Clinical trial NCT02669914
Conditions: Non-Small Cell Lung Cancer Nonsmall Cell Lung Cancer Breast Cancer Cancer of Breast Cancer of the Breast Gastroesophageal Cancer Pancreatic Cancer Cancer of the Pancreas Colorectal Cancer Colorectal Carcinoma Renal Cancer Kidney Cancer Cancer of the Kidney Cancer of Kidney Ovarian Cancer Ovary Cancer Cancer of the Ovary Cancer of Ovary
Sponsor: Washington University School of Medicine
Start date: 2016-09-12; Completion date: 2018-01-11
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Brain metastases are the most common intracranial malignancy occurring in 20-40% of all cancers, and the presence of CNS metastases is associated with a poor prognosis. As such, the median overall survival of patients with symptomatic brain lesions is a dismal 2-3 months regardless of tumor type. Because standard chemotherapy largely does not cross the blood brain barrier at a meaningful concentration, standard treatment is limited and usually involves surgical resection and/or stereotactic radiosurgery for isolated lesions and whole brain radiation for multiple lesions. Unfortunately, the median overall survival is only improved by about 6 months with this multimodality approach2, and there is a paucity of second-line therapies to treat recurrence. Furthermore, re-resection and re-radiation are often not feasible options due to concern for increasing complications or neurotoxicity, respectively. Thus, there is a dire clinical need for additional treatment options for this patient population.

Checkpoint blockade therapy, in particular PD-1 and PD-L1 inhibition, has recently shown clinical efficacy in multiple types of solid tumors. The investigators propose to study the efficacy of checkpoint blockade therapy in patients with solid tumors and refractory/recurrent brain metastases. The investigators will assess the efficacy of MEDI4736, a novel PD-L1 inhibitory monoclonal antibody, in this study.

Detailed description:

Arms: arm 1: -MEDI4736 will be given to all patients \> 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients \< 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks. arm 2: -MEDI4736 will be given to all patients \> 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients \< 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks. arm 3: -MEDI4736 will be given to all patients \> 30 kg actual body weight intravenously at a fixed dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 1 and 15 of each 28-day cycle. Patients \< 30 kg actual body weight will be dosed at 10 mg/kg every 2 weeks.
Interventions: intervention 1: MEDI4736
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 02/23/16 
 
Page 1 of 80 
 
 
A Phase II Study of MEDI4736 (Durvalumab) in Patients with Brain Metastasis from 
Epithelial-derived Tumors 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: Pending 
Version Date: 02/23/16 
 
 
Principal Investigator: 
Ramaswamy Govindan, M.D. 
Phone:  (314) 362-5737 
E-mail:  rgovinda@dom.wustl.edu 
 
Co-Principal Investigators: Gavin Dunn, M.D., Ph.D. (Neurosurgery) 
 
 
 
 
Tanner Johanns, M.D., Ph.D. (Medical Oncology) 
 
Sub-Investigators 
 
 
Modality 
Maria Q. Baggstrom, M.D. 
 
Medical Oncology 
Daniel Morgensztern, M.D.  
Medical Oncology 
Saiama Waqar, M.D.  
 
Medical Oncology 
Ningying Wu, Ph.D.  
 
Biostatistics 
 
 
Study Drug(s): 
 
MEDI4736 (durvalumab) 
 
IND #: 
129501 
ClinicalTrials.gov #: 
NCT02669914 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


Protocol Version: 02/23/16 
 
Page 2 of 80 
 
A Phase II Study of MEDI4736 (Durvalumab) in Patients with Brain Metastasis from 
Epithelial-derived Tumors  
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
mm/dd/yyyy 
Amendment #1 Version 
 
 
 
 
 
 
mm/dd/yyyy 
 
 
 


Protocol Version: 02/23/16 
 
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A Phase II Study of MEDI4736 (Durvalumab) in Patients with Brain Metastasis from 
Epithelial-derived Tumors 
 
SUMMARY 
 
Eligible patients will be enrolled and receive MEDI4736 at a fixed dose of 750 mg every two 
weeks until progression.  Cohort A will enroll patients with metastatic non-small cell lung cancer 
(NSCLC) with at least one measurable brain lesion that does not require corticosteroids for 
symptomatic control.  Cohort B will enroll patients with metastatic solid tumors of epithelial origin 
(excluding NSCLC) with at least one measurable brain lesion that does not require corticosteroids 
for symptomatic control.  Cohort C will enroll patients with metastatic solid tumors of epithelial 
origin (including NSCLC) with at least one measurable brain lesion that requires corticosteroids 
for symptomatic control. 
 
 
 


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Glossary of Abbreviations 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
aPTT 
Active partial thromboplastin time 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMP 
Complete metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DMSO 
Dimethyl sulfoxide 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HCC 
Hepatocellular carcinoma 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
irAE 
Immune-related adverse event 
irRC 
Immune-related response criteria 
IULN 
Institutional upper limit of normal 
IV 
Intravenous 
LCM 
Laser capture microdissection 


Protocol Version: 02/23/16 
 
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LFT 
Liver function tests 
LLN 
Lower limit of normal 
LTP 
Laboratory for Translational Pathology 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OCT 
Optimum cutting temperature 
OHRP 
Office of Human Research Protections  
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PFT 
Pulmonary function tests 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Prothrombin time 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QTc 
QT interval (corrected) 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCCHN 
Squamous cell carcinoma of the head & neck 
SD 
Stable disease 
TIL 
Tumor infiltrating lymphocyte 
TSH 
Thyroid stimulating hormone 
UPN 
Unique patient number 
 
 


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Table of Contents 
SUMMARY ................................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ............................................................................ 8 
1.1 
Metastatic Brain Lesions ......................................................................................... 8 
1.2 
Immunotherapy .......................................................................................................... 8 
1.3 
MEDI4736 (Durvalumab) ....................................................................................... 12 
1.4 
Study Rationale ......................................................................................................... 17 
1.5 
Correlative Studies Background .......................................................................... 18 
2.0 
OBJECTIVES ................................................................................................................. 20 
2.1 
Primary Objective ..................................................................................................... 20 
2.2 
Secondary Objectives .............................................................................................. 20 
2.3 
Exploratory Objective .............................................................................................. 21 
3.0 
PATIENT SELECTION ................................................................................................. 21 
3.1 
Inclusion Criteria ...................................................................................................... 21 
3.2 
Exclusion Criteria .................................................................................................... 22 
3.3 
Inclusion of Women and Minorities ................................................................... 25 
4.0 
REGISTRATION PROCEDURES .............................................................................. 25 
4.1 
Confirmation of Patient Eligibility ....................................................................... 25 
4.2 
Patient Registration in the Siteman Cancer Center Database .................. 25 
4.3 
Assignment of UPN .................................................................................................. 25 
5.0 
TREATMENT PLAN ...................................................................................................... 25 
5.1 
Premedication Administration ............................................................................. 25 
5.2 
Agent Administration .............................................................................................. 26 
5.3 
Evaluability ................................................................................................................. 26 
5.4 
General Concomitant Medication and Supportive Care Guidelines ........ 26 
5.5 
Women of Childbearing Potential ........................................................................ 27 
5.6 
Duration of Therapy ................................................................................................ 28 
5.7 
Duration of Follow-up ............................................................................................. 29 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ............................................................. 29 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ........................................ 43 
7.1 
Adverse Events (AEs) ............................................................................................... 43 
7.2 
Unanticipated Problems ......................................................................................... 43 
7.3 
Noncompliance .......................................................................................................... 43 
7.4 
Serious Noncompliance .......................................................................................... 43 
7.5 
Protocol Exceptions ................................................................................................. 44 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the 
Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University ............................................................................................................................... 44 
7.7 
Reporting to the FDA ............................................................................................... 44 
7.8 
Reporting to Astra Zeneca ..................................................................................... 45 
7.9 
Definition of adverse events of special interest (AESI) ................................. 46 
7.10  Other events requiring reporting ......................................................................... 49 
7.11  Timeframe for Reporting Required Events ....................................................... 51 
8.0 
PHARMACEUTICAL INFORMATION ...................................................................... 51 
8.1 
MEDI4736 ................................................................................................................... 51 
9.0 
CORRELATIVE STUDIES .......................................................................................... 53 


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9.1 
Sample Collection Plan ........................................................................................... 54 
9.2 
Immune Monitoring ................................................................................................. 55 
10.0  STUDY CALENDAR...................................................................................................... 56 
11.0  DATA SUBMISSION SCHEDULE ............................................................................ 57 
12.0  MEASUREMENT OF EFFECT – CNS DISEASE ................................................. 57 
12.1  Antitumor Effect – Solid Tumors ......................................................................... 57 
12.2  Disease Parameters ................................................................................................. 59 
12.3  Methods for Evaluation of Measurable Disease ............................................. 60 
13.0  MEASUREMENT OF EFFECT – NON-CNS DISEASE ....................................... 62 
13.1  RECIST Guidelines .................................................................................................. 62 
13.2  Immune-Related Response Criteria43 ................................................................ 69 
14.0  DATA AND SAFETY MONITORING ......................................................................... 70 
15.0  STATISTICAL CONSIDERATIONS ........................................................................... 70 
15.1  Study Design .............................................................................................................. 70 
15.2  Study Population ...................................................................................................... 71 
15.3  Sample Size/Power Analysis ................................................................................ 71 
15.4  Primary Endpoint ..................................................................................................... 71 
15.5  Secondary Endpoints .............................................................................................. 72 
15.6  Exploratory Endpoints ............................................................................................ 72 
15.7  Accrual ......................................................................................................................... 72 
15.8  Data Analysis ............................................................................................................. 72 
16.0  REFERENCES ............................................................................................................... 76 
APPENDIX A: ECOG Performance Status Scale ........................................................... 79 
APPENDIX B: Cockcroft-Gault Formula .......................................................................... 80 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Metastatic Brain Lesions 
 
Metastatic brain lesions are the most common intracranial malignancy, arising in 20-40% 
of all cancer patients and representing over 200,000 new cases per year in the United States 
alone.1  The presence of brain lesions represents a significant source of morbidity and 
mortality associated with debilitating neurologic deficits and shortened survival.  
Unfortunately, the frequency of brain metastases has increased recently, largely attributed 
to better diagnostic modalities such as MRI and more effective systemic therapy resulting 
in longer overall survival.  In adults, the most common sources of metastatic brain lesions 
are lung, breast, and skin (melanoma) cancers.1  Together, lung and breast cancer represent 
approximately two-thirds of all cases, and melanoma, the tumor that has the highest 
neurotropism, where 20-45% of patients will develop brain lesions, accounts for an 
additional 5-20% of all cases. 
 
Current treatment for brain lesions involves a combinatorial approach including surgery, 
radiosurgery, and/or whole brain radiation.2  Despite the fact that these therapies are often 
effective initially, patients eventually suffer from progression of their disease either locally 
or distantly.  Further limitations of current therapeutic modalities include the treatment of 
patients with multiple lesions, which occurs in 50-75% of cases of brain metastasis.  In 
these cases, surgery and radiosurgery may have less utility, though their role in the 
treatment of such lesions in conjunction with contemporary systemic treatments is 
incompletely understood and remains an area of active investigation.3  Moreover, many 
tumors that metastasize to the brain such as melanoma and renal cell carcinoma are 
relatively radioresistant, which further demonstrates the limitations of these therapies.  As 
such, current treatment of brain metastases is largely palliative and focused on limiting 
neurologic compromise.  Therefore, there is a dire need to expand the available therapeutic 
armament and identify alternate modalities that can be used to enhance response rates, 
extend remission duration, target multiple lesions, and effectively treat both systemic and 
CNS disease simultaneously. 
 
1.2 
Immunotherapy 
 
1.2.1 Immunosurveillance 
 
Immunosurveillance is a term used to describe the role of the immune response in 
controlling tumor development. The role of immunosurveillance in the control 
and/or development of tumors has been described in three steps termed the three 
E’s: Elimination, Equilibrium, and Escape.4 During the elimination phase, the 
immune system is able to recognize aberrantly expressed antigens or molecules that 
signal to the immune system that the cell has undergone a transformative event and 
should be eliminated. Unfortunately, transformed cells eventually adopt evasive 
properties that allow it to subvert detection or destruction by the immune system 
(Equilibrium) permitting it’s eventual outgrowth into a clinically evident tumor 


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(Escape).5 Thus, immunotherapy refers to strategies that attempt to re-establish an 
effective immunosurveillance mechanism to control tumor growth through 
manipulation of the immune response.  Another benefit of cancer immunity is that 
the immune system represents a relatively tumor-specific effector mechanism that 
can simultaneously target multiple disease sites including the CNS, and the 
response can be long-lived often persisting for years.6   
 
One mechanism by which tumors are able to evade immunologic detection is 
through the upregulation of inhibitory signals. For example, PD-L1 and PD-L2 are 
molecules frequently upregulated on many tumor types. Their cognate receptor, 
PD-1, is expressed on the surface of many activated immune cell populations, 
including tumor-infiltrating T lymphocytes, and binding of PD-1 to either of these 
inhibitory ligands results in an “exhausted” or suppressed effector phenotype of 
infiltrating T cells permitting tumor escape.7 Under normal conditions, these 
inhibitory molecules serve to control chronic immune activation representing a 
“checkpoint” mechanism to prevent unregulated inflammatory responses that may 
be potentially detrimental to the host.8  In the context of cancer immunity, however, 
the tumor microenvironment has coopted this checkpoint pathway to permit 
immune escape.7,8  Therefore, one approach to bypass this immunosuppressive 
environment to reestablish immunosurveillance is through the use of monoclonal 
antibodies specific to these inhibitory molecules to allow for the activation and 
expansion of endogenous anti-tumor T cells.  This approach has been termed 
“checkpoint blockade” and initial phase I studies using either anti-PD-1 or anti-PD-
L1 antibodies have demonstrated significant objective, long-term responses in 
patients with various tumor types, including NSCLC.9-13     
 
1.2.2 PD-L1 in NSCLC 
 
PD-L1 is overexpressed in 23-83% of NSCLC samples.14-18 The large discrepancy 
in frequency of PD-L1 expression among these studies is due to differences in the 
definition of “positive.”  All studies use an arbitrary cut-off that varies between 1%, 
5%, and 50% of tumor cells expressing PD-L1 to be considered positive. Despite 
this variability, there is a general consistency among these various studies that 
provide an approximate frequency of PD-L1 expression in NSCLC patients.  For 
example, ~80% of samples will be positive if the cut-off is defined as >1% of tumor 
cells expressing PD-L1 whereas only ~25% of samples will be positive if the cut-
off is >50% of tumor cells expressing PD-L1.17,19 This has important clinical 
implications for two reasons: (1) the relatively high frequency of PD-L1 expression 
in NSCLC makes checkpoint blockade with inhibitory PD-1 or PD-L1 antibodies 
rational and (2) the level of PD-L1 expression has been used as a predictive 
biomarker for response to PD-1 or PD-L1 antibody therapy. 
 
Regarding efficacy of anti-PD-1 or anti-PD-L1 antibodies in patients with NSCLC, 
there are currently at least three different anti-PD-1 and four different anti-PD-L1 
agents being evaluated in clinical trials at various stages of disease and various 
phases of development (phase I, II, and III).19 Perhaps the most illustrative 


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examples of the promise of PD-1/PD-L1 checkpoint blockade are the results from 
two large studies that have recently been published demonstrating efficacy of anti-
PD-1 therapy in metastatic NSCLC.17,18  Brahmer et al18 randomly assigned 272 
patients with advanced (stage IIIB or IV) squamous-cell NSCLC that had 
progressed following first-line platinum-containing chemotherapy to either 
nivolumab or standard of care docetaxel. Impressively, they reported a higher 
objective response rate with nivolumab compared to docetaxel (20% vs 9%, p = 
0.008) and a statistically significant improvement in median overall survival (9.2 
months vs 6.0 months) resulting in a 41% reduction in risk of death with nivolumab 
(HR 0.59; p <0.0001). This study led to the FDA approval of nivolumab for 
treatment of squamous-cell NSCLC as second-line therapy. Garon et al17 extended 
these findings in a cohort of 495 patients with metastatic NSCLC (all histologies) 
that were treated with pembrolizumab. Comparably, they also reported an objective 
response rate of 19.4%, a progression free survival of 3.7 months, and a median 
overall survival of 12.5 months. Importantly, they also report that there are no 
differences in response rate among squamous and adenocarcinoma histology, or in 
treatment naïve compared to treatment refractory patients, which has been 
confirmed in a subsequent study20 suggesting a more broad applicability of these 
results. However, results from randomized phase III studies addressing these 
questions are pending. 
 
Regarding the correlation between PD-L1 expression and response rate, the results 
have been inconclusive. There have been several large meta-analyses of evaluable 
clinical trials assessing response rate and PD-L1 expression in patients with 
NSCLC that have suggested an overall higher response rate associated with higher 
PD-L1 expression,14,16,21 In PD-L1 “positive” patients, the combined overall 
response rate was 23.2% compared to 14.5% in the PD-L1 “negative” group. 
Unfortunately, as different definitions of positive were used (>1% versus >5%), 
direct comparisons cannot be made. However, if all studies using a cutoff of >5% 
PD-L1 expression on tumor cells is applied, the overall response rate remains 22% 
for PD-L1 positive patients and 15.5% for PD-L1 negative patients consistent with 
the above findings. Expanding upon this point, there is likely a linear relationship 
between the level of PD-L1 expression and response rate as demonstrated by Garon 
et al where the objective response rate to pembrolizumab in patients with metastatic 
NSCLC with <1%, 1-24%, 25-49%, 50-74%, and >75% was 8.1%, 12.9%, 19.4%, 
29.6%, and 45.4%, respectively.17 Additionally, it is of further note that there 
remains an 8-15% objective response rate in patients with negative PD-L1 
expression suggesting PD-L1 expression is not an ideal biomarker to predict 
response or survival. As such, there are routinely an additional 10-30% of patients 
in these studies who have stable disease for months to years suggesting that the 
overall effect of these antibodies on overall survival is also not directly related to 
level of PD-L1 expression or an objective response.14-16   
 
1.2.3 Checkpoint Blockade in Brain Metastasis 
 
The effect of checkpoint blockade on the treatment of brain metastasis remains 


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unclear because this patient population is largely excluded from most clinical trials 
to date. However, there is a number of anecdotal reports suggesting that checkpoint 
blockade may be efficacious in brain lesions as well as systemic disease. These 
reports have predominantly been in patients with metastatic melanoma who are 
being treated with ipilimumab, a checkpoint inhibitor that blocks the activity of 
CTLA-4, another co-inhibitory molecule. For example, one case reports a durable 
complete remission in a patient with progressive brain lesions following treatment 
with ipilimumab as part of a compassionate use program.22 In another case report, 
a young female with melanoma and symptomatic brain and spine metastases 
refractory to stereotactic radiosurgery was treated with ipilimumab followed by 
resolution of her neurologic symptoms and stabilization of her disease 
progression.23 Subsequently, several retrospective analyses of phase II and III 
clinical trials of ipilimumab in the treatment of metastatic melanoma have reported 
a disease control rate (stable disease, partial response, or complete response) of 16 
to 27% in patients with stable CNS disease at time of enrollment24-26, which is 
comparable to the disease control rate of non-CNS disease. This lead to a 
prospective phase II study examining the efficacy of ipilimumab in melanoma with 
asymptomatic and symptomatic brain mets.27 Cohort A enrolled 51 patients with 
asymptomatic CNS disease while cohort B enrolled 21 patients with symptomatic 
CNS disease requiring glucocorticoid treatment. Cohort A had disease control rate 
(CR+PR+SD) of 24% (12/51) in CNS disease compared to 28% (14/51) in non-
CNS disease.  The median overall survival was 7 months which is comparable to 
the phase III studies of ipilimumab in metastatic melanoma where CNS disease was 
excluded. Cohort B had a disease control rate of 10% (2/21) in the CNS compared 
to 5% (1/21) in non-CNS disease with a median overall survival of 3.7 months. 
Overall, the objective response rate and survival were comparable to those reported 
in prior studies with patients without CNS disease. 
 
Similarly, there have also been several cases reported that support a similar effect 
of PD-1 checkpoint blockade therapy in having a protective effect in CNS disease 
as well. For example, 5 patients with untreated brain metastases were enrolled in 
the phase II study evaluating nivolumab in patients with metastatic melanoma with 
or without prior ipilimumab therapy.28 While the text states these patients had an 
objective response, there are no further details provided regarding the extent or 
duration of the response. Furthermore, 2 patients with refractory metastatic 
squamous cell NSCLC had stable, asymptomatic CNS disease and were treated 
with nivolumab as part of a phase II study.29 Both patients reportedly had continued 
stable disease of the CNS lesions though further details are also not provided. 
 
In summary, these studies provide some suggestion that checkpoint inhibition may 
have efficacy in CNS disease. However, the data for the effect of PD-1 checkpoint 
blockade is less robust than that for CTLA-4 blockade, and more trials are needed 
to draw any meaningful conclusions. 
 
 


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1.3 
MEDI4736 (Durvalumab) 
 
MEDI4736 is being developed as a potential anticancer therapy for patients with advanced 
solid tumors. MEDI4736 is a human monoclonal antibody (MAb) of the immunoglobulin 
G1 kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-
L1) (B7-H1;, CD274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). 
MEDI4736 is composed of 2 identical heavy chains and 2 identical light chains, with an 
overall molecular weight of approximately 149 kDa. MEDI4736 contains a triple mutation 
in the constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to 
complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved 
in triggering effector function. 
 
1.3.1 Summary of non-clinical experience 
 
The non-clinical experience is fully described in the current version of the 
MEDI4736 Investigator’s Brochure.    
 
MEDI4736 binds with high affinity and specificity to human PD-L1 and blocks its 
interaction with PD-1 and CD80. In vitro studies demonstrate that MEDI4736 
antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in 
their restored proliferation and release of interferon gamma (IFN-γ). Additionally, 
MEDI4736 demonstrated a lack of antibody-dependent cell-mediated cytotoxicity 
(ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional 
assays. In vivo studies show that MEDI4736 inhibits tumor growth in a xenograft 
model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse 
PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when 
given as monotherapy and resulted in complete tumor regression in > 50% of 
treated mice when given in combination with chemotherapy. Combination therapy 
(dual targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-
4]) resulted in tumor regression in a mouse model of colorectal cancer.  
 
Cynomolgus monkeys were selected as the only relevant species for evaluation of 
the pharmacokinetics (PK)/pharmacodynamics and potential toxicity of 
MEDI4736. Following intravenous (IV) administration, the PK of MEDI4736 in 
cynomolgus monkeys was nonlinear. Systemic clearance (CL) decreased and 
concentration half-life (t1/2) increased with increasing doses, suggesting saturable 
target binding-mediated clearance of MEDI4736. No apparent gender differences 
in PK profiles were observed for MEDI4736.  
 
In general, treatment of cynomolgus monkeys with MEDI4736 was not associated 
with any MEDI4736-related adverse effects that were considered to be of relevance 
to humans. Adverse findings in the non-Good Laboratory Practice (GLP) 
PK/pharmacodynamics, dose range-finding study, and a 4-week GLP repeat-dose 
toxicity study were consistent with antidrug antibody (ADA)-associated morbidity 
and mortality in individual animals. The death of a single animal in the non-GLP, 


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PK/pharmacodynamics, and dose range-finding study was consistent with an ADA-
associated acute anaphylactic reaction. The spectrum of findings, especially the 
clinical signs and microscopic pathology, in a single animal in the 4-week GLP 
repeat-dose study was also consistent with ADA immune complex deposition, and 
ADA:MEDI4736 immune complexes were identified in a subsequent non-GLP, 
investigative immunohistochemistry study. Similar observations were reported in 
cynomolgus monkeys administered human mAbs unrelated to MEDI4736. Given 
that immunogenicity of human mAbs in nonclinical species is generally not 
predictive of responses in humans, the ADA-associated morbidity and mortality 
were not considered for the determination of the no-observed-adverse-effect level 
(NOAEL) of MEDI4736.  
 
Finally, data from the pivotal 3-month GLP toxicity study with MEDI4736 in 
cynomolgus monkeys showed that subchronic dosing of MEDI4736 was not 
associated with any adverse effects. Therefore, the NOAEL of MEDI4736 in all the 
general toxicity studies was considered to be 100 mg/kg, the highest dose tested in 
these studies. In addition to the in vivo toxicology data, no unexpected membrane 
binding of MEDI4736 to human or cynomolgus monkey tissues was observed in 
GLP tissue cross-reactivity studies using normal human and cynomolgus monkey 
tissues. 
 
1.3.2 Summary of clinical experience 
 
Clinical experience with MEDI4736 is fully described in the current version of the 
MEDI4736 Investigator’s Brochure. 
 
As of the DCO dates (15Apr2015 to 12Jul2015, MEDI4736 IB Version 8.0), a total 
of 1,883 subjects have been enrolled and treated in 30 ongoing MEDI4736 clinical 
studies, including 20 sponsored and 10 collaborative studies. Of the 1,883 subjects, 
1,279 received MEDI4736 monotherapy, 440 received MEDI4736 in combination 
with tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 
13 MEDI6383), and 150 have been treated with blinded investigational product. No 
studies have been completed or terminated prematurely due to toxicity. 
 
Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 
378 subjects in the dose-escalation and dose-expansion phases of Study CD-ON-
durvalumab-1108 following treatment with MEDI4736 0.1 to 10 mg/kg every 2 
weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum observed 
concentration (Cmax) increased in an approximately dose-proportional manner over 
the dose range of 0.1 to 15 mg/kg. The area under the concentration-time curve 
from 0 to 14 days (AUC0-14) increased in a greater than dose-proportional manner 
over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 3 
mg/kg. These results suggest MEDI4736 exhibits nonlinear PK likely due to 
saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses 
≥ 3 mg/kg. Near complete target saturation (soluble programmed cell death ligand 


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1 [sPD-L1] and membrane bound) is expected with MEDI4736 ≥ 3 mg/kg Q2W. 
Exposures after multiple doses showed accumulation consistent with PK 
parameters estimated from the first dose. In addition, PK simulations indicate that 
following MEDI4736 10 mg/kg Q2W dosing, > 90% of subjects are expected to 
maintain PK exposure ≥ 40 µg/mL throughout the dosing interval. 
 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 
8 of 388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects 
in 10 mg/kg cohort) were ADA positive with an impact on PK/pharmacodynamics 
in 1 subject in the 3 mg/kg cohort. 
 
Safety  
The safety profile of MEDI4736 as monotherapy and combined with other 
anticancer agents was consistent with the pharmacology of the target and other 
agents in the immune checkpoint inhibitor class. No tumor types appeared to be 
associated with unique AEs. Immune-related AEs (irAEs), which are important 
risks of immune checkpoint inhibitors, have been observed with MEDI4736 and 
include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an 
important potential risk particularly with MEDI4736 and tremelimumab 
combination therapy. These events are manageable by available/established 
treatment guidelines as described in the study protocols. 
 
AEs reported with MEDI4736 monotherapy in key clinical studies are described 
below. 
 
Adverse Event Profile of MEDI4736 Monotherapy 
Study CD-ON-durvalumab-1108: The safety profile of MEDI4736 monotherapy 
in the 694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 
1,279 subjects who have received MEDI4736 monotherapy (not including subjects 
treated with blinded investigational product) across the clinical development 
program. The majority of treatment-related AEs were manageable with dose delays, 
symptomatic treatment, and in the case of events suspected to have an immune 
basis, the use of established treatment guidelines for immune-mediated toxicity. As 
of 07 May2015, among the 694 subjects treated with MEDI4736 10 mg/kg Q2W 
in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) experienced a 
treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being 
fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), 
pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment-
related AEs were Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring 
in 65 subjects (9.4%). Treatment-related ≥ Grade 3 events reported in 3 or more 
subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate 
aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase 
(GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 
0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 


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0.4% each). Six subjects had treatment-related Grade 4 AEs (upper gastrointestinal 
hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and 
pneumonitis) and 1 subject had a treatment-related Grade 5 event (pneumonia). 
Treatment-related serious adverse events (SAEs) that occurred in ≥ 2 subjects were 
colitis and pneumonitis (3 subjects each). A majority of the treatment-related SAEs 
were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that resulted 
in permanent discontinuation of MEDI4736 were considered as treatment related 
in 18 subjects (2.6%), with colitis being the most frequent treatment-related AE 
resulting in discontinuation (3 subjects). A majority of the treatment-related AEs 
resulting in discontinuation of MEDI4736 were ≥ Grade 3 in severity and resolved 
with or without sequelae.  
 
Study D4191C00003/ATLANTIC: The safety profile of MEDI4736 monotherapy 
in Study CD-ON-durvalumab-1108 is generally consistent with that of 
Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic 
non-small-cell lung cancer (NSCLC) treated with MEDI4736 10 mg/kg Q2W. As 
of 05May2015, 264 of 303 subjects (87.1%) reported any AE in Study 
D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were 
dyspnea (18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), 
pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-thirds of the 
subjects experienced AEs that were Grade 1 or 2 in severity and manageable by 
general treatment guidelines as described in the current MEDI4736 study protocols. 
Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 
subjects (42.2%) reported AEs that were considered by the investigator as related 
to investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of 
subjects were decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea 
(4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, hypothyroidism, and pyrexia 
(3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting (2.0%). 
Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis (3 
subjects) and increased GGT (2 subjects). There was no treatment-related Grade 4 
or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that 
occurred in ≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, general 
physical health deterioration (2.3% each); pneumonia (2.0%); hemoptysis, 
pulmonary embolism (1.3% each); and pneumonitis, respiratory failure, disease 
progression (1.0% each). Nine subjects had an SAE considered by the investigator 
as related to MEDI4736. Each treatment-related SAE occurred in 1 subject each 
with the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 
subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general physical 
health deterioration, disease progression, hemoptysis, dyspnea [2 subjects each]; 
pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim term 
(VT)], hepatic failure, and sepsis [1 subject each]). None of these events was 
considered related to MEDI4736. Twenty-three of 303 subjects (7.6%) 
permanently discontinued MEDI4736 treatment due to AEs. Events that led to 
discontinuation of MEDI4736 in ≥ 2 subjects were dyspnea, general physical health 
deterioration, and pneumonia. Treatment-related AEs that led to discontinuation 


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were increased ALT and increased hepatic enzyme, which occurred in 1 subject 
each. 
 
Efficacy  
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with 
MEDI4736 10 mg/kg Q2W were evaluable for response (defined as having 
≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 follow-up scan, or 
discontinued due to disease progression or death without any follow-up scan). In 
PD-L1 unselected patients, the objective response rate (ORR), based on 
investigator assessment per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in bladder 
cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% 
in triple-negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous 
melanoma (n = 23). PD-L1 status was known for 383 of the 456 response evaluable 
subjects. Across the PD-L1-positive tumors, ORR was highest for bladder cancer, 
advanced cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% 
each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the head and neck 
(SCCHN; n = 22, 18.2%). In the PD-L1-positive subset, DCR-24w was highest in 
advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 36.0%), HCC and 
bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
 
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) 
treated in Study D4190C00007, 21 subjects had at least 1 post-baseline disease 
assessment. Among these subjects, the best overall responses were marrow 
complete remission (mCR) in 4 subjects (19.0%); stable disease (SD) in 4 subjects 
(19.0%); and progressive disease (PD) in 5 subjects (23.8%). The remaining 8 
subjects (38.1%) did not meet the criteria for complete remission (CR), mCR, 
partial remission (PR), SD, or PD at the date of assessment. 
 
Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or 
unresectable melanoma treated with the combination of MEDI4736 and BRAF 
inhibitor (BRAFi; dabrafenib)/MEK inhibitor (MEKi; trametinib), 63 subjects 
were evaluable for response. A total of 35 subjects (55.6%) had a best overall 
response of confirmed or unconfirmed PR. The disease control rate (DCR; CR + 
PR [regardless of confirmation] + SD ≥ 12 weeks) was 79.4%.  
 
Fixed Dosing  
A population PK model was developed for MEDI4736 using monotherapy data 
from a Phase 1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 
mg/kg Q3W; solid tumors). Population PK analysis indicated only minor impact of 
body weight (WT) on PK of MEDI4736 (coefficient of ≤ 0.5). The impact of body 
WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of MEDI4736 was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 
95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total 
of 1000 patients were simulated using body WT distribution of 40–120 kg. 


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Simulation results demonstrate that body WT-based and fixed dosing regimens 
yield similar median steady state PK concentrations with slightly less overall 
between-subject variability with fixed dosing regimen.   
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, 
Zhang et al, 2012, Narwal et al 2013]. Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform 
similarly, with fixed dosing being better for 7 of 12 antibodies [3]. In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing 
performed better for 12 of 18 in terms of reducing the between-subject variability 
in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012].  
 
A fixed dosing approach is preferred by the prescribing community due to ease of 
use and reduced dosing errors. Given expectation of similar pharmacokinetic 
exposure and variability, we considered it feasible to switch to fixed dosing 
regimens. Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W 
MEDI4736 (equivalent to 10 mg/kg Q2W) is included in the current study. Fixed 
dosing of MEDI4736 is recommend only for subjects with > 30kg body weight due 
to endotoxin exposure.  Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule.  
 
1.4 
Study Rationale 
 
Brain metastases are the most common intracranial malignancy occurring in 20-40% of all 
cancers, and the presence of CNS metastases is associated with a poor prognosis. As such, 
the median overall survival of patients with symptomatic brain lesions is a dismal 2-3 
months regardless of tumor type. Because standard chemotherapy largely does not cross 
the blood brain barrier at a meaningful concentration, standard treatment is limited and 
usually involves surgical resection and/or stereotactic radiosurgery for isolated lesions and 
whole brain radiation for multiple lesions. Unfortunately, the median overall survival is 
only improved by about 6 months with this multimodality approach2, and there is a paucity 
of second-line therapies to treat recurrence. Furthermore, re-resection and re-radiation are 
often not feasible options due to concern for increasing complications or neurotoxicity, 
respectively. Thus, there is a dire clinical need for additional treatment options for this 
patient population. 
 
Checkpoint blockade therapy, in particular PD-1 and PD-L1 inhibition, has recently shown 
clinical efficacy in multiple types of solid tumors.7 Nivolumab and pembrolizumab are PD-
1 checkpoint inhibitors that have been FDA approved for first line therapy in metastatic 
melanoma, while nivolumab has been approved for second line therapy in metastatic 
squamous-cell NSCLC. Moreover, several large phase III studies are pending with 
promising results that will likely lead to the expansion of the number of indications where 
these agents (and others) will be approved [www.clinicaltrials.gov].30  Lastly, there is data 
suggesting that checkpoint inhibitors may also be equally efficacious in treating patients 
with CNS disease (see Section 1.2.3).  
 


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Therefore, we propose to study the efficacy of checkpoint blockade therapy in patients with 
solid tumors and refractory/recurrent brain metastases.  However, as there has already been 
a phase II study evaluating CTLA-4 checkpoint blockade in patients with melanoma and 
CNS disease27 as well as several clinical trials utilizing PD-1 or PD-L1 checkpoint 
blockade specifically in the same patient population [www.clinicaltrials.gov], we will 
specifically exclude patients with melanoma from our analysis. Additionally, given the rare 
occurrence of CNS disease in patients with sarcoma, we will limit our study to solid tumors 
of epithelial origin, and will predominantly focus on patients with NSCLC as it is the most 
common cause of brain metastasis plus has been shown to be responsive to checkpoint 
blockade.  An expansion, basket cohort will include other epithelial malignancies. 
 
While CTLA-4 checkpoint inhibition has proven to be an effective treatment for 
melanoma, results in other solid tumor types has been poor. Thus, we will focus our study 
on the PD-1/PD-L1 pathway as it has been shown to be upregulated in various solid tumors 
and has been associated with an overall poor prognosis.14-16,31,32 Furthermore, inhibiting 
this pathway has been shown to be effective, specifically NSCLC.  To date, there are no 
studies that directly compare PD-1 vs PD-L1 checkpoint inhibitors head-to-head. Though 
while there are similar mechanisms between the two approaches, there are distinct 
differences as well. PD-1 is expressed on immune cells, particularly T cells, and exerts its 
immunosuppressive effects when it recognizes PD-L1 or PD-L2 expressed by the tumor 
cells and/or other infiltrating immune cells such as B cells, dendritic cells or 
macrophages/monocytes. Conversely, PD-L1 is expressed on both tumor cells as well as 
activated immune cells including T cells, and can inhibit T cells directly when it recognizes 
either PD-L1 or PD-L2 as well as the activation molecule, CD80, which is expressed on 
activated antigen presenting cells. Therefore, we hypothesize that inhibition of PD-L1 will 
result in more robust T cell activation than PD-1 inhibition by releasing the inhibitory 
signal on T cells in two ways: (1) directly blocking suppression from the tumor 
microenvironment (i.e. PD-L1 and PD-L2) as well as (2) indirectly leading to more 
efficient priming of tumor-specific T cells by permitting costimulatory molecules on 
activated T cells (i.e. CD28) to freely recognize activation molecules on antigen-presenting 
cells (i.e. CD80). 
 
Therefore, we will assess the efficacy of MEDI4736, a novel PD-L1 inhibitory monoclonal 
antibody, in this study. 
 
1.5 
Correlative Studies Background 
 
The clinical correlates of this study will have two aims: 
 
Aim 1: Identify CNS and systemic biomarkers that predict response to MEDI4736. 
 
Aim 2: Characterize the immune response at baseline and post-MEDI4736 to identify 
immune parameters associated with protection. 
 
Peripheral blood samples and, when available, paired tissue biopsies from primary and 
CNS lesions will be collected.  Peripheral blood samples will be drawn at time of 
enrollment and at day 8, day 15, day 29, 3 months, 6 months, 12 months, and at time of 
progression (no further blood samples will be drawn after progression). 


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1.5.1 Aim 1: Biomarker assessment 
 
 
PD-L1 expression on tumor cells is thought to serve as a clinical biomarker that is 
correlated with response to PD-1 checkpoint blockade. However, there remains 
debate regarding an appropriate cut-off to define positivity. Moreover, there 
remains a substantial percentage of patients who benefit from therapy who are 
considered negative for PD-L1 expression. Furthermore, it is not clear if a similar 
association between PD-L1 positivity and response OR what an appropriate 
definition of positivity should be with PD-L1 checkpoint inhibitors. Lastly, there 
have been no studies to date that have demonstrated concordance/discordance in 
checkpoint inhibitor expression between primary and CNS metastases. Therefore, 
Aim 1 will address three goals: 
 
Quantify expression of PD-1 and PD-L1 by IHC on tumor cells and tumor 
infiltrating lymphocytes to determine if there is a correlation with response and 
if so, to determine the level of PD-L1 expression on either tumor and/or TIL 
that adequately defines positivity to predict patients that would most likely 
benefit from MEDI4736 therapy. 
 
Quantify expression of PD-L2, and CTLA-4 to identify biomarkers associated 
resistance to therapy. Because PD-L1 blockade does not block the interaction 
between PD-L2 and PD-1, it is possible that high expression of either of these 
two molecules may lead to resistance to PD-L1 checkpoint inhibition as it 
provides a bypass mechanism of immunosuppression.  Additionally, since PD-
L1 interacts with PD-1 on T cells, if the immune infiltrate does not express high 
levels of PD-1, there may be no effect of PD-L1 inhibition despite high levels 
of PD-L1 present. Alternatively, CTLA-4 serves as a potential source of 
resistance that is not affected by PD-1/PD-L1 blockade. 
 
Compare checkpoint inhibitor expression levels of PD-1, PD-L1, PD-L2, and 
CTLA-4 in paired primary and CNS biopsies. This data will allow 
determination of frequency of concordant or discrepant expression of various 
mechanisms of checkpoint inhibition between primary and metastatic disease 
sites. For example, if there is high concordance between primary and CNS sites, 
the expression levels from the primary tissue can be used to predict a potentially 
responding individual rather than having to obtain tissue from the CNS, which 
is difficult and relatively more morbid than systemic tissue acquisition. 
Alternatively, if there is high discordance, then obtaining biopsies from the 
CNS would be recommended. Furthermore, a high discordance between 
primary and CNS disease locations may explain the basis of mixed responses.  
 
1.5.2 Aim 2: Immune characterization 
 
The tumor infiltrating lymphocytes (TIL) have been studied in various tumor tissue 
and generally felt to be associated with good prognosis.33-36 The presence of TILs 
has been used as justification for the presence of immunosurveillance and thus the 
basis for the efficacy of immunotherapy.  While the presence of CD8+ cytotoxic T 
cells within the TIL have predominantly been associated with protection, there is 


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often the presence of immunosuppressive subsets such as regulatory T cells (Tregs) 
and myeloid derived suppressor cells (MDSCs) that are associated with poor 
prognosis.37,38 The interplay between these effector and suppressive subsets in 
determining the response to checkpoint inhibitor therapy has yet to be 
elucidated.  Therefore, Aim 2 will characterize the tumor immune infiltrate and 
circulating immune cells using the following approaches: 
 
TCR profiling by spectrotyping and flow cytometry to assess changes in relative 
frequency of TCR gene utilization as a surrogate of clonal expansion and 
selection of the CD4 and CD8 T cell repertoire (i.e. tumor-specific T cell 
response) following MEDI4736. 
 
Flow cytometry and CyTOF to identify and quantify the immunophenotype of 
various effector immune subsets to determine changes in immune profile 
between baseline and post-MEDI4736. Correlations between treatment 
response and resistance will be determined to predict potential patients that will 
benefit from MEDI4736 therapy. The following immune subsets will be 
assessed:  
o T cell: CD3, CD8, CD4, Foxp3 (Tregs), t-bet (Th1), ROR-g (Th2), 
effector memory T cells (Tem), central memory T cells (Tcm); 
intracellular staining for IFN-g, TNF-a, IL-2, IL-17, IL-4, IL-10 will be 
determined to assess functional capacity of T cells before and after 
MEDI4736. 
o NK cell: CD56, CD16 
o MDSC: CD14, HLA-DR 
o Activation markers: ICOS, OX40, CD137, CD25, GITR 
o Inhibitory markers: PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3 
 
Multiplex analysis and QPCR to assess changes in cytokine profile: IFN-a, IFN-
b, IFN-g, IL-2, TNF-a, IL-2, IL-4, IL-5, IL-13, IL-10, IL-6, TGF-b. 
 
Tumor cells will be microdissected from tissue biopsies and sent for whole 
exome sequencing and RNAseq to quantify the mutational landscape as a 
surrogate of antigenic burden. As antigenic burden has been correlated with 
response to checkpoint inhibitor therapy, we will determine if response to 
MEDI4736 is associated with mutational burden.39-41 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the overall response rate of intracranial disease following treatment with 
MEDI4736. 
 
2.2 
Secondary Objectives 
 
1. To determine safety of MEDI4736 in advanced solid epithelial-derived tumor patients 
with brain metastases 
2. To determine the overall disease control rate of intracranial disease.  


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3. To determine the overall response rate and disease control rate of extracranial disease. 
4. To determine the overall response rate and disease control rate considering both 
intracranial and extracranial disease. 
5. To evaluate the duration of response for intracranial disease, extracranial disease, and 
both considered together. 
6. To determine the progression-free survival. 
7. To determine the overall survival  
8. To determine the safety of MEDI4736 in patients with intracranial epithelial-derived 
tumor metastases 
9. To evaluate the influence of concomitant corticosteroid therapy on treatment outcomes 
 
2.3 
Exploratory Objective 
 
To determine the correlation of iRANO criteria with overall response rate and overall 
disease control rate of intracranial disease. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Cohort A: Histologically confirmed metastatic non-small cell lung cancer (all 
histologic subtypes allowed) with radiographic evidence by MRI of at least one 
measurable brain lesion as defined by RANO criteria that does not require 
corticosteroids for symptomatic control. 
 
Cohort B: Histologically confirmed metastatic solid tumor of epithelial origin, 
excluding NSCLC, including but not limited to ovarian cancer, colorectal cancer, 
pancreatic cancer, gastric cancer, renal cancer, bladder cancer, or breast cancer with 
radiographic evidence by MRI of at least one measurable brain lesion as defined by 
RANO criteria that does not require corticosteroids for symptomatic control. 
 
Cohort C: Histologically confirmed metastatic solid tumor of epithelial origin, 
including both NSCLC and non-NSCLC, with radiographic evidence by MRI of at least 
one measurable brain lesion as defined by RANO criteria that requires corticosteroids 
for symptomatic control. 
 
2. At least one prior treatment to a CNS-based lesion is required.  Prior therapy must be 
completed > 2 weeks prior to enrollment.  A previously treated lesion must be 
demonstrated by MRI to have progressed following treatment in order to be eligible.  
The subsequent development of a new CNS lesion that was not previously treated will 
be permitted and dose not require treatment followed by progression prior to 
enrollment.  Treatment of a single CNS lesion with local therapy in the context of 
multifocal disease is permitted as long as at least one untreated lesions meets criteria 
for measurable disease. Patients should have received minimum of one line of systemic 
therapy. 


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3. At least 18 years of age. 
 
4. ECOG performance status of 0 to 2 (Appendix A). 
 
5. Adequate bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcL 
b. Platelets ≥ 100,000/mcL 
c. Hemoglobin ≥ 8.0 g/dL 
d. Serum bilirubin ≤ 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
f. Creatinine clearance ≥ 40 mL/min/1.73 m2 by the Cockcroft-Gault formula 
(Appendix B) or by 24-hour urine collection for determination of creatinine 
clearance 
 
6. Negative antiviral serology: 
a. Negative human immunodeficiency virus (HIV) antibody. 
b. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core 
(HBc) antibody or undetectable hepatitis B (HBV) DNA by quantitative 
polymerase chain reaction (PCR) testing. 
c. Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid 
(RNA) by quantitative PCR. 
 
7. Mean QT interval corrected for heart rate (QTc) < 470 msec calculated from 3 ECGs 
performed at least 2 minutes apart using Frediricia’s Correction. 
 
8. Female subjects must either be of non-reproductive potential (i.e., post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical cause; 
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of 
bilateral oophorectomy) or must have a negative serum pregnancy test upon study 
entry.   
 
9. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
 
1. Diagnosis of leptomeningeal carcinomatosis. 
 
2. Diagnosis of melanoma or other non-epithelial based malignancy such as sarcoma, 
neuroendocrine tumor, small cell lung cancer. 
 
3. Presence of unstable systemic disease (e.g., visceral crisis or rapid progression) in the 
judgment of the investigator. 
 


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4. A history of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
5. Currently receiving any other investigational agents. 
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MEDI4736 or other agents used in the study. 
 
7. Previous treatment with a PD-1 or PD-L1 inhibitor, including MEDI4736, or a CTLA-
4 inhibitory agent. 
 
8. 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 in Cohort C. 
 
9. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) 21 days prior to the first dose of study drug. 
 
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension (>180/110), 
unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, 
active bleeding diatheses, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
11. Active or prior documented autoimmune disease within the past 2 years (Note: subjects 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded). 
 
12. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
 
13. History of prior immunodeficiency. 
 
14. History of allogeneic organ transplant. 
 
15. Known history of previous clinical diagnosis of tuberculosis. 
 
16. Receipt of live attenuated vaccination within 30 days prior to first dose of MEDI4736. 
 
17. Pregnant and/or breastfeeding or female patients of reproductive potential who are not 
employing an effective method of birth control.   
 
18. Any condition that, in the opinion of the investigator, would interfere with evaluation 
of study treatment or interpretation of patient safety or study results 


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3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
All patients must be registered through the Siteman Cancer Center database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
There are no required premedications. 
 
 


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5.2 
Agent Administration 
 
MEDI4736 will be given to all patients > 30 kg actual body weight intravenously at a fixed 
dose 750 mg every 2 weeks over the course of 60 minutes on an outpatient basis on Days 
1 and 15 of each 28-day cycle.  Patients < 30 kg actual body weight will be dosed at 10 
mg/kg every 2 weeks.  Subjects will be monitored during and after the infusion with 
assessment of vital signs. 
  
5.3 
Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment due to 
treatment related adverse events(s) prior to completion of Cycle 2 and have not had any 
disease assessment. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
In the event of a ≤ grade 2 infusion-related reaction, the infusion rate of study drug 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.  For subjects with a ≤ grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is grade 3 or higher in severity, study drug 
will be discontinued. 
 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit subjects to an intensive care unit if necessary. 
 
5.4.1 Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study: 
  
 Any investigational anticancer therapy. 
 Any 
concurrent 
chemotherapy, 
radiotherapy 
(except 
palliative 
radiotherapy), immunotherapy, biologic or hormonal therapy for cancer 
treatment. Concurrent use of hormones for noncancer-related conditions 
(e.g., insulin for diabetes and hormone replacement therapy) is acceptable. 
 Immunosuppressive medications including, but not limited to systemic 


Protocol Version: 02/23/16 
 
Page 27 of 80 
corticosteroids at doses exceeding 4 mg/day of dexamethasone or 
equivalent, methotrexate, azathioprine, and TNF-α blockers. Use of 
immunosuppressive medications for the management of investigational 
product-related AEs (see section 6.0) or 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 (i.e., 30 days 
prior to the first dose, during treatment with MEDI4736, and for 30 days 
post discontinuation of MEDI4736).  Inactivated viruses, such as those in 
the influenza vaccine, are permitted. 
 
5.4.2 Corticosteroids 
 
One of the expected side effects of immunotherapy in general is increased 
inflammation at the site of disease due to immune cell infiltration. As such, subjects 
may experience CNS-related adverse effects related to increased vasogenic edema 
and inflammation. The standard treatment is a short course of corticosteroids such 
as dexamethasone. While subjects in Cohorts A and B must not require 
dexamethasone at time of enrollment or first dose of MEDI4736, a course of 
dexamethasone is permitted in the setting of a flare. Given the immunosuppressive 
effects of corticosteroids, all subsequent doses of MEDI4736 will be held until 
patients are able to be tapered to at least 4 mg daily of dexamethasone or equivalent 
before reinitiating therapy. Alternatively, if patients in Cohorts A or B develop 
evidence of progression requiring immediate treatment while on corticosteroids, 
they will be removed from the study. There will be no maximum time limit 
MEDI4736 can be held before subjects must be withdrawn for study protocol as 
long as there is no evidence of disease progression that requires alternative 
treatment options.  
 
5.5 
Women of Childbearing Potential 
 
Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use 2 methods of effective contraception from screening, and must agree to 
continue using such precautions for 90 days following the last infusion of MEDI4736; 
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 
(i.e., 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 the 
table below. 
 Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see table below) 
from Day 1 and for 90 days after receipt of the final dose of investigational product. 


Protocol Version: 02/23/16 
 
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Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill 
Minipill 
Patch 
a This is also considered a hormonal method. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
 Documented and confirmed CNS disease progression by RANO criteria 
 Documented and confirmed non-CNS disease progression by Immune-related 
Response Criteria (irRC) 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6.1 Permanent Discontinuation of MEDI4736  
 
An individual subject will not receive any further investigational product if any of 
the following occur in the subject in question: 
 
1. Withdrawal of consent or lost to follow-up 
2. Adverse event that, in the opinion of the investigator or the sponsor, 
contraindicates further dosing 
3. Subject is determined to have met one or more of the exclusion criteria for study 


Protocol Version: 02/23/16 
 
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participation at study entry and continuing investigational therapy might 
constitute a safety risk 
4. Pregnancy or intent to become pregnant 
5. Grade ≥ 3 infusion reaction 
6. Initiation of alternative anticancer therapy including another investigational 
agent 
 
5.6.2 Withdrawal of consent 
 
If consent is withdrawn, the subject will not receive any further investigational 
product or further study observation.  
 
5.7 
Duration of Follow-up 
 
Patients will be followed every 6 months for 2 years after completion of treatment or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
For adverse events (AEs) that are considered at least partly due to administration of MEDI4736 
the following dose adjustment guidance may be applied: 
 Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
 If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of MEDI4736 along with appropriate continuing supportive care.  
If medically appropriate, dose modifications are permitted for MEDI4736 (see below). 
 All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
In addition, there are certain circumstances in which MEDI4736 should be permanently 
discontinued.  Following the first dose of MEDI4736, subsequent administration of MEDI4736 
can be modified based on toxicities observed (see the tables below). 
 
Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, 
there is the possibility of observing immune-related adverse events (irAEs) during the conduct of 
this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (e.g., infection or progressive disease) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-related. 
   
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
the tables below.  In addition, management guidelines for adverse events of special interest 
(AESIs) are detailed in Section 7.9. All toxicities will be graded according to NCI CTCAE v4.03. 
 
 


Protocol Version: 02/23/16 
 
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Immune-Mediated Reactions 
Event 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events  
 
(overall 
management for 
toxicities not 
noted below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration modifications of study drug/study regimen will be 
made to manage potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study 
drug/regimen based on CTC grade/severity (table below) , permanently 
discontinue study drug/study regimen for  the following conditions:  
 Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone 
per day (or equivalent) within 12 weeks after last dose of study 
drug/regimen 
 Recurrence of a previously experienced Grade 3 treatment-related 
AE following resumption of dosing. 
It is recommended that management of irAEs follow the guidelines 
presented in this table 
- Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, concomitant medications, 
infections, etc.) 
- In the absence of a clear alternative etiology, all events should be 
considered potentially immune related. 
- Symptomatic and topical therapy should be considered for low-grade 
(Grade 1 or 2, unless otherwise specified) events  
- For persistent  (greater than 3 to 5 days) low-grade (Grade 2)  or severe 
(Grade ≥3) events  promptly start prednisone PO 1-2mg/kg/day or IV 
equivalent  
- If symptoms recur or worsen during corticosteroid tapering 28 days of 
taper), increase the corticosteroid dose (prednisone dose  [e.g. up to 2-
4mg/kg/day or IV equivalent])   until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (> 28 
days of taper) 
 
- More potent immunosuppressives such as TNF inhibitors (e.g. 
infliximab) – (also refer to the individual sections of the immune 
related adverse event for specific type of immunosuppressive) should 
be considered for events not responding to systemic steroids.   
- Discontinuation of study drug is not mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to local tumour response (e.g. 
inflammatory reaction at sites of metastatic disease, lymph nodes etc.). 
Continuation of study drug in this situation should be based upon a 
benefit/risk analysis for that patient  
 
 
 
 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until grade 2 
resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 3 or Grade 4 
• If toxicity improves to baseline then treat at next 
scheduled treatment date 
Study drug/study treatment can be resumed at the next 
scheduled dose once event stabilizes to grade ≤1 
and 5-7 days have passed after completion of 
steroid taper 
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement can be 
retreated with study drug/study regimen on the 
following conditions: 1) the event stabilizes and is 
controlled , 2) the patient is clinically stable as per 
Investigator or treating physician’s clinical 
judgement, and 3) doses of prednisone are at less 
than or equal to 10mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may permanently 
discontinue study drug/study regimen. Please refer to 
guidelines below 
Grade 4 
Permanently discontinue study drug/study regimen  
Note:  For Grade 3 and above asymptomatic amylase or lipase levels 
hold study drug/regimen and if complete work up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
Pneumonitis / 
ILD 
Any Grade 
N/A 
- Monitor patients for signs and symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath or cough).  Patients should be 
evaluated with imaging and pulmonary function tests including other 
diagnostic procedures as described below 
- Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory work-up 
and high-resolution CT scan.  
Grade 1  
(Asymptomatic, 
clinical or diagnostic 
observations 
only, 
intervention 
not 
indicated) 
No dose modification required. 
However, consider holding study 
drug/study regimen dosing as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only) 
-  Monitor and closely follow up in 2-4 days for clinical symptoms, pulse 
oximetry (resting and exertion) and laboratory work-up and then as 
clinically indicated 
-  Consider pulmonary and  infectious disease consult 
Grade 2  
(Symptomatic, 
medical intervention 
indicated, 
limiting 
instrumental ADL)  
Hold study drug/study regimen 
dose until grade 2 resolution to ≤ 
Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• If toxicity improves to baseline 
then the decision to reinitiate 
study drug/regimen at next 
scheduled treatment date will 
be 
based 
upon 
treating 
physician’s clinical judgment.  
Study drug/study treatment can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper   
  
For Grade 2 (Mild to Moderate New Symptoms) 
- Monitor symptoms daily and consider hospitalization 
- Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day or IV 
equivalent) 
- Reimaging as clinically indicated 
- If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started  
- If still no improvement within 3-5 days despite IV methylprednisone at 2-
4/g/kg/day, promptly start immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 weeks). Caution: Important 
to rule out sepsis and refer to infliximab label for general guidance before 
using infliximab  
- Once improving, gradually taper steroids over ≥4 weeks  and consider 
prophylactic antibiotics, antifungal or anti PCP treatment (refer to current  
NCCN guidelines for treatment of  cancer-related infections (Category 2B 
recommendation) 
- Consider pulmonary and infectious disease consult 
- Consider as necessary  discussing with study physician 
Grade 3 or 4  
(Grade 3: Severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated;  
 
Permanently discontinue study 
drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life 
threatening  
- Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- Obtain pulmonary and infectious disease  consult 
- Hospitalize the patient 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention 
indicated [e.g. 
tracheostomy or 
intubation])  
- Supportive Care (oxygen, etc.) 
- If no improvement within 3-5 days, additional workup should be 
considered and prompt treatment with additional immunosuppressive 
therapy such as TNF inhibitors (e.g. infliximab at 5mg/kg every 2 weeks 
dose) started. Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab  
- Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and in particular,  anti PCP 
treatment (please refer to current  NCCN guidelines for treatment of  
cancer-related infections (Category 2B recommendation) 
Diarrhea/ 
Enterocolitis 
Any Grade 
N/A 
- Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits such as increased 
frequency over baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and ileus) 
- Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, infections 
including testing for clostridium difficile toxin, etc.) 
- Steroids should be considered  in the absence of clear alternative 
etiology, even for low grade events, in order to prevent potential 
progression to higher grade event 
- Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis 
Grade 1 diarrhea  
(stool frequency of 
<4 over baseline per 
day)  
No dose modification 
For Grade 1 diarrhea :  
-  Close monitoring for worsening symptoms 
-  Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association colitis 
diet), and loperamide. Use of probiotics as per treating physician’s clinical 
judgment. 
Grade 2 diarrhea 
(stool frequency of 
4-6 over baseline per 
day)  
Hold study drug/study regimen 
until resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat 
as Grade 3 or Grade 4 
• 
If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
Study drug/study regimen can be 
resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 5-7 
For Grade 2 diarrhea:  
- Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association colitis 
diet), and loperamide and/or budesonide  
- Promptly start  prednisone 1 to 2  mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone 
at 1-2 mg/kg/day or IV equivalent, GI consult should be obtained for 
consideration of further workup such as imaging and/or colonoscopy to 
confirm colitis and rule out perforation,   and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- If still no improvement within 3-5 days despite 2-4mg/kg IV 


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Event 
Grade 
Dose Modifications 
Toxicity Management 
days have passed after 
completion of steroid taper    
methylprednisolone, promptly start immunosuppressives such as 
(infliximab at 5mg/kg once every 2 weeks). Caution: Important to rule 
out bowel perforation and refer to infliximab label for general guidance 
before using infliximab   
- Consult study physician if no resolution to ≤ Grade 1 in 3-4 days 
- Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 
Grade 3 or 4 
diarrhea  
 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day;  
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 diarrhea: 
- Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent  
- Monitor stool frequency and volume and maintain hydration   
- Urgent GI consult and imaging and/or colonoscopy as appropriate 
- If still no improvement within 3-5 days of IV methylprednisolone 2 to 
4mg/kg/day or equivalent, promptly start further immunosuppressives 
(e.g. infliximab at 5mg/kg once every 2 weeks).   
- Caution: Ensure GI consult to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab.  
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 
Hepatitis 
(Elevated LFTs) 
 
Any Grade 
Infliximab should not be used for 
management of Immune Related 
Hepatitis 
- Monitor and evaluate liver function test: AST, ALT, ALP and total 
bilirubin  
- Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications)  
Grade 1  
(AST or ALT > 
ULN to 3 times 
ULN and/or TB > 
ULN to 1.5 times 
ULN) 
No dose modification 
If  it worsens, treat as Grade 2 
event 
For Grade 1 AST or ALT and/or TB elevation        
 - Continue LFT monitoring per protocol   
Grade 2  
(AST or ALT > 3 to 
5 times ULN and/or 
TB >1.5-3.0 times 
ULN) 
Hold Study drug/study regimen 
dose until grade 2 resolution to ≤ 
Grade 1 
• If  toxicity worsens then treat 
as Grade 3 or Grade 4 
• If improves to baseline then 
For Grade 2 AST or ALT and or TB elevation :  
- Regular and frequent checking of LFTs (e.g. every 1-2 days) until 
elevations of these are improving or resolved.   
- If no resolution to ≤ Grade 1 in 1-2 days, discuss with study physician. 
- If event is persistent (> 3-5 days) or worsens, promptly start prednisone 
1-2mg/kg/day or IV equivalent.  


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper    
- If still no improvement within 3-5 days despite 1-2mg/kg/day of 
prednisone or IV equivalent, consider additional workup and prompt 
treatment with IV methylprednisolone 2-4mg/kg/day started. 
- If still no improvement within 3-5 days despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil). Discuss with study physician if mycophenolate mofetil is not 
available.  Infliximab should NOT be used. 
- Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 
Grade 3 
(AST or ALT >5-20 
times ULN and/or 
TB > 3.0-10 times 
ULN 
For elevations in transaminases ≤ 
8 × ULN, or elevations in 
bilirubin ≤ 5 × ULN  
-Hold study drug/study 
regimen dose until resolution 
to ≤ Grade 1 or baseline   
-Resume study drug/study 
regimen administration at the 
next scheduled dose if 
elevations downgrade ≤ 
Grade 1 or baseline within 14 
days 
Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to ≤ 
Grade 1 or baseline within 14 
days  
For elevations in transaminases > 
8 × ULN or elevations in 
bilirubin > 5 × ULN, 
discontinue study drug/study 
regimen  
Permanently discontinue study 
drug/study regimen for any 
case meeting Hy’s law criteria 
(ALT > 3x ULN + bilirubin > 
2x ULN without initial 
findings of cholestasis (i.e. 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or 
equivalent  
- If still no improvement within 3-5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent , promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil)  Discuss with 
study physician if mycophenolate is not available. Infliximab should 
NOT be used. 
- Hepatology consult, abdominal workup, and imaging as appropriate. 
- Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
elevated alkaline P04) and  in 
the absence of any alternative 
causei 
Grade 4  
(AST or ALT > 20 
times ULN and/or 
TB > 10 times ULN)  
Permanently discontinue study 
drug/study regimen  
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)  
Any Grade  
N/A 
 
 
 
- Consult with Nephrologist 
- Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. routine urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.)  
- Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, infections etc.) 
- Steroids should be considered in the absence of clear alternative etiology 
even for low grade events (Grade 2) , in order to prevent potential 
progression to higher grade event 
Grade 1 [Serum 
Creatinine > 1-1.5X 
baseline;  > ULN to 
1.5X ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-  Monitor serum creatinine weekly and any accompanying symptom 
 If creatinine returns to baseline, resume its regular monitoring per 
study protocol. 
 If it worsens, depending on the severity , treat as Grade 2 or 3 or 4  
-  Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2 [Serum 
Creatinine>1.5-3.0X 
baseline; >1.5X-
3.0XULN] 
 
Hold study drug/study regimen 
until resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat 
as Grade 3 or Grade 4 
• 
If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
Study drug/study regimen can be 
resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 for 5-7 
days have passed after 
completion of steroid taper    
For Grade 2 elevated creatinine:  
- Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc.  
- Carefully monitor serum creatinine  every 2-3 days and as clinically 
warranted 
- Consult Nephrologist and consider renal biopsy if clinically indicated 
- If event is persistent (> 3-5 days) or worsens,  promptly start  prednisone 
1 to 2 mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone 
at 1-2 mg/kg/day or IV equivalent, additional workup should be 
considered and prompt treatment with IV methylprednisolone at 2-
4mg/kg/day started.  
- Once improving gradually taper steroids over ≥28 days and   consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current NCCN guidelines for treatment of cancer-related infections 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
[Category 2B recommendation]).  
- When event returns to baseline, resume study drug/study regimen and 
routine serum creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 X 
ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN)  
Permanently discontinue study 
drug/study regimen 
- Carefully monitor serum creatinine  on  daily basis 
- Consult Nephrologist and consider renal biopsy if clinically indicated 
- Promptly  start  prednisone 1 to 2  mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days or worsens despite prednisone 
at 1-2 mg/kg/day or IV equivalent, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started.  
- Once improving,  gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]  
Rash (excluding 
Bullous skin 
formations) 
Any Grade  
N/A 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY DRUG 
DISCONTINUED** 
Grade 1  
No dose modification 
For Grade 1: 
- Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
Grade 2 
For persistent (> 1- 2 weeks) 
Grade 2 events, hold 
scheduled study drug/study 
regimen until resolution to ≤ 
Grade 1 or baseline  
 
If  toxicity worsens then 
treat as Grade 3  
 
If  toxicity improves then  
resume administration at 
next scheduled dose 
 
Study drug/study 
regimen can be resumed 
at the next scheduled 
dose once event 
stabilizes to grade ≤1 
and 5-7 days have passed 
after completion of 
steroid taper    
For Grade 2 : 
- Obtain dermatology consult  
- Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
- Consider moderate-strength topical steroid  
- If no improvement of rash/skin lesions occurs within 3-5 days or is 
worsening despite symptomatic treatment and/or use of moderate 
strength topical steroid, discuss with study physician and promptly start 
systemic steroids prednisone  1-2 mg/kg/day or IV equivalent   
- Consider skin biopsy if persistent for >1-2 weeks or recurs 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
Grade 3 
Hold study drug/study regimen 
until resolution to ≤ Grade 1 or 
baseline 
 If temporarily holding the study 
drug/study regimen does not 
provide improvement of the 
Grade 3 skin rash  to ≤ Grade 
1 or baseline within 30 days, 
then permanently discontinue 
Study drug/study regimen  
For Grade 3 or 4: 
- Consult dermatology  
-  Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- Consider hospitalization 
- Monitor extent of rash [Rule of Nines] 
- Consider skin biopsy (preferably more than 1) as clinically feasible. 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 
- Discuss with Study Physician 
Grade 4 
Permanently discontinue study 
drug/study regimen  
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.) 
Any Grade  
N/A 
- Consult Endocrinologist 
- Monitor patients for signs and symptoms of endocrinopathies.  Non-
specific symptoms include headache, fatigue, behavior changes, changed 
mental status, vertigo, abdominal pain, unusual bowel habits, 
hypotension and weakness. 
- Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression including brain metastases, infections, 
etc.) 
- Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine labs depending on suspected endocrinopathy.  
- If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes 
insipidus), the investigator should send a blood sample for appropriate 
autoimmune antibody testing  
Grade 1 
(Depending on the 
type of 
endocrinopathy, 
refer to CTCAE v 
4.03 for definition) 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- Monitor patient with appropriate endocrine function tests 
- If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of range in 2 
subsequent measurements, include FT4 at subsequent cycles as clinically 
indicated and consider endocrinology consult. 
Grade 2  
(Depending on the 
type of 
endocrinopathy, 
refer to CTCAE v 
4.03 for definition) 
 
For Grade 2 endocrinopathy other 
than hypothyroidism, hold 
study drug/study regimen dose 
until  subject is clinically 
stable 
• If  toxicity worsens then treat 
as Grade 3 or Grade 4  
For Grade 2: (including those with symptomatic endocrinopathy) 
- Isolated hypothyroidism may be treated with replacement therapy 
without treatment interruption and without corticosteroids 
- Initiate hormone replacement as needed for management 
- Evaluate endocrine function, and as clinically indicated,  consider 
pituitary scan 


Protocol Version: 02/23/16 
 
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Event 
Grade 
Dose Modifications 
Toxicity Management 
 
• If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper 
   Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
can be retreated with study 
drug/study regimen on the 
following conditions: 1) the 
event stabilizes and is 
controlled ,2) the patient is 
clinically stable as per 
Investigator or treating 
physician’s clinical judgement, 
and 3) doses of prednisone are 
at less than or equal to 
10mg/day or equivalent. 
- For patients with abnormal endocrine work up, except for those  with 
isolated hypothyroidism,  consider short-term, corticosteroids (e.g., 1-
2mg/kg/day methylprednisolone or IV equivalent) and prompt initiation 
of treatment with relevant hormone replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). - 
 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]) 
- For patients with normal endocrine work up (lab or MRI scans), repeat 
labs/MRI as clinically indicated. 
Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, 
refer to CTCAE v 
4.03 for definition)  
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism, hold 
study drug/study regimen dose 
until endocrinopathy symptom(s) 
are controlled 
Resume study drug/study regimen   
administration if controlled at the 
next scheduled dose 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of steroid 
taper    
 
For Grade 3 or 4: 
- Consult endocrinologist 
- Isolated hypothyroidism may be treated with replacement therapy 
without treatment interruption and without corticosteroids 
- Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- Administer hormone replacement therapy as necessary. 
- For adrenal crisis, severe dehydration, hypotension, or shock: 
immediately initiate intravenous corticosteroids with mineralocorticoid 
activity 
- Once improving, gradually taper immunosuppressive steroids over ≥4 
weeks and consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for treatment of  
cancer-related infections [Category 2B recommendation]) 
- Discuss with study physician 
Immune mediated  Any Grade  
N/A 
- Patients should be evaluated to rule out any alternative etiology (e.g., 


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Event 
Grade 
Dose Modifications 
Toxicity Management 
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)   
 
 
 
 
 
 
 
disease progression, infections, metabolic syndromes and medications, 
etc.)  
- Monitor patient  for general symptoms (headache, nausea, vertigo, 
behavior change, or weakness) 
- Consider appropriate diagnostic testing (e.g. electromyogram and nerve 
conduction investigations) 
- Symptomatic treatment with neurological consult as appropriate 
Grade 1 
 No dose modifications 
See “Any Grade” recommendations above. 
Grade 2 
 For acute motor neuropathies or  
neurotoxicity, hold study 
drug/study regimen dose until 
resolution to ≤ Grade 1 
 For sensory 
neuropathy/neuropathic pain, 
consider holding study 
drug/study regimen dose until 
resolution to ≤ Grade 1. 
o If toxicity worsens then treat 
as Grade 3 or Grade 4  
o If  toxicity improves to 
baseline then treat at next 
scheduled treatment date 
 Study drug/study regimen can 
be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 5-7 
days have passed after 
completion of steroid taper    
- 
Discuss with the study physician  
- 
Obtain  Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids prednisone 1-2mg/kg/day or IV 
equivalent  
- 
If no improvement within 3-5 days despite 1-2mg/kg/day 
prednisone or IV equivalent consider additional workup and 
promptly treat with additional immunosuppressive therapy (e.g. 
IVIG)  
 
 
Grade 3 
 Hold Study drug/study regimen 
dose until resolution to ≤ Grade 
1 
 Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ 
Grade 1 within 30 days. 
For Grade 3 or 4: 
- Discuss with study physician 
- Obtain Neurology Consult 
- Consider hospitalization 
- Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent  
- If no improvement within 3-5 days despite IV corticosteroids, consider 
additional workup and promptly treat with additional 
immunosuppressants (e.g. IVIG)  
- Once stable, gradually taper steroids over ≥4 weeks 
Grade 4 
 
Permanently discontinue study 
drug/study regimen 
Immune-
Any Grade 
N/A 
- The prompt diagnosis of immune-mediated peripheral neuromotor 


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Event 
Grade 
Dose Modifications 
Toxicity Management 
mediated 
peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and Myasthenia 
Gravis 
syndromes is important, since certain patients may unpredictably 
experience acute decompensations which can result in substantial 
morbidity or in the worst case, death. Special care should be taken for 
certain sentinel symptoms which may predict a more severe outcome, 
such as prominent dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability 
- Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes and medications, 
etc.). It should be noted that the diagnosis of immune-mediated 
peripheral neuromotor syndromes can be particularly challenging in 
patients with underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) throughout the 
neuraxis. Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological consult 
- Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and  “repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon suspicion of such conditions and 
may be best facilitated by means of a neurology consultation  
Important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. Patients requiring 
treatment should be started  with IVIG and followed by plasmapheresis if 
not responsive to IVIG  
Grade 1 
No dose modification 
- Discuss with the study physician 
- Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above 
- Obtain a neurology consult unless the symptoms are very minor and 
stable 
Grade 2 
Hold study drug/study regimen 
dose until resolution to ≤ 
Grade 1 
Permanently discontinue study 
drug/study regimen if it does 
not resolve to ≤ Grade 1 within 
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability 
 
Grade 2  
- Discuss with the study physician  
- Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above 
- Obtain a Neurology Consult  
- Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to treat Myasthenia Gravis. 
Important to consider that steroid therapy (especially with high doses) 
may result in transient worsening of myasthenia and should typically 
be administered in a monitored setting under supervision of a 


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


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Infusion-Related Reactions 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
 
- Management per institutional standard at the discretion of investigator 
- Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event 
For Grade 1 or Grade 2: 
- Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator  
- Consider premedication per institutional standard prior to subsequent 
doses 
Grade 2 
 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event  
Subsequent infusions may be given at 50% of the initial infusion 
rate 
Grade 3/4 
Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions per institutional standards (e.g., 
IM epinephrine, followed by IV diphenhydramine and ranitidine, and IV 
glucocorticoid) 
 
 
Non-immune Mediated Reactions 
Grade 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to study treatment 
(i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be clinically 
significant. 
Treat accordingly as per institutional standard  
1 
No dose adjustment  
Treat accordingly as per institutional standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 14 days, 
resume study drug/study regimen administration at next scheduled dose. Otherwise, discontinue study 
drug/study regimen 
Treat accordingly as per institutional standard  
 
 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be based 
on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and in consultation 
with the sponsor)  
Treat accordingly as per institutional standard  
 


Protocol Version: 02/23/16 
 
Page 43 of 80 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1 
Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.03 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.2 
Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
7.3 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
7.4 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 


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7.5 
Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.7 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences associated with 
use of the drug (i.e., there is a reasonable possibility that the experience may have 
been caused by the drug) by telephone or fax no later than 7 calendar days after 
initial receipt of the information.  A life-threatening adverse experience is defined 
as any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 Report any serious, unexpected adverse experiences, as well as results from animal 
studies that suggest significant clinical risk within 15 calendar days after initial 
receipt of this information.  A serious adverse drug experience is defined as any 


Protocol Version: 02/23/16 
 
Page 45 of 80 
adverse drug experience occurring at any dose that results in any of the following 
outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
An unexpected adverse drug experience is defined as any adverse drug experience, 
the specificity or severity of which is not consistent with the current investigator 
brochure (or risk information, if an IB is not required or available). 
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.8 
Reporting to Astra Zeneca 
 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period 
immediately following the time that written informed consent is obtained through 90 days 
after the last dose of MEDI4736 or until the initiation of alternative anticancer therapy.  
The investigator and/or Sponsor are responsible for informing the Ethics Committee and/or 
the Regulatory Authority of the SAE as per local requirements. 
 
The investigator and/or sponsor must inform the FDA, via a MedWatch form, of any 
serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to 
AstraZeneca.  A copy of the MedWatch report must be faxed to AstraZeneca at the time 
the event is reported to the FDA.  It is the responsibility of the sponsor to compile all 
necessary information and ensure that the FDA receives a report according to the FDA 
reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time. 
 
* A cover page should accompany the MedWatch form indicating the following: 
 
“Notification from an Investigator Sponsored Study” 
 
The investigator IND number assigned by the FDA 


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 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator. 
 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided to AstraZeneca and the FDA. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events.  This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly.  
 
7.9 
Definition of adverse events of special interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for MEDI4736 include but are not limited to events with a potential inflammatory 
or immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with MEDI4736 monotherapy 
and combination therapy. An immune-related adverse event (irAE) is defined as an adverse 
event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE.  
 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
 
AESIs observed with MEDI4736 include: 
 Colitis 
 Pneumonitis 
 ALT/AST increases / hepatitis / hepatotoxicity  
 Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
 Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 


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 Dermatitis 
 Nephritis 
 Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the MEDI4736 Investigator Brochure. 
 
7.9.1 Pneumonitis 
 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as 
pneumonitis has been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). 
Initial work-up should include high-resolution CT scan, ruling out infection, and 
pulse oximetry. Pulmonary consultation is highly recommended.  
 
Guidelines for the management of subjects with immune-mediated events including 
pneumonitis are outlined in Section 6. 
 
7.9.2 Hypersensitivity Reactions 
 
Hypersensitivity reactions as well as infusion-related reactions have been reported 
with anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the 
administration of any foreign protein and/or other biologic agents, reactions 
following the infusion of MAbs can be caused by various mechanisms, including 
acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid reactions 
against the MAb, and serum sickness. Acute allergic reactions may occur, may be 
severe, and may result in death. Acute allergic reactions may include hypotension, 
dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, 
arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
 
Guidelines for management of subjects with hypersensitivity (including 
anaphylactic reaction) and infusion-related reactions are outlined in Section 6. 
 
7.9.3 Hepatic function abnormalities (hepatotoxicity) 
 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-
PD-1 antibodies (Brahmer et al 2012).  Inflammatory hepatitis has been reported in 
3% to 9% of subjects treated with anti-CTLA-4 monoclonal antibodies (e.g., 
ipilimumab).  The clinical manifestations of ipilimumab-treated subjects included 
general weakness, fatigue, nausea and/or mild fever and increased liver function 
tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin. 
 
Hepatic function abnormality is defined as any increase in ALT or AST to greater 
than 3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN. 
Concurrent findings are those that derive from a single blood draw or from separate 


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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. 
Guidelines for management of subjects with hepatic function abnormality are 
outlined in Section 6. 
 
Cases where a subject shows an AST or ALT ≥ 3x ULN or total bilirubin ≥ 2x 
ULN may need to be reported as SAEs, These cases should be reported as SAEs if, 
after evaluation they meet the criteria for a Hy’s Law case or if any of the individual 
liver test parameters fulfill any of the SAE criteria. 
 
Criteria for Hy’s Law (FDA Guidance 2009) 
 The drug causes hepatocellular injury, generally shown by a higher 
incidence of 3-fold or greater elevations above the ULN of ALT or AST 
than the (non-hepatotoxic) control drug or placebo  
 Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show 
elevation of serum total bilirubin to >2 x ULN, without initial findings of 
cholestasis (elevated serum alkaline phosphatase)  
 No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-
existing or acute liver disease; or another drug capable of causing the 
observed injury. 
 
7.9.4 Gastrointestinal disorders 
 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when 
tremelimumab is used as monotherapy.  In rare cases, colon perforation may occur 
that requires surgery (colectomy) or can lead to a fatal outcome if not properly 
managed.  Guidelines on management of diarrhea and colitis in patients receiving 
durvalumab are provided in Section 6.0. 
 
7.9.5 Endocrine disorders 
 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, 
and hyper- and hypothyroidism.  Guidelines for the management of patients with 
immune-mediated endocrine events are provided in Section 6.0. 
 
7.9.6 Pancreatic disorders 
 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and 
amylase elevation.  Guidelines for the management of patients with immune-
mediated pancreatic disorders are provided in Section 6.0. 
 


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7.9.7 Neurotoxicity 
 
Immune-mediated nervous system events include encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided 
in Section 6.0. 
 
7.9.8 Nephritis 
 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to 
changes in renal function (e.g. routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc)  
 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, infections etc.) 
 
Steroids should be considered in the absence of clear alternative etiology even for 
low grade events (Grade 2), in order to prevent potential progression to higher grade 
event.   Guidelines for the management of patients with immune-mediated 
neurotoxic events are provided in Section 6.0. 
 
7.10 
Other events requiring reporting 
 
7.10.1 Overdose 
 
An overdose is defined as a subject receiving a dose of MEDI4736 in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with MEDI4736, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
the sponsor and AstraZeneca/MedImmune Patient Safety or designee using the 
designated Safety e-mailbox. If the overdose results in an AE, the AE must also be 
recorded as an AE. Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the 
event is serious and must be recorded and reported as an SAE. There is currently 
no specific treatment in the event of an overdose of MEDI4736.  
 
The investigator will use clinical judgment to treat any overdose. 
 
7.10.2 Hepatic function abnormality 
 
Hepatic function abnormality (as defined in Section 7.9.3) in a study subject, with 
or without associated clinical manifestations, is required to be reported as “hepatic 
function abnormal” within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox, 


Protocol Version: 02/23/16 
 
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unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or 
bile duct obstruction) that is unrelated to investigational product has been 
confirmed. 
 
 If the definitive underlying diagnosis for the abnormality has been 
established and is unrelated to investigational product, the decision to 
continue dosing of the study subject will be based on the clinical judgment 
of the investigator. 
 If no definitive underlying diagnosis for the abnormality is established, 
dosing of the study subject must be interrupted immediately. Follow-up 
investigations and inquiries must be initiated by the investigational site 
without delay. 
 
Each reported event of hepatic function abnormality will be followed by the 
investigator and evaluated by the sponsor and AstraZeneca/MedImmune.  
 
7.10.3 Pregnancy 
 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be 
discontinued immediately.   
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive 
medication.  Congenital abnormalities or birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.   
 
If any pregnancy occurs in the course of the study, then the Investigator or other 
site personnel should inform the appropriate AstraZeneca representatives within 1 
day, ie, immediately, but no later than 24 hours of when he or she becomes aware 
of it.   
 
The designated AstraZeneca representative will work with the Investigator to 
ensure that all relevant information is provided to the AstraZeneca Patient Safety 
data entry site within 1 to 5 calendar days for SAEs and within 30 days for all other 
pregnancies.   
 
The same timelines apply when outcome information is available.   
 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the 
study and for 90 days after the last dose of durvalumab monotherapy.   


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Pregnancy of the patient’s partner is not considered to be an AE.  However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) occurring from the date of the 
first dose until 90 days after the last dose should, if possible, be followed up and 
documented.   
 
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner.  
Therefore, the local study team should adopt the generic ICF template in line with 
local procedures and submit it to the relevant Ethics Committees (ECs)/Institutional 
Review Boards (IRBs) prior to use.   
 
7.11 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
MEDI4736 
 
8.1.1 MEDI4736 Description 
 
MEDI4736 is a human monoclonal antibody (MAb) of the immunoglobulin G1 
kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 
(PD-L1) (B7-H1, CD274) to programmed cell death 1 (PD-1; CD279) and CD80 
(B7-1). MEDI4736 is composed of 2 identical heavy chains and 2 identical light 
chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 
contains a triple mutation in the constant domain of the immunoglobulin (Ig) G1 
heavy chain that reduces binding to complement protein C1q and the fragment 
crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
 
8.1.2 Clinical Pharmacology 
 
Please refer to Section 1.3.1. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Please refer to Section 1.3.2. 
 
8.1.4 Supplier(s) 
 
MEDI4736 will be supplied free of charge by Astra Zeneca. 
 


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8.1.5 Dosage Form and Preparation 
 
MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM 
trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.  
 
The investigational product is supplied as a vialed liquid solution in clear 10R glass 
vials closed with an elastomeric stopper and a flip-off cap overseal. Each vial 
contains 500 mg (nominal) of active investigational product at a concentration of 
50 mg/mL (500 mg/vial). The solution will be diluted with 0.9% (w/v) saline for 
IV infusion.  
 
Unopened vials of liquid MEDI4736 must be stored at 2°C to 8°C (36°F to 46°F).  
MEDI4736 must be used within the individually assigned expiry date on the label. 
 
Preparation of infusion bags 
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not be prepared on the ward. 
 
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. 
 
Prior to the start of the infusion, ensure that the bag contents are at room 
temperature to avoid an infusion reaction due to the administration of the solution 
at low temperatures. 
 
Vials should be used for specific subjects and should not be shared between 
subjects. 
 
8.1.6 Storage and Stability 
 
Total in-use storage time from needle puncture of MEDI4736 vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2-8°C 
(36-46°F). If in-use storage time exceeds these limits, a new dose must be prepared 
from new vials. Infusion solutions must be allowed to equilibrate to room 
temperature prior to commencement of administration. MEDI4736 does not contain 
preservatives and any unused portion must be discarded. 
 
8.1.7 Administration 
 
MEDI4736 will be administered at room temperature (approximately 25°C) by 
controlled infusion via an infusion pump into a peripheral vein.   
 


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Following preparation of MEDI4736, the entire contents of the IV bag should be 
administered as an IV infusion over approximately 60 minutes (±5 minutes), using 
a 0.2-μm in-line filter.  
 
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, or complete the infusion according to institutional policy to ensure 
the full dose is administered and document if the line was not flushed.  
 
Since the compatibility of MEDI4736 with other IV medications and solutions, 
other than normal saline (0.9% [weight/volume] 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. 
 
Subjects will be monitored during and after the infusion with assessment of vital 
signs at the times specified in the Schedule of Assessment. 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug 
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.  For 
subjects with a ≤Grade 2 infusion-related reaction, subsequent infusions may be 
administered at 50% of the initial rate.  Acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) or equivalent medications per institutional standard may 
be administered at the discretion of the investigator.  If the infusion-related reaction 
is ≥Grade 3 or higher in severity, study drug will be discontinued. 
 
As with any antibody, allergic reactions to dose administration are 
possible.  Appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis.  The study site must have immediate access to 
emergency resuscitation teams and equipment in addition to the ability to admit 
subjects to an intensive care unit if necessary. 
 
8.1.8 Special Handling Instructions 
 
No special handling instructions. 
 
 
9.0 
CORRELATIVE STUDIES 
 
The basis for the proposed correlative studies is to gain further mechanistic insight into the 
immunologic parameters that dictate response versus resistance to MEDI4736. The first aim, 
biomarker analysis (see Section 1.5.1), will characterize the expression of inhibitory molecules, 
PD-1, PD-L1, PD-L2, CTLA-4, in paired primary and CNS biopsies to identify clinical correlates 
of protection and resistance following MEDI4736. The second study aim, immune characterization 
(see Section 1.5.2), is annotate the immune response before and after MEDI4736 to identify 


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mediators of response and protection to MEDI4736. Overall, these data will provide greater 
understanding of the immunologic basis for MEDI4736 therapy that can be used to design more 
rational trials in the future. 
 
9.1 
Sample Collection Plan 
 
After trial enrollment, patients will undergo their first research blood draw at baseline 
according to standard procedures. Additional blood samples will be obtained on Days 8, 
15, 29, 3 months, 6 months and 12 months post-Cycle 1 Day 1 (see study calendar in 
Section 10.0). Six collection tubes (BD Vacutainer® sodium heparin (green top), REF 
367874, 10 mL each for a total of approximately 60 mL) are filled by venipuncture at each 
time point. Blood samples will be transported to the Dunn laboratory (7th floor BJC Institute 
of Health) within one hour of collection. PBMC will be obtained by Ficoll-Hypaque 
gradient centrifugation and cryopreserved in 10% DMSO according to standard 
procedures. 
 
Exome sequencing of PBMC will be performed to obtain germline sequences for 
comparison to isolated tumor from tissue biopsies (somatic mutations). 
 
In addition to blood samples, tumor samples will be collected from diagnostic biopsies of 
the primary tumor site and surgical biopsy/resection of CNS lesion(s) (when available) and 
will be prioritized for immunohistochemistry and flow cytometry. These samples are 
obtained under the tumor bank consent for the patient’s primary disease site (i.e. lung, 
breast, GI, GU, gynecologic), which authorizes permission for cellular, molecular, and 
genomic characterization and return of information. Patients who enroll in this study and 
are not enrolled in the applicable tumor bank will have archival tissue requested from their 
diagnostic biopsy.  Patients who do not have tissue available from their diagnostic biopsy 
will be allowed to enroll in the study but will not be able to fully participate in the 
correlative studies. 
 
Tumor tissue will be transported to the Tissue Procurement Core and to the Dunn 
laboratory. 
 
OCT embedding: Will be performed according to pre-existing institutional tissue banking 
protocols. Briefly, approximately 10-50 mg of tissue, sectioned into pieces no larger than 
0.5 cm x 0.5 cm, will be prepared. Cryomold will be filled slowly to the top with OCT 
compound. Tissue will be gently submerged into the OCT compound in the cryomold. 
OCT will be hardened by cooling. This will be achieved by placing the cryomold in the 
vapor phase of liquid nitrogen or on dry ice. After the OCT has hardened, the mold will be 
placed in a container and transferred to a -80°C freezer for storage. The frozen tissue will 
be transferred to the Laboratory of Translational Pathology (LTP, BJC-Institute of Health, 
Room 5110) for sectioning, H&E staining, and pathology evaluation. 
 
Nucleic acid isolation: DNA will be isolated from PBMC by the LTP or Dunn laboratory 
personnel for exome sequencing at The Genome Institute. To identify somatic mutations, 
DNA and RNA will be extracted from OCT-embedded banked tissue. The OCT block will 


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be delivered to the LTP where the block will be sectioned and stained in order to confirm 
the presence of tumor, determine tumor/normal ratio, and guide isolation of tumor cells by, 
for instance, laser capture microdissection (LCM). All tissue selected for sequencing will 
be processed into a single-cell suspension by mechanical and enzymatic digestion, and 
used to extract nucleic acids. Tumor DNA + RNA will then undergo tumor exome and 
tumor cDNA-capture sequencing, respectively at The Genome Institute.  
 
Serum separation: PBMC will undergo centrifugation with Ficoll to separate the serum and 
cellular layer (buffy coat) from RBC. While the buffy coat will be used for cellular studies 
discussed below, the serum will be frozen at -80°C to be stored for further studies. 
 
9.2 
Immune Monitoring 
 
 
9.2.1 Immune profiling 
 
Patient-derived PBMC will be used to quantify and characterize the immunologic 
landscape at baseline and at various time points post-MEDI4736. Single cell 
suspensions will be isolated as described above. All correlative studies will 
performed in the laboratory of Dr. Dunn, Dr. Schreiber, or in the Immune 
Monitoring Laboratory at the Center of Human Immunology and Immunotherapy 
Programs at Washington University.  
 
The T cell repertoire pre- and post- MEDI4736 will be further characterized by 
analyzing the TCR gene utilization of circulating PBMCs. This will be done by 
multi-parametric flow cytometry, spectratyping, and sequencing. MHC class I and 
II tetramers will be generated either in the Dunn laboratory, the Immune Monitoring 
Laboratory at the Center of Human Immunology and Immunotherapy Programs at 
Washington University, or the NIH Tetramer Core Facility.  
 
Phenotypic and polyfunctional characterization of tumor-specific T cells will be 
performed by ELISPOT, multi-parametric flow cytometry, and mass cytometry 
(CyTOF). Ex vivo cytotoxicity assays will be performed to determine the cytolytic 
activity of circulating and tumor infiltrating T cells pre- and post-MEDI4736. 
 
Serum will be analyzed for changes in cytokine expression following MEDI4736. 
Cytokine levels will be quantified using ELISA, QPCR, and multiplex analysis. 
 
9.2.2 Microenvironment characterization 
 
Tumor samples obtained from resection or initial biopsy at diagnosis will be 
analyzed for biomarkers that are associated with response to MEDI4736 to identify 
individuals who may benefit most from this therapeutic approach.  
 
IHC staining of OCT embedded tissue will characterize the location of various 
infiltrating lymphocytes relative to tumor. Furthermore, single cell suspensions can 
be made from fresh frozen tissue to characterize the phenotype of various 


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populations 
of 
infiltrating 
leukocytes 
(T 
cells, 
B 
cells, 
NK 
cells, 
monocytes/macrophages, dendritic cells) by multi-parametric flow cytometry and 
mass cytometry. Expression of various activation and inhibitory markers within the 
tumor microenvironment will also be assessed.  
 
TIL cultures will be generated by microdissection or magnetic bead-based isolation 
of single lymphocytes from tumor tissue. A baseline (pre-MEDI4736) assessment 
of the phenotype and functionality of these cells will be performed in a similar 
fashion as described above for PBMCs.  Consideration will be given for T cell 
receptor sequencing of these TIL as well. 
 
 
10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 28 days prior to start of protocol 
therapy. 
 
 
Baseline / 
Screening 
Day 1 of 
Each 
Cycle 
Day 15 
of Each 
Cycle 
End of 
Every Even-
Numbered 
Cycle 
End of 
Treatment 
(Time of 
progression) 
Follow-
Up3 
Informed consent and review of 
eligibility criteria 
X 
 
 
 
 
 
H&P, ECOG PS 
X 
X 
 
 
X 
 
VS, wt, ht 
X 
 
 
 
 
 
VS pre-, during, and post-infusion 
 
X 
X 
 
 
 
CBC 
X 
X 
 
 
 
 
CMP 
X 
X 
 
 
 
 
LFTs 
 
 
X 
 
 
 
TSH, T3, T4 
X 
X 
 
 
 
 
PT, aPTT, INR 
X 
 
 
 
 
 
β-hCG1 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
12-lead ECG4 
X4 
X2 
 
 
 
 
PFTs 
X 
 
 
 
 
 
Transthoracic echocardiogram 
X 
 
 
 
 
 
Brain MRI 
X 
 
 
X 
X 
 
CT C/A/P 
X 
 
 
X 
X 
 
MEDI4736 
 
X 
X 
 
 
 
Blood for correlatives 
 
Please refer to Section 9.0 
 
Acquisition of diagnostic tumor 
specimens from applicable bank or 
archival tissue 
 
Please refer to Section 9.0 
 
AE assessment 
X ------------------------------------------------------------------- X 
 
1. Women of childbearing potential only 
2. Cycle 5 only; should be taken within an hour prior to the start of infusion and 0-3 hours after the end of infusion 
3. Follow for survival every 6 months for 2 years after end of treatment 
4. In triplicate at baseline/screening and if abnormal results are discovered if an ECG is administered clinically 
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Correlatives Form 
Refer to Section 9.4 
Follow Up Form 
Every 6 months for 2 years after end of 
treatment 
Tumor Measurement Form 
Baseline, end of every even numbered 
cycles, and end of treatment 
MedWatch Form 
See Section 7.0 for reporting 
requirements 
 
 
12.0 
MEASUREMENT OF EFFECT – CNS DISEASE 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients will be re-evaluated for recurrence or progression 
every 8 (+/- 1) weeks.  Response and progression will be evaluated in this study using the 
updated response assessment criteria for high-grade gliomas: Response Assessment in 
Neuro-Oncology (RANO) working group guideline 42. 
 
Criteria for Response Assessment Incorporating MRI and Clinical Factors (Adapted from 42) 
Response 
Criteria 
Complete response 
 Requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks. 
 No new lesions; stable or improved nonenhancing (T2/FLAIR) lesions. 
 Patients must be off corticosteroids (or on physiologic replacement 
doses only) and stable or improved clinically. Note: Patients with 
nonmeasurable disease only cannot have a complete response; the best 
response possible is stable disease.  
Partial response 
Requires all of the following:  
 ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained 


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Response 
Criteria 
for at least 4 weeks. 
 No progression of nonmeasurable disease. 
 Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid 
dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
 Stable or improved clinically. Note: Patients with nonmeasurable 
disease only cannot have a partial response; the best response possible 
is stable disease.  
Stable disease 
Requires all of the following:  
 Does not qualify for complete response, partial response, or 
progression. 
 Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent 
follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose.  
Progression 
Defined by any of the following:  
 ≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or 
increasing doses of corticosteroids*. The absolute increase in any 
dimension must be at least 5mm when calculating the products. 
 Significant increase in T2/FLAIR nonenhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy* not caused by comorbid events (e.g. 
radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects). 
 Any new measureable lesion. 
 Clear clinical deterioration not attributable to other causes apart from 
the tumor (e.g. seizures, medication adverse effects, complications of 
therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose. 
 Failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of nonmeasurable disease.  
 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same 
techniques as at baseline. 
 
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion 
recovery. 
 
Stable doses of corticosteroids include patients not on corticosteroids. 


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iRANO criteria for progression: Confirmation of progression on follow-up imaging 3 
months after initial radiographic progression if: 
1. No new or significantly worsened neurologic deficits not due to co-morbid event 
or concurrent medication 
2. < 6 months from initiation of immunotherapy 
 
If follow-up imaging confirms progression, the date of actual progression should be back-
dated to the date of initial radiographic progression. 
 
Otherwise, progressive disease will be defined as radiographic evidence of progression 
with significant clinical decline that is felt to be unrelated to co-morbid event or concurrent 
medication, or if there is radiographic evidence of progression > 6 months after initiation 
of immunotherapy.   
  
12.2 
Disease Parameters 
 
Measurable disease:  Bi-dimensionally measurable lesions with clearly defined margins 
by MRI scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).   
 
Non-measurable or evaluable disease:  Uni-dimensionally measurable lesions or lesions 
with margins not clearly defined such as areas of T2/FLAIR signal abnormality or poorly 
defined enhancing abnormality.  
 
Note: For cystic lesions, the only measurable part is any enhancement area around the cyst 
that is clearly defined and bi-dimensionally measurable. The cyst itself should not be 
considered measurable or non-measureable disease. 
 
Target lesions: All measurable lesions that are residual of the lesion treated with MLA 
should be identified as target lesions and recorded and measured.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion, which can be measured reproducibly should be 
selected.  When there are too many measurable lesions, choose the largest 3 lesions as 
target lesions to follow.  The other measurable lesions should be considered evaluable for 
the purpose of objective status determination. 
 
Non-target lesions:  All non-measurable lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 


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12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler.  All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 2 weeks before the beginning of the treatment. 
 
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI when 
they are  5 mm diameter as assessed using a ruler. 
 
Histology:  This technique can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases when biopsy or surgical resection of a measureable 
lesion is clinically indicated.  
 
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test to 
determine treatment response or disease status.  However, it should not be used as the 
primary or sole method to determine response or disease status.  
 
Brain FDG-PET coupled with head CT or brain MRI: This advanced metabolic 
imaging technique can be used as an adjunct test to determine response or disease status. 
However it should be used as the primary or sole method of determining response or 
disease status. 
 
12.3.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. 
 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all target lesions sustained for at least 4 
weeks. 
 
Progressive Disease (PD):  At least a 25% increase in the sum of products of 
perpendicular diameters of at least 1 target lesion, taking as reference the smallest 
sum of products of perpendicular diameters on study (this includes the baseline sum 
if that is the smallest on study).  The absolute increase in any dimension must be at 
least 5mm when calculating the products of perpendicular diameters. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of products of 
perpendicular diameters while on study. 
 
12.3.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions.  
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 


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Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions on stable or increasing doses 
of corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). Unequivocal progression should not normally trump target lesion status.  
It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.3.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Summary of the RANO Response Criteria (Adapted from 42) 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium 
enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ ≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ Stable or ↓ Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ Stable or ↑ Stable or ↑ 
↓* 
Requirement for 
response 
All 
All 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, 
partial response; SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion 
recovery; NA, not applicable.  
* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration.  
 
12.3.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 


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(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.3.5 Neurological Exam and Performance Status  
 
Patients will be graded using the Karnofsky Performance Status scale and their 
neurological function evaluated as improved, stable or deteriorated in addition to 
objective measurement of tumor size. These parameters will be used to determine 
the overall response assessment. 
 
12.3.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
 
13.0 
MEASUREMENT OF EFFECT – NON-CNS DISEASE 
 
13.1 
RECIST Guidelines 
 
For the purposes of this study, patients should be re-evaluated for response/progression 
every 8 weeks.  A confirmatory scan should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
13.1.1 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 


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


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beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI 
is performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT 


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introduces additional data which may bias an investigator if it is not routinely or 
serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because they 
are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection 
is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.  Specific guidelines for both CA-
125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate 
cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 
1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated 
with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease).  
New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 


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 No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
 FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring.  The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
13.1.3 Response Criteria 
 
13.1.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions 
is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
13.1.3.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 


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normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and 
the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
13.1.3.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
    
 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
13.1.3.4 
Duration of Response 
 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 


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The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
13.1.3.5 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
13.2 
Immune-Related Response Criteria43 
 
For the immune-related response criteria, only index and measurable new lesions are taken 
into account.  At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters of all index lesions (5 lesions per organ, up to 10 visceral lesions 
and 5 cutaneous index lesions) is calculated.  At each subsequent tumor assessment, the 
sum of the products of the two largest perpendicular diameters of the index lesions and of 
new, measurable lesions (≥ 5 x 5 mm; up to 5 new lesions per organ: 5 cutaneous lesions 
and 10 visceral lesions) are added together to provide the total tumor burden. 
 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear.  At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the 
change in tumor burden (after ruling out immune-related progressive disease).  Decreases 
in tumor burden must be assessed relative to baseline measurements.  The immune-related 
response criteria were derived from WHO criteria and, therefore, the thresholds of response 
remain the same. 
 
The overall response according to the immune-related response criteria is derived from 
time-point response assessments (based on tumor burden) as follows: 
 irCR, complete disappearance of all lesions (whether measurable or not, and no 
new lesions) – confirmation by a repeat, consecutive assessment no less than 4 
weeks from the date first documented 
 irPR, decrease in tumor burden ≥ 50% relative to baseline – confirmed by a 
consecutive assessment at least 4 weeks after first documentation 
 irSD, not meeting criteria for irCR or irPR, in absence of irPD 
 irPD, increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor 
burden) – confirmation by a repeat, consecutive assessment no less than 4 weeks 
from the date first documented 
 
 
 


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14.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 
 Expected accrual end date and accrual by cohort 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design 
 
This is an open-label, single center, phase II study evaluating MEDI4736 (durvalumab), a 
PD-L1 checkpoint inhibitor, in patients with advanced epithelial-based malignancies and 
CNS metastasis. 
 


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15.2 
Study Population 
 
In total, three cohorts of patients will be enrolled. Because NSCLC is the most frequent 
source of brain metastasis and PD-1/PD-L1 pathway inhibition has been shown to be 
effective in this patient population, Cohort A will enroll only patients with NSCLC but will 
include all histologies and PD-L1 status. Cohort B will enroll all other non-NSCLC solid 
tumors of epithelial origin. This will include breast, gastroesophageal, pancreatic, 
colorectal, renal, bladder, and ovarian cancers. Melanoma, sarcoma, neuroendocrine 
tumors, and small cell lung cancers will be excluded as they are not of epithelial origin. 
Both Cohorts A and B will enroll patients not on corticosteroids at time of enrollment. 
Cohort C will enroll NSCLC or non-NSCLC patients requiring corticosteroid use. 
  
15.3 
Sample Size/Power Analysis 
 
 Because this study will only enroll patients with previously treated metastatic CNS 
disease, we assume a null hypothesis of 5% ORR in this setting. We further hypothesize 
that an ORR of 20% or higher warrants further investigation. A power analysis was 
performed for three primary cohorts (A: NSCLC without corticosteroids; B: non-NSCLC 
without corticosteroids; C: NSCLC or non-NSCLC requiring corticosteroid use) 
separately. Using Chen and NG’s flexible design (an extension of Simon 2-stage Optimal 
design), a total of N=46 subjects will be enrolled in each cohort. Specifically, 21 subjects 
will be enrolled in the 1st stage in each cohort. If no more than 1 out of 21 subjects (<5%) 
were to have an objective tumor response, then we would conclude insufficient evidence 
for preliminary efficacy and enrollment to that cohort would be stopped. Otherwise, 
25 additional subjects would be accrued for a total of 46 subjects in each cohort. At the 
completion of study, we expect that at least 41 out of 46 subjects would be evaluable for 
efficacy. The null hypothesis would be rejected if ≥5 objective intracranial responses were 
observed in the total of 41–46 evaluable subjects. This design would yield 90% power at a 
1-sided significance level of 0.05 to detect the hypothesized improvement in ORR.  At the 
end of Stage 1, the probability of erroneously proceeding with the study would be 0.27 
under the null hypothesis and the probability of erroneously discontinuing the study would 
be 0.05 under the alternative hypothesis. 
 
If the required Stage 1 intracranial ORR is seen, accrual can proceed in Stage 2 without 
interruption. If the required total number of patients are accrued to Stage 1 but follow-up 
is not sufficiently mature (ie, through the Week 12 radiographic evaluation) in all Stage 1 
patients to reasonably assess the Stage 1 ORR, accrual to Stage 2 may proceed while the 
Stage 1 data are being collated. All available tumor response and progression data will be 
considered at the time of the assessment. At the latest, the interim analysis will occur when 
the last of the Stage 1 subjects has been enrolled and has completed the 12-week tumor 
assessment and these data are available for review.  
 
15.4 
Primary Endpoint 
 
Overall intracranial response rate defined as the proportion of subjects who achieve a CR 
or PR based on assessment of brain lesions using RANO criteria. 


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15.5 
Secondary Endpoints 
 
 Overall intracranial disease control rate, defined as the proportion of subjects who 
achieve a CR, PR, or SD based on assessment of brain lesions using RANO criteria 
 Overall extracranial response rate defined as the proportion of subjects who achieve a 
CR or PR based on assessment of systemic lesions using irRC 
 Overall extracranial disease control rate, defined as the proportion of subjects who 
achieve a CR, PR, or SD based on assessment of systemic lesions using irRC 
 Overall response rate defined as the proportion of subjects who achieve a CR or PR 
based on assessment of brain and systemic lesions using RANO criteria and irRC, 
respectively 
 Overall disease control rate, defined as the proportion of subjects who achieve a CR, 
PR, or SD based on assessment of brain and systemic lesions using RANO criteria 
and irRC, respectively 
 Time to response (TTR), defined as the interval from the start of study therapy to the 
first documentation of an objective response 
 Duration of response (DOR), defined as the interval from the first documentation of 
objective response to the earlier of the first documentation of disease progression or 
death from any cause 
 Progression-free survival (PFS), defined as the interval from the start of study therapy 
to the earlier of the first documentation of disease progression or death from any 
cause 
 Overall survival (OS), defined as the interval from the start of study therapy to death 
from any cause 
 
15.6 
Exploratory Endpoints 
 
Correlation of iRANO criteria with overall response rate and overall disease control rate 
of intracranial disease. 
 
15.7 
Accrual 
 
There are currently no competing clinical trials for this patient population at Siteman 
Cancer Center. As such, it will have top priority for recruitment. We anticipate enrolling 
1-2 patients per month into each cohort with completion of enrollment by 2 years from 
beginning of accrual.  
 
15.8 
Data Analysis 
 
15.8.1 General Considerations 
 
All data will be evaluated as observed, and no imputation method for missing 
values will be used. All data will be presented in a descriptive manner. Each cohort 
will be analyzed separately, and no multiplicity adjustment across cohorts will be 


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performed. All other analyses are considered as exploratory, even if statistical tests 
are used.  
 
Descriptive statistics will be used to summarize the trial results, i.e., statistics for 
continuous variables may include means, medians, ranges and appropriate 
measures of variability. Qualitative variables will be summarized by counts and 
percentages. The uncertainty of estimates will be assessed by confidence intervals. 
Unless otherwise specified, the calculation of proportions will be based on the 
sample size of the population of interest. Counts of missing observations will be 
included in the denominator and presented as a separate category if not otherwise 
specified in the statistical analysis plan (SAP). 
 
15.8.2 Primary Efficacy Endpoint Analysis 
 
The primary endpoint is the overall intracranial response rate defined as the 
proportion of subjects who achieve a CR or PR based on assessment of brain 
lesions. Overall intracranial response rate per investigator assessment will be 
determined according to RANO criteria for CNS disease. Confirmation of the 
response will be required no sooner than 4 weeks after the initial documentation of 
CR or PR.  Incidences of ORR and the corresponding 90% confidence intervals 
will be calculated in the primary cohorts separately. 
 
15.8.3 Secondary Efficacy Endpoint Analyses 
 
Incidences of categorical secondary endpoints (overall intracranial disease control 
rate, overall extracranial response rate, etc., as defined in Section 15.5) and the 
corresponding 90% confidence intervals will be calculated in the primary cohorts 
separately. 
 
Duration of response, according to modified irRC, RECIST 1.1, and RANO, will 
be calculated for each subject and will be analyzed using the Kaplan-Meier method 
in the primary cohorts separately.  
 
PFS time, irPFS time, and OS time will be presented in subject listings and analyzed 
using the Kaplan-Meier method in the primary cohorts separately.   
 
Subgroup analyses of efficacy parameters will be performed according to tumor 
PD-L1 expression status. Subjects will be divided based on PD-L1 expression 
defined by the percentage of the tumor cells showing PD-L1 membrane staining at 
the following predefined cutoffs for positivity: >1% (<1% negative), >5% (<5% 
negative), >20% (<20% negative), and >50% (<50% negative). The percentage 
positive and negative for each cut-off as well as the associated BOR/iBOR and 
DCR/iDCR will be displayed in a histogram and PFS/iPFS and OS will be analyzed 
using the Kaplan-Meier method. The association between PD-L1 expression status 
(positive, negative) and response (according to RANO, RECIST 1.1, and modified 
irRC) will be assessed using Fisher’s exact test. Further exploratory analyses may 


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be performed to investigate the association of PD-L1 expression level as a 
continuous variable and efficacy parameters. Other subgroup analyses of efficacy 
will also be performed as applicable in the given cohort, e.g., with respect to 
demography, histology, number of prior anti-cancer therapy lines, other 
biomarkers, immunologic parameter. Furthermore, paired t-test or paired-sample 
Wilcoxon Signed Rank test will be used to compare the gene expression of TIL and 
immune response in blood as measured before and after treatment. 
 
15.8.4 Safety 
 
15.8.4.1 
Adverse Events 
 
All AEs will be listed. The focus of AE summarization will be on treatment-
emergent adverse events (TEAEs).   
 
AEs will be classified using MedDRA with descriptions by System Organ 
Class and Preferred Term. The severity of AEs will be graded by the 
investigator according to the CTCAE, Version 4.03, whenever possible. If 
a CTCAE criterion does not exist for a specific type of AE, the grade 
corresponding to the appropriate adjective will be used by the investigator 
to describe the maximum intensity of the AE: Grade 1 (mild), Grade 2 
(moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). 
The relationship of the AE to the study drugs will be categorized as related 
or unrelated. 
 
Summary tables will be presented to show the number of subjects reporting 
TEAEs by severity grade and corresponding percentages. A subject who 
reports multiple TEAEs within the same Preferred Term (or System Organ 
Class) is counted only once for that Preferred Term (or System Organ Class) 
using the worst severity grade. AE descriptions will be presented in order 
of decreasing frequency for System Organ Class, and by decreasing 
frequency in the overall or total column for a given Preferred Term. 
 
Separate listings and summaries will be prepared for the following types of 
AEs: 
 Study-drug-related AEs 
 AEs that are Grade ≥3, 4, or 5 in severity 
 AEs leading to study drug interruption and/or dose modification 
 AEs leading to study drug discontinuation 
 SAEs (with categorization of the primary reason that the AE is 
considered serious, eg, life-threatening, hospitalization) 
 
15.8.4.2 
Laboratory Evaluations 
 
All laboratory data will be listed. Summaries of laboratory data will be 
based on observed data and will be reported using conventional units. The 


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focus of laboratory data summarization will be on treatment-emergent 
laboratory abnormalities. A treatment-emergent laboratory abnormality is 
defined as an abnormality that, compared to baseline, worsens by ≥1 grade 
in the period from the first study drug administration to 30 days after the 
last study drug administration. If baseline data are missing, then any graded 
abnormality (i.e., an abnormality that is Grade ≥1 in severity) will be 
considered treatment-emergent.  
 
Test data will be programmatically graded according to CTCAE severity 
grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the 
normal range for the subject’s age, sex, etc. 
 
Test data will be summarized in tables and may be summarized in figures 
showing values over time, if informative. Summary tables will be presented 
for each relevant assay to show the number of subjects by CTCAE severity 
grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity 
grade observed during a period of interest (eg, during the study or during a 
cycle). 
 
Shift tables for hematology and serum biochemistry will also be presented 
by showing change in CTCAE severity grade from baseline to each time 
point. For parameters for which a CTCAE scale does not exist, shift tables 
will be presented showing change in results from baseline (normal, low and 
high [or abnormal]) to each time point (normal, low and high [or 
abnormal]). For selected variables of interest, tables may be prepared to 
show frequencies adjusted for baseline values; for these frequencies, 
subjects with the same or worse grade at baseline are not considered. 
 
 
 
 
 


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16.0 
REFERENCES 
 
1. 
Langer CJ, Mehta MP. Current management of brain metastases, with a focus on 
systemic options. J Clin Oncol 2005;23:6207-19. 
2. 
Soffietti R, Ruda R, Mutani R. Management of brain metastases. Journal of neurology 
2002;249:1357-69. 
3. 
Lee SH. Role of chemotherapy on brain metastasis. Progress in neurological surgery 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development and study coordination services. The Siteman Cancer 
Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 
 


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APPENDIX B: Cockcroft-Gault Formula 
 
 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) x 0.85 
72 x serum creatinine (mg/dL)