Conditions: Advanced Colorectal Cancer
Keywords: MEDI4736 14-109
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, MEDI4736 has on the patient and cancer.

MEDI4736 is a type of medication called an antibody. Antibodies are normal proteins in the body that help fight infections and possibly cancer. MEDI4736 is a special type of an antibody produced in a laboratory. MEDI4736 works by blocking a specific protein called the Programmed Death Ligand-1 (PDL-1), located on tumor cells.

Detailed description:

Arms:
arm 1: This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments.

Interventions: intervention 1: MEDI4736
Intervention descriptions: intervention 1: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Page 1 of 49 
 
 
Approval date: 09-Apr-2019 
Phase II Study to Evaluate the Efficacy of MEDI4736 in Imm 
Advanced Colorectal Cancer 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTO 
Principal Investigator/Department: 
Neil H. Segal, MD, PhD 
unological Subsets of 
COL 
Medicine 
Co-Principal  Investigator(s)/Department: 
Leonard B. Saltz, MD 
Medicine 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Luis Diaz, MD 
Andrew Epstein, MD 
Karuna Ganesh, MD 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Danny Khalil, MD 
Geoffrey Ku, MD 
Diane Reidy-Lagunes, MD 
Nitya P. Raj, MD 
Eileen O‟ Reilly, MD 
Armin Shahrokni, MD 
Zsofia K. Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
James Fuqua, MD 
Jinru Shia, MD 
Constanti nos Sofocleous, MD 
Marinela Capanu, PhD 
Ellen Hollywood, NP 
Jaclyn Norris, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Pamela Raasch, RN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Radiology 
Pathology 
Interventional Radiology 
Epidemiology and 
Biostatistics 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting  Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Luis Diaz, MD 
Andrew Epstein, MD 
Karuna Ganesh, MD 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 


Page 2 of 49 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
 
 
 
 
 
David Kelsen, MD 
Medicine 
Nancy Kemeny, MD 
Medicne 
Danny Khalil, MD 
Medicine 
Geoffrey Ku, MD 
Medicine 
Diane Reidy-Lagunes, MD 
Medicine 
Nitya P. Raj, 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 
Ellen Hollywood, NP 
Nursing 
Jaclyn Norris, NP 
Nursing 
Erica Kaufmann, NP 
Nursing 
Patricia Gabriel, NP 
Nursing 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 3 of 49 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................. 10 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 10 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 18 
4.1 
Design .............................................................................................................................. 18 
4.2 
Intervention ........................................................................................................................... 18 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 19 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 21 
6.1 
Subject Inclusion Criteria .................................................................................................. 21 
6.2 
Subject Exclusion Criteria ................................................................................................ 23 
7.0 
RECRUITMENT PLAN ................................................................................................................... 24 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 24 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 25 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 28 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 32 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 36 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 38 
14.0 
BIOSTATISTICS ............................................................................................................... 39 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES40 
15.1 Research Participant Registration ......................................................................................... 40 
15.2 
Randomization ................................................................................................................... 41 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 41 
16.1 
Quality Assurance ............................................................................................................ 41 
16.2 
Data and Safety Monitoring .................................................................................................. 41 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 41 
17.1 
Privacy ............................................................................................................................. 42 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................. 42 
17.2.1.........................................................................................................................................43 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 44 
19.0 
REFERENCES ...................................................................................................................... 45 
20.0 
APPENDICES ................................................................................................................... 47 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 4 of 49 
 
 
List of Abbreviations 
 
Abbreviation or 
Specialized Term 
Definition 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent  cell-mediated  cytotoxicity 
AE 
adverse event 
ALT 
alanine  aminotransferase 
APC 
antigen presenting cells 
AST 
aspartate  aminotransferase 
CD 
cluster of differentiation 
CI 
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 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-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 
Fc 
fragment  crystallizable 
FFPE 
formalin fixed paraffin embedded 
FTIH 
First-time-in-human 
GCP 
Good Clinical Practice 


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IRB Number: 14-109 A(8) 
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Page 5 of 49 
 
 
 
 
 
Abbreviation or 
Specialized Term 
Definition 
GI 
gastrointestinal 
HCl 
hydrochloride 
HCV 
hepatitis C vi rus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency  virus 
ICF 
informed consent form 
ICH 
International  Conference on Harmonisation 
IDMC 
Independent  Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgG1κ 
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 Activities 
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 
OS 
overall survi val 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 6 of 49 
 
 
 
 
 
Abbreviation or 
Specialized Term 
Definition 
PBMC 
peripheral blood mononuclear cell 
PD 
progressi ve disease 
PD-1 
programmed death 1 
PD-L1 
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 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
SMC 
Safety Monitoring Committee 
SPD 
sum of products of diameters 
SRT 
Safety Revi ew Team 
SUSAR 
suspected unexpected serious adverse reaction 
TIL 
tumor infiltrating lymphocyte 
TNF-α 
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 
World Health Organization 
w/ v 
weight/ vol ume 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 7 of 49 
 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Name of Investigational drug:   MEDI4736 
Title of Study:  Phase II Study to Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced 
Colorectal Cancer 
Study Centers: MSKCC 
Study Period: 24 months 
Phase of Development: II 
Objectives: 
The primary objective of this study is to determine the objective response rate of MEDI4736 in subjects with 
DNA mismatch repair deficient (dMMR) or Tumor Infiltrating Lymphocyte-positive (TIL+) advanced/metastatic 
Colorectal Cancer (CRC), according to RECIST 1.1. 
The secondary objectives are to determine: 
• 
The objecti ve response rate according to immune-related RECIST (irRECIST) of MEDI4736 in dMMR 
or TIL+ CRC 
• 
Progression-free survi val of MEDI 4736 in dMMR or TIL+ advanced/metastatic CRC 
• 
Overall survival of MEDI4736 in dMMR or TIL+ advanced/metastatic CRC 
• 
Safety and tolerability of MEDI4736 in subjects with CRC 
The exploratory objective of this study is to eval uate biomarkers that may correlate with acti vity of MEDI4736 
in CRC, or prospecti vely identify CRC patients likely to respond to MEDI4736 treatment. 
Study De sign: This will be a Simon two-stage design, single arm, phase II study. It will be conducted to 
determine the efficacy and safety of MEDI4736 in subjects with CRC. Subjects will be stratified to ensure that 
we include CRC tumor-types that are considered to be immunogenic and therefore more likely to be effecti vely 
targeted by an augmented immune response. These include patients with DNA mismatch repair proficient 
tumors that are characterized by increased TILs at baseline, as well as subjects with hereditary (Lynch 
syndrome) or acquired dMMR. 
All subjects will recei ve MEDI4736 vi a IV infusion at 10 mg/kg every two weeks (Q2W). Subjects will continue 
treatment Q2W for 12 months, or until progression of disease, initiation of alternative cancer therapy, 
unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment 
period, subjects without evi dence for progressi ve disease or other reason to discontinue treatment will be 
monitored without further treatment. Upon evidence of PD during the monitoring period, administration of 
MEDI4736 may resume at the Q2W schedule, for up to another 12 months. Treatment of isolated, non-target, 
lesions for palliati ve/therapeutic intent is acceptable after discussion with the Principal Investigator (e.g. by 
ablation, surgery or radiation). Tumor measurements and determination of tumor responses for this study will 
be performed according to RECIST 1. 1. Subjects may continue to receive MEDI4736 beyond radiographic 
progression in the absence of clinical deterioration, and after discussion with the Principal Investigator. All 
subjects will be followed up to 2 years for survi val or until the study closes. 
The primary endpoint of this trial is the best response rate in dMMR CRC (cohort 1) and TIL+ CRC (cohort 2) 
patients. A two-stage Simon‟s optimal design will be employed to test the null hypothesis that the true 
response rate is ≤5% vers us the alternative 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 fo r this purpose.  In the fi rst 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 respo nse 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. At the end of the study, if 2 or fewer objecti ve tumor responses are observed in 
a 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 RECIST1. 1 are observed in a cohort, then further investigation of 
MEDI4736 in that patient population will be considered worthwhile. This study requires accrual of a minimum  
of 18 subjects and up to a maximum of 48 subjects if both cohorts are expanded to the second stage. The 
accrual time is estimated to be 2 years. 
Exploratory research studies to evaluate the effect of MEDI4736 will be performed using research blood 
draws, archived tissue and tumor biopsies at baseline and at week 8. Tumor biopsies and research blood will 
be obtained on patients in the fi rst stage only. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 8 of 49 
 
 
 
 
 
Diagnosis and Main Criteria for Inclusion in the Study: 
Inclusion Criteria 
1. 
Written informed consent. 
2. 
Histologically- or cytologically- confirmed CRC. 
3. 
Pre-existing Tumor-Infiltrating Lymphocytes  or DNA mismatch repair deficiency 
4. 
Locally advanced or metastatic CRC. 
5. Subjects have received two or more standard available therapies. 
6. 
Age ≥ 18 years at time of study entry. 
7. 
Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 
8. 
Adequate organ and marrow function, defined as: 
a. 
Absolute Neutrophil Count ≥ 1,500/mm
3.
 
b. 
Platelet count ≥ 90, 000/mm3. 
c. 
AST and ALT ≤ 3 × institutional upper limit of normal (ULN) or ≤ 5 × ULN for subjects with liver 
metastases. 
d. 
Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with documented/suspected Gilbert‟s disease 
e. 
Serum creatinine ≤ 1.5 x ULN. 
9. 
Radiographically measurable disease per RECIST 1. 1. 
10. Life expectancy ≥ 16 weeks. 
11. Consent for tumor biopsies and blood draws for research purposes (required for patients enrolled in 
stage 1). 
12. Consent for use of archived tissue for research purposes. 
13. Adequate method of contraception. 
 
Exclusion Criteria 
1. 
Anticancer therapy, monoclonal antibody or major surgery within 4 weeks prior to the fi rst dose of 
MEDI4736. 
2. 
Any prior Grade ≥ 3 irAE while receiving immunotherapy (including anti -CTLA-4 or anti-CD137 MAb) 
or any unresolved irAE of any grade (controlled irAE endocrinopathies are allowed). 
3. 
Prior exposure to any anti-P D-1 or anti-P D-L1 antibody. 
4. 
Current or prior use of immunosuppressive medication within 28 days before the fi rst dose of 
MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 
5. 
Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy. 
6. 
Active autoimmune disease within the past 2 years, except for mild conditions  not requiring systemic 
treatment, such as vitiligo. 
7. 
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. 
NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable 
(e.g., by local ablation, surgery or radiotherapy ). 
8. 
Active or prior documented inflammatory bowel disease (e.g., Crohn‟s disease, irrit able bowel 
syndrome, ulcerative colitis). 
9. 
Receipt of radiation therapy within 4 weeks prior to starting investigational product, or limited field of 
radiation for palliation within 2 weeks of the first dose of investigational product. 
10. Known allergy or reaction to any component of the MEDI4736 formulation or its excipients. 
11. Known central nervous system (CNS) metastases requiring treatment, such as surgery, radiation or 
steroids. 
12. Known history of confirmed primary immunodeficiency. 
13. History of organ transplant requiring therapeutic immunosuppression. 
14. Other malignancy within 3 years, except for noninvasive malignancies such as cervical carcinoma in 
situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast 
that has/have been surgically cured, or prior malignancy considered by the investigator to be of low 
likelihood for recurrence. 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic 
congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 
active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have 
active hepatitis B, hepatitis C or human immunodeficiency vi rus (HIV), or psychiatric  illness/social 
situations that would limit compliance with study requirements or compromise the ability of the patient 
to gi ve written informed consent. 


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IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 9 of 49 
 
 
 
 
 
 
16. Women who are pregnant, breast-feeding or male or female patients of reproducti ve potential who are 
not employing an effecti ve method of birth control. 
17. Any other condition(s) that, in the opinion of the investigator, would interfere with evaluation of the 
investigational product or interpretation of subject safety or study results 
18. Subjects who are known to be HIV positive. 
19. Receipt of live attenuated vaccinati on within 30 days prior to receiving MEDI4736. 
Number of Subjects: Patient population size is 18-48, including patients with acquired or spontaneous DNA 
mismatch repair deficiency (n=9 to 24) or pre-existing tumor infiltrating lymphocytes identified in a tumor 
biopsy or surgical specimen (n=9 to 24). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
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Page 10 of 49 
 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
The primary objective of this study is to determine the objective response rate of MEDI4736 
in subjects with DNA mismatch repair deficient (dMMR) or Tumor Infiltrating Lymphocyte- 
positive (TIL+) advanced/metastatic CRC, according to RECIST v1.1. 
 
• 
The secondary objectives are to determine: 
o The objective response rate according to immune-related RECIST (irRECIST) of 
MEDI4736 in dMMR or TIL+ CRC 
o Progression-free survival of MEDI 4736 in dMMR or TIL+ advanced/metastatic CRC 
o Overall survival of MEDI4736 in dMMR or TIL+ advanced/metastatic CRC 
o Safety and tolerability of MEDI4736 in subjects with CRC 
 
• 
The exploratory objective of this study is to evaluate biomarkers that may correlate with 
activity of MEDI4736 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
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 canc er death1.  In 2012 in the 
U.S. an estimated 103,170 new cases will be diagnosed with 51,690 deaths 2. 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 20 months3. 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. 
3.2 
IMMUNE THERAPIES 
 
The immune system is capable of identifying tumor-associated antigens and eliminating the 
cancerous cells expressing them. This process of tumor immune surveillance, or tumor 
immunoediting, plays an important role in preventing and combating the growth of tumors. The 
process of immune surveillance is believed to result in a co-evolution of the tumor and immune 
response termed immunoediting, which is thought to follow three stages 
4. During the initial phase of 
elimination, the innate and adaptive immune systems detect and eliminate tumor cells. Elimination 
can result in complete clearance of tumor cells as is seen in rare cases of spontaneous regression 


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Page 11 of 49 
 
 
 
 
of melanoma 5. However, if elimination is incomplete, the immune system and tumor may enter a 
state of equilibrium. During this second phase of immunoediting, the immune response selectively 
eliminates susceptible tumor cells and may prevent tumor progression. As the equilibrium phase 
persists, the tumor may evolve mechanisms to avoid or attenuate the immune response. The 
emergence of tumor cells with reduced immunogenicity or enhanced immunosuppressive 
mechanisms leads to the escape phase of immunoediting. During escape, many factors may 
contribute to the failure of the immune system to control tumor growth including expression of T-cell 
inhibitory molecules, down regulation of tumor antigens, and presence of immunosuppressive 
regulatory T cells or immunosuppressive cytokines within the tumor microenvironment. 
 
Enhancing the immune response may provide a means to regain control of tumors that have 
progressed to the escape phase during immunoediting. Programmed death ligand 1 (PD-L1) (B7-  
H1, CD274) is part of a complex system of receptors and ligands that are involved in controlling T- 
cell activation. In normal tissue, PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, 
mesenchymal stem cells, bone marrow-derived mast cells, as well as various nonhematopoietic 
cells 6. Its normal function is to regulate the balance between T-cell activation and tolerance through 
interaction with its two receptors programmed death 1 (PD-1, CD279) and CD80 (B7-1). PD-L1 is 
also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination 
by the host immune system. In the lymph nodes, PD-L1 on antigen presenting cells (APC) binding to 
PD-1 (CD279) or CD80 (B7-1) on activated T cells delivers an inhibitory signal to the T cell 6. 
Likewise, binding of CD80 on APCs to PD-L1 on T cells leads to inhibitory signaling in the T cell. 
These and bidirectional interactions between CD80 and PD-L1, expressed on both APCs and T 
cells, lead to further inhibition of T-cell activation. These interactions result in reduced T-cell 
activation and fewer activated T cells in the circulation. In the tumor microenvironment, PD-L1 
expressed on tumor cells binds to PD-1 on activated T cells reaching the tumor. This delivers an 
inhibitory signal to those T cells, preventing them from killing target tumor cells, and protecting the 
tumor from immune elimination7. 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types of 
cancer. In a number of these cancers, including lung
8, renal
9- 11, pancreatic
12-14, ovarian
15, and 
colorectal cancer16, the expression of PD-L1 is associated with reduced survival and unfavorable 
prognosis. In ovarian cancer, for example, the 5-year survival rate in patients with low levels of PD- 
L1 was 80.2%, compared to 52.6% in patients with high levels of PD-L115. In lung cancer, only 20% 
of patients with tumors expressing PD-L1 survived for more than 3 years, compared to 49% of 
patients with tumors lacking PD-L18. 
Based on these data, and on assessments of expression of PD-L1 on the surface of human tumors 
using proprietary immunohistochemistry methods for assessment, MEDI4736 has the potential to 
affect multiple types of solid tumors, including CRC. 
 
Blocking PD-L1 is a similar approach to that taken by ipilimumab (anti-CTLA-4), but has some 
potential advantages. Firstly, the expression of CTLA-4 and its ligands is restricted to the 
hematopoietic system; thus the site of action for molecules targeting CTLA-4 is solely the peripheral 
lymphoid organs. In contrast, PD-L1 is expressed not only on cells of the hematopoietic system but 
also on a range of tumor types. Targeting of PD-L1 could therefore have additional effects within the 
tumor microenvironment. Secondly CTLA-4 plays an early and critical role in controlling T-cell 
activation. This is reflected in the phenotype of CTLA-4 knockout mice, which die at an age of 


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Page 12 of 49 
 
 
 
 
between 3 and 4 weeks due to lymphoproliferative disease and tissue destruction. In contrast PD - 
L1, via binding to PD-1, acts later in the process of T-cell activation
17  and is considered more 
dispensable for the control of initial T-cell activation. This is reflected in the phenotype of PD-L1 
knockout mice, which are viable and have normal T-cell numbers and activation levels, but which 
have increased T-cell activation in response to antigen and increased susceptibility in certain 
autoimmunity models18,19. Similarly, PD-1 knockout mice show strain-specific phenotypes milder 
than those seen in CTLA-4 knockouts20,21. Based on these data, inhibition of PD-L1 would be 
expected to have reduced toxicity relative to inhibition of CTLA-4. In support of this, recent Phase 1 
clinical studies testing the tolerability of agents targeting PD-1 have shown a more favorable toxicity 
profile than ipilimumab22-24. 
3.3 IMMUNE THERAPY IN COLORECTAL CANCER 
 
3.3.1 TUMOR-INFILTRATING  LYMPHOCYTES 
 
The levels of TILs, and more specifically cytotoxic T cells, have been correlated to improved 
prognosis in CRC25, suggesting that an antitumor immune response is beneficial to patients. It has 
been shown in vitro that an antibody that blocks the interaction between PD-L1 and its receptors can 
relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor 
T cells26. Based on these findings, an anti-PD-L1 antibody could be used therapeutically to enhance 
the antitumor immune responses in patients with CRC characterized by increased TILs. 
3.3.2 DNA MISMATCH REPAIR DEFICIENCY 
 
dMMR CRC display increased rates of intragenic mutations of short, tandemly repeated DNA 
sequences known as microsatellites. These tumors are characterized by inactivation, mutational 
and/or epigenetic silencing of mismatch repair (MMR) genes. The primary function of the MMR 
system is to eliminate base-base mismatches and insertion/deletion loops that arise as a 
consequence of DNA polymerase slippage during DNA synthesis. As a result mutation rates in 
tumors characterized by MMR deficiency are 100- to 1,000-fold more common as compared to 
normal tissues. 
MMR deficiency is characteristic of the hereditary non-polyposis colorectal cancer (HNPCC) 
syndrome. HNPCC is an autosomal-dominant condition that accounts for approximately 2–3% of all 
CRC. In most cases, the inherited germline alteration is identified in one of the five human MMR 
genes: MSH2, MLH1, MSH6, PMS2, and PMS1. 
 
MMR deficiency can also occur in 10–15% of sporadic non-HNPCC colorectal cancers. In these 
patients, the basis for instability is usually an acquired hypermethylation of the MLH1 promoter with 
subsequent transcriptional silencing. MMR deficient sporadic colorectal tumors frequently 
accumulate mutations at microsatellite sequences in coding regions of specific genes that are 
implicated in tumor progression, such as TGFβRII, IGFIIR, MSH3, MSH6, and BAX. 
Clinically, MMR deficient CRC is characterized by a better prognosis and a lower frequency of 
distant metastases as compared to conventional CRCs. A dense infiltration with lymphocytes is a 
typical feature of MMR deficient CRCs, suggesting recognition by the host immune system. 
 
This ability of the immune system to recognize MMR deficient CRCs is attributed to the multiple 
frameshift peptides (FSPs) that are generated as a direct consequence of MMR deficiency and 


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represent tumor antigens that may be recognized as „„non-self‟‟ by the immune system and elicit an 
immune response of the host. 
 
3.3 
Description of MEDI4736 
 
MEDI4736 is briefly described below. Refer to the current Investigator‟s Brochure for details. 
 
3.3.1 
Product Derivation 
 
MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (MAb) directed 
against human PD-L1. MEDI4736 has an overall molecular weight of approximately 149 kDa, 
including N-linked oligosaccharides. The antibody is composed of 2 identical heavy chains of 
approximately 49,670 Da each, and 2 identical light chains of approximately 23,390 Da each. The 
fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant domain 
of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fcγ 
receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC)27. 
Subsequent to this triple mutation, the anticipated lack of MEDI4736-mediated antibody-dependent 
cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) were confirmed 
using cell-based functional assays. MEDI4736 is selective for recombinant PD-L1 and blocks the 
binding of recombinant PD-L1 to the PD-1 and CD80 receptors. 
 
3.3.2 
Summary of Nonclinical Experience 
 
MEDI4736 has shown the following activity as an anti-PD-L1 molecule: 
 
• 
MEDI4736 binds to PD-L1 and blocks its interaction with PD-1 and CD80 
• 
MEDI4736 can relieve PD-L1-mediated suppression of human T-cell activation in vitro 
• 
MEDI4736 or tremelimumab (an anti-CTLA-4 antibody) or the combination does not 
result in cytokine release when assessed in vitro in assays using whole blood from 
healthy human donors 
• 
MEDI4736 inhibits tumor growth in a xenograft model via a T-cell dependent mechanism 
• 
A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic 
tumor model as monotherapy and resulted in complete tumor regression in > 50% of 
treated mice when given in combination with chemotherapy 
• 
In the same study, anti-mouse PD-L1 antibody-treated mice were completely tumor free 
3 months after tumor implantation and demonstrated long-term immunity during re- 
challenge 
• 
In a subsequent study in the same syngeneic model, the combination of an anti-mouse 
PD-L1 antibody and anti-CTLA-4 antibody resulted in complete tumor regression in all 
mice treated 
• 
Prevalence of PD-L1 expression on the surface of human tumors ranging from 
approximately 0-35%, was demonstrated in a broad survey of samples derived from 
tumor types of interest 
 
The cynomolgus monkey is considered to be the only relevant nonclinical species for evaluation of 
local and systemic toxicities of MEDI4736. This conclusion was based on the high identity of amino 
acid sequence of extracellular domain (ECD) of cynomolgus monkey (cyno)PD-L1 and human 
(h)PD-L1 (95.9% identity), including the conservation of an amino acid in cynoPD-L1 that was 


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identified to be strongly involved in MEDI4736 binding to hPD-L1, and the similar binding affinity of 
MEDI4736 for cynoPD-L1 and hPD-L1. In addition, in vivo in cynomolgus monkeys, MEDI4736 
suppresses soluble (s)B7 H1 in serum and fully occupies membrane PD-L1 on various leukocyte 
subsets at doses equal to or more than 0.1 mg/kg (lowest dose tested) with a dose-related duration 
of suppression and occupancy. 
In general, there were no MEDI4736-related adverse effects in toxicology studies conducted in 
cynomolgus monkeys with MEDI4736 that were of relevance to humans. Adverse findings in the 
non-Good Laboratory Practice (GLP) PK/PD and dose range-finding study (4 doses over 5 weeks), 
and a GLP 4-week repeat-dose toxicity study were consistent with anti-drug antibody (ADA)- 
associated morbidity and mortality in individual animals. The death of a single animal in the non- 
GLP, PK/PD, and dose range-finding study was consistent with an ADA-associated acute 
anaphylactic reaction based on the presence of ADA within days of the first dose, acuteness and 
timing (after repeated dosing) of the death, clinical signs consistent with an anaphylactic reaction, 
lack of remarkable effects on other study parameters, and lack of histopathologic findings consistent 
with any other cause of death. In addition, the spectrum of findings, especially the microscopic 
pathology, in a single animal in the GLP, 4-week, repeat-dose study was also consistent with ADA- 
mediated effects; similar effects have been observed by MedImmune in cynomolgus monkeys 
administered other unrelated human monoclonal antibodies and immune-complexes were identified 
in the affected animal in a subsequent investigative study. Given that immunogenicity of human 
monoclonal antibodies in nonclinical species is not generally predictive of responses in humans, the 
ADA-associated morbidity and mortality were not taken into consideration for the determination of 
the no-observed-adverse-effect level (NOAEL) of MEDI4736, which was 100 mg/kg, the highest 
dose tested in these studies. 
 
The existing body of knowledge suggests that many tumors express PD-L1 in order to suppress or 
evade immune-mediated elimination. To aid in the prioritization of tumor types for inclusion in the 
CD-ON-MEDI4736-1108 study, a wide array of tumor specimens were surveyed for surface 
expression of PD-L1 and found to vary significantly in both the level of expression across tumor 
types as well as in the prevalence of expression within a tumor type. Tumor types with a wide range 
of target expression levels and prevalence of expression were selected for this study in order to test 
the relevance of PD-L1 surface expression in mediating responses to MEDI4736. 


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3.3.3 
Summary of Clinical Experience 
 
To date (as of 18 Feb 2014), 221 subjects have been enrolled and treated in 5 ongoing clinical 
studies of MEDI4736 (2 employing MEDI4736 as monotherapy and 3 as combination therapy) and 
no studies have yet been completed. The majority of the clinical safety data in this IB are from Study 
CD-ON-MEDI4736-1108, which has the greatest number of enrolled subjects as of 18Feb2014. 
Monotherapy Studies: 
• 
Study CD-ON-MEDI4736-1108 is a Phase 1, first-time-in-human (FTIH), multicenter, open- 
label, dose-escalation, and dose-expansion study to determine the maximum tolerated dose 
(MTD) or optimal biologic dose (OBD), safety, PK, immunogenicity, and antitumor activity of 
MEDI4736 in adult subjects with advanced solid tumors refractory to standard therapy or for 
which no standard therapy exists (N = 198 subjects). 
 
• 
Study D4190C00002 is a Phase 1 open-label, dose-escalation and dose-expansion study of 
MEDI4736 in Japanese adult subjects with advanced solid tumors (N =8 subjects). 
Combination Therapy Studies: 
• 
Study D4190C00006 is a Phase 1b open-label, dose-escalation, and dose-expansion study 
of MEDI4736 in combination with tremelimumab in adults with advanced non-small cell lung 
cancer (NSCLC) (N = 7 subjects). 
• 
Study CD-ON-MEDI4736-1161, is an open-label, dose-escalation study of MEDI4736 in 
combination with both dabrafenib and trametinib or in combination with trametinib in adults 
with metastatic melanoma (N = 5 subjects, but no safety data are yet available). 
• 
Study LUD2013-003 is an open-label dose-escalation and dose-expansion study of 
MEDI4736 in combination with tremelimumab in adults with advance solid tumors (N = 3 
subjects, but no safety data are yet available). 
3.3.3.1 
Monotherapy Studies 
Study CD-ON-MEDI4736-1108 
As of 18Feb2014 in Study CD-ON-MEDI4736-1108, a total of 198 subjects have been treated with at 
least one dose of MEDI4736 (ranging from 1 to 27 doses). Of these, 
177 subjects received MEDI4736 10 mg/kg every 2 weeks (Q2W). This study has a dose- escalation 
and a dose-expansion phase. For the purpose of this IB, the safety data were combined from all 177 
subjects treated with the 10 mg/kg Q2W regimen of MEDI4736 (i.e., data from subjects receiving 10 
mg/kg Q2W from both dose escalation and dose expansion were combined). In addition, 21 subjects 
have been enrolled in the following dose-escalation cohorts: 4 subjects in each of the 0.1, 0.3, and 1 
mg/kg Q2W cohorts; 3 subjects in the 3 mg/kg Q2W cohort, and 6 subjects in the 15 mg/kg Q3W 
cohort. 


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Focusing on the largest cohort (177 subjects treated with 10 mg/kg MEDI4736 Q2W), the most 
frequently reported (≥ 10% of subjects) treatment-emergent adverse events (TEAEs) regardless of 
grade or causality were fatigue, dyspnea, nausea, constipation, and decreased appetite. The 
majority of TEAEs were Grades 1 to 2 in severity and manageable by the general treatment 
guidelines as described in the current MEDI4736 study protocols. The Grade 3 or higher TEAEs 
occurring in 2 or more subjects included dyspnea, dehydration, abdominal pain, fatigue, sepsis, 
increased aspartate aminotransferase, increased gamma- glutamyltransferase, hyperbilirubinemia, 
back pain, pulmonary embolism, respiratory failure, hypotension, and “progression of disease” 
(verbatim term). Treatment-related TEAEs (all grades) occurring in 2 or more subjects were fatigue, 
nausea, dyspnea, diarrhea, vomiting, pyrexia, myalgia, hypothyroidism, decreased appetite, 
dizziness, cough, pruritus, rash, abdominal pain, increased aspartate aminotransferase, arthralgia, 
asthenia, influenza-like illness, edema peripheral, increased alanine aminotransferase, headache, 
and dry skin. The SAEs reported for 3 or more subjects were dyspnea, dehydration, abdominal pain, 
and sepsis. Three subjects had treatment-related SAEs: arthralgia (1 subject); pleural effusion and 
pneumonitis (both in the same subject); and muscular weakness and “rule out cord compression” 
(verbatim term) (both in the same subject). For the entire study population, none of the deaths or 
TEAEs resulting in discontinuation of MEDI4736 in this study were considered related to MEDI4736. 
No dose-limiting toxicities (DLTs) have been reported. 
Partial efficacy data are available for Study CD-ON-MEDI4736-1108. Tumor assessments were 
based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines with 
modifications for subjects in the dose-expansion phase. Of the 177 subjects treated with MEDI4736 
10 mg/kg Q2W, 77 have had at least one post-baseline disease assessment as of 18Feb2014. Four 
subjects (5.2%) had a best response of PR (unconfirmed). In addition, 36 subjects (46.8%) had 
stable disease. 
As of 18Feb2014, PK and pharmacodynamic data were available for the first 32 subjects following 
IV dosing of MEDI4736 in Study CD-ON-MEDI4736-1108. MED4736 exhibited nonlinear PK likely 
due to saturable target-mediated clearance. Significant target engagement, as measured by soluble 
PD-L1 (sPD-L1) suppression, was observed following dosing in all individuals tested. Screening for 
ADA has detected positive samples from 3 of the 31 subjects tested, with evidence for an impact on 
PK and target suppression in 1 individual. 
Study D4190C00002 
In Study D4190C00002, 8 subjects have been enrolled and treated with MEDI4736 
(1 or 3 mg/kg Q2W) as of 18Feb2014. The TEAEs reported for more than 1 subject were 
constipation, nausea, vomiting, and nasopharyngitis (each in 2 subjects). All reported TEAEs were 
Grade 1 or 2. No subjects have discontinued from treatment because of AEs, and no DLTs, or 
deaths have been reported in this study. 
3.3.3.2 
Combination Therapy Studies 
 
In Study D4190C00006, preliminary safety data as of 18Feb2014 are available for 7 subjects treated 
with MEDI4736 and tremelimumab. The only TEAE reported for more than 1 subject was fatigue (3 
subjects). All TEAEs were Grade 1 or 2 with the exception of one Grade 3 event of increased 
aspartate aminotransferase. One subject in this study (MEDI4736 3 mg/kg with 1 mg/kg 
tremelimumab) was discontinued from treatment because of an SAE of “disease progression” 
(verbatim term). No DLTs or deaths have been reported in this study. 


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3.4 
CLINICAL EXPERIENCE WITH OTHER MONOCLONAL ANTIBODIES 
TARGETING THE PD-L1/PD-1 PATHWAY 
Other MAbs currently in development that target the PD-1/PD-L1 pathway have shown evidence of 
clinical activity. An antagonist of PD-1, the primary PD-L1 receptor, has a related mechanism of 
action to MEDI4736 and is under development. A Phase 1 clinical study of this antagonist (MDX- 
1106 or BMS-936558) was recently conducted in 39 subjects22. No dose-limiting toxicities (DLTs) 
were observed and an MTD was not identified. One durable complete response (CR) in CRC, 2 
partial responses (PRs) in RCC and melanoma, and 2 mixed responses were observed. In a larger 
Phase 1 study of BMS-936558 (MDX-1106) in 296 subjects, objective responses were seen in 
NSCLC (18%), melanoma (28%), and RCC (27%). Antitumor activity was observed at all dose levels 
and in several cases, these responses appeared to be durable, with responses ongoing past 2 
years28. No objective responses were reported in 19 subjects with CRC. The most common 
treatment-related AEs of any grade observed during this study were fatigue (24%), rash (12%), 
diarrhea (11%), and pruritus (10%). Immune-mediated AEs of Grade 3 or higher occurred in 6% of 
subjects and included pneumonitis (1%), diarrhea (1%), alanine aminotransferase (ALT) increased 
(1%), and aspartate aminotransferase (AST) increased (1%). Based on the activity seen during this 
large Phase 1 study, BMS-936558 is being evaluated in 5 Phase 3 studies as of March 2013. 
 
Evidence of activity has also been reported from a Phase 1 clinical study of the anti-PD-L1 antibody, 
BMS-936559 (MDX-1105)
22. In this study of 207 subjects, objective responses were seen in 
melanoma (17%), NSCLC (10%), RCC (12%), and ovarian cancer (6%) at all doses of 1 mg/kg or 
higher. These responses also appear to be durable, with ongoing responses reported out beyond 23 
months. No objective responses were reported in 18 subjects with CRC. The most commonly 
observed treatment-related AEs of any grade were similar to those observed with BMS-936558 and 
included fatigue (16%), infusion-related reaction (10%), diarrhea (9%), rash (7%), arthralgia (7%), 
pruritus (6%), and nausea (6%). Immune-mediated AEs of Grade 3 or higher occurred in 5% of 
subjects. 
 
Preliminary data from the dose-escalation study of MPDL3280a, another anti-PD-L1 antibody in 
development, was recently presented29 . In this dose-escalation study of 30 subjects, antitumor 
activity was observed in subjects with NSCLC, CRC, SCCHN, RCC, melanoma, gastric, and 
pancreatic cancer. The most common AEs of any grade included fatigue (67%), nausea (50%), 
diarrhea (43%), decreased appetite (40%), chills (37%), pyrexia (37%), dyspnea (33%), headache 
(33%), pain (33%), cough (30%), and night sweats (30%). Three patients experienced Grade 3 or 4 
events including asthenia, colitis, and rash. No pneumonitis was reported and no MTD was 
identified. Taken together, the experience to date with anti- PD-1/PD-L1 MAbs suggests that these 
agents can provide significant clinical activity across a range of tumor types with a manageable 
safety profile that is superior to that of the anti-CTLA-4 class. 
Studies of other agents targeting the PD-1/PD-L1 pathway are also in early-stage development with 
limited data available. CT-011 (anti-PD-1 MAb), has been evaluated in a Phase 1 study in advanced 
hematologic malignancies24. In this study of 17 subjects, CT-011 was well tolerated and no 
treatment-related toxicities were reported. No MTD was identified in this population and clinical 
benefit was observed in 33% of subjects. MK-3475 (anti-PD-1 MAb) is being evaluated in Phase 1 
and 2 studies, with objective responses reported in NSCLC and melanoma30. MPDL3280A 
(anti-PD-L1) and AMP-224 (anti-PD-1 fusion protein) are also being evaluated in Phase 1 clinical 
studies as monotherapy as well as in combination with standard-of-care chemotherapy. 


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3.5 
RATIONALE FOR DEVELOPING IMMUNE THERAPIES IN COLORECTAL CANCER 
 
The development of immune therapy in CRC is compelling for several reasons: (1) we have 
described that genetic instability in CRC leads to a diverse number of mutations, each a potential 
target for a T-cell mediated anti-tumor immune response 31; (2) several investigators have shown 
that effector/memory T-cells infiltrate CRC tumors and have prognostic value 
25,32; and (3) dMMR 
CRC is associated with a profound anti-tumor immune response with evidence of TILs. These 
tumors are immunogenic because they express tumor antigens generated due to frame shift 
mutations caused by insertion/deletions at coding microsatellites. Clinically, these patients usually 
have a more favorable prognosis, possibly from a protective immune response 33-35. 
3.6 
RESEARCH HYPOTHESIS 
 
The objective of this Phase II study is to determine clinical efficacy and safety of MEDI4736 in 
immunological subsets of advanced CRC. Subsets will be prespecified to ensure that we include 
those tumor-types, considered to be immunogenic and therefore more likely to be effectively  
targeted by an augmented immune response. These include patients with dMMR and/or pre-existing 
TILs. 
The research hypothesis is that MEDI4736 will be adequately tolerated in subjects with CRC and 
that such administration will result in clinical benefit. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single arm, phase II study. It will be conducted to determine the efficacy and safety of 
MEDI4736 in the treatment of immunological subsets of advanced CRC. These subsets will be pre- 
specified to ensure that we include those tumor-types, considered to be immunogenic and therefore 
more likely to be effectively targeted by an augmented immune response. These include patients 
with dMMR and/ or pre-existing TILs. 
 
4.3 
Intervention 
 
Subjects with dMMR CRC will enroll into cohort 1 and subjects with TIL+ CRC will enroll into cohort 
2). dMMR status will supersede TIL+ status. All subjects will receive MEDI4736 via IV infusion at 10 
mg/kg every two weeks (Q2W), as determined from the ongoing phase I study, which is currently 
enrolling patients into expansion cohorts at this dose. Subjects will continue treatment at Q2W for 12 
months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, 
or other reasons to discontinue treatment occur. 
 
Following the 12-month treatment period, subjects without evidence for progressive disease or other 
reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD 
(with or without confirmation according to RECIST 1.1) during the monitoring period, administration 
of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The subject will re- 
sign consent form prior to retreatment. The same treatment guidelines followed during the initial 12- 
month treatment period will be followed during the retreatment period, including the same dose and 
frequency of treatments and the same schedule of assessments. Treatment of isolated, non-target, 


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lesions for palliative/ therapeutic intent is acceptable after discussion with the Principal Investigator 
(e.g.: by ablation, surgery or radiation). 
 
Tumor measurements and determination of tumor responses for this study will be performed 
according to RECIST 1.1. 
Subjects may continue to receive MEDI4736 beyond radiographic progression in the absence of 
clinical deterioration, and after discussion with the Principal Investigator. All subjects will be followed 
for survival for up to 2 years. 
 
Exploratory research studies to evaluate the effect of this therapy will be performed in patients using 
research blood draws, and tumor biopsy at baseline and week 8 for research purposes. 
 
4.3 Estimated Duration of Subject Participation 
 
Subjects will be treated until PD, initiation of alternative cancer therapy, unacceptable toxicity, or 
other reasons to discontinue treatment. All subjects will be followed for survival for up to 2 years 
unless the Principal Investigator decides to end the study. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
MedImmune will provide the investigators with adequate quantities of investigational product. 
 
MEDI4736 is supplied as a lyophilized powder containing 200 mg MEDI4736. When reconstituted 
with 4.0 mL of water for injection (WFI), the solution contains 50 mg/mL MEDI4736, 26 m M 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, at 
pH 6.0. 
5.1 
Storage of  MEDI4736 
 
MEDI4736 will be stored at 2-8°C (36-46°F) in a secure area with restricted access. 
 
5.2 
Preparation and Dosing Instructions for MEDI4736 
 
The dose of investigational product for administration must be prepared by the investigator‟s or site‟s 
designated investigational product manager using aseptic technique. Commercially available WFI 
and 0.9% (w/v) saline will be supplied by each site. Total in-use storage time from reconstitution of 
MEDI4736 to start of administration should not exceed 4 hours at room temperature or 24 hours at 
2-8°C (36-46°F). If in-use storage time exceeds these limits, a new dose must be prepared from new 
vials. MEDI4736 does not contain preservatives and any unused portion must be discarded. 
Reconstitution of investigational product 
MEDI4736 requires reconstitution prior to use. The reconstitution should be performed with 4.0 mL 
sterile WFI for each vial with the liquid added gently to the side of the vial to minimize product 
foaming. The vial should be gently rotated or swirled for 5 minutes or until dissolution is complete. 
The vial should not be shaken or vigorously agitated. Reconstituted MEDI4736 should stand 
undisturbed at room temperature for a minimum of 5 minutes or until the solution clarifies. The 
reconstituted solution should appear clear or slightly opalescent. A thin layer of bubbles on the liquid 
surface is considered normal. 


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Doses will be administered using a 250 mL IV bag containing 0.9% (w/v) saline and delivered 
through an IV administration set. The volume of reconstituted MEDI4736 to add to the IV bag is 
calculated as follows: 
 
Volume of MEDI4736 (mL) = 
 
Dose (10 mg/kg) × Subject Weight (kg) ÷ MEDI4736 Concentration (nominal 50 mg/mL) 
 
Subject weight at baseline should be used for dosing calculations unless there is a ≥ 10% change in 
weight. An additional volume of 0.9% (w/v) saline equal to the calculated volume of MEDI4736 to be 
added to the IV bag must be removed from the bag prior to addition of MEDI4736. The calculated 
volume of MEDI4736 is then added to the IV bag, and the bag is mixed by gentle inversion to ensure 
homogeneity of the dose in the bag. Following preparation of the dose, the entire contents of the IV 
bag should be administered as an IV infusion over approximately 60 minutes, using a 0.2-μm in-line 
filter. Flush the IV line with a volume of normal saline equal to the priming volume of the infusion set 
used after the contents of the IV bag are fully administered, or complete the infusion according to 
institutional policy to ensure the full dose is administered and document if the line was not flushed. 
 
Example: For a subject weighing 80 kg and dosed at 10 mg/kg, 16.0 mL [10 mg/kg × 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted in a 250 mL IV bag containing 0.9% (w/v) saline. First, 
16.0 mL of saline is removed from the IV bag, and then 16.0 mL of MEDI4736 is added to the bag. 
The bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag and the diluted 
MEDI4736 is administered as described above. 
5.3 
Dosing Instructions and Schedule 
 
The first day of dosing is considered Day 1. Subjects will receive MEDI4736 as an IV infusion over 
approximately 60 minutes. The IV line will be flushed with a volume of normal saline equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully administered 
(unless prohibited by institutional practice). 
 
Since the compatibility of MEDI4736 with other IV medications and solutions, other than normal 
saline (0.9% [w/v] Sodium Chloride for Injection), is not known, the MEDI4736 solution should not be 
infused through an IV line in which other solutions or medications are being administered. The date, 
start time, interruption, and completion time of MEDI4736 administration must be recorded in the 
source documents. 
 
5.3.1 
Monitoring of Dose Administration 
 
Subjects will be monitored during and after infusion with assessment of vital signs per institutional 
practice. 
 
In the event of Grade ≤ 2 infusion-related reaction, the infusion rate of MEDI4736 may be decreased 
by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial 
rate until completion of the infusion. In subjects experiencing ≤ Grade 2 infusion reaction, 
subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an 
antihistamine (e.g., diphenhydramine) and/or corticosteroids or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the infusion reaction 
is Grade 3 or higher in severity, treatment with MEDI4736 will be discontinued. 


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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 subjects 
to an intensive care unit if necessary. 
5.5 
Concomitant Medications 
 
5.5.1 
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 5.5.2. 
Treatment of isolated lesions for palliative or curative intent is acceptable after discussion with the 
Principal Investigator (e.g., by local surgery, ablation or radiotherapy). 
5.5.2 
Excluded Concomitant Medications 
 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study. The Principal Investigator 
must be notified if a subject receives any of these during the study. 
• 
Any investigational anticancer therapy 
• 
Any concurrent chemotherapy (except as permitted above), immunotherapy, or biologic 
therapy. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable. 
• 
Immunosuppressive medications including, but not limited to systemic corticosteroids (>10 
mg/day prednisone or equivalent), methotrexate, azathioprine, and tumor necrosis factor 
alpha (TNF-α) blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs, in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted 
• 
Live attenuated vaccines within 30 days of MEDI4736 dosing 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
1. Written informed consent obtained. 
 
2. Histologically- or cytologically- confirmed CRC. 
 
3. Pre-existing Tumor-Infiltrating Lymphocytes in an archived tumor specimen or fresh biopsy, 
defined as an average of ≥4 TILs/ High Power Field (HPF) in 5 consecutive HPFs, within the 
area with the highest TILs at low power; or, DNA mismatch repair deficiency, determined by 
immunohistochemistry or polymerase chain reaction per MSKCC institutional standard 
practice. DNA mismatch repair deficient tumors may be TIL positive or negative. 


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4. Locally advanced or metastatic CRC. 
 
5. Subjects have received two or more standard available therapies known to prolong survival 
and for which they would be considered eligible. At a minimum, such therapies should 
include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine 
(e.g., FOLFOX and FOLFIRI or their variants). 
6. Age ≥ 18 years at time of study entry. 
 
7. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. 
 
8. Adequate organ and marrow function as defined below: 
 
• 
Absolute neutrophil count ≥ 1,500/mm3. 
• 
Platelet count ≥ 90,000/mm3. 
• 
AST and ALT ≤ 3 × institutional upper limit of normal (ULN) or ≤ 5 × ULN for subjects 
with liver metastases. 
• 
Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with documented/suspected Gilbert‟s 
disease. 
 
• 
Serum creatinine ≤ 1.5 x ULN; 
 
9. Radiographically measurable disease per RECIST 1.1. 
 
10. Life expectancy ≥ 16 weeks. 
 
11. Willingness to provide consent for use of archived tissue for research purposes. 
 
12. Subjects will be required to agree to a biopsy performed at baseline and again at week 8 of 
the study in order to be eligible for enrollment in stage 1 of the study. 
13. Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use 2 methods of effective contraception from screening, and must agree to continue 
using such precautions for 90 days after the final dose of investigational product; cessation of 
birth control after 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 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative 
medical cause). 
• 
Subjects must use 2 acceptable methods of effective contraception as described in 
below. 
14. Nonsterilized males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception from Day 1 and for 90 days after 
receipt of the final dose of investigational product. 


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Table 6.1 
Effective Methods of Contraception (Two Methods Must be Used) 
 
 
 
 
 
 
 
 
 
 
a This is also considered a hormonal method. 
 
6.3 
Subject Exclusion Criteria 
 
1. Anticancer therapy, monoclonal antibody or major surgery within 4 weeks prior to the first 
dose of MEDI4736. 
• 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable. 
 
2. Any prior Grade ≥ 3 irAE while receiving immunotherapy (including anti-CTLA-4 or anti- 
CD137 MAb) or any unresolved irAE of any grade (controlled irAE endocrinopathies are 
allowed). 
 
3. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody. 
 
4. Current or prior use of immunosuppressive medication within 28 days before the first dose of 
MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or 
an equivalent corticosteroid. 
 
5. Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy. 
 
6. Active autoimmune disease within the past 2 years, except for mild conditions not requiring 
systemic treatment, such as vitiligo. 
 
7. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment. NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative 
intent is acceptable (e.g., by local ablation, surgery or radiotherapy). 
 
8. Active or prior documented inflammatory bowel disease (e.g., Crohn‟s disease, irritable 
bowel syndrome, ulcerative colitis). 
 
9. Receipt of radiation therapy within 4 weeks prior to starting investigational product, or limited 
field of radiation for palliation within 2 weeks of the first dose of investigational product. 
 
10. Known allergy or reaction to any component of the MEDI4736 formulation or its excipients. 
 
11. Known central nervous system (CNS) metastases requiring treatment, such as surgery, 
radiation or steroids. 
 
12. Known history of confirmed primary immunodeficiency. 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
• 
Male condom plus 
spermicide 
• 
Cap plus spermicide 
• 
Diaphragm plus 
spermicide 
• 
Copper T 
• 
Progesterone T 
a
 
• 
Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena®) a 
• 
Implants 
• 
Hormone shot or 
injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 


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Page 24 of 49 
 
 
 
 
13. History of organ transplant requiring therapeutic immunosuppression. 
 
14. Other malignancy within 3 years, except for noninvasive malignancies such as cervical 
carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ 
(DCIS) of the breast that has/have been surgically cured, or prior malignancy considered by 
the investigator to be of low likelihood for recurrence. 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses 
including any patient known to have active hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit 
compliance with study requirements or compromise the ability of the patient to give written 
informed consent. 
 
16. Women who are pregnant, breast-feeding or male or female patients of reproductive 
potential who are not employing an effective method of birth control. 
 
17. Any other condition(s) that, in the opinion of the investigator, would interfere with evaluation 
of the investigational product or interpretation of subject safety or study results . 
 
18. Subjects who are known to be HIV positive. 
 
 
19. Receipt of live attenuated vaccination within 30 days prior to receiving MEDI4736. 
 
 
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 IRB-approved informed consent form prior to 
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 28 days of starting therapy: 
 
• 
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 may be perfromed. Non-contrast CT CAP may be used if the target 
lesion(s) do not require contrast for accurate measurements. 
 
• 
12-lead Electrocardiogram (EKG). 


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• 
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. If the test result is positive related 
to pregnancy, the patient will not be allowed to participate in this study. 
• 
CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, CO2, 
and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, albumin, total 
protein, and CEA 
• 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (negative test acceptable prior to 
screening period) 
 
• 
Blood test for research purposes (for patients enrolled in stage 1 only). 
 
• 
Perform pre-treatment tumor biopsy for research purposes (for patients enrolled in stage 1 only). 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Eligible patients will receive the following treatment every two weeks 
 
• 
MEDI4736 at 10 mg/kg i.v. over approximately 60 minutes. 
 
A treatment may be moved ± 3 days for administrative reasons, including clinic closure for holidays. 
A cycle constitutes one completed administration of MEDI4736. 
Patients will be seen the day of administration of MEDI4736.  A medical history, with particular 
reference to toxicities, including medication review, and physical examination will be conducted at 
each treatment visit. 
Laboratory parameters for treatment on Cycle #1, Day #1 are: 
 
• 
Absolute Neutrophil Count  1500/mm3 
 
• 
Platelet Count  90,000/mm3 
• 
AST and ALT ≤ 3 × ULN or ≤ 5 × ULN for subjects with liver metastases 
• 
Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with Gilbert‟s disease 
• 
Serum creatinine ≤ 1.5 x ULN 
 
Laboratory parameters for subsequent treatments are as follows: 
 
• 
Absolute neutrophil count  1000/mm3 
 
• 
Platelet count  75,000/mm3 
• 
AST and ALT ≤ 3 × ULN or ≤ 5 × ULN for subjects with liver metastases 
• 
Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with Gilbert‟s disease 


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Page 26 of 49 
 
 
 
 
 
• 
Serum creatinine ≤ 1.5 x ULN 
 
If the above parameters are not met, then treatment should be delayed one week (± 3 days) until 
recovered, up to a maximum of 30 days delay. Re-treat as per section 10.1, Dose delay/ 
modification. 
 
9.2 
RESEARCH  BLOOD AND BIOPSY SPECIMENS 
 
9.2.1 Research blood 
 
For patients enrolled in stage 1, blood specimens will be obtained for research purposes within 28 
days prior to treatment or on Day 1, then Week 2, Week 4, and week 8. 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. Whole blood (PAXgene DNA) will be collected from all 
subjects at baseline only (appendix A). Peripheral blood mononuclear cells and plasma will then be 
isolated per institutional practice in the Immune Monitoring Facility (IMF). 
9.2.2 Research biopsy 
For patients enrolled in stage 1, a pre-treatment tumor biopsy will be obtained from an accessible 
metastatic or primary lesion within 28 days of starting treatment and then again at week 8 (± 1 wk). If 
this is done by an interventional radiology or surgical procedure, then informed consent for the will  
be required per standard institutional practice. Where applicable, the same tumor lesion should be 
biopsied at baseline and on-treatment. 
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, the procedure is deemed to be unsafe, or if the patient refuses. 
Tumor lesion planned for biopsy may be an index lesion if  2 cm in at least one diameter. 
If clinically practical, subjects will undergo 5 core biopsies.  Two 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 . The fifth core biopsy will be placed in culture medium  to isolate tumor 
infiltrating lymphocytes or for cell culture (appendix B). 
If the patient undergoes a routine procedure, tissue may be obtained for future correlative analyses. 
Up to 20 x 5m slides (unstained) may be obtained from each routine procedure where tissue was 
extracted.  Tissue from routine procedures may be sent directly to the IMF facility for immediate 
processing (e.g. isolation of Tumor Infiltrating Lymphocytes). 
 
 
9.2 
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. 
9.2.1 
Whole Blood 


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Whole blood (PAXgene DNA) will be collected from all subjects enrolled in stage 1 at baseline and 
may be used to generate genomic DNA for SNP genotyping or genome sequencing. Genotyping 
analyses will focus on SNPs within genes associated with immunity (e.g. Fc gamma receptor genes) 
and with other immunoregulatory signaling pathways to explore the possibility that natural variation 
within those genes is associated with response to MEDI4736 therapy and/or with adverse events 
observed during treatment. HLA genotyping may be completed to support additional analyses 
described below. 
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 CD8+ 
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 IFNγ. 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 (MDSCs), a cell type which appears 
to negatively impact  anti-tumor activity and which has been shown to promote immune escape by 
limiting activated CD8 T-cell infiltration into the tumor microenvironment36. 
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. 
9.2.2 
Plasma 
To understand the prevalence of circulating proteins and the impact they may have on the clinical 
activity and/or safety of MEDI4736 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 IFNγ 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 Invitrogen‟s Protoarray platform(c). Levels of sPD-L1 in peripheral blood may also 
be assessed. 
9.2.3 
Tissue Biopsies and/or archived tissue 
 
The presence of TILs within tumors in response to MEDI4736 treatment will be evaluated baseline 
and on-treatment biopsies and, when feasible, tissue acquired from routine procedures. Archived 
tissue (up to 20 x 5 m slides), tissue acquired from routine procedures (up to 20 x 5 m slides per 
procedure), 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 


Memorial Sloan Kettering Cancer Center 
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Approval date: 09-Apr-2019 
Page 28 of 49 
 
 
 
 
cancer-interacting lymphocytes derived from biopsied material. Other biomarkers may be evaluated 
as determined by additional data. Remaining specimens may be stored for future studies related to 
MEDI4736/ CRC immunity. 
 
 
10.0     EVALUATION DURING TREATMENT/INTERVENTION 
 
STUDY CALENDAR 
 
Period 
Screening 
Treatment 
Monitoring14 
End of 
study 
visit13 
Cycle1 
<28 days2 
1 
2 
3 
4 
5 
6 
7+ 
Months <12 
Month 12+ 
Week 
0 
2 
4 
6 
8 
10 
12+ 
1 
Even 
Q3M 
Informed consent 
x 
Medical history 
x 
EKG 
x 
CT/MRI3 
x 
x 
x 
x 
x 
Height4 
x 
Physical examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs/4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Performance status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Report medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Report side effects 
x 
x 
x 
x 
x 
x 
x 
x15 
x 
CBC5,6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comp5,7 
x 
x 
x 
odd 
cycle 
x 
x 
Thyroid function (TSH, 
fT3,fT4) 
x 
x 
x 
odd 
cycle 
x 
CEA8 
x 
x 
x 
x 
x 
x 
x 
x 
Hepatitis B and C9 
x 
Pregnancy test if female 
(Serum) 
x 
Research blood tests 5,10 
x 
x 
x 
x 
Research tumor biopsy11 
x 
x 
Obtain archived tissue12 
x 
MEDI4736 
x 
x 
x 
x 
x 
x 
x 
1. 
Each cycle is approximately 2 weeks in duration, corresponds to 1 completed treatment. 
2. 
These procedures must be performed within 28 days prior to starting protocol treatment on Cycle 1/Day 1. 
3. 
CT scan (chest, abdomen and pelvis) will be performed during screening, then at 8 week (±1 wk) intervals and at final 
visit if more than 4 weeks from prior imaging. If patient is unable to receive CT contrast or the abdominal/pelvic target 
lesion is indeterminate on CT then MRI with contras t (abdomen and pelvis) plus CT without contrast (chest) may be 
performed. Imaging may be delayed up to 2 weeks if patient is receiving local therapy, such as radiation. During the 
monitoring phase, CT scans will be performed every 8 weeks (+1wk) for the first 12 months then every 3 months (+2 
wks). After 24 months in the monitoring phase, follow up visits and scans can be performed up to every 6 months or 
per investigator discretion. 
4. 
Vital signs to include heart rate, respiratory rate, blood pressure , and weight. 
5. 
Blood to be collected prior to dosing any study medications. 
6. 
Hematology to include standard complete blood cell (CBC) panel. 
7. 
Comprehensive metabolic panel included sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total 
protein, albumin, bilirubin, alkaline phosphatase, AST, ALT, calcium. 


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8. 
CEA to be obtained at baseline, then approximately every 4 weeks during treatment. During the monitoring phase, 
CEA to be obtained every 8 weeks (+1wk) for the first 12 months then every 3 months (+2 wks). After 24 months in the 
monitoring phase, CEA can be obtained up to every 6 months or per investigator discretion. 
9. 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (unless previously tested negative). 
10. Blood draws for research purposes will be performed during screening/ day 1, then weeks 2, 4, and 8 for patients in 
stage 1 only. 
11. Tumor biopsy for research purposes will be performed at baseline and wk 8 (±1 wk) for patients in stage 1 only. 
12. Up to 20 x 5 m slides (unstained) of archived tissue will be requested on all patients for research purposes . For 
patients undergoing routine procedures during the study, additional tissue (up to 20 x 5 m slides (unstained)) may be 
obtained from each routine procedure for research purposes 
13. EOS visit occurs 2-4 weeks after last dose of MEDI4736. CT scan OR MRI to be done only if last imaging was 
conducted greater than four weeks prior to the date of the Final Visit. 
14. Monitoring phase time points are based on time since last dose of MEDI4736 . Evaluations will be performed every 2 
months +/-1 week for the first 12 months then every 3 months +/-2 weeks. After 24 months in the monitoring phase, 
evaluations can be performed up to every 6 months or per investigator discretion. 
15. After the end of treatment, each subject will be followed for 30days for adverse event monitoring. Serious adverse 
events will be collected for 90 days after the end of treatment. 


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10.1 
Dose delay/ modification 
 
Following the first dose of MEDI4736, subsequent administration of MEDI4736 should be modified 
based on toxicities observed as described in Table 10.1 (below). All toxicities will be graded 
according to NCI CTCAE v4.03. Dose reductions are not permitted. Dose modifications will not be 
required for AEs that are clearly not attributed to MEDI4736. 
 
Based on the mechanism of action of MEDI4736, potential irAEs may be similar to those seen with 
the use of ipilimumab and MDX-1106 including immune-mediated enterocolitis, dermatitis, hepatitis, 
and endocrinopathies
22,37. Subjects should be monitored for signs and symptoms of irAEs. In 
absence of alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune related. It is recommended that 
management of such irAEs follow table 10.2 and the guidelines outlined for ipilimumab38. 


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Table 10.1 
MEDI4736 Dose Modification Due to Toxicity 
 
Immune-related Adverse Events (irAEs) a 
All Other Events 
Grade 1 
None required. 
None required. Up to 2 sequential doses may 
be skipped at the discretion of the investigator 
For infu sion -re la te d rea ctions: Refer to 
section 5.3.1 
Grade 2 
For  endocrinopathy: 
Hold MEDI4736 when endocrinopathy is controlled, resume 
MEDI4736 administration at next scheduled dose 
For de rma tologic irAEs: 
MEDI4736 may be dosed at the next scheduled time point 
For pneumonitis: 
Hold MEDI4736 until resolution to ≤Grade 1. If resolution to 
≤ Grade 1 occurs within 3 days of the initiation of maximal 
supportive care (including corticosteroids), resume 
MEDI4736 administration at next scheduled dose. 
Otherwise, discontinue MEDI4736 
For a ll othe r irAEs: 
Hold MEDI4736 until resolution to ≤ Grade 1. If resolution 
to ≤ Grade 1 does not occur within 30 days, discontinue 
MEDI4736 
For infu sion -re la te d rea ctions: Refer to 
section 5.3.1 
For a ll othe r AEs: 
No dose adjustment is required. Up to 2 
sequential doses may be skipped at the 
discretion of the investigator 
Grade 3 
For e ndocrinopa thy : 
Hold MEDI4736 when endocrinopathy is controlled, resume 
MEDI4736 administration at next scheduled dose 
For de rma tologic irAEs: 
Hold MEDI4736 until resolution to ≤ Grade 1 or baseline. 
• 
If resolution to ≤ Grade 1 or baseline does not occur 
within 30 days, discontinue MEDI4736 
For e le va tions in tra nsa mina se s: 
• 
For elevations in transaminases up to 8 × ULN, hold 
MEDI4736 until resolution to ≤ Grade 1 or baseline. If 
elevations downgrade to ≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline within 14 days, 
resume MEDI4736 administration at next scheduled 
dose. Otherwise, discontinue MEDI4736 
• 
For elevations > 8 × ULN, discontinue MEDI4736 
For e le va tions in bilirubin: 
• 
For elevations in bilirubin up to 5 × ULN, hold 
MEDI4736 until resolution to ≤ Grade 1 or baseline. If 
elevations downgrade to ≤ Grade 2 (< 3 × ULN) within 
7 days or resolve to ≤ Grade 1 or baseline within 14 
days, resume MEDI4736 administration at next 
scheduled dose. Otherwise, discontinue MEDI4736 
• 
For elevations in bilirubin > 5×ULN, discontinue 
MEDI4736 
• 
For a ll othe r irAEs: 
Discontinue  MEDI4736. 
For infu sion -re la te d rea ctions: 
Discontinue MEDI4736 
For  incre a se in GGT: 
Hold MEDI4736 until resolution to ≤ Grade 1 
or baseline. For decreases that downgrade to 
≤ Grade 2 within 7 days or resolve to 
≤ Grade 1 or baseline within 14 days, resume 
MEDI4736 administration at next scheduled 
dose. Otherwise, discontinue MEDI4736 
For all other AEs: 
• Hold MEDI4736 until resolution to ≤ Grade 1 
or baseline. For AEs that downgrade to ≤ 
Grade 2 within 7 days or resolve to ≤ Grade 1 
or baseline within 14 days, resume MEDI4736 
administration at next scheduled dose. 
• 
Otherwise, discontinue MEDI4736 
Grade 4 
Discontinue  MEDI4736. 
Discontinue MEDI4736 


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Immune-related Adverse Events (irAEs) a 
All Other Events 
Grade 1 
None required. 
None required. Up to 2 sequential doses may 
be skipped at the discretion of the investigator 
For infu sion -re la te d rea ctions: Refer to 
section 5.3.1 
 
 
 
 
 
 
Table 10.2 
Management of Immune-related Adverse Events 
1 
Subject evaluation to identify any alternati ve etiology 
2 
In the absence of a clear alternati ve etiology, all events of inflammatory nature should be 
considered to be immune related 
3 
Symptomatic and topical therapy should be considered for low grade events 
4 
Systemic corticosteroids should be considered for a persistent low grade event or for a severe 
event 
5 
More potent immunosuppressives should be considered for events not responding to 
systemic steroids 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
MEDI4736 has demonstrated reasonable safety. Based on the current phase I trial of MEDI4736, 
side effects that may occur include: 
 
Likely 
• 
Fatigue 
• 
Diarrhea 
• 
Vomiting 
• 
Dizziness 
• 
Rash 
 
Less Likely 
• 
Anemia 
• 
Nausea 
• 
Influenza-like illness 
• 
Infusion-related reaction 
• 
Dehydration 
• 
Pruritus 
 
In addition, potential irAEs may be similar to those seen with the use of ipilimumab and MDX-1106 
including immune-mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies 


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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. 
A “non-serious” adverse event is any event that does not meet the definition of “serious adverse 
event” as presented, below. 
 
Reporting and Treating Non-Serious Events 
 
It is the responsibility of the investigator to perform regular assessments for AEs.  Subjects will be 
regularly queried about the occurrence of any AEs and will be monitored throughout the study for 
reactions to study drug and/or study procedures.  The investigator and clinical staff will record all 
AEs, whether volunteered by or elicited from the subject, at any time during a subject‟s participation 
in the study.  Abnorm al laboratory findings (e.g., hematology, comprehensive metabolic panel) or 
other abnorm al 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 AEs, including clinically significant laboratory 
abnormalities, will be followed until resolution.  AEs meeting the definition of SAEs require special 
reporting in addition to documentation in the CRDB as described below. 
All AEs, including clinically significant laboratory and assessment abnormalities will be recorded 
according to “Common Terminology Criteria for Adverse Events” V4.0 (CTCAE)  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 after initiation of first dose of study drug should be 
recorded on the Adverse Event page of the CRDB.  AEs should be recorded in the CRDB using the 
medical terminology found in the source documentation.  Whenever possible, diagnoses should be 


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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. 
• 
Severity 
The severity of all adverse events should be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) V4.0. 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 
➢ Life-threatening (CTCAE Grade 4):  Life-threatening of disabling AE 
 
➢ Death (CTCAE Grade 5):  Death-related AE.  See CTCAE Guidelines for assigning Grade 5. 
 
 
11.1.2 
Serious Adverse Events 
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- 


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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. 
Pregnancies 
 
Any pregnancy occurring after the first dosing is considered an immediately reportable event.  Such 
events must be reported within one (1) working day of the investigator becoming aware of the event. 
Subjects who become pregnant during the trial will be immediately discontinued from the study, but 
shall be followed for the duration of the pregnancy.  It is the Principal investigator‟s responsibility to 
provide to the sponsor follow-up information on the outcome of the pregnancy including information 
about any sequelae. 
 
11.1.3 
Other Events of Special Interest 
Hepatic Function Abnormality 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in bilirubin to greater than 2 × 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 investigational product. 
Events  of hepatic  function abnormality (as  defined above) should  be recorded  according to the 
definitions of AE and SAE: 
• 
If an event of hepatic function abnormality is considered to be related to a pre-existing condition 
and does not represent a worsening of this condition and/or is considered to be within the range 
of normal physiological fluctuation for the subject, the event does not meet the definition of an 
AE and does not need to be recorded as such. 
• 
If a definitive diagnosis for an underlying condition unrelated to the investigational product is 
established for an event of hepatic function abnormality, the diagnosis should be recorded as an 
AE/SAE. 
• 
If no definitive diagnosis is determined for an event of hepatic function abnormality, the term 
“hepatic function abnormal” should be used to report the AE/SAE. 


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12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
For the purposes of this study, patients will be evaluated for response every 4 cycles (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. 
MR I scans 
 
• 
MRI 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 imaging device 
should be used for serial evaluations. In case of MRI, 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 -  Must 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). 
• 
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/pericardial 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. 


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• 
Non-target Lesions - It is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g., “multiple enlarged pelvic lymph nodes” 
or “multiple liver metastases”) 
Response Criteria 
Evaluation of Target Lesions 
• 
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” 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 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 MEDI4736. 
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. 


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Table 12 
Evaluation of Overall Response 
Target Lesions 
Non-target  Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
a
 
No 
Partial response 
Complete response 
Non-complete response / 
non-progressi ve disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable b 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable b 
No 
Stable disease 
Not all evaluated 
Non-progressive  disease 
No 
Not evaluable 
No target lesion 
a
 
Not all evaluated 
No 
Not evaluable 
No target lesion a 
Non-complete response / 
non-progressi ve disease 
No 
Non-complete 
response / 
non-progressi ve 
disease 
Progressi ve  disease 
Any 
Yes/No 
Progressi ve  disease 
Any 
Progressi ve  disease 
Yes/No 
Progressi ve  disease 
Any 
Any 
Yes 
Progressi ve  disease 
No target lesion 
a
 
Unequivocal  progressi ve 
disease 
Yes or No 
Progressi ve  disease 
No target lesion a 
Any 
Yes 
Progressi ve  disease 
a Defined as no target lesions at baseline. 
b Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
irRECIST 
Due to the potential for tumors to appear larger, including new lesions, prior to response in 
immunotherapy trials, subjects are permitted to continue treatment beyond progression. In 
order to factor in the appearance of new measurable lesions, the immune-related RECIST 
(irRECIST) is a modified RECIST version 1.1 that includes new measurable lesions into the 
sum of the diameters when determining overall response. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of serious toxicity or complications, all patients will continue treatment for up to 2 
years.  In the absence of treatment delays due to adverse event(s), 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. 


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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. 
 
After the end of treatment, each subject will be followed for 30 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment). 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 telephone (unless not otherwise following up at Memorial Hospital) 
every 3 months for up to 2 years. 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 
 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint of this trial is the best response rate in dMMR CRC (cohort 1) and TIL+ 
CRC (cohort 2) patients according to RECIST 1.1. Currently there is no standard of care for 
this patient population and there is currently no known drug for which the response rate 
would be expected to be greater than about 5% in patients that have failed current regimes. 
A two-stage Simon‟s optimal design will be employed to test the null hypothesis that the true 
response rate is ≤5% versus the alternative 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 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. At the end of the study, if 2 or fewer objective tumor responses are 
observed in a 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 RECIST1.1 are 
observed in a cohort, then further investigation of MEDI4736 in that patient population will be 
considered worthwhile. This study requires accrual of a minimum of 18 subjects and up to a 
maximum of 48 subjects if both cohorts are expanded to the second stage. The accrual time 
is estimated to be 2 years. 
Antitumor Activity 
 
Assessments of antitumor activity will be based on the ORR, PFS, and OS. Response 
Evaluation Criteria in Solid Tumors guidelines (v1.1)39  with modifications to account for the 
unique response patterns observed with immunotherapy will be used to determine tumor 
response. 
 
The ORR is defined as the proportion of subjects CR or PR based on RECIST criteria. The 
exact 95% CI of ORR will be estimated using the binomial distribution. The ORR defined 
based on irRECIST criteria will also be estimated using the binomial distribution and exact 
95%CI will be provided. Progression-free survival will be measured from the start of 
treatment with MEDI4736 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 


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prior to data cutoff, dropout, or the initiation of alternate anticancer treatment. Subjects 
having no tumor assessments after the start of treatment with MEDI4736 will have PFS 
censored on the first date of treatment with MEDI4736. Progression-free survival will be 
evaluated using the Kaplan-Meier method(Kaplan and Meier, 1958). Overall survival will be 
determined as the time from the start of treatment with MEDI4736 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-Meier 
method. 
Safety and Tolerability Analyses 
 
All recorded adverse events will be listed and tabulated by system organ class, preferred 
term and  treatment. Any significant vital signs and clinical laboratory test results will be listed 
and summarized. Any significant physical examination findings, and clinical laboratory results 
will be listed. 
Biomarker Analysis 
 
Exploratory research studies will be done only on the 1st  stage patients to evaluate the effect 
of this therapy will be performed using research blood draws and tumor biopsies at baseline 
and at week 8. Cohorts 1 and 2 will be combined for this analysis given the small sample 
size. 
 
The pharmacodynamic effect of MEDI4736 on Tumor Infiltrating Lymphocytes (TILs), such 
as CD4+ and CD8+ 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 MEDI4736 on markers in peripheral blood, such as 
ICOS, 
HLA-DR, PD-1, CTLA-4; and, serum proteins, such as CXCL9; 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. 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 McNemar‟s test will be used to assess these relationships for binary 
markers. Fisher‟s exact test will be employed to assess associations between categorical 
variables 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 


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During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
n/a 
 
16.1 
DAT A M ANAGEMENT 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 
protocol compliance audits may be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (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 Monitoring of Clinical Trials”, which can be found at  
http://cancertrials.nci.nih.gov/researchers/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_safety%20Monit  
oring07.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. 


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Inclusion of Women and Minorities:  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 Women:  Children have been excluded from this study. 
Colorectal adenocarcinoma is an adult cancer. Thus, the relevance of these drug to the 
pediatric population has not been established. Lactating and pregnant women are also 
excluded because of potential anti-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 survival of 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 complications of 
treatment.  MEDI4736 will be supplied to patients by MedImmune at no cost.  Patients will 
not be responsible for the costs of  blood procurement obtained for research purposes , the 
cost of special testing of any tissue 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. 
 
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. 
17.2 
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). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
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 MEDI4736 or until the 
initiation of alternative anticancer therapy.  The investigator and/or Sponsor are responsible 


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for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per local 
requirements. 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject‟s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
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 
• 
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 subject‟s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
17.2.1  SAFETY REPORTING The Institution will be responsible for: 1)  reporting all 
suspected, unexpected serious adverse reactions (SUSARs) where subject has received 
MedImmune Development Product and provided to MedImmune Patient Safety at the same 
time the report(s) are sent to the local Regulatory Authority; and 2) as the Sponsor, meeting 
regulatory and ethics committee safety reporting requirements and obligations in all 
participating countries. 
 
In accordance with local Regulatory FDA requirements, Institution, as the IND Sponsor, will 
establish and maintain records and submit Safety Reports to the FDA as required by 21 CFR 
312.32 or as required by other applicable regulations.  In the conduct of research under this 
Agreement, the Parties will comply with specific guidelines and policies for reporting adverse 


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events, as well as procedures specified in the Protocol(s).  Collaborator must provide 
MedImmune Patient Safety with a copy of all initial and follow-up Safety Reports CIO MS 
concurrently with their submission to the local Regulatory Authority to  
drugsafety@medimmune.com and AEMailboxClinicalTrialTCS@astrazeneca.com.   The 
Developmental Core Safety Information (DCSI) included in the current Investigator‟s 
Brochure will be used to determine expectedness for regulatory reporting purposes. 
 
When assessing causality, MedImmune Patient Safety uses a binary causality scale 
(“related” or “not related”).  SAEs assessed by the Institution as “definitely, possibly, or 
probably related” will be considered “related” by MedImmune Patient Safety.  SAEs 
assessed as “not related, remotely, or unlikely”, are considered “not related” by MedImmune 
Patient Safety. 
 
Monthly, and not later than 15 calendar days after the end of each calendar month, Institution 
shall provide a copy of all other SAEs (e.g., SAEs assessed as not related, or subject 
received placebo or active comparator), to MedImmune Patient Safety in the form of a 
CIOMS [or CIO MS II line listing] to:  AE MailboxClinicalTrialTCS@astrazeneca.com. 
 
MedImmune will forward SUSARs for a MedImmune Development Product to Investigators 
who are participating in sponsored studies in accordance with local requirements. 
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 IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets 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. 


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19.0 
REFERENCES 
 
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Zhang C, Wu S, Xue X, et al. Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 
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20.0 
APPENDICES 
 
APPENDIX A:  Requisition For Blood Specimens 
APPENDIX B:  Requisition For Biopsy Specimens 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 48 of 49 
 
 
 
 
APPENDIX A:  REQUISITION FOR BLOOD SPECIMENS 
 
 
 
Phase II Study to Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced 
Colorectal Cancer 
 
A) Section A: Patient information 
(To be completed by RSA) 
 
Patient initials:   
  
Patient study ID#: 
_ 
Site:   
  
B) Section B: Sample information 
(To be checked off by RSA) 
4 CPT tubes (10 cc) will be collected at the 
following time points 
[ ]Baseline 
[ ]Week 2 
[ ]Week 4 
[ ]Week 8 
[ ]Week   
 
PAXgene Blood DNA Tubes (8.5 cc) 
[ ]Baseline 
C) Section C: Sample Collection information 
(To be completed by phlebotomy) 
Drawn By:  
 
Date/ Time:  
  
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:   
  
E) Section E: Sample shipping information 
(To be completed by laboratory personnel) 
Sent by:   
 
Date/Time:   
  
 
Received by:   
 
Date/Time:   
  
Sample shipping Instructions 
Ship samples on dry ice to: 
Dr. Jianda Yuan 
Memorial Sloan-Kettering Cancer Center 
Zuckerman Research Building 
425 East 66th street, Z1545 
New York, NY 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-109 A(8) 
Approval date: 09-Apr-2019 
Page 49 of 49 
 
 
 
 
APPENDIX B:  REQUISITION FOR BIOPSY SPECIMENS OR LEFT OVER TISSUE OBTAINED 
DURING A ROUTINE PROCEDURE 
 
Phase II Study to Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced 
Colorectal Cancer 
 
A) Section A: Patient information 
(To be completed by RSA) 
 
Patient initials:   
  
Patient study ID#: 
_ 
Site:   
  
B) Section B: Sample information 
(To be checked off by RSA) 
[ ] Baseline: 
5 Core Biopsies 
[ ] Week 8: 
 5 Core Biopsies 
[ ] Routine Procedure: 5 Cores or divided tumor 
C) Section C: Sample Collection information 
(To be completed by physician or designee) 
Obtained By: 
Procedure:   
 
Date/ Time:  
  
Sample Collection Instructions: 
1. Cores # 1, 2: Place into formalin (3-5 cc) 
2. Cores # 3, 4: Place in sterile Nunc tube and snap 
freeze in liquid nitrogen 
3. Core # 5: Place into 3-5 cc RPMI under sterile 
conditions 
D) Section D: Storage/Processing information 
(To be completed by laboratory personnel) 
Lab ID#:   
        
Received by:   
     
Date/Time:   
  
Sample Storage/ Processing Instructions 
1. Cores # 1, 2: Store at 4-8oC 
2. Cores # 3, 4: Store at -70 to -80oC 
3. Core # 5: Process immediately for TIL isolation 
and/ or tissue culture 
E) Section E: Sample shipping information 
(To be completed by laboratory personnel) 
Sent by:   
 
Date/Time:   
  
 
Received by:   
 
Date/Time:   
  
Sample shipping Instructions 
Ship samples 1, 2, and 5 at room temperature; 
samples 3 and 4 on dry ice, attention: 
Dr. Jianda Yuan 
Memorial Sloan-Kettering Cancer Center 
Zuckerman Research Building 
425 East 66th street, Z154 
New York, NY 10065