convenient point 
that is within the 12 week delay period.  
 
If treatment is delayed >12 weeks, the patient must be permanently discontinued from study 
therapy, except as specified in Section 5.4 (Duration of Therapy).  
 
5.8 
Treatment Beyond Progression  
 
Immunotherapeutic agents such as MEDI4736and tremelimumab may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.  
 
If radiologic imaging shows progressive disease (PD), tumor assessment may be repeated by the 
site approximately 4-8 weeks later in order to confirm continued PD (as compared to the intial 
scan) with the option of continuing treatment per below while awaiting radiologic confirmation 
of progression, provided there are less than 5 new lesions, and the total tumor burden 
demonstrates less than 40% increased growth as compared to the initial scan. Additionally, any 
new CNS lesions must be treated prior to resuming therapy.  If repeat imaging shows a reduction 
or stabilization in the tumor burden compared to the initial scan demonstrating PD, treatment 
may be continued as per treatment calendar. If repeat imaging confirms continued PD, patients 
will be discontinued from study therapy. If reimaging is no worse than the prior scan 4 weeks 
prior, patients may continue therapy and be reimaged in another 8 weeks. If evidence for 
continued, increasing progression with subsequent imaging, the patient will be discontinued. In 
determining whether or not the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions. The decision to continue study treatment 
after the first evidence of disease progression determined by radiologic imaging is at the 
Investigator’s discretion based on the clinical status of the patient as described in the table below.  

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Patients may receive study treatment while waiting for confirmation of continued PD if they are 
clinically stable as defined by the following criteria:  
x 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression  
x 
No decline in ECOG performance status  
x 
Absence of rapid progression of disease  
x 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention  
x 
No urgent need for radiation therapy other than as specified by the protocol  
 
5.9 
Discontinuation of Treatment Following Complete Response  
 
Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR) that have been treated for at least 52 weeks on protocol and had at least 
two treatments with MEDI4736beyond the date when the initial CR was declared.  

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6. DOSING DELAYS/DOSE MODIFICATIONS-  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 

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 General Considerations 
 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management For 
toxicities not 
noted below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Drug administration modifications of study drug/study regimen will 
be made to manage potential immune-related AEs based on severity 
of treatment-emergent toxicities graded per NCI CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of study 
drug/regimen based on CTC grade/severity (table below) , 
permanently discontinue study drug/study regimen for  the following 
conditions:  
x 
Inability to reduce corticosteroid to a dose of ≤10 mg of 
prednisone per day (or equivalent) within 12 weeks after last 
dose of study drug/study regimen 
x 
Recurrence of a previously experienced Grade 3 treatment-
related AE following resumption of dosing. 
It is recommended that management of immune-mediated adverse events 
(imAEs) follows the guidelines presented in this table 
- 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
- 
Whether specific immune-mediated events (and/or laboratory indicators 
of such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections.) to a possible 
immune-mediated event. In the absence of a clear alternative etiology, 
all such events should be managed as if they were immune related. 
General recommendations follow. 
- 
Symptomatic and topical therapy should be considered for low-
grade (Grade 1 or 2, unless otherwise specified) events  
- 
For persistent  (greater than 3 to 5 days) low-grade (Grade 2)  or 
severe (Grade ≥3) events  promptly start prednisone PO 1-
2mg/kg/day or IV equivalent  
- 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myo-carditis, or other similar events even if they are not currently noted 
in the guidelines – should progress rapidly to high dose IV 
corticosteroids (methylprednisolone at 2 to 4 mg/kg/day) even if the 
event is Grade 2, and if clinical suspicion is high and/or there has been 
clinical confirmation. Consider, as necessary, discussing with the study 
physician, and promptly pursue specialist consultation. 
- 
If symptoms recur or worsen during corticosteroid tapering 28 
days of taper), increase the corticosteroid dose (prednisone dose  
[e.g. up to 2-4mg/kg/day PO or IV equivalent])   until 
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (> 28 days of taper)
 
 
− More potent immunosuppressives such as TNF inhibitors 
(e.g. infliximab) – (also refer to the individual sections of 
the immune related adverse event for specific type of 
immunosuppressive) should be considered for events not 
responding to systemic steroids.  Progression to use of 
more potent immunosuppressives should proceed more 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until grade 2 
resolution to ≤ Grade 1** 
• If toxicity worsens then treat as Grade 3 or 
Grade 4 
• 
Study drug/study treatment can be resumed once 
event stabilizes to grade ≤1 after completion of 
steroid taper 
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement 
can be retreated with study drug/study regimen 
on the following conditions: 1) the event 
stabilizes and is controlled , 2) the patient is 
clinically stable as per Investigator or treating 
physician’s clinical judgement, and 3) doses of 
prednisone are at less than or equal to 
10mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines below 

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Grade 4 
Permanently discontinue study drug/study 
regimen  
Note: For Grade ≥3 asymptomatic amylase or lipase 
levels, hold study drug/study regimen, and if complete 
work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
rapidly in events with high likelihood for morbidity and/or 
mortality – e.g., myocarditis, or other similar events even 
if they are not currently noted in the guidelines – when 
these events are not responding to systemic steroids. 
- 
With long-term steroid and other immunosuppressive use, consider 
need for Pneumocystis jirovecii pneumonia (PJP, formerly known as 
Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal 
protection, and glucose monitoring. 
- 
Discontinuation of study drug is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumour 
response (e.g. inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.). Continuation of study drug in this 
situation should be based upon a benefit/risk analysis for that 
patient  
 
 
  
Note: Study drug/study regimen should be permanently discontinued in 
Grade 3 events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other similar events even if 
they are not currently noted in the guidelines – when they do not rapidly 
improve to Grade <1 upon treatment with systemic steroids and following full 
taper 
Note: There are some exceptions to permanent discontinuation of study drug 
for Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes 
mellitus).  
 
** Note: If AE’s develop in an interval where the next scheduled 
treatment is radiation (either low or high dose), radiation may be 
continued at the treating physician’s discretion if the radiation 
treatment field is clearly unrelated to the AE (e.g. liver radiation in a 
patient who develops pneumonitis), provided the patient is clinically 
stable and willing to proceed with radiation treatment. 
 
 
 
 
 
 
 
 
 
Specific Immune -Mediated Reactions 
 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis/ 
Interstitial Lung 
Disease (ILD) 
 
Any Grade 
 General Guidance 
For Any Grade 
- 
Monitor patients for signs and symptoms of pneumonitis or ILD 
(new onset or worsening shortness of breath or cough).  Patients 
should be evaluated with imaging and pulmonary function tests 
including other diagnostic procedures as described below 
- 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory 
work-up and high-resolution CT scan.  
 
 
 
Grade 1  
(Asymptomatic, 
clinical or 
diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. 
However, consider holding study 
drug/study regimen dosing as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only) 
-      Monitor and closely follow up in 2-4 days for clinical symptoms, 
pulse oximetry (resting and exertion) and laboratory work-up and 
then as clinically indicated 
-      Consider Pulmonary and  Infectious disease consult 
Grade 2  
(Symptomatic, 
medical 
intervention 
indicated, limiting 
instrumental ADL)  
 Hold study drug/study regimen 
dose until grade 2 resolution to ≤ 
Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• If toxicity improves to Grade ≤1,   
then the decision to reinitiate 
study drug/regimen at next 
scheduled treatment date will be 
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day 
PO or IV equivalent) 
- 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started  
- 
If still no improvement within 3-5 days despite IV 

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1 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD  
2 NCI CTCAE version 4.03 
3 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”  
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
based upon treating physician’s 
clinical judgment.  
 and after completion of steroid 
taper   
  
methylprednisolone at 2-4/g/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks). Caution: It is important to 
rule out sepsis and refer to infliximab label for general guidance 
before using infliximab  
- 
Once the patient is improving, gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungal or anti PCP 
treatment (refer to current  NCCN guidelines for treatment of  
cancer-related infections (Category 2B recommendation)123 
- 
Consider pulmonary and infectious disease consult 
- 
Consider as necessary  discussing with study physician 
Grade 3 or 4  
(Grade 3: Severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention 
indicated [e.g. 
tracheostomy or 
intubation])  
Permanently discontinue study 
drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life 
threatening  
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day 
or equivalent  
- 
Obtain Pulmonary and Infectious disease  consult; consider, as 
necessary, discussing with study physician. 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks dose) started. Caution: rule 
out sepsis and refer to infliximab label for general guidance before 
using infliximab  
- 
Once the patient is improving, gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungals and in 
particular,  anti PJP treatment (please refer to current  NCCN 

NCI Protocol #:10021 
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4 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
guidelines for treatment of  cancer-related infections (Category 2B 
recommendation)4 
Diarrhea/ Colitis 
Grade of Diarrhea 
(CTCAE version 
4.03) 
Any Grade 
- 
Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in stool) or related to 
bowel perforation (such as sepsis, peritoneal signs and ileus) 
- 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, infections 
including testing for clostridium difficile toxin,  etc.) 
- 
Steroids should be considered  in the absence of clear alternative 
etiology, even for low grade events, in order to prevent potential 
progression to higher grade event 
- 
Use analgesics carefully; they can mask symptoms of perforation 
and peritonitis 
Grade 1 
(Diarrhea:stool 
frequency of <4 
over baseline per 
No dose modification 
For Grade 1 diarrhea :  
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including hydration, electrolyte 

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5 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects   
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
day)                
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations only)  
replacement, dietary changes (e.g., American Dietetic Association 
colitis diet), and loperamide. Use of probiotics as per treating 
physician’s clinical judgment. 
Grade 2 
(Diarrhea:stool 
frequency of 4-6 
over baseline per 
day)               
(Colitis: abdominal 
pain; mucus or blood 
in stool) 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen 
can be resumed  after 
completion of steroid taper    
For Grade 2 diarrhea:  
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or budesonide  
- 
Promptly start  prednisone 1 to 2  mg/kg/day PO or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup such as 
imaging and/or colonoscopy to confirm colitis and rule out 
perforation,   and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started.  
- 
If still no improvement within 3-5 days despite 2-4mg/kg IV 
methylprednisolone, promptly start  immunosuppressives such as  
(infliximab at 5mg/kg once every 2 weeks5). . Caution: It is 
important to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab   
- 
 Consider, as necessary, discussing with study physician if no 
resolution to ≤ Grade 1 in 3-4 days 
- Once the patient is improving, gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
diarrhea  
 
(Grade 3 diarrhea: 
stool frequency of 
≥7 over baseline 
per day;  
 
Grade 4 diarrhea: 
life threatening 
consequences) 
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medi-cal 
intervention indi-
cated, peritoneal 
signs; 
Grade 4 colitis: 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 
if toxicity does not improve to 
Grade ≤1 within 14 days; study 
drug/study regimen can be 
resumed after completion of 
steroid taper. 
Grade 4 
Permanently discontinue  
study drug/study regimen. 
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent  
- 
Monitor stool frequency and volume and maintain hydration   
- 
Urgent GI consult and imaging and/or colonoscopy as appropriate 
- 
If still no improvement within 3-5 days of IV methylprednisolone  
2 to 4mg/kg/day or equivalent, promptly start further 
immunosuppressives (e.g. infliximab at 5mg/kg once every 2 
weeks).   
- 
Caution: Ensure GI consult to rule out bowel perforation and refer 
to infliximab label for general guidance before using infliximab.  
- Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
Hepatitis 
(Elevated LFTs) 
Infliximab 
should not be 
used for 
Grade of Liver 
Function Test 
Elevation (CTCAE 
version 5.0) 
Any Grade 
  
- 
Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin  
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications)  

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6 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by Michael Postow MD 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
management of 
Immune Related 
Hepatitis 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 1 (Based on 
ULN regardless of 
baseline LFT) 
 
(AST or ALT >ULN 
and ≤3.0×ULN 
and/or TB > ULN and  
≤1.5×ULN) 
No dose modifications 
If  it worsens, then treat as Grade 2 
event 
For Grade 1 AST or ALT and/or TB elevation        
  -     Continue LFT monitoring per protocol   
Grade 2 (Based on 
ULN regardless of 
baseline LFT )AST 
or  
ALT >3.0×ULN and 
≤5.0×ULN and/or  
TB >1.5×ULN and  
≤3.0×ULN) 
Hold Study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• If toxicity improves to Grade ≤1 
or baseline, resume study 
drug/study regimen after 
completion of steroid taper    
For Grade 2 AST or ALT and or TB elevation :  
- 
Regular and frequent checking of LFTs (e.g. every 1-2 days) until 
elevations of these are improving or resolved.   
- 
If no resolution to ≤ Grade 1 in 1-2 days,  consider, as necessary, 
discussing with study physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1-2mg/kg/day PO or IV equivalent.  
- 
If still no improvement within 3-5 days despite 1-2mg/kg/day of 
prednisone PO or IV equivalent, consider additional work up and 
start prompt treatment with IV methylprednisolone 2-4mg/kg/day. 
- If still no improvement within 3-5 days despite 2-4mg/kg/day of 
IV methylprednisolone, promptly start immunosuppressives 
(i.e.,mycophenolate mofetil)6 . Discuss with study physician if 
mycophenolate mofetil is not available.  Infliximab should NOT 
be used. 
- Once the patient is improving, gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines for 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
Grade 3 (Based on 
ULN regardless of 
baseline LFT) 
  (Grade 3: AST or  
ALT >5.0×ULN and 
≤20.0×ULN and/or  
TB >3.0×ULN and  
≤10.0×ULN) 
 
For elevations in transaminases ≤ 8 
× ULN, or elevations in bilirubin 
≤ 5 × ULN  
-Hold study drug/study regimen 
dose until resolution to ≤ Grade 
1 or baseline   
-Resume study drug/study 
regimen  if elevations 
downgrade ≤ Grade 1 or 
baseline within 14 days and 
after completion of steroid 
taper. 
Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to ≤ Grade 1 or 
baseline within 14 days  
For elevations in transaminases > 8 
× ULN or elevations in bilirubin 
> 5 × ULN, discontinue study 
drug/study regimen  
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT > 3x ULN + 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent  
- 
If still no improvement within 3-5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent , promptly start treatment 
with immunosuppressive therapy (i.e.,mycophenolate mofetil)  
Discuss with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
- 
Perform hepatology consult, abdominal workup, and imaging as 
appropriate. 
- 
Once the patient is improving, gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
 

NCI Protocol #:10021 
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7 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation  
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis  
(elevated LFTs) 
Infliximab should 
not be used for 
management of 
immune-related 
hepatitis 
 
See instructions at  
bilirubin > 2x ULN without 
initial findings of cholestasis (i.e. 
elevated alkaline P04) and  in the 
absence of any alternative cause7 
 
 
 
 
 
 
 
 
For any grade: 
-Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
-Evaluate for alternative etiologies {e.g., viral hepatitis, disease progression, 
concomitant medications, worsening of liver cirrhosis (e.g., portal vein 
thrombosis).} 
-For HBV+ patients: evaluate quantitative HBV viral load, quantitative HBsAg, or 
HBeAg 
Grade 4  
    (Grade 4: AST or  
ALT >20×ULN 
and/or  
TB >10×ULN) 
 
 
Any Grade 
Permanently discontinue study 
drug/study regimen  
 
 
 
 
 
 
 
 
 
General Guidance  
 
  
THIS shaded 
area is guidance 
only for 
management of 
“Hepatitis 
(elevated 
LFTs)” in HCC

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
bottom of shaded 
area  
if transaminase rise 
is  
not isolated but (at 
any time) occurs in 
setting  
of either increasing 
bilirubin or signs 
of DILI/liver 
decompensation 
 
 
 
 
 
 
-For HCV+ patients: evaluate quantitative HCV viral load 
-Consider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral medications for any patient with an elevated 
HBV viral load >2000 IU/ml 
-Consider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral HCV medications if HCV viral load 
increased by >2 -fold 
-For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above 
 
Grade 1 
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, whether 
normal or elevated at 
baseline) 
x 
No dose modifications. 
x 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat 
as Grade 2 event. 
For all grades, see instructions at bottom 
of shaded area if transaminase rise is not 
isolated but (at any time) occurs in 
setting of either increasing bilirubin or 
signs of DILI/liver decompensation 
 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 2 
(Isolated AST or 
ALT >5.0×ULN and 
≤8.0×ULN, if normal 
at baseline) 
 
(Isolated AST or 
ALT >2.0×baseline 
and ≤12.5×ULN, if 
elevated >ULN at 
baseline) 
x 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1 
or baseline. 
x 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid taper. 
 
 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) until 
elevations of these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal ultrasound, 
including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and investigator suspects 
toxicity to be immune-mediated AE, recommend to start prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, consider additional workup and 
treatment with IV methylprednisolone 2 to 4 mg/kg/day. 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, consider additional abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and consider starting immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss with study physician if mycophenolate mofetil is 
not available. Infliximab should NOT be used. 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 3 
(Isolated AST or 
ALT >8.0×ULN and 
≤20.0×ULN, if 
normal at baseline) 
 
(Isolated AST or 
ALT >12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN at 
baseline) 
x Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
x Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 
or baseline within 14 days and after 
completion of steroid taper. 
x Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause.b 
For Grade 3: 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) until 
elevations of these are improving or resolved. 
− 
Consult hepatologist (unless investigator is hepatologist); obtain 
abdominal ultrasound, including Doppler assessment of liver perfusion; 
and consider liver biopsy. 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, promptly initiate 
empiric IV methylprednisolone at 1 to 4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it has not 
been done already) and promptly start treatment with immunosuppressive 
therapy (mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Grade 4 
(Isolated AST or 
ALT >20×ULN,  
whether normal or 
elevated at baseline) 
 
 
Permanently discontinue 
study drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver biopsy early) 
 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)  
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03) 
 
Any Grade  
 
 
 
 
- 
Consult with Nephrologist 
- 
Monitor for signs and symptoms that may be related to changes in 
renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, 
decrease in urine output, proteinuria, etc.)  
- 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, infections etc.) 
- 
Steroids should be considered in the absence of clear alternative 
etiology even for low grade events (Grade 2) , in order to prevent 
potential progression to higher grade event 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 [Serum 
Creatinine > 1-
1.5X baseline;  > 
ULN to 1.5X ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any accompanying symptom 
x 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
x 
If it worsens, depending on the severity , treat as Grade 2 
or Grade 3 or 4  
-      Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2 [Serum 
Creatinine>1.5-
3.0X baseline; 
>1.5X-3.0XULN] 
 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to  to Grade 
≤1 or baseline, then resume study 
drug/study regimen after 
completion of steroid taper.    
For Grade 2 elevated creatinine:  
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc.  
- 
Carefully monitor serum creatinine  every 2-3 days and as 
clinically warranted 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- 
If event is persistent (> 3-5 days) or worsens,  promptly start  
prednisone 1 to 2 mg/kg/day or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2-4mg/kg/day started.  
- 
Once the patient isimproving gradually taper steroids over ≥28 
days and   consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).  
- 
When event returns to baseline, resume study drug/study regimen 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
and routine serum creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 
X ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN)  
Permanently discontinue study 
drug/study regimen 
- 
Carefully monitor serum creatinine  on  daily basis 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- 
Promptly  start  prednisone 1 to 2  mg/kg/day or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- Once the patient is improving,  gradually taper steroids over ≥28 
days  and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]  
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin Rash  
(Please refer to 
NCICTCAE 
version 4.03 for 
Any Grade 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY DRUG 
DISCONTINUED** 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
definition of 
severity/grade 
depending on  type 
of skin rash)  
Grade 1  
No dose modification 
For Grade 1: 
- 
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream) 
Grade 2 
For persistent (> 1- 2 weeks) Grade 
2 events, hold scheduled study 
drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline  
x 
If  toxicity worsens then 
treat as Grade 3  
x 
If  toxicity improves  Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper. 
For Grade 2 : 
- 
Obtain dermatology consult  
- 
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream) 
- 
Consider moderate-strength topical steroid  
- 
If no improvement of rash/skin lesions occurs within 3-5 days or 
is worsening despite symptomatic treatment and/or use of 
moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids prednisone  1-2 mg/kg/day PO or IV equivalent   
- 
Consider skin biopsy if the event is persistent for >1-2 weeks or 
recurs 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline 
 If temporarily holding the study 
drug/study regimen does not 
provide improvement of the 
Grade 3 skin rash  to ≤ Grade 1 
or baseline within 30 days, then 
permanently discontinue Study 
drug/study regimen  
For Grade 3 or 4: 
- 
Consult dermatology  
- 
 Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent  
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study 
drug/study regimen  
- 
Once the patient is  improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals and anti 
PJP treatment (please refer to current NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
- 
Consider, as necessary, discussing with study physician 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism,  
Type 1 diabetes 
mellitus, 
hypophysitis,  
hypopituitarism, 
adrenal 
insufficiency, etc: 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section). 
Any Grade  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity)  
 
− 
  Consider consulting an  endocrinologist  for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
 
- 
Monitor patients for signs and symptoms of endocrinopathies.  
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, unusual 
bowel habits,  polydipsia, polyuria, hypotension and weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression including brain metastases, 
infections, etc.) 
− 
  Depending on the suspected endocrinopathy, monitor  and evaluate 
thyroid function tests: TSH, free T3 and free T4 and other 
relevant endocrine and  related labs (e.g., blood glucose and ketone 
levels, HgA1c). 
− 
  For modest asymptomatic elevations in serum amylase and lipase, 
corticosteroid treatment is not indicated as long as there are no other signs 
or symptoms of pancreatic inflammation. 
 
- 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should send a blood sample 
for appropriate autoimmune antibody testing  

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- 
Monitor patient with appropriate endocrine function tests 
- 
For suspected hypophysitis/hypopituitarism, consider consultation of an 
endocrinologist to guide assessment of early-morning ACTH, cortisol, 
TSH and free T4; also consider gonadotropins, sex hormones, and 
prolactin levels, as well as cosyntropin stimulation test (though it may not 
be useful in diagnosing early secondary adrenal insufficiency). 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of 
range in 2 subsequent measurements, include Free T4 at 
subsequent cycles as clinically indicated and consider  consultation 
of an endocrinologist. 
Grade 2  
  
For Grade 2 endocrinopathy other 
than hypothyroidism  and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until  
subject is clinically stable 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
•  
Study drug/study regimen can be 
resumed once event stabilizes  
and after completion of steroid 
taper 
   Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following 
conditions: 1) the event stabilizes 
and is controlled ,2) the patient is 
clinically stable as per 
Investigator or treating 
For Grade 2: (including those with symptomatic endocrinopathy) 
-  Consult endocrinologist to guide evaluation of  endocrine function  
and, as indicated by suspected endocrinopathy, and as clinically 
indicated,  consider pituitary scan 
- For all patients with abnormal endocrine work up, except  those  
with isolated hypothyroidism  or Type 1 DM, and as guided by an  
endocrinologist,  consider short-term, corticosteroids (e.g., 1-
2mg/kg/day methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone replacement (e.g. 
hydrocortisone, sex hormones). – 
- 
Isolated hypothyroidism may be treated with replacement therapy, 
without study drug/study regimen interruption, and without 
corticosteroids. 
- 
Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate 
diabetic therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
 
- Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with guidance of 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
physician’s clinical judgement, 
and 3) doses of prednisone are at 
less than or equal to 10mg/day or 
equivalent. 
endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PJP treatment (please refer to 
current NCCN guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- For patients with normal endocrine work up (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI as 
clinically indicated. 
Grade 3 or 4 
 
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism  and Type 
1 diabetes mellitus, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled 
Study drug/study regimen can be 
resumed once event stabilizes  and 
after completion of steroid taper    
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
For Grade 3 or 4: 
- 
 Consult endocrinologist to guide evaluation of endocrine function and, as 
indicated by suspected endocrinopathy and as clinically indicated, 
consider pituitary scan. Hospitalization recommended. 
- 
  For all patients with abnormal endocrine work up, except those with 
isolated hypothyroidism  
  or Type 1 DM, and as guided by an  endocrinologist, promptly  initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent 
- 
 as well as relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
- 
For adrenal crisis, severe dehydration, hypotension, or shock: 
immediately initiate intravenous corticosteroids with 
mineralocorticoid activity 
- 
Isolated hypothyroidism may be treated with replacement therapy, 
without study drug/study regimen interruption, and without 
corticosteroids. 
- 
Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic 
therapy, without study drug/study regimen interruption, and without 
corticosteroids. 
- 
 
- 
Once  patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance of 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PJP treatment (please refer to 
current NCCN guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- 
 
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)   
 
Grade of 
Neurotoxicity  
Depending on the 
type of 
neurotoxicity , refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 
 
Any Grade  
 
 
 
 
 
 
 
- 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes and 
medications, etc.)  
- 
Monitor patient  for general symptoms (headache, nausea, vertigo, 
behavior change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. electromyogram and 
nerve conduction investigations) 
- 
Perform symptomatic treatment with neurological consult as 
appropriate 
 
Grade 1 
 No dose modifications 
See “Any Grade” recommendations above. 
Grade 2 
x 
For acute motor 
- 
 Consider, as necessary, discussing  with the study physician  

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
neuropathies or  
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to ≤ Grade 
1 
x 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to ≤ 
Grade 1. 
o If toxicity worsens 
then treat as Grade 3 
or Grade 4  
x 
Study drug/study regimen 
can be resumed once event 
stabilizes to grade ≤1 and  
after completion of steroid 
taper    
- 
Obtain  Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine) 
- 
Promptly start systemic steroids prednisone 1-2mg/kg/day PO or 
IV equivalent  
- 
If no improvement within 3-5 days despite 1-2mg/kg/day 
prednisone PO or IV equivalent consider additional workup and 
promptly treat with additional immunosuppressive therapy (e.g. 
IVIG)  
 
 
Grade 3 
x 
Hold Study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
x 
Permanently discontinue 
Study drug/study regimen 
if Grade 3 imAE does not 
resolve to ≤ Grade 1 within 
30 days. 
For Grade 3 or 4: 
- 
  Consider, as necessary, discussing  with study physician 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day 
or equivalent  
- 
If no improvement within 3-5 days despite IV corticosteroids, 
consider additional workup and promptly treat with additional 
immunosuppressants (e.g. IVIG)  
- 
Once stable, gradually taper steroids over ≥28 days 
Grade 4 
 
x 
Permanently discontinue 
study drug/study regimen 
Peripheral 
neuromotor 
syndromes (such 
 
Any Grade 
- 
The prompt diagnosis of immune-mediated peripheral neuromotor 
syndromes is important, since certain patients may unpredictably 
experience acute decompensations which can result in substantial 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
as Guillain-Barre 
and Myasthenia 
Gravis) 
morbidity or in the worst case, death. Special care should be taken 
for certain sentinel symptoms which may predict a more severe 
outcome, such as prominent dysphagia, rapidly progressive 
weakness, and signs of respiratory insufficiency or autonomic 
instability 
- 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or  
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the multiple 
potential confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of prompt and 
accurate diagnosis, it is essential to have a low threshold to obtain 
a neurological consult 
- 
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and  “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion of 
such conditions and may be best facilitated by means of a 
neurology consultation  
Important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started  with IVIG and 
followed by plasmapheresis if not responsive to IVIG  
Grade 1 
No dose modification 
- 
 Consider, as necessary, discussing  with the study physician 
- 
Care should be taken to monitor patients for sentinel symptoms of 
a potential decompensation as described above 
- 
Obtain a neurology consult  
Grade 2 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to ≤ Grade 1 within 30 
days or if there are signs of 
Grade 2  
- 
 Consider, as necessary, discussing  with the study physician  
- 
Care should be taken to monitor patients for sentinel symptoms of 
a potential decompensation as described above 
- 
Obtain a Neurology Consult  

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
respiratory insufficiency or 
autonomic instability 
 
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine) 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of a 
consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. Such decisions are 
best made in consultation with a neurologist, taking into 
account the unique needs of each patient. 
o 
If Myasthenia Gravis-like neurotoxicity is present, 
consider starting acetylcholine esterase (AChE) inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
o 
It is important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should 
be started with IVIG and followed by plasmapheresis if 
not responsive to IVIG. 
Grade 3 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue Study 
drug/study regimen if Grade 3 
imAE does not resolve to ≤ 
Grade 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability 
For severe or life threatening (Grade 3 or 4) events:  
- 
Consider, as necessary, discussing  with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study 
drug/study regimen  
neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy 
in addition to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
It is important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IVIG and followed by plasmapheresis if not 
responsive to IVIG 
 
 
 
 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
  Cardiac 
toxicities 
(including 
arrhythmia, 
conduction 
disorder heart 
failure, lV 
dysfunction, 
Myocarditis) 
                 
 
 
 
 
 
 
 
 
Any Grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Guidance 
                                                                    
Discontinue drug permanently       upon 
diagnosis of myocarditis, regardless of 
grade. 
                                                                    
 
 
 
 
 
 
 
 
 
 
 
 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is important, 
particularly in patients with baseline cardiopulmonary disease and 
reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, shortness of breath, peripheral edema). 
As some symptoms can overlap with lung toxicities, simultaneously 
evaluate for and rule out pulmonary toxicity as well as other causes (e.g., 
pulmonary embolism, congestive heart failure, malignant pericardial 
effusion). A Cardiology consultation should be obtained early, with 
prompt assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, cardiac enzymes, 
ECG, echocardiogram (ECHO), monitoring of oxygenation via pulse 
oximetry (resting and exertion), and additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can complement ECHO to assess 
wall motion abnormalities when needed. 
- 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections) 
- 
 

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Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
 
 
 
 
Grade 1 
(asymptomatic with 
laboratory (e.g., BNP, 
EKG, Troponin)  and 
etiology is unclear)    
 
 
 
 
 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with mild to 
moderate activity or 
exertion) 
 
 (Grade 3: Severe 
with symptoms at rest 
or with minimal 
activity or exertion; 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or 
mechanical 
hemodynamic 
support)) 
                  
No dose modifications required unless 
clinical suspicion for myocarditis is 
high, in which case suspected hold  
durvalumab-tremelimumab during 
workup. 
-If myocarditis is excluded, resume after 
complete resolution to Grade 0. 
- If myocarditis is diagnosed, 
permanently discontinue 
durvalumab or tremelimumab 
 
 
 
 
- If Grade 2 -- Hold study drug/study 
regimen  If toxicity rapidly improves 
to Grade 0 AND myocarditis is 
excluded, then the decision to 
reinitiate study drug/study regimen 
will be based upon treating 
physician’s clinical judgment and 
after completion of steroid taper. If 
toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen. 
-If myocarditis is diagnosed, 
permanently discontinue durvalumab or 
tremelimumab 
-If Grade 3-4, permanently discontinue 
study drug/study regimen. 
 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical symptoms,  BNP, 
cardiac enzymes, ECG, ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated. 
Consider using steroids if clinical suspicion is high. 
 
 
 
 
 
 
 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent after 
Cardiology consultation has determined whether and when to complete 
diagnostic procedures including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV methylprednisolone at 2 
to 4 mg/kg/day, promptly start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
- 
Once the patient is improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals, or anti-PJP treatment 
(refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 

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Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
(moderate pain 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 

NCI Protocol #:10021 
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associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(pain associated with 
severe weakness; 
limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 

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Additional Information: 
 
 If drugs are given and then patient develops AE before or during radiation, radiation is also held, stopped, unless the treatment 
field is clearly unrelated to the AE (e.g. liver radiation in a patient who develops pneumonitis), provided the patient is 
clinically stable for radiation treatment. 
 
 If either drugs are held then radiation is also held. If all radiation has not been delivered as per protocol, radiation would 
resume the week following the next drug administration, do not skip. 
 
 If drugs are held, then any remaining radiation is also held until a week after the next cycle begins, per protocol.  
 
 If patient experiences an AE, requiring drug hold/discontinuation, both drugs will be held. 
 
 If drug or radiation is permanently discontinued for toxicity before completion of protocol treatment, the subject would need to 
come off treatment. 
 
treatment of cancer-related infections [Category 2B 
recommendation]).a 

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 Infusion-Related Reactions 
Severity Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
 
- 
Management per institutional standard at the discretion of investigator 
- 
Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator  
- 
Consider premedication per institutional standard prior to subsequent 
doses 
- Steroids should not be used for routine premedication of Grade ≤2 infusion 
reactions. 
Grade 2 
 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution 
of the event  
Subsequent infusions may be given at 50% of the initial 
infusion rate 
Grade 3/4 
 
 
Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions per institutional standards 
(e.g., IM epinephrine, followed by IV diphenhydramine and ranitidine, 
and IV glucocorticoid) 
 
 
 
 
 
 Non-immune Mediated Reactions 
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician”  
CTC Grade/Severity 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly as per institutional 
standard  
1 
No dose modifications  
Treat accordingly as per institutional 
standard  

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 Non-immune Mediated Reactions 
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician”  
CTC Grade/Severity 
Dose Modification  
Toxicity Management  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 
14 days, resume study drug/study regimen administration. Otherwise, discontinue study 
drug/study regimen 
Treat accordingly as per institutional 
standard  
 
 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue should be 
based on accompanying clinical signs/symptoms, Investigator’s clinical judgment and in 
consultation with the sponsor)  
Treat accordingly as per institutional 
standard  
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST 
= aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = 
intramuscular; irAE = immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
i ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD  
ii NCI CTCAE version 5.0 
iiiASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
iv FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
 
 

NCI Protocol #:  10021 
Informed Consent Version Date:  08/30/2019 
Page 94 of 163 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 
CAEPR for MEDI4736 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MEDI4736 (durvalumab, NSC 778709) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 2833 patients. Below is the CAEPR for 
MEDI4736 (durvalumab).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 

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                                                                                                                                               Version 2.4, 
April 17, 20191 
 
 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (idiopathic 
thrombocytopenic purpura)2 
  
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Myocarditis2 
  
 
 
Pericarditis2 
  
ENDOCRINE DISORDERS 
  
 
 
Adrenal insufficiency2 
  
 
 
Endocrine disorders - Other 
(diabetes insipidus) 
  
 
 
Endocrine disorders - Other 
(diabetes mellitus type 1)2 
  
 
Hyperthyroidism2 
 
  
 
 
Hypopituitarism2 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Keratitis2 
  
 
 
Uveitis2 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis2 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastrointestinal disorders -
Other - (gastrointestinal 
perforation)2,3 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
 
Pancreatitis2 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Immune system disorders - 
Other (immune related adverse 
events)2 
  
 
 
Immune system disorders - 
Other (sarcoidosis) 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  Infection4 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  

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 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
 Alanine aminotransferase 
increased2 (Gr 2) 
 
Aspartate aminotransferase 
increased2 
 
 Aspartate aminotransferase 
increased2 (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
  
 
Myalgia 
  
 Myalgia (Gr 2) 
 
 
Myositis2 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2,5 
  
 
 
Myasthenia gravis2 
  
 
 
Nervous system disorders - 
Other (aseptic meningitis)2 
  
 
 
Peripheral sensory neuropathy   
RENAL AND URINARY DISORDERS 
  
 
Dysuria 
 
 Dysuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Cough 
 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Pneumonitis2 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(dysphonia) 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash2,6  
 
 Rash2,6 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (scleroderma) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (severe 
dermatitis)2,7 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
 
 
 
NOTE: Cardiomyopathy, and graft versus host disease, while not observed on clinical trials of MEDI4736 
(durvalumab) at this time, are known events with this class of agent (PD-L1 antagonist). 

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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions (irAEs) have been reported in patients receiving MEDI4736 
(durvalumab).  irAEs can involve any of the organs or systems in the body.  Most irAEs were reversible 
and managed with interruptions of MEDI4736 (durvalumab), administration of corticosteroids and 
supportive care, however, these events can be serious and fatal. 
 
3Gastrointestinal perforations have been observed only in patients receiving MEDI4736 (durvalumab) in 
combination with tremelimumab (CP-675,206). 
 
4Infections includes infection in the lungs, upper respiratory tract, dental and oral soft tissues and other 
organs under the INFECTIONS AND INFESTATIONS SOC.  Infections generally are mild (Gr 1-2) but 
severe infections including sepsis, necrotizing fasciitis, and osteomyelitis have been reported. 
 
5Guillain-Barre Syndrome has been reported in patients receiving MEDI4736 (durvalumab) in combination 
with tremelimumab (CP-675,206) but can potentially occur after durvalumab monotherapy.  
 
6Rash includes the terms: rash erythematous, rash generalized, rash macular, rash maculopapular, rash 
papular, rash pruritic, rash pustular, erythema, and eczema. 
 
7In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or hemorrhagic 
manifectations. 
 
Adverse events reported on MEDI4736 (durvalumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MEDI4736 (durvalumab) caused 
the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (coronary artery 
disease); Pericardial effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right ventricular 
dysfunction; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental caries; Gastrointestinal disorders - 
Other (gastrointestinal hemorrhage); Mucositis oral; Proctitis; Small intestinal obstruction; Upper 
gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Non-cardiac chest 
pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver injury); Serum 
sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound complication 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; Electrocardiogram T wave abnormal; GGT 
increased; Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count 
decreased; Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; 
Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (brain metastasis swelling); Neoplasms 

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benign, malignant and unspecified (incl cysts and polyps) - Other (lung cyst); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (tumor flare, tumor inflammation); Treatment 
related secondary malignancy; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Edema cerebral; Headache; Nervous system 
disorders - Other (axonal neuropathy); Nervous system disorders - Other (hemiparesis); Paresthesia; 
Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension 
 
 
Note: MEDI4736 (durvalumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 
 
 
 
                                                                                                               
 
 
 
7.1.1.2 
CAEPR for tremelimumab  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Tremelimumab (CP-675,206, NSC 744483) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 1642 patients.  Below is the CAEPR for 
tremelimumab (CP-675,206). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
Version 2.1, March 25, 20191 

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 Adverse Events with Possible  
 Relationship to Tremelimumab (CP-675,206) 
 (CTCAE 5.0 Term) 
[n= 1642] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia2 
 
 Anemia2 (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Myocarditis3 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis2 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
 
Enterocolitis2 
  
 
 
Gastrointestinal disorders - 
Other (intestinal perforation)2 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
 
Pancreatitis2 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (autoimmune 
hepatitis)2  
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
 Alanine aminotransferase 
increased2 (Gr 2) 
 
Aspartate aminotransferase 
increased2 
 
 Aspartate aminotransferase 
increased2 (Gr 2) 
 
Lipase increased2 
 
 Lipase increased2 (Gr 2) 
 
Lymphocyte count decreased2 
 
 Lymphocyte count decreased2 (Gr 
2) 
 
Neutrophil count decreased2 
 
 Neutrophil count decreased2 (Gr 2) 
 
Platelet count decreased2 
 
 Platelet count decreased2 (Gr 2) 
 
Serum amylase increased2 
 
 Serum amylase increased2 (Gr 2) 
 
White blood cell decreased2 
 
 White blood cell decreased2 (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Tremelimumab (CP-675,206) 
 (CTCAE 5.0 Term) 
[n= 1642] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypokalemia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  
 
 
Musculoskeletal and 
connective tissue disorders - 
Other (Sjogren's syndrome) 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
Headache2 
 
  
 
 
Myasthenia gravis2,4  
  
 
 
Nervous system disorders - 
Other (encephalitis)2 
  
 
Peripheral motor neuropathy2 
 
  
 
Peripheral sensory neuropathy2 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
  
Nephrotic syndrome2 
  
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Pneumonitis2 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(interstitial lung disease)2  
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin2 
 
 Dry skin2 (Gr 2) 
Pruritus 
 
 
 Pruritus (Gr 2) 
Rash maculo-papular2 
 
 
 Rash maculo-papular2 (Gr 2) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(cutaneous scleroderma-like 
syndrome) 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(Grover's disease) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vascular disorders - Other 
(giant cell temporal arteritis)2 
  
 

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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-related adverse events may occur in any organs including but not limited to the events listed in 
CAEPR table. 
 
3Myocarditis has been reported with other anti-CTLA4 agents; however, it has not yet been observed in 
clinical trials of tremelimumab (CP-675,206). 
 
4Myasthenia gravis was observed in trials of tremelimumab in combination with durvalumab. 
 
 
Adverse events reported on tremelimumab (CP-675,206) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that tremelimumab (CP-675,206) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Graves' disease with ophthalmopathy) 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Gastritis; Gastrointestinal disorders - 
Other (diverticulitis); Ileus; Mucositis oral; Rectal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Pain; Sudden death 
NOS 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (oral herpes); 
Lung infection; Sepsis 
INVESTIGATIONS - GGT increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized muscle 
weakness; Myalgia 
NERVOUS SYSTEM DISORDERS - Dizziness; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pleural effusion; Respiratory, thoracic 
and mediastinal disorders - Other (asthma) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other 
(hemorrhage); Vasculitis 
 
 
Note: Tremelimumab (CP-675,206) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 
 
7.2 
Adverse Events of Special Interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 

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understanding of the Investigational Product and may require close monitoring . An AESI may 
be serious or non-serious.  
 
AESIs for MEDI4736± tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
“These AESIs may require close monitoring in clinical studies with durvalumabmonotherapy 
and durvalumab combination therapy”. An immune-mediated adverse event (imAE) is defined as 
an AESI that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the imAE.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESIs observed with MEDI4736± tremelimumab include: 
x Diarrhea / Colitis and intestinal perforation 
x Pneumonitis / ILD 
x  hepatitis / transaminase increases 
x Endocrinopathies (i.e. events of hypophysitis/ hypopituitarism, adrenal insufficiency,  
hyper- and hypothyroidism and type I diabetes mellitus)  
x Rash / Dermatitis 
x Nephritis /Blood creatinine increases 
x Pancreatitis  / serum lipase and amylase increases   
x Myocarditis 
x Myositis / Polymyositis 
x Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré and myasthenia gravis)Other 
inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to,  pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, haematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological aetiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the  durvalumab and tremelimumab Investigator’s Brochures. More specific guidelines for 
their evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines ( please see Appendix 1). These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these 
types of toxicities.  These guidelines apply to AEs considered causally related to the study 
drug/study regimen by the reporting investigator.. 
 
7.3 
Adverse Event Characteristics  
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 

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4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.4.4. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Expedited Adverse Event Reporting 
 
7.4.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.4.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.4.3 Expedited Reporting Guidelines 
 

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Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions”. 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 

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agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 
7.4.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
x Any grade 1 or grade 2 laboratory abnormality that resolves within 7 days. Any grade 1 
or grade 2 laboratory abnormality lasting for more than 7 days without resolution will 
require Expedited Adverse Event Reporting. 
x Any grade 1 or grade 2 adverse event attributed as not related to study treatment.  
x Any grade 1 or grade 2 adverse event attributed as possibly related or related to study 
treatment and is expected and resolves within 14 days. Any grade 1 or grade 2 adverse 
event attributed as possibly related or related to study treatment and is expected which 
does not resolve within 14 days will require Expedited Adverse Event Reporting.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
Clinician graded CTCAE is the AE safety standard.  Patients will respond to PRO-CTCAE items 
in a manner to complement CTCAE reporting, but no real-time review nor protocol directed 
action will be taken. The patient reported data will be entered directly from the patient’s device 
into the RAVE database and may be available for the review with routine AEs.   
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 

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treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
7.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 MEDI4736 (NSC 778709) 
 
Other Names: MEDI4736(durvalumab) 
 
Classification: Anti-PD-L1 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: MEDI4736 inhibits binding of programmed cell death ligand 1 (PD-L1) 
to PD-1 and CD80.  In-vitro studies demonstrate that MEDI4736 relieves PD-L1-
mediated suppression of human T-cell activation.  MEDI4736 does not trigger antibody-
dependent cellular cytotoxicity or complement-dependent cytotoxicity in cell-based 
functional assays. 
 
Description: MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal 
antibody. 

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How Supplied: MEDI4736 is supplied by AstraZeneca/MedImmune, and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 500 mg/vial 
solution for infusion (50 mg/mL).  MEDI4736 solution for infusion is formulated in 26 
mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, 
pH 6.0.  
 
Preparation: MEDI4736 solution for infusion must be diluted prior to administration.  
To prepare the infusion solution add the dose volume of MEDI4736 to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix 
by gentle inversion to ensure homogeneity of the dose in the bag.  The final concentration 
must be between 1 mg/mL to 20 mg/mL.  Saline bags must be latex-free and can be made 
of polypropylene, polyethylene, polyolefin copolymers, or polyvinyl chloride. 
 
Storage: Store intact vials between 2-8°C (36-46°F).  Do not shake. 
 
If a storage temperature excursion is identified, promptly return MEDI4736 to between 2-
8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going. 
 
Total in-use storage time from needle puncture of MEDI4736 vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-
46°F).   Prior to the start of the infusion, ensure that the bag contents are at room 
temperature (approximately 25°C) to avoid an infusion reaction due to the administration 
of the solution at low temperatures. If there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. 
 
Route of Administration: IV infusion 
 
Method of Administration: Infuse over approximately 60 minutes using an infusion set 
containing a low-protein binding 0.2 μm in-line filter.  No incompatibilities between 
MEDI4736 and polyethylene, polypropylene, polyvinylchloride, or polyolefin 
copolymers have been observed.  Flush the IV line with a volume of normal saline equal 
to the priming volume of the infusion set used at the completion of infusion.  Do not co-
administer other drugs through the same infusion line. 
 
Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
 
Availability 
 
MEDI4736is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 

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MEDI4736is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Tremelimumab (NSC 744483) 
 
Other Names: CP-675,206 
 
Classification: Anti-CTLA-4 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Tremelimumab is specific for human cytotoxic T lymphocyte-associated antigen 
4 (CTLA-4), a cell surface receptor that is expressed primarily on activated T cells.  CTLA-4 
delivers a negative regulatory signal to T cells upon binding of CD80 or CD86 ligands on antigen-
presenting cells.  Tremelimumab blocks the inhibitory signal resulting from CTLA-4 binding to 
CD80/86, leading to prolongation and enhancement of T-cell activation and expansion. 
 
Description: Tremelimumab is a human immunoglobulin G2 kappa (IgG2κ) monoclonal antibody. 
 
How Supplied: Tremelimumab is supplied by AstraZeneca, and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as single-use 400 mg/vial solution for infusion (20 
mg/mL).  Tremelimumab solution for infusion is formulated in 20 mM histidine/histidine-HCl, 222 
mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM disodium edetate dihydrate, pH 
5.5. 
 
Preparation: Tremelimumab solution for infusion must be diluted prior to administration.  Allow the 
required number of vials to equilibrate to room temperature for 30 minutes.  Do not shake the vials.  
To prepare the infusion solution add the dose volume of tremelimumab to an infusion bag containing 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix by gentle inversion to 
ensure homogeneity of the dose in the bag.  The final concentration must be between 0.10 mg/mL to 
10 mg/mL.  Polycarbonate syringes should not be used with tremelimumab.  Saline bags must be 
latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (eg, polyethylene), 
manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP free. 
 
Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze. 
 
If a storage temperature excursion is identified, promptly return tremelimumab to between 2-
8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going.  Total in-use storage time from needle 
puncture of tremelimumab vial to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2-8°C (36-46°F). If there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. 
 

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Route of Administration: IV infusion 
 
Method of Administration: Infuse over approximately 60 minutes using IV infusion lines made of 
PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or polyethylene or polyurethane.  All DEHP-
containing or DEHP-free lines are acceptable.  IV lines should contain a 0.22 or 0.2 μm in-line 
filter.  The in-line filter can be made of polyethersulfone or polyvinylidine fluoride. IV lines 
containing cellulose-based filters should not be used with tremelimumab.  Flush the IV line with 
a volume of normal saline equal to the priming volume of the infusion set used at the completion 
of infusion.  Do not co-administer other drugs through the same infusion line. 
 
 
Availability 
 
Tremelimumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
 
Tremelimumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied investigational agents for the 
study should be ordered under the name of one lead participating investigator at that 
institution.  
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 

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8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.4 Investigator Brochure Access for CTEP IND agents 
 
The current version of the Investigator Brochure (IB) will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status,  a 
“current” password, and active person registration status.  Questions about IB access may 
be directed via email to IBcoordinator@mail.nih.gov or by phone (240) 276-6575 
Monday through Friday between 8:30 am and 4:30 pm (ET). 
 
 
8.1.4.1 
Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP  IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Introduction 
Correlative sciences will include mandatory pre treatment biopsies or archival tissue in all 
patients to use immunohistochemistry to analyze PD-L1 expression by immunohistochemistry as 
well as infiltration of CD3+, CD4+, CD8+ T-cells as a predictor of response to combined 
checkpoint blockade either alone or in combination with lower or higher dose radiation.  The 
biopsies should be taken from the lesion that will be irradiated in the colorectal cohort (cohort 2), 
and this is also encouraged in the lung cancer cohort (cohort 1), although not mandatory. 
Although not mandatory in all patents, repeat biopsies should be obtained in cohort 1 patients 
that receive liver directed radiation therapy.  
 

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Additional biopsies following cycle 2 are required of the irradiated lesion in patients with 
colorectal cancer (cohort 2) to evaluate the effect of radiation on the tumor microenvironment.  
In both cohorts, additional biopsies taken outside of the radiation field before and after radiation 
treatment are encouraged when feasible to evaluate abscopal effects on the molecular and 
cellular level.  
 
Exploratory studies will also be performed on biopsy tissue to examine the relationship between 
mutational burden and outcome and also correlate the transcriptome with protein expression and 
evaluate tumor cell composition with flow cytometry. Mutiplex immunofluorescence will be 
used to evaluate spatial relationships between immunologic factors in the tumor 
microenvironment. Peripheral blood will be obtained before treatment and after one cycle of 
study treatment for cytokine and PBMC analyses.  
 
Assays will be conducted by the Cancer Immune Monitoring and Analysis Centers 
(CIMAC), supplemented by assays performed at DFCI and UC Davis Medical Center. The 
following is a summary of assays and scientific objectives that will be performed on the samples 
collected from this study as approved by the CIMAC leadership: 
 
 
 
Priority 
Biomarker Name 
 
Assay 
(CLIA: Y/N) 
Use in protocol (Integral, 
Integrated or exploratory?)  
Purpose 
Sample types and Time points of 
sample collection 
Mandatory
optional?  
1 
PD-L1 
IHC 
(CLIA: Y) 
x Integrated 
x To identify biomarkers 
of response 
Tumor FFPE  
Baseline, On 
treatment 
M 
2 
Tumor Immune 
phenotyping / spatial 
analysis 
Multiplex IF  
(CLIA: N) 
x Integrated (CD3, CD8) 
and Exploratory 
x Hypothesis generating 
Tumor FFPE 
 
Baseline, On 
treatment 
Optional 
3 
Transcriptome analysis  
RNAseq 
(CLIA: N) 
x Exploratory 
x Hypothesis generating 
Tumor Frozen 
 
Baseline, On 
treatment 
Optional 
4 
WES 
NGS 
(CLIA: N) 
x Exploratory 
x Hypothesis generating 
Tumor, PBL 
 
Baseline, On 
treatment 
Optional 
5 
Circulating immune 
populations 
CyTOF 
(CLIA: N) 
x Exploratory 
x Hypothesis generating 
PBL 
Baseline, On 
treatment 
Optional 

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Priority 
Biomarker Name 
 
Assay 
(CLIA: Y/N) 
Use in protocol (Integral, 
Integrated or exploratory?)  
Purpose 
Sample types and Time points of 
sample collection 
Mandatory
optional?  
6 
Circulating cytokines/  
O-Link 
(CLIA: N) 
x Exploratory 
x Hypothesis generating 
Plasma 
Baseline, On 
treatment 
Optional 
 
 
 

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Additional exploratory mIF analyses will be performed at DFCI, and RNAseq / TCRseq of 
colorectal cohort patients is performed at UC Davis.   
Prioritization 
Given the range of correlative studies proposed for this protocol, there may not be enough tissue 
/ blood to perform all the analyses proposed.  Therefore, the studies will be prioritized as 
follows:  
 
PBMCs 
- 
Whole exome sequencing to determine mutational burden and neoantigen detection 
(normal blood control for tumor samples) 
- 
CyTOF for quantification, immunophenotyping, and functional assessment of PBMCs  
- 
Olink evaluation of plasma for systemic cytokine / chemokine signatures 
 
TISSUE  
- 
IHC to determine intratumoral and stromal PD-L1 (CD274)  
- 
Multiplex IF to score the tumor microenvironment for integrated expression of 
immunologic biomarks 
- 
Whole exome sequencing to determine mutational burden and neoantigen detection 
- 
RNAseq to evaluate infiltrating immune cells population, immune gene signatures and 
neoantigen expression  
 
Rationale 
Because responses to immune checkpoint blockade vary across disease types and generally only 
occur in a minority of patients, identifying patients that derive long-term benefit would be of 
significant benefit. We plan to perform in depth immunological analysis of patient blood and 
tumor samples to identify predictive biomarkers.  Additionally, a major goal of this study is to 
identify the impact of adding radiotherapy to immune checkpoint blockade; therefore, this sudy 
incorporates serial tissues samples pre- treatment, and during therapy when feasible. The design 
of this study allows us to compare immune mechanisms pre- to post-therapy.  These studies will 
also help us evaluate the immunomodulatory effects of different doses of radiotherapy in 
combination with dual checkpoint blockade.    
 
PD-L1 expression,– integrated biomarker  
Tumor PD-L1 expression has been linked to response rates of PD-1 checkpoint blockade[80].  
Response to dual blockade of the PD-1 and CTLA-4 checkpoint may be less dependent on PD-
L1 expression[60].  Pre-clinical data suggests that radiotherapy may upregulate intratumoral PD-
L1 expression[40] but little is known about the dose response of these effects.  Additionally little 
is known about how the pattern of expression (i.e tumor cells vs. infiltrating immune cells) 
affects response.  According to a recent publication[69] roughly 50% of NSCLCs express PD-L1 
in tumor cells and 50% in tumor infiltrating immune cells.  About 15% of CRCs express PD-L1 
in tumor cells but about 50% in tumor infiltrating immune cells.  Data presented at ASCO and 
SITC indicate that MEDI4736monotherapy response rates in NSCLC are 27% in PD-L1 positive 
tumors and 5% in PD-L1 negative tumors.  In patients with dual checkpoint blockade 
(MEDI4736+ tremelimumab) the response rate was 35% in PD-L1 positive tumors and 22% in 
PD-L1 negative tumors. The purpose of these studies is to investigate if PD-L1 expression as a 
biomarker of response in patients treated with radiotherapy + dual checkpoint inhibition and to 

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evaluate the effects of radiotherapy + dual checkpoint inhibition on PD-L1 expression. We 
hypothesize that patients with detectable PD-L1 expression will be more likely to respond to 
therapy.  We further hypothesize that PD-L1 expression will increase after radiotherapy and 
patients who upregulate PD-L1 after radiotherapy will be more likely to respond to therapy. 
 
 
Spatial quantification of the tumor microenvironment  
As described above, based on prior preliminary studies conducted in patients across several 
disease types, PD-L1 expression and greater numbers of infiltrating lymphocytes may predict 
response to PD-1 / PD-L1 inhibitors in certain settings [70, 84-86]. However, the biologic 
activity of PD-1 / PD-L1 inhibitors suggest that expression of PD-1 on tumor-infiltrating 
lymphocytes and PD-L2 on tumor-infiltrating lymphocytes and tumor immune cells could also 
be valuable predictive biomarkers.  Additionally, spatial resolution may be of importance; co-
localization of multiple protein biomarkers on the surface of tumor cells or tumor-infiltrating 
lymphocytes could add extra diagnostic and predictive value, especially when the amount of 
tissue available for analysis is limited.  
 
While traditional immunohistochemistry generally only allows for the evaluation of one or two 
proteins at a time, multiplex immunofluorescence simultaneously evaluates expression and 
provides more quantifiable spatial resolution for multiple biomarkers.  Our initial work has 
demonstrated the reproducibility and feasibility of this technique in identifying various 
populations of tumor infiltrating lymphocytes, as well as PD-L1 expressing tumor cells and PD-
L1 and PD-1 expressing by infiltrating lymphocytes.  
 
In recent studies across multiple patient cohorts of NSCLC patients roughly 25% of patients have 
low TILs (score 0-1), intermediate TILs (score 2), or high TILs (score 3) [81].  For analysis as a 
prognostic biomarker some studies have further grouped patients in to low (0-2) and high (3) 
TILs [82]. In colorectal cancer approximately 42% of patients have high TILs in the tumor 
stroma but 77% at the infiltrating margin [83].  TILs and a T-cell inflamed phenotype have also 
been linked with response to CTLA-4 checkpoint blockade in melanoma[73, 74].  Exclusion of 
T-cells in the tumor microenvironment has also been linked with lack of response to checkpoint 
inhibition[75] with down-regulation of CCL4 mediated dendritic cell recruitment as one 
potential mechanism[75].  RT has been demonstrated to induce TILs[45] and may potentially 
overcome this mechanism of resistance to checkpoint blockade. Our unpublished data suggests 
that RT can induce CCL4 expression and increase TILs. These studies will examine the density 
and subtype of TILS using markers such as CD3, CD4, and CD8. The purpose of these studies is 
to examine if high or low dose radiotherapy in combination with dual checkpoint blockade can 
increase the immunologic infiltrate and to examine T-cell exclusion as a mechanism of resistance 
to checkpoint blockade. We hypothesize that patients with baseline high TILs and patients with 
increased TILs after radiotherapy will be more likely to respond to therapy. 
 
 
Mutational Burden 
Mutational burden and antigenic load are thought to represent a surrogate for tumor antigenicity 
and have been linked with response to checkpoint blockade in NSCLC[76].  The purpose of 

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these studies is to examine mutational load as a biomarker of response to radiotherapy + dual 
checkpoint inhibition and to define potential tumor antigens. 
 
RNA seq 
The purpose of these studies will be to examine the intratumoral and peripheral gene signatures 
and correlate with treatment outcomes in a hypothesis generating manner.  Genes examined will 
include cytokines, chemokines, markers of T-cell exhaustion, and canonical pathways of immune 
activation or suppression including indolamine 2,3 dioxygenase. RNAseq will be used to identify 
infiltrating immune cell populations using deconvolution techniques and also confirm expression 
of predicted neoantigens. 
 
CyTOF 
The purpose of these studies will be a detailed examination of immune cell subsets and 
functionality in the periphery and in the tumor and to correlate these readouts with treatment 
response in a hypothesis generating manner. 
 
Olink 
The purpose of these studies will be to examine systemic cytokine and chemokine signatures pre- 
therapy and during therapy and to correlate these readouts with treatment response in a 
hypothesis generating manner.   
 
Methods: 
 
Sample allocation 
IHC and multiplex immunofluorescence will be performed by the DFCI CIMAC Tissue 
Biomarker Lab led by Dr. Scott Rodig.  Tumor core biopsies will be fixed in 10% neutral 
buffered formalin and paraffin embedded according to standard protocols.  If sufficient tissue is 
available an aliquot will be placed in RNAlater and flash frozen for batched RNA extraction and 
analysis (TCRseq  and RNAseq). Optional: If sufficient tissue is available for biopsies a sample 
will be placed in RPMI media and brought to the laboratory of cancer immunology for 
immediate processing into a single cell suspension and stained for flow cytometry. Blood 
samples will be separated into PBMCs and plasma.  Plasma will be snap frozen and stored at -80 
for batched analysis of systemic cytokine/chemokines.  An aliquot of PBMCs will be 
cryopreserved in cryostor10 solution for batched DNA extraction and flow cytometry.   
 
PD-L1 expression, integrated biomarker 
Biopsies will be obtained as described above. Formalin fixed-paraffin embedded (FFPE) tumor 
slides will be prepared and H&E stained.  PD-L1 staining will be performed on tumor and 
stromal cells. Depending on tissue availability, additional immunologic subsets may also be 
delineated with IHC to complement the findings in regards to PD-L1 expression and TILs using 
some or all of the following antibodies: PD-1, PD-L2, CD68, Ki67, CD25, FoxP3, Indoleamine 
2,3 deoxygenase-1 (IDO1), CD11c, CD83, CD86, CD56, CD14, CD16, TIM-3, Lag-3, and Tie2.  
 
We have recently developed immunohistochemical staining on paraffin embedded tissues for 
immunologic markers such as PD-L1, PD-L2, and PD-1 through the DFCI CIMAC pathology 
lab (Scott Rodig, M.D., Ph.D. Core Director). PD-L1 IHC has recently been established in a 

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CLIA approved laboratory. We have published the methods, protocols, and data establishing the 
sensitivity and specificity of immunohistochemical staining (IHC) assays using the monoclonal 
antibodies recognizing PD-L1 (CD274, B7-H1) and other antibodies mentioned above including 
the standard CD3, CD4, and CD8 lymphocyte markers in several recent manuscripts[78, 79, 87-
89].  
 
Following chromogenic IHC for PD-L1 we will score the percentage of cells staining positively 
for PD-L1. In addition, an intensity score, reflecting the average positive staining intensity on a 
0-3 scale will be determined and used to calculate a modified H-score (range 0-300).  
 
Publications to date have determined various cut-points as the optimal for predicting clinical 
response to immune checkpoint therapy (1%, 5%; 50%).  We examine these cut-points in an 
initial examination of our data.  The percentage of positive staining cells and the modified H-
score will also be analyzed as continuous variables for optimized thresholds as exploratory 
endpoints.   
 
  
Spatial quantification of the tumor microenvironment  
In addition to PD-L1 and tumor infiltrating lymphocytes, other immune markers such as PD-L2 
and CD68 may also indicate tumor mediate immune regulation and could also predict response 
to immune therapy either alone or in conjunction with other markers. Additionally, while 
traditional immunohistochemistry generally only allows for the evaluation of one or two proteins 
at a time, multiplex immunofluorescence (IF) simultaneously evaluates expression and provides 
more quantifiable spatial resolution for multiple biomarkers.  Our initial work has demonstrated 
the reproducibility of this technique in identifying various populations of tumor infiltrating 
lymphocytes, as well as PD-L1 expressing tumor cells and PD-L1 and PD-1 expressing 
infiltrating lymphocytes; therefore we propose to use multiplex IF to explore associations 
between response and expression of PD-1/PD-L1 in the tumor versus tumor/stroma interface, as 
well as co-localized PD-L1 / PD-1 expression.  
 
 
 
Mutational Burden 
WES will be performed by DFCI CIMAC Translational Immunogenomics Lab led by Dr. 
Catherine Wu according to CIMAC approved protocols.   
 
RNA seq 
RNA extraction and integrity will be performed by DFCI CIMAC Translational 
Immunogenomics Lab led by Dr. Catherine Wu and by UC Davis under the direction of Dr. Arta 
Monjazeb.  
 
CyTOF.  
The DFCI CIMAC Immune Assessment Lab led by Mariano Severgnini and Emily Thrash 
offers CyTOF; a single-cell proteomic technology that allows for the analysis of 40+ cellular 
parameters using antibodies tagged with heavy metal isotopes to elucidate complex phenotypic 
and functional characteristics of heterogeneous immune populations. The CIMACs will 

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offer CyTOF analysis for PBMC samples using a standardized panel of over 30 markers, 
delineating immune populations as well as their activation status and checkpoint marker 
expression. Current panel design is under validation across CIMAC centers and includes 14 
immunological core markers (https://cimac-network.org/cytof/). The 10021 panel is likely to 
evaluate the differential effects of treatment arms on the frequency of CD8, CD4 T cells, 
regulatory T cells, B cells, NK cells, and myeloid cell subsets including dendritic cells, 
basophils, and neutrophils, in addition to changes in functional markers (memory, activation, 
chemokine receptors related to Th1/Th2/Th17, costimulatory markers such as ICOS and 
coinhibitory markers such as LAG3, TIM3) across time points. The samples will be run on 
a CyTOF2 mass cytometer (Fluidigm) and analyzed at DFCI scientists using tools such as 
Cytobank and Astrolabe.  
 
 
 
Olink 
The Mt Sinai CIMAC led by Sacha Gnjatic will perform Olink. The Proseek Olink Proteomics 
platform operating on a Fluidigm Biomark HD microfluidic PCR system is a quantitative and 
reproducible assay to measure levels of molecules related to cytokines, chemokines and growth 
factors, and in addition this platform also allows detection of circulating immune co-stimulatory 
and inhibitory molecules, and other relevant immune-oncology markers, in a 92-plex format. The 
assay can be applied to peripheral serum or plasma, as well as tissue culture supernatants, and 
requires only 1 microliter of sample. Mount Sinai-CIMAC is the first center in the US that has 
been trained and certified to perform these assays in house. The Proximity Extension Assay 
(PEA) technology that underlies these assays relies on dual antibody recognition and 
incorporates several innovative QC steps (including three different external controls and two 
internal controls) to evaluate each step of the assay protocol, resulting in an extremely robust 
assay.  
 
 
 
9.1 
Integrated Correlative Studies 
 
9.1.1 PD-L1 expression,  
 
PD-L1 expression has demonstrated variable utility as a predictive marker in the setting of 
immune checkpoint blockade and may be impacted by local radiotherapy.  We hypothesize that 
there will be a correlation between PD-L1 expression levels and response as well as a potential 
increase in the setting of localized radiotherapy. Similarly, we predict that increased T-cell 
infiltration into the tumor microenvironment will predict for response to therapy.   
 
9.1.1.1 
Collection and Handling of Specimen(s) 
 
Immunohistochemical staining of PD-L1, CD3, CD4 and CD8 will be used as integrated markers 
in the clinical trial, which could be used in future trials to identify a group of patients who would 
have a good response to the treatment as a stratification variable. Tumor specimens will be 
collected at baseline in patients enrolled on both cohorts.  Pre-treatment archived specimens will 

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be retrieved if no fresher tissue can be obtained prior to treatment initiation on day 1. Post-
treatment tissues will be collected and fixed by 10% neutral buffered formalin overnight, 
dehydrated and paraffin embedded. Four-micrometer-thick sections will be cut. The paraffin 
blocks and unstained slides will be stored at room temperature. All IF staining will be performed 
in the Center for Immuno-Oncology Pathology Core at Dana-Farber/Harvard Cancer Center 
Specialized Histopathology Core, which will be a central research laboratory for this multiple-
center clinical trial. Unstained slides from other centers will be shipped to Dr Evisa Gjini, Thorn 
building 603B, Brigham and Women Hospital, 75 Francis Street, Boston, MA, 02215. 
 
 
 
9.1.1.2 
Site(s) Performing Correlative Study 
 
Laboratory information 
The IHC staining will be conducted in the DFCI CIMAC Tissue Biomarker Lab, a research 
laboratory with GLP standard by Dr. Scott Rodig, who is a hematopathologist at the Brigham 
and Women’s hospital with prior expertise evaluating PD1, PDL1 and other immunologic 
markers in paraffin embedded tumor samples [92]. 
 
 
 
9.2 
Exploratory/Ancillary Correlative Studies 
 
9.2.1 Monitoring Peripheral Blood for Changes in Immune Function  
 
Correlative sciences will be expanded from our previously determined biology of patients treated 
with both radiation and immune checkpoint blockade.  Subpopulations of PBMCs will be 
isolated, including but not limited to dendritic cells, T cells,  B cells, and CD4+Ki67+, 
CD8+Ki67+, CD4+ICOS+, CD8+ICOS+. populations. Phenotype changes in these cell 
populations by CyTOF will be determined as a function of treatment. These include regulatory 
and effector immune panels, naïve and memory CD4, CD8 and NK lymphocyte populations. 
Given its importance in immune regulation and association, we will evaluate Tie-2 expressing 
monocytes (TEM).  
 
 
9.2.1.1 
Collection and handling of Specimen(s) 
 
Serial blood/plasma samples will be collected at baseline and then prior to cycle 2. A panel of 
cytokines and chemokines will be tested in plasma using Olink. Absolute lymphocyte count 
(ALC) will be monitored.  
Peripheral blood mononuclear cells (PBMCs) will be collected from whole blood to assess 
immune cell populations. PBMCs will be cryoforzen and plasma will be snap frozen for batched 
analysis.  CyTOF will be performed in order to identify different T cell populations, their 
activation status, and the production of different cytokines as well as other immune cell 
populations 
 

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9.2.1.2 
Site(s) Performing Correlative Study 
 
Laboratory information 
CyTOF will be performed by the DFCI CIMAC Immune Assessment Lab led by Dr. Stephen 
Hodi, Mariano Severgnini and Emily Thrash.  Olink will be performed at the Mt. Sinai CIMAC 
led by Dr. Sacha Gnjatic.  
 
9.2.2 Spatial quantification of the tumor microenvironment 
 
We hypothesize that co localization of multiple immune markers including PD-L1, PD-L2, PD-
1, CD3, and CD8 will be associated with favorable response.  We also predict that in the 
colorectal cohort, these factors will be influenced by either low or high-dose radiation.  
 
 
9.2.2.1 
Site(s) Performing Correlative Study 
 
Laboratory information 
The IF staining will be conducted in the DFCI CIMAC Tissue Biomarker Lab, a research 
laboratory with GLP standard under the direction of Dr. Scott Rodig a hematopathologist at the 
Brigham and Women’s hospital with prior expertise evaluating PD1, PDL1 and other 
immunologic markers in paraffin embedded tumor samples [92]. 
 
 
9.2.3 Sequencing of DNA and RNA  
 
Previous studies have suggested that mutational burden may predict for response among patients 
treated with PD-1 or CTLA-4 inhibitors.  Tissue collected from mandatory biopsies in 
conjunction with sequencing performed on peripheral blood will determine mutational burden to 
correlate with response and also RNA expression to better correlate the tumor microenvironment 
and associate with IHC and IF protein expression data.  
 
9.2.3.1 
Collection and handling of Specimen(s) 
 
Tumor specimens will be collected at baseline in patients enrolled on both cohorts.  Pre treatment 
archived specimens will be retrieved if no fresher tissue can be obtained prior to treatment 
initiation on day 1. Post treatment tissues will be collected and fixed by 10% neutral buffered 
formalin overnight, dehydrated and paraffin embedded. Four-micrometer-thick sections will be 
cut. The paraffin blocks and unstained slides will be stored at room temperature.  
 
9.2.3.2 
Site(s) Performing Correlative Study   
 
Laboratory information 
The sequencing will be conducted in the DFCI CIMAC Translational Immunogenomics Lab and 
UC Davis Comprehensive Cancer Center under the direction of Dr. Arta Monjazeb, a research 

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laboratory under the direction of Dr. Catherine Wu  and Dr. Monjazeb have extensive prior 
experience evaluating sequencing and RNA expression data.  
 
9.3.   Electronic Collection of PRO-CTCAE data  
 
Site users of ePRO and the Patient Cloud require the same access as those using Rave. Access to 
the trial in the Patient Cloud is granted through the iMedidata application to all persons with the 
appropriate roles assigned in Regulatory Support System (RSS). 
 
Site users are referred to the Medidata Learning Tool for reference information on Patient Cloud 
ePRO for CRAs.  
 
Patient will view the survey questions on his/her device. The patient will have a window of 48 
hours to complete the survey. Once the patient hits the submit button, the questions will no 
longer be on his/her device and will be directly sent to the RAVE database and available to the 
site CRAs for compliance monitoring. 
 
 

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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <5 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  Note that all study visits in the calendar are specified by 
week, but should be performed on the same day of the week when feasible and every effort 
should be made to schedule them +/-2 days.    
 
Cohort 1 – Non small cell lung cancer  
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13-
52 
Off 
Treatmentc 
MEDI4736(durvalumab) 
 
A 
 
 
 
A 
 
 
 
A 
 
 
 
Ae 
 
Tremelimumab 
 
B 
 
 
 
B 
 
 
 
B 
 
 
 
Be 
 
Radiation therapy 
 
 
C 
 
 
 
C 
 
 
 
C 
 
 
Ce 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE Assessmentsm 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Medical history 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
 
Concurrent medsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Vital signsp 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
CBC w/diff, plts 
X 
X k 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Serum chemistrya 
X 
X k 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
EKGj  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C and HIVn 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor measurements 
X 
 
Tumor measurements should be performed during week 7 or 8 and then repeated 
every 12 weeks +/- 5 days.  Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
 
Radiologic evaluation l 
X 
 
Radiologic measurements should be performed during week 7 or 8 and then every 12 
weeks +/- 5 days while on treatment . 
Xo 
B-HCG 
Xb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
Xe 
Head MRI dh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
Research blood samples 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy of site(s) of disease 
Xf 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
PRO-CTCAEq 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 

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A: 
MEDI4736(durvalumab): Administered intravenously at a dose of 1500mg every 4 weeks for a maximum of 13 doses.  
B: 
Tremelimumab: Administered intravenously at a dose of 75mg  every 4 weeks for a maximum of 4 doses.  
C:    Radiation therapy: Administered only on week 2 for Arm A(high dose radiation) and every 4 weeeks for a maximum of 4 times in Arm B 
(low dose radiation)  
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. Also amylase, creatinine clearance, gamma glutamyltransferase, lipase, and 
magnesium, CPK, TSH. Free T3 or free T4 also measured if TSH is abnormal or if there is clinical suspicion of an AE related to the 
endocrine system. .  
b: 
Serum pregnancy test (women of childbearing potential). Women of child-bearing potential must have a negative serum beta-HCG 
pregnancy test during screening and a negative urine beta-HCG pregnancy test within 24 hours of starting treatment. 
c: 
Every 12 weeks during weeks 12-52 and then 30,60, 90 days after discontinuation  
d:      Every 12 weeks 
e:      Every 4 weeks 
f:       Archival tissue may be used in place of biopsy in this cohort.  
g:      To be performed week 7 or 8. Optional in patients with irradiated lesions outside the liver.  For patients who receive radiation to the liver, 
this second biopsy is required unless unsafe to perform.  
h:      Head CT may be substituted for MRI if patient cannot tolerate MRI. Subsequent MRI’s to be performed only if previously treated brain 
metastases or when clinically indicated.  
i:       At baseline (screening) and then as clinically indicated.  
j:      Abnormal findings should be repeated and require appropriate clinical evaluation. Normal EKGs do not require repeating. 
k:      If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 
1 
l:       CT Chest, Abdomen, and Pelvis (CAP) 
m:     During scheduled history and physical exams and during monitoring of AE’s, attention should be paid to the side effects resulting from 
radiation and any potential enhancement of these due to the administration of immunotherapy.    
n: Negative serologies over the preceding year may replace screening study 
o:  when off treatment for reasons other than progression after week 7-8, until week 52. 
p: Vital signs timepoints for infusions are pre-dose, every 30 minutes; post-dose 30 and 60 minutes (+/- 10 minutes) 
q:  PRO-CTCAE items to be completed at baseline, every 2 weeks for 8 weeks and then every 4 weeks for a total of 8 cycles. All patients on 
any arm of study will answer the same list of PRO-CTCAE questions. 
 
 
 
The following visits and assessments are required after discontinuing study treatment: 
Days following discontinuation: 
30, 60 and 90 days (+/-5 days): physical exam, vital signs, body weight, CBC with diff, serum 
chemistriesa, pregnancy test for WOCB (urine or serum) AE/SAE assessments, concurrent 
medications, and performance status 
 
 
Cohort 2 – Colorectal cancer  
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13-
52 
Off 
Treatmentc 
MEDI4736(durvalumab) 
 
A 
 
 
 
A 
 
 
 
A 
 
 
 
A 
 
Tremelimumab 
 
B 
 
 
 
B 
 
 
 
B 
 
 
 
B 
 
Radiation therapy 
 
 
C 
 
 
 
C 
 
 
 
C 
 
 
C 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE Assessmentsl 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Medical history 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
 
Concurrent medsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Vital signsp 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 

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Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
CBC w/diff, plts 
X 
X h 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
Serum chemistrya 
X 
X h 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
X 
EKGf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C and HIVm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor measurements 
X 
 
Tumor measurements should be performed during week 7-8 and then repeated every 
12 weeks +/- 5 days.  Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
 
Radiologic evaluationk 
X 
 
Radiologic measurements should be performed during week 7 or 8 and then every 12 
weeks +/- 5 days while on treatment. 
Xo 
B-HCG 
Xb 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xe 
Xe 
Research blood samples 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy of site(s) of disease 
Xi 
 
 
 
 
 
 
Xj 
 
 
 
 
 
 
 
PRO-CTCAEq 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
A: 
MEDI4736(durvalumab): Administered intravenously at a dose of 1500mg every 4 weeks for a maximum of 13 doses.  
B: 
Tremelimumab: Administered intravenously at a dose of 75mg  every 4 weeks for a maximum of 4 doses.  
C:    Radiation therapy: Administered only on week 2 for Arm A ( high dose radiation) and every 4 weeeks for a maximum of 4 times in ARM B 
(low dose radiation)  
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. Also Also amylase, creatinine clearance, gamma glutamyltransferase, lipase, and 
magnesium,CPK, TSH. Free T3 or free T4 also measured if TSH is abnormal or if there is clinical suspicion of an AE related to the 
endocrine system..  
b: 
Serum pregnancy test (women of childbearing potential). Women of child-bearing potential must have a negative serum beta-HCG 
pregnancy test during screening and a negative urinebeta-HCG pregnancy test within 24 hours of starting treatment. 
c: 
Every 12 weeks during weeks 12-52 and then 30,60, 90 days after discontinuation   
d:      Every 12 weeks  
e:      Every 4 weeks 
f:      At baseline (screening) and then as clinically indicated.  
g:     Abnormal findings should be repeated and require appropriate clinical evaluation.Normal EKGs do not require repeating. 
h:      If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at 
Day 1. 
i:       Archival tissue may be used in place of biopsy in this cohort.  
j.      To be performed week 7 or 8. Optional in patients with irradiated lesions outside the liver.  For patients who receive radiation to the liver, 
this second biopsy is required unless unsafe to perform. 
k:       CT Chest, Abdomen, and Pelvis (CAP) 
l::     During scheduled history and physical exams and during monitoring of AE’s, attention should be paid to the side effects resulting from 
radition and any potential enhancement of these due to the administration of immunotherapy.    
m: Negative serologies over the preceding year may replace screening study 
o: when off treatment for reasons other than progression after week 7-8, until week 52. 
p: Vital signs timepoints for infusions are pre-dose, every 30 minutes; post-dose 30 and 60 minutes (+/- 10 minutes) 
q:  PRO-CTCAE items to be completed at baseline, every 2 weeks for 8 weeks and then every 4 weeks for a total of 8 cycles. All patients on 
any arm of study will answer the same list of PRO-CTCAE questions. 
 
 
 
The following visits and assessments are required after discontinuing study treatment: 
Days following discontinuation: 
30, 60 and 90 days (+/-5 days): physical exam, vital signs, body weight, CBC with diff, serum 
chemistriesa, pregnancy test for WOCB (urine or serum) AE/SAE assessments, concurrent 
medications, and performance status. 
 

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Table  
Urinalysis 
Urinalysis should be done at baseline (screening) and then as clinically indicated 
Bilirubin 
Ketones 
Blood 
pH 
Color and appearance 
Protein 
Glucose 
Specific gravity 
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high 
power field for red blood cells.  
 
 

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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 12 weeks after 
an initial scan at 7-8 weeks to guide further therapy. In addition to a baseline scan, confirmatory 
scans should also be obtained 6-8 weeks following initial documentation of objective response. 
 
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) [Eur J Ca 45:228-247, 2009].  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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with MEDI4736and tremelimumab. 
 
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.)  
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 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 ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  In this protocol radiation is being tested for its ability to potentiate systemic 
immune therapy.  Therefore, none of the irradiated lesions will be considered measurable 
for the determination of systemic response.  However, local response within in the 
irradiated field will be assessed as below.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 

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lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. Note: When evaluable, response of irradiated lesions will be 
tracked, but these lesions will not count as target lesions when determining systemic 
response.  
 
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.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 

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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. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) 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.  
 
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.  
 
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 (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), 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. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 

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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. 
 
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. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
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. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 

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scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
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 (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum 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 (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
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 
[<1 cm] 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. 
 

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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). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Confirmation is required for this trial. 
***  In exceptional circumstances, unequivocal progression in non-target 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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
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 

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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 
 
11.1.5 Duration of Response 
 
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. 
 
 
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.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
 
N/A 
 
11.2 
Antitumor Effect – Hematologic Tumors 
 
N/A 
 
11.3 
Other Response Parameters 
 
11.3.1 Definition of Tumor Response Using Immune-Related Response Criteria (irRC) 
 
irRC will be used as a secondary endpoint in comparison to the primary endpoint of response as 
per RECIST v1.1 
 
The sum of the longest diameter of lesions (SPD) at tumor assessment using the immune-related 
response criteria (irRC) for progressive disease incorporate the contribution of new measurable 
lesions.  Each net Percentage Change in Tumor Burden per assessment using irRC criteria 
accounts for the size and growth kinetics of both old and new lesions as they appear. 
 

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11.3.2 Impact of New Lesions on irRC 
 
New lesions in and of themselves do not qualify as progressive disease.  However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response.  Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
 
11.3.3 Definition of Target Lesions Response Using irRC 
 
x irComplete Response (irCR): Complete disappearance of all target lesions.  This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
x irPartial Response (irPR): Decrease, relative to baseline, or 50% or greater in the sum of the 
products of the two largest perpendicular diameters of all target and all new measurable target 
lesions (i.e., Percentage Change in Tumor Burden).  Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as progressive 
disease until the SBD increases by >25% when compared to SPD at nadir. 
x irStable Disease (irSD): Does not meet criteria for irRC or irPR, in the absence of progressive 
disease. 
x irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e. 
taking SPD of all target lesions and any new lesions) when compared to SPD at nadir. 
 
11.3.4 Definition of Non-Target Lesions Response Using irRC 
 
x irComplete Response (irCR): Complete disappearance of all non-target lesions.  This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
x irPartial Response (irPR) or irStable Disease (irSD): Non-target lesion(s) are not considered 
in the definition of PR; these terms do not apply. 
x irProgressive Disease (irPD): Increases in number or size of non-target lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases by 
25% (i.e. the SPD at nadir of the target lesions increases by the required amount). 
 
11.3.5 Definition of Overall Response Using irRC 
 
Overall response using irRC will be based on these criteria: 
 
x Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks 
from the date of documentation of complete response. 
x Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all target lesions is measured and captured as the SPD baseline.  At 
each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target 
lesions and of new measurable lesions are added together to provide the Immune Response Sum 
of Product Diameters (irSPD).  A decrease, relative to baseline, of the irSPD compared to the 
previously SPD baseline of 50% or greater is considered an irPR. 
x Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive disease 

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x Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm 
PD by serial imaging.  Any of the following will constitute PD: 
 At least 25% increase in the SPD of all target lesions over baseline SPD calculated for the target 
lesions. 
 At least 25% increase in the SPD of all target lesions and new measurable lesions (irSPD) over 
the baseline SPD calculated for the target lesions. 
 
Criteria for determining overall response by irRC are summarized as follows: 
 
 
11.3.6 Immune-Related Best Overall Response Using irRC (irBOR) 
 
irBOR is the best confirmed overall response over the study as a whole, recorded between the 
date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study.  For the 
assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks 
after the criteria for response are first met. 
 
11.3.7 Local response is defined as irRC applied to the irradiated lesions.  This is not applicable 
in the case of an irradiated bone lesion.  
 
11.3.8 Abscopal response rate  
Abscopal response is defined as described previously [51] to be a decrease in the longest 
diameter of at least 30% in any measurable (>1cm) non-irradiated lesion from baseline. A 

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complete abscopal response is defined as the complete disappearance of a measurable non-
irradiated lesion and a partial abscopal response was defined as at least a 30% decrease in the 
longest diameter. Progressive disease in this context is defined as at least a 20% increase in the 
longest diameter of the best measurable non-irradiated lesion, whereas stable disease was defined 
as insufficient shrinkage or growth to qualify for a partial abscopal response or complete 
abscopal response or progressive disease. 
 
11.3.9 irRECIST 
irRECIST utilizes the principles of iRC described above except uses unidirectional 
measurements as opposed to bidirectional measurements.  This exploratory endpoint will also 
explore % change in the tumor burden as compared to baseline scan.  
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
The Protocol Principal Investigator will have, at a minimum, quarterly conference calls with the 
Study Investigators to review accrual, progress, and pharmacovigilance.  Decisions to proceed to 
the second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and 
the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site Investigator) on either the 

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LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab 
Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
 This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 

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Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
12.2.3 Data Submission for PRO-CTCAE assessments 
 
             Electronic collection of PRO-CTCAE through the ePRO is source documentation. The   
surveys are not stored on the devices. Rather, each survey is available for a window of 48 hours. 
Once the patient submits the survey, the responses go directly into the RAVE database and no 
longer are stored on the device. The site CRAs can access the RAVE workbench and see if the 
patient has completed all the questions and the date of completion. 
 
There are no other records to audit or review. 
 

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12.3 
CTEP Multicenter Guidelines 
 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 

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disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 

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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
 
13.1.1 Primary Endpoint:  The primary endpoint of this study is overall response rate as 
determined by RECIST 1.1.   
 
13.1.2 Secondary Endpoints:  Secondary endpoints include progression-free and overall survival, 
overall response according to irRC, and assessments of safety.  
 
Clinical laboratory tests, vital signs and weight measurements, physical exams, performance status 
evaluations, imaging scans and any other medically indicated assessments, including subject 
interviews, will be performed to detect new abnormalities and deteriorations of any pre-existing 
conditions.   
 
13.2 
Endpoint Definitions 
 
13.2.1 Primary Endpoint 
At each restaging, patients will be classified as achieving one of the following according to 
RECIST criteria: complete response (CR), partial response (PR), stable disease (SD), progressive 
disease (PD), or unevaluable for response, which includes early death from malignancy, toxicity, 
or other causes in addition to missing or unknown response. Best overall response will be 
calculated as the best response recorded from the date of randomization for each patient, taking as 
reference for progressive disease the smallest measurements recorded since the start of treatment. 
Objective response rate (ORR) is defined as the proportion of patients within a treatment arm who 
have a best response of either CR or PR. The denominator used to calculate ORR within a treatment 
will be the number of patients randomized to the respective treatment arm. All randomized patients 
will be used in randomized comparisons across arms.  For single arm evaluation of response, all 
patients who started treatment will be considered evaluable.  
 
13.2.2 Secondary Endpoints 
Progression-free survival (PFS): Time from date of randomization until objective disease 
progression (per RECIST) or death, whichever occurs first. For patients without progression, 
follow-up will be censored at the date of last adequate restaging, unless death occurs within 12 
weeks following the date last known progression-free, in which case the death will be counted as 
a PFS event. 
 
Overall survival (OS): Time from randomization to death from any cause. For patients lost to 
follow-up or who have no documentation of death at the time of final analysis, follow-up will be 
censored at the date of last assessment of vital status. 
 
Objective Response per Immune-Related Response Criteria (irORR):  The proportion of patients 
within a treatment arm who have a best response of irCR or irPR according to Immune-Related 
Response Criteria.  The denominator used to calculate irORR within each treatment will be the 

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number of patients randomized to the respective treatment arm.  
 
13.3 
Randomization 
 
13.3.1 NSCLC 
Patients enrolled in the NSCLC cohort will be randomly assigned in equal proportions to therapy 
with MEDI4736(durvalumab)/tremelimumab alone, MEDI4736(durvalumab)/tremelimumab with 
low-dose RT, or MEDI4736(durvalumab)/tremelimumab with high-dose RT.  Forty patients will 
be assigned to each of the three therapies (120 in total). 
 
13.3.2 Colorectal Cancer 
Patients enrolled in the colorectal cancer cohort will be randomly assigned in equal proportions to 
either MEDI4736(durvalumab)/tremelimumab with low-dose RT or MEDI4736(durvalumab)-
tremelimumab with high-dose RT. A total of 60 patients will be enrolled. 
 
For each disease cohort, the randomization will follow a permuted block scheme with random 
block sizes of 3 or 6 for cohort 1 and 2 or 4 for cohort 2. The randomization schemes will be 
developed by the trial statistician and coordinated via CTEP.  
 
13.4 
Sample Size/Accrual 
 
13.4.1 Sample Size  
 
NSCLC: Best overall response rate is the endpoint on which the sample size for cohort 1 is based.  
We estimate an overall response rate of approximately 5% for the combination of MEDI4736and 
tremelimumab alone based on a comparison of preliminary response rates from patients treated 
with dual checkpoint blockade of PD-1 and CTLA-4 (Hellman et al. ASCO 2016) as compared 
with PD-1 inhibitor monotherapy [6].  Two, pair-wise comparisons of therapy with high- or low-
dose radiation against the control of MEDI4736(durvalumab)/tremelimumab alone will be 
conducted.  Since a positive outcome for each comparison in this trial is the superiority of 
MEDI4736(durvalumab)/tremelimumab 
with 
high- 
or 
low-dose 
RT 
compared 
with 
MEDI4736(durvalumab)/tremelimumab alone, we propose one-sided chi-squared tests for the null 
hypothesis of equality of the response rates with a 10% type-I error for each comparison. To assess 
for early evidence of futility or superiority of MEDI4736(durvalumab)/tremelimumab plus RT, 
each pairwise comparison will be based on a group sequential design with O’Brien-Fleming 
stopping boundaries for superiority and Gamma family boundaries (gamma=1) for futility.   
 
When the total sample size in each comparison is 80 patients (40 per arm), a chi-squared test will 
have 81% power to detect a difference between a 5% response rate and 22% response rate.  Interim 
and final analyses will be conducted after 40 and 80 patients have objective response 
classifications (corresponding to 50% and 100% of the total information). The critical values  of 
the test statistic for superiority of MEDI4736(durvalumab)/tremelimumab with RT in each 
comparison for the interim and final analyses would be 2.054 and 1.317, corresponding to nominal 
significance  levels of 0.02 and 0.094, respectively. If the p-value at the interim analysis is greater 
than 0.463 (i.e., the test statistic is less than 0.0922), there will be insufficient evidence to reject 
 the null hypothesis and the trial for that comparison (and enrollment to the respective RT arm) 

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will stop early for futility. Under this design, the probability of stopping for futility at the  interim 
analysis is 0.56 if the null hypothesis is true. Sample size and power calculations were conducted 
using EaST 5.4.Note that enrollment to the MEDI4736(durvalumab)/tremelimumab-alone arm 
will continue as long as enrollment continues in at least one RT arm.   
 
Colorectal Cancer: Best overall response rate is the endpoint on which the sample size is based for 
cohort 2.  There is a low historical response rate in microsatellite stable colorectal cancer [14]; 
therefore, we will employ two, parallel, Simon optimal two-stage designs to identify therapy 
combinations worthy of further study in this patient population. A promising response rate in this 
population would be 20%.  Sixty patients will be randomly assigned to high-dose or low-dose 
radiotherapy plus MEDI4736(durvalumab)/tremelimumab (30 per therapy).  The high-dose and 
low-dose designs will be conducted separately.  Ten patients will be enrolled in the first stage for 
each therapy.  If there is at least one response among the first ten patients, then an additional 20 
patients will be enrolled to that treatment arm for a total of 30 patients in each comparison.  If four 
or more patients in a comparison have response then that treatment combination would be 
considered promising.  Each design has a type-I error of 5% (target alpha=0.10) and 80% power 
to detect a difference between a null rate of 5% and a promising response rate of 20%.  If the null 
hypothesis is true, the probability is 0.60 that accrual in that treatment arm will stop at the end of 
the first stage.  If the cohort combining LDFRT is stopped early for futility, we will review the 
data and possibly amend the protocol at that time.  
 
 
 
13.5 
Accrual 
The projected accrual to this trial is approximately 6 non-small cell lung cancer patients and 3 
colorectal cancer patients per month.   We estimate that 24 months will be required to complete 
study accrual. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
5 
5 
0 
0 
10 
Asian 
5 
5 
0 
0 
10 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
15 
15 
5 
5 
40 

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Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
White 
40 
40 
10 
10 
100 
More Than One Race 
5 
5 
5 
5 
20 
Total 
70 
70 
20 
20 
180 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.6 
Interim Safety Analysis   
 
NSCLC: For an early and detailed safety assessment, complete review of the adverse event data 
for the first 10 patients assigned to MEDI4736(durvalumab)/tremelimumab/high-dose RT and for 
the first 10 patients assigned to treatment with MEDI4736(durvalumab)/tremelimumab/low-dose 
RT will occur after completion of one  cycle (4 weeks) of therapy. If three of more patients within 
a therapy arm experience one or more dose-limiting toxicities, the addition of RT will be 
considered too toxic and enrollment to that arm will stop. 
 
Colorectal Cancer:  Concurrent with the end of the first stage of each Simon design, a complete 
safety review of adverse event data will be conducted for each treatment after completion of two 
cycles of therapy.  If three of more patients within a therapy experience one or more severe or pre-
specified dose-limiting toxicities, enrollment to that arm will stop. 
 
The table below summarizes the probability of observing three or more severe or unexpected 
toxicities in the first 10 patients of a cohort for various underlying true probabilities. If the true 
incidence of severe or unexpected toxicities is 25% or higher, then the probability is at least 0.47 
that three or more patients will be observed with these toxicities at the time of the early safety 
monitoring.  
Operating Characteristics of Early Safety Monitoring 
True Incidence of Unexpected or Severe 
Toxicity 
Probability of Observing Three or More 
Patients with Toxicity among First 10 
10% 
0.07 
15% 
0.18 
20% 
0.33 
25% 
0.47 
30% 
0.62 
 
 
13.7 
Analysis of Primary Endpoints 
 

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NSCLC:  The proportion of patients with response (CR or PR according to RECIST) will be 
compared for each pair-wise comparison of RT-containing therapy and control using chi-squared 
tests.   The difference between the proportions responding will be presented with a 90% confidence 
interval. 
 
Colorectal Cancer: Response rates within each two-stage design will be calculated and presented 
with one-sided 90% confidence intervals estimated using the method of Atkinson and Brown, 
which allows for the two-stage design. 
 
13.8 
Analysis of Secondary Endpoints 
 
13.8.1 Safety 
Assessments of safety and tolerability will be performed on an ongoing basis. At the conclusion 
of the study, safety data will be summarized for each treatment arm within each cohort.  The 
proportions of subjects with grade-3 or higher adverse events will be presented with exact binomial 
confidence intervals.  Although it is unexpected after a successful early safety assessment, if at 
any time after the early safety review 33% or more of patients in a cohort are observed with severe 
toxicities, the regimen in that cohort will pause and a comprehensive safety analysis will be 
conducted. 
 
13.8.2 Overall Survival and Progression-Free Survival 
The distributions of progression-free and overall survival will be summarized using the method of 
Kaplan-Meier.  Median times for each therapy arm will be accompanied by 90% confidence 
intervals based on log(-log(endpoint)) methodology.  For cohort 1, the pairwise comparisons 
between 
the 
MEDI4736(durvalumab)/tremelimumab 
alone 
and 
MEDI4736(durvalumab)/tremelimumab with RT arms will be conducted using log-rank tests. 
 
13.8.3 Response per irRC 
The proportions of patients with response according to irRC will be presented with 90% exact 
binomial confidence intervals.  For cohort sizes of 30 (cohort 2) and 40 patients (cohort 1), the 
confidence intervals will be no wider than 0.32 and 0.28, respectively.  For cohort 1, the pairwise 
comparisons of irORR between RT and the control arm will be conducted using chi-squared tests. 
 
13.8.4 Local Control Rate and Abscopal Response Rates 
The proportions of patients with local control within the irradiated field will be reported within 
each RT treatment arm and presented with 90% exact binomial confidence intervals.  Similar 
presentations will be used for abscopal response rates.  For cohort sizes of 30 (cohort 2) and 40 
patients (cohort 1), the confidence intervals will be no wider than 0.32 and 0.28, respectively. 
 
13.8.5 Prognostic Effect of PD-L1 Expression 
The prognostic effect of PD-L1 expression within the tumor microenvironment will be 
investigated for each treatment arm.  Each patient will be retrospectively classified according to 
pre-treatment PD-L1 expression (positive or negative).  Clinical response (CR or PR vs. 
SD/PD/Unevaluable) will be compared according to PD-L1 expression using Fisher’s exact tests.   
 

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13.8.6 Prognostic Effect of T-cell infiltration 
The prognostic effect of infiltrating CD8+ T-cells within the tumor microenvironment will be 
investigated for each treatment arm.  Each patient will be retrospectively classified according to 
pre-treatment infiltration (positive or negative).  Clinical response (CR or PR vs. 
SD/PD/Unevaluable) will be compared according to infiltration using Fisher’s exact tests.   
 
Paired biopsies are mandated in the colorectal arm and also in lung cancer patients that receive 
liver directed radiation unless there are concerns regarding safety.  To give a sense of power for 
studies to be done on paired tissue, differences will be taken for all measures and the hypotheses 
is that biomarkers if PD-L1 expression and T-cell infiltration will increase (measured as a 
continuous quantitative variable) post therapy. Thus, assuming that within each cohort we will 
obtain post treatment biopsies of at least 25 patients, using a two-sided 0.05 level paired t-test there 
is at least 80% power to detect a 0.59 SD change in mean of a quantitative correlative parameter 
using a two-sided test with 5% type I error. Quantitative measure will be transformed to attain 
normality or appropriate non-parametric tests will be conducted. Power for these tests will be 
further improved if a greater percentage of paired biopsies are obtained.  We will obtaining biopsy 
samples from participating sites as the trial proceeds and will continuously monitor the percentage 
of patients for whom a post treatment biopsy is not obtained so we can try to address any issues or 
questions regarding this.  Our plan is to pursue paired tissue analyses separately within each cohort, 
but since a goal of the study is to more generally evaluate the impact radiation on PD-L1 expression 
and tumor infiltrating lymphocytes, if needed we can consider analyses that combine data from the 
2 cohorts of patients if numbers are not sufficient in the individual cohorts.   
 
13.8.7  Exploratory Analysis of PRO-CTCAE 
 
The PRO-CTCAE data will be evaluated for data quality, to characterize baseline symptom 
status of patients on study and the change over time, to explore the development of symptomatic 
AEs and the change over time, and to explore the patient scores with other relevant clinical 
information including, but not limited to clinician graded AEs. Feasibility of the electronic 
collection as well compliance of patients with the reporting will be captured. 
 
 
 
 
13.9 
Reporting and Exclusions 
 
13.9.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
MEDI4736and tremelimumab with or without RT. 
 
13.9.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 

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stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 

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This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 

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91. 
Green, M.R., et al., Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand 
expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary 
mediastinal large B-cell lymphoma. Blood, 2010. 116(17): p. 3268-77. 
92. 
Chen, B.J., et al., PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-
associated malignancies. Clin Cancer Res, 2013. 19(13): p. 3462-73. 
93. 
Sznol, M. and L. Chen, Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced 
human cancer--response. Clin Cancer Res, 2013. 19(19): p. 5542. 
 
 

NCI Protocol #:  10021 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
  
Appendix B  
Drug Information and Contact Sheet 
 
  

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Importa
informatio
for participants taking durvalu
with/without tremelim
*Durvalumab = MEDI
durvalumab* with
without tremelimu
People to contact
Remember! If you experience any
side effects while taking durvalumab 
with/without tremelimumab you should 
contact your study doctor or nurse 
immediately. If not treated, these 
side effects could become serious
Important –
what you should do
If you notice any side effects while 
taking durvalumab, with or without  
tremelimumab, tell your study doctor
or nurse immediately
• The sooner you report any side effects, 
the faster they can be treated before 
they get worse
• It is very important that you do not 
ignore your side effects or try to treat 
them on your own
• If you go to the hospital in an emergency, 
or see a doctor who is not your usual 
study doctor, take this information sheet 
with you, so they can better help you
!
Please tell all healthcare professionals 
(doctors, nurses, pharmacists) you see that 
you are being treated with durvalumab
with/without tremelimumab, even if you are 
seeing them for a different reason
Ask them to contact your doctor using the 
contact details on the back of this leaflet
Immune cell attacking
a cancer cell
Important information for  
healthcare providers
Please notify the study investigator
immediately, using the details above, if a 
participant presents with any of the events 
described on this sheet
Prompt, appropriate treatment is 
imperative
Corticosteroids play a pivotal role in 
controlling these side effects. Please obtain 
guidance from the study investigator
Version 3 (January
Study doctor name:
Contact no:
Study nurse name:
Contact no:

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APPENDIX C    Guidance Document for Research Blood Samples
I.
Research blood Sample Requirements:
 4 -5 lavender top (EDTA), 6 ml vacutainer tubes, should be collected at each time 
point, following the protocol, referring to section, 10. Study Calendar.  
 It is important that each tube be filled to at least 5ml, to ensure sufficient sample 
volume. 
 Vacutainer tubes should be immediately inverted 5 times
Sites may either process PBMCs on site, following standard protocols and ship frozen pellets and 
plasma separately (preferred method) or immediately express ship unprocessed vacutainer 
tubes using an overnight courier, ex. Fed Ex. The integrity of the blood samples requires they 
be processed within 24 hours of collection.
Like any other drugs, durvalumab and 
tremelimumab can have side effects, although 
side effects vary and not everybody gets them.
This leaflet will help you to recognise any side 
effects you may have. The ones that have 
been observed are shown on the pages 
opposite
If you do notice any side effects, it’s important 
that you take them seriously and tell your 
doctor or nurse immediately
This will help to ensure your side effects are 
treated before they get worse. Side effects 
may occur at any time during your treatment, 
and sometimes even weeks or months after 
you have finished taking the drug(s)
Welcome
Your immune system protects your
body against diseases; 
durvalumab and tremelimumab
work by helping your immune system
attack and destroy cancer cells
The side effects listed here have been seen in 
other participants treated with durvalumab 
with/without tremelimumab. You may have 
none or some of these side effects
You might also notice new side effects that 
are not listed here, since they have not 
been seen in other participants
Inflammation
in the lungs  
(pneumonitis)
Rash/dry itchy skin
Liver problems
Low thyroid
(hypothyroidism)
High thyroid
(hyperthyroidism)
*Very common: >10%; common: >1% to ≤10%; uncommon: ≤1%
Version 3
Very 
common
Very 
common
Durvalumab &  
tremelimumab
Common
Common
Side effect
Symptoms
• Fatigue (feeling weak or tired)
• Increased sensitivity to cold
• Constipation
• Dry skin
• Unexplained weight gain
• Puffy face
• Muscle weakness
• Slow heart rate
• Thinning hair
• Impaired memory
• Anxiety/feeling nervous
• Weight loss
• Frequent and loose bowel
movements
• Breathlessness
• Feeling hot
• Heart palpitations
• New or worsening cough
• Shortness of breath
• Fever
• Increases in levels of liver 
enzymes (substances found in 
liver cells). 
The enzyme changes are 
unlikely to make you feel 
unwell
• Inflammation of the liver 
(hepatitis) develops rarely, and 
could be fatal. Symptoms 
include yellowing of the skin or 
whites of the eyes, dark urine, 
severe nausea/vomiting, 
pain in the upper right side of 
your abdomen, skin itchiness, 
not feeling hungry and 
bleeding or bruising more 
easily than normal
Kidney problems
Side effect
Symptoms
Nervous system  
problems
• Unusual weakness of legs, 
arms or face
• Numbness or tingling in hands
or feet (contact your study doctor 
right away if you have problems 
swallowing, you start to feel weak 
very quickly or you have trouble 
breathing)
Pituitary gland  
problems  
(hypopituitarism 
or hypophysitis)
• Headache
• Feeling thirsty
• Difficulty seeing or double vision
• Breast milk leakage or irregular  
periods in women
Allergic reaction
• Swelling of the face, lips and 
throat
• Breathing difficulties
• Hives or nettle-like rash
Feeling tired
Diarrhoea
Nausea
Vomiting
Decreased appetite
Shortness of breath
Cough
Fever
Pain in muscles and joints
Inflammation
of the pancreas  
(pancreatitis)
• Upper abdominal pain
• Nausea
• Vomiting
• General weakness
• Increased amylase/lipase
(enzymes that measure the
function of your pancreas)
Inflammation  
of the intestine  
(colitis)
• Abdominal pain
• Diarrhoea with or without blood
• Fever
Adrenal gland  
problems
(adrenal  
insufficiency)
• Stomach pain
• Vomiting
• Muscle weakness and fatigue
• Feeling depressed
• Low blood pressure
• Weight loss
• Kidney problems
• Changes in mood/personality
The side effects you may encounter, their symptoms, and how common* 
are in other participants treated with durvalumab with or without tremelim
Durvalumab
alone
Common
Common
Common
Common
Very
common
Very
common
Common
Common
• Increased creatinine
• Inflammation of the kidneys  
(nephritis) occurs less 
commonly
Uncommon
Common
Uncommon
Uncommon
Uncommon
D
tr
Durvalumab
alone
Very
common
Very
common
Very
common
Very
common
Very
common
Very
common
Very
common
Version 3 (Janua
Uncommon
Uncommon
Common
Common
Infusion-
related
reactions
• Fever or chills
• Change in blood pressure
• Difficult breathing
Common
Type 1 Diabetes 
Mellitus
• Increased blood glucose levels
• Weight loss
• Increased urination
• Increased thirst
• Increased hunger
Uncommon
Very
common
Very
common

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II. 
Research Sample Shipping Directions:  
1. Complete the Blood Sample Shipping Record (Template on next page) and include a 
copy of it with the sample shipment. Please enter the specific information in the 
highlighted areas. 
2. Email the completed Blood Sample Shipping Record to 
Mariano_Severgnini@DFCI.HARVARD.EDU, providing notification of the shipment 
and include in the body of the email the shipping/tracking information (ex., FedEx 
tracking #xxxx).  
3. Do not draw or ship samples the day before a weekend or  
 
 
PBMCs-Ship overnight, Monday-Thursday ONLY, using cryotanks containing liquid nitrogen 
or a styrofoam box containing dry ice, using appropriate labels, following all safety/shipping 
regulations. Shipments must be made by an overnight carrier, such as FedEx or UPS.  Cryotanks 
have temperature monitors connected to an alarm system at Cryoport headquarters.  Shipping 
temperature should be around -150C. Please contact cryoport via email at cs@cryoport.com or at 
(949)470-2300 for further information re: the cryotanks or temperature recorders.  
Plasma-Ship overnight, Monday-Thursday ONLY, using a styrofoam box containing dry ice, 
using appropriate labels, following all safety/shipping regulations. Shipments must be made by 
an overnight carrier, such as FedEx or UPS. 
Ship Samples to the address on the top left corner of the Blood Sample Shipping Record 
 Blood Sample Shipping record 
 
 
 
 
 
 
Ship To: 
Mariano Severgnini 
Immune Assessment Core Laboratory, (CIO) 
Dana-Farber Cancer Institute 
450 Brookline Ave, JF406 
Boston, MA 02215 
 
From: 
[Insert name, nam
site, site # and add
here] 
Phone: 
(617) 632-2421 or  
(617) 632-2422 
 
Phone: 
[Insert phone #] 
 
Email: 
Mariano_Severgnini@DFCI.HARVARD.EDU 
 
Email: 
[Insert email] 
 
 
  
Unprocessed EDTA tubes: must be shipped on the day of collection 
Samples are to be shipped overnight, Monday-Thursday ONLY, at ambient temperature, by overnight 
carrier, such as FedEx or UPS. 
Processed samples: it is suggested to batch ship these samples at a time agreed upon by the collection site 
and DFCI.  

NCI Protocol #:  10021 
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Subject ID  
[Unique Patient Identifier#] 
List of Samples 
[example-  unprocessed EDTA tubes/frozen PBMCs/frozen plasma # vials, sampl
date, Cycle time point] 
[example-  unprocessed EDTA tubes/frozen PBMCs/frozen plasma # vials, sampl
date, Cycle time point]  
 
Subject ID  
[Unique Patient Identifier#] 
List of Samples 
[example-  unprocessed EDTA tubes/frozen PBMCs # vials, sample date, Cycle 
time point ] 
[example-  unprocessed EDTA tubes/frozen PBMCs/frozen plasma # vials, sampl
date, Cycle time point]  
 
 
Subject ID  
[Unique Patient Identifier#] 
List of Samples 
[example-  unprocessed EDTA tubes/frozen PBMCs/frozen plasma # vials, sampl
date, Cycle time point] 
[example-  unprocessed EDTA tubes/frozen PBMCs/frozen plasma # vials, sampl
date, Cycle time point]  
 
*Please include a copy of this completed document with the shipment and email the recipient 
above to provide notification* 
Comments: 
 
 
Guidance Document for Research Tissue Samples 
 
I.       Research Tissue Sample Requirements: 
 
 Archival, pre-, and on-treatment tissue -Formalin-fixed paraffin 
embedded block(s) and or unstained/unbaked slides (15-20), stored at 
room temperature.  
o In general, samples should be placed in fixative at a 10:1 ratio and 
fixed for at least 24-48 hours but thicker tissue samples may 
require longer fixation. 
 Optional: If sufficient excess tissue is available at biopsy (generally if 
more than one biopsy has been performed) then at least 10mg and 
preferably 20 - 50mg of tumor tissue can be placed in RNAlater (1mL), 
then snap frozen in liquid nitrogen and stored at -70 to -80°C. These 
samples can batched and then shipped overnight on dry ice. 
 All specimens shall be collected following the protocol, referring to 
section, 10. Study Calendar.   
  

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For labelling the blocks please refer to the following guidance; 
The block label should be unique and should indicate a) the subject ID and b) time 
of the biopsy. 
------------------------------------------------------------------------------------------------------------
--------------------------------- 
examples: 
Pre-treatment biopsies should be labeled as: XXXXX-XXX PRE, 
Week 7 biopsies should be labeled as: XXXXX-XXX W7 
On-treatment biopsies should be labeled as: XXXXX-XXX ONTX 
Post-treatment biopsies should be labeled as: XXXXX-XXX POST 
where XXXXX-XXX is the unique subject id (EXAMPLE: WI020-027) 
------------------------------------------------------------------------------------------------------------
--------------------------------- 
 
II.   Research Sample Shipping Directions:  
 
1. Complete the Tissues Sample Shipping Record (Template on next page) and    
include a copy of it with the sample shipment. Please enter the specific information 
in the highlighted areas. Please also include a copy of the Pathology report (de-
identified, noting subject # on the report) that correlates to the tissue specimens. 
   
1. Email the completed Tissue Sample Shipping Record to, 
Evisa_Gjini@DFCI.HARVARD.EDU.                                                                           
In the email please include the shipping/tracking information (ex., FedEx tracking #xxxx).   
 
2.  Please ship all tissue and or slides following your site specific shipping policies to 
ensure safe handling, travel and arrival.  
 
 
Ship Samples to the address on the top left corner of the Tissue Sample Shipping Record 
Tissue Sample Shipping Record 
 
 
 
 
 
 
Ship 
To: 
Dr. Evisa Gjini  
Brigham & Women’s Hospital 
20 Shattuck Street  
Thorn building 603B  
Boston, MA 02215 
 
 
From: 
[Insert name,  
name of site,  
site # and address 
here] 
Phone: (617) 732-8289 
 
Phone: 
[Insert phone #] 
 
  

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Email: 
Evisa_Gjini@DFCI.HARVARD.EDU  
Email: 
[Insert email] 
 
 
Subject ID  
[Unique Patient Identifier#] 
List of Sample(s) 
[example- Accession #xxxxx and sample type -1 tissue block] 
[example- Accession #xxxxx and sample type -20 slides] 
Timepoint of Sample(s) 
[example – pretreatment, on treatment, on progression, archival prior t
previous PD-1 therapy (NSCLC cohort only)] 
Location from which 
tissue was obtained (if 
known).   
[Please be as specific as possible: example – irradiated liver lesion, 
unirradiated liver lesion, irradiated lung lesion, etc.] 
 
 
Subject ID  
[Unique Patient Identifier#] 
List of Sample(s) 
[example- Accession #xxxxx and sample type -1 tissue block] 
[example- Accession #xxxxx and sample type -20 slides] 
Timepoint of Sample(s) 
[example – pretreatment, on treatment, on progression, archival prior t
previous PD-1 therapy (NSCLC cohort only)] 
Location from which 
tissue was obtained (if 
known).   
[Please be as specific as possible: example – irradiated liver lesion, 
unirradiated liver lesion, irradiated lung lesion, etc.] 
 
 
*Please include a copy of this completed document, the related path report (if applicable) with 
the shipment and email the recipient above to provide notification* 
 
Comments: 
 
 
 
 
 
 
 
 
 
APPENDIX D: RECIST GUIDELINE (version 1.1) 
 
 https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf#search=%22Recist 
1.1%22 
 
APPENDIX E: PRO-CTCAE Items for Collection 
  

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PRO-CTCAE is intended to enhance the quality of adverse event data reporting in clinical trials, 
provide data that complements and extends the information provided by clinician reporting 
using CTCAE, represent the patient perspective of the experience of symptomatic adverse 
events, and improve detection of potentially serious adverse events.   
 
 
The selection of PRO-CTCAE should be complementary to the clinician identified AEs for 
ongoing monitoring.   
 
Please refer to the PRO-CTCAE Terms of Use for more information. 
 
 
A Phase 2 Study of MEDI4736(durvalumab) and Tremelimumab Alone or in Combination 
with High or Low-Dose Radiation in Metastatic Colorectal and NSCLC 
   NSCLC Cohort: To assess safety and tolerability of combined checkpoint blockade with 
MEDI4736(durvalumab) and tremelimumab alone or with high or low-dose radiation in 
NSCLC 
   Colorectal Cohort: To assess safety and tolerability of combined checkpoint blockade with 
MEDI4736 and tremelimumab with high or low-dose radiation 
For Protocol 10021: 
System Organ Class  
MEDI4736 
(Durvalumab
) 
Adverse 
event term - 
CAEPR 
Tremelimumab      
Adverse event 
term - CAEPR 
Possible 
Related 
PRO-CTCAE 
Items 
Attributes  
Gastrointestinal 
Disorders  
Diarrhea 
Diarrhea 
Diarrhea 
Frequency 
Nausea 
Nausea 
Nausea 
Frequency & 
Severity 
Vomiting 
Vomiting 
Vomiting 
Frequency & 
Severity 
  
Abdominal pain 
Abdominal 
pain  
Frequency, 
Severity, & 
Interference 
General Disorders 
Fatigue 
Fatigue 
Fatigue 
Severity & 
Interference 
  
Pain 
Pain 
General 
Pain 
Frequency, 
Severity, & 
Interference 
Metabolism and 
Nutrition Disorders 
Anorexia 
Anorexia 
Decreased 
appetite 
Severity & 
Interference 
Nervous System 
 
Headache 
Headache 
Frequency, 
  

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Disorders 
Severity, & 
Interference 
  
Pneumonitis 
Shortness 
of breath 
Severity & 
Interference 
Respiratory, Thoracic 
Disorders 
  
Pneumonitis 
Cough 
Severity & 
Interference 
Pruritus 
Pruritus 
Itching 
Severity 
Skin and 
Subcutaneous Tissue 
Disorders 
Rash maculo-
papular 
Rash maculo-
papular 
Rash 
Presence/absence 
  
Dry Skin 
Skin 
dryness 
Severity 
 
 
References 
o PRO-CTCAE Website:  https://healthcaredelivery.cancer.gov/pro-ctcae/ 
o PRO-CTCAE Items Library 
o PRO-CTCAE NCI Scientific Leadership Team 
o PRO-CTCAE Development Team 
o Publications 
 
 
1. APPENDIX F 
MEDIDATA PATIENT CLOUD REGISTRATION 
a. Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata Patient Cloud 
ePRO is preferred but not mandatory.  Traditional paper submission is the other option. 
Patients who will be submitting PRO data via Patient Cloud ePRO must be registered to 
Patient Cloud ePRO by an authorized site user after the patient has been registered to the 
study. Patients may use their own device or one provisioned by the site.  
Sites can use a site-specific tablet for multiple study participants.  If a site-specific tablet is 
used, CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study 
participants log in to Patient Cloud ePRO with their passwords or their PIN codes on the 
same device.  
 
 
b. CRA Site Users 
Site users of Patient Cloud ePRO require the same access as Rave. Access to the trial in the 
Patient Cloud ePRO is granted through the iMedidata. Site users will receive an invitation to 
Patient Cloud ePRO and the site user must accept the invitation to begin patient 
registration. Users who have not previously activated their iMedidata/Rave account at the 
time of initial approval of site registration will also receive a separate invitation from 
  

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iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Please note, site users will not be able to access the study in 
the Patient Cloud ePRO until all required Rave and study specific trainings are completed. 
Additional information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-
5923 or by e-mail at ctsucontact@westat.com.   
 
c. CRA Instructions for Setting the Patient Cloud ePRO App to Multi-User 
Mode 
Sites conducting studies entirely on-premise, where participants travel to the sites to fill 
out questionnaires, can use multi-user mode. Multi-user mode lets multiple study 
participants log in to Patient Cloud with their passwords or their PIN codes on the same 
device.  . If patients will be using devices supplied by the institution, site staff will need 
to help the patient to access the device if the device is locked. 
 The study provider will download the Patient Cloud ePRO app to the device and set the 
Patient Cloud ePRO App to multi-user mode if applicable. 
 To switch from personal mode (default setting) to multi-user mode: 
1.     Tap About at the bottom of the log in screen. 
2.     Scroll to the bottom and tap Advanced User. 
3.     Tap Mode, then select Multi-User. 
4.     Tap Yes to confirm. 
5.     Tap the back arrows to return to the log in screen. 
Note: If enabling multi-user mode on a device, it is highly recommended that 
completion reminders are turned off on that device. 
For a video demonstration, see Show Me How to Switch to Multi-User Mode. 
 
d. Patient Users 
To use the Patient Cloud ePRO, patients will need to use their own device (IOS, 
Android phone or tablet).  Short term data will only appear on the patient’s device 
until responses are completed and submitted.  The patient data will import directly 
into the database once the patient selects the “Submit” button and will no longer 
be visible on the patient's device.  
 
Sites can provide a site-specific tablet for multiple study participant use on site.  If 
a site-specific tablet is used, study staff need to setup the tablet for multiple users.  
Multi-user mode lets multiple study participants log into Patient Cloud ePRO with 
their passwords or their PIN codes on the same device. Refer to Appendix E on 
Setting the Patient Cloud ePRO App to Multi-User Mode.   
 
  

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e. Patient Instructions for Accessing the Patient Cloud Using Your Personal 
Device 
Downloading the Patient Cloud ePRO App 
If you are using your personal device, and you do not have the Patient Cloud ePRO app, 
use the following instructions. When downloading the app, you must use the Apple ID 
or Google account associated with the device. If the Patient Cloud ePRO app is already 
on the device, or if you are using a provider's device, you can skip this section. 
You will need an email address that you agree to use for this purpose. The e-mail 
address is needed to identify you on the Patient Cloud Application and for you to 
receive notifications to let you know when forms are due. Your e-mail address will only 
be used for this survey study, and will not be used for mail or marketing purposes. 
If you decide to use the electronic method to complete the questionnaires, and do not 
have an e-mail address, you may sign up for one at no charge at many different 
websites.  A few sites that are commonly used and will allow you to create an email 
address very easily are Yahoo, Gmail, and Outlook. 
For iOS:  
 
1. An Apple ID is required for downloading the Patient Cloud ePRO app. 
2. Tap the App Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
Note: Patient Cloud ePRO is listed as an iPhone App in the App store. When using an 
iPad, please view the search results under iPhone apps. 
   
For Android: 
1. A Google account is required for downloading the Patient Cloud ePRO app 
2. Tap the Play Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
Registering 
You must register in order to complete and submit your study forms. When you register, 
you will create a username, which is your email address, and a password that allows you 
to log in to the Patient Cloud ePRO app. 
 
Note: You must have an activation code to begin this process. If you do not have an 
activation code, please contact your provider.  
There are two possible ways to register. Your provider may have sent you a link to a web 
address where you may register from any web browser, including the one on your 
device. The other way to register is on the Patient Cloud ePRO app. 
1. If registering from the Patient Cloud app, tap Register on the bottom of the 
log in page. If registering on the web, open the URL shield.imedidata.com 
on a web browser. 
  

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2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. Enter and confirm your email address. Tap Next. 
6. Enter and confirm your password. Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to 
display the question of your choice. 
8. Enter your security question response. 
9. Tap Create my account to complete your registration.  
 
If you registered on the Patient Cloud ePRO app, it automatically logs you out. If you 
registered on the web, you are presented with the option to download the Patient 
Cloud ePRO app. You can then proceed to log in with the credentials you created. 
 
Logging in to the App 
1. Enter your Email and Password that you created during the registration 
process. (If you previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided. 
 
Setting a PIN Code 
The first time you log in to the Patient Cloud ePRO app, you are given the option to 
create a PIN code. A PIN code allows you to bypass the step of entering your email and 
password every time you need to log in to the Patient Cloud ePRO app. Instead, you can 
enter a four-digit PIN. 
1. If you wish to set a PIN code the first time you log in, tap Yes when 
prompted. 
2. Note: You can also set your PIN at a later time by tapping the options 
menu on the top left of most pages and selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
If you forget your PIN code, tap Forgot PIN and you can access the app using your email 
and password. You may reset your PIN by tapping the options menu on the top left of 
most pages and selecting Set PIN. 
 
Resetting Your Password 
You can reset your password by using the options menu at the top left of most pages. 
1. Tap the options menu icon. 
2. Tap Reset Password. 
  

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3. Follow the instructions to reset your password.
Completing and Submitting Forms
Once logged in, forms related to your study display on the Tasks page. If you are 
enrolled in multiple studies, select the appropriate study first, and then select a form. 
New forms can appear on the Tasks page at any time, depending on how the study is 
designed.
There are two types of forms displayed on the Task List page:
x
Scheduled Forms (with a 
icon): These forms have a "Due Date" indicator 
in them so you are aware of the last day by which you will need to complete 
the form. If the form is due in less than one day, you will see the due time in 
hours.
x
Anytime Forms (with a
icon): These forms have "Last Completed Time" 
indicator on them which tells the most recent date or time when you 
completed the form. If you start a form, but do not complete it, you will see an 
'Incomplete" status beneath the form name, along with a half-moon icon. 
1. Select the appropriate form.
2. Follow the on-screen instructions until you reach the end of the form 
where you are given the opportunity to review and change your responses 
prior to submitting.
3. Review your responses by scrolling down the list.
4. If you need to change an answer, tap the question to go back and change 
the answer.
5. When you are ready to submit, tap Submit Your Data.
Note: Once a form is submitted, you will be unable to edit any of your responses. In 
some cases, you may be asked to acknowledge your submission by entering your 
password. 
f.
Patient Compliance
The patient data imports directly from a device into the Rave database.  There are 
no documents to audit.  The patient-submitted electronic responses are the source 
documentation.
g. Security
All data is encrypted on the device (256 bit encryption and Hyper Text Transfer Protocol 
Secure [https]) and the app requires each user to have a unique username and 
password for access.  If the user is idle for too long (5 minutes inactivity time), the app 
will time out and the user will need to log in again.
The data will only reside on the device for a short period of time.  Once the user clicks 
“Submit,” the data is securely transferred over HTTPS between the device and internal 

NCI Protocol #:  10021 
Informed Consent Version Date:  08/30/2019 
Page 163 of 163 
 
  
relay to the Rave database.  Except for the patient's email address, no identifying 
information is stored in iMedidata. The email address is stored for what purpose?  The 
patient’s email links the device (used) and (ePRO) account to where the data is stored.  
The patient’s email is not visible to anyone in the system. 
The Patient information (email/password) does not reside in Medidata Rave EDC and 
the patient accounts are hidden in iMedidata from sites and LPOs. 
The Patient Cloud ePRO application is 21 CFR Part 11 compliant and acts as a gateway 
between the device and Medidata Clinical Cloud (MCC).   
Messages and information communicated to and from the Patient Cloud ePRO are 
encrypted and therefore this information cannot be read if intercepted while in transit. 
h. Site checklist for activities prior to consenting a patient 
 Site staff must have already completed required eLearning for the Patient 
Cloud ePRO application. See last bullet with hyperlink to training video 
library.Contact the LPO to request appropriate Rave access to register patients 
in Patient Cloud ePRO 
 Accept study invitation at iMedidata.com 
o Note: you must be rostered in RSS and have received an invitation to 
Patient Cloud ePRO 
 Verify the IOS or Android operating system is using the most current version 
 Verify Patient Cloud ePRO app is using the most current version 
 If using institutional shared devices, first patient only: Verify Patient Cloud 
ePRO app is in Multi-User mode  
 Refer to Review Quick Reference Guides for videos and other procedural 
information