Clinical trial NCT03122509
Conditions: Metastatic Colorectal Cancer
Keywords: Durvalumab Tremelimumab Radiation Therapy Ablation 17-139
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-04-24; Completion date: 2021-04-28
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the safety and effectiveness of two investigational drugs (drugs that are not currently approved by the FDA) given in combination with radiation therapy or ablation.

Detailed description:

Arms: arm 1: Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. Radiotherapy (RT) will be performed using external beam ionizing radiation as standard therapy in accordance with institutional standard practice. RT will be initiated within 7 days after the first of durvalumab and tremelimumab. arm 2: Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on Week 16. Tremelimumab will be administered first. Durvalumab infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. The ablation will be performed percutaneously under image guidance as standard therapy at the discretion of the interventional radiologist in accordance with institutional standard practice. Ablation will be performed within 7 days after the first of durvalumab and tremelimumab.
Interventions: intervention 1: durvalumab intervention 2: tremelimumab intervention 3: Radiotherapy (RT) intervention 4: ablation
Intervention descriptions: intervention 1: 1500 mg durvalumab via IV infusion intervention 2: 75 mg tremelimumab via IV infusion intervention 3: Radiotherapy (RT) will be performed using external beam ionizing radiation as standard therapy in accordance with institutional standard practice. intervention 4: Ablation will be performed percutaneously under image guidance as standard therapy at the discretion of the interventional radiologist in accordance with institutional standard practice.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 1of 86 
 
 
 
 
 
 
 
Phase IIStudy to Assess the Efficacy of Durvalumab (MEDl4736) and 
Tremelimumab Plus Radiotherapy or Ablation in Patients with Metastatic Colorectal 
Cancer 
 
PROTOCOL FACE PAGE FOR 
MSK THE RAPEUTIC/D !AGNOSTIC PROTOCOL 
 
 
 
Principal Investigator/Department: 
Neil H.Segal, MD, PhD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Leonard B. Saltz, MD 
Josh Yamada, MD 
Stephen Solomon, MD 
Medicine 
Radiation Oncology 
lnterventional Radiology 
Investigator{s)/Department: 
Ghassan Abou-Alfa, MD 
Medicine 
Andrea Cercek, MD 
Medicine 
Luis Diaz, MD 
Medicine 
Andrew Epstein, MD 
Medicine 
Karuna Ganesh 
Medicine 
James Harding, MD 
Medicine 
David llson, MD, PhD 
Medicine 
Yelena Janjigian, MD 
Medicine 
David Kelsen, MD 
Medicine 
Nancy Kemeny, MD 
Medicine 
Danny Khalil, MD 
Medicine 
Geoffrey Ku, MD 
Medicine 
Diane Reidy-Lagunes, MD 
Medicine 
Eileen O'Reilly, MD 
Medicine 
Armin Shahrokni, MD 
Medicine 
Zsofia K. Stadler, MD 
Medicine 
Anna Varghese, MD 
Medicine 
Rona Yaeger, MD 
Medicine 
Kenneth Yu, MD 
Medicine 
Nitya Raj, MD 
Medicine 
Wungki Park, MD 
Medicine 
Juan Manuel Schvartzman, MD 
Medicine 
Ellen Hollywood, NP 
Nursing 
Natasha Pinheiro, NP 
Nursing 
Jaclyn Norris, NP 
Nursing 
Patricia Gabriel, NP 
Nursing 
Erica Kaufman, NP 
Nursing 
Pamela Vaiskauskas, RN 
Nursing 
Michal Segal, RN 
Nursing 
Vanessa Grant, RN 
Nursing 
Robin Brenner, RN 
Nursing 
Abraham Wu, MD 
Radiation Oncology 
Christopher Crane, MD 
Radiation Oncology 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 2of 86 
 
 
 
 
 
Daniel Higginson, MD 
Adam Schmitt, MD 
T. Jonathan Yang, MD, PhD 
Krishna Juluru, MD 
Constantinos Sofocleous, MD, PhD 
Joseph P. Erinjeri, MD, PhD 
Jinru Shia, MD 
Marinela Capanu, PhD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiology 
lnterventional Radiology 
lnterventional Radiology 
Pathology 
Epidemiology and 
Biostatistics 
Consenting 
Ghassan Abou-Alfa, MD 
Medicine 
Professional(s)/Department: 
Andrea Cercek, MD 
Medicine 
Luis Diaz, MD 
Medicine 
Andrew Epstein, MD 
Medicine 
Karuna Ganesh, MD 
Medicine 
James Harding, MD 
edicine 
Danny Khalil, MD 
Medicine 
David llson, MD, PhD 
Medicine 
Yelena Janjigian, MD 
Medicine 
David Kelsen, MD 
Medicine 
Nancy Kemeny, MD 
Medicine 
Geoffrey Ku, MD 
Medicine 
Diane Reidy-Lagunes, MD 
Medicine 
Eileen O'Reilly, MD 
Medicine 
Armin Shahrokni, MD 
Medicine 
Leonard B. Saltz, MD 
Medicine 
Neil H. Segal, MD, PhD 
Medicine 
Zsofia K. Stadler, MD 
Medicine 
Anna Varghese, MD 
Medicine 
Rona Yaeger, MD 
Medicine 
Kenneth Yu, MD 
Medicine 
Nitya Raj, MD 
Medicine 
Wungki Park, MD 
Medicine 
Juan Manuel Schvartzman, MD 
Medicine 
Natasha Pinheiro, NP 
Nursing 
Ellen Hollyvrood, NP 
Nursing 
Patricia Gabriel, NP 
Nursing 
Erica Kaufman, NP 
Nursing 
Jaclyn Norris, NP 
Nursing 
 
 
Please Note: A Consenting Professional1TL1st have COIT1Jleted the mandatory Human 
Subjects  Education and Certification Program. 
 
 
 
OneMSK Sites 
l\lenhattan 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 3of 86 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 4of 86 
 
 
 
 
List of Abbreviations 
 
Abbreviati on or 
Specialized Term 
Definition 
ADA 
anti-<lrug antibody 
ADCC 
antibody-<lependent  cell-mediated cytotoxicity 
AE 
adverse event 
ALT 
alanine aminotransferase 
APC 
antigen presenting cells 
AST 
aspartate  aminotransferase 
CD 
cluster of differentiation 
Cl 
confidence interval 
CIS 
carcinoma in situ 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
C"TlA-4 
cytotoxic T-lymphocyte antigen 4 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
enzyme-linked immunosorbent assays 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EU 
European Union 
Fe 
fragment  crystallizable 
FFPE 
formalin fixed paraffin embedded 
FTIH 
First-time-in-human 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 5of 86 
 
 
 
 
 
Abbreviation or 
Specialized Term 
Definition 
GI 
gastrointestinal 
HCI 
hydrochloride 
HCV 
hepatitis C .,;rus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency \irus 
ICF 
infonned consent fonn 
ICH 
International Conference on Hannonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
interferon 
lgG1K 
immunoglobulin G1 kappa 
IHC 
immunohistochemistry 
IL 
interleukin 
IM 
immunogenicity 
IRB 
Institutional Review Board 
irAE 
immune-related adverse event 
irRC 
immune-related response criteria 
IV 
intravenous(ly) 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Acti'<ities 
MDSC 
Myeloid derived suppressor cell 
miRNA 
micro ribonucleic acid 
MMR 
mismatch repair 
mRNA 
messenger ribonucleic acid 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no-observed  adverse-effect-level 
NSCLC 
non-small cell lung cancer 
OBD 
optimal biological dose 
ORR 
objective response rate 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 6 of 86 
 
 
 
 
 
Abbreviation or 
Specialized Term 
Definition 
OS 
overall sur\ival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressiw  disease 
PD-1 
programmed death 1 
PD-L 1 
programmed death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
Q2W 
every 2 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
Radiofrequency  ablation 
RT 
Radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject  identification 
SMC 
Safety Monitoring Committee 
SPD 
sum of products of diameters 
SRT 
Safety Re\iew Team 
SUSAR 
suspected unexpected serious adverse reaction 
TIL 
tumor infiltrating lymphocyte 
TNF-0 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
USA 
United States of America 
WFI 
water for injection 
WHO 
Wod Health Organization 
w/v 
weight/\Clume 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 7 of 86 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA................................................................ 8 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 10 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 11 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 23 
4.2 Design ........................................................................................................................... 24 
4.3 Intervention .................................................................................................................... 24 
5.0 
THERAPEUTIC/DIAGNOSTI C /lGENTS ...........................................................................25 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 26 
6.2 
Subject Inclusion Criteria ........................................................................................... 26 
6.3 
Subject Exclusion Criteria ............................................................................................ 27 
7.0 
RECRUITMENT PLAN ...................................................................................................... 28 
8.0 
PRETREATMENT EVALUATION ................................................................................. 29 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 29 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 39 
11.0 
TOXICITIES/SIDE EFFECTS ...................................................................................... 41 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 50 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .................................................................. 52 
14.0 
BIOSTATISTICS........................................................................................................... 53 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES55 
15.1  Research Participant Registration ............................................................................... 55 
15.2 
Randomization ................................................................................................................... 55 
16.1 
DATA MAN/lGEMENT ISSUES .................................................................................... 55 
16.2 
Quality k;surance. ................................................................................................ 55 
16.3 
Data and Safety Monitoring ......................................................................................... 56 
17.1 
PROTECTION OF HUMAN SUBJECTS ............................................................................. 56 
17.2 
Privacy ..................................................................................................................... 57 
17.3 
Serious Adverse Event (SAE) Reporting .................................................................. 57 
17.2.1            .........................................................................................................................................58 
18.0 
INFORMED CONSENT PROCEDURES ...................................................................... 59 
19.0 
REFERENCES ............................................................................................................ 59 
20.0 
APPENDICES ................................................................................................................... 60 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 8 of 86 
 
 
 
 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Names of lnvestiaational druas: Durvalumab and Tremelimumab 
Title of Study:  Phase II Study to Assess the Efficacy of Durvalumab and Tremelimumab plus Radiotherapy or 
Ablation in Patients with Metastatic Colorectal Cancer 
Study Centers: MSKCC 
Study Period: 24 months 
I Phase of Development: II 
Objectives: 
The primary objective is Overall Response Rate in disease that is not ablated or radiated (Complete 
Response and Partial Response). 
The secondary objectives are: 
1. 
Safety and tolerability of durvalumab and tremelimumab plus radiotherapy (RT) or ablation 
2. 
Oi.erall Sun.ival of durvalumab and tremelimumab plus RT or ablation 
3. 
Progression free survival rate at 1 year 
4. 
Progression free survival rate at 2 years 
The exploratory objectives are to evaluate biomarkers that may correlate with activity of durvalumab and 
tremelimumab plus RT or durvalumab and tremelimumab plus ablation in colorectal cancer (CRC), or 
orosoectii.elv identifv CRC oatients likelv to resoond to treatment. 
Study Design: This will be a Simon two-stage design, phase II study. It will be conducted to determine the 
efficacy and safety of (1) durvalumab and tremelimumab plus RT in subjects with metastatic CRC who are 
undergoing RT as standard therapy; and, (2) durvalumab and tremelimumab plus ablation in subjects with 
metastatic CRC who are undergoing ablation as standard therapy. Eligible patients will hai.e metastatic 
colorectal cancer and received at least two prior standard therapies for metastatic disease for which they are 
considered appropriate. Patients will be stratified according to eligibility for RT (cohort 1) or ablation (cohort 2). 
Patients in cohort 1will have at least one metastatic lesion for which palliatiw RT is considered appropriate 
standard therapy, and at least one other measurable index lesion that will not undergo RT. Patients in cohort 
2 will have at least one metastatic lesion for which palliatii.e ablation is considered appropriate standard 
therapy, and at least one other measurable index lesion that will not undergo ablation. All subjects will undergo 
ablation or begin RT within 7 days after dose #1 of durvalumab and tremelimumab. Subjects will receii.e 
durvalumab and tremelimumab every four weeks (Q4W), for 4 months, and then continue durvalumab alone 
every four weeks (Q4W) until confirmed progression of disease, initiation of alternative cancer therapy, 
unacceptable toxicity, or other reasons to discontinue treatment occur. Patients who had a prior response, 
continued on durvalumab monotherapy and did not discontinue tremelimumab due to toxicity may resume 
combination therapy with tremelimumab plus durvalumab for 4 doses upon disease progression, followed by 
durvalumab monotherapy. Repeat palliative RT in cohort 1, or ablation in cohort 2, will be permitted in select 
cases. Repeat palliatii.e RT or ablation may include measurable index lesion(s) that is(are) being followed for 
response measurements if at least one index lesions remains to be followed. Patients will be evaluated by 
physical exam and routine blood tests ei.ery 2 weeks during the first 4 months then every 4 weeks during the 
study period. CT or MRI will be performed during screening, and then at 8 week intervals. Tumor 
measurements and determination of tumor responses will be performed according to RECIST 1.1. Subjects 
may continue to receive durvalumab and tremelimumab beyond radiographic progression in the absence of 
clinical deterioration. All subjects will be followed up to 2 years for survival or until the study closes. The 
primary endpoint of this trial is the response rate in CRC treated with RT plus durvalumab and tremelimumab 
(cohort 1) or ablation plus durvalumab and tremelimumab (cohort 2). A two-stage Simon's optimal design will 
be employed to test the null hypothesis that the true response rate is S5% versus the altematii.e hypothesis 
that the true response rate is at least 25% with type I and II error rates of 10% each. Each cohort will be 
evaluated separately for this purpose. In the first stage, we will accrue 9 patients in each cohort. If 0 objectii.e 
tumor responses (PR or CR) are observed among the 9 subjects treated in a cohort, then subject enrollment 
will be terminated in that cohort. If at least 1 response is observed among the 9 subjects treated in either 
cohort, then the study will be expanded to enroll a total of 24 treated subjects in that cohort. If one cohort is 
filled and at least 1 response is observed, it may be expanded under the investigator's discretion, regardless of 
the other cohort's accrual status. In the likelihood that we observe at least one resoonse in each of the 9 


Page 9 of 86 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-201S 
 
 
.
• 
 
 
 
subjects treated in stage 1 of the two cohorts, iiwill be at the discretion of the investigators which cohort to 
expand based on phannacodynamic data (such as circulating CEA, changes in composition/activation status 
of 
lymphocyte 
subsets 
present in 
peripheral blood mononuclear 
cell 
preparations 
or 
tumor 
immunohislochemistry analysis, and/or circulating cytokines/ chemokines). At the end of the study, if 2 or less 
objective tumor responses are observed in a cohort, then the study will be considered not worthy of further 
imestigation in that particular cohort. If at the end of the study 3 tumor responses  per RECIST 1.1 are 
observed in a cohort, then further investigation of durvalumab and tremelimumab plus RT and/or durvalumab 
and tremelimumab plus ablation will be considered worthwhile. The study will complete when all subjects have 
either progressed or discontinued from the study for other reasons. This study requires accrual of a minimum 
of 1S subjects and up to a maximum of 33 subjects. The accrual time is estimated to be 2 years. Baseline and 
on treatment tumor biopsies for research purposes will be mandatory in the first 9 patients in each cohort. On 
treatment biopsies will be perfonned 1 week after the completion of radiation or ablation (of the radiated/ 
ablated lesion) and then 4 weeks after dose #1 of durvalumab andlremelimumab (of a non-radiated/ ablated 
lesion). Tumor immunohistochemistry may be perfonned for PD-L 1 expression and quantification of tumor 
infiltrating lymphocyte (TIL) subtypes, including CDS+ T-cells, CD4+ T-cells, Regulatory T-cells (Treg), and 
Myeloid Derived Suppressor Cells (MDSCs). Peripheral blood samples  will  be obtained in all patients al 
baseline then weeks 2, 4 and S. Plasma may be analyzed for change in antibody responses to a broad panel 
of antigens (seromics). Flow cytometry may be perfonned for peripheral blood immune cell phenotype and 
their activation status, including CDS+ T-cells, CD4+ T-<:ells, Tregs, and MDSCs. The amount of PDL-1 
expression, changes in immune cell repertoire and activation status within the tumor and peripheral blood as 
well as immune responses against specific tumor antigens will be correlated with clinical outcome in an 
exploratory manner in order to identify predictiw makers for response, and to further our understanding of 
durvalumab and tremelimumab plus RT, and durvalumab and tremelimumab plus ablation in CRC. 
Diagnosis and Main Criteria for Inclusion in the Study: 
Inclusion Criteria 
1. 
Willing and able to provide written infonned consent. 
2. 
Hislologically- or cylologically- confinned CRC. 
3. 
Metastatic CRC. 
4. 
Subjects have received at least two standard chemotherapy regimens for which they would be 
considered eligible (al least one containing a 5-ft uoropyrimidine), or systemic chemotherapy is not 
indicated in the setting of low volume metastatic disease. 
5. 
Al least one tumor for which palliative RT is considered appropriate standard therapy (cohort 1); 
or, at least one tumor for which pallialiw ablation is considered  appropriate standard therapy 
(cohort 2). 
6. 
Al least one index lesion that will  not undergo RT or ablation, and is measurable based on 
RECIST 1.1. 
7. 
1S years of age on day of signing infonned consent. 
S. 
Consent for tumor biopsies (stage 1only) and blood draws (all patients) for research purposes. 
9. 
Consent for use of available archived tissue and tumor obtained during a standard procedure, for 
research purposes. 
10. 
Perfonnance status of ECOG 0 or 1. 
11. 
Female subjects must either be of non-reproductiw 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 pregnancylest upon study entry. 
12. 
Adequate organ function, defined as: 
• 
Absolute Neutrophil Count 
1,500/mm3 
• 
Platelet count 
100,000/mm3 
• 
Serum crealinine s 1.5 x ULN or CrCI 
O mUmin. 
• 
AST and ALT s 2.5 x ULN or s 5 x ULN for subjects with liwr metastases. 
• 
Bilirubin s 1.5 x ULN or Direct bilirubin s ULN. 
• 
Hemoglobin 
S.O g/dl 
 
Exclusion Criteria 
1. 
Currently  participating  in/  has  participated in  a study  of an invesligalional agent or  using an 
inwstigational device within 4 weeks. 
2. 
Chemotheranv, monoclonal antibodv, taroeted small molecule theranv, within 4 weeks orior to 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 10 of 86 
 
 
 
 
 
dose #1 or who has not recovered (i.e., s Grade 1 or at baseline) from adverse events due to a 
previously administered agent (excluding alopecia or toxicity not anticipated to interfere with 
planned treatment on study). 
3. 
Known or suspected MSl-H CRC. 
4. 
Any prior Grade ;,3 immune-related adverse event (irAE) while receiving any previous, 
immunotherapy agent, or any unresolved irAE >Grade 1, except endocrinopathies and 
asymptomatic  amylase/lipase. 
5. 
If subject receiwd major surgery, they must haw recovered adequately from the toxicity and/or 
complications from the intervention per clinical discretion  of the investigator prior to starting 
therapy. 
6. 
Concurrent active malignancy that requires systemic treatment. 
7. 
Untreated CNS metastases and/or carcinomatous meningitis. 
8. 
Actiw autoimmune disease requiring systemic immune suppressive treatment within the past 2 
years. 
9. 
Actiw, non-infectious pneumonitis. 
10. 
Actiw or prior documented inflammatory bowel disease 
11. 
Prior allogeneic organ transplant. 
12. 
Actiw infection requiring systemic therapy. 
13. 
Psychiatric/ substance abuse disorders that would interfere with cooperation with the requirements 
of the trial. 
14. 
Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. 
Known actiw and untreated Hepatitis B or C. 
16. 
Liw vaccine within 30 days prior to the first dose of trial treatment. 
17. 
Current or prior use of immunosuppressiw medication within 14 days before the first dose of 
durvalumab or tremelimumab with the exceptions of premedication and intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 
10mg/day of prednisone, or an equivalent corticosteroid. The use of topical steroids is permitted. 
18. 
Hypersensiti-.ity to durvalumab or tremelimumab, or any excipients on the formulation. 
19. 
Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results. 
20. 
Female patients who are pregnant or breastfeeding or male or female patients of reproductiw 
potential who are not willing to employ effective birth control from screening to 180 days after the 
last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy, whichever is the longer time period 
21. 
QT interval corrected for heart rate (QTc) ;, 470ms calculated from  1 electrocardiogram (ECG) 
using Fridericia's Correction 
22. 
History of primary immunodeficiency 
23. 
Known history of pre-.ious clinical diagnosis of tuberculosis 
24. 
Subjects with uncontrolled seizures 
Number of Subjects:  18 to 33, including patients in cohort 1 (n-9) and cohort 2 (n-9), if response is 
observed, the cohort with the hiaher resnnnse rate mav enroll uo to 24 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• The primary objective is Overall Response Rate in disease that is not ablated or radiated of 
durvalumab and tremelimumab plus RT or durvalumab and tremelimumab plus ablation in 
subjects with metastatic CRC, according to RECIST v1.1. A response in a non-ablated or 
non-radiated lesion is an abscopal effect. 
• The secondary objectives are to determine: 
o 
Safety and tolerability of durvalumab and tremelimumab plus RT or ablation 
o 
Overall Survival of durvalumab and tremelimumab plus RT or ablation 
o 
Progression free survival rate at 1 year 
o 
Progression free survival rate at 2 years 


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IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
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• The exploratory objectives are to evaluate biomarkers that may correlate with actMty of 
durvalumab and tremelimumab plus RT or ablation in CRC, or prospectively identify CRC 
patients likely to respond to treatment. 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 
Immune responses against cancer 
 
Immune responses directed against tumors are one of the body's natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from i'nmune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells. Programmed cell death ligand 1 (PO-L1) is one such protein, and is 
upregulated in a broad range of cancers with a high frequency, with up to BB% expression in some 
tumor types. In a number of these cancers, including lung (Ml et al, 2011), renal (Thompson et al, 
2005; Thompson et al, 2006; Krambeck et al, 2007), pancreatic (Nomi et al, 2007; Loos et al, 200B; 
Wang et al, 2010), ovarian cancer (Hamanishi et al, 2007), and hematologic malignancies (Andorsky 
et al, 2011; Brusa et al, 2013) tumor cell expression of PO-L1 is associated with reduced survival 
and an unfavorable prognosis. 
 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PO-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by the 
host immune system tumor response. In the lymph nodes, PO-L1 on antigen-presenting cells binds 
to P0-1 or COBO on activated T cells and delivers an inhibitory signal to the T cell (Keir et al, 200B; 
Park et al, 2010). This results in reduced T-cell activation and fewer activated T cells in circulation. 
In the tumor microenvironment, PO-L1 expressed on tumor cells binds to P0-1 and COBO  on 
activated T cells reaching the tumor. This delivers an inhibitory signal to those T cells, preventing 
them from killing target cancer cells and protecting the tumor from immune elimination (Zou and 
Chen, 200B). 
 
Immune  responses  directed  against  tumors  are  one  of  the  body's  natural  defenses  against 
the growth and proliferation of cancer cells. T cells play a critical role in antitumor immunity and their 
infiltration and activity have been linked to improved prognosis in a number of cancers (Pages et al, 
2010; Nakano et al, 2001; Suzuki et al, 2011; Burt et al, 2011). Immune evasion, primarily through 
suppression of T-cell activity, is now recognized as one of the hallmarks of cancer. Such evasion 
can occur via a range of mechanisms including production of suppressive cytokines such as IL-10, 
secretion of chemokines and growth factors that recruit and sustain suppressive regulatory T cells 
(Tregs) and inflammatory macrophages, and expression of inhibitory surface molecules such as 
B7-H1. Tumor  types  characterized  as  being  responsive  to  immunotherapy-based  approaches 
include melanoma  (Weber  et al, 2012),  renal cell carcinoma (RCC;  McOennott,  2009),  bladder 
cancer (Krescmik and Griffith, 2009), and malignant mesothelioma (Bograd et al, 2011). Inhibition of 
CTL.A4 signaling is a validated approach to cancer therapy, as shown by the approval in 2011 of 
ipilimumab for the treatment of metastatic melanoma based on statistically significant and clinically 
meaningful improvement in OS (Hodi et al, 201O; Robert et al, 2011). 


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In general,tumor response rates to anti-CTLA-4 therapy are low (-10%). However, in patients who 
respond, the responses are generally durable, lasting several months even in patients with 
aggressive tumors such as refractory metastatic melanoma. Because these agents work through 
activation of the immune system and not by directly targeting the tumor, responses can occur late 
and some patients may have perceived progression of their disease in advance of developing 
disease stabilization or a tumor response. In some cases, early growth of pre-existing lesions or the 
appearance of new lesions may have been due to immune-cell infiltration into the tumor and not 
due to proliferation and extension of neoplastic cells, per se (Wolchok et al,2009). Overall, 
although the impact on conventionally-defined PFS can be small, durable response or stable 
disease seen in a proportion of patients can lead to significant prolongation of OS. The melanoma 
data with ipilimumab clearly demonstrate that a small proportion of patients with an objective 
response had significant prolongation of OS, supporting the development of this class of agents in 
other tumors. Although Phase 2 and Phase 3 studies of tremelimumab in metastatic melanoma did 
not meet the primary endpoints of response rate and OS, respectively, the data suggest activity of 
tremelimumab in melanoma {Kirkwood et al,2010; Ribas et al, 2013). In a large Phase 3 
randomized study comparing tremelimumab with dacarbazine {DTIC}/temozolomide in patients with 
advanced melanoma, the reported median OS in the final analysis was 12.58 months for 
tremelimumab versus 10.71 months for DTIC/temozolomide {HR = 1.1416, p = 0.1272; Ribas et al, 
2013). 
3.2 
Durvalumab 
The non-clinical and clinical experience is fully described in the current version of the durvalumab 
Investigator's Brochure {IB Version 9.0). 
 
Durvalumab is a human monoclonal antibody {mAb} of the immunoglobulin G {lgG} 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/Med Immune for use 
in the  treatment  of  cancer. 
(Medlmmune  is  a wholly  owned  subsidiary  of  AstraZeneca; 
AstraZeneca/Medl mmune will be referred to as AstraZeneca throughout this document.} 
As 
durvalumab is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or 
complement-dependent  cytotoxicity. 
The  proposed  mechanism  of action for  durvalumab is 
interference of the interaction of PD-L1. 
 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types of 
cancers. In a number of these cancers, including lung, the expression of PD-L1 is associated with 
reduced survival and an unfavorable prognosis.  In lung cancer, only 12% of patients with tumors 
expressing PD-L1 survived for more than 3 years, compared with 20% of patients with tumors 
lacking PD-L1 (Mu et al 2011.). Based on these findings, an anti-PD-L1 antibody could be used 
therapeutically to enhance anti-tumor immune responses in patients with cancer. Results of several 
non-clinical studies using mouse tumor models support this hypothesis, where antibodies directed 
against PD-L1 or its receptor PD-1 showed anti-tumor activity {Hirano et al 2005, lwai et al 2002, 
Okudaira et al 2009, Zhang et al 2008.). 
 
Durvalumab has been given to humans as part of ongoing studies as a single drug or in combination 
with other drugs. As of the DCO dates {15Apr2015 to 12Jul2015, durvalumab IB Version 9.0), a total 
of  1,883 subjects  have  been  enrolled  and  treated  in  30 ongoing  durvalumab  clinical  studies, 


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including 20 sponsored and 10 collaborative studies. Of the 1,883 subjects, 1,279 received 
durvalumab monotherapy, 440 received durvalumab in combination with tremelimumab or other 
anticancer agents, 14 received other agents (1 gefitinib, 13 MEDl6383), and 150 have been treated 
with blinded investigational product. No studies have been completed or terminated prematurely due 
to toxicity. 
 
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose­ 
expansion phases of Study CD-ON-durvalumab-1108 following treatment with durvalumab 0.1 to 
10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum observed 
concentration (Cmax) increased in an approximately dose-proportional manner over the dose range of 
0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUCo.1•) increased 
in a greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased 
dose-proportionally at <!: 3 mg/kg. These results suggest durvalumab exhibits nonlinear PK likely due 
to saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses <!: 3 mg/kg. 
Near complete target saturation (soluble programmed cell death ligand 1 [sPD-L1] and membrane 
bound} is expected with durvalumab <!: 3 mg/kg Q2W. Exposures after multiple doses showed 
accumulation consistent with PK parameters estimated from the first dose. In addition, PK 
simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 90% of subjec1s are 
expected to maintain PK exposure <!: 40 µg/mL throughout the dosing interval. 
 
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 subjects 
(1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjec1s in 10 mg/kg cohort) were ADA 
positive with an impact on PK/pharmacodynami cs in 1 subject in the 3 mg/kg cohort. 
 
3.3   Tremelimumab 
The non-clinical and clinical experience is fully described in the current version of the tremelimumab 
Investigator's Brochure (IB Version 6.0). 
Tremelimumab is an lgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte­ 
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152). This is an 
immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the treatment of 
cancer. 
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 [IFN] gamma) production  in vitro in whole blood or peripheral blood mononuclear cell 
(PBMC) cultures (Tarhini and Kirkwood 2008.). In addition, blockade of CTLA-4 binding to B7 by 
anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and anti-tumor activity in 
animal models, including killing of established murine solid tumors and induction of protective anti­ 
tumor immunity. (Refer to the tremelimumab IB, Edition 5.0, for more information.) 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 anti-tumor activity in patients with solid tumors. 
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab both 
as monotherapy and combination therapy with conventional anticancer agents to support various 
cancer indications using different dose schedules.  As of the data cut-off date of 12 November 2014 


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(for all studies except D4190C00006, which has a cut-off date of 4 December 2014), 973 patients 
have received tremelimumab monotherapy (not including 497 patients who have been treated in the 
blinded Phase 2b study, D4880C00003) and 208 patients have received tremelimumab in 
combination with other agents. Details on the safety profile of tremelimumab monotherapy are 
summarized in Section 0. Refer to the current tremelimumab IB for a complete summary of non-
clinical and clinical information; see Section 6.6 for guidance on management of tremelimumab­ 
related toxicities. 
 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of  22 days. 
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab. 
 
3.4     Durvalumab in combination with tremelimumab 
The rationale for combining durvalumab and tremelimumab is that the mechanisms of CTLA-4 and 
PD-1 are non-redundant, suggesting that targeting both pathways may have additive or synergistic 
activity (Pardall 2012.). In fact, combining immunotherapy agents has been shown to result in 
improved response rates (RRs) relative to monotherapy. For example, the concurrent administration 
of nivolumab and ipilimumab to patients with advanced melanoma induced higher objective 
response rates (ORRs) than those obtained with single-agent therapy. lmportanUy, responses 
appeared to be deep and durable (Walchak et al 2013.). 
Similar results have been observed in an ongoing study of durvalumab + tremelimumab in NSCLC 
(Antonia et al 2014.). Study D4190C00006 is a Phase lb dose-escalation study to establish safety, 
PK/PDx, and preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in 
patients with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or 
every 4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up to 
Week 24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The study is 
ongoing and continues to accrue. 
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK (n = 26) 
data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following durvalumab 
every 4 weeks (Q4W) or QM dosing in combination with tremelimumab Q4W regimens. An 
approximately dose-proportional increase in PK exposure (Cmax and area under the concentration­ 
time curve from 0 to 28 days [AUCo.2aD of both durvalumab and tremelimumab was observed over 
the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 10 mg/kg tremelimumab Q4W. 
Exposures following multiple doses demonstrated accumulation consistent with PK parameters 
estimated from the first dose. It is to be noted that steady state PK parameters are based on lmited 
numbers of subjec1s. The observed PK exposures of durvalumab and tremelimumab following 
combination were consistent with respective monotherapy data, indicating no PK interaction 
between these 2 agents. 
 
As of 20Feb2015, ADA data were available from 60 subjects for durvalumab and 53 subjects for 
tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for anti-durvalumab 
antibodies post treatment. One of 53 subjec1s was ADA positive for anti-tremelimumab antibodies 
post treatment. There was no clear relationship between ADA and the dose of either durvalumab or 
tremelimumab, and no obvious association between ADA and safety or efficacy. 


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Durvalumab has also been combined with other anticancer agents, including gefitinib, dabrafenib, 
and trametinib. To date, no PK interaction has been observed between durvalumab and these 
agents. 
 
3.5 
Safety 
 
3.5.1 
Durvalumab safety 
Potential risks, based on the mechanism of action of durvalumab and related molecules, include 
immune-mediated 
reactions, 
such 
as 
enterocolitis, 
dermatitis, 
hepatitis/hepatotoxicity, 
endocrinopathy, pneumonitis, and neuropathy or neurologic events. Additional important potential 
risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious allergic reactions, 
serious infections, and immune complex disease. 
 
Study  CD-ON-durvalumab-1108:  The  safety  profile   of   durvalumab   monotherapy   in  the 
694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab- 
1108 has been broadly consistent with that of the overall 1,279 subjects who have received 
durvalumab monotherapy (not including subjects treated with blinded investigational product) across 
the clinical development program. 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. As of 07May2015, among 
the 694 subjects treated with durvalumab 10 mg/kg Q2N in Study CD-ON-durvalumab-1108, a total 
of 378 subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in :!! 
5% of subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), 
pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were 
Grade 1 or Grade 2 in severity with :!! Grade 3 events occurring in 65 subjects (9.4%). Treatment­ 
related :!! Grade 3 events reported in 3 or more subjects (:!! 0.4%) were fatigue (12 subjects, 1.7%); 
increased 
aspartate 
aminotransferase 
(AST; 
7 
subjec1s, 
1.0%); 
increased 
gamma­ 
glutamyltransferase (GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 
0.7%); and colitis, vomiting,  decreased  appetite,  and  hyponatremia  (3 subjects,  0.4%  each). 
Six subjects had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, 
dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related 
Grade 5 event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in :!! 2 
subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related SAEs 
were Grade 3 in severity and resolved with or without sequelae. AEs that resulted in permanent 
discontinuation of durvalumab were considered as treatment related in 18 subjects (2.6%), with 
colitis being the most frequent treatment-related AE resulting in discontinuation (3 subjects). A 
majority of the treatment-related AEs resulting in discontinuation of durvalumab were :!! Grade 3 in 
severity and resolved with or without sequelae. 
 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study CD-ON­ 
durvalumab-1108 is generally consistent with that of Study D4191C00003/ATLANTIC in subjects 
with locally advanced or metastatic non-small-cell lung cancer (NSCLC) treated with durvalumab 10 
mg/kg  Q2N.  As   of   05May2015,  264 of   303 subjects   (87.1%)   reported  any  AE   in  Study 


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D4191C00003/ATLANTIC. Overall, events reported in :?: 10% of subjec1s were dyspnea (18.8%), 
fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), 
and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that were Grade 1 or 2 in 
severity and manageable by general treatment guidelines as described in the current durvalumab 
study protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 
subjects (42.2%) reported AEs that were considered by the investigator as related to investigational 
product. Treatment-related AEs (all grades) reported in :?: 2% of subjects were decreased appetite 
(6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting 
(2.0%). Treatment-related Grade 3 AEs reported in :?: 2 subjects were pneumonitis (3 subjects) and 
increased GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four of 
303 subjects (31.0%) reported any SAE. SAEs that occurred in :?: 1.0% of subjects were dyspnea 
(6.6%); pleural effusion, general physical health deterioration (2.3% each); pneumonia (2.0%); 
hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, respiratory failure, disease 
progression (1.0% each). Nine subjects had an SAE considered by the investigator as related to 
durvalumab. Each treatment-related SAE occurred in 1 subject each with the exception of 
pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an AE 
(pneumonia [3 subjects]; general physical health deterioration, disease progression, hemoptysis, 
dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim 
term (Vf)], hepatic failure, and sepsis [1 subject each]). None of these events was considered 
related to durvalumab. Twenty-three of 303 subjects (7.6%) permanently discontinued durvalumab 
treatment due to AEs. Events that led to discontinuation of durvalumab in :?: 2 subjects were 
dyspnea, general physical health deterioration, and pneumonia. Treatment-related AEs that led to 
discontinuation were increased ALT and increased hepatic enzyme, which occurred in 1 subject 
each. 
 
3.5.2 
Tremelirnumab  safety 
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated gastrointestinal (GI) events including enterocolitis, 
intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and decreased appetite 
(anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; endocrinopathies including 
hypophysitis, adrenal insufficiency, and hyperthyroidism and hypothyroidism; hepatitis including 
autoimmune hepatitis and increased serum ALT and AST; pancreatitis including autoimmune 
pancreatitis and lipase and amylase elevation; respiratory tract events including pneumonitis and 
interstitial lung disease (ILD); nervous system events including encephalitis, peripheral motor and 
sensory  neuropathies,  and  Guillain-Barre  syndrome;  cytopenias  including  thrombocytopenia, 
anemia, and neutropenia; infusion-related reactions; anaphylaxis; and serious allergic reactions. 
The profile of 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). Overall, 944 of the 973 patients (97.0%) treated with 
tremelimumab monotherapy as of the data cutoff date of 12 November 2014 (for all studies except 
D4190C00006 that has a cutoff date of 04 December 2014 and not including 497 patients who have 


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been treated in the ongoing blinded Phase llb Study D4880C00003) experienced at least 1PE. The 
events resulted in discontinuation of tremelimumab in 10.0% of patients, were serious in 36.5%, 
were Grade <!:3 in severity in 49.8%, were fatal in 67.7%, and were considered to be treatment 
related in 79.1% of patients. The frequency of any /!Es and Grade <!:3 /!Es was generally similar 
across the tremelimumab dose groups. However, a higher percentage of patients in the 10 mg/kg 
every 28 days and 15 mg/kg every 90 days groups compared with the All Doses <10 mg/kg group 
experienced treatment-related /!Es, SPEs, /!Es resulting in discontinuation of investigational product 
(IP}, and deaths. 
3.5.3 Durvalumab + tremelimumab safety 
No safety studies in animals have been performed combining tremelimumab with durvalumab. /!143 
both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune cells, their 
potential to induce cytokine release was tested in a whole-blood assay system. Durvalumab and 
tremelimumab, either alone or in combination, did not induce cytokine release in blood from any 
donor. 
Study D4190C00006: The safety profile of durvalumab and tremelimumab combination therapy in 
the 102 subjects with advanced NSCLC in Study D4190C00006 is generally consistent with that 
observed across 177 subjec1s treated with durvalumab and tremelimumab combination therapy (not 
including subjects treated with blinded investigational product). /!143 of 15Apr2015, 95 of 102 subjects 
(93.1%) reported at least  1 PE. All subjects in the tremelimumab 3 and 10 mg/kg dose cohorts 
experienced /!Es; subjects in the durvalumab 20 mg/kg and tremelimumab 1 mg/kg Q4W cohort 
experienced the lowest PE rate (77.8%). Treatment-related /!Es were reported in 74 of 102 subjects 
(72.6%), with events occurring in > 10% of subjec1s being diarrhea (27.5%), fatigue (22.5%), 
increased amylase and pruritus (14.7% each}, rash (12.7%), colitis (11.8%), and increased lipase 
(10.8%). Treatment-related <!: Grade 3 /!Es reported in <!: 5% of subjects were colitis (8.8%), diarrhea 
(7.8%), and increased lipase (5.9%). Five subjects reported treatment-related Grade 4 events 
(sepsis, increased ALT, and increased AST in 1 subject; increased amylase in 2 subjec1s; 
myasthenia gravis in 1 subject; and pericardia! effusion in 1 subject) and 2 subjects had treatment­ 
related Grade 5 events (polymyositis and an uncoded event of neuromuscular disorder [VT]); the 
Grade 4 event of myasthenia gravis and Grade 5 polymyositis occurred in 1 subject. There were 
2 subjects (both in the MEDl4736 20 mg/kg + tremelimumab 3 mg/kg Q4W cohort) with dose-limiting 
toxicities (DLTs): 1 subject with Grade 3 increased AST, and 1 subject with Grade 3 increased 
amylase and Grade 4 increased lipase. Fifty-six subjects (54.9%) reported SPE.s, with events 
occurring in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). Thirty-six subjects (35.3%) 
experienced treatment-related S/!Es. Twenty-seven subjec1s (26.5%) permanently discontinued 
treatment due to /!Es. Treatment-related /!Es resulting in discontinuation in <!: 2 subjects were colitis 
(7 subjects), pneumonitis (5 subjects), diarrhea (3 subjects), and increased AST (2 subjec1s). 
Additional safety results from this study are presented in Section 1.3.1 and the durvalumab IB. 
 
In the literature (Walchak et al 2013.), using  the  combination  of  the  same  class  of  drugs 
(e.g., anti-PD-1 and anti-CTLM antibodies), specifcally nivolumab + ipilimumab in a study involving 
patients with malignant melanoma, the safety profile of this combination had shown occurrences of 
/!Es assessed by the Investigator as treatment-related in 93% of treated patients, with the most 
frequent events being rash (55% of patients), pruritus (47% of patients), fatigue (38% of patients), 
and diarrhea (34% of patients).  Grade 3 or 4 /!Es, regardless of causality, were noted in 72% of 


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patients, with Grade 3 or 4 events assessed by the Investigator as treatment-related in 53%. The 
most frequent of these Grade 3 or 4 events assessed by the Investigator as treatment-related 
include increased lipase (in 13% of patients), AST (in 13%), and ALT levels (in 11%). Frequent 
Grade 3 or 4 selected PE.s assessed by the Investigator as treatment-related in the combination 
therapy included hepatic events (in 15% of patients), GI events (in 9%), and renal events (in 6%). 
Isolated cases of pneumonitis and uveitis were also observed. 
 
 
 
 
3.6   Colorectal cancer 
Worldwide, CRC is the third most common form of cancer in men, with 663,000 cases (10% of the 
total) and second most common in women, with 571,000 cases (9.4% of the total) per year. Each 
year there are about 608,000 deaths from colon cancer which is approximately 8% of all cancer 
deaths making colorectal cancer the fourth most common cause of cancer death (Ferlay, Shin et al. 
2010). In 2012 in the U.S. an estimated 103,170 new cases were diagnosed with 51,690 deaths . 
Treatment of CRC depends largely on the stage of the disease, which is most commonly rated 
according to tumor, nodes, and metastasis (TNM) criteria. The initial treatment is surgery. However, 
post-surgery metastatic disease occurs in 40%-60% of patients and the prognosis for patients who 
develop advanced metastatic disease is poor. Over the past decade, progress has been made in the 
role of systemic therapy for the palliation of advanced colorectal cancer. With the introduction of 
oxaliplatin, irinotecan, anti-VEGF therapies, and anti-EGFR therapies, the median life expectancy of 
patients has been increased to about 29 months (Meyerhardt and Mayer 2005). Despite these 
therapeutic advances, patients with unresectable, metastatic and/or recurrent CRC, remain 
incurable. There is a substantial unmet medical need for more effective and less toxic therapies, 
especially for those patients with advanced disease that have not responded or have become 
resistant to the existing standard treatments. The development of novel approaches to treatment is 
greatly needed in order to improve outcomes in such patients. 
 
3.6.1 Immune Augmentation in Colorectal Cancer 
 
Immune augmentation, including checkpoint-directed therapies, has been studied in patients with 
CRC, and isolated tumor responses have been observed. Our group performed a study of CTLA-4 
blockade with tremelimumab (15 mg/kg every 90 days) in 47 patients with previously treated CRC. 
Grade 3/4 treatment-related adverse events (PE.s) included diarrhea (n = 5; 11%), ulcerative colitis 
(n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopeni a (n = 1; 2%), and hypokalemia (n = 1; 
2%). Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one 
discontinuation). Twenty-one patients (45%) lived 180 days after enrollment. One patient (2%; 
90% Cl, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass 
(partial response) (Chung, Gore et al. 2010). Another study was a dose escalation study of PDL-1 
blockade with MPDL3280A (0.01-20 mg/kg every three weeks) in 20 patients with solid tumors and 
lymphoma. Tumor regression was observed in 1 of 4 patients with CRC (partial response). In a first­ 
in-human single-dose, dose-escalation (0.3 to 10 mg/ kg) study of PD-1 blockade with nivolumab in 
solid tumors, 14 patients with CRC were enrolled. In the phase I multi-dose, dose escalation (1 to 10 
mg/kg every 2 weeks) study, 19 patients with CRC were enrolled. Treatment was reasonably well 


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tolerated in both studies. Durable  tumor regression (complete response) beyond 3 years was 
observed in one patient (Brahmer, Drake et al. 2010, Topalian, Hodi et al. 2012, Lipson, Sharfman et 
al. 2013). 
 
3.6.1.1 PD/L-1 and CTLA-4 Combination Therapy in Colorectal Cancer 
 
Combination immune augmentation, including anti-PD/L-1 plus anti-CTLA-4, is being studied in 
patients with CRC. One isolated response has been observed, similar to resul1s of PD/L-1 blockade 
or CTLA-4 blockade alone. Checkmate-142 (NCT02060188) is an ongoing study of nivolumab plus 
ipilimumab in CRC. One response was observed out of 20 patients. 10 MSS colorectal patients were 
treated with nivolumab 1 mg/kg +ipilimumab 3 mg/kg, and 10 MSS colorectal patients were treated 
with nivolumab 3 mg/kg + ipilimumab 1 mg/kg. Toxicities were consistent with other studies of this 
combination therapy (Overman, Kopetz et al. 2016). NCT01975831 (IRB#13-198) is an ongoing 
study of durvalumab plus tremelimumab in multiple tumor types, including CRC (n=15). This study is 
ongoing and results have not yet been reported. 
 
3.6.2 Rationale for immune therapy plus radiotherapy or ablation in colorectal cancer 
 
RT and ablation, such as cryoablation or radiofrequency ablation, are both standard therapies  in 
patients with metastatic colorectal cancer. Ablation results in tumor destruction by direct heat or 
cold, and RT results in tumor destruction by ionizing radiation. Either ablation or RT alone is not 
expected to result in objective systemic benefit alone. However, each modality has been associated 
with induction of systemic inmunity that can be augmented by co-stimulatory blockade with PD-1 
leading to potential for tumor shrinkage. 
 
The phenomenon of tumor destruction by RT or ablation leading to shrinking of tumors away from 
the site of initial treatment has been termed the abscopal effect. Albeit rare, when the abscopal 
effect occurs, the clinical implications can be profound. 
 
The rationale of the abscopal effect is that in situ tumor destruction releases a large amount of tumor 
antigens. Antigen-presenti ng cells, such as dendritic cells, then take up these antigens in the 
periphery and migrate to lymph nodes where they activate CD4+ and CDS+ T-lymphocytes that 
recognize these tumor-antigens. Immune augmentation via immune co-stimulatory molecules then 
permits the ensuing immune response to strengthen and destroy cancer. 
 
The combination of tumor cryoablation and immunomodulation has been shown in animal models, 
by our colleagues, to generate such a systemic anti-tumor response (Waitz, Fasso et al. 2012). 
Specifically, local tumor destruction with cryoablation can lead to exposure of DCs with sufficient 
quantities of tumor antigens to ultimately lead to DC maturation and activation. Recently, our 
collaborators (Dr. James Allison's group at MSKCC) showed that combination therapy with 
cryoablation and CTLA4 blockade successfully mediated rejection of metastatic prostate cancer 
lesions and prevented the growth of secondary tumors in preclinical murine models (Waitz, Fasso et 
al. 2012). Levy et al. from MSKCC showed in a BALB/c mouse model of metastatic colon cancer 
that cryoablation of a solitary tumor mass plus cyclophosphamide, to selectively depletes regulatory 
T cells (Tregs), leads to regression of established tumors and protection against tumor rechallenge 
(Levy, Sidana et al. 2009). Den Brok et al. have also demonstrated this effect in vAlo using the well­ 
defined murine B16-0VA melanoma cell line using RFA They demonstrated that RFA alone results 


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in a weak but detectable immune response against OVA, as well as other 816 antigens. Whereas, 
the combination of co-stimulatory blockade by anti-CTLA-4 together with RFA approximately 
doubled the number of mice alive at 70 days post-tumor rechallenge compared with mice that 
received control antibody plus ablation alone (den Brok, Sutmuller et al. 2004). 
 
A similar effect has been shown with RT and blockade of PD-1/PDL-1 interaction. Deng et al. 
showed that anti-PDL-1 enhanced the  effect of RT in a fl..1C38 colorectal tumor model, with 
substantial delay in tumor growth 34 days after treatment with combination therapy. Tumors 
measured 27.85 (± 27.85) mm after canbination therapy, compared to 278.6 (± 94.20) mm and 
457.6 (± 44.24) mm after RT alone, or anti-PDL-1 alone, respectively.A similar benefit was shown in 
the TUBO breast cancer cell line, with reduced TUBO tumor growth after mice were re-challenged in 
the opposite flank, implying systemic immunity. This immunological effect was associated with 
activation of COB+ T-cells and reduced tumor-infiltrating myeloid-derived suppressor cells (MDSC) 
(Deng, Liang et al. 2014). 
 
More recently, Dr. Postow from our group reported this abscopal effect in a patient who developed a 
systemic response to localized RT after having had disease progression while receiving CTLA-4 
blockade (ipilimumab). Specifically, a right hilar lymph-node and spleen metastases, which were not 
the target of RT, showed regression only after the patient received palliative RT after several months 
of CTLA-4 blockade. A delayed response to the ipilimumab was considered unlikely  (Postow, 
Callahan et al. 2012). 
 
The preclinical models and the clinical observation provide compelling rationale to further study 
tumor ablation and RT in combination with immune augmentation by co-stimulatory blockade. 
 
CRC is an appropriate target for such a study because this disease is (1) frequently associated with 
Tumor Infiltrating Lymphocytes (Tlls), is (2) routinely treated with combination therapies including 
RT or ablation, and (3) there is substantial unmet need for novel therapies beyond the currently 
available systemic therapies. 
 
A study of  RT or ablation, plus single agent pembrolizumab (PD-1 blockade) alone is ongoing at 
MSKCC in metastatic CRC (IRB #15-069/ NCT02437071 ). Initial results have been presented at 
ASCO and showed that PD-1 blockade has a manageable safety profile when administered in 
combination with either RT or ablation in patients with mCRC. Grade 1-2 drug-related AEs occurred 
in 95% and 75% of patients who received RT or ablation, respectively. There were no grade 3 drug­ 
related AEs, or drug-related AEs that led to pembrolizumab discontinuation. Responses were not 
observed in patients  who received microwave ablation or cryoablation plus pembrolizumab (no 
patients underwent RFA). Pembrolizumab plus RT showed modest clinical activity in pMMR CRC, 
with one partial response and two mixed responses (Segal et al. ASCO 2016 #3539). 
 
The current study is investigating whether the CTLA4 plus PDL-1 blockade will have additive or 
synergistic activity in combination with tumor ablation or radiation therapy. 
 
3.7 Rationale for dose and schedule 


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The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal of 
selecting an optimal combination dose of durvalumab and tremelimumab that would yield sustained 
target suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable safety profile. 
 
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 20 mg/kg durvalumab q4w. PK simulations from the durvalumab monotherapy data 
indicated that a similar area under the plasma drug concentration-time curve at steady state (AUC••; 
4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w durvalumab. The observed 
durvalumab PK data from the D4190C00006 study were well in line with the predicted monotherapy 
PK data developed preclinically. This demonstrates similar exposure of durvalumab 20 mg/kg q4w 
and 10 mg/kg q2w, with no alterations in PK when durvalumab and tremelimumab (doses ranging 
from 1to 3 mg/kg) are dosed together. While the median Cmax at steady state (Cmax,ss) is expected to 
be higher with 20 mg/kg q4w (approximately 1.5 fold) and median trough concentration at steady 
state (Cirough,ss) is expected to be higher with 10 mg/kg q2w (approximately 1.25 fold), this is not 
expected to impact the overall safety and efficacy profile, based on existing preclinical and clinical 
data. 
 
l'vbnotonic increases in PDx activity were observed with increasing doses of tremelimumab relative 
to the activity observed in patients treated with durvalumab monotherapy. There was evidence of 
augmented PDx activity relative to durvalumab monotherapy with combination doses containing 1 
mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 1 mg/kg 
tremelimumab combinations. 
 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 
10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg tremeli'numab 
cohorts treated at the q2w schedule, the number of patients reporting any AE, Grade 3 AEs, SAEs, 
and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohort 
than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A similar pattern was noted in the 
q4w regimens, suggesting that, as the dose of tremelimumab increased above 1 mg/kg, a higher 
rate of treatment-related events may be anticipated. Further, the SAEs frequently attributed to 
immunotherapy, pneumonitis and colitis, were more commonly seen in cohorts using either 3 or 10 
mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. Together, these data suggest that a 
combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity when 
combined with durvalumab. As  a result, all combination doses utilizing either the 3 or 10 mg/kg 
doses of tremelimumab were eliminated in the final dose selection. 
 
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremeli'numab 
did not show an increase in the rate of AEs. The data suggested that increasing doses of 
durvalumab may not impact the safety of the combination as much as the tremelimumab dose. 
Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in 
safety events with increasing dose of durvalumab. 


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In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade <!:3 AEs, SAEs, and 
treatment discontinuations due to AEs, but still showed strong evidence of clinical actMty. This 
cohort had a lower number of treatment-related Grade <!:3 AEs or treatment-related SAEs. No dose­ 
limiting toxicities were reported. 
 
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear to 
change with increasing doses of tremelimumab. The 15- and 20-mg/kg durvalumab q4w cohorts 
demonstrated objective responses at all doses of tremelimumab, and increasing doses of 
tremelimumab did not provide deeper or more rapid responses. 
 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort may 
demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 11 patients in the 
20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for efficacy with at least 8 
weeks of follow-up. Of these, there were 2 patients (40%) with partial response (PR), 1 patient 
(20%) with stable disease (SD), and 1 patient (20%) with progressive disease (PD). (The fifth 
patient had only a single scan, which was conducted outside the window for these evaluations.) 
 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort had the 
fewest AEs, Grade <!:3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed some 
evidence of clinical actMty. All together, the data suggested that a 20 mg/kg durvalumab + 1 mg/kg 
tremelimumab dose combination should be selected for further development. 
 
3.7.1 Rationale for 4 cycles of combination therapy followed by durvalumab   monotherapy 
Long-term  follow  up on  melanoma  patients  treated  with  ipilimumab,  an  anti-CTL.A4  targeting 
antibody  (dosed every 3 weeks  [q3w] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term  benefit, with a 3-year OS rate of approximately 22%. 
Furthermore, the survival curve in this population reached a plateau at 3 years and was maintained 
through 10 years of follow up (Schadendorf et al 2013.). 
 
Similar data have been presented for other anti-PD-1/PD-L 1 targeting antibodies: 
 
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation and 
expansion study, and showed responses were maintained for a median of 22.94 months for 
melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), and 
12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data analysis 
(Hodi et al 2014, Brahmer et al 2014, Drake et al 2013.). Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped nivolumab treatment 
(either due to protocol specified end of treatment, complete response [CR], or toxicity) for up to 
56 weeks at the time of data analysis (Topalian et al 2014.). 
 
lltPDL3280a (anti-PD-L 1) and the combination of nivolumab with ipilimumab, in which patients were 
dosed for a finite time period and responses maintained beyond treatment discontinuation have 
been reported (Herbst et al 2013, Wolchok et al 2013.). 


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h, 
h 
h, 
h 
 
 
 
Similar long term results may be expected with use of other immune-mediated cancer therapeutics 
including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1antibodies such as durvalumab, 
or the combination of the two. 
 
3.7.2 Fixed dosing for durvalumab and tremelimumab 
 
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of s 0.5). The impact of body WT-based (10 mg/kg Q2W) and f1JCed dosing (750 mg 
Q'Z!N) of durvalumab was evaluated by comparing predicted steady state PK concentrations (51 
median and 951 percentiles) using the population PK model. A fixed dose of 750 mg was selected to 
approximate 1O mg/kg (based on median body WT of -75 kg). A total of 1000 patients were 
simulated using body WT distribution of 40-120 kg. Simulation results demonstrate that body WT­ 
based and fixed dosing regimens yield similar median steady state PK concentrations with slightly 
less overall between-subject variability with fixed dosing regimen. 
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 through 
Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang et al. 2014]. 
Population PK model indicated minor impact of body WT on PK of tremelimumab (coefficient of s 
0.5). The WT-based (1 mg/kg Q4W) and f1JCed dosing (75 mg/kg Q4W; based on median body WT of 
-75 kg) regimens  were compared  using predicted  PK concentrations  (51 
median  and  951 
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 f1JCed dosing regimen. 
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012,Narwal et al 2013]. Wang and colleagues  investigated  12 monoclonal  antibodies  and found 
that f1JCed and body size-based dosing perform similarly, with f1JCed dosing being better for 7 of 12 
antibodies . In addition, they investigated 18 therapeutic  proteins  and  peptides  and  showed  that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-subject variability in 
pharmacokinetic/pharmacodynamics  parameters  [Zhang et al 2012]. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we considered 
it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 
750 mg Q2W lllEDl4736 (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the 
current study. 
 
Fixed dosing of durvalumab and tremelimumab is recanmended only for subjects with > 30kg body 
weight due to endotoxin exposure.  Patients with a body weight less than or equal to 30 kg should 
be dosed using a weight-based dosing schedule. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 


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4.2 
Design 
 
This will be a Simon two-stage design, phase II study. It will be conducted to determine the efficacy 
and safety of (1) durvalumab and tremelimumab plus RT in subjects with metastatic CRC who are 
undergoing RT as standard therapy; and, (2) durvalumab and tremelimumab plus ablation in 
subjects with metastatic CRC who are undergoing ablation as standard therapy. 
 
 
4.3 
Intervention 
 
Patients will be stratified according to eligibility for RT (cohort 1) or ablation (cohort 2). Patients in 
cohort 1 will have at least one metastatic lesion for which palliative RT is considered appropriate 
standard therapy, and at least one other measurable index lesion that will not undergo RT. Patients 
in cohort 2 will have at least one metastatic lesion for which palliative ablation is considered 
appropriate standard therapy, and at least one other measurable index lesion that will not undergo 
ablation. Subjects in cohort 2 may undergo tumor ablation of one or more lesions at the discretion of 
the interventional radiologist. All subjects will undergo ablation or begin RT within 7 days after 
starting durvalumab and tremelimumab. 
 
Subjects will receive durvalumab and tremelimumab every four weeks (Q4W), for 4 months, and 
then continue durvalumab every four weeks (Q4W) until confirmed progression of disease, initiation 
of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. 
Patients who had a prior response, continued on durvalumab monotherapy and did not discontinue 
tremelimumab due to toxicity may, after discussion with the Principal Investigator, continue 
treatment beyond disease progression with either durvalumab monotherapy or resume combination 
therapy with tremelimumab plus durvalumab for 4 doses upon disease progression, followed by 
durvalumab  monotherapy. 
 
Repeat palliative RT in cohort 1, or ablation in cohort 2, will be permitted in select cases. Repeat 
palliative RT or ablation may include measurable index lesion(s) that is (are) being followed for 
response measuremen1s if at least one index lesions remains to be followed. Patients will be 
evaluated by physical exam and routine blood tests every two weeks during the first 4 months of the 
study period, then every 4 weeks. CT or MRI will be performed during screening, and then at 8 week 
intervals. Tumor measurements and determination of tumor responses will be performed according 
to RECIST 1.1. 
Subjects with evidence of disease progression during the durvalumab + tremelimumab combination 
portion of the treatment regimen may continue to receive durvalumab and tremelimumab beyond 
radiographic disease progression in the absence of clinical deterioration, and after discussion with 
the Principal Investigator. 
 
All subjects will be followed for 2 years for survival or until the study closes. Exploratory research 
studies to evaluate the effect of this therapy wil Ibe performed in patients using research blood 
draws (all patients), and tumor biopsy at baseline, one week after completing radiation/ablation and 
four weeks after starting immunotherapy for research purposes (stage 1only). 
 
4.4 Estimated Duration of Subject Participation 


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Subjects will continue treatment every four weeks until confirmed progression of disease, initiation of 
alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. 
All subjects will be followed for survival for 2 years unless the Principal Investigator or Medlmmune/ 
Astra Zeneca decides to end the study. 
 
 
 
5.1 
THERAPEUTIC/DIAGNOSTIC   AGENTS 
 
5.2 
Ablation 
 
The ablation will be performed percutaneously under image guidance as standard therapy at the 
discretion of the interventional radiologist in accordance with institutional standard practice. 
 
Ablation will be performed within 7 days after the first of durvalumab and tremelimumab. Up to 3 
lesions measuring up to 3 cm may be ablated, as long as at least one measurable lesion remains to 
measure the abscopal effect. 
 
5.3 
Radiotherapy 
 
Radiotherapy (RT} will be performed using external beam ionizing radiation as standard therapy in 
accordance with institutional standard practice. 
 
RT will be initiated within 7 days after the first of durvalumab and tremelimumab. Up to 3 lesions 
may be radiated, as long as at least one measurable lesion remains to measure the abscopal effect. 
 
Target volumes for RT will be defined in accordance with International Commission on Radiation 
Units and l'v'easurements (ICRU} Report #50: Prescribing, Recording and Reporting Photon Beam 
Therapy, and ICRU Report #71: Prescribing, Recording and Reporting Electron Beam Therapy. 
 
The target lesion for RT will be defined as the gross tumor volume (GTV}. The clinical target volume 
(CTV} will be the same as the GTV. The planning target volume (PTV} will be a minimum volumetric 
expansion of the GTV by 2 mm (5 mm recommended}, but ultimately will be left to the discretion of 
the attending radiation oncologist. 
 
CT simulation will be performed for planning purposes. Details of the CT simulation (40 CT, gating, 
use of contrast, immobilization} will be left to discretion of the attending radiation oncologist. 
 
RT will be planned in 3-D and may be delivered using conventional, IMRT or rapid arc methodology. 
6-18 MV photons and/or electron beam RT will be used as determined by the specific clinical 
situation. 95% of the PTV should receive the prescription radiation dose, as determined appropriate 
by the radiation oncologist. Normal tissue constraints will not be exceeded during the planning 
process. 
 
When photon therapy is used, portal imaging, cone beam CT, or 20 kV on board imaging for QC will 
occur for each treatment. When electron therapy is used, light field verification of the target wil Ioccur 
at the start of treatment. 


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6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
1. Be willing and able to provide written informed consent for the trial. 
 
2. Histologically- or cytologically- confirmed CRC. 
 
3. Metastatic CRC. 
 
4. Subjects have received at least two standard chemotherapy regimens for which they would 
be considered eligible (at least one containing a 5-fluoropyrimidine), or systemic 
chemotherapy is not indicated in the setting of low volume metastatic disease. 
 
5. M. least one tumor for which palliative RT is considered appropriate standard therapy (cohort 
1); or, at least one tumor for which palliative ablation is considered appropriate standard 
therapy (cohort 2). 
 
6. Pl. least one index lesion that will not undergo RT or ablation, and which is measurable based 
on RECIST  1.1. 
 
7. Be 
18 years of age on day of signing informed consent. 
 
8. Consent for tumor biopsies (for patients enrolled in stage 1 only) and blood draws for 
research purposes (for all patients). 
 
9. Consent for use of available archived tissue and tumor obtained during a standard 
procedure, for research purposes. 
 
10. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
11. Female subjects 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 within 2 weeks prior to 
starting treatment. 
 
12. Demonstrate adequate organ function as defined in Table 6.1, all screening labs should be 
performed within 4 weeks prior to treatment initiation. 
 
Table 6.1 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Hemoglobin 
<!: 8.0 g/dL 
Absolute neutrophil count (ANC) 
<?:1,500 hncL 
Plalele1s 
<?:100,000 / mcL 
Renal 
Serum creatinine 
OR 
Measured or calculated" creatinine 
S1.5 X upper limit of nonnal (ULN) 
OR 
Serum creatinine CL>40 mL.tnin bythe Cockcroft-Gault 


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-vreatinine clearance should be calrulated per institutional standard. 
 
 
 
clearance (GFR can also be used in 
place of creatinine or CrCI) 
formula (Cockcroft and Gault 1976) or by24-hwr urine 
collection for determination of creatinine clearance. 
Hepatic 
Serum total bilirubin 
S 1.5 XULN QB 
Direct bilirubin s ULN for subjecls with total bilirubin lewis > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
S 2.5 XULN  OR 
:S 5 XULN for subjecls with liwr metastases 
 
 
 
6.3 
Subject Exclusion Criteria 
 
1. Is currently participating in or has participated in a study of an investigational agent or using 
an investigational device within 4 weeks of the first dose of treatment. 
 
2. Chemotherapy, monoclonal antibody, targeted small molecule therapy, within 4 weeks prior 
to dose #1 or who has not recovered (i.e., :S Grade 1 or at baseline) from adverse events due 
to a previously administered agent (excluding alopecia or toxicity not anticipated to interfere 
with planned treatment on study}. 
 
3. Known or suspected MSl-H CRC. 
 
4. Ally prior Grade 3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1, including anti-PD-1, anti-PD-L1, 
anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell 
co-sti'nulation or checkpoint pathways, except for endocrinopathies and asymptomatic 
amylase/lipase, 
 
5. If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention per clinical discretion of the investigator prior to 
starting therapy. 
 
6. Concurrent active malignancy that requires systemic treatment. 
 
7. Known CNS metastases and/or carcinomatous meningitis. Subjects with previously treated 
brain metastases may participate provided they are stable without evidence of new or 
enlarging brain metastases, and are not using steroids for at least  7 days prior to trial 
treatment. The use of topical steroids is permitted. 
 
8. Active autoimmune disease requiring systemic immune suppressive treatment within the past 
2 years. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
 
9. Has active, non-infectious pneumonitis. 
 
10. Active or prior documented inflammatory bowel disease. 
 
11. History of allogeneic organ transplant. 
 
12. Has an active infection requiring systemic therapy. 


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13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
14. Has a known history of Human Immunodeficiency Virus (HIV) {HIV 1/2 antibodies). 
 
15. Has known active and untreated  Hepatitis B (e.g., HBsAg reactive) or active  Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). 
 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
17. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab or tremelimumab with the exceptions of premedication and intranasal, topical 
and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not 
to exceed 10mg/day of prednisone, or an equivalent corticosteroid. 
 
18. Hypersensitivity to durvalumab or tremelimumab, or any excipients on the formulation. 
 
19. Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results. 
 
20. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening to 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period 
 
21. QT interval corrected for heart rate (QTc) <: 470ms calculated from  1 electrocardiogram 
(ECG) using Fridericia's Correction 
 
22. History of primary immunodeficiency 
 
23. Known history of previous clinical diagnosis of tuberculosis 
 
24. Subjects with uncontrolled seizures 
 
 
 
7.1 
RECRUITMENT  PLAN 
This study will be available to all patients seen at Memorial Hospital,who meet the eligibility criteria 
outlined in section 6.0. 
 
Memorial Hospital  is a referral center for CRC. In  addition, the study may be placed on the 
institutional Website to maximize patient recruitment.  Patients will be identified from  medical 
oncology clinics for treatment of their disease. 
 
The investigators take due notice of the NIH policy concerning inclusion of women and minorities in 
clinical research populations. There will be no limitation to access with regard to race or gender. 
Patients will be required to read, agree to, and sign an IRS-approved informed consent form prior to 


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registration on this trial. The registration procedure will be conducted as described in section 15.0. 
Patients will not receive payment for their participation on this study. 
 
 
8.0 
PRETREATMENT  EVALUATION 
 
To be completed within 4 weeks prior to starting durvalumab and tremelimumab: 
 
• CT scan with contrast (chest, abdomen and pelvis). If patient is unable to receive CT contrast, or 
the abdominal/pelvic target lesion is indeterminate on CT scan then MRI with contrast (abdomen 
and pelvis) plus CT chest without contrast may be perfromed. Non-contrast CT CAf' may be 
used if the target lesion(s) do not require contrast for accurate measurements. 
 
• 12-lead Electrocardiogram (EKG). 
 
• Signed informed consent for study participation. 
 
• History and physical examination, including height, weight, vital signs (temperature, pulse rate, 
respiration rate, blood pressure), and performance status (ECOG). 
• Serum pregnancy test for all women of childbearing potential (within two weeks prior to day #1 of 
treatment). 
• CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, C02, 
and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, albumin, total 
protein,TSH (Free T3, Free T4 if TSH abnormal), GGT, PT/PTT, amylase/lipase and CEA 
 
• Urinalysis 
 
• Serology for  HepBsAg,  HepBcAb and hepatitis C antibody (negative test acceptable prior to 
screening period) 
 
• Blood test for research purposes. 
 
• Perform baseline tumor biopsy for research purposes (for patients enrolled in stage 1 only). 
 
9.0 
TREATMENT/INTERVENTI ON PLAN 
 
 
9.1 
lnvestigational Products 
 
The lnvestigational Products Supply section of AstraZeneca/Medl mmune will supply durvalumab 
and tremelimumab to the investigator as a solution for infusion after dilution. 
9.1.1 
Formulation/packaging/storage 
Durvalumab: 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after dilution. The 
solution contains 50 mg/ml durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mMtrehalose 


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dihydrate, and 0.02% {weight/volume) polysorbate SO; it has a pH of 6.0. The nominal fill volume is 
10 ml. Investigational product vials are stored at 2°C to S°C {36°F to 46°F) and must not be frozen. 
Durvalumab must be used within the individually assigned expiry date on the label. 
Tremelimumab 
 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after dilution. 
The solution contains 20 mg/ml of tremelimumab, 20 mM histidine/histidine hydrochloride, 222 mM 
trehalose dihydrate, 0.02% {w/v) polysorbate SO, and 0.27 mMdisodium edetate dihydrate {EDTA); 
it has a pH of 5.5. The nominal fill volume is 20 ml. lnvestigational product vials are stored at 2°C to 
S°C {36°F to 46°F) and must not be frozen. Tremelimumab must be used within the individually 
assigned expiry date on the label. 
 
9.1.2 
Dose and treatment regimens 
9.1.2.1 
Durvalumab + tremelimumab combination therapy 
 
Patients will receive 1500 mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg 
tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab 
q4w starting on Week 16. Tremelimumab will be administered first. Durvalumab infusion will start 
approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 
hour for each infusion. A 1-hour observation period is required after the first infusion of durvalumab 
and tremelimumab. If no clinically significant infusion reactions are observed during or after the first 
cycle, subsequent infusion observation periods can be at the Investigator's discretion (suggested 30 
minutes after each durvalumab and tremelimumab infusion). 
9.1.2.2 
Duration of treatment and criteria for retreatment 
Retreatment with durvalumab + tremelimumab is allowed {once only) for patients meeting the 
retreatment criteria below. The same trea1ment guidelines followed during the initial treatment 
period will be followed during the retreatment period, including the same dose and frequency of 
treatments and the same schedule of assessments. 
 
Patients  receiving  durvalumab  monotherapy  may undergo retreatment  with  the combination  of 
durvalumab + tremelimumab, described below: 
 
1. Patients who complete the 4 dosing C}Cles of the combination of durvalumab and 
tremelimumab portion of the regimen {with clinical benefit per Investigator judgment), but 
subsequently have evidence of PD  during the durvalumab monotherapy portion of the 
combination regimen, with or without confirmation according to RECIST 1.1, may restart 
treatment with the combination. 
 
Before restarting their assigned treatment, the Investigator should ensure that the patient: 
 
1. Does not have any significant, unacceptable, or irreversible toxicities that indicate continuing 
treatment will not further benefit the patient 
 
2. Still fulfills the eligibility criteria for this study, including re-consenting to restart durvalumab 
and tremelimumab 


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3. Has had a baseline tumor assessment within 28 days before restarting their assigned 
treatment; all further scans should occur with the same frequency as during the initial months 
of treatment until study treatment is stopped 
 
During the retreatment period, patients receiving durvalumab + tremelimumab may resume 
durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses each. Patients 
will then continue with durvalumab monotherapy at 1500 mg q4w, beginning at Week 16, 4 weeks 
after the last dose of combination therapy. 
 
Treatment through progression is at the Investigator's discretion, and the Investigator should ensure 
that patients do not have any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not further  benefit the patient. A patient with a confirmed progression 
receiving durvalumab + tremelimumab cannot continue therapy or obtain retreatment if dosing is 
ongoing in the combination portion of therapy {q4w dosing) and progression occurs in a target lesion 
that has previously shown a confirmed response. 
 
Patients who the Investigator determines may not continue treatment will enter follow-up. 
 
9.1.2.3 Study drug preparation of durvalumab and tremel imumab 
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. 
Preparation of durvalumab doses for administration with an IV bag 
 
The dose of durvalumab for administration must be prepared by the Investigator's or site's 
designated IP manager 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) 
 
• 
4 hours at room temperature 
 
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 of 1500mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 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.  Remove 
30.1 mlof IV solution from the IV bag prior to addition of durvalumab. Next, 30.0 mlof durvalumab 
(i.e., 1500 mg of durvalumab} is added to the IV bag such that final concentration is within 1 to 20 
mg/ml (IV bag volumes 100 to 1000 ml). Mx the bag by gently inverting to ensure homogeneity of 
the dose in the bag. 


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Patient weight at baseline should be used for dosing calculations unless there is a <!:10% change in 
weight. Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard. 
For patients <30kg, Calculate the dose volume of durvalumab and tremelimumab and number of 
vials needed for the subject to achieve the accurate dose. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion 
via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the 
entire contents of the IV bag should be administered as an IV infusion over approximately 60 
minutes (±5 minutes), using a 0.2, or 0.22-µm in-line filter. Less than 55 minutes is considered a 
deviation. 
The IV line will 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. The table below summarizes tine 
allowances and temperatures. 
 
Durvalumab hold and infusion times 
 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 
s·c 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
 
In the event that either preparation time or infusion time exceeds the time limits ouUined in the table, 
a new dose must be prepared from new vials. Durvalumab does not contain preservatives, and any 
unused portion must be discarded. 
 
 
Preparation of tremelimumab doses for administration with an IV bag 
 
The dose of tremelimumab for administration must be prepared by the Investigator's or site's 
designated IP manager 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) 
 
• 
4 hours at room temperature 
 
It is recommended that the prepared final IV bag be stored in the dark at 2"C-8°C (36°F-46°F) until 
needed.  If storage time exceeds these limits, a new dose must be prepared from new vials. The 


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refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room 
temperature for about 2 hours prior to administration. Tremelimumab does not contain preservatives 
and any unused portion must be discarded. 
 
No incompatibilities between tremelimumab and polyvinylchloride or polyoletin IV bags have been 
observed. Doses of 75 mg tremelimumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline or dextrose, with a final tremelimumab concentration ranging from 0.1 
mg/ml to 10 mg/ml, and delivered through an IV administration set with a 0.2 µm or 0.22 µm in-line 
tilter. Remove 3.8 mlof IV solution from the IV bag prior to addition of tremelimumab. Next, 3.8 ml 
of tremelimumab (i.e., 75 mg of tremelimumab) is added to the IV bag such that final concentration 
is within 0.1 mg/ml to 10 mg/ml (IV bag volumes 50 to 500 ml). Mx the bag by gently inverting to 
ensure homogeneity of the dose in the bag. 
 
Patient weight at baseline should be used for dosing calculations unless there is a <:10% change in 
weight. Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard. 
 
For patients <30 kg, Calculate the dose volume for tremelimumab and number of vials needed for 
subject to achieve the accurate dose. 
 
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled infusion 
via an infusion pump into a peripheral or central vein. Following preparation of tremelimumab, the 
entire contents of the IV bag should be administered as an IV infusion over approximately 60 
minutes (±5 minutes), using a 0.2, or 0.22-µm in-line filter. Less than 55 minutes is considered a 
deviation. 
 
The IV line will be flushed with a volume of 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.  The table below summarizes ti'ne 
allowances and temperatures. 
 
Tremelimumab hold and infusion times 
 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 
8°c 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in the table, 
a new dose must be prepared from new vials. Tremelimumab does not contain preservatives, and 
any unused portion must be discarded. 


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9.1.2.4 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the times 
specified in the Study Protocol. 
 
In the event of a sGrade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the initial rate 
until completion of the infusion. For patients with a SGrade 2 infusion-related reaction, subsequent 
infusions may be administered at 50% of the initial rate. Acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at 
the discretion of the investigator. If the infusion-related reaction is <!:Grade 3 or higher in severity, 
study drug will be discontinued. 
 
As with any antibody, allergic reactions to dose administration are possible. 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. The study site must have immediate 
access to emergency resuscitation teams and equipment in addition to the ability to admit patients to 
an intensive care unit if necessary 
9.1.2.5 
Accountability  and dispensation 
Disposition of unused investigational study drug 
The site will account for all investigational study drug dispensed and also for appropriate destruction. 
Certificates of delivery and destruction must be signed. 
 
9.2 
Concomitant Medications 
 
9.2.1 
Permitted Concomitant Medication 
 
Investigators may  prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for 
those medications identified as "excluded" as listed in Section 9.2.2. 
9.2.2 
Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study. 
 
1. Any investigational anticancer therapy, other than the protocol specified therapies 
 
2. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment, other than any stated comparator or combination regimens. Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.  Local surgery for treatment of isolated lesions for 
palliative intent is acceptable. 
 
3. lmmunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathiopri ne, and 


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TNF-a blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of topical steroids, inhaled and intranasal corticosteroids are permitted. 
 
4.  Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (i.e., 30 
days prior to the first dose, during treatment with durvalumab and tremelimumab for 30 days 
post discontinuation of durvalumab and tremelimumab.)  Inactivated vaccines, such as the 
injectable influenza vaccine, are permitted. 
 
9.3 
Dose Modification and Toxicity Management 
 
Durvalumab and tremelimumab 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab the 
following dose adjustment guidance may be applied: 
 
• Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab or tremelimumab along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for durvalumab 
and tremelimumab (see Appendix A). 
• All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of durvalumab 
or tremelimumab can be modified based on toxicities observed (see Appendix A).  Dose reductions 
are not permitted. 
 
Based on the mechanism of action of durvalumab or tremelimumab leading to T-cell activation and 
proliferation, there is the possibility of observing immune related Adverse Events (irAEs) during the 
conduct of this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, 
and endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (e.g., infection or PD) signs or S}fllptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune-related. 
 
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Appendix A 
 
In addition, management guidelines for adverse events of special interest (AESls) are detailed 
below. All toxicities will be graded according to NCI CTCAE v4.03 


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9.4 Diet/Activity/Other Considerations 
 
9.4.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE. such as 
diarrhea, nausea or vomiting. 
 
9.4.2 Contraception 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use 2 methods of effective contraception (Table 1) from the time of screening and must agree to 
continue using such precautions for 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the 
longer time period; cessation of birth controlafter this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of birth control. 
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectany) or post-menopausal 
(defined 12 months with no menses without an alternative medical cause). 
 
Non-sterilized males who are sexually active with a female partner of childbearing potential must use 
2 acceptable methods of effective contraception (see Table 1) from screening through 180 days 
after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after 
receipt of the final dose of durvalumab monotherapy, whichever is the longer time period. 
 
Table 1 
Highly Effective• Methods of Contraception 
. Copper T intrauterine device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.3. Blood donation 
 
Subjects should not donate blood while participating in this study,or for at least 90 days following 
the last infusion of durvalumab or tremelimumab. 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Levonorgesterel -releasing 
intrauterine system (e.g., Mrena®)b 
• Etonogestrel implants: e.g. lmplanon or Norplan 
• lntravaginaldevice:  e.g.ethinylestradioland 
etonogestrel 
• Medroxyprogesterone injection :e.g.Depa- 
Provera 
• Normal and low dose combined oral 
contraceptive pill 
• Norelgestromin/ethinylestradiol    transdermal 
system 
• Cerazette (desogestrel) 
" 
lighly effecwe (i.e.failure ratect <1% PEI' yea-) 
b 
This is also cor&idered a horrTDnal rrethod 


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9.5   Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1.  Quality or quantity of data recording is inaccurate or incomplete 
 
2. Poor adherence to protocol and regulatory requirements 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
 
4. Plans to modify or discontinue the development of the study drug 
 
In the event of Med Immune/ Astra Zeneca decision to no longer supply study drug, ample 
notification will be provided so that appropriate adjustments to subject treatment can be made. 
9.7 
RESEARCH BLOOD AND BIOPSY SPECIMENS 
 
9.7.1 Research blood 
 
For all patients, blood specimens will be obtained for research purposes during screening or on day 
1,then at weeks 2, 4 and 8 (± 3 days). An additional blood draw beyond week 8 is permitted based 
upon interesting clinic/immunological findings. 
Specimens should be collected prior to drug administration. Four (4) tubes of blood are to be 
collected in BD Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin. Each tube should 
contain approximately 10 cc of blood. Peripheral blood mononuclear cells and plasma will then be 
isolated per institutional practice in the Immune l'v'onitoring Facility (IMF). 
9.7.2 Research biopsy 
For patients enrolled in stage 1, a pre-treatment tumor biopsy will be obtained during screening. On­ 
treatment biopsies will be performed 1week after completing radiation or ablation (from the radiated/ 
ablated lesion), and then 4 weeks after dose #1 of durvalumab plus tremelimumab (from a non­ 
radiated/ ablated lesion) 
 
Patients will be permitted to continue enrollment and  treatment on protocol in the event that 
insufficient material was obtained from the biopsy. The on treatment biopsy will not be required if this 
is no longer considered appropriate at the time of the planned procedure, for example, if the tumor is 
no longer accessible or the procedure is deemed to be unsafe. Tumor lesion planned for on­ 
treatment biopsy may be an index lesion if ;:: 2 cm in at least one diameter. 
If clinically practical, subjects will undergo up to 5 core biopsies. Three core biopsies will be placed 
in formalin and processed for FFPE, 2 core biopsies will be immediately frozen in liquid nitrogen and 
then stored at -80°C (appendix C). All tissue obtained during biopsy procedures will be sent to the 
IMF facility for analysis  under this study as  indicated  below.  If the  patient undergoes a routine 
procedure, tissue may be obtained for future correlative analyses. 
 
9.7.3 
Correlative studies 
 
Pharmacodynamic changes may be evaluated for associations with clinical activity, and safety 
(adverse event) data. Tissue may be used for correlative studies such as IHC, tumor mutation 
analysis, proteomic analysis, and immunodiversity. PDL-1 immunohistochemistry will be done by a 


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MedImmune/ 
Ira Zeneca designated laboratory or at MSKCC using the Ventana SP263 assay in 
accordance with the package insert on Ventana Benchmark platform. Archived samples submitted 
for PD-L1 testing should be s 3 months old. 
 
 
 
 
9.7.3.1 
Whole Blood 
 
Flow cytometry will be performed at baseline and during treatment to assess baseline and changes 
in composition/activation status of lymphocyte subsets present in peripheral blood mononuclear cell 
preparations (PBMCs). Lymphocyte subsets to be assayed may include, but are not limited to CDS+ 
and CD4+ T-cell subsets (activated; effector/memory; regulatory) and populations of those cells as 
defined by the expression of activation, exhaustion, or signaling markers such as ICOS, HLA-DR, 
PD-1, CTLA-4, and/or intracellular IFNy. NK cell populations may be monitored in a similar fashion 
with a focus on characterizing subsets defined by the expression of activation markers (e.g. NKG2D; 
IL-21R) and/or by markers that are associated with the potential of NK cells to lyse target cells (e.g., 
CD107a, granzyme, perforin). Additional flow cytometry-based assays will focus on defining and 
monitoring the abundance of myeloid-derived suppressor cells (l'vDSCs), a cell type which appears 
to negatively impact  anti-tumor actMty and which has been shown to promote immune escape by 
limiting activated CDS T-cell infiltration into the tumor microenvironment (Lesokhin, Hohl et al. 2012). 
Immune cells may be evaluated using HLA-A2-restricted tetramer assays to detect and quantify the 
presence of T cells directed against specific antigens which are anticipated to be presented to the 
immune system due to study treatment. Detecting on-treatment increases in these T cell populations 
may be considered evidence of adaptive immune responses in CRC. 
9.7.3.2 Plasma 
To understand the prevalence of circulating proteins and the impact they may have on the clinical 
activity and/or safety of durvalumab and tremelimumab treatment, the protein concentrations of a 
panel of cytokines, chemokines, and other relevant immunomodulatory, soluble factors may be 
investigated by ELISA and/or other relevant multiplex-based protein assay methods. Examples of 
analytes to be assessed may include but are not limited to factors induced by IFNy signaling (e.g., T 
cell chemoattractants CXCL9; CXCL10) and other factors generally involved in inflammatory 
processes. Plasma may be used also to assess the presence and/or concentration of anti-tumor 
antibodies using a mulitplex platform such as lnvitrogen's Protoarray platform(c). Levels of sPD-L1 
in peripheral blood may also be assessed. 
9.7.3.3 Tissue Biopsies and/or archived tissue 
 
The presence of TILs within tumors in response to durvalumab and tremelimumab treatment will be 
evaluated baseline and on-treatment biopsies. Archived tissue (approximately 20 x 5 µm slides) and 
biopsy tissue may be analyzed using immunohistochemistry for PD-L1 expression and other 
immune-related genes, and gene expression (microarray and/or RT- QPCR) research platforms. 
Laser Capture Microdissection may be utilized to enrich specific regions of tumor material for use in 
similar or additional downstream applications, which may include in-situ hybridization, flow 
cytometry, ELISA, and/or assessment of miRNA In all cases, the goal may be to determine the 
abundance of a battery of immunoregulatory genes or proteins associated with cancer cells and/or 


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cancer-interacting lymphocytes derived from biopsied material. DNAwill be extracted from tumor 
samples and normal blood lymphocytes and undergo sequence analysis, such as whole exome 
sequencing in order to (1) search for tumor mutations that may correlate with immune response; and 
(2) to search for tumor specific mutations that are absent from germ line DNA and be potential novel 
immune targets, neo-epitopes. Other biomarkers may be evaluated as determined by additional 
data. Remaining specimens may be stored for future studies related to CRC immunity. 
 
10.0 
EVALUATION  DURING TREATMENTnNTERVENTION 
 
Study Calendar 
 
Period 
Screening 
Treabnent 
Endof study 
vlslt17 
Cycle1 
<4 weeke2 
1 
2-4 
5+ 
odd 
even 
Day 
1 
1:9 
(:t7 
dawl 
1 
1:9 
(:t7 
dawl 
1 
1 
Informed consent 
x 
Medical history 
x 
EKG 
x 
CT/MRl3 
x 
x 
x 
x 
Height4 
x 
Physical examination 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs/ Performance status 
4
 
x 
x 
x 
x 
x 
x 
x 
x 
Report medicatiais 
x 
x 
x 
x 
x 
x 
x 
x 
Pulse oJCimetry 
x 
x 
x 
x 
x 
x 
x 
Report side effects 
x 
x 
x 
x 
x 
x 
CBCs,6 
x 
x 
x 
x 
x 
x 
x 
x 
Comps,7 
x 
x 
x 
x 
x 
x 
x 
x 
Thyroid function (TSH, fT3,fT4)s,8 
x 
x 
x 
GGr8 
x 
Amytase9 
x 
Lipase9 
x 
CEA10 
x 
x 
x 
x 
x 
PT/PTT 
x 
Hepatitis Band C 
x 
Pregnancy test if female (Serum)12 
x 
Urinalysis 
x 
Researdl blood tests s.13 
x 
x 
x 
x 
Obtainarchived tissue '" 
x 
Researdl b.Jmor biopsy 15 
x 
x 
RT (Cohort 1) •D 
x 


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Jlblation (Cohort 2) •• 
x 
Durvalumab 
x 
x 
x 
Tremelimumab 
x 
x 
 
1. Each cy::le is approJCimately 4 weeks ilduration. Cle X Day 15 loisiis may occur within ±7 days of scheduled date. 
2. 
Procedures must be perfonned within 4 weeks prior to dose 1 of durvalumab and tremelimumab on Day 1. 
3. 
CT or MRI will be perfonned prior to starting RT or ablation and during screening, then at 8 week (±1 wk) intervals and 
at final loisit if more than 8 weeks from prior imaging. If patient is unable to receive CT contrast or the abdominal/ 
pelloic target lesion is indetenninate on CT then MRIwith contrast (abdomen and pell.is) plus CT without contrast 
(chest) may be perfonned. Imaging may be dela)9d up to 2 weeks if patient is receiloing additional RT or ablation. 
4. 
Vital signs to indude heart rate, respiratory rate, temperature and blood pressure 
5. 
Blood to be collected up to 72 hours prior to sdleduled dosing. 
6. 
Hematology to include standard complete blood cell (CBC) panel. 
7. 
Comprehensive metabolic panel included sodium, potassium, chloride, bicarbonate, BUN, creatinine, gluoose, total 
protein, albumil, bilirubin, alkaline phosphatase, AST,  ALT, calcium. 
8. 
Free T3, free T4, and TSH 
9. 
Tesis done at baseline then as clinically indicate 
10. CEA to be obtained during screening, day 1 and then within two weeks (or on day) of subsequent imaging. 
11. Serology for HepBsAg, HepBcJlb and hepatitis C antibody (unless preloiouslylesled negatiw). 
12. Serum pregnancy lest is required within 2 weeks prior to day #1 treatment 
13. Blood draws for research purposes perfonned during screening or day 1,then weeks 2, 4 and 8 for all patienis. 
14. ApproJCimately 20 x5 µm slides (unstained) will be requested on all patients for research purposes. 
15. Research tumor biopsywill be perfonned at baseline, then 1week (±3 days) after completing radiation or ablation 
(from the radiated/ablated lesion) and 4 weeks (±1 week) after dose #1 of durvalumab plus tremelimumab (from a 
non-radiated/ablated lesion). 
16. RT begins or ablation is perfonned during cy::le 1,within 7 days after starting durvalumab and tremelimumab. 
17. EOS loisit occurs 4 weeks (±1 wk) after discontinuing the study. CT scan or MRI to be done only if last imaging was 
conducted greater than eight weeks prior to the date of the Final Visit. 
 
10.1Assessments 
Physical examination 
Physical examinations will  be performed according to  institutional practice and according to the 
assessment schedule in the calendar. 
 
Electrocardiograms 
Resting 12-lead EKGs will be recorded at screening and as clinically indicated throughout the study. 
ECGs should be obtained after the patient has been in a supine position for approximately 5 minutes 
and recorded while the patient remains in that position. 
At. Screening, a single ECG will be obtained on which QTcF must be <470 ms. 
 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12- 
lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. 
 
Situations in which ECG results should be reported as AEs are described in Section 10.0. 
 
Vital signs 
Vital  signs  (blood  pressure  [BP],  pulse,  temperature,  and  respiration  rate)  will  be  evaluated 
according to the assessment schedules. 


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On infusion days, patients receiving durvalumab + tremelimumab treatment will be monitored during 
and after infusion of IP as presented in the bulleted list below. 
 
Supine BP will be measured using a semi-automatic BP recording device with an appropriate cuff 
size, after the patient has rested for at least 5 minutes. BP and pulse will be collected from patients 
receiving durvalumab + tremelimumab treatment before, during, and after each infusion at the 
following times (based on a 60-minute infusion): 
• Prior to the beginning of the infusion (measured once from approximately 30 minutes before 
up to 0 minutes [i.e., the beginning of the infusion]). 
• Approximately 30 minutes during the infusion (halfway through infusion). 
• M the end of the infusion (approximately 60 minutes ±5 minutes). 
• A 1-hour observation period is required after the first infusion of durvalumab and 
tremelimumab. 
• If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator's discretion (suggested 
30 minutes after each durvalumab and tremelimumab infusion). 
 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated.  The date and 
time of collection and measurement will be recorded on the appropriate eCRF. Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated. 
 
11.0  TOXICITIES/SIDE EFFECTS 
 
11.1 
SAFETY MONITORING 
Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and 
reported as described below. Safety will also be monitored by performing physical exams and 
routine laboratory procedures. 
 
11.1.1 
Adverse Events and Serious Adverse Events 
Definitions of AEs, non-serious AE, and serious adverse events (SAEs) are provided in this section. 
Additionally, provided in the sections below are reporting guidelines for any AE or SAE occurring 
during this study. 
Definition of Adverse Event and Non-Serious Adverse Event 
 
The following definition of AE will be used for the study: "Any untoward medical occurrence in a 
subject or clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not 
related to medicinal (investigational) product." 
This definition includes any abnormalities or anomalies that were not seen at baseline or which 
worsened during the course of the study, if present at baseline. 


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A "non-serious" adverse event is any event that does not meet the definition of "serious adverse 
evenf' as presented, below. 
 
Reporting and Treating Non-Serious Events 
 
It is the responsibility of the investigator to perform regular assessments for AE.s. Subjects will be 
regularly queried about the occurrence of any AE.s and will be monitored throughout the study for 
reactions to study drug and/or study procedures. The investigator and clinical staff will record all 
AE.s, whether volunteered by or elicited from the subject, at any time during a subject's participation 
in the study. Abnormal laboratory findings (e.g., hematology, comprehensive metabolic panel) or 
other abnormal assessments (e.g., vital signs) will be recorded as AEs if they are judged as 
clinically significant by the investigator. 
All subjects experiencing an AE will be evaluated by the investigator and monitored until resolution 
of the events or until the investigator deems the event clinically stable and/or at an acceptable level. 
Unless the event requires hospitalization (SAE), medical treatment will be provided to the subjects at 
the unit and treatment medication and/or medical procedures will  be provided  per the treating­ 
investigator's clinical discretion. All clinically significant AE.s, including clinically significant laboratory 
abnormalities, will be followed until resolution. AE.s meeting the definition of SAE.s require special 
reporting in addition to documentation in the CRDB as described below. 
All AE.s, including clinically significant laboratory and assessment abnormalities will be recorded 
according to "Common  Terminology Criteria for Adverse  Events" V4.03 (CTCAE) and must  be 
recorded in the CRDB.  Events occurring prior to initiation of first dose should be recorded on the 
Medical History page of the CRDB. Any AE occurring at initiation of first dose of study drugs should 
be recorded on the Adverse Event page of the CRDB.  AE.s should be recorded in the CRDB using 
the medical terminology found in the source documentation.  Whenever possible, diagnoses should 
be given  when  signs  and  symptoms  are  due  to  a common  etiology. 
It  is  the  investigator's 
responsibility to provide his/her assessment of the relationship of the event to the study drug and the 
severity of the event using the following scales: 
 
• Relationship 
> Unrelated: The AE is clearly attributable to a concurrent illness, concurrent medication, clinical 
state, or environmental factor other than the investigative agent. 
> Unlikely: The occurrence of the AE does not follow the study in a temporal sequence and/or 
based upon available subject information, e.g., medical history, disease process, known 
pharmacology of drug, a relationship between the drug and AE is unlikely. 
> Possible: The AE follows a reasonable temporal sequence from the time of study drug 
administration, but it is possible that other factors; e.g., subject's clinical state or concomitant 
mediations, environmental factors, or the drug's pharmacology may have caused the AE. 
> Probable: The AE follows a reasonable temporal sequence from the time of study drug 
administration, follows a known response pattern of the medication class, and cannot be 
reasonably explained by other factors. 


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• Severity 
 
The severity of all adverse events should be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) V4.03. For those adverse events not listed in the CTCAE, the 
following grading system should be employed: 
> Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily tolerated 
and no interference with subject's daily activities 
> Moderate  (CTCAE  Grade  2):  Marked  signs/symptoms  that  interfere  with  subject's  usual 
activities, but still acceptable 
> Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable interference 
with the subject's daily activities, unacceptable 
> Ufa-threatening (CTCAE Grade 4):  Life-threatening of disabling AE 
> Death (CTCAE Grade 5):  Death-related AE.  See CTCAE Guidelines for assigning Grade 5. 
 
Definition of Serious Adverse Event 
 
The following definition of SAE applies for the study: "A serious AE means any AE occurring at any 
dose that results in any of the following outcomes: death, a life-threatening AE, inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, 
a 
persistent 
or 
significant 
disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life threatening, or require hospitalization may be considered a serious AE when, 
based upon appropriate medical judgment, they may jeopardize the subject or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. A life­ 
threatening AE is any AE that places the subject or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred (e.g., it does not include a reaction that, had 
it occurred in a more severe form, might have caused death)." Reporting and Treating Serious 
Adverse Events as per section 17.2. 
Recording Adverse events 
 
Adverse events will be recorded using a recognized medi::al term or diagnosis that accurately 
reflects the event. Adverse events will be assessed by the investigator for severity, relationship to 
the investigational product, possible etiologies, and whether the event meets criteria of an SAE and 
therefore requires immediate notification to AstraZeneca/Med Immune Patient Safety. 
 
The following variables will be collected for each AE: 
 
• AE (verbatim) 
• The date when the AE started and stopped 
• Changes in NCI CTCAE grade and the maximum CTC grade attained 
• Whether the AE is serious or not 
• Investigator causality rating against durvalumab or tremelimumab (yes or no) 
• Action taken with regard to durvalumab + tremelimumab/comparator/combinati on agent 


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• OutcCJTle 
 
In addition, the following variables will be collected for SAEs as applicable: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of serious AE 
• AE is serious due to ... 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Description of AE 
• Causality assessment in relation to Study procedure(s) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE during 
the study. 
 
Ally overdose of a study subject with durvalumab + tremelimumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the 
A<;traZeneca/Medl mmune Patient Safety or designee using the designated Safety a-mailbox. If the 
overdose results in an AE, the AE must also be recorded as an AE. 
 
Study recording period and follow-up for adverse events and serious adverse events 
Adverse events and serious adverse events will be recorded frCJTl time of signature of  informed 
consent, throughout the treatment period and including the follow-up period (90 days after the last 
dose of durvalumab or tremelimumab). 
 
During the course of the study alIAEs and SAEs should be proactively followed up for each subject. 
Every effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. 
 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation. 
 
All SAEs will be reported, whether or not considered causally related to the investigational product, 
or to the study procedure(s). The reporting period for SAEs is the period immediately following the 
time that written informed consent is obtained through 90 days after the last dose of durvalumab or 
tremelimumab or until the initiation of alternative anticancer therapy. The investigator and/or 
Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of the 
SAE as per local requirements. 


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The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any serious 
or unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 
312.32, and will concurrently forward all such reports to AstraZeneca. A  copy  of the 
MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is reported to the 
FDA It is the responsibility of the sponsor to compile all necessary information and ensure that the 
FDA receives a report according to the FDA reporting requirement timelines and to ensure that 
these reports are also submitted to AstraZeneca at the same time. 
 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
 
• 
"Notification from an Investigator Sponsored Study" 
• 
The investigator IND number assigned by the FDA 
 
• 
The investigator's name and address 
 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-15-11668 
 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as 
determined by the  principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca's 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported 
to AstraZeneca  preferably using the  MedDRA coding language for serious adverse events.   This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly. 
 
 
11.2 
Other events requiring reporting 
Overdose 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess of 
that specified in the Investigator's Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab + tremelimumab, with or without asscx;iated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/Med Immune Patient Safety or designee using the designated Safety e-mailbox. If the 
overdose results in an AE, the AE must also be recorded as an AE. Overdose does not 
automatically make an AE serious, but if the consequences of the overdose are serious, for example 
death or hospitalization, the event is serious and must be recorded and reported as an SAE. There 
is currently no specific treatment in the event of an overdose of durvalumab or tremelimumab. The 
investigator will use clinicaljudgment to treat any overdose. 


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Hepatic function abnormality 
 
Hepatic function abnormality (as defined in Section 11.3.) in a study subject, with  or without 
associated clinical manifestations, is required to be reported as "hepatic function abnormal" within 
24 hours of knowledge of the event to the sponsor and AstraZeneca/Med Immune Patient Safety 
using the designated Safety a-mailbox (see above for contact information), unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated 
to investigational product has been confirmed. 
 
• If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject will 
be based on the clinical judgment of the investigator. 
 
• If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and  inquiries must be 
initiated by the investigational site without delay. 
 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/Med Immune. 
 
Pregnancy 
 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately. 
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or 
birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from the 
study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but no 
later than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 calendar days 
for SAEs and within 30 days for all other pregnancies. 
 
The same timelines apply when outcome information is available. 


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Paternal exposure 
11/ele patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab canbination therapy or 90 days after 
the last dose of durvalumab monotherapy, whichever is the longer time period. 
Pregnancy of the patient's partner is not considered to be an AE. l-lowever, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible,be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtainthe consent of the patienfs partner. Therefore,the local study team should 
adopt the generic ICF template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/lnstitutional Review Boards (IRBs) prior to use. 
 
 
11.3   Durvalumab + tremelimumab adverse events of special interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the lnvestigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. AA AESI may be serious or non-serious. The 
rapid reporting of AES Is allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
AESls 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 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESls are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. AA immune-related adverse event (irAE) 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 irAE diagnosis. Appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 
 
If the Investigator has any questions in regards to an  adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
 
AESls observed with durvalumab and tremelimumab include: 
• Colitis 
• Pneumonitis 
• M..T/AST increases I hepatitis I hepatotoxicity 
• Neuropathy I neuromuscular toxicity  (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barre, and myasthenia gravis) 


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• Endocrinopathy 
(i.e.  events of   hypophysitis,   adrenal insufficiency,   and   hyper-   and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis   (or labs suggestive of pancreatitis - increased serum  lipase, increased serum 
amylase) 
Further information on these risks (e.g. presenting symptoms) can be found in the current version of 
the durvalumab and tremelimumab Investigator Brochure. For durvalumab and tremelimumab, 
AESls will comprise the following: 
 
Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with 
use of anti-PD-1 mAbs (but not with anti-PD-L 1 mAbs). Initial work-up should include a high­ 
resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. Guidelines for the management of patients with immune-related AEs (irAEs) 
including pneumonitis are provided in Appendix A 
 
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring fran the start of 
IP infusion up to 48 hours after the infusion start time. For all infusion reactions, SAEs should be 
reported to AstraZeneca Patient safety as described in Section 11.1. 
 
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L 1 
and anti-PD-1 therapy (Brahmer et al, 2012.).   As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of mAbs can be caused by various 
mechanisms, including acute anaphylactic (lgE-mediated) and anaphylactoid reactions against the 
mAbs and serum sickness.  Acute allergic reactions may occur, may be severe, and may result in 
death. Acute allergic reactions  may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue,  headache,  hypertension, myalgia, vomiting,  and  unresponsiveness. 
Guidelines  for  the 
management of patients with hypersensitivity (including anaphylactic reaction) and infusion-related 
reactions are provided in Append ix A 
 
Hepatic function abnormalities (hepatotoxicity) 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 x ULN and 
concurrent increase in total bilirubin to be greater than 2 x ULN. Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other. 
Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence that 
clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the IP. Guidelines for management of patients with hepatic 
function abnormality are provided in Appendix A 


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Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimLJTiab is 
used as monotherapy. In rare cases, colon perforation may occur that requires surgery (colectomy) 
or can lead to a fatal outcome if not properly managed. Guidelines on management of diarrhea and 
colitis in patients receiving tremelimumab are provided in Appendix A 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism. Guidelines for the management of patients with immune-mediated  endocrine 
events are provided in Appendix A 
 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase elevation. 
Guidelines for the management of patients with immune-mediated pancreatic disorders are provided 
in Appendix A 
 
Neirotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barre, and myasthenia gravis. Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Appendix A 
Nephritis 
 
Immune-mediated nephritis includes autoimmune nephritis, renal dysfunction, and elevated serum 
creatinine. Guidelines for the management of patients with immune-mediated nephritis events are 
provided in Append ix A 
Immune-related adverse events 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation and 
proliferation, there is a possibility of observing irAEs during the conduct of this study. Potential irAEs 
may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-1 mAb), and BMS- 
936559 (anti-PD-L1 mAb} and may include immune-mediated enterocolitis, dermatitis, hepatitis 
(hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al 2010, Brahmer et al 2012, Topalian 
et al 2012.). These AEs are inflammatory in nature and can affect any organ. With anti-PD-L 1 and 
anti-CTLA-4 combination therapy, the occurrence of overlapping or increasing cumulative toxicities 
that  include irAEs  could potentially occur  at higher frequencies than with  either durvalumab or 
tremelimumab monotherapy. Patients should be monitored for signs and symptoms of irAEs. In the 
absence of an alternate etiology  (e.g., infection or PD), an immune-related etiology should be 
considered for signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and 
endocrinopathy. In addition to the dose modification guidelines provided in Appendix A, it is 
recommended that irAEs are managed according to the general treatment guidelines outlined for 
ipilimumab (Weber et al 2012.).  These guidelines recommend the following: 
• Patients should be evaluated to identify any alternative etiology. 


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• In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered immune related. 
• Symptomatic and topical therapy should be considered for low-grade events. 
• Systemic  corticosteroids  should be considered for  a persistent  low-grade  event or for a 
severe event. 
• IVore  potent  immunosuppressives  should  be  considered  for  events  not  responding  to 
systemic steroids (e.g., infliximab or mycophenolate). 
 
If the Investigator has any questions in regards to an PE being an ir/lE, the Investigator 
should immediately contact the Study Physician. 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
For the purposes of this study, patients will be evaluated for response every 2 cycles (approximately 
8  weeks),   or  as  clincially  indicated  if  interim  toxicity  occurs  mandating  cancer  staging  re­ 
assessment. RECIST 1.1 criteria will be used. 
CT scan with contrast of the chest. abdomen. and pelvis 
 
• CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral 
CT should be performed using a 5-mm contiguous reconstruction algorithm. 
II/RI scans 
 
• II/RI of the abdomen and pelvis is acceptable for measurement of lesions provided that the 
same anatomical plane is used for serial assessments. If possible, the same inaging device 
should be used for serial evaluations. In case of II/RI, measurements will be preferably 
performed in the axial (transverse) plane on contrast-enhanced T1-weighted images. However, 
there are no specific sequence recommendations. 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
 
• Measurable Lesions - M.lst be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
• 10 mm caliper measurement by clinical exam (when superficial) 
 
• Malignant lymph nodes are considered pathologically enlarged and measurable, a lymph 
node must be <!: 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 


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• Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or sites of 
disease), including small lesions (longest diameter < 10 mm or pathological lymph nodes with 
<!: 10 to < 15 mm short axis). Lesions considered truly nonmeasurable include the following: 
leptomeningeal disease, ascites, pleural/pericardia! effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
• Target Lesions • All lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions 
per organ) representative of all involved organs should be identified as target lesions. It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible measurement 
in which circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
 
• Non-target Lesions • It is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g., "multiple enlarged peMc lymph nodes· or 
"multiple liver metastases") 
Response Criteria 
Evaluation of Target Lesions 
• Complete Response • Disappearance of all target lesions. Ally pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may not 
be "O" if there are target nodes). 
• Partial Response • At. least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease • At. least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression.) 
• Stable Disease·Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-target Lesions 
• Complete Response • Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• Non-complete response/Non-progressive disease • Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
• Progressive Disease • Unequivocal progression of existing non-target lesions will be defined 
as the overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  In the absence of measurable disease, change in non-measurable 
disease comparable in magnitude to the increase that would be required to declare PD for 


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measurable disease. Examples include an increase in a pleural effusion from 'trace' to 'large,' 
an increase in lymphangitic disease from localized to widespread. 
Appearance of New Lesions 
 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. Considering 
the unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive treatment with durvalumab and tremelimumab. 
Evaluation of Overall Response 
 
Table 12 provides overall responses for all possible combinations of tumor responses in target and 
non-target lesions with or without the appearance of new lesions. 
Table 12 
Evaluation of Overall Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Not evaluable is dEi1ned as eitha-when no a only asumet c:l las10n rreaslJ"ell'Snts are rrede at an assess111Bnt. 
 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of treatment delays due to adverse event(s), or serious toxicity or complications, 
treatment may continue until one of the following criteria applies: 
 
• Disease progression (unless the patient continues treatment beyond progression). 
• Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial. 
• Unacceptable toxicity or any adverse event that precludes further participation in the trial. 
• The investigator removes the patient from the trial in the best interests of the patient. 
• Patient death . 
Target Lesions 
Non-target  Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
No 
Partial response 
Complete response 
Non-complete response I 
non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable a 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable a 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
Progressiw  disease 
Any 
Yes/No 
Progressiw  disease 
Any 
Progressiw  disease 
Yes/No 
Progressiw  disease 
Any 
Any 
Yes 
Progressiw  disease 


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• Study completion or discontinuation for any reason. 
• Patient withdraws consent to continued participation in the trial or is lost to follow up. 
 
Subjects who are permanently discontinued from receiving investigational product will return for end 
of study visit, unless consent is withdrawn, the subject is lost to follow-up or begins another 
treatment. All subjects will be followed for survival by phone (if not otherwise following up at 
Memorial Hospital) approximately every 3 months for 2 years or until study closes. 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 
 
 
After the end of treatment, each subject will be followed for 28 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment). Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up, for 2 years or until study closes. After documented disease 
progression each subject will  be followed  by telephone  (unless  not otherwise following  up at 
Memorial Hospital) for overall survival until death, withdrawal of consent, the end of the study, or 2 
years. 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint of this trial is the response rate in CRC treated with RT plus durvalumab and 
tremelimumab (cohort 1) or ablation plus durvalumab and tremelimumab (cohort 2). Based on 
historical controls, 1/20 responses may be observed in a non-radiated or non-ablated lesion with 
these current therapies and we consider a response rate S5% as unacceptable (Overman, Kopetz et 
al. 2016). A two-stage Simon's optimal design will be employed to test the null hypothesis that the 
true response rate is S5% versus the alternative hypothesis that the true response rate is at least 
25% with type Iand II error rates of 10% each. Each cohort will be evaluated separately for this 
purpose. Patients will be considered evaluable if they have received at least one dose of 
durvalumab and/or tremelimumab and undergone ablation/RT. Response will be determined only in 
disease that is not ablated or radiated. In the first stage, we will accrue 9 patients in each cohort. If 0 
objective tumor responses (PR or CR) are observed among the 9 subjects treated in a cohort, then 
subject enrollment will be terminated in that cohort.  If at least 1 response is observed among the 9 
subjects treated in a cohort, then the study will be expanded to enroll a total of 24 treated subjects in 
that cohort. In the likelihood that we observe at least one response in each of the 9 subjects treated 
in stage 1 of the two cohorts, it will be at the discretion of the investigators which cohort to expand 
based on pharmacodynamic data (such as circulating CEA, changes in composition/activation status 
of lymphocyte subsets present in peripheral blood mononuclear cell preparations or tumor 
immunohistochemistry analysis, and/or circulating cytokines/ chemokines). The cohort to be 
expanded will enroll an additional 15 patients for a total of 24 treated subjects. At. the end of the 
study, if 2 or less objective tumor responses are observed in the expanded cohort, then the study 
will be considered not worthy of further investigation in that particular cohort.  If at the end of the 
study <!3 tumor responses per RECIST 1.1 are observed in the expanded cohort, then further 
investigation of durvalumab and tremelimumab plus RT and/or durvalumab and tremelimumab plus 
ablation will be considered worthwhile. 


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IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
 
 
 
 
 
Secondary outcomes, including toxicity, the additional measures of efficacy and exploratory 
objectives will be summarized by cohort. 
 
The study will complete when all subjects have either progressed or discontinued from the study for 
other reasons. This study requires accrual of a minimum of 18 subjects and up to a maximum of 33 
subjects if one cohort is expanded to the second stage. The accrual time is estimated to be 9 
months to 2 years for both cohorts. 
Antitumor Activity 
 
Assessmen1s of antitumor activity will be based on the ORR, PFS, and OS. Response Evaluation 
Criteria in Solid Tumors guidelines (v1.1) (Eisenhauer, Therasse et al. 2009). 
 
The ORR is defined as the proportion of subjec1s CR or PR based on RECIST criteria. The exact 
95% Cl of ORR will be estimated using the binomial distribution. Progression-free survival will be 
measured from the start of treatment with durvalumab and tremelimumab until the documentation of 
disease progression or death due to any cause, whichever occurs first. Progression-free survival will 
be censored on the date of last tumor assessment documenting absence of tumor progression for 
subjects who are still alive  prior to data cutoff,  dropout,  or the initiation of  alternate  anticancer 
treatment. Subjects having no tumor assessmen1s after the start of treatment with durvalumab and 
tremelimumab will  have  PFS  censored  on  the  first  date  of  treatment  with  durvalumab  and 
tremelimumab.  These  patients  will  be counted  as  non  responders  and  considered  evaluable. 
Progression-free survival will  be evaluated  using the Kaplan-lv'eier method (Kaplan and  Meier, 
1958). Overall survival will be determined as the time from the start of treatment with durvalumab 
and tremelimumab until death. For subjects who are alive at the end of study or lost to follow-up, OS 
will be censored on the last date when subjects are known to be alive. The OS will be evaluated 
using the Kaplan-lv'eier method. Progression free survival at 1 and 2 years will be estimated by the 
Kaplan-lv'eier. 
Safety and Tolerability Analyses 
 
All recorded adverse events will be listed and tabulated by system organ class, preferred term and 
treatment. Ally significant vital signs and clinical laboratory test results will be listed and 
summarized. Ally significant physical examination findings and clinical laboratory results will be 
listed. 
Biomarker Analysis 
 
Exploratory research studies will be done to evaluate the effect of this therapy will be perfonmed 
using research blood draws and tumor biopsies at baseline, week 1 and at week 4. 
 
The phanmacodynamic effect of durvalumab and tremelimumab and RT or ablation on Tumor 
Infiltrating Lymphocytes (TILs), such as CD4+ and COB+ T-cells, and expression of tumor markers, 
such as PD-L1, will be assessed by summary statistics, and investigated graphically to explore 
patterns of change from pre-treatment to post-treatment specimens. 
 
The pharmacodynamic effect of durvalumab and tremelimumab and RT or ablation on markers in 
peripheral blood, such as    ICOS, HI.A-DR, PD-1, CTL.A-4; and, serum proteins, such as CXCL9; 


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CXCL10, will be assessed by summary statistics, and investigated graphically to explore patterns of 
change over time, i.e.: pretreatment, then week 2, week 4 and week 8. 
 
In  addition,  the  relationship  of  TIL changes  and  tumor  marker  expression  with  measures  of 
peripheral blood markers will be summarized descriptively. 
 
Associations between the markers and response by RECIST will be explored. 
 
Fisher's exact test will be employed to assess associations between categorical variables while 
Spearman's rank correlation will be used for continuous variables. Wilcoxon signed rank test will be 
used to test for differences in continuous expression tumor markers between pre- and post­ 
treatment specimens while 11/k:Nemar's test will be used to assess these relationships for binary 
markers. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for PatienUSubject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific  Eligibility Checklist. 
 
 
15.3 
Randomization 
 
NIA 
 
16.1 
DAT A MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
The data collected for this study will be entered into a secured database (Clinical Research 
Database, CRDB) at Memorial Sloan-Kettering Cancer Center. Source documentation will be 
available to support the computerized patient record. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 


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Approval date: 09-0ct-2018 
 
 
 
 
protocolcompliance audits may be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
 
 
16.2     Data and Safety Monitoring 
 
The Data and Safety  M>nitoring (DSM) Plans at  Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies  set forth  by the  NCI in the  document entitled "Policy of the  National Cancer 
Institute  for   Data   and  Safety   M>nitoring   of   Clinical  Trials",  which  can  be  found  at 
http://cancertrials.nci.nih. gov/researche rs/dsm/index. html.   The  DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC DSM Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at 
http://mskweb5.mskcc.org/intranet/  assets/ tables/content/359689/Data safetv%20M>nitori 
ng07.pdf 
 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. 
 
Inclusion of Women and Mnorities: Memorial Sloan-Kettering Cancer Center has filed forms 
HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 
(age discrimination); we also take due notice of the NIH policy concerning inclusion of 
women and minorities in clinical research populations. Patients of all races, both male and 
female, will be accepted into the protocol. The proposed study population is as described in 
section 7.0. 
 
Exclusion of Lactating or Pregnant Wcrnen: Children have been excluded from this study. 
Colorectal adenocarcinoma is an adult cancer. Thus, the relevance of these drugs to the 
pediatric population has not been established. Lactating and pregnant women are also 
excluded because of potentialanti-proliferative effects of chemotherapy that may be harmful 
to the developing fetus or nursing infant. 
 
Benefits: It is possible that this treatment will result in shrinkage of colorectal cancer or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether these or 
any other favorable events will occur. It is not known whether this treatment will affect the 
overall survivalof the patients. 
 
Costs: The patient will be responsible for the costs of standard medical care, including, CT 
scans, all drug administration fees and all hospitalizations, even for ccrnplications of 
treatment. Durvalumab and tremelimumab will be supplied to patients by MedImmune/ Atstra 
Zeneca at no cost. Patients will not be responsible for the costs of blood procurement 
obtained for research purposes or the cost for obtaining the tumor biopsy for research 
purposes. 
 
Incentives:  No incentives will be offered to patients/subjects for participation in the study. 


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Approval date: 09-0ct-2018 
 
 
 
 
 
Alternatives:  Patients may be eligible for other investigational studies, or focus on palliative 
care options. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patient's name or any other personally identifying 
information will not be used in reports or publications resulting from this study. The Food and 
Drug Administration or other authorized agencies (e.g., qualified monitors) may review 
patients' records and pathology slides, as required. 
17.1 
Privacy 
 
MSKCC's Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they mayjeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 90-days after the participant's last investigational treatment or intervention. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 'Reporting of Serious 
Adverse Events', the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 


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Memorial Sloan Kettering Cancer Center 
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Approval date: 09-0ct-2018 
 
 
 
 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mslu:c. org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mslu:c.org. All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• Subject's initials 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subjecfs condition 
o Indication if the subject remains on the study 
• If an amendment will need to be made to the protocoland/or consent form 
• If the SAE is an Unanticipated Problem 
The Pl's signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
17.2.1 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Medlmmune/ Ac>tra Zeneca product, must be reported within 5 calendar days to the MSKCC 
Safety Office. 
 
Non-serious Even1s of Clinical Interest will be forwarded to 1\11edlmmune/ Ac>tra Zeneca Global 
Safety andwill  be handled in the saTie mainer as  SAEs. 


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Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Med Immune/ Astra Zeneca product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to MedImmune/ Astra Zeneca. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRS/PB-approved consent 
form indicating their consent to participate. This consent form mee1s the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
1. 
"American Cancer Society. Cancer Facts and Figures 2011." 
2. 
Brahmer, J. R , C. G. Drake, I. Wollner, J. D. Powdey. J. Picus, W. H. Sharfman, E. StankelAch, A. 
Pons, T. M. Salay, T. L. McMiller, M. M. Gilson, C. Wang, M. Selby, J. M. Taube, R. Anders, L. Chen, A. J. 
Korman, D. M. Pardall, I. Lowy and S. L. Topalian (2010). "Phase Istudy of single-agent anti-programmed 
death-1 (MDX-1106) in refractory solid tumors: safety, clinical actilAty, pharmacodynamics, and immunologic 
correlates." J Clin Oneel 28(19): 3167-3175. 
3. 
Chung, K. Y., I. Gore, L. Fong, A. Venook, S. B. Beck, P. Dorazio, P. J. Criscitiello, D. I. Healey, B. 
Huang, J. Gomez-Navarro and L. B. Saltz (2010). "Phase II study of the anti-cytotoxic T-lymphocyte­ 
associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal 
cancer." J Cli n Oneel 28(21): 3485-3490. 
4. 
den Brok, M. H., R. P. Sutmuller, R. wn der Voort, E. J. Bennink, C. G. Figdor, T. J. Ruers and G. J. 
Adema (2004). "In situ tumor ablation creates an antigen source for the generation of antitumor immunity." 
Cancer Res 64(11): 4024-4029. 
5. 
Deng, L., H. Liang, B. Burnette, M. Beckett, T. Darga, R. R. Weichselbaum and Y. X  Fu (2014). 
"Irradiation and anti-PD-L1 treatment  synergistically  promote antitumor immunity  in mice." J Clin Invest 124(2): 
687-695. 


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IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 60 of 86 
 
 
 
 
6. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe and J. Verweij 
(2009). "New response evaluation criteria in solid tumours:  rellised RECIST guideline (version  1.1)."  Eur J 
Cancer 45(2): 228-247. 
7. 
Farlay, J., H. R. Shin, F. Bray, D. Forman, C. Mathers and D. M. Parkin (2010). "Estimates of 
worldwide burden of cancer in 2008: GLOBOCAN 2008." Int J Cancer 127(12): 2893-2917. 
8. 
Lesokhin, A. M., T. M. Hohl, S. Kitano, C. Cortez, D. Hirschhom -Cymerman, F. Avogadri, G. A. 
Rizzuto, J. J. Lazarus, E. G. Pamer, A. N. Houghton, T. Merghoub and J. D. Wolchok (2012). "Monocytic 
CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CDS T-cell infiltration 
into the tumor microenllironment." Cancer Res 72(4): 876-886. 
9. 
Le11Y, M. Y., A. Sidana, W. H. Chowdhury, S. B. Solomon, C. G. Drake, R. Rodriguez and E. J. Fuchs 
(2009). "Cyclophosphamide  unmasks an antimetastatic  effect of local tumor cryoablation."  J Pharmacol Exo  
Ther  330(2): 596-601. 
10. 
Lipson, E. J., W. H. Sharfman, C. G. Drake, I. Wollner, J. M. Taube, R. A. Anders, H. Xu, S. Yao, A. 
Pons, L. Chen, D. M. Pardall, J. R. Brahmer and S. L. Topalian (2013). "Durable Cancer Regression Off­ 
Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody." Clin Cancer Res 19(2): 462-468. 
11. 
Meyerhardt, J. A. and R. J. Mayer (2005). "Systemic therapy for colorectal canc er." N Engl J Med 
352(5): 476-487. 
12. 
Postow, M. A., M. K. Callahan, C. A. Barker, Y. Yamada, J. Yuan, S. Kitano, Z. Mu, T. Rasalan, M. 
Adamow, E. Ritter, C. Sedrak, A. A. Jungbluth, R. Chua, A. S. Yang, R. A. Roman, S. Rosner, B. Benson, J. 
P. Allison, A. M. Lesokhin, S. Gnjatic and J. D. Wolchok (2012). "Immunologic correlates of the abscopal effect 
in a patient with melanoma." N Engl J Med 366(10): 925-931. 
13. 
Topalian, S. L., F. S. Hedi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. 
Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J. Antonia, L. Hom, C. G. 
Drake, D. M. Pardall, L. Chen, W. H. Sharfman, R. A. Anders, J. M. Taube, T. L. McMiller, H. Xu, A. J. 
Korman, M. Jure-Kunkel, S. Agrawal, D. McDonald, G. D. Kellia, A. Gupta, J. M. Wigginton and M. Sznol 
(2012). "Safety, actillity, and immune correlates of anti-PD-1 antibody in cancer."  N Engl J Med 366(26):  2443- 
2454. 
14. 
Waitz, R., M. Fasso and J. P. Allison (2012). "CTLA-4 blockade synergizes with cryoablation to 
mediate tumor rejection." Oncoimmunology 1(4): 544-546 
 
.20.0 
APPENDICES 
 
APPENDIX A:. 
 Dosing Modification and Toxicity Management Guidelines for Immune­ 
mediated, Infusion Related, and Non Immune-mediated Reactions 
APPENDIX B: 
APPENDIX C: 
Requisition For Blood Specimens 
Requisition For Tumor Specimens 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lnmune-mediated, 
Infusion Related, and Non lnmune-mediated Reactions 
The following table is a guide to the management of immune-related toxicity, and is subject to physician 
discretion. 
 
Table A Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Immune- 
related 
Adverse 
Events 
(Overall 
Manageme 
nt For 
toxicities 
not noted 
below) 
Drug administration modifications of study 
drug/study regimen will be made to manage 
potential immune-related AEs based on 
severity of treatment-emergent toxicities 
graded per NCI CTCAE v4.03. 
In addition to the criteria for penmanent 
discontinuation of study drug/regimen based 
on CTC grade/severity (table below) , 
permanently discontinue study drug/study 
regimen for  the following conditions: 
• Inability to reduce corticosteroid to a 
dose of S10 mg of prednisone per day 
(or equivalent) within 12 weeks after 
last dose of study drug/regimen 
• Recurrence of a previously 
experienced Grade 3 treatment- 
related AE following resumption of 
dosing. 
It is recommended that management of irAEs 
follow the guidelines presented in this table 
- 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 PO 1-2mg/kg/day or IV 
equivalent 
- If symptoms recur or worsen during 
corticosteroid tapering 28 days of 
taper), increase the corticosteroid 
dose (prednisone dose  [e.g. up to 2- 
4mg/kg/day or IV equivalent]) until 
stabilization or improvement of 
symptoms, then resume corticosteroid 
tapering at a slower rate (28 days of 
taper) 
- More potent immunosuppressives 
such as TNF inhibitors (e.g. infliximab) 
- (also refer to the individual sections 
of the immune related adverse event 
for specific type of 
immunosuppressive) should be 
considered for events not responding 
to systemic steroids. 
- Discontinuation of study drug is not 
mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to 
Grade 1 
No dose modification 
Grade 2 
• Hold study drug/study 
regimen dose until grade 2 
resolution to s Grade 1 
• If toxicity worsens then treat 
as Grade 3 or Grade 4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
• Study drug/study treatment 
can be resumed at the next 
scheduled dose once event 
stabilizes to grade s1 and 5- 
7 days have passed after 
completion of steroid taper 
• Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement can be 


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Page 63 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lnmune-mediated, 
Infusion Related, and Non lnmune-mediated Reactions 
The following table is a guide to the management of immune-related toxicity, and is subject to physician 
discretion. 
 
retreated with study 
drug/study regimen on the 
following conditions: 
1) the event stabilizes and is 
controlled 
2) the patient is clinically 
stable as per Investigator or 
treating physician's clinical 
judgment, and 
3) Doses of prednisone are 
at less than or equal to 
10mg/day or equivalent. 
local tumour response {e.g. 
inflammatory reaction at sites of 
metastatic disease, lymph nodes etc.). 
Continuation of study drug in this 
situation should be based upon a 
benefit/risk analysis for that patient 
Grade 3 
 Depending on the individual 
toxicity, may permanently 
discontinue study drug/study 
regimen. Please refer to 
guidelines below 
Grade 4 
 Permanently discontinue study 
drug/study regimen 
Note:  For Grade 3 and above 
asymptomatic amylase or lipase levels hold 
study drug/regimen and if complete work up 
shows no evidence of pancreatitis, may 
continue or resume study drug/regimen 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ 
ILD 
Ally Grade 
• lvlonitor patients for signs and symptoms 
of pneumonitis or ILD (new onset or 
worsening shortness of breath or 
cough}.  Patients should be evaluated 
with imaging and pulmonary function 
tests including other diagnostic 
procedures as described below 
• Initial work-up may include clinical 
evaluation, monitoring of oxygenation 
via pulse oximetry (resting and 
exertion), laboratory work-up and high- 
resolution CT scan. 
Grade 1 
(Asymptomatic, 
clinical or 
diagnostic 
observations 
only, intervention 
not indicated) 
No dose modification 
required. However, 
consider holding study 
drug/study regimen 
dosing as clinically 
appropriate and during 
diagnostic work-up for 
other etiologies 
For Grade 1 (Radiographic Changes Only) 
• lvlonitor and closely follow up in 2-4 
days for clinical symptoms, pulse 
oximetry (resting and exertion) and 
laboratory work-up and then as clinically 
indicated 
• Consider pulmonary and infectious 
disease consult 
Grade 2 
(Symptomatic, 
medical 
intervention 
indicated, 
limiting 
instrumental 
ADL) 
• Hold study drug/study 
regimen dose until 
grade 2 resolution to s 
Grade 1 
• If toxicity worsens 
then treat as Grade 3 
or Grade 4 
• If toxicity improves to 
baseline then the 
decision to reinitiate 
study drug/regimen at 
next scheduled 
treatment date will be 
based upon treating 
physician's clinical 
judgment 
• Study drug/study 
treatment can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade S1 and 5-7 davs 
For Grade 2 (Mild to Moderate New 
Symptoms) 
• lvlonitor symptoms daily and consider 
hospitalization 
• Promptly start systemic steroids (e.g., 
prednisone 1-2mg/kg/day 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 methylprednisone at 2- 
4/g/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibiters (e.g. infliximab at 5mg/kg 
every 2 weeks). Caution: Important to 
rule out sepsis and refer to infliximab 
label for general guidance before using 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
have passed after 
completion of steroid 
taper 
infliximab 
• Once improving, gradually taper steroids 
over 
weeks  and consider 
prophylactic antibiotics, antifungal or 
anti PCP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections (Category 28 
recommendation} 123 
• Consider pulmonary and infectious 
disease consult 
• Consider as necessary  discussing with 
study physician 
Grade 3 or 4 
(Grade 3: 
Severe 
symptoms; 
limiting self-care 
AOL; oxygen 
indicated; 
Grade 4: Iife 
threatening 
respiratory 
compromise, 
urgent 
intervention 
indicated [e.g. 
tracheostomy or 
intubation]) 
Penmanently discontinue 
study drug/study regimen 
For Grade 3 or 4 (severe or new 
symptoms, newiWorsening hypoxia, life 
threatening 
• 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.) 
• If no improvement within 3-5 days, 
additional workup should be considered 
and prompt treatment with additional 
immunosuppressive therapy such as 
TNF inhibitors (e.g. infliximab at 5mg/kg 
every 2 weeks dose) started. Caution: 
rule out sepsis and refer to infliximab 
label for general guidance before using 
infliximab 
• Once improving, gradually taper steroids 
over 
28 
days 
and 
 
consider 
prophylactic antibiotics, antifungals and 
in particular, anti  PCP  treatment 
(please 
refer 
to 
current 
 
NCCN 
auidelines  for  treatment  of     cancer- 
 
 
1 ASCO Educational Book 2015 "Managing Imnmne Checkpoint Blocking Anubody Side Effects" by Michae! Postow 
MD 
2 NCI CTCAE version 4.03 
3 ASCO Educational Book 2015. Michael Postow MD. "Managing Immune Checkpoint Blocking Antibody Side 
Effects" 


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Approval date: 09-0ct-2018 
Page 66 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
related 
infections 
(Category 
28 
recommendation)' 
Diarrhea/ 
Enterocolitis 
Ally Grade 
• Monitor for symptoms that may be 
related 
to 
diarrhea/enterocol 
itis 
(abdominal pain, cramping, or changes 
in bowel habits such as increased 
frequency over baseline or blood in 
stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and 
ileus) 
• Patients should be thoroughly evaluated 
to rule out any alternative etiology (e.g., 
disease progression, other medications, 
infections 
including 
testing 
for 
clostridium difficile toxin, etc.) 
• Steroids should be considered in the 
absence of clear alternative etiology, 
even for low grade events, in order to 
prevent potential progression to higher 
grade event 
• Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis 
Grade 1 diarrhea 
(stool frequency 
of <4 over 
baseline per 
day) 
No dose modification 
For Grade 1 diarrhea : 
• 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 4-6 over 
baseline per 
• Hold study drug/study 
regimen until 
resolution to s Grade 1 
• If toxicity worsens 
For Grade 2 diarrhea: 
• Consider symptomatic treatment 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
 
 
4 ASCO Educational Book 2015 "Managing Imnnme Checkpoint Blocking Antibody Side Effects" by Michae! Postow 
MD 


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Approval date: 09-0ct-2018 
Page 67 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
day) 
then treat as Grade 3 
or Grade 4 
• If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade S1 and 5-7 days 
have passed after 
completion of steroid 
taper 
American Dietetic Association colitis 
diet), and loperamide and/or budesonide 
• Promptly start  prednisone 1 to 2 
mg/kg/day or IV equivalent 
• If event is not responsive within 3-5 
days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, GI 
consult should be obtained for 
consideration of further workup such as 
imaging and/or colonoscopy to confirm 
colitis and rule out perforation,   and 
prompt treatment with IV 
methylprednisolone 2-4mg/kg/day 
started. 
• If still no improvement within 3-5 days 
despite 2-4mg/kg IV 
methylprednisolone, prompUy start 
immunosuppressives such as  infliximab 
at 5mg/kg once every 2 weeks ). 
Caution: Important to rule out bowel 
perforation and refer to inftiximab label 
for general guidance before using 
inftiximab 
• Consult study physician if no resolution 
to s Grade 1 in 3-4 days 
• Once improving, gradually taper steroids 
over :!:28 days and consider 
prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to 
current  NCCN guidelines for treatment 
of cancer-related infections [Category 
2B recommendation]) 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 ASCO Educational Book 2015 Michael Postow Ml"Managing mmune Checkpoint Blocking Antibody Side Effecis 


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IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 68 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
diarrhea 
(Grade 3: stool 
frequency of  7 
over baseline 
per day; 
Grade 4: Iife 
threatening 
consequences) 
Permanently  discontinue 
study drug/study regimen 
For Grade 3 or 4 diarrhea: 
• Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent 
• Monitor stool frequency and volume and 
maintain hydration 
• Urgent GI consult and imaging and/or 
colonoscopy as appropriate 
• If still no improvement within 3-5 days of 
IV methylprednisolone 2 to 4mg/kg/day 
or equivalent, promptly start further 
immunosuppressives (e.g. infliximab at 
5mg/kg once every 2 weeks}. 
• Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab 
label for general guidance before using 
infliximab. 
• Once improving, gradually taper steroids 
over   28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current 
NCCN guidelines for treatment of 
cancer-related infections [Category 2B 
recommendation]) 
Hepatitis 
(Elevated 
LFTs) 
Any Grade 
• Monitor and evaluate liver function test: 
AST, ALT, ALP and total bilirubin 
• Evaluate for alternative etiologies (e.g., 
viral hepatitis, disease progression, 
concomitant medications) 
• lnfliximab should not be used for 
management of Immune Related 
Hepatitis 
Grade 1 
(AST or ALT > 
ULN to 3 times 
ULN and/or TB > 
ULN to 1.5 times 
ULN) 
• No dose modification 
• If it worsens, treat as 
Grade 2 event 
For Grade 1 AST or ALT and/or TB 
elevation 
• Continue LFT monitoring per protocol 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
(AST or ALT > 3 
to 5 times ULN 
and/or TB >1.5- 
3.0 times ULN) 
• Hold Study drug/study 
regimen dose until 
grade 2 resolution to s 
Grade 1 
• If toxicity worsens 
then treat as Grade 3 
or Grade 4 
• If improves to baseline 
then treat at next 
scheduled treatment 
date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade s1 and 5-7 days 
have passed after 
completion of steroid 
taper 
For Grade 2 AST or ALT and or TB 
elevation : 
• Regular and frequent checking of LFTs 
(e.g. every 1-2 days) until elevations of 
these are improving or resolved. 
• If no resolution to s Grade 1 in 1-2 days, 
discuss with study physician. 
• If event is persistent (> 3-5 days) or 
worsens, pranptly start prednisone 1- 
2mg/kg/day or IV equivalent. 
• If still no improvement within 3-5 days 
despite 1-2mg/kg/day of prednisone or 
IV equivalent, consider additional 
workup and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day 
started. 
• If still no improvement within 3-5 days 
despite 2-4mg/kg/day of IV 
methylprednisolone, prompUy start 
immunosuppressives (mycophenolate 
mofetil}6  •  Discuss with study physician if 
mycophenolate mofetil is not available. 
lnfliximab should NOT be used. 
• Once improving, gradually taper steroids 
over :!:28 days and consider 
prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to 
current  NCCN guidelines for treatment 
of cancer-related infections [Category 
2B recommendation]) 
Grade 3 
(AST or ALT >5- 
20 times ULN 
and/or TB > 3.0- 
10 times ULN 
• For elevations in 
transaminases s 8 x 
ULN, or elevations in 
bilirubin s 5 x ULN 
• Hold study drug/study 
regimen dose until 
resolution to s Grade 1 
or baseline 
For Grade 3 or 4 AST or ALT and/or TB 
elevation: 
• Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day 
or equivalent 
• If still no improvement within 3-5 days 
despite 1 to 4 mg/kg/day 
 
 
6 ASCO Educational Book 2015 "Managirg Immune Checkpoint Blocking Antibody Side Effecis" ,by Mchael Poslow MD 


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Approval date: 09-0ct-2018 
Page 70 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• Resume study 
drug/study regimen 
administration at the 
next scheduled dose if 
elevations downgrade 
s Grade 1 or baseline 
within 14 days 
• PermanenUy 
discontinue study 
drug/study regimen if the 
elevations do not 
downgrade to s Grade 1 
or baseline within 14 
days 
• For elevations in 
transaminases > 8 x 
ULN or elevations in 
bilirubin > 5 x ULN, 
discontinue study 
drug/study regimen 
• PermanenUy 
discontinue study 
drug/study regimen for 
any case meeting Hy's 
law criteria (ALT > 3x 
ULN + bilirubin > 2x 
ULN without initial 
findings of cholestasis 
(i.e. elevated alkaline 
P04) and  in the 
absence of any 
alternative cause' 
methylprednisolone IV or equivalent , 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil) Discuss with 
study physician if mycophenolate is not 
available. lnfliximab should NOT be 
used. 
• Hepatology consult, abdominal workup, 
and imaging as appropriate. 
• Once improving, gradually  taper steroids 
over <!:28 days  and consider 
prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to 
current  NCCN guidelines for treatment 
of cancer-related infections [Category 
2B recommendation]) 
Grade 4 
(AST or ALT > 
20 times  ULN 
and/or TB > 1O 
times ULN) 
Permanently  discontinue 
study drug/study regimen 
 
 
 
 
 
 
 
7 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury - Premarketing Clinical Evaluation 


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Approval date: 09-0ct-2018 
Page 71 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine) 
Ally Grade 
• Consult with Nephrologist 
• tvlonitor for signs and symptoms that 
may be related to changes in renal 
function (e.g. routine urinalysis, elevated 
serum BUN and creatinine, decreased 
creatinine clearance, electrolyte 
imbalance, decrease in urine output, 
proteinuria, etc.) 
• Patients should be thoroughly evaluated 
to rule out any alternative etiology (e.g., 
disease progression, infections etc.) 
• Steroids should be considered in the 
absence of clear alternative etiology 
even for low grade events (Grade 2), in 
order to prevent potential progression to 
higher grade event 
Grade 1 [Serum 
Creatinine > 1- 
1.5X baseline;  > 
ULN to 1.5X 
ULN] 
• No dose modification 
• If toxicity worsens, 
depending on the 
severity, treat as 
Grade 2 or Grade 3 or 
4 
For Grade 1 elevated creatinine: 
• tvlonitor 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 [Serum 
Creatinine>1.5- 
3.0X baseline; 
>1.5X-3.0XULN] 
• Hold study drug/study 
regimen until 
resolution to s Grade 
1 
• If toxicity worsens 
then treat as Grade 3 
or Grade 4 
• If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
For Grade 2 elevated creatinine: 
• Consider symptomatic treatment 
including hydration, electrolyte 
replacement, diuretics, etc. 
• Carefully monitor serum creatinine 
every 2-3 days and as clinically 
warranted 
• Consult Nephrologist and consider renal 
biopsy if clinically indicated 
• If event is persistent (> 3-5 days) or 
worsens,  prompUy start prednisone 1 
to 2 mg/kg/day or IV equivalent 
• If event is not responsive within 3-5 
davc: or worsens deso ite orednisone at 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related,and Non lrrmune-mediated Reactions 
 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
scheduled dose once 
event stabilizes to 
grade s1 for 5-7 days 
have passed after 
completion of steroid 
taper 
1-2 mg/kg/day or IV equivalent, 
additional workup should be considered 
and prompt treatment with IV 
methylprednisolone at 2-4mg/kg/day 
started. 
• Once improving gradually taper steroids 
over <!:28 days and consider 
prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to 
current NCCN guidelines for treatment 
of cancer-related infections [Category 
28 recommendation]). 
• When event returns to baseline, resume 
study drug/study regimen and routine 
serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: 
Serum 
Creatinine > 3.0 
X baseline; >3.0- 
6.0 X ULN 
Grade 4: Serum 
Creatinine > 6.0 
X ULN) 
PenmanenUy discontinue 
study drug/study regimen 
• Carefully monitor serum creatinine on 
daily basis 
• Consult Nephrologist and consider renal 
biopsy if clinically indicated 
• Promptly start prednisone 1 to 2 
mg/kg/day or IV equivalent 
• If event is not responsive within 3-5 
days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, 
additional workup should be considered 
and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day 
started. 
• Once improving, gradually taper 
steroids over 0!:28 days and consider 
prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to 
current  NCCN guidelines for treatment 
of cancer-related infections [Category 
28 recommendation] 
Rash 
(excluding 
Bullous skin 
fonmations 
Ally Grade 
(Please refer to 
NCI CTCAE 
version 4.03 for 
definition of 
• 11/bnitor for signs and symptoms of 
dermatitis (rash and pruritus) 
• **IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY PHYSICIAN 
SHOULD BE CONTACTED AND 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
severity/ grade 
depending on 
type of skin 
rash) 
STUDY DRUG DISCONTINUED** 
Grade 1 
No dose modification 
For Grade 1: 
• Consider symptomatic treatment 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream) 
Grade 2 
• For persistent (> 1- 2 
weeks) Grade 2 
events, hold scheduled 
study drug/study 
regimen until 
resolution to s Grade 1 
or baseline 
• If toxicity worsens 
then treat as Grade 3 
• If toxicity improves 
then  resume 
administration at next 
scheduled dose 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade s1 and 5-7 days 
have passed after 
completion of steroid 
taper 
For Grade 2 : 
• Obtain dermatology consult 
• Consider symptomatic treatment 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream) 
• Consider moderate-strength topical 
steroid 
• If no improvement of rash/skin lesions 
occurs within 3-5 days or is worsening 
despite symptomatic treatment and/or 
use of moderate strength topical steroid, 
discuss with study physician and 
promptly start systemic steroids 
prednisone  1-2 mg/kg/day or IV 
equivalent 
• Consider skin biopsy if persistent for >1- 
2 weeks or recurs 
Grade 3 
• Hold study drug/study 
regimen until 
resolution to s Grade 1 
or baseline 
• If temporarily holding 
the study drug/study 
regimen does not 
provide improvement 
of the Grade 3 skin 
rash  to s Grade 1or 
baseline within 30 
For Grade 3 or 4: 
• Consult dermatology 
• PrompUy initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent 
• Consider hospitalization 
• 11/bnitor extent of rash [Rule of Nines] 
• Consider skin biopsy (preferably more 
than 1) as clinically feasible. 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
days, then 
penmanenUy 
discontinue Study 
drug/study regimen 
• Once improving, gradually taper steroids 
over  28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of cancer- 
related infections [Category 28 
recommendation]) 
• Discuss with Study Physician 
Grade 4 
Penmanently discontinue 
study drug/study regimen 
Endocrinopat 
hy (e.g. 
hyperthyroidi 
sm, 
hypothyroidis 
m, 
hypopituitaris 
m, adrenal 
insufficiency, 
etc.) 
Any Grade 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity) 
• Consult Endocrinologist 
• 11/bnitor patients for signs and symptoms 
of endocrinopathies. Non-specific 
symptoms include headache, fatigue, 
behavior changes, changed mental 
status, vertigo, abdominal pain, unusual 
bowel habits, hypotension and 
weakness. 
• Patients should be thoroughly evaluated 
to rule out any alternative etiology (e.g., 
disease progression including brain 
metastases, infections, etc.) 
• 11/bnitor and evaluate thyroid function 
tests: TSH, free T3 and free T4 and other 
relevant endocrine labs depending on 
suspected endocrinopathy. 
• 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 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC grade 
1) 
No dose modification 
For Grade 1: (including those with 
asymptomatic TSH elevation) 
• 11/bnitor patient with appropriate 
endocrine function tests 
• If TSH < 0.5X LLN, or TSH >2X ULN or 
consistenUy out of range in 2 
subsequent measurements, include FT4 
at subsequent cycles as clinically 
indicated and consider endocrinology 
consult. 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity 2) 
• For Grade 2 
endocrinopathy  other 
than hypothyroidism, 
hold study drug/study 
regimen dose until 
subject is clinically 
stable 
• If toxicity worsens then 
treat as Grade 3 or 
Grade 4 
• If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade s1 and 5-7 days 
have passed after 
completion of steroid 
taper 
• Patients with 
endocrinopathies  who 
may require prolonged 
or continued steroid 
replacement can be 
retreated with study 
drug/study regimen on 
the following 
conditions: 1) the 
event stabilizes and is 
controlled ,2) the 
patient is clinically 
stable as per 
Investigator or treating 
physician's  clinical 
judgment, and 3) 
doses of prednisone 
are at less than or 
equal to 1Omg/day or 
equivalent. 
For Grade 2: (including those with 
symptomatic  endocrinopathy} 
• Isolated hypothyroidism may be treated 
with replacement therapy without 
treatment interruption and without 
corticosteroids 
• Initiate hormone replacement as needed 
for management 
• Evaluate endocrine function, and as 
clinically indicated,  consider pituitary 
scan 
• For patients with abnormal endocrine 
work up, except for those with isolated 
hypothyroidism, consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) 
and prompt initiation of treatment with 
relevant hormone replacement (e.g. 
Levothyroxine, hydrocortisone, or sex 
hormones). 
• Once improving, gradually taper steroids 
over 
8 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of cancer- 
related infections [Category 28 
recommendation]) 
• For patients with normal endocrine work 
up (lab or MRIscans), repeat labs/MRI 
as clinically indicated. 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity 3 
or 4) 
• For Grade 3 or 4 
endocrinopathy  other 
than hypothyroidism, 
hold study drug/study 
regimen dose until 
endocrinopathy 
symptom(s) are 
controlled 
• Resume study 
drug/study regimen 
administration if 
controlled at the next 
scheduled dose 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade s1 and 5-7 days 
have passed after 
completion of steroid 
taper 
For Grade 3 or 4: 
• Consult endocrinologist 
• Isolated hypothyroidism may be treated 
with replacement therapy without 
treatment interruption and without 
corticosteroids 
• Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
• Administer hormone replacement 
therapy as necessary. 
• For adrenal crisis, severe dehydration, 
hypotension, or shock: immediately 
initiate intravenous corticosteroids with 
mineralocorticoid activity 
• Once improving, gradually taper 
immunosuppressive steroids over 
weeks and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of  cancer- 
related infections [Category 28 
recommendation]) 
• Discuss with study physician 
Immune 
mediated 
Neurotoxicity 
(to include 
but not 
limited to 
limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain- 
Barre) 
Any Grade 
(Depending on 
the type of 
neurotoxicity , 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity 
• 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) 
• Symptomatic treatment with 
neurological consult as appropriate 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 1 
No dose modifications 
See "Arly Grade" recommendations above. 
Grade 2 
• For acute motor 
neuropathies or 
neurotoxicity, hold 
study drug/study 
regimen dose until 
resolution to s Grade 1 
• For sensory 
neuropathy/neuropathi 
c pain, consider 
holding study 
drug/study regimen 
dose until resolution to 
s Grade 1 
• If toxicity worsens then 
treat as Grade 3 or 
Grade 4 
• If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade s1 and 5-7 days 
have passed after 
completion of steroid 
taper 
• Discuss with the study physician 
• 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 or IV 
equivalent 
• If no improvement within 3-5 days 
despite 1-2mg/kg/day prednisone or IV 
equivalent consider additional workup 
and prompUy treat with additional 
immunosuppressive therapy (e.g. IVIG} 
Grade 3 
• Hold Study drug/study 
regimen dose until 
resolution to s Grade 1 
• PermanenUy 
discontinue Study 
drug/study regimen if 
Grade 3 irAE does not 
resolve to s Grade 1 
within 30 days. 
For Grade 3 or 4: 
• Discuss with study physician 
• Obtain Neurology Consult 
• Consider hospitalization 
• Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
• If no improvement within 3-5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
Grade 4 
Permanently discontinue 


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Page 78 of 86 
 
 
 
 
 
Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
study drug/study regimen 
with additional immunosuppressants 
(e.g. IVIG} 
• Once stable, gradually taper steroids 
over 
weeks 
Immune- 
mediated 
peripheral 
neuromotor 
syndromes, 
such as 
Guillain- 
Barre and 
Myasthenia 
Gravis 
Any Grade 
• The prompt diagnosis of immune- 
mediated peripheral neuromotor 
syndromes is important, since certain 
patients may unpredictably experience 
acute decompensations which can 
result in substantial morbidity or in the 
worst case, death. Special care should 
be taken for certain sentinel symptoms 
which may predict a more severe 
outcome, such as prominent dysphagia, 
rapidly progressive weakness, and signs 
of respiratory insufficiency or autonomic 
instability 
• Patients should be evaluated to rule out 
any alternative etiology (e.g., disease 
progression, infections, metabolic 
syndromes 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 
• Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve 
conduction investigations, and 
"repetitive stimulation" if myasthenia is 
suspected} are routinely indicated upon 
suspicion of such conditions and may be 
best facilitated by means of a neurology 
consultation 
• Important to consider that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. Patients r""uirina treatment 


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IRB Number: 17-139 A(2) 
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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
should be started  with IVIG and 
followed by plasmapheresis if not 
responsive to IVIG 
Grade 1 
No dose modification 
• Discuss with the study physician 
• Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as described 
above 
• Obtain a neurology consult unless the 
symptoms are very minor and stable 
Grade 2 
• Hold study drug/study 
regimen dose until 
resolution to s Grade 1 
• Permanently 
discontinue study 
drug/study regimen if it 
does not resolve to s 
Grade 1 within 30 days 
or if there are signs of 
respiratory 
insufficiency or 
autonomic instability 
• Discuss with the study physician 
• Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as described 
above 
• Obtain a Neurology Consult 
• Sensory neuropathy/neuropathi c pain 
may be managed by appropriate 
medications (e.g., gabapentin, 
duloxetine, etc.) 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to 
treat llllyasthenia Gravis. Important to 
consider      that      steroid      therapy 
{especially with high doses) may result 
in transient worsening of myasthenia 
and should typically be administered in 
a monitored setting under supervision 
of a consulting neurologist. 
o Patients unable to tolerate  steroids 
may be candidates for treatment with 
plasmapheresis 
or 
IVIG. 
 
Such 
decisions are best made in consultation 
with a neurologist, taking into account 
the unique needs of each patient. 
o If Myasthenia Gravis-like neurotoxicity 
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: 


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Appendix A Dosing Modification and Toxicity Management Guidelines for lrrmune-mediated, 
Infusion Related, and Non lrrmune-mediated Reactions 
 
Event 
Event Grade 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
o  Important to consider here that the use 
of steroids as the primary treatment of 
Guillain-Barre is not typically 
considered effective. Patients requiring 
treatment should be started with IVIG 
and followed by plasmapheresis if not 
responsive to IVIG. 
Grade 3 
• Hold study drug/study 
regimen dose until 
resolution to s Grade 1 
• PermanenUy 
discontinue Study 
drug/study regimen if 
Grade 3 irAE does not 
resolve to s Grade 1 
within 30 days or if 
there are signs of 
respiratory 
insufficiency or 
autonomic instability 
For severe or life threatening (Grade 3 or 
4) events: 
• Discuss with study physician 
• Recommend hospitalization 
• l\llonitor symptoms and obtain 
neurological consult 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to 
treat Myasthenia Gravis.  It should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o Patients unable to tolerate steroids may 
be candidates for treatment with 
plasmapheresis or IVIG. 
o If Myasthenia Gravis-like neurotoxicity 
present, consider starting acetylcholine 
esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce 
the diagnosis. 
GUILLAIN-BARRE: 
• 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 4 
Permanently  discontinue 
study drug/study regimen 


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IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
Page 81 of 86 
 
 
 
 
 
 
 
Appendix A  Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions 
Table B. Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
- Management per institutional standard at 
the discretion of investigator 
- Monitor patients for signs and symptoms 
of infusion-related reactions {e.g., fever 
and/or shaking chills, flushing and/or 
itching, alterations in heart rate and blood 
pressure, dyspnea or chest discomfort, 
skin rashes etc.} and anaphylaxis {e.g., 
generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.} 
Grade 1 
The infusion rate of study 
drug/study regimen may be 
decreased by 50% or temporarily 
interrupted until resolution of the 
event 
For Grade 1 or Grade 2: 
- Acetaminophen and/or antihistamines may 
be administered per institutional standard 
at the discretion of the investigator 
- Consider premedication per institutional 
standard prior to subsequent doses 
Grade 2 
The infusion rate of study 
drug/study regimen may be 
decreased 50% or temporarily 
interrupted until resolution of the 
event 
Subsequent infusions may be 
given at 50% of the initial infusion 
rate 
Grade 3/4 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions 
per institutional standards (e.g., IM 
epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid} 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
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Appendix A 
Dosing  Modification  and  Toxicity  Management  Guidelines  for  lnmune- 
mediated,Infusion Related, and Non lrrmune-mediated Reactions 
Table C. Non-inmune Mediated Reactions 
(Note:  /!is applicable, for early phase studies, the following sentence may be added: "Any 
event greater than or equal to Grade 2, please discuss with Study Physician" 
CTC 
Grade/Severity 
Dose Modification 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for adverse 
events not deemed to be related to study treatment 
(i.e. events due to underlying disease) or for 
laboratory abnormalities not deemed to be clinically 
significant. 
Treat accordingly as per 
institutional standard 
1 
No dose adjustment 
Treat accordingly as per 
institutional standard 
2 
Hold study drug/study regimen until resolution to 
s Grade 1 or baseline 
Treat accordingly as per 
institutional standard 
3 
Hold study drug/study regimen until resolution to 
s Grade 1 or baseline 
For AEs that downgrade to s Grade 2 within 7 days 
or resolve to s Grade 1or baseline within 14 days, 
resume study drug/study regimen administration at 
next scheduled dose. Otherwise, discontinue study 
drug/study regimen 
Treat accordingly as per 
institutional standard 
4 
Discontinue Study drug/study regimen (Note for 
Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and 
as per Investigator's clinical judgment and in 
consultation with the sponsor) 
Treat accordingly as per 
institutional standard 


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Page 83 of 86 
 
 
 
 
 
.APPENDIX B: REQUISITION FOR BLOOD SPECIMENS 
 
Phase IIStudyto Assess the Efficacy of Durvalumab and Tremelirrumab Plus Radiotherapy 
or Ablation in Patients with Metastatic Colorectal Cancer 
 
A)  Section A:. Patient information 
(To be completed by RSA) 
 
Patient initials: -------- 
Patient study ID#: 
_ 
Site:  ------------ 
Drawn By: 
_ 
Date/ Time: ------- 
B) Section B:Sample Information 
(To be checked off by RSA) 
4 CPT tubes (10 cc) will be collecl&d at the 
following time points 
[ ]Baseline [ ]Week 2 
[ ]Week 4 
[ ]Week 8 
[ ]Week _ 
Sample Collection Instructions: 
1. Gently invert all tubes 8-10 times at room 
temperature immediately after collection 
2.  Write patient initials, date, and time of 
collection on each tube 
3. Place all collected tubes in biohazard ziplock 
bag 
4. Send all specimens at room temperature via 
Stat Messengers to 
_ 
D) Section D: Sample Processing information 
(To be completed by laboratory personnel) 
 
Lab ID#:------ 
Received by: 
_ 
 
Date/Time:------- 
 
 
 
Sent by: 
_ 
Date/Time:------- Received 
by: 
 _ 
Date/Time: -------- 
Sample shipping Instructions 
Ship samples on dry ice to: 
MSKCC lrvF 
ZUckerman Research Building 
425 East 66th street, Z1545 
New York, NY 10065 


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APPENDIX C: REQUISITION FOR BIOPSY SPECIMENS OR LEFT OVER TISSUE OBTAINED 
DURING A ROUTINE PROCEDURE 
 
Single Arm Phase IIStudyto Assess the Efficacy of Durvalumab and tremelimumab Plus 
Radiotherapy or Ablation in Metastatic ColorectalCancer Patients 
 
 
Patient initials: --------- 
Patient study ID#: 
_ 
Site:    ------------ 
 
 
Obtained By:  
_ 
Procedure: -------- 
Date/  Time:--------- 
[] Baseline: 5 Core Biopsies 
[] Week 1: 5 Core Biopsies 
[] Week 4:   5 Core Biopsies 
[] Routine Procedure:5 Cores or divided tumor 
Sample Collection Instructions: 
1. Cores # 1, 3,5: Place into formalin (3-5 cc) 
2.  Cores # 2, 4: Place in sterile Nunc tube and snap 
freeze in liquid nitrogen 
3.  Core #_: Place in RPM/ (5 cc) 
[ff tissue remains, collect/ process as for core #5] 
D) Section D: Storage/Processi ng information 
Sample Storage/ Processing I nstructions 
(To be completed by laboratory personnel) 
1. Cores # 1, 3, 5:Store at 4-8°C 
2.  Cores # 2, 4: Store at -70 to -80°C 
Lab ID#: 
_ 
3. Core #_: Process inmediate/y for isolation of 
tumor infiltrating lymphocytes. 
Received by: 
_ 
 
DatefTime: ------- 
E) Section E: Sanple shipping information 
Sample shipping Instructions 
(To be completed by Iaboratory personnel) 
Ship samples 1, 3, and 5 at room temperature; 
samples 2 and 4 on dry ice, attention: 
Sent by: 
_ 
 
DatefTime: -------- 
Received by: 
_ 
 
DatefTime: -------- 


Page 85 of 86 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-139 A(2) 
Approval date: 09-0ct-2018 
 
 
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