Clinical trial NCT03007407
Conditions: Colorectal Cancer Metastatic
Keywords: microsatellite stable MSS durvalumab tremelimumab mCRC NSABP
Sponsor: NSABP Foundation Inc
Start date: 2017-07-31; Completion date: 2019-08-09
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to look at the safety and response to the combination of two investigational drugs, tremelimumab and durvalumab, when given after radiation therapy for patients with microsatellite stable (MSS) metastatic colorectal cancer. Tremelimumab and durvalumab recognize specific proteins on the surface of cancer cells and trigger the immune system to destroy the cancer cells.

In order to learn more about certain characteristics of colorectal cancer tumors, this study includes special research tests using samples from diagnostic tumors, fresh tumor samples from an area where the cancer has spread, and blood samples.

Detailed description:
The FC-9 study is designed as a phase II, open label, single arm study of the dual immune checkpoint blockade with the combination of durvalumab and tremelimumab following hypofractionated palliative radiation in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) who have progressed on chemotherapy. The primary aim is to determine the anti-tumor efficacy of the dual immune checkpoint blockade with durvalumab plus tremelimumab. The secondary aims are to determine the clinical benefit rate, duration of response, tolerability and correlates of response. Tumor response at unirradiated target lesions will be measured at baseline and every 2 cycles using RECIST 1.1.

Following three doses of hypofractionated palliative radiation (Days -2, -1, and Day 0 prior to Cycle 1), patients will receive the combination of tremelimumab (75 mg IV infusion) and durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles. Beginning with Cycle 5 through Cycle 24, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day cycle.

The sample size will be between 12 and 21 evaluable patients. Twelve evaluable patients will be treated in the first stage of the study. If there are no responses among the 12 evaluable patients, the study will be terminated. If the study goes on to the second stage, a total of 21 evaluable patients will be studied.

Submission of tumor tissue and blood samples for FC-9 correlative science studies will be a study requirement for all patients. Requirements will include archived tumor samples from the diagnostic biopsy; additional biopsies of fresh tissue from an accessible lesion prior to radiation therapy and after 2 cycles of study therapy; and blood sample collections.

Arms: arm 1: None
Interventions: intervention 1: durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: Following three doses of hypofractionated palliative radiation (Days -2, -1, and Day 0 prior to Cycle 1), patients will receive durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles (in combination with tremelimumab). Beginning with Cycle 5 through Cycle 12, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day cycle. intervention 2: Following three doses of hypofractionated palliative radiation (Days -2, -1, and Day 0 prior to Cycle 1), patients will receive tremelimumab (75 mg IV infusion) on Day 1 for 4 cycles (in combination with durvalumab).

Protocol documents:
Prot_SAP_000.pdf: 
Confidential 
 
Page 1 
NSABP PROTOCOL FC-9 
 
 
A Phase II Study of the Dual Immune Checkpoint Blockade with Durvalumab 
(MEDI4736) plus Tremelimumab Following Palliative Hypofractionated 
Radiation in Patients with Microsatellite Stable (MSS) Metastatic 
Colorectal Cancer Progressing on Chemotherapy 
 
 
 
 
 
NSABP Foundation, Inc. 
 
 
 
TELEPHONE: 
 
E-MAIL: 
 
CLINICAL QUESTIONS: 
 
 
 
 
 
KEY STUDY PERSONNEL 
NSABP Chair: Norman Wolmark, MD 
NSABP Medical Director: Samuel Jacobs, MD 
Protocol Chair: James J. Lee, MD, PhD 
Protocol Officer:  Thomas George, MD 
Protocol Statistician: Greg Yothers, PhD 
Radiation Therapy Co-Chair: Dwight Heron, MD 
 
 
 
Protocol FC-9 IND #132833 (Durvalumab), (Tremelimumab) 
sponsored by the NSABP Foundation, Inc. 
 
 
 
 
 
Version Date: April 17, 2019 (Replaces all other versions) 
 
CONFIDENTIAL


 
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PROTOCOL REVISION RECORD 
 
Original Version: 
October 17, 2016 
Amendment #1: 
November 22, 2016 
Amendment #2: 
January 25, 2017 
Amendment #3: 
March 28, 2017 
Amendment #4: 
June 26, 2017 
NSABP FC-9 Protocol and consent amended prior to activation of the study. 
Amendment #5: 
May 8, 2018 
Title page 
Protocol Revision Record 
Section 4.0 
 
4.2,10, 4.2.20 
Section 8.0: 
 
8.4 (Table 7), 8.5, 8.5.1, 8.5.2, 8.5.3, 8.5.4, 8.5.5, 8.5.6, 8.5.7, 8.5.8, 8.5.9,  
 
 
 
8.5.10, 8.5.11, 8.5.12, 8.5.13 (added) 
Section 9.0 
 
9.5 
Section 10.0 
 
10.2 
Section 16.0 
 
Reference updated 
The NSABP FC-9 consent has been amended. 
Amendment #6: 
November 15, 2018 
Title page 
Protocol Revision Record 
Section 1.0 
 
Overview, Schema 
Section 5.0 
 
Table 2 
Section 7.0 
 
7.1 (Table 4) 
Section 9.0 
 
9.1.4, 9.2.4 
Section 14.0 
 
14.1 
Amendment #7  
April 17, 2019 
Title page 
Protocol Revision Record 
Section 10.0 
 
10.2 
Appendix C 
 
 


 
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TABLE OF CONTENTS 
Information Resources .................................................................................................................................. 5 
Glossary of Abbreviations and Acronyms .................................................................................................... 6 
1.0 
OVERVIEW OF STUDY DESIGN .............................................................................................. 10 
2.0 
BACKGROUND ........................................................................................................................... 12 
2.1 
Colorectal Cancer ............................................................................................................. 12 
2.2 
The role of Programmed Death 1 (PD-1) pathway in antitumor immune responses ........ 12 
2.3 
Durvalumab ...................................................................................................................... 12 
2.4 
Tremelimumab .................................................................................................................. 14 
2.5 
The combination of durvalumab and tremelimumab ........................................................ 15 
2.6 
Effect of radiation on immune response to cancer cells ................................................... 16 
2.7 
The combination of radiation and immune checkpoint inhibitors .................................... 17 
2.8 
Rationale for the combination of radiation and dual checkpoint blockade ....................... 18 
2.9 
Translational opportunities ............................................................................................... 19 
3.0 
STUDY AIMS AND ENDPOINTS .............................................................................................. 21 
3.1 
Primary aim and endpoint ................................................................................................. 21 
3.2 
Secondary aims and endpoints .......................................................................................... 21 
3.3 
Exploratory Translational Science .................................................................................... 21 
4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY ........................................................................ 22 
4.1 
Conditions for patient eligibility ....................................................................................... 22 
4.2 
Conditions for patient ineligibility .................................................................................... 23 
5.0 
REQUIREMENTS FOR STUDY ENTRY, DURING TREATMENT, AND FOLLOW-UP ...... 25 
6.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES ...................................................... 28 
6.1 
Overview of requirements................................................................................................. 28 
6.2 
Use of specimens .............................................................................................................. 28 
6.3 
Required tumor and blood sample submission procedures ............................................... 29 
6.4 
Correlative Science Studies .............................................................................................. 29 
7.0 
TREATMENT REGIMEN ............................................................................................................ 31 
7.1 
Study therapy .................................................................................................................... 31 
7.2 
Supportive therapy ............................................................................................................ 33 
7.3 
Contraindications and precautions .................................................................................... 33 
7.4 
Participation in other clinical trials ................................................................................... 33 
8.0 
TREATMENT MANAGEMENT ................................................................................................. 34 
8.1 
General instructions .......................................................................................................... 34 
8.2 
Treatment management for durvalumab and tremelimumab ............................................ 34 
8.3 
Dose modifications for durvalumab and tremelimumab ................................................... 34 
8.4 
Dose modification and management of toxicities ............................................................. 35 
8.5 
Immune-mediated adverse events (imAEs) ...................................................................... 41 
8.6 
Management of radiation toxicity ..................................................................................... 56 
8.7 
Liver dysfunction (Hy's Law) ........................................................................................... 57 
9.0 
DRUG INFORMATION ............................................................................................................... 58 
9.1 
Tremelimumab .................................................................................................................. 58 
9.2 
Durvalumab (MEDI4736) ................................................................................................. 59 
9.3 
Procurement ...................................................................................................................... 60 
9.4 
Shipping ............................................................................................................................ 60 
9.5 
Storage requirement and stability ..................................................................................... 60 


 
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9.6 
Transfer of study therapy .................................................................................................. 61 
9.7 
Destruction of study therapy ............................................................................................. 61 
9.8 
Drug inventory records ..................................................................................................... 61 
10.0 
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 62 
10.1 
Definition of an AE ........................................................................................................... 62 
10.2 
Definition of adverse events of special interest (AESI) .................................................... 62 
10.3 
Definition of an SAE ........................................................................................................ 63 
10.4 
Events requiring expedited reporting ................................................................................ 64 
10.5 
Pregnancy.......................................................................................................................... 65 
10.6 
Grading the severity of the AE ......................................................................................... 66 
10.7 
Expedited reporting instructions ....................................................................................... 66 
10.8 
Time period and frequency for routine reporting of AEs ................................................. 66 
10.9 
Documentation requested following death ....................................................................... 67 
11.0 
ASSESSMENT OF EFFECT ........................................................................................................ 68 
11.1 
Definitions of measurable and non-measurable disease ................................................... 68 
11.2 
Response criteria ............................................................................................................... 68 
11.3 
Symptomatic deterioration ................................................................................................ 69 
12.0 
PATIENT ENTRY PROCEDURES .............................................................................................. 70 
12.1 
Patient consent form ......................................................................................................... 70 
12.2 
Study entry ........................................................................................................................ 70 
12.3 
Patient study number and treatment assignment ............................................................... 70 
12.4 
Investigator-initiated discontinuation of study therapy .................................................... 70 
12.5 
Patient-initiated discontinuation of study therapy ............................................................ 70 
12.6 
Patient-initiated withdrawal from the study ...................................................................... 71 
13.0 
DATA HANDLING AND RECORDKEEPING .......................................................................... 72 
14.0 
STATISTICAL CONSIDERATION ............................................................................................. 73 
14.1 
Study design ...................................................................................................................... 73 
14.2 
Statistical design and sample size analysis ....................................................................... 73 
14.3 
Monitoring ........................................................................................................................ 73 
15.0 
PUBLICATION INFORMATION ................................................................................................ 74 
16.0 
REFERENCES .............................................................................................................................. 75 
APPENDIX A DETERMINATION OF PERFORMANCE STATUS ...................................................... 79 
APPENDIX B HYPOFRACTIONATED RADIATION THERAPY GUIDELINES ............................... 80 
APPENDIX C CONTRACEPTION ........................................................................................................... 84 
Figure 1 
FC-9 Schema 
11 
Figure 2 
PD-1 Blockade Antagonizes Acquired Resistance to Radiation plus anti-CTLA4 
Therapy ............................................................................................................................. 19 
Table 1 
Tests, exams, and other requirements prior to study entry ............................................... 25 
Table 2 
Tests, exams, and other requirements following study entry ............................................ 26 
Table 3 
Summary of FC-9 patient sample submission requirements ............................................ 28 
Table 4 
Study therapy (tremelimumab and durvalumab) .............................................................. 31 
Table 5 
Dose levels for durvalumab .............................................................................................. 35 
Table 6 
Dose levels for tremelimumab .......................................................................................... 35 
Table 7 
Treatment management for study therapy (durvalumab and tremelimumab) ................... 36 
Table 8 
Determination of response ................................................................................................ 69 
Table 9 
Highly Effective methods of contraception (<1% failure rate) ......................................... 85 


 
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INFORMATION RESOURCES 
NSABP Department of Site and Study Management 
NSABP Operations Center 
 
 
Phone: 
  E-mail: 
 
For questions regarding: 
• 
IRB review & informed 
consent 
• 
Submission of IRB 
approval 
• 
Study entry information 
• 
Eligibility 
• 
Treatment regimen 
• 
Dose modifications/delays 
• 
Other clinical aspects of 
the trial 
• 
Adverse event reporting 
including SAE reporting 
• 
eCRF completion 
Department of Site and Study 
Management (DSSM) 
Phone: 
 
E-mail: 
 
For questions regarding data 
management 
Department of Site and Study 
Management (DSSM) 
Phone: 
 
E-mail: 
 
Request for blood sample 
collection kits 
NSABP Division of Pathology 
 
 
Phone: 
 
Email:
 
Refer to the FC-9 Pathology and 
Correlative Science Instructions 
Requests for durvalumab and 
tremelimumab 
Department of Site and Study 
Management (DSSM) 
E-mail: 
 
Questions regarding drug 
shipment 
Department of Site and Study 
Management (DSSM) 
Phone: 
 
E-mail: 
 
 
 
 


 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
5-FU 
 
 
5-fluorouracil 
AChE  
 
acetylcholine esterase 
ADA 
 
 
antidrug antibody 
ADCC  
 
antibody dependent cell-mediated cytotoxicity  
AE 
 
 
adverse event 
Alk phos 
 
alkaline phosphatase 
ALT (SGPT) 
alanine aminotransferase 
AML  
acute myelogenous leukemia 
ANC 
 
 
absolute neutrophil count 
ASCO  
 
American Society of Clinical Oncology 
AST (SGOT) 
 
aspartate aminotransferase 
ATP 
 
 
adenosine triphosphate 
BNP 
 
 
Brain natriuretic peptide 
BRAF  
 
v-raf murine sarcoma viral oncogene homolog B1 
BRAFi  
 
BRAF inhibitor 
BSC 
 
 
best supportive care 
BUN 
 
blood, urea, nitrogen 
CBC 
 
 
complete blood count 
CBCT  
 
cone-beam CT 
CDC 
 
 
complement-dependent cytotoxicity  
cDNA  
 
circulating DNA 
CEA 
 
 
carcinoembryonic antigen 
ChemoRT 
 
chemo-radiotherapy 
CI 
 
 
confidence interval 
CPT-11  
 
irinotecan 
CR 
 
 
complete response  
CRC 
 
 
colorectal cancer 
CRT 
 
 
calreticulin 
CT 
 
 
computed tomography 
CTEP  
 
Cancer Therapy Evaluation Program 
CTCAE v4.0 
 
Common Terminology Criteria for Adverse Events Version 4.0 
CTLA-4 
 
cytotoxic T-lymphocyte-associated protein 4 
D/C 
 
 
discontinue 
DAMP  
 
damage-associated molecular patterns 
DC 
 
 
dendritic cell 
DCO 
 
 
data cutoff 
dL 
 
 
deciliter 
DNA 
 
deoxyribonucleic acid 
DSSM 
Department of Site and Study Management 
ECOG  
 
Eastern Cooperative Oncology Group 
eCRF  
 
electronic case report form 
EGRF  
 
epidermal growth factor receptor  


 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (Continued) 
Fcγ 
 
 
fragment crystallizable gamma  
FACS  
 
fluorescence-activated cell sorting 
FDA 
 
 
Food and Drug Administration 
FDG-PET 
 
Fluorine-18-fluorodeoxyglucose Positron Emission Tomography 
FFPE  
 
formalin-fixed paraffin embedded 
G-CSF  
 
granulocyte-colony stimulating factor 
GCP 
 
 
Good Clinical Practice 
GGT 
 
 
gamma-glutamyl transferase 
GITR  
 
glucocorticoid-induced tumor necrosis factor receptor related protein 
GLP 
 
 
Good Laboratory Practice  
GTV 
 
 
gross tumor volume 
GY 
 
 
gray 
H&P 
 
 
history and physical 
HCC 
 
 
hepatocellular carcinoma 
HMGB1 
 
high-mobility group box 1 protein  
HR 
 
 
hazard ratio 
IB 
 
 
Investigators Brochure 
ID 
 
 
identification 
IDO 
 
 
indoleamine 2, 3-Dioxygenase 
IFN-γ  
 
interferon gamma 
Ig 
 
 
immunoglobulin  
IgG1κ  
 
immunoglobulin G1 kappa  
IGRT  
 
Image-Guided Radiation Therapy 
IHC 
 
 
immunohistochemistry 
ILD 
 
 
interstitial lung disease 
IM 
 
 
intramuscular 
IND 
 
 
investigational new drug 
iNOS  
 
inducible nitric oxide synthase 
INR 
 
 
international normalized ratio 
imAE  
 
immune-related adverse event 
IRB 
 
 
institutional review board 
IU/L 
 
 
international units per liter 
IV 
 
 
intravenous 
kDa 
 
 
kilo Dalton 
kg 
 
 
kilogram 
KRAS  
 
V-Ki-ras2Kirsten rat sarcoma viral oncogene homolog 
LAG-3  
 
lymphocyte-activation protein 3 
LD 
 
 
longest diameter 
LDH 
 
 
lactate dehydrogenase 
LFT 
 
 
liver function tests 
LLN 
 
 
lower limit of normal 
MAb 
 
 
monoclonal antibody 


 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (Continued) 
mCR 
 
 
molecular complete remission 
mCRC  
 
metastatic colorectal cancer 
MDS 
 
 
myelodysplastic syndrome 
MDSC  
 
myeloid-derived suppressor cells 
mg 
milligram 
MHC-1 
major histocompatibility complex-1 
MI 
myocardial infarction 
MLC 
multi-leaf collimator 
mo 
month 
MRI 
magnetic resonance imaging 
ms 
millisecond  
MSI 
microsatellite instability 
MSI-H 
microsatellite instability-high 
MSS 
microsatellite stable 
NaCl 
sodium chloride 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSABP 
NSABP Foundation, Inc. 
NSCLC 
non-small cell lung cancer  
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
p-value 
calculated probability 
PBMC 
peripheral blood mononuclear cells 
pCR 
pathologic clinical response 
PD 
progressive disease 
PD-1 
Programmed cell death-1, proficient 
PD-L1 
programmed death ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PJP 
pneumocystis jirovecii pneumonia 
PK 
pharmacokinetics 
PO 
by mouth 
PR 
partial response 
PT/INR 
prothrombin time/international normalized ratio 
PTV 
planning target volume 
q 
every 
Q2W 
every 2 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
 
 


 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (Continued) 
RILD 
radiation-induced liver disease  
RNA 
ribonucleic acid 
RR 
response rates 
RT 
radiation therapy 
SAE 
serious adverse event 
SARRP 
small animal radiation research platform  
SBRT 
stereotactic body radiation 
SCCHN 
squamous cell carcinoma of the head and neck  
SD 
stable disease 
SOC 
standard of care 
T1DM 
Type 1 Diabetes Mellitus 
T-cell 
T lymphocyte 
TB 
total bilirubin 
TCR 
T-cell receptor 
TIA 
transient ischemic attacks 
TIL 
tumor-infiltrating lymphocytes 
TNF 
tumor necrosis factor 
TTR 
time to response 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor  
WNL 
within normal limits 
WOCBP 
women of childbearing potential 
WT 
weight 
 
 
 


 
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1.0 
OVERVIEW OF STUDY DESIGN 
The FC-9 study is designed as a phase II, open label, single arm study of the dual immune 
checkpoint blockade with the combination of durvalumab and tremelimumab following 
hypofractionated palliative radiation in patients with microsatellite stable (MSS) metastatic 
colorectal cancer (mCRC) who have progressed on chemotherapy.  The primary aim is to 
determine the anti-tumor efficacy of the dual immune checkpoint blockade with durvalumab plus 
tremelimumab.  The secondary aims are to determine the clinical benefit rate, duration of 
response, tolerability and correlates of response.  Tumor response at unirradiated target lesions 
will be measured at baseline and every 2 cycles using RECIST 1.1. 
Following three doses of hypofractionated palliative radiation (Days −2, −1, and Day 0 prior to 
Cycle 1), patients will receive the combination of tremelimumab (75 mg IV infusion) and 
durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles.  Beginning with Cycle 5 through Cycle 
24, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day cycle. 
Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 4.0. 
The sample size will be between 12 and 21 evaluable patients.  Patients who complete both  
Cycle 1 and Cycle 2, and undergo the first restaging scan after Cycle 2 for the determination of 
tumor response will be determined evaluable.  Non-evaluable patients will be replaced.  Twelve 
evaluable patients will be treated in the first stage of the study.  If there are no responses among 
the 12 evaluable patients, the study will be terminated.  If the study goes on to the second stage, a 
total of 21 evaluable patients will be studied.  If the total number responding is less than or equal 
to 2, the combination will be rejected.  If 3 or more responses are observed after the second stage 
of the study, the combination will be considered for further study. 
Submission of tumor tissue and blood samples for FC-9 correlative science studies will be a study 
requirement for all patients.  Requirements will include archived tumor samples from the 
diagnostic biopsy; additional biopsies of fresh tissue from an accessible lesion prior to radiation 
therapy and after 2 cycles of study therapy; and blood sample collections. 
 
 


 
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Figure 1 
 
FC-9 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypofractionated 
SBRT¥ 
(Days −2, −1, and Day 0 
before Cycle 1 begins [SOC]) 
Cycles 1-4 
Tremelimumab* 
+ 
Durvalumab** 
 
Cycles 5-24 
Durvalumab** 
(See note.) 
Microsatellite stable (MSS) 
metastatic colorectal adenocarcinoma 
progressing on chemotherapy 
¥Hypo-fractionated stereotactic body radiation therapy (SBRT) 
Three doses of palliative hypo-fractionated radiation at 9 Gy/dose will be delivered to a 
single lesion on Days – 2, −1, and Day 0 before Cycle 1 of the study begins.  See 
Appendix B. 
*Tremelimumab cycles 1-4  
•
Tremelimumab: 75 mg IV infusion on Day 1 of Cycle 1 through Cycle 4 (4 doses 
total). 
**Durvalumab cycles 1-24 
Note: With Amendment 6, study therapy (as durvalumab alone) is extended from Cycle 
5 through Cycle 12 to Cycle 5 through Cycle 24 (approximately 2 years).  
•
Durvalumab: 1500 mg IV on Day 1 of Cycle 1 through Cycle 24 (up to 24 doses 
total). 
Note: The duration of each cycle is 28 days.  
 
Study Entry 


 
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2.0 
BACKGROUND 
2.1 
Colorectal Cancer 
Colorectal cancer (CRC) is a major public health problem in the U.S. and globally.  In the U.S., 
nearly 50,000 deaths are attributed to this disease on an annual basis (Siegel 2015).  When 
metastatic disease is diagnosed, metastatic CRC (mCRC) is usually associated with poor 
prognosis, with 5-year survival rates in the 5-8% range.  Chemotherapy has been the mainstay 
approach for patients with metastatic CRC (mCRC).  For nearly 40 years, the main drug used was 
the fluoropyrimidine, 5- fluorouracil (5-FU).  Over the past decade, four new cytotoxic anticancer 
agents have been approved by the U.S. Food and Drug Administration (FDA).  These compounds 
include the topoisomerase I inhibitor irinotecan (CPT-11), the third-generation platinum analog 
oxaliplatin, the oral fluoropyrimidine capecitabine, and most recently the oral nucleoside  
TAS-102.  Since 2004, six biologic agents have been approved by the FDA, and they include the 
anti–vascular endothelial growth factor (VEGF) bevacizumab, the anti–epidermal growth factor 
receptor (EGFR) antibodies cetuximab and panitumumab, an anti-VEGF recombinant fusion 
protein aflibercept, a multikinase small molecule inhibitor regorafenib, an anti-VEGFR2 antibody 
ramucirumab. 
Significant advances have been made in chemotherapy treatment options for patients with mCRC 
with median OS of 24-26 months.  Median OS with best supportive care (BSC) alone in patients 
with mCRC after progression with standard treatment options is historically about 5 months.  
However, these results continue to fall far short of durable curative treatment of patients with 
mCRC.  There is clearly a significant unmet need for new agents and/or treatment regimens, 
which may enhance the efficacy of the available anticancer agents, reduce the toxicities of current 
anticancer agents, and/or improve overall quality of life. 
2.2 
The role of Programmed Death 1 (PD-1) pathway in antitumor immune responses 
PD-1 pathway blockade enhances tumor antigen-specific CD8+ T cell responses (Pardoll 2012, 
Postow 2015).  Recently significant advances in the treatment of several tumor types, including 
melanoma, non-small cell lung cancer, renal cell cancer, bladder cancer, and Hodgkin disease 
have been made by targeting this specific immunologic signaling pathway.  The responses have 
been highly durable and achieved with minimal toxicity (Brahmer 2012; Patnaik 2012; Topalian 
2012; Hamid 2013; Herbst 2014; Ansell 2015). 
PD-1 blockade showed a significant antitumor activity in microsatellite instability (MSI)-high 
colorectal cancer (Le 2015).  However, immune checkpoint blockade monotherapy including  
PD-1 blockade or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) therapy has 
not shown any significant antitumor activity in microsatellite stable (MSS) colorectal cancer (Le 
2015; Chung 2010; Brahmer 2010). 
2.3 
Durvalumab 
Durvalumab (MEDI4736) is a human monoclonal antibody (MAb) of the immunoglobulin G1 
kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1), (B7 
homolog 1 [B7-H1], cluster of differentiation [CD]274), and CD80 (B7-1) to programmed cell 
death 1 (PD-1; CD279) (Ibrahim 2015).  Durvalumab is composed of 2 identical heavy chains 
and 2 identical light chains, with an overall molecular weight of approximately 149 kDa. 
Durvalumab contains a triple mutation in the constant domain of the immunoglobulin (Ig) G1 
heavy chain that reduces binding to complement protein C1q and the fragment crystallizable 
gamma (Fcγ) receptors involved in triggering effector function. 
 
 


 
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2.3.1 
Summary of clinical experience 
As of the data cutoff (DCO) dates, April 15, 2015 to September 18, 2015, (MEDI4736 
IB), a total of 1,910 patients have been enrolled and treated in 30 ongoing durvalumab 
clinical studies, including 20 sponsored and 10 collaborative studies.  Of the 1,910 
patients, 1,279 received durvalumab monotherapy, 454 received durvalumab in 
combination with tremelimumab or other anticancer agents, 14 received other agents  
(1: gefitinib, 13: MEDI6383), and 163 have been treated with blinded investigational 
product.  No studies have been completed or terminated prematurely due to toxicity. 
2.3.2 
Safety 
The safety profile of durvalumab as monotherapy and combined with other anticancer 
agents was consistent with the pharmacology of the target and other agents in the immune 
checkpoint inhibitor class.  No tumor types appeared to be associated with unique AEs.  
Immune-related AEs (imAEs), which are important risks of immune checkpoint 
inhibitors, have been observed with durvalumab and include colitis, pneumonitis, 
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, 
and nephritis.  In addition, pancreatitis is an important potential risk particularly with 
durvalumab and tremelimumab combination therapy.  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.  The adverse event profile from two durvalumab 
monotherapy studies is summarized below: 
AEs of any 
grade in ≥ 5% 
of patients 
CD-ON-1108 
10mg/kg dose 
N=694 
AEs of any 
grade in ≥ 10% 
of patients 
D4191C00003 
10 mg/kg dose 
N=303 
Fatigue 
17.7% 
Dyspnea 
18.8% 
Nausea 
8.6% 
Fatigue 
12.8% 
Diarrhea 
7.3% 
Decreased 
appetite 
17.5% 
Decreased 
appetite 
6.8% 
Cough 
14.2% 
Pruritus 
6.3% 
Pyrexia 
12.2% 
Rash 
6.1% 
Asthenia 
11.9% 
Vomiting  
5.0% 
Nausea 
11.2% 
Treatment-related ≥ Grade 3 events reported in 3 or more patients (≥ 0.4%) in  
CD-ON-1108 were fatigue (12 patients, 1.7%); increased aspartate aminotransferase 
(AST; 7 patients, 1.0%); increased gamma-glutamyl transferase (GGT; 6 patients, 0.9%); 
increased alanine aminotransferase (ALT; 5 patients, 0.7%); and colitis, vomiting, 
decreased appetite, and hyponatremia (3 patients, 0.4% each).  Six patients had  
treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, 


 
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dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 patient had a  
treatment-related Grade 5 event (pneumonia). 
In study D4191C00003, treatment-related Grade 3 AEs reported in ≥ 2 patients were 
pneumonitis (3 patients) and increased GGT (2 patients).  There were no treatment-
related Grade 4 or 5 AEs. 
2.3.3 
Efficacy 
Efficacy varied by disease and by PD-L1 selection.  In PD-L1 unselected patients, the 
objective response rate (ORR), based on investigator assessment per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma 
(N = 23) to 20.0% in bladder cancer (N = 15).  Across the PD-L1-positive tumors, ORR 
was highest for bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma  
(HCC; N = 3 each, 33.3% each), NSCLC (N = 86, 26.7%), and squamous cell carcinoma 
of the head and neck (SCCHN; N = 22, 18.2%).  Of the 32 patients with myelodysplastic 
syndrome (MDS) treated in Study D4190C00007, 21 patients had at least 1 post-baseline 
disease assessment.  Among these patients, the best overall responses were molecular 
complete remission (mCR) in 4 patients (19.0%). 
2.4 
Tremelimumab 
Tremelimumab is an anti-CTLA-4 IgG2 monoclonal antibody, which blocks the inhibitory signal 
of CTLA-4/B7 pathway, leading to indirect prolongation and enhancement of T-cell activation 
and expansion. 
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7 
ligands and enhance human T-cell activation as demonstrated by increased cytokine (interleukin 
[IL]-2 and interferon gamma [IFN-γ]) production in vitro in whole blood or peripheral blood 
mononuclear cell cultures (Tarhini 2008).  In addition, blockade of CTLA-4 binding to B7 by 
anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor activity in 
animal models, including killing of established murine solid tumors and induction of protective 
antitumor immunity (Tremelimumab IB).  Therefore, it is expected that treatment with an anti-
CTLA-4 antibody, such as tremelimumab, will lead to increased activation of the human immune 
system, increasing antitumor activity in patients with solid tumors. 
An extensive program of nonclinical and clinical studies has been conducted for tremelimumab 
both as a monotherapy and as combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules.  As of the data cutoff date  
(November 1, 2015 for monotherapy studies and April 15, 2015 to July 12, 2015 for combination 
therapy studies), 34 sponsored clinical studies have been conducted as part of the tremelimumab 
clinical development program.  Of these, 13 studies have completed and 21 are ongoing.  Eight 
tremelimumab monotherapy studies have been completed and 3 are ongoing.  As of the data 
cutoff date of November 1, 2015, 973 patients received tremelimumab in completed monotherapy 
studies and the ongoing Study D4881C00024 and 569 patients have been treated in the ongoing 
blinded Phase IIb monotherapy Study D4880C00003 [DETERMINE]).  In the 3rd ongoing 
monotherapy study (D4884C00001), no patients have been treated as of the data cutoff.  In 
addition, approximately 59 patients have been treated with tremelimumab in monotherapy arms 
of combination studies.  Five studies of tremelimumab in combination with other anticancer 
agents have been completed and 18 are ongoing.  In total, 250 patients with a variety of tumor 
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The profile of adverse events (AEs) and the spectrum of event severity have remained stable 
across the tremelimumab clinical program and are consistent with the pharmacology of the target.  
To date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to patients with melanoma).  As of the data cutoff date for monotherapy 
studies of November 1, 2015, AEs (all grades, regardless of causality) reported in >10% of 
patients in the completed and rollover tremelimumab monotherapy studies (N=973, integrated 
data) were diarrhea (45.3%), fatigue (37.5%), nausea (32.5%), rash (28.9%), pruritus (27.4%), 
decreased appetite (22.8%), vomiting (22.5%), pyrexia (15.3%), cough (15.0%), constipation 
(14.4%), abdominal pain (13.9%), headache (13.8%), dyspnea (12.4%), and decreased weight 
(10.3%).  Based on integrated data from completed studies of tremelimumab in combination with 
other agents (N=116), AEs (all grades, regardless of causality) reported in >15% of patients were 
diarrhea (54.3%); nausea (40.5%); fatigue (38.8%); rash (35.3%); pruritus, decreased appetite 
(30.2% each); vomiting (27.6%); pyrexia (26.7%); influenza like illness (20.7%); arthralgia 
(19.8%); constipation (19.0%); thrombocytopenia, injection site reaction (18.1% each); and 
increased aspartate aminotransferase (AST; 15.5%).  Most of these events occurred at a higher 
rate with tremelimumab plus sunitinib than with other combinations.  The events of diarrhea, 
rash, and pruritus are considered identified risks of tremelimumab.  Acute renal failure was 
reported in patients who received the combination of tremelimumab and sunitinib; however, acute 
renal failure has not been an expected AE for single-agent tremelimumab.  The incidence and/or 
severity of many of the AEs observed following administration of tremelimumab can be reduced 
by following current guidelines for the management of immune-related toxicities (Tremelimumab 
IB). 
Chung et al. reported the result of a phase II study of tremelimumab monotherapy in patients with 
chemo-refractory mCRC (Chung 2010).  Patients received tremelimumab 15 mg/kg intravenously 
(IV) every 90 days until disease progression.  Tremelimumab monotherapy did not demonstrate 
clinically meaningful activity in this patient population (N = 45).  However, twenty-one patients 
(45%) lived >180 days after enrollment, and one patient had partial response (PR).  Grade 3/4 
treatment-related adverse events (AEs) were diarrhea (N = 5; 11%), ulcerative colitis  
(N = 1; 2%), fatigue (N = 1; 2%), autoimmune thrombocytopenia (N = 1; 2%), and hypokalemia 
(N = 1; 2%). 
2.5 
The combination of durvalumab and tremelimumab 
Pre-clinical and clinical data suggest that combination of immune checkpoint inhibitors targeting 
non-overlapping pathways such as durvalumab and tremelimumab may induce synergistic effect 
leading to improved tumor response in comparison to monotherapy with either agent alone 
(Pardoll 2012).  The combination of agents targeting PD-1/PD-L1 and CTLA-4 has profound and 
durable clinical benefit in patients with metastatic melanoma (Larkin 2015). 
Antonia et al. reported a phase 1, open-label dose escalation and expansion study of durvalumab 
plus tremelimumab to assess the safety/tolerability and antitumor activity in patients with 
advanced NSCLC (Antonia 2015).  An ORR of 27% was observed in 63 patients.  AEs were 
manageable and generally reversible using standard treatment guidelines.  Increasing doses of 
tremelimumab were generally associated with greater frequency of AEs.  Across all dose cohorts, 
related Grade 3/4 events were reported in 41/102 (40%) patients.  Most frequently reported events 
were colitis, diarrhea, elevated lipase, and elevated liver function tests. 32/102 (31%) patients 
used corticosteroids.  Twenty out of 102 (20%) patients discontinued study therapy due to drug-
related AEs.  Based on the result of the phase I study of durvalumab/tremelimumab combination, 
Antonia et al. concluded that the schedule of durvalumab 20 mg/kg every 4 weeks in combination 
with tremelimumab 1 mg/kg every 4 weeks is appropriate for further development because the 
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2) demonstrates a manageable safety profile; 3) incorporates a biologically active dose of 
tremelimumab associated with clinical activity (Antonia 2015). 
2.5.1 
Rationale for fixed dosing of durvalumab and tremelimumab  
A population PK model was developed for durvalumab using monotherapy data from a 
Phase 1 study (study 1108; N = 292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; 
solid tumors).  Population PK analysis indicated only minor impact of body weight (WT) 
on PK of durvalumab (coefficient of ≤ 0.5).  The impact of body WT-based (10 mg/kg 
Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing 
predicted steady state PK concentrations (5th, median and 95th percentiles) using the 
population PK model.  A fixed dose of 750 mg was selected to approximate 10 mg/kg 
(based on median body WT of approximately 75 kg).  A total of 1000 patients were 
simulated using body WT distribution of 40–120 kg.  Simulation results demonstrated 
that body WT-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-subject variability with fixed dosing 
regimens. 
Similarly, a population PK model was developed for tremelimumab using data from 
Phase 1 through Phase 3 (N = 654; doses = 0.01 to 15 mg/kg Q4W or Q90D; metastatic 
melanoma).  Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤ 0.5).  The WT-based (1 mg/kg Q4W) and fixed dosing 
(75 mg/kg Q4W; based on median body WT of approximately 75 kg) regimens were 
compared using predicted PK concentrations (5th, median and 95th percentiles) using 
population PK model in a simulated population of 1000 patients with body weight 
distribution of 40 to 120 kg.  Similar to durvalumab, simulations indicated that both body 
WT-based and fixed dosing regimens of tremelimumab yield similar median steady state 
PK concentrations with slightly less between-subject variability with fixed dosing 
regimen (Wang 2014). 
A fixed dosing approach is preferred by the prescribing community due to ease of use 
and reduced dosing errors.  Given expectation of similar pharmacokinetic exposure and 
variability, we considered it feasible to switch to fixed dosing regimens.  Based on 
average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to  
20 mg/kg Q4W), and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W); is 
included in the current study.  
Fixed dosing of durvalumab and tremelimumab is recommended only for patients with 
> 30kg body weight due to endotoxin exposure.  Patients with a body weight less than or 
equal to 30 kg should be dosed using a weight-based dosing schedule. 
2.6 
Effect of radiation on immune response to cancer cells 
2.6.1 
Immunogenic Cell Death by Radiation 
Radiation causes immunogenic cell death of cancer cells, modulates antigen presentation 
by cancer cells, and alters the microenvironment within the irradiated field (Esposito 
2015).  The immunogenic cell death of cancer cells involves a multistep process.  The 
release of fractalkine, nucleotides, and adenosine triphosphate (ATP) attract phagocytes 
or dendritic cells, and the expression of calreticulin (CRT) facilitates recognition by 
phagocytes or dendritic cells.  The release of danger-associated molecular patterns such 
as high-mobility group box 1 protein (HMGB1) and ATP, which enable dying tumor 
cells to lose the propensity to induce tolerance and to stimulate powerful anticancer 
immune responses (Zitvogel 2010; Golden 2012).  Immunogenic cell death by 


 
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radiotherapy involves the cell surface exposure of CRT, and the release of HMGB1, and 
ATP that triggers dendritic cell (DC) engulfment of dying cells, antigen presentation, and 
production of interleukin (IL)-1β, ultimately leading to activation of CD8+ T cells 
(Esposito 2015). 
Low-dose radiation programs the differentiation of iNOS+ M1 macrophages that 
orchestrate CTL recruitment into and killing within solid tumors through iNOS by 
inducing endothelial activation and the expression of Th1 chemokines and by suppressing 
the production of angiogenic, immunosuppressive, and tumor growth factors.  iNOS+ 
macrophages in the tumor microenvironment are both required and sufficient to mediate 
effector T cell recruitment into tumor tissue and successful tumor immune rejection 
through an NO-dependent mechanism (Klug 2013). 
2.6.2 
Abscopal effect of radiation 
The abscopal effect is a phenomenon in which local radiotherapy is associated with the 
regression of other metastatic lesions distant from the irradiated site.  Postow et al. 
(Postow 2012) reported a case of the abscopal effect in a patient with melanoma treated 
with ipilimumab and palliative radiation.  Localized radiation therapy was administered 
to the metastasis for pain control.  The target tumor decreased and, in addition, the distant 
metastatic disease in lymph nodes and spleen also regressed.  The off-target regression in 
progressive metastatic disease after local irradiation with immunotherapy was correlated 
with activation of a T-cell population suggesting that radiation may have played an 
immunomodulatory role (Postow 2012).  Thus, this “abscopal effect” 
(immunomodulatory effects on systemic cancer burden with local radiotherapy) appears 
related to a host of effects related to local radiation-induced release of damage-associated 
molecular patterns (DAMP), such as cancer-associated neoantigens, secretion of  
pro-inflammatory cytokines without concurrent systemic immunosuppressive effects, 
upregulation of immunogenic cell surface markers on cancer and surrounding stroma, 
increased homing of immune cells to tumors and improved antigen presentation by 
antigen-presenting cells (Formenti 2009, Formenti 2012 Formenti 2013; Gaipl 2014). 
Anecdotal reports describe durable abscopal effects in patients who received palliative 
doses of radiation during treatment with immunomodulatory therapies such as  
anti-CTLA-4 or PD-1/PD-L1 pathway blockade (Sagiv-Barfi 2014, Postow 2012). 
2.7 
The combination of radiation and immune checkpoint inhibitors 
2.7.1 
Radiation plus ipilimumab promotes regression of unirradiated tumors in patients with 
melanoma 
Twyman-Saint Victor et al. reported major tumor regressions in a subset of patients with 
metastatic melanoma treated with an anti-CTLA4 antibody (ipilimumab) and radiation 
(Twyman-Saint Victor 2015).  To examine the feasibility and efficacy of radiation 
combined with immune check-point blockade, Twyman-Saint Victor et al. initiated a 
phase I clinical trial of 22 patients with multiple melanoma metastases.  A single index 
lesion was irradiated with hypofractionated stereotactic body radiation (SBRT; 2-3 doses 
of 6-8 Gy radiation delivered on separate days), followed by four cycles of the  
anti-CTLA4 anti-body ipilimumab.  Evaluation of the unirradiated lesions by RECIST 
demonstrated that 18% of patients had a partial response as best response, 18% had stable 
disease, and 64% had progressive disease.  Of note, one patient showed a large reduction 
in the size of unirradiated tumors and a partial metabolic response by positron emission 
tomography (PET).  None of the 12 patients evaluated by PET had progressive metabolic 
disease in the irradiated lesion.  The median progression-free survival and overall 


 
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survival was 3.8 and 10.7 months with median follow-up of 18.4 and 21.3 months (18.0 
and 21.3 months for patients without event), respectively. 
2.7.2 
Radiation in combination with PD-1 blockade 
There are a number of preclinical studies in which radiation has been combined with  
PD-1 blockade which demonstrate an abscopal effect.  Deng et al. reported that radiation 
in combination with anti-PD-L1 generated an abscopal effect greatly reducing the growth 
of a secondary unirradiated TUBO flank tumor in murine models (Deng 2014).  
Rechallenge experiments and tumor rejection in mice suggested the generation of 
prolonged protective immunity by combined treatment of anti-PD-1 antibodies and 
radiation.  Dovedi et al. showed that radiation combined with anti-PD-1 and anti-PD-L1 
antibodies improved long-term survival in murine cancer models and protection against 
tumor rechallenge (Dovedi 2014).  In another example, Park et al. showed abscopal effect 
of radiation combined with PD-1 blockade in murine melanoma (B16) and renal cell 
carcinoma models.  Of note, the immune-mediated effects of radiation in combination 
with PD-1 blockade are tumor specific (Park 2015).  Radiation of one tumor type (renal 
cell carcinoma) induced protective immune responses that did not cross over to other 
tumor types (4T1) in the same mice. 
In another model, Sharabi et al. reported that stereotactic radiation induces endogenous 
antigen-specific immune responses when it is combined with PD-1 checkpoint blockade 
(Sharabi 2015a).  Using a small animal radiation research platform (SARRP),  
image-guided stereotactic radiation was delivered to B16-OVA melanoma or 4T1-HA 
breast carcinoma tumors resulting in the development of antigen-specific T cell– and B 
cell–mediated immune responses.  These immune-stimulating effects of stereotactic 
radiation were significantly increased in combination with PD-1 pathway blockade, 
resulting in improved local tumor control.  Stereotactic radiation is reported to have 
several effects on the immune system including increasing the percentage of  
antigen-experienced T cells and effector memory T cells, upregulating tumor-associated 
antigen–MHC complexes, enhancing antigen cross-presentation in the draining lymph 
node, and increasing T-cell infiltration into tumors. 
2.7.3 
The optimal dose and schedule of radiation when combined with immune checkpoint 
inhibitors  
The optimal fractionation regimen for augmenting immunogenicity of tumors and 
inducing immune response in patients is unknown (Demaria 2012).  In this study, three 
daily doses of palliative SBRT at 9 Gy per day in a total of 27 Gy will be administered 
three days (Days −2, −1, and Day 0) prior to the initial administration of study therapy 
(durvalumab/tremelimumab).  The choice of dose and schedule is based on observations 
by Twyman-Saint Victor et al. (Twyman-Saint Victor 2015) and Sharabi et al. (Sharabi 
2015b), that hypofractionated radiation at a dose of 5–20 Gy per fraction is considered to 
be better than conventionally fractionated schedule of 1.8–2.2 Gy fractions and that 
concurrent checkpoint blockade starting on the day of or during radiation was better than 
starting checkpoint blockade after the completion of radiation (Sharabi 2015b).  
2.8 
Rationale for the combination of radiation and dual checkpoint blockade 
Twyman-Saint Victor et al. reproduced the synergistic effect of radiation and anti-CTLA4 
therapy in mouse models to further characterize the mechanism (Twyman-Saint Victor 2015).  
Although combined treatment improved responses in irradiated and unirradiated tumors, 
resistance to the combination therapy was common.  Analyses of these mouse models revealed 
that resistance to the combination of radiation and anti-CTLA4 treatment was due to upregulation 


 
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of PD-L1 on tumor cells, resulting in T-cell exhaustion.  In an attempt to reduce T-cell 
exhaustion, the radiation and dual checkpoint blockade with anti-CTLA4 and anti-PD-L1/PD-1 
was combined and showed significant synergistic antitumor activity in murine melanoma and 
pancreatic cancer models (Figure 2) (Twyman-Saint Victor 2015).  
Figure 2: PD-1 Blockade Antagonizes Acquired Resistance to Radiation plus anti-CTLA4 Therapy 
Figure 2: A. Survival of mice with B16-F10 tumors (murine melanoma) according to treatment 
group (N = 18 for RT + C4, N = 5 for others).  Shown are overall log-rank P values, Radiation 
(RT); C4, anti-CTLA4 antibody; PD1, anti-PD-L1. 
B. Survival of mice with pancreatic tumors from a cell line derived from KPC mice 
(KrasLSL-G12D+; p53LSL-R172H+; Pdx-1-Cre) (N = 5 for each group).  Overall P value is shown. 
Further analysis of these murine models (Twyman-Saint Victor 2015) revealed that:  
• 
Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the 
CD8+ T-cell to Treg ratio (CD8+/Treg); 
• 
Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral  
T cells; and 
• 
The addition of PD-L1/PD-1 blockade reverses T-cell exhaustion. 
Similarly to these results from murine models, melanoma patients with high PD-L1 expression 
did not respond to radiation plus anti-CTLA4, consistent with persistent T-cell exhaustion 
(Twyman-Saint Victor 2015).  Taken together, this data suggest that the combination of radiation, 
anti-CTLA4 and anti-PD- L1 may promote antitumor immune response through synergistic 
mechanisms. 
2.9 
Translational opportunities 
Pre-clinical and clinical data suggest that combination of immune checkpoint inhibitors targeting 
non-overlapping pathways such as durvalumab and tremelimumab may induce synergistic effect 
leading to improved tumor response in comparison to monotherapy with either agent alone.  We 
hypothesize that the combination of radiation and dual immune checkpoint blockade with 
durvalumab plus tremelimumab may have synergistic effect on effector T cell activation (Pardoll 
2012). 


 
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This study serves as a platform allowing for detailed assessment of the mechanisms of immune 
stimulation, predictive markers of response or resistance and rational development of the next 
generation of combination immunomodulatory interventions (Taube 2014, Topalian 2012).  
Samples will be collected that may be used in post-hoc analyses including but, not limited to: 
• 
peripheral lymphocytes analysis for immune cell gene expression and quantitative changes of 
lymphocyte subpopulation and immune-related cells. 
• 
collection of tumor tissues from unirradiated tumor sites prior to radiation and after two 
cycles of therapy for further analysis of immune response in tumor. 
• 
analysis of gene expression related to immune checkpoint pathways.  
• 
analysis of frequency of mutation-associated neoantigens in tumor tissues.  
 
 


 
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3.0 
STUDY AIMS AND ENDPOINTS 
3.1 
Primary aim and endpoint 
Aim: To determine the efficacy of the dual immune checkpoint blockade with durvalumab plus 
tremelimumab following a small dose of hypofractionated palliative radiation in patients with 
MSS mCRC who have progressed on chemotherapy. 
Endpoint: Overall objective response rate (ORR) as measured by RECIST 1.1 criteria. 
3.2 
Secondary aims and endpoints 
3.2.1 
Clinical benefit rate 
Aim: To determine objective tumor decrease and stable disease (SD) at 16 weeks. 
Endpoint: Measurement of disease status by continuous tumor measurement (any partial 
response [PR], any complete response [CR] and SD at 16 weeks). 
3.2.2 
Duration of response 
Aim: To determine the duration of response of mCRC to study therapy. 
Endpoint: Measurement of time from study entry until documentation of progression as 
determined by RECIST 1.1. 
3.2.3 
Safety and Toxicity 
Aim: To determine the safety of the combination of dual immune checkpoint blockade 
with durvalumab plus tremelimumab following hypofractionated palliative radiation in 
patients with MSS mCRC who have progressed on chemotherapy. 
Endpoint: Frequency and severity of adverse events categorized using the NCI Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). 
3.3 
Exploratory Translational Science  
Aim: To explore the effect of the combination of dual immune checkpoint blockade with 
durvalumab plus tremelimumab following hypofractionated palliative radiation on 
immune response in blood and in tumor tissue. 
Aim:  To correlate the frequency of mutation-associated neoantigens in tumor tissues and 
clinical response. 
 
 


 
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4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY 
4.1 
Conditions for patient eligibility 
A patient cannot be considered eligible for this study unless all of the following conditions are 
met: 
4.1.1 
The patient must have consented to participate and, prior to beginning specific study 
procedures, must have signed and dated an appropriate IRB-approved consent form that 
conforms to federal and institutional guidelines for study treatment and for submission of 
tumor and blood samples as required by FC-9 correlative science studies (see Section 6.0). 
4.1.2 
Patients must be ≥ 18 years old. 
4.1.3 
The ECOG performance status must be 0 or 1 (see Appendix A). 
4.1.4 
There must be histologic confirmation of a diagnosis of colorectal adenocarcinoma.  
4.1.5 
The tumor must have been determined to be microsatellite stable (MSS). 
4.1.6 
There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has 
evidence of measurable metastatic disease per RECIST 1.1.   
4.1.7 
Patients must have an accessible metastatic lesion for pretreatment core biopsy.  
4.1.8 
Unless either drug is medically contraindicated, patients must have received oxaliplatin 
and irinotecan as part of standard metastatic chemotherapy regimens.  
4.1.9 
The patient must have multiple sites of metastatic disease with at least one lesion 
amenable to treatment with stereotactic radiation therapy (SBRT) in the lung or liver and 
at least one lesion not being irradiated and meeting RECIST 1.1. (See Appendix B). 
4.1.10 At the time of study entry, blood counts performed within 2 weeks prior to study entry 
must meet the following criteria: 
• 
ANC must be ≥ 1500/mm3, 
• 
Platelet count must be ≥ 100,000/mm3; and 
• 
Hemoglobin must be ≥ 9 g/dL. 
4.1.11 The following criteria for evidence of adequate hepatic function performed within  
2 weeks prior to study entry must be met: 
• 
Total bilirubin must be ≤ 1.5 x ULN (upper limit of normal) for the lab unless the 
patient has a bilirubin elevation > 1.5 x ULN to 3 x ULN due to Gilbert’s disease or 
similar syndrome involving slow conjugation of bilirubin; and  
• 
AST and ALT must be ≤ 2.5 x ULN for the lab with the following exception: for 
patients with documented liver metastases, AST and ALT must be ≤ 5 x ULN. 
4.1.12 Adequate renal function within 4 weeks prior to study entry, defined as serum creatinine 
≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance > 40 mL/min by 
Cockcroft-Gault formula. 
4.1.13 All hematologic, gastrointestinal, and genitourinary chemotherapy toxicities must be  
< Grade 2 at the time study therapy is to begin.  (Note: Transfusions may be used to 
correct hemoglobin for patients experiencing anemia from therapy who otherwise would 
be eligible for the study. 
4.1.14 Patients with reproductive potential (male/female) must agree to use accepted and highly 
effective methods of contraception while receiving study therapy and for at least  


 
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6 months after the completion of study therapy.  The definition of effective method of 
contraception will be based on the investigator's discretion.  See Appendix C.  
Female patients must either be of non-reproductive potential (i.e., post-menopausal by 
history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause; 
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral 
oophorectomy) or must have a negative serum pregnancy test upon study entry. 
4.2 
Conditions for patient ineligibility 
Any patient with one or more of the following conditions will be ineligible for this study: 
4.2.1 
Diagnosis of anal or small bowel carcinoma. 
4.2.2 
Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid. 
4.2.3 
Previous therapy with any PD-1 or PD-L1 inhibitor including durvalumab or anti-CTLA4 
(including tremelimumab) for any malignancy. 
4.2.4 
Receipt of live attenuated vaccination within 30 days prior to study entry or within  
30 days of receiving study therapy. 
4.2.5 
Active or chronic hepatitis B or hepatitis C. 
4.2.6 
Symptomatic or uncontrolled brain metastases requiring concurrent treatments, 
uncontrolled spinal cord compression, carcinomatous meningitis, or new evidence of 
brain or leptomeningeal disease; uncontrolled seizures. 
4.2.7 
Active infection or chronic infection requiring chronic suppressive antibiotics. 
4.2.8 
Active or documented inflammatory disease. 
4.2.9 
Known history of human immunodeficiency virus (HIV) or acquired immunodeficiency-
related (AIDS) illnesses. 
4.2.10 Current or prior use of immunosuppressive medication within 28 days before the first 
dose of study therapy with the exceptions of intranasal corticosteroids or systemic 
corticosteroids at physiological doses that do not exceed 10mg/day of prednisone or an 
equivalent corticosteroid. 
4.2.11 History of allogeneic organ transplantation. 
4.2.12 Any of the following cardiac conditions: 
• 
Documented NYHA Class III or IV congestive heart failure, 
• 
Myocardial infarction within 6 months prior to study entry, 
• 
Unstable angina within 6 months prior to study entry, 
• 
Symptomatic arrhythmia. 
4.2.13 Uncontrolled high blood pressure defined as systolic BP ≥ 150 mmHg or diastolic  
BP ≥ 100 mmHg with or without anti-hypertensive medication.  Patients with initial BP 
elevations are eligible if initiation or adjustment of BP medication lowers pressure to 
meet entry criteria. 
4.2.14 Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative 
colitis). 
4.2.15 Ongoing or active gastritis or peptic ulcer disease. 


 
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4.2.16 Active bleeding diatheses.  
4.2.17 Known history of previous diagnosis of tuberculosis. 
4.2.18 History of hypersensitivity to durvalumab or tremelimumab or any excipients of these 
drugs. 
4.2.19 Known history or confirmation of active pneumonia, pneumonitis, symptomatic 
interstitial lung disease, or definitive evidence of interstitial lung disease described on CT 
scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current 
continuous oxygen therapy. 
4.2.20 Active or prior documented autoimmune disease or inflammatory condition requiring 
ongoing immunosuppressive medications.  (Note: Patients with vitiligo, Grave disease, or 
psoriasis not requiring systemic treatment within the past 2 years are eligible.) 
4.2.21 Other malignancies unless the patient is considered to be disease-free and has completed 
therapy for the malignancy ≥ 12 months prior to study entry.  Patients with the following 
cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ 
of the cervix, and basal cell and squamous cell carcinoma of the skin. 
4.2.22 Psychiatric or addictive disorders or other conditions that, in the opinion of the 
investigator, would preclude the patient from meeting the study requirements or interfere 
with interpretation of study results. 
4.2.23 Pregnancy or lactation at the time of study entry.  (Note: Pregnancy testing should be 
performed within 14 days prior to study entry according to institutional standards for 
women of childbearing potential.) 
4.2.24 Use and/or receipt of the last dose of anti-cancer therapy (i.e., chemotherapy, 
immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor 
embolization, monoclonal anti-bodies) within 14 days prior to the first dose of study 
therapy. (Note: SBRT is required prior to beginning study therapy.) 
4.2.25 Use of any investigational agent within 4 weeks of starting study therapy.   
 
 


 
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5.0 
REQUIREMENTS FOR STUDY ENTRY, DURING TREATMENT, AND FOLLOW-UP 
Tests and exams required before study entry are listed on Table 1.  Requirements following study 
entry are outlined on Table 2. 
Table 1.  Tests, exams, and other requirements prior to study entry 
Requirements 
Prior to Study Entry 
Consent form for FC-9 signed by the patient 
X 
Agreement of local Pathology department to release the primary 
tumor tissuea 
X 
History & physical examb 
X 
Within 4 weeks 
Performance status (see Appendix A) 
X 
Height & weight 
X 
Sodium, potassium, chloride, bicarbonate or carbon dioxide, 
calcium, glucose, total protein, LDH 
X 
Thyroid function tests: TSHc 
X 
Urinalysis 
X 
CEA 
X 
PET/CT (if available) or CT scan of chest, abdomen, and pelvis 
with IV/oral contrast (MRI can be substituted for the CT scan)d 
X 
APTT and INR 
X 
CBC/differential/platelet count 
X 
Within 2 weeks 
Total bilirubin (direct and indirect), AST (SGOT), ALT (SGPT), 
alkaline phosphatase; albumin, lipase, and amylase, creatinine, 
BUN 
X 
Pregnancy teste 
X 
Required study blood samplesf 
X 
Prior to beginning 
radiation therapy 
Core biopsy to procure tumor samples for submission to the 
NSABP Division of Pathologyg 
X 
a The archived primary tumor tissue from the diagnostic biopsy (or other previous surgery) must be 
requested and the Pathology department must agree before study entry to release an archived 
paraffin tumor block or slides if the block is unavailable (see Section 6.0).  Submit the tumor tissue 
within 60 days after study entry.  Note: With confirmation from DSSM, patients whose diagnostic 
sample was previously submitted for participation in NSABP MPR-1 will have met this study 
requirement.  Provide the MPR-1 Patient ID number to DSSM for confirmation of MPR-1 tumor 
sample submission.  
b Complete H&P by physician or other healthcare professional (on FDA Form 1572). 
c 
If TSH abnormal, (outside normal range) obtain free triiodothyronine (T3) and thyroxine (T4). 
d The same method (PET/CT scan, CT or MRI) used for baseline tumor measurements should be 
used at all other tumor measurement time points. 
e 
For WOCBP: Pregnancy testing should be performed according to institutional standards. 
f 
Blood samples collected for research study purposes should be drawn concurrently with blood 
samples required for study entry. See Section 6.0.  
g 
This additional biopsy and overnight submission of fresh tumor samples is a study requirement.  
See Section 6.0.  
Refer to FC-9 Pathology and Correlative Science Instructions for additional information on 
blood and tissue collection. 


 
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Table 2.  Tests, exams, and other requirements following study entry 
Required studies 
(see footnote a) 
Within  
72 hours before Day 1 
(Beginning with Cycle 1 through 
Cycle 4) 
unless indicated otherwise 
1 cycle = 28 days 
Within  
72 hours before Day 1 
(Beginning with Cycle 5 through Cycle 24) 
unless indicated otherwise 
1 cycle = 28 days 
Follow-up 
(Within 30 days following 
completion or discontinuation of 
study therapy) 
History & physical exama,b 
X 
X 
X 
Vital signsc 
X 
X 
X 
Adverse event assessmentb,d 
X 
X 
X 
Measurement of target lesionse 
X 
(After Cycles 2 and Cycle 4) 
X 
(After every even cycle) 
 
CBC/differential/platelets 
X 
X 
X 
Sodium, potassium, chloride, 
bicarbonate or carbon dioxide, 
calcium, BUN or urea, creatinine, 
glucose, total protein 
X 
X 
X 
Total bilirubin, AST, ALT, alkaline 
phosphatase; albumin, LDH, lipase, 
amylase 
X 
X 
X 
CEAf 
X 
(After every 2 cycles with scans) 
X 
TSHg 
X 
(Every 2 cycles) 
X 
(Every 2 cycles) 
 
Urinalysis 
X 
X 
 
Blood samplesh 
X 
(Day 15/Cycle 1 and 
Day 1/Cycles 2, 4)  
X 
(Day 1, Cycle 6) 
 
Tumor samplei 
X 
(Following completion of Cycle 2) 
[at 8 weeks] 
 
 
Table 2 continued on next page. 
 
 


 
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Table 2.  Tests, exams, and other requirements following study entry (continued) 
a 
At the discretion of the investigator, additional exams, bloodwork, x-rays, ECGs, scans, and other testing may be performed as clinically 
indicated. 
b 
Note: Confirmation must be made that resolution of all hematologic, gastrointestinal and genitourinary toxicities are < Grade 2 before 
beginning the first study therapy infusion.  Updated H&P with exams, adverse event assessment, and assessments during therapy and 
follow-up by physician or other appropriate healthcare professional (on FDA Form 1572). 
c 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured and recorded. On study therapy treatment days, 
vital signs will be measured within an hour prior to start of tremelimumab and durvalumab administration, at 30 minutes during the infusion 
(± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion.  If the 
infusion takes longer than 60 minutes, then blood pressure and pulse measurements should follow the time increments as outlined at the end 
of the infusion or more frequently if clinically indicated.  For subsequent doses of study therapy, there will be a 30 minute observation 
period and vital sign check between tremelimumab and durvalumab doses to monitor potential infusion-related reactions.  See Table 4. 
d 
AE assessments 90 days (+/− 14 days) after the last dose of study therapy. Should the patient stop study therapy (e.g. due to disease 
progression or second primary) and begin a new treatment prior to the last dose of durvalumab assessment, AE assessments should be 
collected only up to the date the new therapy begins. See Section 10.7. 
e 
The same imaging method (PET/CT scan, CT scan or MRI), used at baseline should be used every 2 cycles from start of therapy.  
Assessment of measurable disease is every 2 cycles by RECIST 1.1.  See Section 11.0. 
f 
CEA levels should be obtained every 2 cycles to correlate with disease imaging. 
g If TSH abnormal, (outside normal range) obtain free triiodothyronine (T3) and thyroxine (T4). 
h Blood samples will be collected on Cycle 1/Day 15, and prior to beginning cycles 2, 4 and 6.  Blood samples collected for research study 
purposes should be drawn concurrently with blood samples required for study.  See FC-9 Pathology and Correlative Science Instructions for 
required correlative study blood collection instructions.  See Section 6.0. 
i 
Submission of core biopsy specimens of an accessible metastatic lesion collected after completion of cycle 2 (approximately 8 weeks) is a 
study requirement. 
NOTE: Refer to the FC-9 Pathology and Correlative Science Instructions for tumor and blood sample submission instructions. 


 
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6.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES 
6.1 
Overview of requirements 
Collection and submission of all patient samples (blood, tumor) as listed below is a requirement 
for all patients participating in the NSABP FC-9 study.  By signing the FC-9 consent form, the 
patient has agreed to all required sample collections and submissions. 
Non-submission of required patient samples will be a protocol violation.   
 
Table 3. Summary of FC-9 patient sample submission requirements 
Study 
Requirements 
for 
ALL Patients 
(unless indicated 
otherwise) 
Prior to Study 
Entry 
Before radiation 
therapy begins 
(Prior to Day −2) 
Cycle 1, Day 
15 
Up to 3 days prior to Day 
1 of Cycles 2, 4 and 6  
Therapy Begins 
Submission of 
treatment-naive 
tumor (primary 
or metastatic 
diagnostic tumor 
[FFPE block]) 
Yesa 
N/A 
 
N/A 
Submission of 
fresh tumor 
samplesb 
Yes 
 
 
Yes 
(Following completion of 
cycle 2 
[at 8 weeks]) 
Collection & 
submission of 
blood samplesc 
Yes 
 
Yes 
Yes 
a 
Archived paraffin block of primary tumor tissue is preferable.  Refer to FC-9 Pathology and 
Correlative Science Instructions for acceptable alternative submissions.   
Note: After confirmation by DSSM, patients whose diagnostic sample was previously submitted for 
participation in NSABP MPR-1 will have met this study requirement.  Provide the MPR-1 Patient ID 
number to DSSM for confirmation of MPR-1 tumor sample submission.  
b Submission of core biopsy specimens of an accessible metastatic lesion collected prior to beginning 
radiation therapy and following completion of Cycle 2 (at 8 weeks on study therapy) is a study 
requirement.   
c 
Blood sample collections: Pre-treatment prior to beginning radiation therapy, Day 15 of Cycle 1, and 
Day 1 of Cycles 2, 4, and 6.  See Section 6.3.2. 
Refer to the FC-9 Pathology and Correlative Science Instructions for tumor and blood sample 
submission instructions. 
6.2 
Use of specimens 
The blood and tumor samples collected in this study will be used for FC-9 studies as described in 
Section 6.4 and for analyses to be conducted in the future related to the purposes of the FC-9 
study but not currently described in the protocol.  Additionally, the specimens procured may be 
used for future studies involving gene and proteins conferring susceptibility to cancer or other 
diseases.  Results of the correlative science studies, including raw sequencing data, will not be 
reported directly to the patient or the physician and will not have any bearing on patient 
treatment. 


 
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The results of the study will be communicated through publication, in peer reviewed scientific 
literature and/or through presentations at scientific meetings.  However, anonymized or  
de-identified research data (as deemed appropriate by the NSABP), including genome sequencing 
data, may be submitted to public research databases for data sharing with scientific researchers 
outside of the NSABP. 
6.3 
Required tumor and blood sample submission procedures 
6.3.1 
Archived primary tumor tissue 
Submission of archived primary tumor block prepared from the diagnostic biopsy or 
other surgery is a study requirement.  If the tumor block is not available, refer to FC-9 
Pathology and Correlative Science Instructions for details on alternative submission.   
Note: After confirmation by DSSM, patients whose diagnostic sample was previously 
submitted for participation in NSABP MPR-1 will have met this study requirement.  
Provide the MPR-1 Patient ID number to DSSM for confirmation of MPR-1 tumor 
sample submission. 
6.3.2 
Study blood samples 
Blood samples will be collected and submitted at 5 time points for each patient: 
− 
Pre-treatment (prior to beginning radiation therapy), 
− 
Cycle 1, Day 15 
− 
Cycle 2, Day 1; 
− 
Cycle 4, Day 1, and 
− 
Cycle 6, Day 1. 
6.3.3 
Fresh tissue collection 
Required tumor samples will be collected at 2 time points for each patient: 
− 
At pre-treatment prior to radiation; and  
− 
After Cycle 2 (8 weeks). 
6.4 
Correlative Science Studies 
The following correlative science studies are planned to determine the effect of the combination 
of radiation and dual immune checkpoint blockade with durvalumab plus tremelimumab on 
immune response in blood and in tumor tissues. 
6.4.1 
Immune monitoring of peripheral blood 
• 
Blood lymphocytes may be analyzed for immune cell gene expression and 
quantitative changes of lymphocyte subpopulation and immune-related cells prior to 
radiation and while receiving study therapy.  
• 
Peripheral blood mononuclear cells (PBMC) may be assessed by fluorescence-
activated cell sorting (FACS) or with gene expression for changes in cell subsets 
including, but not limited to, naive and memory CD8+ and CD4+ T cells, MDSCs, 
NK, and B cells.  The PBMCs may be used to screen for immune response and for 
functional assays such as an assessment of antibody dependent cell mediated 
cytotoxicity (ADCC). 
6.4.2 
Analysis of circulating tumor DNA and circulating tumor cells 
Peripheral blood mononuclear cells (PBMCs) may also be archived to isolate circulating 
tumor cells (CTCs) and/or cell free DNA (cfDNA).  The cfDNA may be used to profile 
circulating tumor DNA for mutations, amplifications, gene fusions or other genetic 


 
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abnormalities arising during the course of disease or in response to therapy.  Analyzing 
detected cfDNA and CTCs in PBMC may provide further understanding of patient 
response and explain resistance or sensitivity to therapy.  
6.4.3 
Analysis of tumor infiltrating immune cell populations 
It is expected that immunogenic cell death of cancer cells induced by radiation of an 
index lesion enhance antitumor immune response.  Tumor tissues from unirradiated 
tumor sites will be procured at baseline prior to radiation and after cycle 2 for further 
analysis of immune response in tumor.  The extent of intratumoral CD8+ T and other 
immune cell infiltrates in tumor tissues may be analyzed and the immunoscore may be 
determined as reported previously (Tumeh 2014, Galon 2006, Pages 2005, Llosa 2015).  
We will use the most appropriate technology at that time. 
The tumor/immune microenvironment may be assessed by IHC staining of multiple 
immune markers utilizing the PerkinElmer's opal-7 color staining system and their 
Vectra® quantitative pathology imaging systems with the inForm® Advanced Image 
Analysis system.  Multiplex staining of up to 6 different markers enables the 
identification of helper B cells (CD20), T cells (CD4), cytotoxic T cells (CD8), memory 
T cells (CD45RO) and regulatory T-cells (FOXP3) in a single section of tissue.  Other 
markers such as PD-L1, PD-1 can also be multiplexed with these immune markers.  This 
allows for not only the quantification of specific types of immune cells but also localizes 
these cells with respect to the tumor and with respect to each other, an important 
consideration for assessment of the immune environment. 
6.4.4 
Analysis of gene expression involved in immune checkpoint pathways in tumor tissues 
It is known that multiple immune checkpoint pathways are involved in antitumor immune 
response.  Expression of genes involved in immune checkpoint pathways including  
PD-L1/2, LAG-3, OX40, GITR, TIM-3, CD137, IDO, markers for MDSCs, and markers 
associated with immunogenic cell death (Bezu 2015) may be analyzed by IHC in tumor 
tissue biopsied at pre-treatment prior to radiation and after cycle 2 (8 weeks) (Tumeh 
2014, Llosa 2015).  RNA-Seq and/or the nCounter Vantage™ RNA: Protein Immune 
Cell profiling panel from NanoString which interrogates the expression of 770 genes and 
30 proteins may be used to assess the expression of both the tumor and immune 
microenvironment. 
6.4.5 
Analysis of the frequency of mutation-associated neoantigens in tumor tissues 
It has been shown that the frequency of mutation-associated neoantigens in tumor tissues 
correlates with clinical response to immune checkpoint inhibitors in melanoma, lung 
cancers and MSI-high colorectal cancer (Le 2015, Alexandrov 2013, Snyder 2014,  
Rizvi 2015).  The frequency of mutation-associated neoantigens in tumor tissues may be 
analyzed for any significant correlation with clinical response to the study treatment (Le 
2015, Vogelstein 2013, Alexandrov 2013, Snyder 2014, Yadav 2014, Rizvi 2015).  
6.4.6 
Proteomic analysis of signaling pathways 
Protein lysates generated from archived tissue may be used to interrogate signaling 
pathways using microarrays or related technologies depending on the state of the art at 
the time these experiments are undertaken.  High throughput assays (such as Reverse 
Phase Protein Microarrays-RPPA for example) allow simultaneous evaluation of the 
activation status of multiple signaling pathways, by probing for protein phosphorylation, 
expression levels and other related parameters.  Analyzing such changes may provide 
further understanding of patient response and explain resistance or sensitivity to therapy. 


 
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7.0 
TREATMENT REGIMEN 
Study therapy (Cycle 1/Day1) should begin following three doses of 9 Gy hypofractionated 
SBRT to a single index lesion on Day – 2, Day −1, and Day 0 prior to Cycle 1. 
The lesion selected for radiation should be a lesion that can be safely radiated with focal 
irradiation (SBRT) for which radiation at the limited, palliative doses contemplated would be 
considered medically appropriate and in accord with acceptable radiation oncology practice.  For 
SBRT guidance, see Appendix B. 
7.1 
Study therapy 
Note: See Section 9.0 for specific study drug information and preparation instructions.  Study 
therapy must be administered in the order outlined in Table 4.  See Table 7 for study therapy dose 
level management. 
Table 4.  Study therapy (tremelimumab and durvalumab) 
Drug 
Dose 
Administration 
Dosing Interval 
Planned 
Duration 
Cycles 1–4 
Tremelimumaba,c,d 
75 mg 
IV infusion 
(See footnotes a and c for 
administration 
instructions) 
1 dose every 4 weeks 
on Day 1 of cycles  
1, 2, 3 and 4 
(1 cycle = 4 weeks) 
4 cycles 
 
Durvalumabb,c,d 
1500 mg 
IV infusion 
(See footnotes b and c for 
administration 
instructions) 
1 dose every 4 weeks 
on Day 1 of cycles  
1, 2, 3 and 4 
(1 cycle = 4 weeks) 
4 cycles 
 
Cycles 5-24 
Durvalumabb,c,d 
1500mg 
IV infusion 
(See footnotes b and c for 
administration 
instructions) 
1 dose every 4 weeks 
on Day 1 of cycles  
5 through 24 
(1 cycle = 4 weeks) 
20 cycles 
Table 4 continued on next page. 
 
 


 
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Table 4.  Study therapy (tremelimumab and durvalumab) (continued) 
a 
Tremelimumab will be administered as a controlled IV infusion using a low protein binding 
 
0.2 or 0.22 µm in-line filter via infusion pump into peripheral or central venous access.  See Section 9.1. 
− 
The entire contents of the IV bag should be administered over 60 minutes (+/− 5 minutes) at room 
temperature (approximately 25˚C). 
− 
In the event of a ≤ Grade 2 infusion reaction, the infusion rate may be decreased or interrupted until 
resolution of the event and re-initiated at 50% of the initial infusion rate. Subsequent infusions may be 
administered at 50% of the initial infusion rate. 
− 
The standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 8 hours at room 
temperature, (otherwise requires new infusion preparation).   
− 
Following completion of the tremelimumab infusion, flush the IV line with a volume of  
IV solution equal the volume contained in the tubing or complete the infusion according to institutional 
policy to assure the full dose is administered. 
Note: A one hour observation period is required between the first dose of tremelimumab and durvalumab 
and after the first dose of durvalumab.  See Table 2.  For subsequent doses a 30 minute observation period is 
recommended between tremelimumab and durvalumab and after durvalumab.  See Table 2. 
b 
Durvalumab will be administered as a controlled IV infusion using a low protein binding 0.2 or 0.22 µm  
in-line filter via infusion pump into peripheral or central venous access.  See Section 9.2. 
− 
On Day 1 of Cycles 1, 2, 3 and 4, durvalumab will be administered approximately 1 hour after the 
completion of the tremelimumab IV infusion.   Durvalumab (Day 1 of Cycles 5 through and including 
24) will be administered as monotherapy.  
− 
The entire contents of the IV bag should be administered over 60 minutes (+/− 5 minutes) at room 
temperature (approximately 25˚C).  
− 
In the event of a ≤ Grade 2 infusion reaction, the infusion rate may be decreased or interrupted until 
resolution of the event and re-initiated at 50% of the initial infusion rate. Subsequent infusions may be 
administered at 50% of the initial infusion rate. 
− 
The standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 8 hours at room 
temperature, with maximum total time at room temperature not exceeding 8 hours (otherwise requires 
new infusion preparation).   
− 
Following completion of the durvalumab infusion, flush the IV line with a volume of  
IV solution equal the volume contained in the tubing or complete the infusion according to institutional 
policy to assure the full dose is administered. 
c 
Vital Signs will be measured within an hour prior to start of tremelimumab and durvalumab administrations, 
at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 
minutes) and 60 minutes (± 5 minutes) post-infusion.  If the infusion takes longer than 60 minutes, then blood 
pressure and pulse measurements should follow the time increments as outlined at the end of the infusion or 
more frequently if clinically indicated.  For subsequent doses of study therapy, a 30 minute observation 
period and vital sign check is required unless a patient experiences an infusion-related reaction and requires 
additional monitoring. 
d 
Allergic reactions to durvalumab and tremelimumab are possible.  See Sections 8.5.1 and 8.5.2. 
− 
A 1-hour observation period is required following the first infusion of both study drugs. 
− 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.   
− 
The infusion rate of study drug may be decreased by 50% or interrupted as described above 
− 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis. 
 
 


 
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7.2 
Supportive therapy 
7.2.1 
Growth factor support 
Use of growth factor support (e.g., G-CSF, GM-CSF) is prohibited. 
7.2.2 
Erythropoietin 
The use of erythropoiesis-stimulating agents is prohibited. 
7.2.3 
Other supportive care 
Patients should receive supportive care for other treatment-related symptoms at the 
investigator's discretion. 
7.2.4 
Targeted therapy 
While on study, administration of targeted therapy for malignancy is prohibited. 
7.3 
Contraindications and precautions 
• 
Study therapy, durvalumab and tremelimumab is contraindicated in patients who are pregnant 
or lactating.  See Section 10.5 and Appendix C. 
• 
Immunosuppressive doses of steroids or other immunosuppressive medications through 90 
days post last dose of study therapy. See 4.2.10.  Note however, use of immunosuppressive 
medications for the management of study therapy-related AEs (see Section 8.5) or in patients 
with contrast allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids 
is permitted. 
• 
Drugs with laxative properties and herbal or natural remedies for constipation should be 
avoided through 90 days post last dose during the study because of the potential for 
exacerbation of diarrhea. 
• 
Live attenuated vaccinations during the study or up to 180 days following the last dose of 
investigational product. 
• 
Patients should not donate blood while participating in this study or for at least 180 days 
following the last infusion of study therapy. 
7.4 
Participation in other clinical trials 
If a patient on the FC-9 trial is considering participation in another clinical trial (including 
supportive therapy trials), contact the DSSM (see Information Resources.) 
 
 


 
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8.0 
TREATMENT MANAGEMENT 
8.1 
General instructions 
• 
The NCI CTCAE v4.0 must be used to grade the severity of AEs. 
• 
All treatment decision must be based on the AE requiring the greatest modification. 
• 
Drug doses that have been reduced may not be re-escalated. 
• 
All hematologic, gastrointestinal, and genitourinary toxicities must be < Grade 2 prior to 
initiating Dose 1 of study therapy.  Patients unable to receive Dose 1 will be considered 
screen failures. 
8.2 
Treatment management for durvalumab and tremelimumab 
The study treatment schedule should be maintained.  If necessary, the timing of a treatment may 
be adjusted to 3 days earlier or 3 days later than the scheduled date of treatment. All doses 
administered or missed must be recorded. 
8.2.1 
Treatment decisions when therapy must be held 
• 
In the event systemic steroid therapy is initiated for toxicity management, study 
therapy must be held.  The steroid taper should be completed within 28 days.  Study 
therapy may then be resumed after completion of the steroid taper on Day 1 of the 
next scheduled cycle.  
• 
Note: Should the steroid taper require a slower rate for completion (i.e., > 28 days), 
further study therapy doses must be discontinued. 
• 
See Table 7 for treatment management. 
8.2.2 
Treatment decisions when therapy must be discontinued 
Treatment must be discontinued if: 
• 
If either durvalumab or tremelimumab must be held for > 28 days of continuous 
delay for other than steroid taper (e.g., toxicity). 
• 
Consent is withdrawn or patient is lost to follow-up.  If consent is withdrawn, the 
patient will not receive any further investigational product or further study 
observation. 
• 
An adverse event occurs that, in the opinion of the investigator or sponsor, 
contradicts further dosing. 
• 
The patient becomes pregnant or intends to conceive a child while actively on study. 
• 
Grade 3 or greater infusion reaction occurs. 
• 
Bullous rash. 
• 
Diagnosis of Guillain-Barre and/or Myasthenia Gravis. 
• 
Initiation of alternate cancer therapy including another investigational agent. 
• 
If tumor progression occurs during study therapy, durvalumab must be discontinued.  
See Section 11.0. 
See Table 7 for additional treatment management requirements.  Patients who 
prematurely discontinue study therapy should complete assessments on Table 2. 
8.3 
Dose modifications for durvalumab and tremelimumab 
The instructions for management of toxicities during durvalumab and tremelimumab are outlined 
in Table 7.  Dosing of study therapy will be done in tandem: 
• 
When study therapy doses are to be maintained, both durvalumab and tremelimumab doses 
will be maintained on the same dose level. 


 
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• 
When a dose reduction is indicated, both durvalumab and tremelimumab will be reduced to 
the same dose level (e.g., Dose level 1).  
• 
When discontinuation of study therapy is indicated, durvalumab and tremelimumab will be 
discontinued at the same time. 
Table 5.  Dose levels for durvalumab 
Durvalumab 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose Level −2 
1500 mg 
750 mg  
Discontinue 
Table 6.  Dose levels for tremelimumab 
Tremelimumab 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose Level −2 
75 mg 
40 mg 
Discontinue 
8.4 
Dose modification and management of toxicities 
All toxicities will be graded according to CTCAE version 4.0.  Following the first dose of 
durvalumab and tremelimumab, subsequent administration of durvalumab and tremelimumab can 
be modified based on toxicities observed as described in Sections 8.5, 8.6, and 8.7.  For adverse 
events (AEs) that are considered at least partly due to administration of durvalumab or 
tremelimumab, the following general guidance may be applied: 
• 
Treat each of the toxicities with maximum supportive care (including holding the study 
therapy suspected of causing the toxicity where required). 
• 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
• 
In addition to the criteria for permanent discontinuation of study therapy based on toxicity 
grade, permanently discontinue study therapy for the conditions outlined in Section 8.2.2. 
 
 


 
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Table 7.  Treatment management for study therapy (durvalumab and tremelimumab) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Cardiac Disorders 
Myocarditis  
(See Sections 8.5.1 and 
8.5.12) 
1 
For suspected myocarditis: 
Hold study therapy until full diagnostic work up.  Initiate 
steroid therapy and appropriate management.  If study 
therapy is held, resume after complete resolution to Grade 0 
after completion of the steroid taper, resume at the next 
scheduled dose. 
2 
Hold study therapy dose until resolution to Grade 0. If 
toxicity rapidly improves to Grade 0, then: 
The decision to reinitiate study therapy will be based upon 
treating physician’s clinical judgment and after completion 
of steroid taper.  
If toxicity does not rapidly improve, permanently: 
Discontinue study therapy. 
 
3-4 
Discontinue study therapy 
Endocrine disorders 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and adrenal 
insufficiency; exocrine event 
of amylase/lipase increased 
also included in this section) 
(See Sections 8.5.1 and 
8.5.8). 
 
1 
No dose modifications. 
2 
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 and prompt initiation of treatment with 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
Hold study therapy dose until patient is clinically stable.   
− If systemic steroid therapy has been initiated − after 
completion of the steroid taper, resume. 
− If steroid taper completion is > 28 days: discontinue 
further study therapy. 
Patients with endocrinopathies who may require prolonged 
or continued steroid replacement (e.g., adrenal 
insufficiency) can be retreated with study therapy on the 
following conditions:  
− The event stabilizes and is controlled. 
− The patient is clinically stable as per investigator or 
treating physician’s clinical judgement.  
− Doses of prednisone are ≤10 mg/day or equivalent. 
Table 7 continued on next page. 
 
 


 
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Table 7.  Treatment management for study therapy (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Endocrine disorders (continued) 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, hypopituitarism, 
and adrenal insufficiency; 
exocrine event of 
amylase/lipase increased also 
included in this section) 
(See Sections 8.5.1 and 
8.5.8). 
 
3-4 
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 and prompt initiation of treatment with 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
Hold study therapy dose until patient is clinically stable.   
− If systemic steroid therapy has been initiated − 
after completion of the steroid taper, resume study 
therapy. 
− If steroid taper completion is > 28 days: 
discontinue further study therapy. 
Patients with endocrinopathies who may require prolonged 
or continued steroid replacement (e.g., adrenal 
insufficiency) can be retreated with study therapy on the 
following conditions:  
− The event stabilizes and is controlled. 
− The patient is clinically stable as per investigator or 
treating physician’s clinical judgement.  
Doses of prednisone are ≤10 mg/day or equivalent. 
Gastrointestinal disorders 
Diarrhea/Enterocolitis 
(See Sections 8.5.1 and 
8.5.4.) 
1 
Maintain study dose schedule without delay; adjust 
antidiarrheal medication. 
2 
Hold study therapy and adjust antidiarrheal medication.  
Once event is stabilized to ≤ Grade 1 after completion of 
the steroid taper, then resume:  
↓ one dose level. 
If steroid taper completion is > 28 days: Discontinue 
further study therapy. 
3 
Hold study therapy and adjust antidiarrheal medication.  If 
event is stabilized to ≤ Grade 1 within 14 days, after 
completion of the steroid taper, resume:  
↓ one dose level. 
If there is no improvement within 14 days or steroid taper 
completion is > 28 days: 
Discontinue further study therapy. 
4 
Discontinue study therapy 
Hepatobiliary Disorders 
Hepatitis/hepatotoxicity 
(See Sections 8.5.5, 8.6.2, 
and 8.7.) 
3, 4 
Discontinue study therapy 
Table 7 continued on next page. 
 
 


 
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Table 7.  Treatment management for study therapy (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Immune System Disorders 
Allergic reaction/ 
Infusion reaction 
(See Table 4 and Sections 
8.5.1 and 8.5.2.) 
 
1 
The infusion rate of study therapy may be decreased by 
50% or temporarily interrupted until resolution of the 
event. 
Maintain study dose level. 
2 
The infusion rate of study therapy may be decreased 50% 
or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
Once event is stabilized to ≤ Grade 1, after completion of 
the steroid taper, resume:  
↓ one dose level. 
If steroid taper completion is > 28 days: Discontinue 
further study therapy. 
3,4 
Discontinue study therapy 
Investigations 
Immune-mediated 
hepatitis as indicated by: 
• Alanine transferase 
(ALT) increased 
• Alkaline phosphatase 
increased 
• Aspartate 
aminotransferase (AST) 
increased 
• Blood bilirubin increased 
Note:  Permanently 
discontinue study therapy 
for any case meeting Hy's 
Law criteria. 
 (See Sections 8.5.5, 8.6.2, 
and 8.7[Hy's Law].) 
1 
Monitor LFTs; Maintain study dose level. 
2 
Note: For patients with metastatic liver disease who enter 
the study with Grade 2 transaminases: Maintain dose and 
continue study therapy without holding.  Otherwise: 
Hold study therapy.  Once elevations have resolved to  
≤ Grade 1 and, 
• No systemic steroid therapy has been initiated then 
resume: 
Maintain dose level 
• Systemic steroid therapy has been initiated − after 
completion of the steroid taper, resume: 
↓ one dose level or discontinue. 
• If steroid taper completion is > 28 days: Discontinue 
further study therapy. 
Table 7 continued on next page. 
 
 


 
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Table 7.  Treatment management for study therapy (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Investigations (continued) 
Immune-mediated 
hepatitis as indicated by: 
• Alanine transferase 
(ALT) increased 
• Alkaline phosphatase 
increased 
• Aspartate 
aminotransferase (AST) 
increased 
• Blood bilirubin increased 
Note:  Permanently 
discontinue study therapy 
for any case meeting Hy's 
Law criteria. 
 (See Sections 8.5.5, 8.6.2, 
and 8.7[Hy's Law].) 
3 
Elevations in transaminases ≤ 8 x ULN and bilirubin ≤ 5 x 
ULN: 
Hold study therapy; if elevations resolve to ≤ Grade 1 or 
base line within 14 days, and if 
• no systemic steroid therapy has been initiated: then 
resume:   
Maintain dose or↓ one dose level. 
• systemic steroid therapy has been initiated − after 
completion of the steroid taper, resume:  
↓ one dose level or discontinue. 
•  If steroid taper completion is > 28 days: discontinue. 
Note: If elevations do not downgrade to ≤ Grade 1 within 
14 days OR for elevations in transaminases > 8 x ULN or 
bilirubin >5 x ULN: Discontinue further study therapy. 
Discontinue study therapy for any case meeting Hy’s law 
criteria and in the absence of any alternative cause. 
4 
Discontinue study therapy 
Creatinine increased 
(Nephritis) 
(See Sections 8.5.1 and 
8.5.6.) 
1 
Maintain study dose level 
2 
Hold study therapy until resolved to ≤ Grade 1 after 
completion of the steroid taper, resume: 
↓ one dose level. 
If steroid taper completion is > 28 days: Discontinue 
further study therapy. 
3, 4 
Discontinue study therapy 
Platelet count decreased 
(See Section 8.5.11.) 
2 
Hold until ≤ Grade 1 or 
baseline, then resume and: 
Maintain dose or ↓ one dose 
level. 
Hold until ≤ Grade 1 or 
baseline, then resume and: 
Maintain dose 
3 
Hold until ≤ Grade 1 or 
baseline, then resume and: 
↓ one dose level. 
Hold until ≤ Grade 1 or 
baseline, then resume and: 
Maintain dose 
4 
Discontinue study therapy 
Musculoskeletal and connective tissue disorders 
Myositis/Polymyositis 
(See section 8.5.13) 
1 
No dose modifications. 
2 
Hold study therapy dose until resolution to Grade ≤1.  
Discontinue study therapy if it does not resolve to Grade 
≤1 within 28 days or if there are signs of respiratory 
insufficiency. 
3 
Hold study therapy dose until resolution to Grade ≤1. 
Discontinue study therapy if Grade 3 imAE does not 
resolve to Grade ≤1 within 28 days or if there are signs of 
respiratory insufficiency. 
4 
Discontinue study therapy 
Table 7 continued on next page. 


 
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Table 7.  Treatment management for study therapy (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Nervous system disorders 
Neurotoxicity 
(to include but not be limited 
to limbic encephalitis and 
autonomic neuropathy, 
excluding Myasthenia Gravis 
and Guillain-Barre) 
(See Sections 8.5.1 and 
8.5.9.) 
1 
Hold study therapy during neurotoxicity work-up.  If 
diagnosis of Myasthenia Gravis or Guillain-Barre is 
confirmed, discontinue study therapy. Otherwise, maintain 
study dose level. 
2,3 
Hold study therapy during neurotoxicity work-up.   
Once elevations have resolved to ≤ Grade 1, and if 
• no systemic steroid therapy has been initiated, then 
resume: 
 ↓ 1 dose level. 
• systemic steroid therapy has been initiated −after 
completion of the steroid taper: resume  
↓ 1 dose level or discontinue If steroid taper completion 
is > 28 days: discontinue further study therapy. 
4 
Discontinue study therapy 
Peripheral neuromotor 
syndrome 
(such as Guillain-Barre and 
myasthenia gravis) 
(See Sections 8.5.1 and 
8.5.10.) 
1 
No dose modifications. 
2 
Hold study therapy dose until resolution to Grade ≤1. 
Permanently discontinue study therapy if it does not 
resolve to Grade ≤1 within 28 days or if there are signs of 
respiratory insufficiency or autonomic instability. 
3 
Hold study therapy dose until resolution to Grade ≤1. 
Permanently discontinue study therapy if it does not 
resolve to Grade ≤1 within 28 days or if there are signs of 
respiratory insufficiency or autonomic instability. 
4 
Discontinue study therapy 
Respiratory, thoracic, and mediastinal disorders 
Pneumonitis/pulmonary 
infiltrates/other pulmonary 
events 
• Dyspnea 
• Hypoxia 
• Pneumonitis 
• ILD 
• Pulmonary fibrosis 
(See Sections 8.5.1, 8.5.3, and 
8.6.1.) 
Hold study treatment until pneumonitis is evaluated. 
1 
Maintain study therapy schedule without delay. 
2 
Hold study therapy.  At physician's discretion, once event is 
stabilized to ≤ Grade 1 after completion of the steroid taper, 
then resume: 
↓ one dose level. 
If steroid taper completion is > 28 days: discontinue further 
study therapy. 
3,4 
Discontinue study therapy 
Table 7 continued on next page. 
 
 
 


 
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Table 7.  Treatment management for study therapy (continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
v4.0 
Grade 
Action to be Taken with Study Therapy 
Tremelimumab 
Durvalumab 
Skin and subcutaneous tissue disorders  
Rash/dermatitis 
(e.g., acneiform, maculo-
papular) 
(See Sections 8.5.1 and 
8.5.7.) 
1 
Maintain dose level 
2 
Hold study therapy until resolution to ≤ Grade 1 or 
baseline and if 
• no systemic steroid therapy has been initiated−resume: 
Maintain dose level or ↓ one dose level.  
• systemic steroid therapy has been initiated −after 
completion of the steroid taper:  
Maintain dose level or ↓ one dose level.  
If steroid taper completion is > 28 days: discontinue 
further study therapy. 
3 
Hold study therapy until resolution to ≤ Grade 1 or 
baseline and if 
• no systemic steroid therapy has been initiated−resume: 
↓ one dose level or discontinue.  
• systemic steroid therapy has been initiated −after 
completion of the steroid taper:  
↓ one dose level or discontinue.  
If steroid taper completion is > 28 days: Discontinue 
further study therapy. 
4 
Discontinue study therapy 
Rash  
(e.g., bullous skin formations) 
(See Section 8.5.7) 
All 
Grades 
Discontinue study therapy 
AEs of Non-Immune Mediated Reactions 
AEs of non-immune 
mediated reaction 
requiring dose modification 
per investigator 
(e.g., Section 8.5.1) 
1 
Maintain dose 
2 
Hold study therapy until resolution to ≤ Grade 1 or 
baseline then resume: 
Maintain dose or ↓ one dose level. 
3 
Hold study therapy until resolution to ≤ Grade 1 or 
baseline, then resume: 
↓ one dose level or discontinue at physician's discretion. 
4 
Discontinue study therapy 
8.5 
Immune-mediated adverse events (imAEs) 
Immune-mediated adverse events/imAEs are important risks of interest and include: 
pneumonitis/ interstitial lung disease (ILD), diarrhea/colitis, hepatitis and increases in 
transaminases, nephritis and increases in serum creatinine, dermatitis/rash and pruritus, 
endocrinopathy (hypo- and hyperthyroidism, adrenal insufficiency, hypophysitis/hypopituitarism 
and Type I diabetes mellitus), myocarditis, neuropathy/neuromuscular toxicity (such as 
myasthenia gravis and Guillain-Barre) and pancreatitis.  In addition, infusion-related reactions 
and hypersensitivity/anaphylactic reactions with a different underlying pharmacologic etiology 
are also considered AESIs.  See Section 10.2. 


 
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Other inflammatory responses that are rare with a potential immune related etiology are also 
considered as AESIs and include but are not limited to pericarditis, sarcoidosis, uveitis, and other 
events involving the eye, skin, hematological and rheumatological events.  It is possible that 
events with an inflammatory or immune mediated mechanism could occur in nearly all organs 
(Durvalumab IB 2018).   
Thorough evaluation of these events should be performed to rule out any alternative etiology 
(e.g., disease progression, concomitant medications, or infections).  In the absence of a clear 
alternative etiology, all events should be considered potentially immune related.  For study 
treatment dose management related to imAEs, see Table 7. 
The following guidelines are recommended as management of the following immune-mediated 
reactions. 
8.5.1 
Overall management for imAEs  
• 
Patients should be thoroughly evaluated to rule out any alternative etiology  
(e.g., disease progression, concomitant medications, infections, etc.). 
• 
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related. 
• 
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 1-2mg/kg/day PO or IV equivalent unless otherwise 
noted in subsequent sections. 
• 
Some 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 – 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 2-4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (> 28 days of taper). 
• 
More potent immunosuppressives such as TNF inhibitors (e.g. infliximab) should be 
considered for events not responding to systemic steroids.  Progression to use of 
more potent immunosuppressives should proceed more rapidly in events with high 
likelihood for morbidity and/or mortality – e.g., myocarditis, or other similar events 
even if they are not currently noted in the guidelines – when these events are not 
responding to systemic steroids. 
• 
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 therapy is not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response (e.g., inflammatory reaction at sites of 
metastatic disease and lymph nodes).  Continuation of study therapy in this situation 
should be based upon a benefit-risk analysis for that patient. 
Note: Non-imAEs should be treated as per institutional standard. 
8.5.2 
Infusion reactions 
Management of reactions should be per institutional standard at the discretion of 
investigator.  Monitor patients for signs and symptoms of infusion-related reactions  


 
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(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.).  See 
Section 8.5.1 and Table 7. 
The following are recommended management practices for infusion reactions: 
• 
Grade 1: 
− 
The infusion rate of study therapy may be decreased by 50% or temporarily 
interrupted until resolution of the event. 
− 
Acetaminophen and/or antihistamines may be administered per institutional 
standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to subsequent doses. 
Note:  Steroids should not be used for routine premedication of < Grade 2 infusion 
reactions. 
• Grade 2: 
− 
The infusion rate of study drug may be decreased 50% or temporarily interrupted 
until resolution of the event.  Subsequent infusions may be given at 50% of the 
initial infusion rate. 
− 
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. 
− 
Report event to DSSM. 
• 
Grade 3 and 4: 
− Permanently discontinue study therapy. 
− Report event to DSSM. 
Manage severe infusion-related reactions per institutional standards (e.g., IM 
epinephrine, followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
8.5.3 
Pneumonitis/ILD 
Monitor patients for signs and symptoms of pneumonitis or interstitial lung disease (ILD) 
(e.g., new onset or worsening shortness of breath or cough).  Patients should be evaluated 
with imaging and pulmonary function tests including other diagnostic procedures.  
Prompt treatment with steroids is important per guidelines below. 
• 
Patients should be instructed to call the clinic to report any respiratory symptoms or 
changes they experience including: 
− cough 
− shortness of breath 
− dyspnea upon exertion 
− fever, and/or 
− chest pain. 
For study treatment dose management related to imAEs, see Section 8.5.1 and Table 7. 
• 
Grade 1: 
− 
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. 
− 
Consider holding study therapy as clinically appropriate and during diagnostic 
workup for other etiologies. 
 


 
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• 
Grade 2: 
− 
Hold study therapy until Grade 2 resolution to ≤ Grade 1. 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1-2 mg/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 methylprednisolone at  
2-4/g/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, if administered, refer to infliximab label for general guidance. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungal or anti-pneumocystis pneumonia (PJP) 
treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).   
− 
Consider Pulmonary and Infectious Disease consult. 
− 
Consider as necessary discussing with study physician. 
− 
Report event to DSSM. 
• 
Grade 3 or 4: 
− 
Discontinue study therapy. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent.  
− 
Obtain Pulmonary and Infectious Disease consult. 
− 
Hospitalize the patient. 
− 
Supportive Care (oxygen, etc.). 
− 
Report event to DSSM. 
− 
If no improvement within 3-5 days, additional workup should be considered and 
prompt treatment with additional immunosuppressive therapy such as TNF 
inhibitors started (e.g., infliximab at 5 mg/kg every 2 week dose).  Caution: It is 
important to rule out sepsis and, if administered, refer to infliximab label for 
general guidance. 
− 
Once improving, gradually taper steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals and in particular, anti PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
8.5.4 
Diarrhea/enterocolitis 
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.  For study 
treatment dose management related to imAEs, see Section 8.5.1 and Table 7. 
 
 


 
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• 
Grade 1: 
(Diarrhea: stool frequency of <4 over baseline per day; Colitis: asymptomatic; 
clinical or diagnostic observations only) 
− 
Close monitoring for worsening symptoms. 
− 
Consider symptomatic treatment including hydration, electrolyte 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 to 6 over baseline per day) (Colitis: abdominal pain; 
mucus or blood in stool) 
− 
Hold study therapy until resolution to Grade ≤ 1. 
− 
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, obtain GI consult for consideration of 
further workup such as imaging and/or colonoscopy to confirm colitis and rule 
out perforation, and prompt treatment with IV methylprednisolone 2-4 mg/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 
weeks).  Caution: Important to rule out bowel perforation and, if administered, 
refer to infliximab label for general guidance before using infliximab. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).   
− 
Report event to DSSM. 
• 
Grade 3 or 4: 
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, medical intervention indicated, peritoneal signs; Grade 4 colitis: life-
threatening consequences, urgent intervention indicated. 
− 
Permanently discontinue study therapy for Grade 3 if toxicity does not improve 
to Grade ≤1 within 14 days; study therapy can be resumed after completion of 
steroid taper. 
− 
Discontinue study therapy for Grade 4. 
− 
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. 
− 
Report event to DSSM. 
− 
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 5 mg/kg once every 2 weeks).   
− 
Caution: Ensure GI consult to rule out bowel perforation and, if administered, 
refer to infliximab label for general guidance before using infliximab. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 


 
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NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
8.5.5 
Hepatitis/hepatotoxicity 
(Elevation in AST, ALT, ALP and total bilirubin) 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin (TB).  
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant 
medications).  Infliximab should not be used for management of immune-related 
hepatitis.  Prompt treatment with steroids is important per guidelines below.  For study 
treatment dose management related to imAEs, see Section 8.5.1 and Table 7. 
• 
Grade 1 AST or ALT and/or TB elevation: 
− 
Continue LFT monitoring per protocol. 
• 
Grade 2 AST or ALT and/ or TB elevation:  
Note: For patients with metastatic liver disease who enter the study with Grade 2 
transaminases, maintain dose and continue study therapy without holding.  Otherwise 
Hold study therapy. 
− 
Regular and frequent checking of LFTs (e.g. every 1-2 days) until elevations are 
improving or resolved. 
− 
If no resolution to ≤ Grade 1 (or baseline) in 1-2 days, discuss with study 
physician.  If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1-2 mg/kg/day PO or IV equivalent.  
− 
If still no improvement within 3-5 days despite prednisone 1-2mg/kg/day PO or 
IV equivalent, consider additional workup and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 
− 
If still no improvement within 3-5 days despite 2-4 mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil).  Discuss with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).  
− 
Report event to DSSM.  
Grade 3 or 4 AST or ALT and/or TB elevation: 
.For Grade 3: 
− For elevations in transaminases ≤8 × ULN, or elevations in bilirubin ≤5 × ULN: 
− Hold study therapy dose until resolution to Grade ≤1 or baseline. 
− Resume study therapy if elevations downgrade to Grade ≤1 or baseline within 14 
days and after completion of steroid taper. 
− Permanently discontinue study therapy 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 therapy. 
− Permanently discontinue study therapy for any case meeting Hy’s law criteria 
(AST and/or ALT >3 × ULN + bilirubin >2 × ULN without initial findings of 
cholestasis (i.e., elevated alkaline P04) and in the absence of any alternative 
cause. 
 
 


 
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Grade 4 
− Discontinue study therapy.  
Grade 3 or 4: 
− 
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 (mycophenolate mofetil).  Discuss with study 
physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Obtain a Hepatology consult, abdominal workup, and imaging as appropriate. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
− 
Report event to DSSM. 
8.5.6 
Nephritis 
(serum creatinine elevation) 
Obtain a Nephrology consult.  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.).  Prompt treatment with steroids is 
important and 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.  For study treatment dose management related to imAEs, see Section 8.5.1 and 
Table 7. 
• 
Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying symptom. 
− 
If creatinine returns to baseline, resume its regular monitoring per study protocol. 
− 
Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc. 
• 
Grade 2: 
− 
Hold study therapy until resolution to Grade ≤1 or baseline. 
− 
Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc. 
− 
Carefully monitor serum creatinine every 2-3 days and as clinically warranted. 
− 
Consult Nephrology 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 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, additional workup should be considered and 
prompt treatment with IV methylprednisolone at 2-4 mg/kg/day started.  
− 
Once improving gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).   


 
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− 
When event returns to baseline, resume durvalumab (and tremelimumab if 
applicable) at the next scheduled study dose and routine serum creatinine 
monitoring per study protocol (see Table 2). 
− 
Report event to DSSM. 
• 
Grade 3 or 4: 
− 
Discontinue study therapy. 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult Nephrology and consider renal biopsy if clinically indicated. 
− 
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 or IV equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2-4mg/kg/day started. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]. 
− 
Report event to DSSM. 
8.5.7 
Dermatitis/rash 
Monitor for signs and symptoms of dermatitis (rash and pruritus).  Prompt treatment with 
steroids (topical or systemic based on severity) is important per management guidelines 
below. 
Note:  If there is any bullous formation of any grade, report event to DSSM 
immediately and discontinue study therapy. 
For study treatment dose management related to imAEs, see Section 8.5.1 and Table 7. 
• 
Grade 1: 
− 
Consider symptomatic treatment including oral antipruritics  
(e.g., diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream). 
• 
Grade 2: 
− 
Hold study therapy. 
− 
Consider 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, 
discuss with study physician and promptly start systemic steroids prednisone  
1-2 mg/kg/day PO or IV equivalent.   
− 
Consider skin biopsy if persistent for >1-2 weeks or recurs. 
− 
Report event to DSSM. 
• 
Grade 3 or 4: 
For Grade 3, hold study therapy until resolution to Grade ≤1 or baseline. 
− 
If temporarily holding the study therapy does not provide improvement of the 
Grade 3 skin rash to Grade ≤1 or baseline within 28 days, then permanently 
discontinue study therapy, see Table 7.   
− 
For Grade 4, discontinue study therapy. 
− 
Obtain a Dermatology consult. 


 
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− 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Recommend skin biopsy (preferably more than 1) as clinically feasible. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
− 
Report event to DSSM. 
8.5.8 
Endocrinopathy 
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.  Consult 
Endocrinology as medically indicated.  Patients should be evaluated to rule out any 
alternative etiology (e.g., disease progression including brain metastases, infection, etc.).  
For study treatment dose management related to imAEs, see Section 8.5.1 and Table 7. 
• 
Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and other 
relevant endocrine labs depending on suspected endocrinopathy (e.g., blood glucose 
and ketone levels, HgA1c).  Prompt initiation of hormone replacement is important 
for hypothyroidism.  
• 
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 (Weber 2012, Di Giacomo 2010). 
• 
If a patient experiences an AE that is thought to be possibly of autoimmune nature 
(e.g., thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the investigator 
should send a blood sample for appropriate autoimmune antibody testing.   
• 
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.  
• 
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 < 0.5 x LLN, or TSH >2 x ULN or consistently out of range in 2 
subsequent measurements, include free T4 at subsequent cycles as clinically 
indicated and consider endocrinology consult. 
• 
Grade 2: (including those with symptomatic endocrinopathy) 
For Grade 2 endocrinopathy other than hypothyroidism and Type 1 diabetes mellitus, 
hold study therapy dose until patient is clinically stable.  If toxicity worsens, then 
treat as Grade 3 or Grade 4.  Study therapy can be resumed once event stabilizes and 
after completion of steroid taper.  See Table 7. 
− Consult endocrinologist to guide evaluation of endocrine function and, as 
indicated by suspected endocrinopathy and as clinically indicated, consider 
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− For all patients with abnormal endocrine work up, except those with isolated 
hypothyroidism or Type 1 DM, and as guided by an  endocrinologist, consider 
short-term corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone PO 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 
treatment interruption and without corticosteroids.   
− Patients with T1DM may be treated with appropriate diabetic therapy, without 
study therapy interruption, and without corticosteroids. 
− 
Once improving, gradually taper steroids (28 days of taper) and consider 
prophylactic antibiotics, antifungals and anti PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).  
− 
For patients with normal endocrine work up (lab or MRI scans), repeat labs/MRI 
as clinically indicated. 
− 
Report event to DSSM. 
• 
Grade 3 or 4: 
For Grade 3 or 4 endocrinopathy other than hypothyroidism and Type 1 diabetes 
mellitus, hold study therapy dose until endocrinopathy symptom(s) are controlled.  
Study therapy 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 therapy on the 
following conditions: a) the event stabilizes and is controlled; b) the patient is 
clinically stable as per investigator or treating physician’s clinical judgement; c) 
doses of prednisone are ≤10 mg/day or equivalent. 
− 
Consult Endocrinology 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 
therapy interruption, and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic 
therapy, without study therapy interruption, and without corticosteroids.  
− 
Once improving, gradually taper immunosuppressive steroids (28 days of taper) 
and consider prophylactic antibiotics, antifungals and anti PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
− 
Report event to DSSM. 
8.5.9 
Neurotoxicity 
Neurotoxicity (to include but not limited to limbic encephalitis autonomic neuropathy, 
excluding Myasthenia Gravis and Guillain-Barre) 


 
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• 
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) inclusive of neurology consult as indicated. 
− 
Perform symptomatic treatment with neurological consult as appropriate. 
− 
For study treatment dose management related to imAEs, see Section 8.5.1 and 
Table 7. 
• 
Grade 2: 
− 
Report event to DSSM. 
− 
Obtain Neurology consult.  
− 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
− 
Promptly start systemic steroids prednisone 1-2mg/kg/day PO or IV equivalent. 
− 
If no improvement within 3-5 days despite prednisone 1-2mg/kg/day PO or IV 
equivalent consider additional workup and promptly treat with additional 
immunosuppressive therapy (e.g. IVIG). 
• 
Grade 3: 
Hold study therapy dose until resolution to Grade ≤1.  Permanently discontinue study 
therapy if Grade 3 imAE does not resolve to Grade ≤1 within 28 days. 
− 
Report event to DSSM. 
− 
Obtain Neurology consultation. 
− 
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 (28 days of taper) and consider prophylactic 
antibiotics, antifungals and anti PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B recommendation]).  
Permanently discontinue study therapy if Grade 3 imAE does not resolve within 
28 days. 
• 
Grade 4: 
− 
Discontinue study therapy. 
− 
Report event to DSSM. 
− 
Obtain Neurology consultation. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day PO 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 (28 days of taper) and consider prophylactic 
antibiotics, antifungals and anti PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B recommendation]).  
 
 


 
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8.5.10 Peripheral neuromotor syndromes 
(Immune-mediated peripheral neuromotor syndromes such as Guillain-Barre and 
Myasthenia Gravis) 
The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is 
important, since certain patients may unpredictably experience acute decompensations 
which can result in substantial morbidity or in the worst case, death.   
Patients should be monitored for signs and symptoms that may include peripheral sensory 
neuropathy, muscle weakness, peripheral neuropathy (including numbness, tingling, and 
sensitivity to touch).  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 and medications, etc.).  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.  If Myasthenia Gravis or Guillain-Barre is confirmed, 
discontinue study therapy.   
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.  
It is important to consider that the use of steroids as the primary treatment of Guillain-
Barre is not typically considered effective.  Patients requiring treatment should be started 
with IV IG and followed by plasmapheresis if not responsive to IV IG.  See Table 7. 
• 
Grade 1: 
− 
Hold study therapy. 
− 
Contact DSSM. 
− 
Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above. 
− 
Obtain a Neurology consult unless the symptoms are very minor and stable. If 
Myasthenia Gravis or Guillain-Barre is confirmed, discontinue study therapy and 
report event to DSSM. 
• 
Grades 2, 3 and 4: 
− 
Hold study therapy during work-up of symptoms.  If Myasthenia Gravis or 
Guillain-Barre is confirmed, discontinue study therapy.  If negative hold therapy 
until ≤ Grade 1 and prednisone dose is ≤ 10 mg/day or the equivalent. 
− 
Report event to DSSM. 
− 
Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above. 
− 
Obtain a Neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.). 
MYASTHENIA GRAVIS 
 
Steroids may be successfully used to treat Myasthenia Gravis.  Important to 


 
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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. 
 
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. 
 
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. 
• 
Grade 3:  
− 
Hold study therapy dose until resolution to Grade ≤1. 
− 
Discontinue study therapy if Grade 3 imAE does not resolve to ≤ Grade 1 in  
28 days. 
− 
Recommend hospitalization. 
− 
Obtain Neurology consult. 
− 
Report event to DSSM. 
• 
Grade 4:  
− 
Discontinue study therapy. 
− 
Report event to DSSM. 
8.5.11 Hematologic effect 
Tremelimumab can suppress bone marrow function with myelosuppression as the dose-
limiting toxicity.  Monitor complete blood cell counts including platelet counts. 
• Patients must not begin a new cycle of treatment unless the absolute neutrophil count 
(ANC) is ≥ 1500 cells/mm3 and platelet count is ≥ 75,000/mm3.  Follow study 
therapy management and dose modifications as instructed in Table 6 and Table 7. 
Patients with previous history of bleeding and/or who are taking anticoagulant 
medication may have a higher risk of subsequent bleeding; special attention to 
monitoring these patients in the context of possible bleeding is warranted (Durvalumab 
IB 2018). 
8.5.12 Myocarditis 
The prompt diagnosis of immune-mediated myocarditis is important, particularly in 
patients with baseline cardiopulmonary disease and reduced cardiac function.  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. 


 
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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).   See Table 7.  Patients with pre-existing 
cardiac disorders should be closely monitored for deterioration in their cardiac condition, 
which could suggest new onset myocarditis. For all grades contact DSSM. 
• 
For Grade 1 (no definitive findings) 
− Monitor and closely follow up in 2 to 4 days for clinical symptoms. 
− Obtain cardiology consult. 
− Institute full cardiac work-up (including exclusion of other alternate causes 
 such as infection). 
− Institute appropriate cardiac management. 
− Consider using steroids  
• 
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]). 
8.5.13 Myositis/polymyositis 
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.  Contact DSSM. 


 
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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).  See Table 7. 
• 
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. 
• 
For Grade 2 
− Monitor symptoms daily and consider hospitalization. 
− 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]). 
• 
For Grade 4 
− 
Discontinue study therapy. 
− 
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 treatment of cancer-related infections 
[Category 2B recommendation]). 
See Section 8.5.1 and Table 7. 


 
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8.6 
Management of radiation toxicity 
8.6.1 
Radiation pneumonitis 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of 
the end bronchioles and alveoli.  Any patient suspected of having radiation pneumonitis 
should be evaluated immediately by a treating investigator.  Radiation pneumonitis may 
present with fatigue, fever, shortness of breath, nonproductive cough, and a pulmonary 
infiltrate on chest x-ray.  
An effort also must be made to distinguish symptoms of radiation pneumonitis from 
those of an immune-related event possibly related to durvalumab and tremelimumab 
(Section 8.5 and Table 7).  Pneumonitis has been observed as a toxicity associated with 
multiple agents blocking the PD-1/PD-L1 pathway, occurring at a frequency between 1% 
and 5%, and generally low grade when caught early and treated with either withholding 
of the agent and/or a course of steroid immunosuppression. 
Given that delayed radiation toxicities may be at least in part immunologically mediated, 
it is possible that adding three doses of SBRT to durvalumab/tremelimumab may 
exacerbate the severity and/or the frequency of these events.  It may therefore not be 
straightforward to attribute such events exclusively to durvalumab/tremelimumab or to 
radiation, and such events may need to be attributed to the combination.  
The infiltrate on chest x-ray should include the area treated to high dose, but may extend 
outside of these regions.  The infiltrates may be characteristically “geometric” 
corresponding to the radiation portal, but may also be ill defined.  
Mild radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents. 
More significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet. Infections should be treated with antibiotics.  
8.6.2 
Radiation induced liver toxicity 
It is expected that a proportion of patients treated for right lower lobe lung or liver lesions 
will have transient elevation of liver enzymes following treatment.  If up to Grade 3 
elevation of liver enzymes is observed, more frequent measurements (at least twice 
weekly) of the liver enzymes are recommended until the enzymes stabilize or return to 
baseline levels.  Repeat of blood work for all Grade 4 elevations is required at least  
5 days following the first abnormal lab value to determine if the Grade 4 levels are 
transient (defined as lasting < 5 days) or persistent.  
Radiation-induced liver disease (RILD) is a clinical syndrome of anicteric ascites, 
hepatomegaly and elevation of alkaline phosphatase relative to other transaminases that 
may occur 2 weeks to 3 months following radiation to the liver (Guha 2011).  An 
increase in ALP must be at least 2-fold above the baseline alkaline phosphatase.  RILD is 
unlikely to occur after a mean liver dose of approximately 30 Gy in conventional 
fractionation.  By maintaining a low mean liver dose and sparing a “critical volume” of 
liver from radiation, stereotactic delivery techniques allow for the safe administration of 
higher tumor doses.  Patients with pre-existing liver disease (e.g., Child-Pugh score of B 
or C) are at an increased risk (Guha 2011).  Treatment of RILD with repeat paracenteses, 
diuretics, and close follow-up is recommended (Guha 2011).  See Table 7 for specific 
study therapy dose modification instructions. 
 
 


 
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8.7 
Liver dysfunction (Hy's Law) 
Hy’s Law is based on the observation that pure hepatocellular injury sufficient to cause 
hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver 
injury.  A diagnosis of potential drug-induced liver injury caused by a study drug can only be 
determined/inferred by excluding other potential causes of liver injury (e.g., other drugs or viral 
hepatitis) and by ruling out an obstructive cause for the elevated bilirubin (e.g., alkaline 
phosphatase should not be substantially elevated) (FDA 2009; Temple 2006). 
8.7.1 
Definition of cases potentially meeting Hy's Law criteria 
Patients who present with the following laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values: 
• 
Patients with AST or ALT baseline values within the normal range who subsequently 
present with AST or ALT > 3 times the ULN concurrent with a total bilirubin  
> 2 times the ULN with no evidence of hemolysis and an alkaline phosphatase  
< 2 times the ULN or not available. 
• 
Patients with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT > 2 times the baseline values and > 3 times 
the ULN, or ≥ 8 times the ULN (whichever is smaller) concurrent with a total 
bilirubin of > 2 times the ULN and increased by one ULN over baseline or > 3 times 
the ULN (whichever is smaller) with no evidence of hemolysis and an alkaline 
phosphatase < 2 times the ULN or not available. 
8.7.2 
Evaluation of potential Hy's Law cases 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation 
should include laboratory tests, detailed history, and physical assessment.  In addition to 
repeating AST and ALT, laboratory tests should include albumin, creatine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), international 
normalized ratio (INR) and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, recreational drug and supplement consumption, 
family history, sexual history, travel history, history of contact with a jaundiced patient, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should 
be collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging 
(e.g. biliary tract) may be warranted.  The possibility of progressive disease should be 
considered. 
Potential Hy's Law cases should be reported as serious adverse events (see  
Sections 10.4.2 and 10.7.2). 
 
 


 
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9.0 
DRUG INFORMATION 
9.1 
Tremelimumab 
9.1.1 
Description 
Tremelimumab is a human IgG2 monoclonal antibody targeting against CTLA-4. 
Tremelimumab has an overall molecular weight of approximately 149 kDa including 
oligosaccharides. 
9.1.2 
Formulation 
Tremelimumab will be supplied as a 400 mg vial solution for infusion after dilution.  The 
solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine-hydrochloride, 
222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate and 0.02% (w/v) 
polysorbate 80; it has a pH of 5.5.  The nominal fill volume is 20 mL.  Tremelimumab 
must be used within the individually assigned expiry date on the label. 
9.1.3 
Toxicity 
Refer to the current tremelimumab IB for toxicity information. 
9.1.4 
Preparation 
The dose of tremelimumab for administration must be prepared using aseptic technique.  
Total time from needle puncture of the tremelimumab vial to the start of administration 
should not exceed 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature.  
If total time exceeds these limits, a new dose must be prepared from new vials. 
Tremelimumab does not contain preservatives, and any unused portion must be 
discarded. 
A dose of tremelimumab (75 mg) will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration ranging from 
0.10 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm 
in-line filter.  A volume of IV solution equal to the volume of tremelimumab to be added 
to the IV bag must be removed from the bag prior to the addition of tremelimumab.  The 
required volume of tremelimumab is then added to the IV bag such that final 
concentration is within 0.10 to 10 mg/mL.  Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags 
have been observed. However, administration set containing cellulose-based filters 
should not be used with tremelimumab. 
Dose calculation of tremelimumab  
The volume of tremelimumab (in mL) to be added to the IV bag is calculated as follows: 
• 
mL = Intended Dose (mg) ÷ tremelimumab concentration (nominal: 20 mg/mL) 
− 
Tremelimumab 75 mg dose: 75 mg ÷ 20 mg/mL = 3.8 mL 
− 
Tremelimumab 40 mg dose: 40 mg÷ 20 mg/mL = 2.0mL 
The corresponding volumes of tremelimumab should be rounded to the nearest 
tenth of an mL (0.1 mL).  See Table 6. 
9.1.5 
Administration 
Infusion solutions must be allowed to equilibrate to room temperature prior to 
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at room temperature (approximately 25°C) by controlled infusion via an infusion pump 
into a peripheral or central vein using an IV administration set with a 0.2- or 0.22-µm in-
line filter over approximately 60 minutes (+/−5 minutes). 
The IV line should be flushed with a volume of IV solution equal to the priming volume 
of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is 
administered and document if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.  In the event that the 
infusion time exceeds this time limit, a new dose must be prepared from new vials. See 
Section 7.0, Table 4. 
9.2 
Durvalumab (MEDI4736) 
9.2.1 
Description 
Durvalumab, a human IgG1 kappa monoclonal antibody directed against PD-L1, contains 
a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to 
C1q and the Fcγ receptors. 
9.2.2 
Formulation 
Durvalumab will be supplied as a 500 mg vial solution for infusion after dilution.  The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride,  
275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 
6.0.  The nominal fill volume is 10 mL.  Durvalumab must be used within the 
individually assigned expiry date on the label. 
9.2.3 
Toxicity 
Refer to the current durvalumab (MEDI4736) IB for toxicity information. 
9.2.1 
Contraindications 
The use of durvalumab is contraindicated in patients who are pregnant or nursing. 
9.2.2 
Concomitant medications and other substances 
No formal drug-drug interaction studies have been conducted with durvalumab.  There 
are no known clinically significant interactions of durvalumab with other medicinal 
products. 
9.2.3 
Preparation 
The dose of durvalumab for administration must be prepared using aseptic technique.  
Total time from needle puncture of the durvalumab vial to the start of administration 
should not exceed 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature.  
If total time exceeds these limits, a new dose must be prepared from new vials.  
Durvalumab does not contain preservatives, and any unused portion must be discarded. 
A dose of durvalumab (1500mg) will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose with a final durvalumab concentration ranging from 1 
to 20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-
line filter.  A volume of IV solution equal to the volume of durvalumab to be added to the 
IV bag must be removed from the bag prior to the addition of durvalumab.  The required 
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1 to 20 mg/mL.  Mix the bag by gently inverting to ensure homogeneity of the dose in the 
bag. 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags 
have been observed.  
Dose calculation of durvalumab 
The volume of durvalumab (in mL) to be added to the IV bag is calculated as follows: 
• 
mL = Intended Dose (mg) ÷ durvalumab concentration (nominal: 50 mg/mL) 
− 
Durvalumab 1500 mg dose: 1500 mg ÷ 50 mg/mL = 30.0 mL 
− 
Durvalumab 750 mg dose: 750 mg ÷ 50 mg/mL = 15.0 mL. 
The corresponding volumes of durvalumab should be rounded to the nearest tenth of an 
mL (0.1 mL).  See Table 5. 
9.2.4 
Administration 
Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration.  Durvalumab diluted in IV bag will be administered at 
room temperature (approximately 25°C) by controlled infusion via an infusion pump into 
a peripheral or central vein using an IV administration set with a 0.2- or 0.22-μm in-line 
filter over approximately 60 minutes (+/−5 minutes). 
The IV line should be flushed with a volume of IV solution (0.9% [w/v] saline) equal to 
the priming volume of the infusion set used after the contents of the IV bag are fully 
administered, or complete the infusion according to institutional policy to ensure the full 
dose is administered and document if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.  In the event that the 
infusion time exceeds this time limit, a new dose must be prepared from new vials.  See 
Section 7.0, Table 4. 
9.3 
Procurement 
Durvalumab and tremelimumab will be supplied free of charge by AstraZeneca and distributed 
via an external vendor.  Durvalumab and tremelimumab must be requested by the principal 
investigator (or his/her authorized designee) at each participating institution (see Information 
Resources).  The initial supply of Durvalumab and tremelimumab may be requested at the time 
the first patient signs the FC-9 consent form.  Durvalumab and tremelimumab will be shipped 
directly to the investigator whose sites are participating in FC-9. 
9.4 
Shipping 
Vials of durvalumab and tremelimumab are shipped at 2°C to 8°C (36°F to 46°F) by overnight 
express delivery Monday through Thursday excluding holidays. 
9.5 
Storage requirement and stability 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  
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recommended that Durvalumab is stored in opaque containers during storage to prevent excessive 
exposure to light. 
9.6 
Transfer of study therapy 
Study therapy (durvalumab and tremelimumab) may not be used outside the scope of FC-9, nor 
can study therapy be transferred or licensed to any party not participating in this clinical trial. 
9.7 
Destruction of study therapy 
At the end of an infusion for an individual patient, any remaining or unused study drug should be 
destroyed at the site according to the institution’s policy for drug destruction.  At the completion 
of the study, all unused study drugs will also be destroyed at the site as per institutional policy for 
drug destruction after the monitoring review is completed by DSSM. 
Maintain appropriate records of the disposal, including dates and quantities. 
9.8 
Drug inventory records 
It is the responsibility of the investigator to ensure that a current record of study drug disposition 
is maintained at each study site where drug is inventoried and disposed. 
Records or logs must comply with applicable regulations and guidelines, and should include: 
• 
Amount received and placed in storage area, 
• 
Amount currently in storage area, 
• 
Label ID number or batch/lot number, 
• 
Dates and initials of person responsible for each study drug inventory entry/movement, 
• 
Amount dispensed and returned for each patient, including unique patient identifiers, 
• 
Amount transferred to another area for dispensing or storage, 
• 
Non-study disposition (e.g., lost, wasted, broken), and 
• 
Amount destroyed. 
 
 


 
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10.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or a serious adverse event (SAE), as provided in this 
protocol.  Routine, adverse events of special interest (AESI), and expedited adverse event report 
forms and their supporting documentation must be submitted to DSSM according to the 
instructions in Sections 10.4, 10.7, and 10.8. 
10.1 
Definition of an AE 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
laboratory findings, or other physiologic observations occurring in a patient participating in  
FC-9.  The event does not need to be causally related to study therapy or other requirements of 
the FC-9 trial to be considered an AE. 
• 
Examples of an AE include, but are not limited to, the following: 
− 
Any toxicity related to study therapy. 
− 
Any clinically significant worsening of a pre-existing condition. 
− 
An AE occurring from a symptomatic overdose of any study therapy, whether accidental 
or intentional.  Overdose is a dose greater than that specified in the protocol. 
− 
A symptomatic AE that has been associated with the discontinuation of the use of any of 
the agents included in the study therapy. 
− 
An AE occurring during a clinical study that is not related to the study therapy, but is 
considered by the investigator or sponsor to be related to the study requirements, for 
example, an AE may be an untoward event related to a medical procedure required by the 
protocol. 
• 
A laboratory test result should be reported as an AE if it meets any of the following criteria: 
− 
Accompanied by clinical symptoms. 
− 
Results in a change in study treatment (e.g., dosage modification, treatment interruption 
or treatment discontinuation). 
− 
Results in medical intervention (e.g., potassium supplementation for hypokalemia) or 
treatment discontinuation. 
− 
Clinically significant per the investigator. 
• 
Examples of clinical events that should not be considered AEs: 
− 
Medical or surgical procedure (e.g., endoscopy, appendectomy).  Note, the condition that 
leads to the procedure may be an AE, but the procedure itself is not. 
− 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.2 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor.  An AESI may be serious or non-serious.  The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
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These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy.  An immune-mediated adverse event (imAE) is defined as an adverse event 
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.  See Section 8.5. 
If the Investigator has any questions in regards to an adverse event (AE) being an imAE, the 
Investigator should promptly contact DSSM.  For instructions on reporting AESIs, see Sections 
10.4.2 and 10.7.2. 
AESIs observed with durvalumab/tremelimumab include: 
• 
Diarrhea/colitis 
• 
Pneumonitis/ILD 
• 
Hepatitis/ increases in transaminases 
• 
Neuromuscular toxicity (i.e. events of Guillain-Barre and Myasthenia Gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, hypopituitarism, adrenal insufficiency, and 
hyper- and hypothyroidism, Type I diabetes mellitus) 
• 
Dermatitis/rash  
• 
Nephritis 
• 
Pancreatitis  
• 
Infusion reaction 
• 
Hypersensitivity/anaphylactic reaction. 
• 
Myocarditis 
• 
Myositis/polymyositis 
Other inflammatory responses that are rare with a potential immune related etiology are also 
considered as AESIs and include but are not limited to: pericarditis, sarcoidosis, uveitis, and other 
events involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis, and non-infectious encephalitis.  It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs.  Further information on these risks 
(e.g. presenting symptoms) can be found in Section 8.5 and the current versions of the 
durvalumab and tremelimumab Investigator Brochures. 
10.3 
Definition of an SAE 
An SAE is any untoward medical occurrence that, at any dose, causes one of the following: 
• 
Results in death. 
• 
Is life-threatening. 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event.  It does not refer to an event, which might have 
caused death, if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization 
Hospitalization is any inpatient admission to a health care facility even if for less than  
24 hours.  Hospitalization or prolongation of a hospitalization constitutes a criterion for an 
AE to be serious; however, it is not in itself considered an SAE.  In the absence of an AE, a 
hospitalization or prolongation of a hospitalization should not be reported as an SAE.  For 
example, the following hospitalizations would not require expedited reporting for an SAE: 
− 
a hospitalization or prolongation of hospitalization needed for a procedure required by the 
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− 
a hospitalization for a pre-existing condition that has not worsened. 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
This is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma  
(e.g., sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect. 
Also, appropriate medical judgment should be exercised in deciding whether SAE reporting 
is required in other situations, such as important medical events that may not result in death, 
be life-threatening, or require hospitalization, but may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the definition 
of an SAE.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or development of drug dependency or drug abuse. 
10.4 
Events requiring expedited reporting 
All events listed in Sections 10.2, 10.3 and 10.4 must be reported in an expedited manner 
according to the instructions in Section 10.7. 
10.4.1 SAEs 
All events meeting the definition of an SAE (see Section 10.3) require expedited 
reporting. 
10.4.2 Other events requiring expedited reporting 
Other events (such as AESIs ≥ Grade 2) must be recorded, reported, and followed up as 
indicated for an SAE in an expedited manner.  See Section 10.2, 10.3 and 10.7 for 
reporting procedures.  This includes the following events: 
• 
Pregnancy exposure to study therapy.  (If a pregnancy is confirmed, use of study 
therapy must be discontinued immediately.  See Section 10.5.) 
• 
Lactation exposure to study therapy. 
• 
Medication errors involving study therapy with or without AE symptoms, including 
product confusion and potential product confusion.  (A medication error is any 
preventable event that may cause or lead to inappropriate use or harm while the study 
therapy is in control of the healthcare professional or patient.  Examples of reportable 
medication error include administration of unassigned treatment and administration 
of expired study therapy.) 
• 
Overdose 
− 
An overdose is defined as a study patient receiving a dose of durvalumab and/or 
tremelimumab in excess of that specified in the Investigator’s Brochure, unless 
otherwise specified in this protocol. 
− 
Any overdose of a study patient with tremelimumab or durvalumab, with or 
without associated AEs/SAEs, is required to be reported within 24 hours of 
knowledge of the event to DSSM.  See Section 10.7.  There is currently no 
specific treatment in the event of an overdose of durvalumab or tremelimumab. 
The investigator will use clinical judgment to treat any overdose. 
• 
Any death, excluding death due to progression of colon cancer. 
• 
Potential Hy's Law cases (see Sections 8.7 and 10.7.2). 


 
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• 
Adverse events of special interest (AESIs) ≥ Grade 2 (see Section 10.2 and 10.7.2). 
10.4.3 Clinical laboratory abnormalities 
• 
Abnormal laboratory findings (e.g., clinical chemistry and hematology) or other 
abnormal assessments (e.g., x-rays and scans) will be recorded as AEs or SAEs if 
they meet the definition of an AE or SAE, as defined in Sections 10.1, 10.2, 
respectively, and if the abnormality meets reporting requirements as described in 
Section 10.4. 
• 
Special reporting requirements related to Hy’s Law: All cases confirmed on repeat 
testing as meeting one of the criteria described in Section 8.7 with no other cause for 
LFT abnormalities identified at the time should be considered potential Hy’s Law 
cases regardless of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be 
reported as serious adverse events (see Section 10.7.2). 
10.4.4 Disease-related events and/or disease-related outcomes not qualifying as SAEs 
An event that is part of the natural course of colorectal cancer does not need to be 
reported as an SAE.  Progression colorectal cancer will be reported in the appropriate 
eCRF. 
Note: Any occurrence of secondary malignancy (leukemia secondary to oncology 
chemotherapy [AML], myelodysplastic syndrome [MDS]) and/or treatment-related 
secondary malignancy is to be reported as an SAE. 
10.5 
Pregnancy 
• 
If a patient becomes pregnant while receiving study therapy, discontinue study therapy and 
notify DSSM (see Information Resources).  The investigator will record pregnancy 
information on the Pregnancy Notification Form (eCRF) and submit it as an expedited 
report (within 24 hours) upon learning of a patient’s pregnancy.  (See separate consent for 
release of pregnancy outcome information.) 
• 
Information about the use in pregnancy encompasses the entire course of pregnancy and 
delivery, and perinatal and neonatal outcomes even if there were no abnormal findings.  
Information on the status of the mother and child will be forwarded to DSSM.  Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will also be reported. 
• 
Should a female partner become pregnant by a male patient participating in the study, the 
investigator must be notified immediately.  (See separate consent for release of pregnancy 
outcome information.)  If the female partner signs consent, the outcome of the pregnancy 
will be reported. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or SAE.  A spontaneous abortion is always considered to be an SAE 
and will be reported as such. 
• 
Any SAE occurring in association with pregnancy brought to the investigator's attention after 
the patient has completed the study and considered by the investigator as possibly related to 
study therapy, must be reported to the DSSM. 
 
 


 
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10.6 
Grading the severity of the AE 
The NCI CTCAE v4.0 must be used to determine the grade of the AE.  The CTCAE provides 
descriptive terminology and a grading scale for each AE listed.  Information regarding the 
CTCAE can be found on the CTEP Web site at http://ctep.cancer.gov.  If you need further 
assistance, contact DSSM (see Information Resources). 
10.7 
Expedited reporting instructions 
10.7.1 Time period for reporting SAEs and other events requiring expedited reporting 
• 
All SAEs and other events as noted in Sections 10.3, and 10.4 regardless of 
relationship to study therapy will be reported in an expedited manner as described in 
Section 10.7.  Reporting SAEs (and other applicable events) regardless of 
relationship to study therapy begins with the first dose of study therapy and continues 
until 90 days after the last dose of study therapy. 
• 
Any SAE assessed as related to study participation (e.g., protocol-mandated 
procedures) will be recorded from the time a patient consents to participate in the 
study up to and including any follow-up contact. 
• 
Following the AE assessment 90 days after the last dose of study therapy, only SAEs 
determined to be related to study therapy will be reported in an expedited manner 
using FC-9 Form SAER. 
• 
The investigator must follow up on all SAEs until the events have subsided, until 
values have returned to baseline, or until the condition has stabilized. 
10.7.2 Reporting instructions 
• 
All SAEs and other events requiring expedited reporting (e.g., AESIs ≥ Grade 2) 
must be reported using FC-9 Form SAER (eCRF) and submitted to DSSM within 24 
hours of the study site personnel's initial notification of the event. 
• 
When reporting potential Hy's Law cases, Form SAER should include the following: 
− 
Seriousness Criteria = Important Medical Event 
− 
Assessments and narrative: Include the term “Potential Hy’s Law case” in the 
narrative; the text should also detail what additional study results are available at 
the time of reporting and what other studies are planned or results pending to 
further investigate alternative causes of the abnormal ALT/AST or bilirubin that 
triggered the report.  The timing of planned patient follow-up should also be 
noted. 
• 
NSABP will forward expedited report forms that meet reporting requirements to the 
FDA and to Astra Zeneca/MedImmune Pharmacovigilance. 
• 
Investigators are responsible for reporting AEs that meet specific criteria to their 
local IRBs. 
10.8 
Time period and frequency for routine reporting of AEs 
• 
Patients will be monitored for the occurrence of AEs at each scheduled assessment and 
during any contact with the patient during the study. 
• 
All AEs, including SAEs and other AEs that have been reported on FC-9 Form SAER, 
regardless of relationship to study therapy, will be recorded on Form AE of the CRF from the 
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• 
If the patient stops study therapy and begins a new treatment, AE assessments should be 
collected only up to the date the new therapy begins. 
• 
For routine reporting, all ≥ Grade 1 AEs will be reported on Form AE of the CRF. 
• 
The investigator must follow up on all AEs until the events have subsided, until values have 
returned to baseline, or until the condition has stabilized. 
• 
Following the AE assessment 90 days after the last dose of study therapy, routine reporting is 
no longer required.  (See Section 10.4 for expedited reporting requirements.) 
10.9 
Documentation requested following death 
For deaths that occur within 30 days of the last dose of study therapy: 
• 
Autopsy reports should be secured whenever possible and should be submitted to DSSM. 
• 
A copy of the death certificate should be forwarded to DSSM if it is readily available or if it 
contains important cause-of-death information that is not documented elsewhere. 
• 
Submit the last clinic/office note made before the death or the investigator’s note 
summarizing events resulting in death. 
 
 


 
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11.0 
ASSESSMENT OF EFFECT 
Response to study treatment in this patient population will follow standard RECIST criteria 
except in the documentation of progressive disease (PD).  In this protocol, patients with 
progressive radiographic metastatic disease who are clinically asymptomatic and without other 
significant reason to discontinue therapy (i.e., toxicity, physician's judgement or patient's decision 
to stop therapy) may continue to receive study therapy per protocol until the next scheduled 
tumor assessment (Table 2) to confirm progression.  If progression is confirmed the date of 
progression will be at the time of the initial scan indicating progression.   
11.1 
Definitions of measurable and non-measurable disease  
11.1.1 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 with conventional techniques 
(PET/CT, CT scan, or MRI) or as ≥ 10 mm with spiral CT scan with 5 mm cuts.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).  The same method (CT, MRI, or PET/CT) used at baseline should be used 
at all other tumor measurement time points. 
11.1.2 Non-measurable disease 
All other lesions, including small lesions (longest diameter < 20 mm with conventional 
techniques or < 10 mm using spiral CT scan with 5 mm cuts) are considered to be non-
measurable disease. 
11.1.3 Target lesions 
Up to a maximum of five measurable lesions should be identified as target lesions and 
recorded and measured at baseline.  Target lesions (maximum 2 lesions per organ) should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements by CT scan or MRI.  A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
11.1.4 Non-target lesions 
All sites of disease which are not used as target lesions should be identified as non-target 
lesions.  Location of individual lesions within the liver does not have to be specifically 
recorded.  All sites of non-target lesions must be assessed along with the target lesions. 
11.2 
Response criteria  
11.2.1 Evaluation of target lesions 
• 
Complete response (CR) 
Disappearance of all target lesions 
• 
Partial response (PR) 
At least a 30% decrease in the sum of the of LD of target lesions, taking as reference 
the baseline sum LD 
 
 


 
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• 
Progressive disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since baseline or the appearance of one or more new 
lesions 
• 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since baseline 
11.2.2 Evaluation of non-target lesions 
• 
Complete response (CR): disappearance of all non-target lesions, 
• 
Incomplete response/stable disease (SD): persistence of one or more non-target 
lesion(s). 
• 
Progressive disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
11.2.3 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). 
Refer to Table 8 for a summary of the criteria that contribute to the determination of 
response. 
Table 8.  Determination of response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD* 
Any 
PD 
Yes or No 
PD* 
Any 
Any 
Yes 
PD* 
*Confirmation of PD in a patient with new lesion(s) or suspected tumor flare is required as outlines in 
Sections 11.2.1 and 11.2.2. 
11.3 
Symptomatic deterioration 
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."  This is also true for "symptomatic deterioration" after therapy is completed.  
Every effort should be made to document objective progression even after discontinuation of 
treatment. 
 
 


 
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12.0 
PATIENT ENTRY PROCEDURES 
12.1 
Patient consent form 
Before study entry, the consent form including any addenda, must be signed and dated by the 
patient and the person obtaining informed consent.  In addition, before study entry, a copy of 
the signed and dated consent form must be forwarded to DSSM.  All patient signatures 
(except initials of first, middle, and last names) should be expunged prior to submission. 
12.2 
Study entry 
DSSM will verify that the research site has current IRB approval for the study.  Entry will not 
take place if the IRB approval is not current with IRB oversight responsibility. 
All patients must be enrolled through DSSM.  Once the entry eCRFs have begun to be entered, 
submit copies of the redacted signed consent form, and supporting documents to 
  
The entry material must be received by DSSM no later than 4:00 p.m. Eastern Time, Monday 
through Friday, excluding holidays.  Once received the review process will begin.  When the 
review is complete and approved, an enrollment confirmation will be sent.  This process could 
involve some unavoidable delays.  Therefore, it is necessary to plan adequate time (at least 
24 hours) between study entry and the initiation of the patient’s study therapy. 
12.3 
Patient study number and treatment assignment 
After all the entry materials have been reviewed and approved, the institution will receive the 
following via e-mail: 
• 
confirmation of registration and study entry; 
• 
Patient Identification number. 
12.4 
Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy if one of the following occurs: 
• 
the patient develops a serious side effect that cannot be tolerated or that cannot be controlled 
with other medications, 
• 
the patient’s health gets worse, 
• 
the patient is unable to meet the study requirements, or 
• 
new information about the study drugs or other treatments for colon cancer becomes 
available. 
If study therapy is stopped, study data and other materials should be submitted according to the 
study schedule unless the patient withdraws consent from the study or until there is a diagnosis of 
a secondary malignancy. 
12.5 
Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, the patient may stop study therapy at any 
time.  If study therapy is stopped, no new therapy begins and the patient still allows the study 
doctor to submit information, study data and other materials should be submitted according to the 
study schedule (Table 2). 
 
 


 
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12.6 
Patient-initiated withdrawal from the study 
If a patient chooses to have no further interaction regarding the study, the investigator must 
provide DSSM with written documentation of the patient’s decision to fully withdraw from the 
study.  Any data collected up to the time of withdrawal from the study will continue to be used. 
 
 


 
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13.0 
DATA HANDLING AND RECORDKEEPING 
Refer to the "FC-9 eCRF Completion Guidelines" for detailed instructions regarding data 
collection, AE reporting, and electronic case report form completion. 
 
 


 
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14.0 
STATISTICAL CONSIDERATION 
14.1 
Study design 
FC-9 is a single arm, study using the combination of durvalumab and tremelimumab for 4 cycles 
followed by durvalumab as monotherapy cycles 5 through 24 (1 cycle = 28 days).  Study therapy 
will be initiated following 3 doses of palliative hypofractionated radiation on Days −2, −1 and 
Day 0, prior to beginning Cycle 1. 
14.2 
Statistical design and sample size analysis 
The optimal two-stage design (Simon 1989) to test the null hypothesis that ORR0 ≤ 0.05 versus 
the alternative that ORRA ≥ 0.20 has an expected sample size of 16.14 and a probability of early 
termination of 0.54.  If the combination study therapy is actually not effective, there is a 0.080 
probability of concluding that it is (the target for this value was alpha = 0.10).  If the combination 
study therapy is actually effective, there is a 0.197 probability of concluding that it is not (the 
target for this value was beta = 0.20). 
Patients who complete both Cycle 1 and Cycle 2, and undergo the first restaging scan after  
Cycle 2 for the determination of tumor response will be determined as evaluable.  Non-evaluable 
patients will be replaced.  
After testing the study therapy combination on 12 evaluable patients in the first stage, the trial 
will be terminated if 0 patients respond.  If the trial goes on to the second stage, a total of  
21 evaluable patients will be studied.  If the total number responding is less than or equal to 2, the 
combination is rejected.  If 3 or more responses are observed (ORR ≥ 14.3%) after the second 
stage of the study, the combination will be considered for further study. 
14.3 
Monitoring 
• 
A medical review team comprising of the Protocol Chair, NSABP Medical Director, study 
statistician, designated physician(s), and designated DSSM staff will formally monitor the 
study on a monthly basis to identify accrual, toxicity, and any endpoint problems that might 
be developing. 
• 
During the trial, the protocol officer, and designated DSSM staff will participate in a weekly 
Web-ex with investigators who have a patient enrolled on the FC-9 study. Investigators who 
have a patient receiving study therapy are required to participate. All FC-9 study staff are 
encouraged to attend. 
• 
The maximum grade for each type of toxicity will be recorded for each patient, and frequency 
tables will be reviewed to determine toxicity patterns. 
 
 


 
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15.0 
PUBLICATION INFORMATION 
The publication or citation of study results will be made in accordance with the publication policy 
of the NSABP that is in effect at the time the information is to be made publicly available. 
 
 


 
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16.0 
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APPENDIX A 
DETERMINATION OF PERFORMANCE STATUS 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all 
pre-disease performance without 
restriction 
90–100% 
1 
Restricted in physically 
strenuous activity but 
ambulatory 
70–80% 
2 
Ambulatory and capable of self-
care, but unable to carry out any 
work activities 
50–60% 
3 
Capable of only limited self-
care; confined to bed or chair 
more than 50% of waking hours 
30–40% 
4 
Completely disabled 
10–20% 
 
 
NCI DEFINITION FOR ACTIVITIES OF DAILY LIVING 
Activities of daily living (ADL) are the tasks of everyday life.  These activities include: 
• 
eating 
• 
dressing 
• 
getting into or out of bed or chair 
• 
taking a bath or shower 
• 
using the toilet 
 
 


 
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APPENDIX B 
HYPOFRACTIONATED RADIATION THERAPY GUIDELINES 
The lesion selected for radiation should be a lesion that can be safely radiated with focal irradiation 
(SBRT) for which radiation at the limited, palliative doses contemplated would be considered medically 
appropriate and in accord with acceptable radiation oncology practice.  Appendix B offers guidance for 
this study. 
1.0 
Dose Specification 
1.1 Hypofractionated SBRT 
Stereotactic Body Radiation Therapy (SBRT) is the treatment modality utilized for this 
protocol.  Here, stereotactic refers to the targeting, planning, and direction of radiation 
treatment along any trajectory towards a well-defined and visualized 3-D target.  The exact 
coordinates of this 3D target is what differentiates it from conventional radiation therapy 
where skin or bony landmarks serve as tumor surrogates.  This treatment will require 3-
dimensional targeting of the tumor either by fiducial placement or by target visualization 
using a pre-treatment cone-beam CT (CBCT). 
1.2 Dose fractionation 
All patients will be treated to a single target with a total dose of 27.0 Gy delivered at 9.0 Gy 
per fraction on three consecutive days with a minimum of 18 hours between treatments 
required. 
1.3 Target lesion 
A single target lesion identified within the lung or liver will be treated with SBRT as a 
component of this study.  The target lesion should be ≤ 100 cm3. 
1.4 Premedications 
Analgesic premedication to avoid general discomfort during long treatment duration is 
recommended when appropriate.  Anti-emetics (e.g., Compazine) should be prescribed for 
those where the 50% isodose line approaches the stomach or bowel.  Pretreatment with 
corticosteroids (e.g., dexamethasone) is not recommended. 
2.0 
Technical Factors 
2.1 Physical factors 
Only 6 mV photons (x-ray) beams produced by a linear accelerator is allowed for this 
protocol. 
2.2 Treatment platforms 
This trial allows for commercially available photon producing treatment units equipped with 
a linear accelerator with image (or fiducial) guidance (e.g. Cyberknife, TrueBeam, Trilogy). 
3.0 
Localization, Simulations, and immobilization 
3.1 Patient positioning 
Patients will be positioned in a stable, reproducible position using either a vac bag or 
thermoplastic mask (lung lesions above the carina) immobilization device.  The treatment 
position should be reproducible from treatment to treatment. 


 
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APPENDIX B (continued) 
3.2 Internal organ motion 
Special considerations must be made to account for the effect of internal organ motion or 
target positioning and reproducibility.  For the purpose of this protocol, accelerator beam 
gating with the respiratory cycle using the RPM respiratory motion management system is 
the preferred approach.  For those patients treated on the Cyberknife treatment platform, 
fiducial tracking is also acceptable.  Respiratory gating (or tracking) must be reliable 
enough to insure that the GTV motion is accounted if motion is greater than 0.5 cm.   
3.3 Localization 
Isocenter localization images should be obtained on the treatment unit immediately before 
treatment to ensure proper alignment of the simulated fields. These IGRT images can be 
obtained with planar kV imaging devices.  For the Cyberknife system agreement between 
the treatment unit isocenter or reference point in space must be checked for agreement with 
the imaging isocenter prior to treatment.  For lesions where respiratory gating is utilized, 
fluoroscopy should be used to confirm the appropriate gating window. 
4.0 
Treatment Planning and Target Volumes 
4.1 Patient simulation and image acquisition 
Computed tomography is the primary image platform for targeting and treatment planning. 
The planning CT scans must allow simultaneous view of the patient anatomy and fiducial 
placement if necessary.  Intravenous (I.V) contrast during the planning CT is optional but 
recommend but can be avoided if a diagnostic CT with contrast was obtained to delineate 
the tumor and organs at risk within 8 weeks of simulation is available.  Image slice 
thickness should be 1.25 mm per slice. 
The target lesion will be outlined by an appropriately trained physician and designated the 
gross tumor volume (GTV).  The target will be drawn using CT with appropriate 
windowing for the target (lung – pulmonary windows, liver – hepatic windows); however, 
additional diagnostic images can be fused to assist in target delineation.  This includes 
FDG-PET as well as MRI which is the preferred modality for liver lesions.  The target 
lesion for this study is limited to a GTV volume ≤ 100 cm3. 
Planning target volume (PTV) generation will be created following the motion management 
simulation (i.e., 4D CT).  Here, the physician will delineate the primary target and with the 
assistance of physics support analyze the phases of the respiratory cycle and associated 
movement in relationship to the tumor in its most superior extent.  Respiratory gating 
should be utilized for tumors with excursion greater than 0.5 cm.  A minimum of 0.3-0.5 cm 
should be added to the movement determined on the motion assessment to generate the 
PTV.  
4.2 Dosimetry 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed 
for each dose to deliver highly conformal prescription dose distributions.  Non-opposing, 
non-coplanar beams are preferred.  Typically > 10 beams will be used with roughly equal 
weighting.  Generally, more beams are used for larger lesions.  When static beams are used, 
a minimum of 7 non-opposing beams should be used.   
For arc rotation techniques, a minimum of 340 degrees (cumulative for all beams) should be 
utilized.  In order to obtain acceptable coverage, field aperture size and shape should  


 
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APPENDIX B (continued) 
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 should be when observing the minimum field dimension of  
3.5 cm when treating small lesions. 
As such, prescription lines covering the PTV will typically be the 60-90% line (where the 
maximum dose is 100%); however, higher isodoses (hotspots) must be manipulated to occur 
within the target and not in adjacent normal tissue.  The treatment isocenter or setup point in 
stereotactic coordinates will be determined from system fiducials (and can be adjusted  
pre-treatment depending on the results from localization imaging studies) and translated to 
the treatment record. 
Prescription Dose Constraints for Treatment Planning 
• Maximum dose: The treatment plan should be created such that 100% 
corresponds to the maximum dose delivered to the patient.  This point must exist 
within the PTV. 
• Prescription isodose: The prescription isodose surface must be > 80% and < 
90% of the maximum dose. 
• Prescription Isodose Surface Coverage: The prescription isodose surface will 
be chose such that 95% of the PTV is conformally covered by the prescription 
isodose surface and 99% of the PTV receives a minimum of 90% of the 
prescription dose.   
• High Dose Spillage: The cumulative volume of all tissue outside the PTV 
receiving a dose > 105% of the prescription dose should be no more than 15% of 
the PTV volume.   
• Conformality of PTV coverage will be judged such that the ratio of the volume 
of the prescription isodose to PTV is ideally < 1.2. 
5.0 
Critical structures 
5.1 Pulmonary lesions 
• Skin: A skin contour should be created for all patients.  This will be equal to the body 
contour minus 3 mm.  The maximum dose should be less than the prescription dose  
(i.e., < 27 Gy). 
• Lung: Both lungs minus the PTV should be contoured as part of the study.  The dose 
tolerance is below that of the prescription dose.  Conformality as described above 
including conformality index should be achieved.  
• Carina and bronchial tree:  The distal 2 cm of the 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 
bronchi should be contoured.  The dose to this structure should be less than the 
prescription dose (i.e. < 27.0 Gy). 
• Esophagus:  Max dose < 27.0 Gy. 
 
 


 
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APPENDIX B (continued) 
5.2 Liver lesions 
• Skin: See above. 
• Liver: The entire liver should be contoured.  As with the lung, the conformality index 
should be achieved for target coverage.  The GTV should be limited to ≤100 cm3.  For 
the liver V12 < 700 cc. 
• Stomach or Bowel should be contoured 2 cm above and below the target.  The maximum 
dose should be less than the prescription dose (i.e. < 27 Gy). 
 
 


 
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APPENDIX C 
CONTRACEPTION 
 
Female patient of child-bearing potential 
• 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
− 
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 menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
• 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use at least 1 highly effective method of contraception (Table 9) from the time of screening and 
must agree to continue using such precautions for 6 months after the last dose of durvalumab and 
tremelimumab combination therapy and for an additional 3 months after the last dose of 
durvalumab monotherapy.  Non-sterilized 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 6 months after receipt of the final 
dose of durvalumab and tremelimumab combination therapy and for an additional 3 months 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 (Table 9). 
 
 


 
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Highly effective methods of contraception 
Highly effective methods of contraception defined as one that results in a low failure rate (i.e., less than 
1% per year) when used consistently and correctly are described in Table 9.  Note: 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). 
 
Table 9.  Highly Effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine Methods 
Hormonal Methods 
− 
Copper T intrauterine device 
− 
Levonorgesterel releasing intrauterine  
system (e.g., Mirena)a 
− 
Etonogestrel implants: e.g., Implanon or 
Norplant 
− 
Intravaginal device: e.g., ethinylestradiol and 
etonogestrel 
− 
Medroxyprogesterone injection: e.g., Depo- 
Provera 
− 
Normal and low dose combined oral 
contraceptive pill 
− 
Norelgestromin/ethinylestradiol  transdermal 
system 
− 
Cerazette (desogestrel) 
aThis is also considered a hormonal method. 
 
 
 


 
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Page 1 of 10 
 
Statistical Analysis Plan 
 
 
SPONSOR:  
NSABP 
 
PROTOCOL 
TITLE: 
A Phase II Study of the Dual Immune Checkpoint Blockade with 
Durvalumab (MEDI4736) plus Tremelimumab Following Palliative 
Hypofractionated Radiation in Patients with Microsatellite Stable 
(MSS) Metastatic Colorectal Cancer Progressing on Chemotherapy 
STUDY 
CODE: 
NSABP Protocol FC-9 
 
 
Version 
Draft July 06, 2019 
 
 
For Biostatistics: 
Author: Greg Yothers, PhD, Consulting Statistician 
 
For Sponsor: 
Reviewer: Alicia Detweiler, Project Data Manager 
Approver: Samuel Jacobs, Clinical Research Physician 
 


 
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Page 2 of 10 
 
Table of Contents 
 
1. 
INTRODUCTION ................................................................................. 3 
2. 
STUDY DESIGN AND OBJECTIVES ...................................................... 3 
2.1 Study Objectives...................................................................................... 3 
2.1.1 
Co-Primary Objectives ....................................................................... 3 
2.1.2 
Secondary Objectives ........................................................................ 3 
2.2 Study Design ........................................................................................... 3 
2.2.1 
Stage I futility analysis ...................................................................... 3 
2.2.2 
Stage II ........................................................................................... 3 
2.3 Sample Size Justification ........................................................................... 4 
3. 
GENERAL ANALYSIS DEFINITIONS .................................................... 4 
3.1 Study Period and Visit Window Definitions ................................................... 4 
3.1.1 
Study Periods ................................................................................... 4 
3.1.2 
Entry, Treatment, and Follow-up ......................................................... 4 
3.2 Planned Analyses ..................................................................................... 4 
3.2.1 
Stage I Analysis ................................................................................ 4 
3.2.2 
Final Analysis .................................................................................... 5 
3.3 Definition of Analysis Populations ............................................................... 5 
3.3.1 
Intent-to-Treat Population (ITT) .......................................................... 5 
3.4 Calculated Variables ................................................................................. 5 
3.5 Changes to Protocol ................................................................................. 5 
4. 
STUDY PATIENTS ............................................................................... 5 
4.1 Disposition of Patients .............................................................................. 5 
4.2 Protocol Deviations .................................................................................. 5 
4.3 In- and Exclusion Criteria .......................................................................... 6 
5. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................ 6 
6. 
SAFETY EVALUATION ......................................................................... 6 
6.1 Extent of Exposure ................................................................................... 6 
6.2 Adverse Events ........................................................................................ 6 
6.3 Deaths ................................................................................................... 7 
7. 
EFFICACY ANALYSIS .......................................................................... 7 
7.1 Primary Analysis of Stage II: Objective Response Rate ................................. 7 
7.2 Secondary Efficacy Analyses ...................................................................... 7 
7.2.1 
Clinical Benefit Rate ........................................................................... 7 
7.2.2 
Duration of Response ......................................................................... 8 
8. 
EXPLORATORY TRANSLATIONAL STUDIES ......................................... 8 
9. 
APPENDICES ...................................................................................... 8 
APPENDIX 1: LIST OF STATISTICAL TABLES .............................................. 9 
APPENDIX 3: LIST OF DATA LISTINGS ..................................................... 10 


 
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1. 
Introduction 
This Statistical Analysis Plan (SAP) is written for the clinical trial protocol NSABP FC-
9, version dated November 7, 2016. The ICH guideline E3 “Structure and Content of 
Clinical Study Reports” was used as a guide to the writing of the plan. 
 
2. 
Study Design and Objectives 
The FC-9 study is designed as a phase II, open label, single arm study of the dual 
immune 
checkpoint 
blockade 
with 
the 
combination 
of 
durvalumab 
and 
tremelimumab following hypofractionated palliative radiation in patients with 
microsatellite stable (MSS) metastatic colorectal cancer (mCRC) who have 
progressed on chemotherapy.  
Study design is a Simon two-stage design (12 patients stage I, 9 patients stage 
II). 
If at least one patient in the first stage have an objective response, the study will 
proceed to Stage II (expansion cohort).  The expansion cohort will enroll 9 
additional patients.  If ≥ 3 patients have objective response, the study therapy will 
be considered for further testing. 
There will be up to 21 evaluable patients (unevaluable patients will be replaced). 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary aim of the study is to estimate the objective response rate (ORR). 
2.1.2 Secondary Objectives 
The secondary objectives of the study will be analyzed separately and are:  
 
Clinical benefit rate (CBR) 
 
Duration of Response (DOR) 
 
Toxicity profile 
In addition, exploratory studies will be performed on available data, with the aim: 
 
Discovering markers that predict treatment benefit 
2.2 Study Design 
2.2.1 Stage I futility analysis 
If at least one patient in the first stage has an objective response, the study will 
proceed to Stage II (expansion cohort), otherwise the study will stop for futility.  
2.2.2 Stage II  
If ≥ 3 patients of the combined stage I and II evaluable patients have an 
objective response, the study therapy will be considered for further testing. 


 
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2.3 Sample Size Justification 
The hypothesis tested to determine the activity of Dual Immune Checkpoint 
Blockade with Durvalumab plus Tremelimumab expressed in terms of ORR: 
  
H0: ORR <0.05 
  
HA: ORR >0.20 
With the specified null and alternative hypotheses, a type I error rate of 0.10 one-
sided and power of 0.80 to reject H0 if the true response rate is 20%, a Simon two 
stage design consists of initially treating 12 evaluable patients.  Enrolment should 
end for an inadequate response (futility) if no patients have an objective response.  
If at least one patient has an objective response, enrolment continues to a total of 
21 patients.  If at least 3 responses are seen (ORR > 0.143), the treatment will be 
considered worth testing further. 
 
3. 
General Analysis Definitions 
Data will be analyzed using SAS v 9.4.  
Descriptive statistics will be tabulated as follows:  
 Categorical data will be summarized in contingency tables presenting 
frequencies and percentages. 
 Continuous data will be summarized using number of non-missing values (n), 
mean, standard deviation, median, minimum and maximum values. 
3.1 Study Period and Visit Window Definitions 
3.1.1 Study Periods 
The accrual period is expected to be 24 months. 
Enrolled patients will receive the combination of tremelimumab (75 mg IV infusion) 
and durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles. Beginning with Cycle 
5 through Cycle 12, patients will receive durvalumab alone (1500 mg/IV infusion) 
on Day 1 of each 28 day cycle. 
All AEs will be recorded from the first dose of study therapy until 90 days after the 
last dose of study therapy or at the cessation of study therapy if the patient 
initiates new anti-cancer therapy, whichever is earlier. 
3.1.2 Entry, Treatment, and Follow-up 
Requirements for study entry and during treatment and follow-up are outlined in 
section 5 of the protocol. 
3.2 Planned Analyses 
3.2.1 
Stage I Analysis 


 
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The first analysis of ORR will be performed when 1 or more stage I patients have 
an objective response or 2 years after the last stage I patient is entered, whichever 
comes first.  
3.2.2 
Final Analysis 
The second and final analysis of ORR will be performed when all patients have 
completed protocol therapy.  
3.3 Definition of Analysis Populations 
3.3.1 Intent-to-Treat Population (ITT) 
The Intent-To-Treat population (ITT) will consist of patients who complete both 
Cycle 1 and Cycle 2, and undergo the first restaging scan after Cycle 2 for the 
determination of tumor response will be determined as evaluable. Non-evaluable 
patients will be replaced.  
3.3.2 Safety Population 
The Safety population will consist of all patients who receive at least one dose of 
any study medication. 
3.4 Calculated Variables 
 Study day 1 is defined as the first day any of the study therapy was received. 
 The baseline is defined as the last assessment done before or on study day 1. 
 Duration of Response (months): (earliest date of censoring, progression, or 
death – earliest date of response + 1) * 365.25 / 12. 
 The cycle start date is the first date of administration of any study drug (with a 
non-missing dose) by treatment cycle (as reported in the eCRF). 
 The visit of premature discontinuation of each drug will be derived from [the 
date of the last dose reported on the form of discontinuation. This date will be 
merged with the date of drug administration to determine to which cycle of 
treatment it corresponds. 
3.5 
Changes to Protocol 
No change has been done from the analyses planned in the protocol. 
 
4. 
Study Patients 
4.1 Disposition of Patients 
Table describing number of patients screened, entered, treated, and evaluable. 
4.2 Protocol Deviations 
Protocol deviations will not be analyzed since they are not recorded on the eCRF. 


 
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4.3 In- and Exclusion Criteria 
This will not be analyzed since specific criteria are not collected on the eCRF. 
 
5. 
Demographic and Other Baseline Characteristics 
Descriptive statistics with respect to patient characteristics at baseline will be 
displayed for [the ITT population].  
The summary of demographic data and baseline disease characteristics will present 
the following variables: 
 
Age, sex, race, and ethnicity 
 
ECOG performance status (0 to 1) 
 
Time since initial diagnosis of colon cancer 
 
6. 
Safety Evaluation 
The safety analyses will be presented on the [ITT population]. 
6.1 Extent of Exposure 
The exposure to each study drug will be summarized in terms of: 
 
Number of started cycles  
 
Total cumulative dose  
6.2 Adverse Events 
Frequency and severity of adverse events categorized using the NCI Common 
Terminology Criteria for Adverse Events version [4.0 (CTCAE v4.0)] will be 
tabulated. The adverse events are coded using MedDRA Version [18.1]. AE rates 
will be described by dose level without regard to attribution. Treatment Emergent 
Adverse events (TEAEs) will be analyzed in terms of their type, incidence and 
severity. An adverse event is treatment emergent if it occurs on or after the date 
of the first administration of study drug. According to the protocol, only treatment 
emergent AEs are collected on this study. 
A summary table including the number of AEs and the number of patients with at 
least one: 
- 
AE 
- 
Grade 1/2 AE 
- 
Grade 3 or 4 AE 
- 
Serious AE 
- 
AE leading to permanent discontinuation of either one of both study treatments 
- 
Fatal AE 
- 
AE leading to death 


 
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will be presented. 
Tabulations of the number of patients who experienced treatment emergent 
adverse events as well as grade of the events will be presented by system organ 
class and preferred term. Patients will only be counted once for each preferred 
term. In case a patient experienced the same event more than once, the worst 
grade will be presented.  
Listings of all AEs detailing all AE information by patient with flags for SAE, AE 
leading to treatment discontinuation, Fatal AE, and AE leading to death. 
6.3 Deaths 
The number of deaths will be tabulated together with the primary cause of death. 
The details of the ‘other will be included in the listing. 
7. 
Efficacy Analysis 
The efficacy analyses will use data from tumor assessments for all subjects at 
baseline and then after every 2 cycles (8 weeks) of treatment. The overall 
response to the treatment is classified as Complete Response (CR), Partial 
Response (PR), Stable Disease (SD) or Progressive Disease (PD) and is recorded in 
the eCRF at each tumor assessment.  
7.1 Primary Analysis of Stage II: Objective Response Rate 
The ITT population will be used to test the effects of therapy on ORR. 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). Confirmation of 
complete or partial response IS NOT required.  
A summary table presenting % of patients with a best overall response of CR, PR, 
SD and PD will be made. ORR will be calculated as % of patients with CR or PR at 
any time during the treatment (including unscheduled assessments). The 95 % 
confidence interval of the ORR proportion will be reported using exact method 
based on the binomial distribution (Clopper-Pearson method). The denominator will 
be the number of patients in the ITT population. 
The primary objective of the trial will be reached if at least 3 responses are 
observed among 21 evaluable patients (14.3%). 
7.2 Secondary Efficacy Analyses 
The secondary endpoints will be analyzed with a descriptive intent only. The 
secondary objectives for stage II of the study will be analyzed separately on the 
ITT population. 
7.2.1 Clinical Benefit Rate 
CBR is defined as the proportion of patients with no progression or death at 16 
weeks.  


 
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The 95% confidence interval of the CBR will be reported using exact method based 
on the binomial distribution (Clopper-Pearson method). The denominator will be 
the number of patients in the ITT population. 
 
7.2.2 Duration of Response 
DOR is defined as the time (in months) from best response to progression, 
censoring, or death) among patients with a response.  
The median and a 95 % confidence interval of DOR will be reported using Kaplan-
Meier methods.  
8. 
Exploratory Translational Studies 
Immune markers will be explored by NSABP out of the scope of this SAP. 
 
9. 
Appendices 
Appendix 1: List of Statistical Tables 
Appendix 2: List of Data Listings 


 
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Appendix 1: List of Statistical Tables  
Table Number 
Table Title 
Population
Table 01.01 
Patient Disposition 
All enrolled 
patients 
Table 01.02 
Completion Status and Discontinuation from 
study drugs 
ITT 
Table 01.03 
Completion Status and Discontinuation from the 
Study 
ITT 
 
 
 
Table 02.01 
Demographic and Other Baseline Characteristics 
ITT 
 
 
 
Table 03.01 
Extent of Exposure 
ITT 
 
 
 
Table 04.01 
Summary of Adverse Events 
Safety 
Table 04.02 
Grade 1/2 Adverse Events by SOC and PT 
Safety 
Table 04.03 
Grade 3/4 Treatment-Emergent Adverse Events 
by SOC, PT 
Safety 
Table 04.04 
Adverse Events Leading to Discontinuation of 
Study Therapies, by SOC and PT 
Safety 
Table 04.05 
Fatal Adverse Events by SOC and PT 
Safety 
Table 04.06 
AEs leading to Death by SOC and PT 
Safety 
Table 04.07 
Deaths 
Safety 
 
 
 
Table 05.01 
Best overall response 
ITT 
Table 05.02 
Objective Response Rate 
ITT 
Table 05.03 
Clinical Benefit Rate at 16 weeks 
ITT 
Table 05.04 
Duration of Response 
ITT 
Figure 05.05 
Kaplan-Meier Duration of Response Plot 
ITT 
 
 


 
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Appendix 3: List of Data Listings  
Listing Number 
Listing Title 
Population 
Listing 01.01 
Patient Disposition 
All 
Listing 01.02 
Patient Completion of Study Treatment and of 
Study 
All 
Listing 02.01 
Demographic and Other Baseline Characteristics 
All 
Listing 03.01 
Study Drug Administration 
All 
Listing 04.01 
Adverse Events  
All 
Listing 04.02 
Serious Adverse Events 
All 
Listing 04.03 
Fatal Adverse Events 
All 
Listing 04.04 
Deaths 
All 
Listing 05.01 
Tumor response (including ORR and CBR 
indicators) 
All 
Listing 05.02 
Duration of Response 
All