A Phase II, Open Label, Clinical Trial Of Pre-Surgical and Adjuvant Treatment of Recurrent Malignant Glioma With Tremelimumab and Durvalumab (MEDI4736) Alone and in Combination to Determine Immunologic Changes From Treatment
Phase: PHASE2
Conditions: Malignant Glioma, Recurrent Glioblastoma
Sponsor: Northwestern University

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A Phase II, open label, clinical trial of pre-surgical and adjuvant treatment of 
recurrent Glioblastoma with Tremelimumab and Durvalumab (MEDI4736) 
alone and in combination to determine immunologic changes from treatment
Principal Investigator:
Karan Dixit, MD 
Department of Neurology
Northwestern University
710 N.Lake Shore Dr.Abbott Hall, Room 1123
Chicago, IL 60611
Phone: 312-503-4724
Fax: 312-908-5073
E-mail: karan.dixit@northwestern.edu
Sub-Investigator(s):
Jeffrey Raizer, MD
Northwestern University, Dept. of Neurology 
jeffrey.raizer@nm.org
Priya Kumthekar, MD
Northwestern University, Dept. of Neurology 
p-kumthekar@northwestern.edu
Matthew Tate MD, PhD
Northwestern University, Dept. of Neurosurgery 
matthew.tate@northwestern.edu
James Chandler, MD
Northwestern University, Dept. of Neurosurgery 
j-chandler@northwestern.edu
Biostatistician:
Alfred Rademaker, PhD
rademaker@northwestern.edu
Study Intervention(s):
Tremelimumab
Durvalumab (MEDI4736)
IND Number:
131237
IND Holder:
Karan Dixit, , MD
Funding Source:
Astra Zeneca/MedImmune
Version Date: 11.29.18
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Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL 60611
http://cancer.northwestern.edu/research/clinical-trials-office/index.html
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Table of Contents
LIST OF ABBREVIATIONS.........................................................................................................................................4
STUDY SCHEMA .........................................................................................................................................................6
STUDY SUMMARY .....................................................................................................................................................7
1.0
INTRODUCTION – BACKGROUND & RATIONALE ...............................................................................10
2.0
OBJECTIVES & ENDPOINTS 
.......................................................................................................................................................................................31
3.0
PATIENT ELIGIBILITY .................................................................................................................................31
4.0
TREATMENT PLAN......................................................................................................................................35
5.0
STUDY PROCEDURES .................................................................................................................................77
6.0
ENDPOINT ASSESSMENT...........................................................................................................................81
7.0
ADVERSE EVENTS.......................................................................................................................................83
8.0
DRUG INFORMATION .................................................................................................................................94
9.0
CORRELATIVES/SPECIAL STUDIES........................................................................................................101
10.0
STATISTICAL CONSIDERATIONS ...........................................................................................................103
11.0
STUDY MANAGEMENT .............................................................................................................................104
REFERENCES ............................................................................................................................................................108
APPENDIX A – COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.03 (CTCAE) ..............111
APPENDIX B – ACCEPTABLE METHODS OF CONTRACEPTION ...................................................................112
APPENDIX C – KARNOFSKY PERFORMANCE SCALE (KPS) .........................................................................113
APPENDIX D – PROTOCOL SUMMARY OF CHANGES ....................................................................................114
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LIST OF ABBREVIATIONS
AE
Adverse Event
AChE
Acetylcholine esterase
ADA
American Dietetic Association
ADL
Activities of Daily Living
AE
Adverse Event
ALT
Alanine Aminotransferase 
ALC
Absolute Lymphocyte Count 
ALP
Alkaline phosphatase
AST
Aspartate Aminotransferase
aPTT                                  Activated Partial Thromboplastin Time 
ASCO                                American Society of Clinical Oncology 
BUN                                  Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee 
ECOG
Eastern Cooperative Oncology Group 
FT4
Free Thyroxine
GI
Gastrointestinal
H&PE
History & Physical Exam
INR
International Normalized Ratio 
irAE
Immune- Related Adverse Event 
IRR
Infusion Related Reaction
IDS
Infectious Disease Service 
ILD
Interstitial Lung Disease 
IM
Intramuscular
IV
Intravenous
IVIG
Intravenous Immunoglobulin 
KPS
Karnofsky Performance Status 
LFT
Liver Function Test
LLN
Lower Limit of Normal MTD
Maximum Tolerated Dose 
MRI
Magnetic Resonance Imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PCP
Pneumocystis Pneumonia
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
PT
Prothrombin time
PTT
Partial Thromboplastin Time
RT
Radiotherapy
RANO
Response Assessment in Neuro-Oncology
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
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TB
Total Bilirubin
TMZ
Temozolomide
TNF
Tumor Necrosis factor
TFTs
Thyroid function tests
TSH
Thyroid Stimulating Hormone
ULN
Upper limit of normal
WBC
White Blood Cells
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STUDY SCHEMA
rGBM
Presurgical Treatment (14 days prior to surgery): 
Tremelimumab or
MEDI4736 or
Tremelimumab and MED4736
Resection of Tumor
Post-surgery Treatment (same arm as pre-surgery, 
restarted 14 days post-surgery)
1) Tremelimumab or
2) MED4736 or
3) Tremelimumab and MEDI4736
CT or MRI w 
contrast every 2 
cycles
Tumor Progression or 24 months of treatment
Off Trial
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STUDY SUMMARY
Title
A Phase II, open label, single center study of pre-surgical and adjuvant treatment of 
recurrent glioblastoma with Tremelimumab and MEDI4736 alone and in combination to 
determine immunologic changes from treatment.
Version
11.29.18
Study Design
Phase II trial
Study Center(s)
Robert H. Lurie Cancer Center of Northwestern University.
Objectives
Primary:
1)   To determine the T-cell changes that occur in recurrent GBM treated with 
tremelimumab and durvalumab as single agents and in combination.
Secondary:
1)   To evaluate the safety of either tremelimumab or MEDI4736 alone and in 
combination in patients with recurrent GBM.
2)   To determine post-surgery, the time to progression (per Modified RANO criteria and 
iRANO criteria, see below) for patients treated with either Tremelimumab or 
MEDI4736 alone and in combination of both.
3)   To determine post-surgery, the overall survival for patients treated with Tremelimumab 
or MEDI4736 alone and in combination of both.
4)   To assess post-surgery, the MRI changes in patients treated with either Tremelimumab 
or MEDI4736 alone and in combination of both.
Exploratory:
To correlate T-cell changes and PDL1 expression with patient outcomes.
Sample Size
There will be three groups of patients, one group on each agent alone and one group 
treated with the combination agents. A total of 10 evaluable patients per group will be 
necessary for study endpoints.  To attain 10 patients in each arm who are evaluable for 
the primary endpoint, a total of 45 patients will be accrued to the study. Sample sizes of
10 per group allow for the estimation of the proportion of responders in evaluable 
patients to be within 31% of its true value with 95% confidence. Mean change will be 
compared between arms. Using standard deviations of change, a sample size of 10 per 
group will allow the detection of differences of 1.25 standard deviations between groups 
with 80% power assuming a two-tailed test and a Type I error rate of 5%.
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Key Eligibility
Criteria
1)   Patients must have a grade IV glioma that has failed standard RT and TMZ.
2)   Patients must have had radiographic evidence of tumor progression by brain MRI
or CT scan with contrast.
3)   Patients must be > 12 weeks from completion of radiation therapy unless there is 
tissue confirmation of tumor recurrence or there is progression outside the radiation 
treatment field.
4)   Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, 
but the patient must have subsequent histologic documentation of recurrence, 
unless the recurrence occurs remote from the treated site.
5)   Patients must be surgical resection candidates.
6)   Have resolved toxicity (>CTCAE grade < 2) from previous anti-cancer therapy.
7)   Life expectancy of > 12 weeks
8)   Patients can only be on non-enzyme inducing anti-convulsants. If they are on an 
enzyme inducing anti-convulsant, they may be converted to a non-enzyme inducing 
anti-convulsants but they will need a 2 week wash out period from time of drug 
discontinuation.
Treatment Plan
Patients will be randomly assigned to each arm using block randomization.
Treatment Arms:
Arm 1) Tremelimumab- 75 mg every 4 weeks. The 1st dose will be given 14 days
pre-surgery. The drug will be restarted 14 days after surgery once the surgical wound 
has healed and then every 4 weeks after surgery. If there is no progression of disease, 
they will continue on treatment for up to 24 months.
Arm 2) MEDI4736- 750 mg every 2 weeks.  The 1st dose will be given 14 days pre- 
surgery. The drug will be restarted 14 days after surgery once the surgical wound has 
healed and then every 2 weeks after surgery.  If there is no progression of disease, they 
will continue on treatment for up to 24 months
Arm 3) Tremelimumab 75 mg + MEDI4736 750mg.  The 1st dose will be given 14 days 
pre-surgery. The drug will be restarted 14 days after surgery once the surgical wound has 
healed. Tremelimumab will be administered IV every 4 weeks (Day 1 of each cycle) and 
MEDI4736 750mg every 2 weeks (Day 1 and Day 15 of each cycle) until the patients 
have received 7 doses of Tremelimumab and 14 doses of MEDI4736. Thereafter, from 
Cycle 7 (Week 25), Tremelimumab will be given every 12 weeks (+/-7 days) and 
MEDI4736 will be given every 2 weeks (+/- 2 days) until permanent discontinuation 
criteria (e.g. disease progression) is met. If there is no progression of disease, they will 
continue on treatment for up to 24 months.
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Statistical
Methodology
Immunologic measures will be summarized over the three or more time points (pre- 
treatment, following first treatment/pre-surgery, and post-surgery) and changes in these 
measures will be assessed using repeated measures analysis of variance or Cochran’s Q, 
followed by the paired t-test or the signed rank test for pairwise comparisons using 
Bonferroni corrections. Safety of the agents alone or in combination will be assessed by 
summarizing the frequency of adverse events by type, timing, grade and attribution. 
Immunologic changes will be correlated with MRIs in a descriptive fashion. The 
secondary endpoint of progression-free survival as well as overall survival will be 
analyzed using Kaplan-Meier curves. Immunologic changes of T-cells and PDL1 levels 
will be correlated to survival outcomes using Cox regression analysis. MRI changes will 
be summarized using means or proportions and statistically analyzed using the signed 
rank test.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
Malignant gliomas are unfortunately a uniformly fatal tumor in most cases. Despite aggressive 
surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these tumors almost always 
recur. Patients seen in academic centers are often recruited to clinical trials that utilize novel agents 
in combination with standard therapy in newly diagnosed patients or those with recurrent disease. 
We know that gliomas are highly vascular tumors and there is data from the “Brain Trial” and
“NIH trial” showing high response rates and reasonably good progression free survival at 6 months
1, 2
for patients treated with bevacizumab.
Unfortunately, data using bevacizumab in newly
diagnosed patients with GBM did not provide any survival benefit but it did improve PFS at 6
3
months in the AVAGLIO trial but not RTOG trial.
1.1.2
Glioblastoma
For clinical trials in glioblastoma (GBM), many have looked at target specific agents 
added to standard therapy; however none of them has been of benefit to date. There've
also been a few trials looking at patients with an unmethylated MGMT promoter but none 
have shown a significant impact in this patient population, but it remains a group where 
more work is needed.
More novel approaches in oncology and in neuro-oncology are to use immunologic 
therapies. In GBM, there are vaccine therapies that are either derived from the patient's 
known tumor (HSPPC-96) or are designed to target specific epitopes on the tumor cells 
such as EGFRvIII (CDX-110) or a number of other epitopes (ICT-107) targeted by other 
vaccines. Phase II data using CDX-110, ICT 107, HSPPC-96 and others have shown some 
promise. While preliminary data looks promising with these agents, the most advanced has 
not proven effective in a randomized phase 3 study (ICT-107) (Press Release) but data
will be emerging on CDX-110 as the trial is completing enrollment.
Currently there are several agents under investigation that target the local tumor immune- 
protection in solid tumors-particularly melanoma, such CTLA-4 blockade, PD1 and PDL1 
blockade. While the majority of trials have occurred in melanoma, there is recent data in
4 5, 6
other cancers such as renal cell and small cell lung cancer
. While expected in
melanoma and renal cell due to immunologic aspects of these diseases, the efficacy in other 
tumors was less clear but benefit has been shown in lung cancer. Recently MK-3475 was 
approved in US for advanced melanoma.
A recent review highlighted the many immunologic approaches to GBM.
More relevant
to gliomas is the research that shows gliomas can upregulate B7-H1 expression in 
circulating monocytes and tumor-infiltrative macrophages through modulation of
autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.
Glioma-associated cancer-initiating cells have been shown to express the co-stimulatory
9
inhibitory molecule B7-H1 which has previously been shown to be a key factor
10
11
mediating immune resistance in gliomas
and can induce T-cell apoptosis . Direct cell-
to-cell contact experiments have shown that the glioma-associated cancer-initiating cells
induced T-cell apoptosis in the setting of B7-H1 expression. Wei et al.
found that
cancer-initiating cells markedly inhibited T-cell proliferation and activation, induced 
regulatory T cells, and triggered T-cell apoptosis that was mediated by B7-H1 and soluble 
Galectin-3. Loss of tumor suppressor PTEN function increases B7-H1 expression and
10
immunoresistance in glioma.
It also been shown that glioma associated cancer initiating
cells induce immunosuppression thereby allowing tumor cells to evade
12
immunosurveillance. Yao et al.
found that B7-H1 was correlated with the malignancy
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19, 20
21
grade of human astrocytic tumors, but preferentially in the non-dividing tumor cells. It was
also upregulated at the growing edge of the tumors and had a negative correlation with 
tumor-infiltrating CD8T-cells.
Importantly, tumor infiltrating lymphocytes and PD-L1 expression are seen in the majority
13
of GBM samples
14
and rationale for these using checkpoint inhibitors is reviewed by Kim
and Lim   .
1.2
PD-1 and PD-1
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein, and is 
upregulated in a broad range of cancers with a high frequency, with up to 88% expression in some
tumor types. In a number of these cancers, including lung
, renal
16-18, pancreatic
, ovarian
cancer , and hematologic malignancies
22, 23 tumor cell expression of PD-L1 is associated with
reduced survival and an unfavorable prognosis.
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by the 
host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells binds 
to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to the T cell (Keir, 2008}. 
This results in reduced T-cell activation and fewer activated T cells in circulation. In the tumor 
microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on activated T cells 
reaching the tumor. This delivers an inhibitory signal to those T cells, preventing them from killing 
target cancer cells and protecting the tumor from immune elimination (Zou and Chen, 2008).
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades24. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various
11, 25-28
malignancies.
In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon
29, 30
engagement of its ligands (PD-L1 and/or PD-L2).
The structure of murine PD-1 has been
resolved [9].  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits 
the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading 
to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are
29, 31-33
involved in the CD3 T-cell signaling cascade.
The mechanism by which PD-1 down
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be expressed on 
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activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural
34, 35
Killer cells.
Expression has also been shown during thymic development on CD4-CD8-
36
(double negative) T-cells as well as subsets of macrophages and dendritic cells.
The ligands for
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PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types,
36-39
including non-hematopoietic tissues as well as in various tumors.
Both ligands are type I
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and 
contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand
to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid
40
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-
41
specific T-cell expansion in subjects with melanoma (MEL).
This suggests that the PD-1/PD-L1
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pathway plays a critical role in tumor immune evasion and should be considered as an attractive 
target for therapeutic intervention.
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 homolog 1 
[B7-H1], cluster of differentiation [CD]274) 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
Durvalumab (MEDI4736) Background
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 homolog 1 
[B7-H1], cluster of differentiation [CD] 274) 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
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 and 
dose range-finding study, and a GLP 4-week 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, PK/pharmacodynamics, and dose range- 
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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 GLP, 4-week, 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.
As of the data cutoff date of 14Jul2014, a total of 509 subjects have been enrolled and 
treated with MEDI4736 in 10 ongoing clinical studies: 5 employing MEDI4736 as 
monotherapy and 5 as combination therapy. No studies have yet been completed. Clinical 
experience with MEDI4736 is fully described in the current version of the MEDI4736
Investigator’s Brochure.
1.3.2
Pharmacokinetics and Product Metabolism
MEDI4736 monotherapy exhibited nonlinear (dose-dependent) PK. 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 15 mg/kg and approached linearity at ≥
3 mg/kg, suggesting that the nonlinear PK of MEDI4736 is likely due to saturable target- 
mediated clearance. Exposures following multiple doses (currently up to a maximum of
26 doses) demonstrated accumulation consistent with PK parameters estimated from the 
first dose.
Suppression of free soluble PD-L1 (sPD-L1) was correlated with MEDI4736 PK 
concentrations. Following administration of MEDI4736 monotherapy, free sPD-L1 levels 
were below the lower limit of quantitation (LLOQ) in the majority of subjects with 
available data (n = 38) at all timepoints following IV doses ≥ 1 mg/kg every 2 weeks 
(Q2W).
Overall, a low incidence of ADA was observed. Of the 220 subjects who received 
MEDI4736 monotherapy and for whom PK/ADA data were available, 5 were detected 
ADA positive, with an impact on PK/pharmacodynamics reported in 1 subject.
1.3.3
Safety
As of 14Jul2014, no identified risks are clearly associated with the use of MEDI4736. 
Important potential risks based on the mechanism of action of MEDI4736 and its related
molecules include immune-mediated reactions such as enterocolitis, dermatitis, 
hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, and neuropathy. Additional 
important potential risks include infusion-related reactions, hypersensitivity, serious 
allergic reactions, serious infections, and immune complex disease.
The majority of the safety data are from the monotherapy study, CD-ON-MEDI4736-
1108, specifically the 10 mg/kg Q2W cohort (N = 393). In this cohort, the most frequently 
reported (≥ 10% of subjects) adverse events (AEs; all grades, regardless of causality) were 
fatigue (29.8%), nausea (20.1%), dyspnea (19.6%), decreased appetite (19.1%), 
constipation (14.0%), diarrhea and vomiting (12.5% each), cough (11.5%), pyrexia and 
back pain (10.4% each), and rash (10.2%). In approximately half of the subjects, the 
highest AE severity was Grade 1 (25.2% of subjects) or Grade 2 (22.9% of subjects).
Most of these events were managed clinically without the need for dose modifications or 
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delays. Grade 3 or higher AEs that occurred in > 1% of subjects were dyspnea (5.1%), 
increased gamma-glutamyltransferase (3.3%), fatigue, general physical health 
deterioration, increased aspartate aminotransferase, and back pain (2.3% each), anemia 
and dehydration (1.8% each), and abdominal pain, vomiting, sepsis, syncope, and 
hypotension (1.3% each). Treatment-related Grade 3 AEs in 2 or more subjects were 
fatigue (4 subjects), increased gamma-glutamyltransferase (3 subjects), and vomiting,
increased alanine aminotransferase, increased aspartate aminotransferase, and arthralgia (2 
subjects each). There were 2 subjects with treatment-related Grade 4 events 
(hypercalcemia, fatigue) and 1 subject with a treatment-related Grade 5 event
(angiopathy). In general, Grade 3 or higher AEs were manageable and reversible with 
standard toxicity management guidelines.
Serious adverse events (SAEs) and other significant AEs occurred in fewer than one-third 
of subjects treated with MEDI4736 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108. 
The most frequently reported SAEs (regardless of causality; > 5 subjects) were dyspnea 
(15 subjects), general physical health deterioration (9 subjects), pyrexia (8 subjects), back 
pain and abdominal pain (7 subjects each), and dehydration and pleural effusion (6 subjects 
each). One subject (with Stage IV lung cancer and a history of cardiac disease) died due to 
angiopathy considered by the investigator as related to MEDI4736. Adverse events that 
resulted in permanent discontinuation of MEDI4736 in ≥ 2 subjects were dyspnea (7 
subjects), general physical health deterioration (5 subjects), and death, increased 
transaminases, pulmonary embolism, and respiratory failure (2 subjects each).
No dose-limiting toxicities (DLTs) have been reported in any of the dose-escalation 
cohorts of the monotherapy studies. Overall, the AE profile of MEDI4736 was consistent 
with the pharmacology of the target. No tumor types appeared to be associated with 
unique AEs.
This section summarizes the safety profile of MEDI4736 and data from studies in the 
context of relevant or similar therapies, AESIs that may impact the risk-benefit balance of 
MEDI4736. The probability of these events occurring with MEDI4736 use continue to be 
characterized based on the overall strength of evidence, from greatest to least, clinical data, 
nonclinical data, and pharmacologic class effects/mechanism of action. Clinically 
significant risks of interest include immune-mediated reactions such as enterocolitis, 
hepatitis/hepatotoxicity, dermatitis, neuropathy, endocrinopathy, pneumonitisand their 
associated signs and symptoms, risks due to immunogenicity and other events 
suchpotential risks.
All tabulations of treatment-emergent AEs are based on available clinical safety data from 
sponsored MEDI4736 clinical studies as serious infections, infusion-related of the DCO 
for this IB.
1.3.3.1   Immune-mediated Reactions
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Immune-mediated reactions, anaphylaxis or /irAEs, also considered to be AESIs, 
are important risks of immune checkpoint inhibitors, and are being closely 
monitored in clinical studies with MEDI4736 monotherapy and combination 
therapy. irAEs observed with MEDI4736 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.
Other inflammatory responses with potential immune-mediated etiology reported 
with MEDI4736 and similar molecules include, but are not limited to, 
myocarditis, pericarditis, and uveitis.
Colitis
Immune-mediated colitis is an inflammation of the small intestine and/or colon 
caused by dysregulation of gastrointestinal mucosal immunity, and can involve 
any part of the bowel but most commonly the descending colon 
42-44. Endoscopic 
findings have revealed mucosal inflammation with ulceration and biopsies 
demonstrating neutrophilic, lymphocytic, or mixed neutrophilic- lymphocytic
42, 45
infiltrates
. Mild to severe diarrhea is the most frequently observed
sign/symptom potentially associated with immune-mediated colitis, and may be 
accompanied by other signs and symptoms including changes in bowel habits 
from baseline, abdominal pain, nausea/vomiting, or hematochezia. In severe 
cases, patients may experience significant dehydration, fever, peritoneal signs,
46
bowel perforation, or ileus   .
Across the Phase 1 to Phase 3 clinical studies with MEDI4736 monotherapy, as 
of the DCO dates for this IB, treatment-emergent colitis-type events, regardless 
of causality, were reported in 9 of 1,149 subjects (0.8%) receiving 10 mg/kg 
MEDI4736 IV Q2W. The time to onset ranged from 43 to 138 days post first 
dose. The severity of colitis was Grade 1 (1 case), Grade 2 (4 cases), Grade 3 (3 
cases), and Grade 4 (1 case). Investigators are instructed to begin diarrhea 
management early to minimize the risk of colitis. Early initiation of diarrhea 
treatment guidelines has been shown to reduce bowel perforation and colectomy 
rates, drug- related diarrhea, and serious gastrointestinal irAEs by up to 50% in
43
patients treated with ipilimumab   .
Pneumonitis
Immune-mediated pneumonitis is characterized by inflammation focally or 
diffusely affecting the lung parenchyma that may be result of effects of
47
checkpoint inhibitors against the normal lung parenchyma
. Presentations of
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pneumonitis range from asymptomatic lung infiltrates to those that mimic severe 
bacterial pneumonia. For symptomatic patients, complaints and findings may 
include dyspnea, cough, tachypnea, pleuritic chest pain, and hypoxia.
In clinical studies with MEDI4736 monotherapy, as of the DCO dates for this IB,
23 of 1,149 subjects (2.0%) reported 24 serious allergic reaction, and immune 
complex and non- serious events (10 serious; 14 non-serious) of 
pneumonitis/interstitial lung disease across all doses and indications in 4 of the 5 
open-label monotherapy studies (MEDI4736-1108, D4190C00002, 
D4190C00007, D4191C00003). There were no events from study 
D4193C00001. In the largest study population (Study CD-ON-MEDI4736-
1108), the reporting rate of pneumonitis was highest at 1.8% (n/N = 13/736). 
Most AEs were non- serious and Grade 1 or 2 in severity. Across the MEDI4736 
clinical studies, moderate to severe immune-mediated pneumonitis, as assessed
by the investigator, was reported in 0.4% of subjects (n/N = 5/1,149). Time to 
onset for pneumonitis post first dose ranged from 4 to 10 weeks (4/5 subjects) to 
occurring 2 months after discontinuing MEDI4736 (1/5 subjects). With steroid 
treatment 80 mg/day, 2 subjects recovered within 3 days and 2 subjects within 1 
to 2 weeks. One subject died from the event of pneumonitis and did not receive 
steroids as treatment for the event.
Hepatitis/Hepatotoxicity
Immune-mediated hepatitis/ hepatic toxicity is the inflammation of the liver due 
to the dysregulation of host immunity caused by immune checkpoint inhibitors 
and often manifests as asymptomatic elevated levels of hepatic transaminases 
(ALT, AST, bilirubin. In anti-CTLA-4-treated patients, clinical manifestations of 
hepatitis included nonspecific symptoms of mild fever, general weakness,
fatigue, nausea and/or abdominal pain.
Across approximate 1,200 subjects who have received MEDI4736 monotherapy
10 mg/kg Q2W, 0.3% of subjects experienced an event of ‘hepatitis’. One of the
4 subjects received steroids to treat the event. In Study CD-ON-MEDI4736-
1108, 3 subjects (0.4%) reported an event of autoimmune hepatitis. Two of the 3 
subjects were ≥ Grade 3, the other was Grade 2 in severity. In Study 
D4191C00003 Cohort 2, one event of hepatitis toxic was reported. The subject 
had elevated ALT and AST. MEDI4736 dosing was delayed and the subject 
received treatment with ursodeoxycholic acid and glutathione sodium. The events 
resolved and the subject continues on treatment with no further increases in liver 
enzymes.
Neuropathy/Neuromuscular Toxicity
Acquired peripheral neuropathies may be caused by infections or autoimmune 
disorders affecting nerve tissue. Some neuropathies are caused by inflammation 
resulting from immune system activities. Inflammatory neuropathies can develop 
quickly or slowly, and chronic forms can exhibit a pattern of alternating remission 
and relapse. Symptoms of peripheral neuropathy include numbness, tingling, 
paresthesia (pins and needles sensations), sensitivity to touch, or muscle 
weakness. In subjects with extreme symptoms, they may present with burning 
pain, muscle wasting, paralysis, or organ dysfunction. Acute inflammatory 
demyelinating neuropathy, better known as Guillain-Barre syndrome, can
damage motor, sensory, and autonomic nerve fibers. Most people recover from 
this syndrome although severe cases can be life-threatening. Neuropathy can be 
difficult to assess due to the transient and non-specific nature of events. Subjects 
should be monitored for signs and symptoms that may include peripheral sensory 
neuropathy, muscle weakness, peripheral neuropathy including numbness, 
tingling, and sensitivity to touch.
Endocrinopathy
Immune-mediated endocrinopathy is the inflammation of any organ in the 
hypothalamic- pituitary-adrenal axis, but is most typically reported to affect the 
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pituitary, thyroid and/or adrenal glands in patients treated with checkpoint 
inhibitors, leading to hypophysitis, thyroid dysfunction, and/or adrenal 
insufficiency 48. The clinical presentation of immune-mediated endocrinopathies 
most often include hypothyroidism, hyperthyroidism, and nonspecific symptoms 
of headache and fatigue, but may also include myalgias, visual field defects, 
behavioral changes, electrolyte disturbances, loss of appetite and hypotension 43. 
Subjects will generally have abnormal endocrine laboratory test results that 
include thyroid-stimulating hormone, free T4, total and free T3, cortisol, 
adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating
hormone, and testosterone.
Dermatitis
Immune-mediated dermatitis is generally mild and presents as mild local or 
diffuse maculopapular, erythematous rash on the trunk or extremities, which may 
be accompanied by pruritus, alopecia, and vitiligo, suggestive of inflammatory
49
response to melanocytes
. In rare cases, severe dermatitis has been reported to
manifest as Stevens-Johnson syndrome, toxic epidermal necrolysis, or rashes 
complicated by dermal ulceration or necrotic, bullous, or hemorrhagic
43, 46
manifestations
.
Nephritis
The major clinical syndromes produced by immune-mediated renal injury include 
nephrotic syndrome, rapidly progressive glomerulonephritis, and acute renal
50
failure . In association to immune-checkpoint inhibitors, two different forms of
ipilimumab-induced renal damage are reported, acute kidney injury due to 
predominant acute granulomatous tubulointerstitial nephritis and nephrotic
51
syndrome in lupus nephritis
. Signs and symptoms include increase in serum
creatinine, decrease in urine output, peripheral edema, hematuria, loss of appetite. 
Subjects should be monitored for elevated serum creatinine prior to and 
periodically during treatment.
Pancreatitis
Immune-mediated pancreatitis, an important potential risk, is an inflammatory 
condition of the pancreas that typically manifests initially as asymptomatic 
elevations of amylase and lipase in patients treated with immune checkpoint 
inhibitors. Clinical presentation frequently includes low-grade abdominal pain
52, 53
with accompanying fever and malaise
Biopsies showed diffuse T-cell
infiltrate consistent with immune- mediated pancreatitis {Weber, 2012}. Across 
the clinical development program for ipilimumab, immune-mediated pancreatitis 
has been reported in ≤ 1% ito 3% of patients (Yervoy, 2015)
52, 53. In
monotherapy clinical studies of anti-PD-1 agents in melanoma, clinically 
significant immune-mediated pancreatitis was reported in < 1% of treated 
patients (Keytruda, 2015; Opdivo, 2015). Grade 3 or 4 treatment-related 
increased lipase was reported in 2% to 5% and increased amylase in < 10% of 
patients (Opdivo, 2015). In nivolumab and ipilimumab combination therapy
studies, Grade 3 or 4 elevations in lipase and amylase were reported, respectively, 
in 16% and 5% of renal cell carcinoma patients, and 8% and 4% of NSCLC
44, 54
patients
. Subjects should be monitored for signs and symptoms of
pancreatitis including Grade 3 or 4 elevations in lipase and/or amylase. 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. In ongoing sponsored studies with MEDI4736 and 
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tremelimumab combination therapy, cumulatively, 4 serious events that occurred 
in 3 subjects (pancreatitis in 1 subject, pancreatitis acute in
1 subject, and amylase increased and lipase increased in 1 subject) have 
been assessed by the investigator as related to MEDI4736 and tremelimumab 
combination therapy.
1.3.3.2   Hypersensitivity Reactions
Drugs that activate the immune system by delivering agonistic signals through
55
activating receptors, such as CD28
. Such agents, have an increased potential to
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55
trigger systemic, nonspecific activation of T cells since they can exert their effects  
in the absence of any antigen-specific T-cell receptor signals. In contrast,
agents . Agents that act via antagonism of an inhibitory pathway modulate an
existing antigen-specific T--cell receptor signal and have a limited potential to 
drive systemic, nonspecific activation of T cells. This is exemplified clinically by 
molecules targeting CTLA--4 and PD--1, which are not associated with acute,
56, 57, 45
severe adverse effects, such as cytokine storm
. Like these molecules,
45, 56, 57
MEDI4736 antagonizes an inhibitory receptor (PD-L1).
. With the
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administration of polyclonal immunoglobulin preparations and mAbs, major 
safety concerns associated with immunogenicity include serious allergic
reactions and anaphylaxis, cytokine-release syndrome, infusion-related reactions, 
and delayed hypersensitivity associated to immune complex disease, which can 
potentially be severe or life-threatening leading to death.
Infusion-related Reactions
Adverse reactions that occur during or shortly after infusion may include fever, 
chills, hypotension, dyspnea, tachycardia, cyanosis, respiratory failure, urticarial 
and pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension rash, headache, flushing, sweating, 
myalgia, nausea, vomiting, unresponsiveness, and hemodynamic instability. The 
typical onset can be within 30 minutes to 2 hours after the initiation of drug 
infusion, although symptoms may be delayed for up to 24 hours. The majority of 
reactions occur after the first or second exposure to the agent, but between 10% 
and 30% occur during subsequent treatments {Lenz, 2007}. Cytokine-release 
syndrome is described as an exaggerated systemic immune response involving the 
potential release of more than 150 inflammatory mediators and occurs during or 
immediately after an infusion. Certain mAb therapeutics have been shown to 
induce a range of acute infusion reactions including cytokine-release syndrome 
that can lead to AEs in subjects.
In clinical studies with MEDI4736 as a monotherapy, the incidence of reported 
potential infusion-related reaction was low. In particular for the serious case 
reports of investigator assessed infusion-related reaction, 10 of 1,265 subjects 
treated with MEDI4736 in 5 sponsored monotherapy studies (CD-ON- 
MEDI4736-1108, D4190C00002, D4190C00007, D4191C00003, and 
D4193C00001) reported 14 cases of infusion-related reactions, giving an overall 
frequency of 0.8% (10/1,265). These events/reactions respond to antihistamine, 
drug interruption/withdrawal, decrease in infusion rate and supportive treatment. 
Comorbidities include concurrent systemic illnesses, history of allergies/asthma, 
multiple concomitant medications and recent history of infusion-related reactions.
Anaphylaxis and Serious Allergic Reactions
Anaphylaxis is a systemic, immediate hypersensitivity reaction that is mediated 
by interactions between factors released from IgE and mast cells; these 
interactions result in an antigen-antibody reaction. Clinical manifestations of 
acute allergic reactions may range from localized skin reactions at the injection 
site to AEs, which can include, but are not limited to, those events similar to 
infusion-related reactions. Severe reactions including anaphylaxis, drug 
hypersensitivity syndromes, Stevens-Johnson syndrome and toxic epidermal 
necrolysis are also associated with significant morbidity and mortality. These 
reactions are more common with higher doses, higher rates of infusion, and in
subjects with a history of allergies. MEDI4736 antagonizes an inhibitory receptor 
(PD-L1). As such, in the absence of an antigen-specific T-cell receptor signal, 
inhibition of function of PD-L1 is not anticipated to elicit any response. This 
expectation is supported by published data showing no effect for anti-PD- L1
58
antibodies in the absence of a T-cell receptor stimulus 
Immune-complex Disease
Treatment of humans with mAbs carries the theoretical risk of induction of
ADA responses and adverse effect as the consequence of the formation of ADA: 
drug immune complexes. Manifestations of so-called immune complex disease 
include arthralgia, serum-sickness, nephritis, and vasculitis. Additionally, ADA 
may mediate enhanced clearance or neutralization of mAbs and biologics in 
general. The potential risk of immune complex disease for MEDI4736 is 
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th
th
theoretical based on the known risk associated with mAbs and other proteins. The 
incidence of MEDI4736 ADA-positive subjects in clinical studies is low, and 
hence the risk of immune complex disease is likely to be low. Subjects in clinical 
studies will be closely monitored for induction of ADA, and signs and symptoms 
of immune complex disease.
1.3.3.3   Other Potential Risks Serious Infections
The potential risk of serious infections is based on safety findings from 
nonclinical studies with MEDI4736 that demonstrated that MEDI4736 partially 
suppressed the primary antibody response to a T-cell dependent antigen (KLH). 
Secondary antibody responses to this antigen were normal. The relevance of this 
finding with respect to a human immune response is that it could be a potential 
risk; a reduction in humoral immunity may result in a reduced primary antibody 
response to vaccination and an increased risk of infection. Serious and/or ≥ 
Grade 3 infections requiring hospitalization including, but not limited to, sepsis,
pneumonia, lung infections, have been reported in clinical trials with MEDI4736, 
but are often confounded by underlying disease and use of concomitant 
medications (i.e., steroids and other immunosuppressives) that may cause 
opportunistic infections. Subjects should be monitored for serious infections while 
receiving MEDI4736.
For complete details on MEDI4736 safety experience, please refer to current IB. 
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
(5  , median and 95
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. Simulation results demonstrate that body WT-based and fixed dosing 
regimens yield similar median steady state PK concentrations with slightly less 
overall between-subject variability with fixed dosing regimen.
Similarly, a population PK model was developed for tremelimumab using data 
from Phase 1 through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D;
61
metastatic melanoma).
Population PK model indicated minor impact of body
WT on PK of tremelimumab (coefficient of ≤ 0.5). The WT-based (1 mg/kg
Q4W) and fixed dosing (75 mg/kg Q4W; based on median body WT of ~75 kg)
th
regimens were compared using predicted PK concentrations (5
th
, median and
95   percentiles) using population PK model in a simulated population of 1000
patients with body weight distribution of 40 to 120 kg. Similar to MEDI4736, 
simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly 
less between-subject variability with fixed dosing regimen.
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Similar findings have been reported by others.
62-65 Wang and colleagues
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64
investigated 12 monoclonal antibodies and found that fixed and body size-based
63
dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies.
In addition, they investigated 18 therapeutic proteins and peptides and showed 
that fixed dosing performed better for 12 of 18 in terms of reducing the between-
subject variability in pharmacokinetic/pharmacodynamics parameters.
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), 1500 mg Q4W MEDI4736 
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 
mg/kg Q4W) is included in the current study.
1.3.4
Efficacy
As of 14Jul2014, partial efficacy data are available for 2 monotherapy studies (CD-ON- 
MEDI4736-1108 and D4190C00002) and 1 combination therapy study of MEDI4736 plus 
tremelimumab (D4190C00006). Tumor assessments were based on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 guidelines (Eisenhauer et al,
2009).
Clinical activity has been observed across the 3 studies. In Study CD-ON-MEDI4736-
1108, 169 of 414 subjects treated with MEDI4736 (all dose levels) were evaluable for 
response analysis, which included subjects who had at least 24 weeks of follow-up as of 
the data cutoff date and had either at least 1 post-baseline tumor assessment or 
experienced clinical progressive disease (PD) or death. Nineteen subjects (11.2%) had a 
best overall response of complete response (CR)/partial response (PR; confirmed and
unconfirmed). The disease control rate (DCR; CR + PR + stable disease [SD] ≥ 12 weeks) 
was 32% (54 of 169 subjects). Tumoral programmed cell death ligand 1 status was known 
for 143 of the 169 evaluable subjects, of whom 30 had tumors that were PD- L1 positive. 
A best overall response of CR/PR (confirmed and unconfirmed) was observed in 7 of 30 
(23.3%) PD-L1-positive subjects and in 6 of 113 (5.3%) PD-L1- negative subjects. By 
tumor type, responses were observed in subjects with non-small- cell lung cancer 
(NSCLC), squamous cell carcinoma of the head and neck (SCCHN), hepatocellular 
carcinoma (HCC), cutaneous melanoma, gastroesophageal cancer, and pancreatic 
adenocarcinoma. In Study D4190C00002, 12 of 18 subjects had at least 1 post-baseline 
tumor assessment. One subject had a best overall response of PR (unconfirmed) and 6 
subjects had SD (irrespective of tumoral PD-L1 expression). In Study D4190C00006, 13 
of 18 subjects had at least 1 tumor assessment. Five subjects had best overall responses of 
PR (1 confirmed and 4 unconfirmed) and 3 subjects had SD (again irrespective of tumoral 
PD-L1 expression).
1.4
Tremelimumab Background
Tremelimumab (formerly CP-675,206) is a human immunoglobulin (Ig) G2 monoclonal antibody 
(mAb) being investigated as a cancer immunotherapeutic agent. Tremelimumab is specific for 
human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; cluster of differentiation [CD]152), 
a cell surface receptor that is expressed primarily on activated T cells and acts to inhibit their 
activation.
Summary of non-clinical experience: Tremelimumab has no cross-reactivity to related human 
proteins, or to mouse, hamster, rat, or rabbit CTLA-4, but it does demonstrate cross reactivity to 
cynomolgus monkey CTLA-4. Cytotoxic T lymphocyte-associated antigen 4 delivers a negative 
regulatory signal to T cells upon binding of B7.1 (CD80) or B7.2 (CD86) ligands on antigen- 
presenting cells. Tremelimumab completely blocks the interaction of human CTLA-4 with B7.1
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and B7.2, resulting in increased release of cytokines (interleukin [IL]-2 and interferon [IFN]-γ) 
from human T cells, peripheral blood mononuclear cells (PBMCs) and whole blood, and 
cynomolgus monkey whole blood cultured in the presence of activating stimuli. In contrast, 
addition of tremelimumab to human whole blood in the absence of additional stimuli does not
induce levels of cytokines in vitro that would be predictive of cytokine-release syndrome in vivo. In 
addition, tremelimumab shows minimal specific binding to constant fragment of antibodies (Fc) 
receptors, does not induce natural killer (NK) cell-mediated antibody-dependent cell-mediated 
cytotoxicity (ADCC) activity, and does not deliver inhibitory signals following plate-bound 
aggregation. As tremelimumab does not cross-react with mouse CTLA-4, an anti-mouse CTLA-4 
surrogate mAb (9H10) was used to assess the antitumor activity of anti-CTLA-4 in the SA1N mouse 
model of fibrosarcoma. Antibody 9H10 demonstrated dose-dependent antitumor activity
and, at the maximum dose tested, resulted in tumor regression in 4 of 5 treated animals. These 
animals were shown to be resistant to tumor rechallenge, demonstrating a durable antitumor 
immunity. Antitumor activity was observed in the model when antibody was present at a plasma 
concentration of 30 μg/mL. Thus, a concentration of 30 μg/mL 9H10 was identified as the 
target plasma concentration for tremelimumab.
The toxicology program conducted for tremelimumab consisted of in vivo general toxicology studies 
in cynomolgus monkeys for up to 6-months duration, an embryo-fetal development study in 
monkeys, tissue cross-reactivity studies in both monkey and human tissues, and blood compatibility 
studies.
1.4.1
Pharmacokinetics and Product Metabolism
The pharmacokinetics (PK) of tremelimumab was linear (dose-proportional) within the 
dose range examined following single and multiple administrations. Overall, tremelimumab 
toxicities in monkeys were consistent with inhibition of CTLA-4 and with clinical safety 
findings, and indicated that chronic clinical use of tremelimumab may lead to adverse 
effects on the gastrointestinal tract, skin, lymphoid organs, thyroid tissues, and 
hematological parameters. Clinical dose-limiting toxicities (DLTs; gastrointestinal effects) 
and non-DLTs (e.g., skin rash) were appropriately identified in a chronic toxicity study in 
monkeys. Most toxicities were reversible or showed a trend towards reversibility.
An embryo-fetal development study was conducted in pregnant cynomolgus monkeys 
during the period of organogenesis. Tremelimumab administered intravenously (IV) once 
weekly from Day 20 to Day 50 of gestation at doses of 0, 5, 15, or 30 mg/kg did not elicit 
maternal toxicity, developmental toxicity, or teratogenicity.
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a 
cutoff date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of 
the tremelimumab clinical development program. Of these studies, 13 have been 
completed and 9 are ongoing. Tremelimumab has been administered as monotherapy to
973 subjects participating in 10 of the 22 clinical studies, 2 of which are ongoing. An 
additional 497 subjects have received tremelimumab or placebo in the ongoing double- 
blinded, Phase 2b mesothelioma study, D4880C00003 (DETERMINE; data remain 
blinded). Tremelimumab in combination with other anticancer agents has been 
administered to 208 subjects with a variety of tumor types in 12 of the 22 clinical studies,
7 of which are ongoing.
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following IV 
infusion. The estimate of clearance (CL), volume of distribution at steady state (Vss), and 
terminal-phase half-life is 0.132 mL/h/kg, 81.2 mL/kg and 22.1 days, respectively. These 
values are consistent with those of natural IgG2.
Across the clinical development program for tremelimumab, a pattern of efficacy has 
emerged, also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears 
to be consistent across tumor types for this mechanism of action. Response rates to anti-
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CTLA-4 antibodies are generally low, approximately 10%. However, in subjects who 
respond, the responses are generally durable, lasting several months even in subjects with 
aggressive tumors such as refractory metastatic melanoma. Some subjects may have what is 
perceived to be progression of their disease in advance of developing disease stabilization 
or a tumor response. Overall, the impact on conventionally-defined progression-free 
survival (PFS) can be small; however, the durable response or stable disease seen in a 
proportion of subjects can lead to significant prolongation of overall survival (OS). 
Recently, ipilimumab was shown to significantly improve OS in both first- and second-line 
treatment of subjects with metastatic melanoma. The melanoma data with ipilimumab 
clearly demonstrate that a small proportion of subjects with an objective response and a 
small impact on PFS rates can lead to significant prolongation of OS, and support 
development of this class of agent in other tumors. In a large, single-arm Phase 2 
tremelimumab study in subjects with advanced refractory and/or relapsed melanoma, 
objective responses (primary endpoint) following tremelimumab 15 mg/kg administered 
once every 90 days (Q90D) were observed in 7% of subjects. In each case, the response 
was durable (present at ≥ 6 months from enrollment). A Phase 3, open-label, randomized 
study comparing tremelimumab 15 mg/kg Q90D (Arm A) to either dacarbazine or 
temozolomide (Arm B) in subjects with advanced melanoma was terminated following a 
pre-specified interim futility analysis. Based on the final analysis, the median OS (primary 
endpoint) was 12.6 months in Arm A and 10.7 months in Arm B (hazard ratio [HR] =
1.1416, p = 0.1272).
1.4.2
Safety
The profile of adverse events (AEs) and the spectrum of event severity have remained 
stable across the tremelimumab clinical program and are consistent with the pharmacology 
of the target. To date, no tumor type or stage appears to be associated with unique AEs 
(except for vitiligo that appears to be confined to subjects with melanoma). As of the data 
cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cutoff date of
04Dec2014), AEs (all grades, regardless of causality) reported in > 10% of subjects in the 
completed and rollover tremelimumab monotherapy studies (N = 973, integrated data) 
were diarrhea (45.3%), fatigue (37.5%), nausea (32.5%), rash (28.9%), pruritus (27.3%), 
decreased appetite (22.8%), vomiting (22.5%), pyrexia (15.3%), cough (15.0%), 
constipation (14.4%), abdominal pain (13.9%), headache (13.8%), dyspnea (12.4%), and 
decreased weight (10.2%). Based on integrated data from completed studies of 
tremelimumab in combination with other agents (N = 116), AEs (all grades, regardless of 
causality) reported in > 15% of subjects were diarrhea (54.3%); nausea (40.5%); fatigue 
(38.8%); rash (35.3%); pruritus, decreased appetite (30.2% each); vomiting (27.6%); 
pyrexia (26.7%); influenza like illness (20.7%); arthralgia (19.8%); constipation (19.0%); 
thrombocytopenia, injection site reaction (18.1% each); and increased aspartate 
aminotransferase (15.5%). Most of these events occurred at a higher rate with 
tremelimumab plus sunitinib than with other combinations. The events of diarrhea, rash, 
and pruritus are considered identified risks of tremelimumab. Acute renal failure was 
reported in subjects who received the combination of tremelimumab and sunitinib; 
however, acute renal failure has not been an expected AE for single-agent tremelimumab. 
The incidence and/or severity of many of the AEs observed following administration of 
tremelimumab can be reduced by following current guidelines for the management of 
immune-related toxicities.
MEDI4736 and tremelimumab
The safety profile of MEDI4736 and tremelimumab combination therapy in the 102 
subjects with advanced NSCLC in Study D4190C00006 is generally consistent with that 
observed across 177 subjects treated with MEDI4736 and tremelimumab combination 
therapy (not including subjects treated with blinded investigational product). As of
15Apr2015, 95 of 102 subjects (93.1%) reported at least 1 AE. All subjects in the 
tremelimumab 3 and 10 mg/kg dose cohorts experienced AEs; subjects in the
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MEDI4736 20 mg/kg and tremelimumab 1 mg/kg Q4W cohort experienced the lowest 
AE rate (77.8%). Treatment-related AEs were reported in 74 of 102 subjects (72.6%), 
with events occurring in > 10% of subjects being diarrhea (27.5%), fatigue (22.5%),
increased amylase and pruritus (14.7% each), rash (12.7%), colitis (11.8%), and increased 
lipase (10.8%). Treatment-related ≥ Grade 3 AEs reported in ≥ 5% of subjects were colitis 
(8.8%), diarrhea (7.8%), and increased lipase (5.9%). Five subjects reported treatment- 
related Grade 4 events (sepsis, increased ALT, and increased AST in 1 subject; increased 
amylase in 2 subjects; myasthenia gravis in 1 subject; and pericardial effusion in 1 subject) 
and 2 subjects had treatment-related Grade 5 events (polymyositis and an uncoded event
of neuromuscular disorder [VT]); the Grade 4 event of myasthenia gravis and Grade 5 
polymyositis occurred in 1 subject. There were 2 subjects (both in the MEDI4736 20 
mg/kg + tremelimumab 3 mg/kg Q4W cohort) with dose-limiting toxicities (DLTs): 1 
subject with Grade 3 increased AST, and 1 subject with Grade 3 increased amylase and 
Grade 4 increased lipase. Fifty-six subjects (54.9%) reported SAEs, with events occurring 
in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). Thirty-six subjects (35.3%) 
experienced treatment-related SAEs. Twenty-seven subjects (26.5%) permanently 
discontinued treatment due to AEs. Treatment-related AEs resulting in discontinuation in
≥ 2 subjects were colitis (7 subjects), pneumonitis (5 subjects), diarrhea (3 subjects), and 
increased AST (2 subjects).
MEDI4736 and Tremelimumab Fixed Dosing Regimens
A population PK model was developed for MEDI4736 using monotherapy data from the 
Phase 1 study, CD-ON-MEDI4736-1108 (N = 292; doses of 0.1 to 10 mg/kg Q2W or 15 
mg/kg Q3W; solid tumors). Population PK analysis indicated only minor impact of body 
weight on PK of MEDI4736 (coefficient of ≤ 0.5). The impact of body weight-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 weight of ~75 kg). A total of 1000 subjects were simulated using body 
weight distribution of 40 to 120 kg. Simulation results demonstrate that body weight- based 
and fixed dosing regimens yield similar median steady-state PK concentrations with slightly 
less overall between-subject variability with fixed dosing regimen.
Similarly, a population PK model was developed for tremelimumab using data from Phase
1 through Phase 3 (N = 654; doses of 0.01 to 15 mg/kg Q4W or every 90 days; metastatic 
melanoma; Wang et al, 2014). The population PK model indicated minor impact of body 
weight on PK of tremelimumab (coefficient of ≤ 0.5). The weight-based (1 mg/kg Q4W) 
and fixed dosing (75 mg/kg Q4W; based on median body weight of ~75 kg) regimens 
were compared using predicted PK concentrations (5th, median and 95th percentiles) using 
population PK model in a simulated population of 1,000 subjects with body weight 
distribution of 40 to 120 kg. Similar to MEDI4736, simulations indicated that both body 
weight-based and fixed dosing regimens of tremelimumab yield similar median steady 
state PK concentrations with slightly less between-subject variability with fixed dosing 
regimen.
Similar findings have been reported by others (Ng et al, 2006; Wang et al, 2009; Zhang et 
al, 2012; Narwal et al, 2013). Wang and colleagues investigated 12 mAbs and found that 
fixed and body size-based dosing perform similarly, with fixed dosing being better for 7
of 12 antibodies (Wang et al, 2009). In addition, they investigated 18 therapeutic proteins 
and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-subject variability in PK/pharmacodynamics parameters (Zhang et 
al, 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and
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reduced dosing errors. Given expectation of similar PK exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on an average body 
weight of 75 kg, a fixed dose of 750 mg Q2W MEDI4736 is equivalent to 10 mg/kg 
Q2W, 1500 mg Q4W MEDI4736 is equivalent to 20 mg/kg Q4W, and 75 mg Q4W 
tremelimumab is equivalent to 1 mg/kg Q4W.
Dosing schedule for Tremelimumab and Durvalumab
The two drugs will be administered in 3 different arms as per current IB specifications: 
Treatment Arms:
On all arms, patients will be given the 1st dose(s) of study treatment 14 days pre-surgery. 
Patients will then undergo standard surgical resection. Dosing will then resume 
approximately 14 days after surgery (once the surgical wound has healed) and will follow 
the schedule outlined below (depending on the arm to which they were assigned):
Arm 1) Tremelimumab- 75 mg every 4 weeks. The drug will be restarted 14 days after 
surgery once the surgical wound has healed and then every 4 weeks after surgery. If there 
is no progression of disease, they will continue on treatment for up to 24 months
Arm 2) MEDI4736- 750 mg every 2 weeks.  The drug will be restarted 14 days after 
surgery once the surgical wound has healed and then every 2 weeks after surgery.  If there 
is no progression of disease, they will continue on treatment for up to 24 months
Arm 3) In the combination arm,14 days after surgery, the drugs will be administered as 
follows: Tremelimumab will be administered IV every 4 weeks (Day 1 of each cycle) and 
MEDI4736 750mg every 2 weeks (Day 1 and Day 15 of each cycle) until the patients
have received 7 doses of Tremelimumab and 14 doses of MEDI4736. Thereafter, from 
Cycle 7 (Week 25), Tremelimumab will be given every 12 weeks (+/-7 days) and 
MEDI4736 will be given every 2 weeks (+/- 2 days) until permanent discontinuation 
criteria (e.g. disease progression) is met. If there is no progression of disease, they will 
continue on treatment for up to 24 months.
(Note: This change to a 12 week regimen for tremelimubab after the first 6 doses is based 
on the current IB specifications and recent trial data).
Please refer to current Tremelimumab and Durvalumab IBs for more details
1.5
Rationale for the Current Study
The preclinical activity in glioma and the data in other solid tumors suggest that checkpoint 
inhibitors may be beneficial in GBM and should be evaluated especially since there is a high degree 
of PD-L1 seen in GBM.  However, to further understand the effects of a cancer immunology 
approach in tumors, a pre-treatment trial to assess the immunologic changes in tumors prior to 
surgery would be important in understanding the effect of treatment.
This trial will assess the effect of each agent alone and then in combination.
1.5.1
Exploratory Studies
For patients who progress on trial and remain surgical candidates, tissue post treatment 
with Tremelimumab or MEDI4736 or the combination will be analyzed and compared to 
the prior specimen.
Additional exploratory studies will include assessment of:
1)   Profile peripheral blood lymphocytes (PBL)
2)   Tumor-infiltrating lymphocytes (TIL) throughout treatment.
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3)   Serum for tryptophan and downstream catabolites, as well as for cytokines.
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoints
To determine the T-cell changes that occur in recurrent GBM treated with Tremelimumab and 
MEDI4736 as single agents and in combination. The changes from baseline will be assessed in blood 
samples and tissue samples before treatment and post-surgery for all patients in the 3 arms. A 
comparison between the changes observed in the 3 arms will be made.
2.2
Secondary Objectives & Endpoints
2.2.1
To evaluate the safety of either Tremelimumab or MEDI4736 alone and in combination in 
patients with recurrent GBM. The endpoints will be the number, frequency, and severity 
of adverse events (as defined by the NCI Common Terminology Criteria for Adverse 
Events or CTCAE version 4.03).
2.2.2
To determine post-surgery, the time to progression(per Modified RANO  criteria and 
iRANO criteria see below)  for patients treated with either Tremelimumab or MEDI4736 
alone and in combination of both, This will be defined as the number of months from the 
time of first dose of study treatment until progression of disease or death by any cause.
2.2.3
To determine post-surgery the overall survival for patients treated with Tremelimumab or 
MEDI4736 alone and in combination of both. This will be defined as the number of 
months surviving from the time of first dose of study treatment until death by any cause.
2.2.4
To assess post-surgery, MRI changes in patients treated with either Tremelimumab or
MEDI4736 alone and in combination of both.
2.3
Exploratory Objectives & Endpoints
2.3.1
To correlate T-cell changes and PDL1 expression with patient outcomes.
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with recurrent glioblastoma. This will be a single-center trial 
conducted at neuro-oncology clinic of Northwestern University.
A total of 30 evaluable subjects will be needed for this trial. The accrual cap is 45 patients, in order to cover 
those patients that do not make it to the first evaluable time point. Hence, the total accrual per arm will be
up to 15. Approximately 4 potentially eligible patients are seen per month, and it is anticipated that at least 2 
per month will be accrued. Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Karan Dixit ,  at (312) 503-4724.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers are not 
permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered.
3.1
Inclusion Criteria
3.1.1
Patients must have a prior diagnosis of Grade IV glioma (Glioblastoma) per 2016 WHO
criteria that has progressed after standard radiotherapy (RT) and Temozolomide (TMZ).
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(Note: Pathology will need to be reviewed locally but registration can occur based on 
pathology report).
3.1.2
Patients must have had radiographic evidence of tumor progression by brain MRI or CT
scan with contrast.
3.1.3
Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the 
patient must have subsequent histologic documentation of recurrence, unless the 
recurrence occurs remote from the treated site.
3.1.4
Patients must be surgical resection candidates.
3.1.5
Patients must have had no more than 3 prior lines of chemotherapy. This includes the 
initial treatment and two relapses. Concurrent and adjuvant TMZ-based chemotherapy, 
including the combination of TMZ with another agent, is considered one line of 
chemotherapy. For clarification, please contact the PI, Dr. Karan Dixit at (312) 503-4724
3.1.6
Patients must be age ≥ 18 years. Both male and female are eligible.
3.1.7
Patients must exhibit a KPS > 70 (Appendix C).
3.1.8
Life expectancy of > 12 weeks (per treating investigator’s discretion).
3.1.9
Patients must be on a stable or decreasing dose of corticosteroids within 5 days prior to
CT scan or MRI (which is done to determine eligibility). Patients must be on no more than
8 mg a day but an attempt should be made to keep the dose at 4 mg or less. Please contact 
the PI if doses of > 4 mg are needed.
3.1.10
Patients must have adequate organ and bone marrow function within 14 days prior to 
registration, as defined below.
(Note: The CBC and chemistries will be repeated within 72 hours of 1st dose of study 
treatment if baseline tests were more than 7 days prior to dosing).
 
leukocytes
≥ 3,000/mcL
 
absolute neutrophil count
≥ 1,500/mcL
 
platelets
≥ 100,000/mcl
 
hemoglobin (Hb)
>10.0 g/dL (can be transfused to this level)
 
INR, PT, or APTT as follows:
o
In the absence of therapeutic intent to anticoagulate the patient:

INR < 1.5, or

PT < 1.5×ULN, or

aPTT < 1.5×ULN
o
In the presence of therapeutic intent to anticoagulate the patient:

INR or PT and aPTT within therapeutic limits (according to
the medical standard in the institution) and the patient has 
been on a stable dose of anticoagulants for at least 2 weeks 
before registration.
 
total bilirubin
< 1.5 x ULN (except in patients with
Gilbert’s disease)
 
AST (SGOT)/ALT (SPGT)
≤ 2.5 x institutional upper limit of normal
(ULN)
 
Serum creatinine
< 1.5 x ULN
 
Serum creatinine CL
>40 mL/min by the Cockcroft-Gault formula 
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(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of
creatinine clearance:
Males:
Creatinine CL (mL/min)
Weight (kg) x (140 – Age) x 1.0
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)
3.1.11
Females of child-bearing potential (FOCBP) and males must agree to use adequate 
contraception (e.g. hormonal or barrier method of birth control – see appendices 
acceptable birth control methods) prior to registration, for the duration of study 
participation, and for 180 days after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 or tremelimumab 
monotherapy. Should a female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets both of the following criteria:
 
Has not undergone a hysterectomy or bilateral oophorectomy.
 
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months).
3.1.12
FOCBP must have a negative pregnancy test (serum or urine) within 7 days prior to 
registration on study.
3.1.13
Patients must have the ability to understand and the willingness to sign a written informed 
consent prior to registration on study.
3.1.14
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up.
3.1.15
Patients must have given written, signed and dated informed consent prior to registration 
on the study. NOTE: no study-specific screening procedures may be performed until 
consent has been given.
3.2
Exclusion Criteria
3.2.1
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site); Previous enrolment or randomization in the present 
study.
3.2.2
Has received prior therapy with an anti-PD-1, anti-PD-L2, anti-CD137, or anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways).
3.2.3
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
3.2.4
Known active human immunodeficiency virus (HIV1/2 antibodies).
3.2.5
Treatment with radiation therapy within 12 weeks prior to the first dose of study 
treatment, unless there is tissue confirmation of tumor recurrence or there is progression 
outside the treatment field.
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3.2.6
Administration of any of the following within the specified timeframe prior to the first 
dose of study drug:
 
4 weeks for TMZ,
 
6 weeks for nitrosoureas,
 
3 weeks for a biologic or targeted agent (i.e. small molecule)
 
4 weeks for a VEGF inhibitor (i.e. bevacizumab)
3.2.7
Patient has history of primary immunodeficiency OR has received any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment, 
excluding intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses. Attempts should be made to have patient on lowest possible dose of
steroids (acceptable range4-8 mg. please contact PI if dose is >4 mg), and weaned to off as 
is feasible.
3.2.8
Patients receiving any other investigational chemotherapeutic agents within 28 days prior 
to the first dose of trial treatment.
3.2.9
Patients on an enzyme-inducing anti-convulsant who cannot be switched to a non- 
enzyme-inducing anti-convulsant with a 2 week wash-out period from time of drug 
discontinuation until Day 1 of study treatment.
3.2.10
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from an 
electrocardiograms (ECGs) using Bazett’s Correction. If first ECG is abnormal, then the 
mean will be calculated from 3 consecutive ECGs (taken 2-5 minutes apart). Please 
contact the PI for further clarification.
3.2.11
Active or prior documented history of immunologic disorder including 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.
3.2.12
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis).
3.2.13
History of allogeneic organ transplant.
3.2.14
Uncontrolled intercurrent illness including, but not limited to:
 
ongoing or active infection,
 
symptomatic congestive heart failure,
 
uncontrolled hypertension
 
unstable angina pectoris,
 
cardiac arrhythmia,
 
active peptic ulcer disease or gastritis,
 
active bleeding diatheses, or
 
psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the subject to give written informed 
consent.
3.2.15
Known history of previous clinical diagnosis of tuberculosis.
3.2.16
History of leptomeningeal carcinomatosis.
3.2.17
Patients with a history of active malignancy within 3 years prior to registration. Note: 
exceptions to this requirement include adequately treated non-melanoma skin cancer or 
lentigo maligna or carcinoma in situ without evidence of disease or prostate cancers with a 
Gleason score < 8 and with prostatectomy and no lymph node involvement.
3.2.18
Receipt of live attenuated vaccination within 30 days prior to study entry (or due to 
receive one within 30 days of receiving either MEDI4736 or tremelimumab).
3.2.19
Female subjects who are pregnant, breast-feeding or male or female patients of 
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reproductive potential who are not employing an effective method of birth control.
3.2.20
Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results.
3.2.21
Subjects with uncontrolled seizures.
3.2.22
Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to MEDI3475 are not eligible.
4.0
TREATMENT PLAN
4.1
Overview
Patients will be treated with either Tremelimumab 75 mg alone, MEDI4736 750 mg alone, or both 
in combination. Patients will be randomly allocated using block randomization to ensure equal 
sample sizes per arm. Up to 45 patients (15 per arm) will be randomized to ensure that 30 patients 
are evaluable for immunologic response (10 per arm).
Patients will then undergo a surgical resection of their tumor that is part of their medical care 2 
weeks later to remove the tumor. Two weeks is expected to be enough time for immunologic 
changes to occur in the tumor. Standard pre-surgical testing will be done prior to surgery. At the 
time of surgery, tissue will be removed for local pathology review and send to Dr. Bloch’s 
Laboratory for evaluation (see Section 9.0 for details).
Post-operative care will be standard for patients who undergo a craniotomy and tumor resection at 
NMH.  Patients will have a standard post-operative MRI or CT scan of the brain within 72 hours of 
surgery. Following surgery, patients will resume treatment on the same regimen they were assigned 
to receive before surgery. Treatment may continue until disease progression or unacceptable 
toxicity.
4.2
Treatment Administration
Treatment Administration Summary
Arm
Treatment
Dose
Route
Schedule
Supportive
Therapies**
1
Tremelimumab 
monotherapy
75 mg
IV at
250ml/hr
Once within 14 d 
(+/-3) pre-surgery. 
Adjuvant: Every 4 
weeks
Acetaminophen 
and/or antihistamine 
or equivalent
3
2
MEDI4736 
monotherapy
750 mg
IV over
60min+/-5 mins
2
Once within 14 d 
(+/-3) pre-surgery. 
Adjuvant: Every 2 
weeks
Acetaminophen 
and/or antihistamine 
or equivalent
3
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3
Tremelimumab
+ MEDI4736 
combination 
therapy
75 mg +
750mg
IV
1
1 hour for each 
drug
Once within 14 d 
(+/-3) pre-surgery. 
Then, treme every
4 weeks (for 7 
doses post- 
surgery) + MEDI 
every 2 weeks (for
14 doses post- 
surgery); then 
Treme every 12 
weeks and MEDI 
every 2 weeks 
from C7 (wk 25).
Acetaminophen 
and/or antihistamine 
or equivalent
3
1 Tremelimubab administered first, then MED14736 infused after a gap of 1 hour for the first cycle. If tolerated, 
then can be given one after the other for subsequent infusions (at discretion of PI)
2 Use a 0.2 micron in-line filter
3 As per institutional policy, at the discretion of the investigator. May also be used as pre-medications for infusions
**Antiemetic therapy may be used as needed; 5HT antagonists are recommended. Hematopoietic growth factors
(G-CSF) may be used per ASCO guidelines after cycle one. Corticosteroids should be used in the smallest dose to 
control symptoms of cerebral edema and mass effect, and should be discontinued if possible. Febrile neutropenia 
may be managed according to the institution’s infectious disease/ASCO guidelines.
Patients will be allocated randomly using block randomization to ensure equal sample sizes per arm, 
with up to 12 patients being enrolled into each arm (in order to achieve 10 evaluable per arm). On 
all arms, patients will be given the 1st dose(s) of study treatment 14 days pre-surgery. Patients will 
then undergo standard surgical resection. Dosing will then resume approximately 14 days after 
surgery (once the surgical wound has healed) and will follow the schedule outlined above 
(depending on the arm to which they were assigned). For the combination Arm 3. Tremelimumab 
will be administered IV every 4 weeks (Day 1 of each cycle) and MEDI4736
750mg every 2 weeks (Day 1 and Day 15 of each cycle) until the patients have received 7 doses of 
Tremelimumab and 14 doses of MEDI4736, post-surgery.  Thereafter, from Cycle 7 (Week 25), 
Tremelimumab will be given every 12 weeks (+/-7 days) and MEDI4736 will be given every 2 
weeks (+/- 2 days) until permanent discontinuation criteria (e.g. disease progression) is met. On all  
arms, if there is no progression of disease, patients may continue on treatment for up to 24 months. 
If at the time of progression, the patient is a candidate for surgery, tissue will again be sent to Dr. 
Bloch’s laboratory for evaluation.
Any patient who has disease progression as defined in section 6.0 or clinical decline and undergoes 
further surgery will have the option to use their tumor tissue for research to understand the 
immunologic changes occurring at the time of presumed drug failure. If on pathologic review, there 
is no evidence of significant tumor and the changes on MRI were likely treatment related, the patient 
will be allowed re-start treatment. The patient will be advised of the pathology results and that they 
may not derive any further benefit from therapy and they will need to re-sign the informed consent 
prior to starting therapy.
4.3
Supportive Care Guidelines & Concomitant Medications/Restrictions on Study
4.3.1
Supportive Care
All medications used by patients during the study, with the reasons for use, will be 
recorded in the medical record and documented in the appropriate eCRF. For all 
subsequent visits, all concomitant therapy that is continuing or has been added, 
discontinued, or had a dosage change since the previous visit must be recorded in the 
medical record/eCRF as well.
 
Antiemetic therapy may be used as needed and will be recorded in the 
medical record; 5HT antagonists are recommended.
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 
Hematopoietic growth factors (G-CSF) may be used per American Society of
Clinical Oncology (ASCO) guidelines after cycle one.
 
Corticosteroids should be used in the smallest dose to control symptoms of 
cerebral edema and mass effect, and should be discontinued if possible. Please 
confirm appropriate use with the PI.
 
Febrile neutropenia may be managed according to the institution’s infectious 
disease/ASCO guidelines. Measures may include appropriate laboratory testing, 
including blood and urine cultures and the initiation of broad-spectrum 
antibiotics. If a source for the fever is not identified or the fever resolves when 
the neutrophil count recovers, antibiotics may be discontinued and the patient 
observed. In this case growth factors may be used.
 
If neurosurgical intervention is required for indications not related to tumor 
progression, these procedures must be documented, including the 
indications for surgery, surgical operative note, and pathology report.
4.3.2
Restrictions While on Treatment
Contraception
Females of childbearing potential who are sexually active with a nonsterilised male partner 
must use 2 methods of effective contraception (refer to appendices) from screening, and 
must agree to continue using such precautions for 90 days after the final dose of 
investigational product, or for at least 90 days following the last infusion of MEDI4736 or 
until after 4-5X the half-life of Tremelimumab, whichever occurs longest; 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).
Non-sterilised males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see appendices) from 
Day 1 and for 90 days after receipt of the final dose of investigational product.
Blood donation
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of MEDI4736 or until after 4-5X the half-life of 
Tremelimumab, whichever occurs longest.
4.3.3
Permitted concomitant medications
 
Investigators may prescribe concomitant medications or treatments (e.g., 
acetaminophen, diphenhydramine) deemed necessary to provide adequate 
prophylactic or supportive care
 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable.
 
Local treatment of isolated lesions for palliative intent is acceptable (e.g., by 
local surgery or radiotherapy)
 
Use of immunosuppressive medications for the management of investigational 
product-related AEs or in subjects with contrast allergies is acceptable. In addition, 
use of inhaled and intranasal corticosteroids is permitted. A temporary period of 
steroids will be allowed for different indications, at the discretion of the principal 
investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.). 
Dexamethasone may be used but attempts should be made to keep
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it less than 4 mg/day.
 
Inactivated vaccines, are permitted.
4.3.4
Prohibited concomitant medications
The following medications are considered exclusionary during the study.
 
Any investigational anticancer therapy other than the protocol specified therapies
 
Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment, other than 
any stated comparator or combination regimens.)
 
Immunosuppressive medications including methotrexate, azathioprine, and
Tumor Necrosis Factor alpha-blockers (TNF-α blockers).
 
Enzyme inducing anti-convulsants (e.g.: Carbamazepine, Phenytoin, Primidone, 
Topiramate). Please check with PI if have further questions.
 
Live attenuated vaccines within 30 days of MEDI4736 and/or Tremelimumab 
dosing (i.e., 30 days prior to the first dose, during treatment with MEDI4736 
and/or Tremelimumab and for 30 days post discontinuation of MEDI4736 and/or 
Tremelimumab).
4.4
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of study therapy will be evaluable for toxicity endpoints. 
Each patient will be assessed for the development of toxicity according to the timeframe referenced 
in the Schedule of Events table. Toxicity will be assessed according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. Following the first dose of MEDI4736 and/or 
tremelimumab, subsequent administration of MEDI4736 and/or tremelimumab can be modified 
based on toxicities observed (see Table 1, 2, and 3 below). Dose reductions are not permitted.
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 
General Considerations
Dose Modifications
Toxicity Management
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/study 
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/study regimen.
 
Recurrence of a previously 
experienced Grade 3 treatment- 
related AE following resumption 
of dosing.
Grade 1: No dose modification
Grade 2: Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1.
If toxicity worsens, then treat as Grade 3 
or Grade 4. Study drug/study regimen 
It is recommended that management of immune-mediated adverse events
(imAEs) follows the guidelines presented in this table:
−
It is possible that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs, some of them not noted specifically in these guidelines.
−
Whether specific immune-mediated events (and/or laboratory indicators of such events) are 
noted in these guidelines or not, patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant medications, and infections) to a 
possible immune-mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General recommendations follow.
−
Symptomatic and topical therapy should be considered for low-grade
(Grade 1 or 2, unless otherwise specified) events.
−
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade
≥3) events, promptly start prednisone 1 to 2 mg/kg/day PO or IV
equivalent.
−
Some events with high likelihood for morbidity and/or mortality – e.g., myo-carditis, or other 
similar events even if they are not currently noted in the guidelines – should progress rapidly 
to high dose IV corticosteroids (methylprednisolone at 2 to 4 mg/kg/day) even if the event is 
Grade 2, and if clinical suspicion is high and/or there has been clinical confirmation. Consider, 
as necessary, discussing with the study physician, and promptly pursue specialist consultation.
−
If symptoms recur or worsen during corticosteroid tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [e.g., up to 2 to 4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate 
(>28 days of taper).
−
More potent immunosuppressives such as TNF inhibitors

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NU15C03 protocol Version date 11.29.18/Amend 6
can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid 
taper. Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement can be retreated with 
study drug/study regimen on the 
following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically 
stable as per Investigator 
or treating physician’s 
clinical judgement.
3.
Doses of prednisone are at 
≤10 mg/day or equivalent.
Grade 3: Depending on the individual toxicity, 
study drug/study regimen may be 
permanently discontinued. Please refer to
guidelines below.
Grade 4: Permanently discontinue study 
drug/study regimen. Note: For Grade ≥3 
asymptomatic amylase or lipase levels, 
hold study drug/study regimen, and if 
complete work up shows no evidence of 
pancreatitis, study drug/study regimen 
may be continued or resumed. Note: 
Study drug/study regimen should be 
permanently discontinued in Grade 3 
events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or 
other similar events even if they are not 
currently noted in the guidelines. 
Similarly, consider whether study 
drug/study regimen should be 
e.g infliximab(also refer to individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives should proceed more rapidly in events 
with high likelihood for morbidity and/or mortality – e.g., myocarditis, or other similar events 
even if they are not currently noted in the guidelines – when these events are not responding to 
systemic steroids.
−
With long-term steroid and other immunosuppressive use, consider need for Pneumocystis 
jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) prophylaxis, 
gastrointestinal protection, and glucose monitoring.
−
Discontinuation of study drug/study regimen is not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response (e.g., inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study drug/study regimen in this
situation should be based upon a benefit-risk analysis for that patient.

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NU15C03 protocol Version date 11.29.18/Amend 6
               permanently discontinued in Grade 2 
events with high likelihood for morbidity
                and/or mortality – e.g., myocarditis, or 
other similar events even if they are not 
currently  noted in the guidelines – when
   they do not rapidly improve to Grade 
<1 upon treatment with systemic 
steroids and following full taper
               Note: There are some exceptions to 
permanent discontinuation of study
drug for Grade 4 events(i.e 
hyperthyroidism, hypothyroidism, Type 1 
diabetes mellitus)
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth.
Pediatric Considerations
Dose Modifications
Toxicity 
Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
−
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used for 
pediatric patients.
−
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old. For dosing in children 
younger than 6 years old, consult with a pediatric specialist.
−
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist.

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NU15C03 protocol Version date 11.29.18/Amend 6
−
With long-term steroid and other immunosuppressive use, consider need for
PJP prophylaxis, gastrointestinal protection, and glucose monitoring
Specific Immune-Mediated 
Reactions
Adverse Events
       Severity Grade of the
Event (NCI CTCAE
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
-Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below.
-Initial work-up may include clinical evaluation, monitoring 
of oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up , and high-resolution CT scan
Pneumonitis/Interstitial
Lung Disease (ILD)
Grade 1
(asymptomatic, clinical or 
diagnostic observations only; 
intervention not indicated)
No dose modifications 
required. However, 
consider holding study 
drug/study regimen 
dose as clinically 
appropriate and during 
diagnostic work-up for 
other etiologies.
For Grade 1 (radiographic changes only):
−
Monitor and closely follow up in 2 to 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.

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade 2
(symptomatic medical 
intervention indicated;limiting 
instruemental ADL)
Hold study drug/study 
regimen dose until 
Grade 2 resolution to 
Grade ≤1.
 
If toxicity  
worsens, then treat 
as Grade 3 or 
Grade 4.
 
If toxicity 
improves to Grade 
≤1, then the 
decision to 
reinitiate study 
drug/study 
regimen will be 
based upon 
treating 
physician’s 
clinical judgment 
and 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 to
2 mg/kg/day PO or IV equivalent).
−Reimage as clinically indicated.
−If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started.
−If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is
important to rule out sepsis and refer to infliximab 
label for general guidance using infliximab.
-Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, or anti-PJP treatment (refer 
to current NCCN guidelines for treatment of 
cancer-related infections[Category 2B 
recommnedation]a
-Consider pulmonary and infectious disease consult 
-Consider, as necessary, discussing with study 
physician.

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade 3 or 4 
(Grade 3:severe symptoms;limiting self-
care ADL;oxygen indicated)
(Grade4:life-threatening respiratory 
compromise;
urgent intervention
indicated[e.g.,tracheostomy or 
intubation]) 
Permanently 
discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening):
Promptly initiate empiric IV methylprednisolone 1 to
4 mg/kg/day or equivalent.
−
Obtain Pulmonary and Infectious disease consult;
consider, as necessary, discussing with study physician.
−
Hospitalize the patient.
−
Supportive care (e.g., oxygen).
−
If no improvement within 3 to 5 days, additional 
workup should be considered and prompt treatment 
with additional immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 
       weeks’ dose) started. Caution: rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab.
−
Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, and, in particular, anti-PJP 
treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections[Category 2B 
recommendation]).a
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade:
-Monitor 
for 
symptoms 
that 
may 
be 
related 
to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or  blood 
in stool) or related to bowel perforation (such as 
sepsis,peritoneal signs, and ileus).
-Patients should be thoroughly evaluated to rule out any 
alternative 
etiology(e.g 
disease 
progression, 
other 
medications,or 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.

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade 1
(Diarrhea: stool frequency of <4 
over baseline per day) (Colitis: 
asymptomatic; clinical or 
diagnostic observations only)
No dose modifications.
For Grade 1:
-Monitor closely for worsening symptoms.
−Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment
Grade 2
(Diarrrhea:
stool frequency of 4 to 6 over 
baseline per 
day)(Colitis:abdominal 
pain;mucus or blood in stool)
Hold study drug/study 
regimen until 
resolution to Grade ≤1
 If toxicity worsens, 
then treat as
Grade 3 or Grade 
4.
 If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of 
steroid taper.
For Grade 2:
-Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV
equivalent.
-
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup, such as imaging 
and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started.
-
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg 
once every 2 weeksa. Caution: it is important to rule 
out bowel perforation and refer to infliximab label for
general guidance before using infliximab.
-
Consider, as necessary, discussing with study physician if 
no resolution to Grade ≤1 in 3 to 4 days.
-
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 

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NU15C03 protocol Version date 11.29.18/Amend 6
infections [Category 2B recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea: stool frequency of 
≥7 over baseline per day;
Grade 4 diarrhea: life threatening 
consequences) (Grade 3 colitis: severe 
abdominal pain, change in bowel 
habits, medical intervention indi- 
cated, peritoneal signs;
Grade 4 colitis: life- threatening 
consequences, urgent intervention
indicated)
Grade3
Permanently 
discontinue study 
drug/study regimen for 
Grade 3 if toxicity does 
not improve to Grade 
≤1 within 14 days; 
study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper.
Grade 4
Permanently 
discontinue study 
drug/study 
regimen.
For Grade 3 or 4:
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 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g., 
infliximab at 5 mg/kg once every 2 weeks). Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab.
−
Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer 
to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
Hepatitis
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis
Any Grade
General Guidance
For Any Grade:
- Monitor and evaluate liver 
function test: AST, ALT, ALP, and 
TB.
- Evaluate for alternative etiologies 
(e.g viral hepatitis,disease 
progression,concomitant 
medications).

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade 1
(Based on ULN regardless of 
baseline LFT)
(AST or ALT >ULN and 
≤3.0×ULN and/or TB > ULN 
and ≤1.5xULN)
No dose-
modifications.
 If it worsens, then 
treat as Grade 2 
event.
For Grade 1:
Continue LFT 
monitoring 
per protocol.
PLEASE SEE shaded area 
immediately below this 
section to find guidance for 
management of “Hepatitis 
(elevated LFTS)” in HCC 
patients
Grade 2
(Based on
ULN regardless of
baseline LFT)
(AST or
ALT >3.0×ULN and
≤5.0×ULN and/or
TB >1.5×ULN and
≤3.0×ULN)
Hold study drug/study 
regimen dose until 
Grade 2 resolution to 
Grade ≤1.
 
If toxicity worsens,   
then treat as
Grade 3 or Grade 4.
 
If toxicity improves 
to Grade ≤1 or 
baseline, resume 
study drug/study 
regimen after 
completion of 
steroid taper.
For Grade 2:
−
Regular and frequent checking of LFTs (e.g., every 1 to 2 days)
until elevations of these are improving or resolved.
−
If no resolution to Grade ≤1 in 1 to 2 days, consider, 
as necessary, discussing with study physician.
−
If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 3 to 5 days despite 1 to
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional work up and start prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used.
-Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics,antifungals, and anti-
PJP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections[Category 2B recommendation])a

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade 3 or 4
  
(Based on ULN regardless of
baseline LFT)
(Grade 3: AST or
ALT >5.0×ULN and
≤20.0×ULN and/or
TB >3.0×ULN and
≤10.0×ULN)
(Grade 4: AST or
ALT >20×ULN
and/or
TB >10×ULN)
For Grade 
3:
For elevations in 
transaminases
≤     8 × ULN, or 
elevations in bilirubin
≤5 × 
ULN:
   Hold study 
drug/study 
regimen dose until 
resolution to Grade 
≤1 or baseline
Resume study 
drug/study regimen if 
elevations downgrade 
to Grade
≤1or baseline 
within 14 days and 
after completion of 
steroid taper.
   Permanently 
discontinue study 
drug/study 
regimen if the 
elevations do not 
downgrade to 
Grade ≤1 or 
baseline within
14 days
For elevations in 
transaminases
>8 × ULN or 
elevations in bilirubin
>5 × ULN, 
discontinue 
study 
For Grade 3 or 4:
-
Promptly initiate empiric IV methylprednisolone at 1 to
4 mg/kg/day or equivalent.
−
If still no improvement within 3 to 5 days despite 1 to
4 mg/kg/day methylprednisolone IV or 
equivalent, promptly start treatment with 
immunosuppressive.
therapy (i.e., mycophenolate mofetil). Discuss with 
study physician if mycophenolate is not available. 
Infliximab should NOT be used.
−
Perform hepatology consult, abdominal workup, and
imaging as appropriate.
-
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a

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NU15C03 protocol Version date 11.29.18/Amend 6
drug/study 
regimen.
Permanently 
discontinue study 
drug/study regimen 
for any case meeting 
Hy’s law criteria 
(AST and/or ALT 
>3 × ULN + 
bilirubin
>2 × ULN without 
initial findings of 
cholestasis (i.e., 
elevated alkaline P04) 
and in the absence of 
any alternative cause.b
For Grade 4: 
Permanently 
discontinue 
study 
drug/study 
regimen.
THIS shaded area is guidance only for management of “Hepatitis (elevated LFTs)” in HCC patients

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NU15C03 protocol Version date 11.29.18/Amend 6
immune-related 
hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
−
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral medications for any patient with an elevated 
HBV viral load >2000 IU/ml
−
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral HCV medications if HCV viral load increased 
by ≥2-fold
−
For HCV+ with HBcAB+: Evaluate for both HBV and
HCV as above

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NU15C03 protocol Version date 11.29.18/Amend 6
 
No dose modifications.
Grade 1
 
If ALT/AST elevations represents
(Isolated AST or ALT
significant worsening based on
>ULN and ≤5.0×ULN,
investigator assessment, then treat as 
whether normal or
Grade 2 event.
elevated at baseline)        For all grades, see instructions at bottom of 
shaded area if transaminase rise is not 
isolated but (at any time) occurs in setting 
of either increasing bilirubin or signs of
DILI/liver decompensation
bilirubin or signs of 
DILI/liver 
decompensation
Grade 2
 
Hold study drug/study regimen
For Grade 2:
(Isolated AST or
dose until Grade 2 resolution to
−
Regular and frequent checking of LFTs (e.g., every 1 to
ALT >5.0×ULN and
Grade ≤1 or baseline.
3 days) until elevations of these are improving or
≤8.0×ULN, if normal    
If toxicity worsens, then treat as
resolved.
at baseline)
Grade 3 or Grade 4.
−
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver
If toxicity improves to Grade ≤1 or
perfusion.
baseline, resume study drug/study
(Isolated AST or
−
Consider, as necessary, discussing with study physician.
regimen after completion of steroid
ALT >2.0×baseline
−
If event is persistent (>3 to 5 days) or worsens, and
and ≤12.5×ULN, if
taper.
investigator suspects toxicity to be immune-mediated
AE, recommend to start prednisone 1 to 2 mg/kg/day PO
elevated >ULN at
or IV equivalent.
baseline)
−
If still no improvement within 3 to 5 days despite 1 to
        

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NU15C03 protocol Version date 11.29.18/Amend 6
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to
4 mg/kg/day of IV methylprednisolone, consider 
additional abdominal workup (including liver biopsy)
and imaging (i.e., liver ultrasound), and consider starting 
immunosuppressives (i.e., mycophenolate mofetil).a 
Discuss with study physician if mycophenolate mofetil is 
not available. Infliximab should NOT be used.
Grade 3
   Hold study drug/study regimen
For Grade 3:
dose until resolution to Grade ≤1
(Isolated AST or
or baseline
−
Regular and frequent checking of LFTs (e.g., every 1-2
ALT >8.0×ULN and
days) until elevations of these are improving or resolved.
≤20.0×ULN, if
   Resume study drug/study regimen
−
Consult hepatologist (unless investigator is hepatologist);
if elevations downgrade to Grade
obtain abdominal ultrasound, including Doppler
normal at baseline)
≤1 or baseline within 14 days and
assessment of liver perfusion; and consider liver biopsy. 
after completion of steroid taper.
−
Consider, as necessary, discussing with study physician.
(Isolated AST or
   Permanently discontinue study
−
If investigator suspects toxicity to be immune-mediated, 
ALT >12.5×ULN
drug/study regimen if the
promptly initiate empiric IV methylprednisolone at 1 to
elevations do not downgrade to
and ≤20.0×ULN, if
Grade ≤1 or baseline within
4 mg/kg/day or equivalent.
elevated >ULN at
14 days
−
If no improvement within 3 to 5 days despite 1 to
baseline)
Permanently discontinue study
4 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) and
drug/study regimen for any case
promptly start treatment with immunosuppressive 
meeting Hy’s law criteria, in the
therapy (mycophenolate mofetil). Discuss with study
absence of any alternative cause.b
physician if mycophenolate is not available. Infliximab 
should NOT be used.
−
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Grade 4
Permanently discontinue study drug/study
For Grade 4:
(Isolated AST or ALT
regimen.
Same as above

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NU15C03 protocol Version date 11.29.18/Amend 6
>20×ULN, whether 
normal or elevated at
baseline)
(except would recommend obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):
-
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise
-
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise
-
Grade 3-4: Permanently discontinue study drug/study regimen
Nephritis or renal 
dysfunction
(elevated serum 
creatinine)
Any Grade
General Guidance
For Any Grade:
−
Consult with nephrologist.
−
Monitor for signs and symptoms that may be related to 
changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine
output, or proteinuria).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or 
infections).
−
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 to 1.5 × baseline;
> ULN to 1.5 × 
ULN)
No dose modifications.
For Grade 1:
−
Monitor serum creatinine weekly and any accompanying 
symptoms.
 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol.
 
 
If creatinine worsens, depending on the 

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NU15C03 protocol Version date 11.29.18/Amend 6
severity, treat as Grade 2, 3, or 4.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
Grade 2
(serum creatinine
>1.5 to 3.0 ×
baseline; >1.5 to 3.0
× ULN)
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.
 
If toxicity worsens, then treat as
Grade 3 or 4.
 If toxicity improves to Grade ≤1 
or baseline, then resume study 
drug/study regimen after 
completion of steroid taper.
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
−
Carefully monitor serum creatinine every 2 to 3 days and 
as clinically warranted.
−
Consult nephrologist and consider renal biopsy if 
clinically indicated.
−
If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone at 2 to
4 mg/kg/day started.
−
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
−
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 × baseline; >3.0 
to 6.0 × ULN;
Grade 4: serum 
creatinine >6.0 × 
ULN)
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
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 PO or IV
equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2 to

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NU15C03 protocol Version date 11.29.18/Amend 6
4 mg/kg/day started.
−
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Rash
(excluding bullous skin 
formations)
Any Grade
(refer to NCI CTCAE 
v 4.03 for definition 
of severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:
−
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
−
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED.
Grade 1
No dose modifications.
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 to 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 to Grade ≤1 
or baseline, then resume 
drug/study regimen after 
completion of steroid taper.
For Grade 2:
−
Obtain dermatology consult.
−
Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream).
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions occurs within 3 to
5 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, consider, 
as necessary, discussing with study physician and 
promptly start systemic steroids such as prednisone 1 to
2 mg/kg/day PO or IV equivalent.
−
Consider skin biopsy if the event is persistent for >1 to
2 weeks or recurs.

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Grade 3 or 4
For 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 4:
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 the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
hypothyroidism, Type
1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase 
increased also included 
in this section)
Any Grade
(depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE
v4.03 for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Consider consulting an endocrinologist for endocrine 
events.
−
Consider, as necessary, discussing with study physician.
−
Monitor patients for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and weakness.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including 
brain metastases, or infections).
−
Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine and related labs 
(e.g., blood glucose and ketone levels, HgA1c).
−
For modest asymptomatic elevations in serum amylase
 
and lipase, corticosteroid treatment is not indicated as 

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NU15C03 protocol Version date 11.29.18/Amend 6
long as there are no other signs or symptoms of 
pancreatic inflammation.
−
If a patient experiences an AE that is thought to be 
possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample for appropriate 
autoimmune antibody testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH
elevation):
−
Monitor patient with appropriate endocrine function 
tests.
−
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though it 
may not be useful in diagnosing early secondary adrenal 
insufficiency).
−
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently 
out of range in 2 subsequent measurements, include free 
T4 at subsequent cycles as clinically indicated and 
consider consultation of an endocrinologist.
Grade 2
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1
diabetes mellitus, hold study 
drug/study regimen dose until patient 
is clinically stable.
 
If toxicity worsens, then treat as
Grade 3 or Grade 4.
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper.
Patients with endocrinopathies who
For Grade 2 (including those with symptomatic 
endocrinopathy):
−
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy 
and as clinically indicated, consider pituitary scan.
−
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and
as guided by an endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones).
−
Isolated hypothyroidism may be treated with

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NU15C03 protocol Version date 11.29.18/Amend 6
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are
≤10 mg/day or equivalent.
replacement therapy, without study drug/study regimen 
interruption, and without corticosteroids.
−
Isolated Type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, without study 
drug/study regimen interruption, and without 
corticosteroids.
−
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B 
recommendation]).a
−
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and Type
1 diabetes mellitus, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled.
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper.
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as
For Grade 3 or 4:
−
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy 
and as clinically indicated, consider pituitary scan. 
Hospitalization recommended.
−
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and
as guided by an endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent, as well as relevant hormone replacement 
(e.g., hydrocortisone, sex hormones).
−
For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity.
−
Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study regimen 
interruption, and without corticosteroids.
−
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids.
−
Once patients on steroids are improving, gradually taper

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NU15C03 protocol Version date 11.29.18/Amend 6
per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are
≤10 mg/day or equivalent.
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B 
recommendation]).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain- 
Barre)
Any Grade
(depending on the 
type of neurotoxicity, 
refer to NCI CTCAE 
v4.03 for defining
the CTC
grade/severity)
General Guidance
For Any Grade:
−
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes, or medications).
−
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing
(e.g., electromyogram and nerve conduction 
investigations).
−
Perform symptomatic treatment with neurological 
consult as appropriate.
−
Grade 1
No dose modifications.
For Grade 1:
−
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.
If toxicity worsens, then treat as
Grade 3 or 4.
Study drug/study regimen can be
For Grade 2:
−
Consider, as necessary, discussing with the study 
physician.
−
Obtain neurology consult.
−
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (e.g., gabapentin or 
duloxetine).
−
Promptly start systemic steroids prednisone 1 to
2 mg/kg/day PO or IV equivalent.
−
If no improvement within 3 to 5 days despite 1 to
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG).
 
resumed once event improves to 

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NU15C03 protocol Version date 11.29.18/Amend 6
Grade ≤1 and after completion of 
steroid taper.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose 
until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within
30 days.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Consider, as necessary, discussing with study physician.
−
Obtain neurology consult.
−
Consider hospitalization.
−
Promptly initiate empiric IV methylprednisolone 1 to
2 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g., IV IG).
−
Once stable, gradually taper steroids over ≥28 days.
Peripheral 
neuromotor 
syndromes
(such as Guillain-Barre 
and myasthenia gravis)
Any Grade
General Guidance
For Any Grade:
−
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain 
patients may unpredictably experience acute 
decompensations that can result in substantial morbidity 
or in the worst case, death. Special care should be taken 
for certain sentinel symptoms that may predict a more 
severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability.
−
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients 
with underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of prompt 
and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult.
 
−   Neurophysiologic diagnostic testing 

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NU15C03 protocol Version date 11.29.18/Amend 6
(e.g., electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if myasthenia 
is suspected) are routinely indicated upon suspicion of 
such conditions and may be best facilitated by means of
a neurology consultation.
−
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should 
be started with IV IG and followed by plasmapheresis if 
not responsive to IV IG.
Grade 1
No dose modifications.
For Grade 1:
−
Consider, as necessary, discussing with the study 
physician.
−
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above.
−
Obtain a neurology consult.
Grade 2
Hold study drug/study regimen dose 
until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability.
For Grade 2:
−
Consider, as necessary, discussing with the study 
physician.
−
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above.
−
Obtain a neurology consult
−
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (e.g., gabapentin or 
duloxetine).
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider 
that steroid therapy (especially with high doses) 
may result in transient worsening of myasthenia 
and should typically be administered in a 
monitored setting under supervision of a

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NU15C03 protocol Version date 11.29.18/Amend 6
consulting neurologist.
o
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IV IG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each patient.
o
If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective.
o
Patients requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen dose 
until resolution to Grade ≤1.
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability.
For Grade 4:
Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4 (severe or life-threatening events):
−
Consider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
myasthenia gravis. They 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 
IV IG.
o
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in 
addition to steroids. Such therapy, if successful, 
can also serve to reinforce the diagnosis.

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GUILLAIN-BARRE:
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective.
o
Patients requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG.
Cardiac toxicities   
(including arrhythmia,
Conduction disorder heart
 Failure,IV dysfunction,
Myocarditis
                           Any GradeGeneral Guidance
Discontinue drug permanently
upon diagnosis of myocarditis, 
regardless of grade.
For Any Grade:
−
The prompt diagnosis of immune-mediated myocarditis 
is important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.
−
Consider, as necessary, discussing with the study 
physician.
−
Monitor patients for signs and symptoms of myocarditis 
(new onset or worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema). As some 
symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary
embolism, congestive heart failure, malignant pericardial 
effusion). A Cardiology consultation should be obtained 
early, with prompt assessment of whether and when to 
complete a cardiac biopsy, including any other
diagnostic procedures.
−
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), and additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can complement 
ECHO to assess wall motion abnormalities when needed.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
Grade 1
-No dose modifications required
For Grade 1 (no definitive findings):
    (asymptomatic with 
unless clinical suspicion for 
myocarditis is high, in
-
Monitor and closely follow up in 2 to 4 days for clinical

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NU15C03 protocol Version date 11.29.18/Amend 6
laboratory (e.g., 
BNP,EKG,Trop
onin) and 
etiology is 
unclear )
which case suspected, hold 
durvalumab-tremelimumab during  
work- up . 
-If myocarditis is excluded, resume 
after complete resolution to Grade 0.
- If myocarditis is diagnosed,
permanently discontinue
   durvalumab or tremelimumab
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up 
as clinically indicated.
-
Consider using steroids if clinical suspicion is high.
Grade 2, 3 or 4
(Grade 2: Symptoms 
with mild to 
moderate activity or 
exertion)
(Grade 3: Severe 
with symptoms at 
rest or with minimal 
activity or exertion; 
intervention 
indicated)
(Grade 4: Life- 
threatening 
consequences; urgent
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support))
-  If Grade 2 -- Hold study drug/study 
regimen 
   -If toxicity rapidly improves to 
Grade 0 AND myocarditis is 
excluded, then the decision to 
reinitiate study drug/study regimen 
will be based upon treating 
physician’s clinical judgment and 
after completion of steroid taper.
- If toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen.
-If myocarditis is diagnosed,
permanently discontinue
-    durvalumab or
     tremelimumab
- If Grade 3-4, permanently 
discontinue study drug/study 
regimen.
For Grade 2-4:
−
Monitor symptoms daily, hospitalize.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent after Cardiology consultation has 
determined whether and when to complete diagnostic 
procedures including a cardiac biopsy.
−
Supportive care (e.g., oxygen).
−
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab.
−
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a

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Myositis/Polymyositis
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:
−
Monitor patients for signs and symptoms of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles including upper arms, thighs, shoulders, hips, 
neck and back, but rarely affects the
extremities including hands and fingers; also difficulty 
breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset 
falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, 
and/or reaching up.
−
If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. 
Given breathing complications, refer to guidance under 
Pneumonitis/ILD.
Given possibility of an existent (but previously
unknown) autoimmune disorder, consider Rheumatology 
consultation.
−
Consider, as necessary, discussing with the study 
physician.
−
Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory work- 
up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether a 
rheumatologist consultation is indicated and could guide 
need for rheumatoid factor, antinuclear antibody, anti-
smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory 
testing may include electromyography, nerve conduction 
studies, MRI of the muscles, and/or a muscle biopsy. 

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Consider Barium swallow for evaluation of dysphagia or 
dysphonia.
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or 
infections).
Grade 1
(mild pain)
-  No dose modifications.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days for clinical

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

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drug/study regimen if Grade 3 imAE
does not resolve to Grade ≤1 within
30 days or if there are signs of 
respiratory insufficiency.
For Grade 4:
-  Permanently discontinue study 
drug/study regimen.
physician.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant.
−
If after start of IV methylprednisolone at 2 to
4 mg/kg/day there is no improvement within 3 to 5 days, 
consider start of immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab.
−
Consider whether patient may require IV IG, 
plasmapheresis.
−
Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI 
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  
By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal.

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Infusion-Related Reactions
Severity Grade of the
Event (NCI CTCAE
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Manage 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, or skin rashes) and anaphylaxis
(e.g., generalized urticaria, angioedema, wheezing, 
hypotension, or tachycardia).
Grade 1 or 2
For 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 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.
For Grade 1 or 2:
−
Acetaminophen and/or antihistamines may be administered 
per institutional standard at the discretion of the 
investigator.
−
Consider premedication per institutional standard prior to 
subsequent doses.
−
Steroids should not be used for routine premedication of
Grade ≤2 infusion reactions.
Grade 3 or 4
For Grade 3 or 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).
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.

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Non–Immune-Mediated Reactions
Severity Grade of the Event
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs 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.
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2
Hold study drug/study regimen until resolution to ≤Grade
1 or baseline.
Grade 3
Hold study drug/study regimen until resolution to ≤Grade
1 or baseline.
For AEs that downgrade to ≤Grade 2 within 7 days or 
resolve to ≤Grade 1 or baseline within 14 days, resume 
study drug/study regimen administration. Otherwise, 
discontinue study drug/study regimen.
Grade 4
Discontinue study drug/study regimen (Note: For Grade 4 
labs, decision to discontinue should be based on 
accompanying clinical signs/symptoms, the Investigator’s 
clinical judgment, and consultation with the Sponsor.).
Treat accordingly, as per institutional standard. 
Treat accordingly, as per institutional standard.
Treat accordingly, as per institutional standard.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study
Physician.”
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.

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4.5
Duration of Therapy
Patients on all arms will remain on study as long as there is no disease progression for up to 24 
months or until any of the following occur:
 
Disease progression
 
Development of an inter-current illness that prevents further administration of 
treatment
 
Unacceptable adverse event(s)
o
See section on dose modifications: Treatment delay of > 4 weeks due to 
treatment related toxicities.
o
Protracted (>2 weeks) medically concerning grade 2 cardiac, pulmonary, renal, 
gastrointestinal, skin, or CNS toxicities.
 
The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures).
4.6
Duration of Follow Up
All subjects will be followed for survival for up to 2 years/ 24 months from stopping study 
treatment. Subjects who decline to return to the site for evaluations will be offered follow-up by 
phone every 8-16 weeks as an alternative.
Note that patients who discontinue treatment permanently for any reason other than progression 
will be followed for evidence of tumor response and disease status.
Any patient who withdraws their consent, will be considered as an early discontinuation, and may 
be replaced if this occurs before they have received the first dose of treatment. Patients who 
withdraw consent but receive at least one dose of treatment will be evaluable for toxicity even if 
they are not fully evaluable for response. The accrual goal has been set to allow up to 45 patients 
to be enrolled in order to allow for early discontinuations.
If a patient withdraws consent, no further treatment or study-specific testing will be completed. The 
primary reason for a patient’s withdrawal from the study is to be recorded in the source documents. 
All patients will be followed until death or 2 years/24 months from stopping treatment.
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued treatment.
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety for 30 days  post last-dose visit including the collection of any protocol- 
specified blood specimens, unless consent is withdrawn or the subject is lost to follow-up or 
enrolled in another clinical study. If a subject is enrolled in another clinical study, they will be 
followed until all AEs are resolved or stable. If enrolled onto another clinical study, it is not 
necessary to follow the subject for survival or progression.
4.7
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their own 
request, or they may be withdrawn from study treatment at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation from study 
treatment must be clearly documented on the appropriate eCRF and may include:
 
Patient voluntarily withdraws from treatment (follow-up permitted)
 
Patient withdraws consent (no follow-up permitted)
 
Patient is unable to comply with protocol requirements
 
Patient demonstrates disease progression
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 
Patient experiences unacceptable toxicity
o
See section on dose modifications: Treatment delay of > 4 weeks due to 
treatment related toxicities.
o
Protracted (>2 weeks) medically concerning grade 2 cardiac, pulmonary, 
renal, gastrointestinal, skin, or CNS toxicities.
 
Grade ≥ 3 infusion reaction
 
Treating physician determines that continuation on the study would not be in the 
patient’s best interest
 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk
 
Patient becomes pregnant or wants to become pregnant
 
Patient develops a second malignancy that requires treatment which would interfere 
with this study
 
Patient becomes lost to follow-up (LTF)
 
Initiation of alternative anticancer therapy including another investigational agent
 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with MEDI4736
4.8
Patient Replacement/ Addition
 
Any patient who is consented but does not receive at least one dose of investigational 
drug will be replaced.
 
Any patient who withdraws their consent or otherwise discontinues study for any reason 
prior to undergoing surgery, will be considered as an early discontinuation, and another 
patient may be added as necessary.
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1
2
3
5.0
STUDY PROCEDURES
5.1
Pre-Surgery & Surgery
Assessment/Activity
Screening &
2
Baseline
14 days 
(+/- 3 d) 
prior to 
surgery
Within 7 
days prior 
to
Surgery
Day of surgery
Within 72 
hours Post- 
surgery
Informed Consent3
X
Review of eligibility criteria
X
Medical History
X
Concomitant Medications
X
X
X
X
1
Neurologic and Physical Exam
X
X
X
KPS
X
X
Serum or Urine Pregnancy Test
X
4
Brain MRI or CT with contrast
X
X
4
CBC with diff & clinical
9
chemistry
X
X
X
Magnesium and
Phosphorus
X
X
X
10
Thyroid testing
X
11
PTT/PT/INR
X
5
12-lead ECG
X
Urinalysis with micro
X
Creatinine Clearance
X
12
Hepatitis serologies
X
Toxicity assessment
X
X
X
1st Dose Study Treatment
6
X
1
7
Archival Tissue for research
X
Fresh Tissue for research
X
13
8
Blood for research
X
X
Includes vital signs (pulse, temperature, blood pressure, & weight). Height required at baseline only.
On the first day of treatment , vital signs will be measured within an hour prior to start of initial study drug 
administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at
30  and 60 minutes (± 5 minutes each) post-infusion. If the infusion takes longer than 60 minutes, blood 
pressure and pulse measurements should follow the principles described here or more frequently if clinically 
indicated.
Baseline procedures (with the exception of informed consent and archival tissue) must be obtained within 14 days
st
of registration. The CBC and chemistries will be repeated within 72 hours of 1
baseline tests were more than 7 days prior to dosing.
Informed consent should be obtained within 28 days prior to registration.
4
dose of study treatment if
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5
6
7
9
10
11
12
13
The baseline MRI can be up to 21 days prior to registration. The post-surgical MRI of brain should be done within
72 hours after surgery.
Twelve-lead ECGs will be obtained after the subject has been resting in a supine position for at least 5 minutes.
ECG will be in triplicate (taken 2-5 minutes apart).
Patients will receive one dose of tremelimumab 75 mg (if on Arm 1), MEDI4736 750 mg (if on Arm 2) or the
      combination of both (if on Arm 3) approximately 2 weeks (14 days +/- 7 days) before surgery.
Tumor from prior surgeries will be requested on all patients. Tissue will be analyzed in the Bloch Laboratory.
Please refer to Section 9.3 and laboratory manual for details.
8
st
Blood samples will be collected for various research tests at 1
pre-operative treatment, day of surgery, C1D1 and
at each adjuvant treatment imaging visits (i.e. every 2 cycles or 8 weeks):
a) 10ml blood in one 10ml Sodium heparin tube: To be collected and processed by the Bloch lab for 
peripheral blood lymphocytes (PBLs).
b) 8m (2x4ml) blood in two 5ml EDTA (purple top) tubes: To be collected and processed by the Wainwright 
lab for gene expression profile using mononuclear cells.
c) 10ml blood in one 10ml red top tube: To be collected and processed by the Wainwright lab for analysis 
of tryptophan catabolites and cytokines.
Please refer to section 9.0 and laboratory manual for more details
Chemistries should include electrolytes, calcium, , albumin, alkaline phosphatase, bilirubin (total), SGPT(ALT), 
SGOT(AST), serum creatinine, and BUN.
TSH, T4, T3
Required at baseline only but may be repeated as clinically indicated thereafter.
Includes hepatitis A antibody, hepatitis B (HBsAg reactive), and Hepatitis C (HCV RNA [qualitative] detection). 
Please refer to Section 9.1 and the laboratory manual for details.
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1
2
3
4
5
5.2
Post-Surgery/Adjuvant Therapy
Time Period
Adjuvant Treatment
8
Off Treatment
Assessment/Activity
Cycle 1
Day 1
2
(+/- 2d)
Cycle 2
Day 1 
(+/- 2d)
Cycle 3+ 
Day 1 
(+/- 2d)
Treatment
Discontinuation
90 Days 
Post Last 
Dose
(+/- 7d)
Follow-up
11
Concomitant medications
X
X
X
Toxicity assessment
X
X
X
X
X
Neurological exam and
4
KPS
X
X
X
X
X
1
Vital signs & weight
X
X
X
3
CBC with diff
X
X
X
X
Comprehensive Chemistry
Panel
X
X
X
X
X
6
Thyroid Function Tests
X
X
X
X
7
ECG
X
X
Tumor Imaging (MRI/CT)
X
5
X
5
X
5
Tremelimumab
12
monotherapy
X
X
X
13
MEDI4736 monotherapy
X
X
X
14
Combination therapy
X
X
X
14
Research tissue
X
10
9
Research blood
X
X
9
Survival status
X
Includes weight, BSA, and vital signs (temperature, blood pressure, pulse rate, and). Following the initial pre- 
surgery dose, for subsequent doses, the post dose vitals and 1-hour observation period will not be required 
unless a subject experiences an infusion-related reaction. Vital signs will be measured within an hour prior 
to start of study drug administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion 
(+ 5 minutes). If needed, vital signs will be done at 30 and 60 minutes (± 5 minutes each) post-infusion. If 
the infusion takes longer than 60 minutes, blood pressure and pulse measurements should follow the 
principles described here or more frequently if clinically indicated.
Adjuvant treatment (cycle 1 day 1) will resume approximately 14 days (+/- 7 days) after surgery, once the surgical 
wound has healed.
Will be done every other week while on adjuvant treatment.
Will be done prior to each cycle (monthly) while on adjuvant treatment.
If patients are unable to start treatment within 21 days of the post-surgical imaging, then repeat imaging with
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6
7
8
10
11
12
13
14
enhanced MRI or CT scan should be performed prior to initiation of adjuvant therapy. During adjuvant 
treatment, contrast-enhanced MRI or CT scan will be done approximately every 2 cycles or 8 weeks (prior 
to each odd cycle). If there is no progression of disease, patients will continue on treatment for up to 24 
months. If a patient has disease progression (as defined in section 6.4) or clinical decline and undergoes 
further surgery but is found to have no pathologic evidence of significant tumor, the patient may then re-start 
treatment.
Thyroid function tests will be done every 2 cycles (approximately every 2 months) during treatment. TSH will be 
done each time; free T3 and free T4 only if TSH is abnormal.
ECGs are required within 1 hour prior to starting study treatment and at least once after the infusion is completed 
(anywhere from 0-3 hours) on Cycle 1 Day 1, again after approximately 16 weeks on treatment, and at the 
end of treatment. ECGs may be repeated at any other time point if clinically indicated. ECGs recorded during 
the treatment phase will be single tracing. Twelve-lead ECGs will be obtained after the subject has been 
resting in a supine position for at least 5 minutes in each case.
During adjuvant treatment, one cycle is defined as 4 weeks for patients on Arms 1 and 2. For patients on Arm 3, 
please refer to the schedule outlined in footnote #14.
9
st
Blood samples will be collected for various research tests at 1
pre-operative treatment, day of surgery, C1D1 and
at each adjuvant treatment imaging visits (i.e. every 2 cycles or 8 weeks):
a)
10ml blood in one 10ml Sodium heparin tube: To be collected and processed by the Bloch lab for peripheral 
blood lymphocytes (PBLs).
b)   8m (2x4ml) blood in two 5ml EDTA (purple top) tubes: To be collected and processed by the Wainwright 
lab for gene expression profile using mononuclear cells.
c)
10ml blood in one 10ml red top tube: To be collected and processed by the Wainwright lab for analysis of 
tryptophan catabolites and cytokines.
Please refer to section 9.0 and laboratory manual for more details
Any patient who undergoes further surgery will have the option to use their tumor tissue for research to understand 
the immunologic changes occurring at the time of presumed drug failure. Please refer to Section 9 and 
laboratory manual for details.
Follow up for disease progression (if not already documented) and survival will occur every 8-16 weeks once off 
treatment. All patients will be followed until death or 2 years/24 months from stopping treatment.
Patients enrolled on Arm 1 will receive tremelimumab monotherapy: one 75 mg dose IV on day 1 (+/- 2 days) per 
cycle (every 4 weeks) up to 24 months.
Patients enrolled on Arm 2 will receive MEDI4736 monotherapy: one 750 mg dose IV on days 1 and 15 (+/- 2 days 
allowed for each) per cycle (every 2 weeks) up to 24 months.
Patients enrolled on Arm 3 will receive combination therapy (tremelimumab 75 mg + MEDI4736 750 mg) according 
to the following schedule: Tremelimumab will be administered IV every 4 weeks (Day 1 of each cycle) and 
MEDI4736 750mg every 2 weeks (Day 1 and Day 15 of each cycle) until the patients have received 7 doses 
of Tremelimumab and 14 doses of MEDI4736.  Thereafter, from Cycle 7 (Week 25), Tremelimumab will be 
given every 12 weeks (+/-7 days) and MEDI4736 will be given every 2 weeks (+/- 2 days) until permanent 
discontinuation criteria (e.g. disease progression) is met. If there is no progression of disease, they will 
continue on treatment for up to 24 months.
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6.0
ENDPOINT ASSESSMENT
6.1
Primary Endpoint
To determine the T-cell changes (immunologic changes) that occur in recurrent GBM treated with 
Tremelimumab and MEDI4736 as single agents and in combination. The changes from baseline 
will be assessed in blood samples and tissue samples before treatment and post-surgery for all 
patients in the 3 arms. A comparison between the changes observed in the 3 arms will be made.
Only patients who have had pre-treatment blood sampling, have undergone surgery with pre-surgical 
blood sampling, and are able to continue to post-operative drug treatment with blood sampling prior 
to the first post-surgical dose will be evaluable for this endpoint.
6.2
Secondary Endpoints
1.
To evaluate the safety of either Tremelimumab or MEDI4736 alone and in combination 
for patients with recurrent GBM. The endpoints will be the number, frequency, and 
severity of adverse events (as defined by the NCI Common Terminology Criteria for 
Adverse Events or CTCAE version 4.03). Only patients who have been administered at 
least one dose of investigational drug will be evaluable for this endpoint.
2.
To determine post-surgery, the time to progression (per Modified RANO criteria and 
iRANO criteria see below) for patients treated with either Tremelimumab or MEDI4736 
alone and in combination of both. This will be defined as the number of months from the 
time of first dose of study treatment until progression of disease or death by any cause. 
Only patients who have been administered at least one dose of investigational drug and 
undergone surgery will be evaluable for this endpoint.
3.
To determine post-surgery the overall survival for patients treated with Tremelimumab 
or MEDI4736 alone and in combination of both. This will be defined as the number of 
months surviving from the time of first dose of study treatment until death by any cause. 
Only patients who have been administered at least one dose of investigational drug and 
undergone surgery will be evaluable for this endpoint.
.
4.
To assess post-surgery, the MRI changes in patients treated with either Tremelimumab or 
MEDI4736 alone and in combination of both. Only patients who have been administered 
at least one dose of investigational drug, undergone surgery, and have undergone at least 
one post-surgery disease assessment will be evaluable for this endpoint.
6.3
Exploratory Endpoints
1.
To correlate T-cell changes and PDL1 expression with patients outcome. Only patients 
who have been administered at least one dose of investigational drug and undergone 
surgery will be evaluable for this endpoint.
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6.4
Response Assessment (Modified RANO criteria)
66
RANO Criteria for Response
CR
PR
SD
PD
T1 gadolinium enhancing disease
None
≥ 50%
decrease
< 50% decrease but <
25% increase
≥ 25%
increase
T2/FLAIR
Stable or 
decrease
Stable or 
decrease
Stable or decrease
increase
New lesion
None
None
None
Present1
Corticosteroids
None
Stable or 
decrease
Stable or decrease
n/a
Clinical status
Stable or 
increase
Stable or 
increase
Stable or increase
decrease
Requirement for response
All
All
All
Any
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013):
 
Response to immunotherapy may be delayed
 
Response to immunotherapy may occur after PD by conventional criteria
 
The appearance of new lesions may not represent PD with immunotherapy
 
SD while on immunotherapy may be durable and represent clinical benefit
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti- 
cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti- 
cancer compounds, the study use a modified RANO criteria to define PD:
Progressive disease post-baseline is defined as one or more of the following:
 
New contrast-enhancing lesion outside of radiation field on decreasing, stable, or 
increasing doses of corticosteroids.
 
Increase by > 50% (modified from >25% according to published RANO criteria) 
enhancement from the first post-surgical scan, or a subsequent scan with smaller tumor 
size, and the scan 8 weeks or later on stable or increasing doses of corticosteroids.
 
Clinical deterioration not attributable to concurrent medication or comorbid conditions is 
sufficient to declare progression on current treatment.
Treatment with MEDI4736, Tremelimumab or both would continue between the initial assessment 
of progression and confirmation for progression. In addition, subjects may continue to receive 
MEDI4736, Tremelimumab or both beyond confirmed PD in the absence of clinically significant 
deterioration and if investigators consider that subjects continue to receive benefit from treatment.
As a secondary measure, for all response assessments, iRANO will be used for assessment.
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RANO and iRANO criteria (iRANO= immunotherapy Response Assessment in Neuro-Oncology)
Response
Malignant glioma
Low-grade glioma
Brain metastasis
1. Complete Response
Disappearance of all 
enhancing disease for ≥4 
weeks; no new lesions; 
stable or improved 
T2/FLAIR; no more than 
physiological steroids; 
clinically stable or 
improved
Disappearance of all 
enhancing and 
T2/FLAIR disease for
≥4 weeks; no new 
lesions; no more than 
physiological
steroids; clinically stable 
or improved
Disappearance of all 
enhancing target and 
non-target lesions for ≥
4 weeks; no new 
lesions; no steroids; 
clinically stable or 
improved
2. Partial response
≥50% decrease in the 
sum of biperpendicular 
diameters of enhancing 
disease for ≥4 weeks; no 
new lesions; stable or 
improved T2/FLAIR; 
stable or decreased 
steroid dose; clinically 
stable or improved
≥50% decrease in the 
sum of biperpendicular 
diameter of T2/FLAIR 
disease for ≥4 weeks; no 
new lesions; stable or 
decreased steroid dose; 
clinically stable or 
improved
≥30% decrease in sum 
of longest diameters of 
target lesions for ≥4 
weeks; no new lesions; 
stable or decreased 
steroid dose; clinically 
stable or improved
3. Stable Disease
NA
25–49% decrease in the 
sum of biperpendicular 
diameters of T2/FLAIR 
disease for ≥4 weeks; no 
new lesions; clinically 
stable or improved
NA
4.
Progressive Disease
≥25% decrease in the sum 
of biperpendicular 
diameters
of enhancing disease; or 
new lesions; or substantial 
worsened T2/FLAIR; or 
substantial clinical decline
≥25% decrease in the 
sum of biperpendicular 
diameters
of T2/FLAIR disease; or 
new lesions; or 
substantial clinical 
decline
≥20% decrease in the 
sum of longest 
diameters of target 
lesions; or 
unequivocal 
progression of 
enhancing
non-target lesions; or 
new lesions; or 
substantial clinical 
decline
The iRANO criteria integrate into the existing RANO criteria for malignant glioma, low-grade glioma, and brain metastases 
by providing recommendations for the interpretation of progressive imaging changes.
Specifically, iRANO recommends confirmation of disease progression on follow-up imaging 3 months after initial 
radiographic progression if there is no new or substantially worsened neurological deficits that are not due to comorbid 
events or concurrent medication, and it is 6 months or less from starting immunotherapy. If follow-up imaging confirms 
disease progression, the date of actual progression should be back-dated to the date of initial radiographic progression. The 
appearance of new lesions 6 months or less from the initiation of immunotherapy alone does not define progressive disease. 
FLAIR=fluid attenuated inversion recovery; N/A=not applicable
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the Robert H. 
Lurie Comprehensive Cancer Center of Northwestern University. The level of risk attributed to this study
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requires high intensity monitoring, as outlined in the DSMP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial (see Section 5 for timepoints). In addition, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be followed until:
 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;
 
any abnormal laboratory values have returned to baseline;
 
there is a satisfactory explanation other than the study drug for the changes observed; or
 
death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
The International Conference on Harmonization (ICH) Guideline for Good Clinical
Practice (GCP) E6 (R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that 
requires an action or intervention by the investigator, or a finding judged by the 
investigator to represent a change beyond the range of normal physiologic fluctuation, 
should be reported as an AE.
Adverse events may be treatment emergent (i.e., occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any 
new sign or symptom, disease, or other untoward medical event that begins after written 
informed consent has been obtained but before the subject has received investigational 
product.
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior 
to the subject being enrolled into the study) for a documented pre-existing condition, that 
did not worsen from baseline, is not considered an AE (serious or nonserious). An 
untoward medical event occurring during the prescheduled elective procedure or routinely 
scheduled treatment should be recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.
7.2.2
Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4.03 is available at 
http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:
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 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities.
 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.
 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status.
 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.
 
Fatal (grade 5): the event caused death.
All deaths that occur during the study, or within the protocol-defined 90-day post-last 
dose of study drug safety follow-up period must be reported as follows:
 
Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE.
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as a SAE within 24 hours (see Section 7.3.3 for 
further details). The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and contributory causes of 
death.
Deaths with an unknown cause should always be reported as a SAE. Deaths that occur 
following the protocol-defined 90-day post-last-dose of study drug safety follow-up 
period will be documented as events for survival analysis, but will not be reported as an 
SAE.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed consent, 
through 90 days after the last administration of study drug, must be reported upon 
discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence that:
 
Results in death.
o
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.
 
Is life-threatening.
o
The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.
 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
 
Results in persistent or significant disability or incapacity.
 
Is a congenital anomaly/birth defect in the offspring of the subject.
 
Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above.
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious adverse 
event. The event may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event”. For example: allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; 
convulsions that may not result in hospitalization; development of drug abuse or drug 
dependency.
The causality of SAEs (their relationship to all study treatment/procedures) will be
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assessed by the investigator(s) and communicated to AstraZeneca.
7.2.4
Adverse events of special interest (AESI)
Adverse events of special interest (AESIs) are events of scientific and medical interest 
specific to the further understanding of the MEDI4736 and/or Tremelimumab safety 
profile and require close monitoring and rapid communication by the investigator to the 
sponsor. MEDI4736 and/or Tremelimumab AESIs may be serious or non-serious. The 
rapid reporting of these AESIs allows ongoing analysis of these events in order to 
characterize and understand them in association with the use of this investigational 
product.
MEDI4736, an anti-PD-L1 antibody, and Tremelimumab, an anti-CTLA-4 antibody 
belong to a class of anticancer therapies, called “checkpoint-inhibitors” that amplify 
antitumor immune responses by blocking inhibitory signaling pathway modulated by the 
co-inhibitory or co-stimulatory receptors, CTLA-4 and PD-1, expressed on T cells
(Callahan and Wolchok, 2013). This class of drugs can have a wide spectrum of immune- 
mediated reactions that have been considered inflammatory in nature and can affect any 
organs of the body. Based on this mechanism of action of MEDI4736 and related 
molecules Adverse events of special interest include immune-mediated reactions such as 
enterocolitis, dermatitis, hepatotoxicity or hepatitis, pancreatitis endocrinopathy, 
neuropathy and pneumonitis.
7.2.4.1   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 Table 1.
Immune-mediated pneumonitis is characterized by inflammation focally or 
diffusely affecting the lung parenchyma that may be result of off-target effects of 
checkpoint inhibitors against the normal lung parenchyma. (Chow, 2013) 
Presentations of pneumonitis range from asymptomatic lung infiltrates to a
mimic of severe bacterial pneumonia. For symptomatic patients, complaints and 
findings may include dyspnea, cough, tachypnea, pleuritic chest pain, and 
hypoxia. The frequency of immune-mediated pneumonitis in clinical trials with 
immune checkpoint-inhibitors ranged from ≤1% to 4%. (Topalian et al, 2012; 
Brahmer et al, 2012).
Because pneumonitis can quickly escalate and become fatal, early recognition is 
essential. Initial workup includes chest imaging; however, pneumonitis can have 
highly variable appearances on chest CT scans.  In patients with pulmonary 
metastases or cardiopulmonary comorbidities, evaluation can be particularly 
challenging as it can be difficult to differentiate between infection, early 
pulmonary edema, alveolar hemorrhage, immune-mediated pneumonitis, 
immune-related tumor inflammation, and tumor progression (Topalian et al,
2012). Pneumonitis has also been reported as a complication of cancer treatment 
associated with lung and breast cancer.
Guidelines for the management of subjects with immune-mediated events 
including pneumonitis are outlined in Table 1.
7.2.4.2   Anaphylaxis and Serious Allergic Reactions
As with the administration of any foreign protein and/or other biologic agents,
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reactions following the infusion of MAbs can be caused by various mechanisms, 
including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against 
the MAb, and serum sickness. Hypersensitivity reactions as well as infusion- 
related reactions have been reported with anti-PD-L1 and anti-PD-1 therapy 
(Brahmer et al 2012).
Acute allergic reactions may occur, may be severe, and may result in death. 
Acute allergic reactions may include hypotension, dyspnoea, cyanosis,
respiratory failure, urticaria, pruritis, angioedema, hypotonia, urticaria, 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 Table 1.
7.2.4.3   Infusion-Related Reactions
The frequency of Infusion-related reactions (IRR) in clinical trials with immune 
checkpoint-inhibitors ranged from ≤1% to 10%. A high frequency of mild 
infusion reactions, was observed with anti-PD-L1 and anti-PD-1 therapy 
(Brahmer et al 2012).
Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory 
failure, urticaria, pruritis, angioedema, hypotonia, urticaria, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, 
myalgia, vomiting and unresponsiveness. The typical onset can be within 30 
minutes to two hours after the initiation of drug infusion, although symptoms 
may be delayed for up to 24 hours. The majority of reactions occur after the first 
or second exposure to the agent, but between 10 and 30 percent occur during 
subsequent treatments (Lenz, 2007).
7.2.4.4   Hepatic function abnormalities (hepatotoxicity)
Immune-mediated hepatitis/ hepatic toxicity is the inflammation of the liver due 
to the dysregulation of host immunity related to immune checkpoint inhibitors 
and often manifests as asymptomatic elevated levels of hepatic transaminases 
(ALT, AST,) and bilirubin) (Kim et al, 2013). In clinical trials, the frequency of 
immune-mediated hepatitis was typically around ≤1%. (Brahmer et al, 2012; 
Topalian et al, 2012; Hamid et al, 2013; Tarhini, 2013). In published studies
with anti-CTLA-4 mAbs, immune-mediated hepatitis, manifesting as elevations 
in AST and ALT, has been reported to occur in 3-9% of treated patients (Weber 
et al, 2012).
In Ipilimumab-treated patients, clinical manifestations of hepatitis included 
nonspecific symptoms of mild fever, general weakness, fatigue, nausea and/or 
abdominal pain. In the absence of clinical symptoms, treatment-emergent 
hepatitis presented asymptomatically as elevated hepatic transaminases. 
Ultrasonograms of the liver can appear normal or may demonstrate homogenous 
hepatomegaly, edema, or enlarged perihepatic lymph nodes. Biopsy of the liver 
most commonly shows a diffuse T-cell infiltrate. Other reported pathology 
patterns include inflammation focused around either hepatocytes or bile ducts.
If subject presents with liver dysfunction, a high suspicion for irAE(Infusion 
Related Adverse Event) hepatitis is warranted, however, it is important to 
distinguish treatment-related toxicity and rule out other causes of hepatic injury, 
such as infection, preexisting medical conditions, immunosuppression, metabolic 
or cardiovascular derangements, other medications, or tumor progression.
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Hepatic function abnormality is defined as any increase in ALT or AST 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 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 Table 1.
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.
7.2.4.5   Dermatitis
Grade 1 and 2 dermatologic toxicities are among the most commonly seen irAEs 
in patients treated with immune checkpoint inhibitors. Mild dermatitis manifests 
as a local or diffuse maculopapular rash or erythroderma. Pruritus can accompany 
the rash or, less commonly, can present as an isolated complaint in the absence of 
skin findings. Blisters are rarely seen, and their presence signals significant 
toxicity. Grade 3 to 4 dermatologic irAEs that constitute severe and fatal 
dermatologic inflammation include Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or 
hemorrhagic manifestations (Tarhini, 2013; Kaehler, et al 2010).
The frequency of immune-mediated dermatitis (including eczema, eythema, rash 
maculopapular, rash and pruritus) in clinical trials with immune checkpoint- 
inhibitors ranged from 1.5% to 33%. (Brahmer et al, 2012; Topalian et al, 2012; 
Hamid et al, 2013; Tarhini, 2013). Other Life-threatening dermatologic 
complications such as Steven’s Johnson Syndrome or toxic epidermal necrolysis 
have been seen in fewer than1% of patients. It is important to accurately qualify 
and quantify cutaneous toxicities.
Pathologic evaluations of biopsy specimens of affected skin often demonstrate 
eosinophilic infiltration or leukocytoclastic vasculitis; or, they may reveal a 
lymphocytic predominance characterized by CD8+ T cells, sometimes with 
tropism for melanin-containing cells. Specifically, in metastatic melanoma 
patients, the rash associated with immune-checkpoint inhibitors may be 
indicative of immune response to melanocytes and may progress to vitiligo in 
some cases. Biopsies showed severe dermatitis with papillary dermal edema,
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sometimes accompanied by perivascular lymphocytic infiltrate.
Guidelines for the management of subjects with immune-mediated events 
including dermatitis are outlined in Table 1.
7.2.4.6   Enterocolitis
Immune-mediated enterocolitis/colitis generally manifests as mild to severe 
watery diarrhea accompanied by any changes in normal bowel habits or changes 
from baseline, abdominal pain, nausea/vomiting, or hematochezia. Any grade 
diarrhea has been the most frequently observed sign/symptom potentially 
associated with immune-mediated colitis. In severe cases, patients may
experience significant dehydration, fever, ileus or peritoneal signs consistent with 
bowel perforation. Deaths secondary to bowel perforation have occurred.
The frequency of immune-mediated enterocolitis/colitis in clinical trials with 
immune checkpoint-inhibitors typically ranges from ≤1-8% (Brahmer et al,
2012; Topalian et al, 2012; Hamid et al, 2013; Tarhini, 2013).
Patients with mild symptoms (e.g., grade 1 abdominal pain or diarrhea) should be 
evaluated for infection, including Clostridium difficile infection. Endoscopy 
performed in these cases may identify an inflamed mucosa with ulceration,
which can involve any part of the bowel but most commonly the descending 
colon (Weber et al, 2012; Wolchock et al, 2010). Tissue biopsies of the colon 
typically reveal significant inflammatory cell infiltrate.
Guidelines for the management of subjects with immune-mediated events 
including enterocolitis are outlined in Table 1.
7.2.4.7   Endocrinopathy (hypothyroidism, hyperthyroidism, hypopituitarism) 
Immune-mediated endocrinopathies frequently reported in patients treated with 
checkpoint inhibitors include thyroiditis (hypo- or hyper-), hypopituitarism, 
hypophysitis, and/or adrenal insufficiency. The frequency of immune-mediated 
endocrinopathies in clinical trials with immune checkpoint-inhibitors ranged 
from ≤ 1% to 17%. (Tarhini, 2013; Topalian et al, 2012; Hamid et al, 2013). The 
most common endocrinopathy seen with ipilimumab is hypophysitis. In clinical 
trials with other PD-1/PD-L1 inhibitors, endocrine irAEs reported were similar
to those reported for ipilimumab, but in contrast, generally milder with fewer 
events of severe to life-threatening (grades 3–4) irAEs (Sznol and Chen, 2013; 
Topalian et al, 2012; Wolchok et al, 2013; Hamid et al; 2013).
Clinical presentations of these endocrinopathies include a range of nonspecific 
symptoms resembling other causes, such as brain metastases or progression of 
underlying disease. The most common clinical presentation of endocrine irAEs 
includes nonspecific headache and fatigue, but may also include myalgias, visual 
field defects, behavioral changes, electrolyte disturbances, loss of appetite and 
hypotension. (Tarhini, 2013). Patients will generally have abnormal endocrine 
laboratory test results, that include TSH, free T4, total and free triiodothyronine 
(T3), cortisol, ACTH, luteinizing hormone, follicle-stimulating hormone, and 
testosterone (in men).
It is important to note that despite vague symptomatic presentation, there is a risk 
for serious morbidity or death if the endocrinopathy is not promptly identified and 
treated. Guidelines for the management of subjects with immune- mediated 
events including endocrinopathy are outlined in Table 1.
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7.2.4.8   Neuropathy/Neuromuscular Events (to include MG and GB)
The frequency of immune-mediated neuropathy (including peripheral sensory 
neuropathy, neuropathy peripheral and peripheral motor neuropathy) in clinical 
trials with immune checkpoint-inhibitors ranged from ≤1% to 4.5%. (Sznol and 
Chen, 2013; Topalian et al, 2012; Wolchok et al, 2013; Hamid et al; 2013) 
Although they are rare, severe neuropathies and myopathies have been observed 
in patients treated with immune checkpoint inhibitors and include Guillain-Barré 
syndrome, transverse myelitis, or myasthenia gravis, among other diagnoses. 
Neuropathies associated with ipilimumab have been difficult to assess because 
these irAEs are transient and present with vague symptoms. Presentations of 
neurotoxicity may include a mild peripheral sensory neuropathy or muscle 
weakness. Symptoms of peripheral neuropathy include numbness, tingling, 
paresthesia (pins and needles sensations), sensitivity to touch, or muscle 
weakness. In patients with extreme symptoms, they may present with burning 
pain, muscle wasting, paralysis, or organ dysfunction. Symptoms are typically
detected with physical examination findings ranging from sensory changes to 
loss of deep-tendon reflexes.
Depending on presentation, patients may require neuroimaging, nerve 
conduction studies, and, potentially, nerve or muscle biopsy to arrive at the 
diagnosis. Guidelines for the management of subjects with immune-mediated 
events including neuropathy or neuromuscular events are outlined in Table 1.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following criteria:
 
Is unanticipated in terms of nature, severity, or frequency
 
Places the research subject or others at a different or greater risk of harm
 
Is deemed to be at least possibly related to participation in the study.
Any AE deemed to be a UPIRSO will be reported to the local IRB as well as the NU 
QAM/DSMC.
7.2.5
Overdose
An overdose is defined as a subject receiving a dose of MEDI4736 or Tremelimumab in 
excess of that specified in the Investigator’s Brochure, unless otherwise specified in this 
protocol.
Any overdose of a study subject with MEDI4736 Tremelimumab, with or without 
associated AEs/SAEs, is required to be reported along the same timeframe as an SAE (see
7.3.3). If the overdose results in an AE, the event 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 Tremelimumab. The treating investigator will use clinical 
judgment to treat any overdose.
7.2.6
Hepatic function abnormality
Hepatic function abnormality (as defined previously) 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 QAM and 
AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox (see
7.3.3.4), 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
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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 treating investigator and evaluated by the PI and 
AstraZeneca/MedImmune.
7.2.7
Pregnancy
Pregnancy itself, or pregnancy of a subject’s partner, is not regarded as an adverse event 
unless there is a suspicion that the investigational product under study may have interfered 
with the effectiveness of a contraceptive medication. Congenital abnormalities/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 any conception 
occurring from the date of the first dose until 90 days after the last dose (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital 
abnormality) should be followed up and documented even if the subject was withdrawn 
from the study.
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to the QAM and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e- 
mailbox (7.3.3.4).
Subjects who become pregnant during the study period must not receive additional doses 
of investigational product but will not be withdrawn from the study. The pregnancy will 
be followed for outcome of the mother and child (including any premature terminations) 
and should be reported to AstraZeneca/MedImmune Patient Safety or designee after
outcome. Male subjects should refrain from fathering a child or donating sperm during the 
study and for through 180 days after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 or tremelimumab 
monotherapy.
Should the investigator become aware of a pregnancy in the partner of a male study 
subject who has received investigational product this should be reported within 24 hours 
of knowledge of the event to the QAM and AstraZeneca/MedImmune Patient Safety or 
designee using the Safety Fax Notification Form. The funding sponsor will endeavor to 
collect follow-up information on such pregnancies provided the partner of the study 
subject provides consent.
7.3
Adverse Event Reporting
7.3.1 Routine Reporting
Adverse events will be recorded using a recognized medical term or diagnosis that accurately 
reflects the event. Adverse events will be assessed by the investigator for severity, relationship to 
the investigational product, possible etiologies, and whether the event meets criteria of an SAE 
and therefore requires immediate notification to the QAM and AstraZeneca/MedImmune Patient 
Safety.
The following variables will be collected for each AE:
 
AE (verbatim)
 
The date when the AE started and stopped
 
Changes in NCI CTCAE grade and the maximum CTC grade attained
 
Whether the AE is serious or not
In addition, the following variables will be collected for SAEs as applicable:
 
Date AE met criteria for serious AE
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 
Date Investigator became aware of serious AE
 
AE is serious due to
 
Date of hospitalization
 
Date of discharge
 
Probable cause of death
 
Date of death
 
Autopsy performed
 
Description of AE
 
Causality assessment in relation to Study procedure(s)
All routine adverse events, such as those that are expected, or are unlikely or definitely not related 
to study participation, are to be reported on the appropriate eCRF. Routine AEs will be reviewed 
by the Data and Safety Monitoring Committee (DSMC) according to the study’s phase and risk 
level, as outlined in the DSMP.
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the last 
dose of MEDI4736 or tremelimumab or the combination of both). During the course of the study 
all AEs and SAEs should be proactively followed up for each subject. Every effort should be
made to obtain a resolution for all events, even if the events continue after discontinuation/study 
completion.
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments.
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. AstraZeneca/MedImmune retains the 
right to request additional information for any subject with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 90 days of the last dose of protocol treatment.
1)   Identify the type of adverse event using the NCI CTCAE v 4.03.
2)   Grade the adverse event using the NCI CTCAE v 4.03.
3)   Determine whether the adverse event is related to the protocol therapy.
Attribution categories are as follows:
 
Definite: AE is clearly related to the study treatment.
 
Probable: AE is likely related to the study treatment.
 
Possible: AE may be related to the study treatment.
 
Unlikely: AE not likely to be related to the study treatment.
 
Unrelated: AE is clearly NOT related to the study treatment.
4)   Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in:
 
the current protocol
 
the drug package insert
 
the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1   Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of becoming
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aware of the event. Completion of the NU CTO SAE Form is required.
The completed form should assess whether or not the event qualifies as a
UPIRSO. The report should also include:
 
Protocol description and number(s)
 
The patient’s identification number
 
A description of the event, severity, treatment, and outcome (if known)
 
Supportive laboratory results and diagnostics
 
The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DSMC at their next meeting.
7.3.3.2   Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their 
local IRB guidelines for reporting to their local IRBs.
   Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the 
NU IRB within 24 hours of notification.
   Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)
   Any death of a non-NU subject that is unanticipated and at least
possibly related and any other UPIRSOs will be reported to the NU IRB
within 5 working days of notification.
   All other deaths of NU subjects not previously reported, other non-NU 
subject deaths that were unanticipated and unrelated, and any other 
SAEs that were not previously reported as UPIRSOs will be reported to 
the NU IRB at the time of annual continuing review.
7.3.3.3   Reporting to the FDA
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening.
The FDA will be notified within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life- 
threatening. This includes any previous SAEs that were not initially deemed 
reportable, but are later determined to meet the criteria for reporting (i.e. by the 
DSMC).
All other SAEs will be reported on an annual basis as part of the annual FDA
report.
7.3.3.4   Reporting to AstraZeneca/MedImmune
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.
NOTE TO AUTHOR: For trials conducted in the United States, the following 
must be included (similar language must be included, referencing the appropriate 
health authority and reporting mechanism, for studies conducted outside of the
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United States). Note that all serious or unexpected adverse events must be 
reported to AstraZeneca regardless of the country where the study is conducted.
The investigator and/or sponsor must inform the FDA as outlined in 7.3.3.3 
above, 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.
The NU CTO SAE report should accompany the MedWatch form indicating the 
following:
 
“Notification from an Investigator Sponsored Study”
 
The investigator IND number assigned by the FDA
 
The investigator’s name and address
 
The trial name/title and AstraZeneca ISS reference number (ESR-14-
10508)
The NU CTO SAE report will indicate 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 the SAE report and accompanying cover page by way of e-mail 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 (as applicable). 
Serious adverse events that do not require expedited reporting to the FDA still 
need to be reported to AstraZeneca using the NU CTO SAE form. This 
information should be reported on a monthly basis and under no circumstance 
less frequently than quarterly.
8.0
DRUG INFORMATION
8.1
MEDI4736
8.1.1
Other names
Durvalumab
8.1.2
Classification - type of agent
MEDI4736, a human IgG1κ mAb directed against PD-L1, contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to C1q and the Fcγ
receptors
8.1.3
Mode of action
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 homolog 1 [B7-H1], cluster of differentiation [CD]274) 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.
8.1.4
Storage and stability
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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.
Lyophilized formulation: MEDI4736 is formulated at 50 mg/mL. The investigational 
product is supplied as a white to off-white lyophilized powder in clear 10R glass vials 
closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 200 mg 
(nominal) of active investigational product. MEDI4736 should be reconstituted with
4.0 mL sterile WFIwater for infusion to give a final concentration of 50 mg/mL.
Liquid formulation: MEDI4736 is formulated at 50 mg/mL. 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.
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.
8.1.5
Protocol dose specifics
MEDI4736 will be dosed at 750 mg intravenously (IV) every 2 weeks. Patients on Arm 2 
will receive MEDI4736 monotherapy and patients on Arm 3 will receive MEDI4736 in 
combination with tremelimumab.
8.1.6
Preparation
MEDI4736 will be supplied in liquid form. Each vial is formulated at 50 mg/mL in 26 mM 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) 
polysorbate 80, pH 6.0. Calculate the dose volume of MEDI4736 and number of vials 
needed for the subject to achieve the accurate dose.
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not to be prepared on the floor. The reconstituted solution (for 
lyophilized product) or liquid product is to be diluted with 0.9% (w/v) saline or 5% (w/v) 
dextrose for IV infusion.
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 250 ml 0.9% (w/v) saline 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.
Total in-use storage time from reconstitution of MEDI4736 to start of administration
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If 
storage time exceeds these limits, a new dose must be prepared from new vials.
8.1.7
Route of administration for this study
MEDI4736 will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral vein. A central line can be used if needed. 
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.
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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. Document 
if the line was not flushed.
8.1.8
Incompatibilities
No formal drug-drug interaction studies have been conducted with MEDI4736. There are 
no known clinically significant interactions of MEDI4736 with other medicinal products. 
No incomtabilities between MED14736 and polyethylene, polypropylene, 
polyvinylchloride, or polyolefin copolymers have been observed.
Since the compatibility of MEDI4736 with other IV medications and solutions, other than 
normal saline (0.9% [w/v][sodium chloride for injection), is not known, the MEDI4736 
solution should not be infused through an IV line in which other solutions or medications 
are being administered.
8.1.9
Availability & Supply
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
MEDI4736 to the investigator at Northwestern University as a concentrate for solution for 
infusion.
Investigational products will be supplied by Medimmune in containers with identical 
appearances in coded kits for each product respectively. Each investigational product kit 
has a unique number that is printed on all labels within the kit (ie, the outer carton label 
and the label of each container within the carton). Each carton and vial is labeled with the 
same unique sequence number range. 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).
8.1.10
Side effects
Frequent - Expected to occur in 10% to 25% of people (10 to 25 out of 100 people):
 
Fatigue (13.5%)
Not Frequent – Expected to occur in 2% to less than 10% of people (2 to less than 10 
out of 100 people):
 
Nausea (8.4%)
 
Diarrhea (5.3%)
 
Decreased appetite (5.3%)
 
Rash (5.3%)
 
Vomiting (4.8%)
 
Itchiness (4.1%)
 
Difficulty breathing (3.8%)
 
Fever (3.1%)
 
Low thyroid (2.8%)
 
Increased liver enzymes (2.5%)
 
Cough (2.5%)
 
Muscle pain (2.3%)
 
Stomach pain (2.0%)
 
Dizziness (2.0%)
Related and serious side effects reported in subjects receiving MEDI4736 alone 
were:
 
Blockage in the urinary tract
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 
Fluid in the space surrounding the lung and inflammation of the lung
 
Increase in calcium in the blood
 
Joint pain
 
Worsening of cancer
Increase in liver enzymes and blockage of the tract between the liver and small 
intestine
 
Spinal cord swelling
 
Irregular heart beat or rhythm
 
Chest pain and fluid in the abdomen
 
Dehydration
 
Disorder in the blood vessels of the organs
 
Swelling of the tumor
 
Lack of muscle control during walking or picking up objects
Uncommon side effects (≤1% - Expected to occur in less than 1 out of 100 people):
 
Myocarditis
 
Neutropenia
 
Increased risk of  infection e.g. pneumonia
 
Myositis,
 
Cerebral vasculitis,
 
Sarcoidosis
 
Arthritis, including arthritis of the jaw,
 
Papilledema
 
Cytokine release syndrome (CRS)
There was one death felt to be related to MEDI4736 when administered alone. The 
subject who had a prior history of cardiac illness including a prior heart attack died due to 
a disorder of the blood vessels. The Study Doctor also indicated possible other causes of 
the fatal event.
Please refer to current IB for more details and a complete list of side-effects.
8.1.11
Nursing implications
Subjects will be monitored during and after the infusion with assessment of vital signs 
(temperature, pulse, blood pressure and respiratory rate) at the times specified in the 
Schedule of Assessment (see Section 5.0). On treatment days, vital signs will be measured 
within an hour prior to start of drug administration, at 30 minutes during the infusion (± 5 
minutes), at the end of infusion (+5 minutes), and at 30 minutes (± 5 minutes) and 60 
minutes (± 5 minutes) post-infusion. If the infusion takes longer than 60 minutes, then 
blood pressure and pulse measurements should follow the principles described here or 
more frequently if clinically indicated. For subsequent doses, the 1-hour observation 
period will not be required unless a subject experiences an infusion-related reaction.
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
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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.
8.1.12
Return and Retention of Study Drug
Any unused study drug will be destroyed per Northwestern policy.
8.1.13
Accountability and dispensation
Drug supply will be kept in the research pharmacy at Northwestern Memorial Hospital.
8.2
Agent Tremelimumab
8.2.1
Other names
8.2.2
Classification - type of agent
Tremelimumab is a human IgG2 anti-CTLA-4 mAb.
8.2.3
Mode of action
Tremelimumab is a human IgG2 mAb directed against CTLA-4. Tremelimumab has an 
overall molecular weight of approximately 149 kDa including oligosaccharides. Cytotoxic 
T lymphocyte-associated antigen 4 is a critical regulatory signal for T-cell expansion and 
activation following an immune response, and it serves as a natural braking mechanism 
that maintains T-cell homeostasis. During T-cell activation, T cells upregulate CTLA-4, 
which binds to B7 ligands on antigen-presenting cells, sending an inhibitory signal that 
limits T-cell activation. Tremelimumab blocks the inhibitory signal resulting from CTLA-
4 binding to B7, leading to prolongation and enhancement of T-cell activation and 
expansion.
8.2.4
Storage and stability
Tremelimumab is supplied as a sterile IV solution, filled in 20 mL clear glass vials with a 
rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of
20 mL accounting to 400 mg/vial) of Tremelimumab, in an isotonic solution at pH 5.5.
Tremelimumab should be stored at refrigerated temperatures (2°C to 8°C), and should not 
be frozen. The 20 mg/mL solution will be diluted into a saline bag for IV infusion. Vials 
containing Tremelimumab may be gently inverted for mixing, but should not be shaken. 
Total in-use storage time from needle puncture of the product vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F).  
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Tremelimumab does not contain preservatives and any unused portion must be discarded.
8.2.5
Protocol dose specifics
Tremelimumab will be given at a dose of 75 mg IV every 4 weeks. Patients on Arm 1 will 
receive tremelimumab monotherapy and patients on Arm 3 will receive tremelimumab in 
combination with MEDI4736.
8.2.6
Preparation
Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in
20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH
5.5.
The Drug Product is supplied as a sterile IV solution in 20 mL clear glass vials with a 
rubber stopper and aluminum seal. Each vial contains 20 mg/mL of tremelimumab with a 
nominal fill of 20 mL (accounting to 400 mg/vial). Vials containing tremelimumab must 
be stored at 2o C to 8°C (36°F to 46°F) and must not be frozen. Vials containing
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tremelimumab may be gently inverted for mixing, but should not be shaken.
The product should be protected from light when not in use. Tremelimumab does not 
contain preservatives and any unused portion must be discarded. Preparation of 
tremelimumab and preparation of the IV bag are to be performed aseptically. Total in-use 
storage time from needle puncture of the  investigational product vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C 
(36°F to 46°F). It is recommended that the prepared final IV bag be stored in the dark at
2°C to 8°C until needed. If storage time exceeds these limits, a new dose must be prepared 
from new vials. The refrigerated infusion solutions in the prepared final IV bag should be 
equilibrated at room temperature for about 2 hours prior to administration.
For dose preparation steps, the following ancillary items are required:
 
IV infusion bags of 0.9% (w/v) sodium chloride injection (250 mL size).
 
Saline bags must be latex-free and can be made of polyvinyl chloride (PVC)
 
or polyolefins (eg, polyethylene), manufactured with DEHP or DEHP-free. IV 
infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate or polyethylene or 
polyurethane. All DEHP-containing or DEHP-free lines are acceptable. Lines 
should contain a 0.22 or 0.2 μm in-line filter. The in-line filter can be made of 
polyethersulfone or polyvinylidene fluoride. Lines containing cellulose-based 
filters should not be used with tremelimumab.
 
Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and 
stainless steel and/or PVC components.
 
Syringes made of polypropylene and latex-free. Polycarbonate syringes should not 
be used with tremelimumab.
 
Needles made of stainless steel.
8.2.7
Route of administration for this study
Tremelimumab is to be administered as an IV solution at a rate of 250 mL/hr., followed by 
observation for 60 minutes.
For the combination arm, tremelimumab will be administered first. MEDI4736 infusion 
will start approximately 1 hour after the end of the tremelimumab infusion for the first 
infusion only. If there are no clinically significant concerns after the first cycle, the 
MEDI4736 infusion may be administered immediately after the tremelimumab infusion 
has finished in all other cycles, at the discretion of the investigator. The duration of each 
infusion will be approximately 1 hour.
8.2.8
Incompatibilities
No formal drug-drug interaction studies have been conducted with tremelimumab. 
However, in RCC studies, acute renal failure has been reported with the combination of 
tremelimumab and sunitinib. It is unknown whether a similar reaction will be observed 
when tremelimumab is combined with other tyrosine kinase inhibitors.
8.2.9
Availability & Supply
Investigational products will be supplied by Medimmune in containers with identical 
appearances in coded kits for each product respectively. Each investigational product kit 
has a unique number that is printed on all labels within the kit (ie, the outer carton label 
and the label of each container within the carton). Each carton and vial is labeled with the 
same unique sequence number range.
Tremelimumab is formulated at 20 mg/mL in 20 mM histidine/histidine-HCl, 222 mM 
trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM disodium edetate 
dihydrate, pH 5.5. The investigational product is supplied as a clear to opalescent,
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colorless to yellowish liquid in a 20-mL clear, glass vial with a rubber stopper aluminum 
seal. Each vial contains 400 mg (nominal) of active investigational agent. The standard 
supply of tremelimumab is delivered in a white carton with 16 vials of tremelimumab 
within foam inserts.
Tremelimumab will be provided to Northwestern University by MedImmune. 
Northwestern University will request tremelimumab submitted via email. Please allow 
approximately 10 days for drug delivery.
8.2.10
Side effects
Below are safety data from 973 subjects with various types of cancer who received 
tremelimumab alone. Related side effects reported in subjects receiving tremelimumab 
alone were:
Very Frequent – Expected to occur in more than 25% of people (more than 25 out of
100 people):
 
Diarrhea (41.2%)
 
Itching (25.1%)
Frequent - Expected to occur in 10% to 25% of people (10 to 25 out of 100 people):
 
Fatigue (23.8%)
 
Nausea (21.9%)
 
Vomiting (13.5%)
 
Decreased appetite (11.3%)
Not Frequent – Expected to occur in more than 5% to less than 10% of people
(more than 5 to less than 10 out of 100 people):
 
Headache (7.2%)
 
Fever (7.0%)
 
Stomach pain (6.7%)
 
Inflammation of the large intestine (5.5%)
Related and serious side effects reported in more than 1% of people (more than 1 out 
of 100 people) receiving tremelimumab alone were:
 
Diarrhea (9.2%)
 
Inflammation of the large intestine (3.6%)
 
Vomiting (2.3%)
 
Nausea (1.8%)
 
Dehydration (1.8%)
Deaths thought to be related to tremelimumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people). There were five 
deaths reported that were thought to be related to side effects caused by tremelimumab. 
The deaths per subject are summarized with the causes noted (where known):
Sudden death in a subject with advanced skin cancer who had a history of smoking. The 
subject had a family history of sudden cardiac death and had recently changed 
antidepressant medications. While on tremelimumab treatment, the subject had symptoms 
that might be consistent with decreased blood flow to the heart. However, the exact cause 
of death was not confirmed.
Lack of oxygen to the brain due to sudden and unexpected loss of heart function in a 
subject whose skin cancer had spread to the lungs. The subject had a history of medical 
conditions that could increase the risk for heart problems including diabetes, increased 
blood pressure, elevated levels of fat in the blood and diarrhea. One week before loss of
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heart function, the subject experienced kidney failure, dehydration, fever and increased 
creatinine (a compound in the blood removed by the kidney that when high can indicate 
poor kidney function). The study doctor thought there was a possibility that the side 
effects and loss of heart function could be related to tremelimumab.
Imbalance of essential minerals necessary for body function due to long lasting diarrhea in 
a subject with advanced skin cancer. Blood clot in the lungs in a subject with advanced skin 
cancer that had worsened. In a subject with advanced skin cancer, respiratory failure in 
relation to an infection that occurred after complications from surgery performed to
treat inflammation and bleeding of the large intestine was the immediate cause of death. 
The study doctor thought the large intestine inflammation and complications that followed 
after surgery were related to tremelimumab.
Subjects will be monitored during and after the infusion with assessment of vital signs at 
the times specified in the Schedule of Assessment (see Section 6.2)
On treatment days, vital signs will be measured within an hour prior to start of drug 
administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+
5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion.
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements 
should follow the principles described here or more frequently if clinically indicated. For 
subsequent doses, the 1-hour observation period will not be required unless a subject 
experiences an infusion-related reaction
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.
8.2.12
Return and Retention of Study Drug
Any unused study drug will be destroyed per Northwestern policy.
8.2.13
Accountability and dispensation
Drug will be kept in the research pharmacy at Northwestern Memorial Hospital.
9.0
CORRELATIVES/SPECIAL STUDIES
9.1
Tumor and peripheral lymphocyte changes
Samples will be collected and sent to the laboratory of: 
Dr. Orin Bloch
300 E Superior Street-Tarry Bldg 2-725
Chicago, IL 60611
Lab Phone: (312) 503-4345
Office Phone: (312) 695-3799
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Tissue and blood samples from the operating room and from clinic will be collected by laboratory 
personnel and sent to the laboratory of Dr. Orin Bloch in Tarry 2-725 for processing.
Fresh Tumor tissue: removed at surgery will be used to extract tumor-infiltrating lymphocytes 
(TIL) for analysis. In addition, fresh frozen and formalin fixed paraffin embedded tissue will be 
banked for analysis. Extracted TILs will be used to evaluate the tumor infiltrative lymphocyte 
population by flow cytometry and paraffin embedded tissue will be used to evaluate TILs in situ by 
immunohistochemistry. If a patient has progression of disease and undergoes further surgery, they 
will have the option of allowing tissue to be analyzed for the above.
Blood sample: 10ml blood in one 10ml Sodium heparin tube. This will be collected at 1st pre- 
operative treatment, day of surgery, C1D1, and at each adjuvant treatment imaging visits (i.e. 
every 2 cycles or 8 weeks).
Blood collected prior to treatment on 1st pre-operative treatment day will be used for baseline 
evaluation of activated peripheral lymphocytes. Patients will then have blood drawn on day of 
surgery, and on the day of each MRI scan (i.e. every 2 cycles or 8 weeks) with extraction and 
banking of peripheral blood leukocytes (PBL).
PBLs obtained prior to drug administration will be studied by flow cytometry to identify relative 
populations of CD8 T cells (CD3+, CD8+, PD1+/-), CD4 T cells (CD3+, CD8+, PD1+/-), 
regulatory T cells (CD4+, CD25+, FoxP3+), and suppressive monocytes (CD45+, CD11b+, PD- 
L1+). Repeat assessment of PBL markers will be determined by flow cytometry of subsequent 
samples taken on the day of surgery, post operatively (C1D1) and then on MRI days. Additionally, 
TILs extracted from patient tissue will be evaluated for relative populations of activated CD8 T cells 
(CD3+, CD8+, IFN-g+, PD1+/-), activated CD4 T cells (CD3+, CD8+,  IFN-g+, PD1+/-), 
regulatory T cells (CD4+, CD25+, FoxP3+), and suppressive monocytes (CD45+, CD11b+, 
CD163+, PD-L1+). CTLA-4 expression on effector and regulatory T cells can also be measured
by flow cytometry. Double-labeled tissue immunofluorescence can also be performed on FFPE 
sections to obtain immune effector cell counts, reported as # cells / 10 hpf. Optimized labeling 
schemes include: CD8/IFN-g, CD4/IFN-g, CD8/PD-1, CD4/PD-1, CD68/PD-L1, GFAP/PD-L1 
(to identify PD-L1+ tumor cells).
We will use our stimulation protocol for IFN-g from PBL to look for increased peripheral T cell 
reactivity before and after drug treatment
Banked PBLs, TILs and FFPE tissue from prior patients treated without the study drug will serve 
as comparative controls.
NOTE: Any leftover tissue from the study patients will be banked for future use. This should be 
clearly stated in the consent form.
Please refer to laboratory manual for further details on collection, labeling, shipping, processing 
and storage.
9.2
Peripheral blood analysis for gene expression, tryptophan metabolism and cytokine 
abundance
Additional blood samples will be collected at 1st  pre-operative treatment, day of surgery, C1D1, 
and at each adjuvant treatment imaging visits (i.e. every 2 cycles or 8 weeks):
a)
8m (2x4ml) blood in two 5ml EDTA (purple top) tubes: PBMCs will be isolated, 
separated and analyzed to generate a gene expression profile.
b)   10ml blood in one 10ml red top tube: Serum will be analyzed 1) via HPLC for 
tryptophan and downstream catabolites, as well as for 2) cytokines via an array-based 
platform.
Responders and non-responders (if separable) will be identified based on progression free- and/or
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overall-survival and cross-referenced with gene expression/tryptophan catabolite/cytokine analysis.
Samples will be picked up by laboratory personnel and sent to: 
Dr. Derek Wainwright’s laboratory.
300 E Superior Street-Tarry Bldg 2-703 (Office); 2-725 (Lab) 
Chicago, IL 60611
Lab Phone: (312) 503-5168; 
Office Phone: (312) 503-3161
Please refer to laboratory manual for further details on collection, shipping, processing and storage.
9.3
Archival Tissue for PD- L1 analysis
Four unstained slides cut at 5µ from a representative tumor block will be delivered to the Bloch lab 
for PD-L1 analysis (see section 9.1 for contact information).
An additional 3 unstained slides cut at 5 microns will be hand delivered to PCF IHC within 7 days 
of sectioning for commercial analysis of PD-L1. We will use the commercially available assay 
[e.g. Ventana Medical Systems, Inc. (Ventana)].
Please refer to laboratory manual for further details on collection, shipping, processing and storage.
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
To determine the T-cell changes that occur in recurrent GBM treated with Tremelimumab and
MEDI4736 as single agents and in combination.
 
To evaluate the safety of either Tremelimumab or MEDI4736 alone and in combination in 
patients with recurrent GBM.
 
To determine the time to progression for patients treated with either Tremelimumab or
MEDI4736 alone and in combination of both post-surgery.
 
To  determine  the  overall  survival  for  patients  treated  with  Tremelimumab  or
MEDI4736 alone and in combination of both post-surgery.
 
To correlate T-cell changes and PDL1 expression with patients outcome.
 
To assess MRI changes in patients treated with either Tremelimumab, or MEDI4736 
alone, and in combination of both post-surgery.
10.3
Sample Size, Accrual and Data Analyses Plans
There will be three groups of patients, one group on each agent alone and one group treated with the 
combination agent. There will be 10 patients per group for a total of 30 patients. These 30 patients 
must be evaluable for the primary endpoint, meaning that they must have undergone surgery and 
their blood and tissue samples are available at both the pre- and post-surgery times. In order to 
attain 10 evaluable patients in each arm, a total of 45 patients will be accrued to the study. Sample 
sizes of 10 per group allow for the estimation of the proportion of responders in evaluable patients 
to be within 31% of its true value with 95% confidence. Mean change will be compared between 
arms.
Using standard deviations of change, a sample size of 10 per group will allow
the detection of differences of 1.25 standard deviations between groups with 80% power assuming 
a two-tailed test and a Type I error rate of 5%.
Immunologic measures will be summarized over the three or more time points (pre-treatment, 
following first treatment/pre-surgery, post-surgery) and changes in these measures will be assessed 
using repeated measures analysis of variance or Cochran’s Q, followed by the paired t-test or the 
signed rank test for pairwise comparisons using Bonferroni corrections. Safety of the agents alone 
or in combination will be assessed by summarizing the frequency of adverse events by type,
timing, grade and attribution. Response criteria will be based on RANO (including upcoming
Immunologic RANO criteria) but since all patients will be post-surgery, the degree, if any, of
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residual disease will vary. A patient is evaluable for efficacy if they have undergone at least one 
follow-up MRI after adjuvant therapy. Immunologic changes will be correlated with MRIs in a 
descriptive fashion. The secondary endpoint of progression-free survival as well as overall survival 
will be analyzed using Kaplan-Meier curves. Immunologic changes of T-cells and PDL1 levels
will be correlated to survival outcomes using Cox regression analysis. MRI changes will be 
summarized using means or proportions and statistically analyzed using the signed rank test.
Performance Status: Patients will be graded according to Karnofsky Performance
Status (KPS)(see appendix C).
Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment as per NCI CTCAE version 4.03
Time to Progression: From date of first treatment to the date of first observation of definitive 
progressive disease, non-reversible neurologic progression or increasing steroid requirements 
(applies to stable disease only), death due to any cause, or early discontinuation of treatment. 
Patients not reaching the progression endpoint at last follow-up will be censored at that time.
Time to Death: From date of first treatment to date of death due to any cause. Patients alive at last 
follow-up will be censored at that time.
11.0
STUD
11.1
Y MANAGEMENT
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance with
federally mandated regulations. The IRB should approve the consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to ICH/Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include 
all the relevant elements currently required by the FDA Regulations and local or state regulations. 
Once this essential information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient will
be asked to give consent to participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or informed 
consent. All amendments will be subject to the review and approval of the appropriate local, 
institutional, and governmental regulatory bodies, as well as by Astra Zeneca/MedImmune 
Amendments will be distributed by the lead institution (Northwestern) to all affiliate sites upon 
approval by the Northwestern University IRB.
11.3
Registration Procedures
BEFORE a patient can be treated on study, please complete and submit the following items to 
confirm eligibility and receive a subject identification number:
 
Eligibility eCRF (complete in NOTIS)
 
Eligibility checklist (signed and dated by the treating physician – upload in NOTIS)
 
Signed and dated informed consent document (upload in NOTIS)
 
Pathology Report (upload in NOTIS)
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The QAM will review the registration, register the patient, assign an identification number, and 
send a confirmation of registration to involved personnel. Registration will then be complete and 
the patient may begin study treatment.
11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted according to the 
study procedures table (see Section 5.0). Generally, for all phase II patients, data are due at the end 
of every cycle.
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11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of 
the Robert H. Lurie Comprehensive Cancer Center of Northwestern. The level of risk attributed 
to this study requires high intensity monitoring, as outlined in the DSMP. The assigned QAM, 
with oversight from the Data and Safety Monitoring Committee, will monitor this study in 
accordance with the study phase and risk level.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and well-being of 
the study patient requires alternative treatment, the study shall be conducted exactly as described in 
the approved protocol.
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form must be 
completed within 5 business days of making the change, and the QAM must be notified 
within 24 hours of such change.
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM using the 
appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol that:
 
Is generally noted or recognized after it occurs.
 
Has no substantive effect on the risks to research participants.
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).
A protocol deviation may be considered an instance of Reportable New Information
(RNI) if it:
 
Has harmed or increased the risk of harm to one or more research participants.
 
Has damaged the scientific integrity of the data collected for the study.
 
Results from willful or knowing misconduct on the part of the investigator(s).
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
 
Any deviation that would constitute an instance of Reportable New Information 
must be reported to the Northwestern IRB within 5 business days of knowledge 
or notification.
11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The PI is responsible for personally overseeing the treatment of all study patients. The PI must 
assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected, entered onto the appropriate eCRFs, and submitted within the 
study-specific timeframes. Periodically, monitoring visits may be conducted and the Principal
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entry. The study may also be subject to routine audits by the Audit Committee, as outlined in the
DSMP.
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, posters, 
clinicaltrials.gov releases) must be approved in accordance with the policies and processes set forth 
in the Lurie Cancer Center DSMP. For trials that require high intensity monitoring the assigned 
QAM will prepare a preliminary data summary (to be approved by the DSMC) no later than 3 
months after the study reaches its primary completion date (the date that the final subject is 
examined or receives an intervention for the purposes of final data collection for the primary 
endpoint). If the investigator’s wish to obtain DSMC-approved data prior to this point (or prior to 
the point dictated by study design), the PI must send a written request for data to the QAM which 
includes justification. If the request is approved, data will be provided no later than 4 weeks after 
this request approval. The data will be presented to the DSMC at their next available meeting, and a 
final, DSMC-approved dataset will be released along with any DSMC decisions regarding 
publication. The investigators are expected to use only DSMC-approved data in future publications. 
The investigators should submit a copy of the manuscript to the biostatistician to confirm that the 
DSMC-approved data are used appropriately. Once the biostatistician gives final approval, the 
manuscript may be submitted to external publishers.
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patients based on population pharmacokinetic analysis. Pharmaceutical research 2006;23:1275-1284.
63.  Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. Journal of clinical pharmacology 2009;49:1012-1024.
64.  Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of therapeutic 
peptides and proteins in adults. Journal of clinical pharmacology 2012;52:18-28.
65.  Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational anti- 
interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clinical pharmacokinetics
2013;52:1017-1027.
66.  Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: 
response assessment in neuro-oncology working group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2010;28:1963-1972.
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APPENDIX A – COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.03 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 will be utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html)
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a
APPENDIX B – ACCEPTABLE METHODS OF CONTRACEPTION
Table 5 - 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
This is also considered a hormonal method.
NOTE:
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of birth control.
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APPENDIX C – KARNOFSKY PERFORMANCE SCALE (KPS)
Points
Description
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or to do active work
60
Requires occasional assistance but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated. Death not imminent
20
Very sick; hospitalization necessary; active support treatment necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
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APPENDIX D – PROTOCOL SUMMARY OF CHANGES
Amendment 1 –January 15th, 2016 
(before initial IRB submission)
Sections(s) Affected
Prior Version
Amendment 1
Changes
Rationale
Section 1.3.3
Durvalumab safety
Previous safety 
information
Added: additional 
safety information 
based on updated IB 
version 9
Per new Investigator’s
Brochure(IB) (v9)
Section 1.4.2
Tremelimumab safety
Previous safety 
information
Added: Additional 
safety information 
about Durvalumab and 
Tremelimumab 
combination therapy
Per new Investigator’s
Brochure(IB) (v9)
Section 4.5
Toxicity management 
tables
Previous tables
Deleted previous 
tables
Inserted Updated 
tables according to 
new IB
Per new Investigator’s
Brochure(IB) (v9)
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Table 2
Infusion-Related
Reactions
Grade 2
The infusion rate of 
study drug/study 
regimen may be 
decreased 50% or 
temporarily 
interrupted until 
resolution of the 
event (upto 4 hours).
Updated:
Grade 2
The infusion rate of 
study drug/study 
regimen may be 
decreased 50% or 
temporarily 
interrupted until
resolution of the event
Per new Investigator’s
Brochure(IB) (v9)
Section 8.1.4
Durvalumab Storage and
Stability
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% 
(weight/volume 
[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.
Lyophilized 
formulation: 
MEDI4736 is 
formulated at 50 
mg/mL. The 
investigational product 
is supplied as a white
to off-white 
lyophilized powder in 
clear 10R glass vials 
closed with an 
elastomeric stopper 
and a flip-off cap 
overseal. Each vial 
contains 200 mg 
(nominal) of active 
investigational 
product. MEDI4736
should be reconstituted 
with
4.0 mL sterile 
WFIwater for infusion 
to give a final 
concentration of 50 
mg/mL.
Per new Investigator’s
Brochure(IB) (v9)
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Section 8.1.6
Durvalumab preparation
Previous 
information
Added
. The reconstituted 
solution (for 
lyophilized product) or 
liquid product is to be 
diluted with 0.9%
(w/v) saline or 5% 
(w/v) dextrose for IV 
infusion.
Per new Investigator’s
Brochure(IB) (v9)
Amendment 2 –July 05, 2016
Sections(s) Affected
Prior Version
Changes made
Rationale
Throughput 
Study Schema 
Study summary 
Section 4.2
Section 4.6
Section 5.2
The FDA reviewer 
noted that protocol was 
inconsistent throughout 
with respect to the 
duration of treatment of 
patients on the 
combination arm (Arm
3).
Language added to clarify that
‘In all arms, if there is no 
progression of disease, patients 
will continue on treatment for 
up to 24 months.’
In response FDA 
request for 
clarification.
Title;
A Phase II, open label, 
clinical trial of pre- 
surgical and adjuvant 
treatment of recurrent 
malignant glioma with 
Tremelimumab and 
Durvalumab 
(MEDI4736) alone and 
in combination to 
determine immunologic 
changes from treatment.
A Phase II, open label, clinical 
trial of pre-surgical and 
adjuvant treatment of recurrent 
Glioblastoma with 
Tremelimumab and 
Durvalumab (MEDI4736) 
alone and in combination to 
determine immunologic 
changes from treatment.
In response to FDA 
request for 
clarification.
The clinical protocol 
was inconsistent
with respect to the 
study population to 
be enrolled. 
Language has been 
added/modified to 
clarify this.
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Section 3.1
Study population to be 
enrolled:
Grade III or IV glioma 
patients
Study population to be 
enrolled:
Patients with prior diagnosis of
Grade IV glioma (glioblastoma)
, according to WHO 2016 
criteria
In response to FDA 
request for 
clarification.
The clinical protocol 
was inconsistent
with respect to the 
study population to 
be enrolled. 
Language has been 
added/modified to 
clarify this.
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Study summary; Section
2.1, 2.2; 3.0; 6.1;
6.2;10.1
patient population was 
stated as glioblastoma
Added the word recurrent to 
state ‘recurrent glioblastoma’
In response to FDA 
request for 
clarification.
The clinical protocol 
was inconsistent
with respect to the 
study population to 
be enrolled. 
Language has been 
added/modified to 
clarify this.
Section 4.2
“Any patient who has 
disease progression as 
defined in section 6.0 or 
clinical decline and 
undergoes further 
surgery will have the 
option to use their tumor 
tissue for research to 
understand the 
immunologic changes 
occurring at the time of 
presumed drug failure.
If on pathologic review, 
there is no evidence of 
significant tumor and
the changes on MRI 
were likely treatment 
related, the patient can 
re-start treatment.”
Modified 
sentence:
“If on pathologic review, there 
is no evidence of significant 
tumor and the changes on MRI 
were likely treatment related, 
the patient will be allowed to
re-start treatment.”
Added language:
“The patient will be advised of 
the pathology results and that 
they may not derive any further 
benefit from therapy and they 
will need to re-sign the 
informed consent prior to 
starting therapy.”
In response to FDA 
request for 
clarification.
FDA requested that 
in Section 4.2 the 
said patients should 
be re-consented
prior to re-treatment 
to inform them of
the uncertain nature 
of a “negative” 
pathology finding 
and the possibility 
that they may derive 
no benefit from re- 
treatment.”
Study summary; 
Section 4.1 and 4.2
Patients will be 
randomly allocated
using variable size block 
randomization to ensure 
equal sample sizes per 
arm
Patients will be randomly 
allocated using block 
randomization to ensure equal 
sample sizes per arm.
Per statistician
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Section 3.1.13
“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)
72 x serum creatinine (mg/dL)”
Modified Language: “Males:  
Creatinine CL 
(mL/min)=Weight (kg) x (140
– Age) x 1.0
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)”
Correction in 
formula.
Schema
Added Text Box:
“CT or MRI w contrast every
2 cycles”
Clarification
Section 3.1 & 3.2
“ 3.1.18 Malignancy treated 
with curative intent and with no 
known active disease ≥3 years 
before the first dose of study 
drug and of low potential risk 
for recurrence. NOTE: the 
exceptions to this requirement 
include adequately treated non- 
melanoma skin cancer or
lentigo maligna or carcinoma in 
situ without evidence of 
disease.”
“3.1.19 Patients can only be on 
non-enzyme inducing anti- 
convulsants. If they are on an 
enzyme inducing anti- 
convulsant, they may be 
converted to a non-enzyme 
inducing anti-convulsants but 
they will need a 2 week wash 
out period from time of drug 
discontinuation until day 1 of 
study treatment.”
Reworded and moved from 
Inclusion to Exclusion 
Criteria
“3.2.7 Patients on an enzyme- 
inducing anti-convulsant who 
cannot be switched to a non- 
enzyme-inducing anti- 
convulsant with a 2 week 
wash-out period from time of
drug discontinuation until Day
1 of study treatment.”
“3.2.15 Patients with a history 
of active malignancy within 3 
years prior to registration. 
Note: exceptions to this 
requirement include 
adequately treated non- 
melanoma skin cancer or 
lentigo maligna or carcinoma 
in situ without evidence of 
disease.”
Administrativ 
e
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Section 4.3.4
“Enzyme inducing anti- 
convulsants”
Added:
“Enzyme inducing anti- 
convulsants (eg: 
Carbamazepine, Phenytoin, 
Primidone, Topiramate). 
Please check with PI if have 
further questions.”
To Add
Clarity
Table 1 & List of
Abbreviations
Removed Abbreviations 
from the End of Table 1 in 
Section 4.5 and incorporated 
them into the List of 
Abbreviations
Administrativ 
e
Section 4.7
“Subjects who are permanently 
discontinued from receiving 
investigational product will be 
followed for safety including 
the collection of any protocol- 
specified blood specimens, 
unless consent is withdrawn or 
the subject is lost to follow-up 
or enrolled in another clinical 
study.”
Added Language:
“Subjects who are permanently 
discontinued from receiving 
investigational product will be 
followed for safety for 30 days 
post last-dose visit including
the collection of any protocol- 
specified blood specimens, 
unless consent is withdrawn or 
the subject is lost to follow-up 
or enrolled in another clinical 
study. If a subject is enrolled 
in another clinical study, they 
will be followed until all AEs 
are resolved or stable. If 
enrolled onto another clinical 
study, it is not necessary to 
follow the subject for survival 
or progression.”
To Add
Clarity
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Section 4.7
“Subjects who decline to return 
to the site for evaluations will 
be offered follow-up by phone 
every 3 months as an 
alternative.”
Changed to:
“Subjects who decline to 
return to the site for 
evaluations will be offered
follow-up by phone every 8-16 
weeks as an alternative.”
Correction
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Amendment 3 – November 22, 2016
Sections(s) Affected
Prior Version
Changes made
Rationale
Study summary
First key eligibility criteria 
read” grade or IV glioma”
Corrected to read” grade IV
glioma”
Correction of 
typographical 
error.
Study summary; 
Section 4.2 treatment 
administration; 
Section 5.2 Study
procedures table (Post- 
Surgery/Adjuvant 
Therapy)
Day 1 tremelimumab + 
MEDI4736, Day 15 MEDI4736. 
This will be followed until 
patients have received 14 and 7 
doses of tremelimumab and 
MEDI4736 respectively. 
Thereafter, both drugs will be 
given together once every 12 
weeks up to 24months
Language modified to : 
Tremelimumab will be 
administered IV every 4 
weeks (Day 1 of each cycle) 
and MEDI4736 750mg every
2 weeks (Day 1 and Day 15 of 
each cycle) until the patients 
have received 7 doses of 
Tremelimumab and 14 doses 
of MEDI4736.  Thereafter, 
from Cycle 7 (Week 25), 
Tremelimumab will be given 
every 12 weeks (+/-7 days) 
and MEDI4736 will be given 
every 2 weeks (+/- 2 days) 
until permanent 
discontinuation criteria (e.g. 
disease progression) is met. If 
there is no progression of 
disease, they will continue on
treatment for up to 24 months.
To increase 
clarity 
regarding 
dosing 
schedule
Section 1.4.2
background and rationale
language regarding fixed dosing 
of
MEDI4736 and 
tremelimumab
Inserted language regarding 
dosing schedule for both 
Tremelimiumab and 
durvalumab in the 3 Arms. 
Arm 3 language updated as in 
rest of protocol.
To increase 
clarity
Study summary
Section 3.1.5
Inclusion criteria
“patients must be surgical 
candidates”
Modified to state “Patients 
must be surgical resection 
candidates”
To increase 
clarity and 
specificity
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Section 3.1.11
Inclusion criteria
The goal should be 
dexamethasone 4 mg or less at 
the time of starting treatment. If 
patient requires > 4mg of 
steroid, please check with the
PI. Requirement for greater than
10mg of steroid will make the 
patient ineligible.
Modified to :
“Patient’s must be on no more 
than 8 mg a day but an attempt 
should be made to keep the 
dose at 4 mg or less. Please 
contact the PI if doses of > 4 
mg are needed.”
For clarity 
and flexibility
Section 3.2.6
Exclusion criteria
Patients receiving any other 
investigational 
chemotherapeutic agents within
30 days prior to the first dose of 
trial treatment.
The window has been changed 
from 30 days to ‘28 days’.
For 
convenience 
and to be in 
alignment 
with other 
windows in 
the study.
Study summary 
Section 4.2 and 
Section 5.2
Arm 3 MED14736 dose was 
stated as 10mg/kg
Modified to state fixed dosing 
of MED14736, which is
750mg (per sponsor 
specifications).
To be 
consistent 
with rest of
the protocol. A
memo was 
sent out 
earlier
regarding this
Section 4.2 Table
Treatment administration
Arm 3:
Treme every 4 weeks 
(for 7 doses) + MEDI 
every 2 weeks (for 14 
doses); then T every 12 
weeks together
Arm1 and 2: Only 
adjuvant therapy dose 
listed
Updated to : Treme every 4 
weeks (for 7cycles) + MEDI 
every 2 weeks (for 14 doses); 
then Treme every 12 weeks
and MEDI every 2 weeks from
C7(wk. 25).
Updated to include pre- 
surgery and adjuvant doses
For 
consistency, in 
keeping with 
modifications 
made to 
treatment 
administration
Section 4.4
Events Requiring Dose
Modification
A couple of sentences referring 
to DLT was inserted in error
All DLT language removed
Correction of 
error.
DLT language 
not required
in this
protocol  since 
it is a Phase II 
trial.
Section 4.5
Toxicity Management & 
Dose 
Delays/Modifications 
Table 2
Table 2 describing Infusion- 
Related Reactions
A row added in the table 
stating Grade 3 –first 
occurrence specifications.
Next row renamed as “Grade 3 
repeat occurrence or if /Grade
4”
To maintain 
consistency 
with Merck 
template 
specifications 
that are stated 
in section 4.4
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Study table(Pre-surgery 
and surgery) Section 5.1
Screening MRI window was 14 
days.
.
Added language to footnote 4 
stating that screening MRI 
window can be up to 21 days 
prior to registration.
The window 
has been 
increased by 
the PI so that 
previously 
done MRIs 
can be used.
Section 5.1 and 5.2
Pre-surgery and Post- 
Surgery/Adjuvant Therapy 
tables.
Footnote 1: instruction 
regarding vital sign 
monitoring
“On treatment days, vital signs 
will be measured within an hour 
prior to start of study drug 
administration.”
“For subsequent doses,  1-hour 
observation period will not be 
required unless a subject 
experiences an infusion-related 
reaction.”
Respiratory rate included as part 
of vitals in both tables.
Footnote 1 in 5.1. Modified to 
indicate that pre and post
vitals will be done for the first 
dose.
Footnote 1 in 5.2 modified to 
indicate that for subsequent 
doses, the post dose 30 and 60 
minute vitals and 1-hour 
observation period will be
done only if there is an 
infusion related reaction.
Removed respiratory rate from 
vitals in both tables
For clarity 
and 
convenience.
Section 7.3
Adverse Event Reporting
Inconsistency regarding AE 
reporting period wherein 30 
days and 60 days are stated in 
two different sub-sections
AE reporting period stated to 
be 60 days
Correction to 
improve 
clarity and 
consistency
Section 8.1.10
List of side effects of
MED14736
Added language:
Please refer to current IB for 
more details and a complete 
list of side-effects.
To 
accommodate 
any future IB 
updates.
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Section 5.1 and 5.2(study 
procedures table) & 
Section 9.0
Correlative/Special studies
Research blood: 5 ml in EDTA
tube and 5 ml in red top tube.
Updated to
a)
10ml  blood  in  one
10ml Sodium heparin 
tube:  To be collected 
and processed by the 
Bloch 
lab 
for 
peripheral 
blood 
lymphocytes (PBLs).
b)   8m (2x4ml) blood in 
two 5ml EDTA 
(purple top) tubes: To 
be collected and 
processed by the 
Wainwright lab for 
gene expression 
profile using 
mononuclear cells.
c)
10ml  blood  in  one
10ml red top tube: To 
be 
collected 
 
and 
processed    by     the
Per updates 
from Dr.Bloch 
and 
Dr.Wainwrigh
t
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Wainwright 
lab 
for 
analysis of tryptophan 
catabolites 
and 
cytokines.
Samples to be collected: At 1st 
pre-operative treatment, day of 
surgery, C1D1 and at each 
adjuvant 
treatment 
imaging 
visits (i.e. every 2 cycles or 8 
weeks).
Also
added:   Details   about 
archival tissue use for PD-L1 
analysis(consistent
with 
laboratory manual language).
Language
added
to
make
‘fresh’  and  ‘archival’  tissue 
sections distinct.
Section 9.0 updated with 
similar language .
All information made 
consistent with the current 
laboratory manual .
Sentence inserted in protocol 
“Please refer and laboratory 
manual for more details”. 
The ‘X’s in the tables have 
been updated accordingly.
Pager number for  Dr.Bloch’s 
lab added in section 9.0
Section 7.2.4.6
Adverse Event of special
Interest
Spelling error ‘Entercolitis’
Corrected to ‘Enterocolitis’
Correction of 
typographical 
error
Section 7.3.3.4
Reporting to AstraZeneca
AstraZeneca’s designated 
mailbox: 
AEMailboxLPTCSnaP@astraze 
neca.com
Updated to : 
AEMailboxClinicalTrialTCS
@astrazeneca.com
Per 
information 
received from 
AstraZeneca
Section 8.1.10 
side effects of 
MED14736
Listing of  main side-effects
Added language “Please refer 
to current IB for more details 
and a complete list of side- 
effects.”
To 
accommodate 
for any 
updates to the 
IB and list of 
side effects.
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Amendment 4
5.19.17 ( 10.20.17 with additional changes after initial SRC approval)
Section(s) Affected
Prior Version
Amendment 4 changes
Rationale
Protocol page
Dr.Jeffrey Raizer as PI
and IND holder
Removed Dr.Raizer as PI 
and added Dr.Orin Bloch 
as PI and IND holder 
Dr.Raizer is included as 
one of the sub- 
investigators
Added Karan Dixit, MD
as Sub-Investigator
Dr.Raizer has handed 
over the study to 
Dr.Bloch due to COI 
issues
Study summary
Primary and secondary 
objectives stated
Objectives reworded to be 
consistent with the rest of 
the protocol
For consistency
Section 2.1
and Section 6.1
Blood samples will be 
used for assessment
Both blood and tissue 
samples will be used for 
assessment. Language in 
both sections updated for 
consistency
Per PI, for flexibility
Section 2.2.1, 2.2.2, 2.2.3,
2.2.4
Secondary objectives 
stated
Secondary objectives 
reworded to be consistent 
with section 6
For consistency
Section 3.1.3
Inclusion criteria
“Patients must be > 12 
weeks from completion of 
radiation therapy unless 
there is tissue
confirmation of tumor 
recurrence or there is 
progression outside the 
radiation treatment field.”
It has been converted into 
an exclusion criteria
3.2.5 and the timepoint of 
former treatment
exposure is to the start of 
study drug and not to 
registration.
For clarity and 
convenience
Section 3.1. 6(now 3.1.5) 
Inclusion criteria
Had contact information 
of PI, Dr.Raizer
Replaced with Dr.Orin 
Bloch with his contact 
information
Orin Bloch, MD is the 
new PI, as stated above
Section 3.1.7
Specifications for patients 
on some drugs to be 
included in the
14 
study.
Has been converted to 
exclusion criteria 3.2 .6
All other footnotes re- 
numbered to match the 
changes.
For clarity
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Section 3.1.12 (now
3.1.10) inclusion criteria
The baseline blood tests 
for organ and bone 
marrow function were
required to be done within
7 days of registration
The window has 
been extended to 14 
days. A note has 
been added: “The 
CBC and 
chemistries will be 
repeated within 72 
hours of 1st dose of 
study treatment if 
baseline tests were 
more than 7 days 
prior to dosing.”
For convenience
Section 3.2.15
Exclusion criteria
Patients with a history of 
active malignancy within
3 years prior to 
registration. Note: 
exceptions to this 
requirement include 
adequately treated non- 
melanoma skin cancer or 
lentigo maligna or 
carcinoma in situ without 
evidence of disease
Added  prostate cancer to 
this list of exceptions: 
“prostate cancers with a 
Gleason score < 8 and 
with prostatectomy and
no lymph node 
involvement.”
For ease of enrollment
Section 4.4
Events requiring dose 
modifications
List of events requiring 
dose modifications 
anytime during the study.
Removed this section
Conflicts with 
information provided in 
section 4.5, which also 
lists dose 
delays/modifications.
Footnote 9 has list of 
serum chemistries which 
included magnesium and 
phosphorus
Removed magnesium and 
phosphorus from this list 
and inserted them in a 
separate row in the table.
Section 5.1 Study 
procedures table for pre- 
surgery and surgery
Informed consent was to 
be obtained within 14 
days of registration
Informed consent to be 
obtained within 28 days
of registration. Footnote 2 
and 3 updated to reflect 
this.(Footnote 3 was 
earlier related to MRI but 
is now redundant. So this 
was deleted and updated 
with information
regarding ICF).
For clarity and 
convenience, since 
magnesium and 
phosphorus are not part 
of the routine serum 
chemistry.
For convenience.
Section 6.2
Secondary endpoints
Secondary endpoints 
stated
Language added to state 
evaluable subjects for 
each endpoint. Also, 
language updated to be 
consistent with section 2
For clarity and 
consistency
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Section 7.3.1 
and 7.3.2
AEs and SAEs will be 
recorded from time of 
signature of ICF, 
throughout the treatment 
period and including the 
follow-up period (60 days 
after the last dose of 
Durvalumab or 
Tremelimumab or 
combination of both).
Changed the window 
from 60 to 90 days.
Expedited reporting 
would include all events 
that occur within 90 days 
of the last dose of 
protocol treatment
Correction of error. To 
maintain consistency with 
the rest of the protocol.
Section 8.1.10
Side effects of
Durvalumab
List of side effects
List updated based on 
updates made to ICF 
based on UPIRSOs
In compliance with 
recommendations made 
by NU  IRB
Amendment 5
3.20.18
Section(s) Affected
Prior Version
Amendment 4 changes
Rationale
Title page
and section 7.3.3.4
Coordinating center was 
stated as Clinical 
Research Office of 
RHLCCC
Updated to “Clinical 
Trials Office” and the 
link to the website has 
been added.
Administrative.
List of abbreviations 
and section 7.3
DSMB was listed as one 
of the abbreviations
Replaced by DSMC-Data 
and Safety Monitoring 
Committee
Administrative.
Throughout
A total of 30 subjects will 
be needed for this trial. 
The accrual cap was 36 
patients and total accrual 
per arm will was 12
The accrual cap has been 
increased to 45 patients 
with each arm enrolling
15 patients in order to 
obtain 30 evaluable 
patients (10 in each arm) 
for immunologic 
response.
Per DSMC approval, in 
order to help the study 
obtain its primary 
objective.
Study summary and
Section 6.
Stated as one of the 
secondary objectives: 
“To correlate T-cell 
changes and PDL1 
expression with patient 
outcomes.”
This objective has been 
moved to Exploratory 
Objective
For consistency with
Section 2. 
Correction of error.
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Section 3.0
Patient eligibility
PI was listed as Dr.Jeffrey
Raizer.
PI name updated to 
Dr.Orin Bloch with 
contact information.
The new PI information 
was not updated earlier in 
this section, in error.
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A total of 30 subjects will 
be needed for this trial. 
The accrual cap is 36 
patients, in order to cover 
those patients that do not 
make it to surgery.
Language modified to 
“A total of 30 evaluable 
subjects will be needed 
for this trial. The accrual
cap is 45 patients, in order 
to cover those patients
that do not make it to the 
first evaluable time 
point.”
To be in alignment with 
changes made to the rest 
of the protocol.
Section 3.2.7
Exclusion criteria
Acceptable range of 
steroid was stated as 4-
10mg.
Modified the range to 4-
8mg.
(For safety, the steroid 
dose should remain at no 
more than 8mg daily at 
enrollment with a goal of
4mg or less).
For safety and to be in 
alignment with inclusion 
criteria 3.1.9.
Section 3.2.14
Exclusion criteria
Uncontrolled 
hypertension defined as
150/90mmHg
Removed the specific 
defining level of 
hypertension 
(150/90mmHg). The 
treating physician will 
decide if the patient has 
uncontrolled 
hypertension.
For flexibility
Section 4.2
Treatment administration 
summary table
Arm 3
Tremelimumab
+MEDI4736 combination 
therapy. Only post- 
surgery doses were stated.
The footnote with “**” 
was not assigned to 
anything specific in the 
table.
Added the first 
combination dose within
14d (+/-3 days) pre- 
surgery. The rest 
specified as post-surgery 
doses.
The footnote with 
“**”has been assigned to 
the Supportive treatment 
column.
For increased clarity and 
completeness.
Section 4.4
Toxicity 
management/dose delay 
and modifications
Previous table
Replaced by new table: 
Dosing Modification and 
Toxicity Management 
Guidelines for Immune- 
Mediated, Infusion- 
Related, and
Non-Immune–Mediated
Reactions (MEDI4736
Monotherapy or 
Combination Therapy 
With Tremelimumab or 
Tremelimumab 
Monotherapy) 1
November 2017 Version
Updated table with latest 
toxicity management 
guidelines sent by 
Astrazenaca
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Section 5.1
Study procedures for Pre- 
surgery and surgery
The first column heading 
was blank
The heading of 
“Assessment/Activity” 
has been inserted.
For increased clarity and 
completeness.
Section 5.2
Study procedures table for 
Post-Surgery/Adjuvant 
Therapy
CBC and differential was 
required to be done 
weekly while on adjuvant 
treatment.
CBC and differential is 
now required to be done 
every other week while 
on adjuvant treatment.
For convenience, and to 
avoid unnecessary testing 
on patients.
Section 6.1
Primary Endpoint
Evaluable patient for 
primary endpoint defined 
as
“Only patients who have 
undergone surgery will be 
evaluable for this 
endpoint.”
Reworded as
“Only patients who have 
had pre-treatment blood 
sampling, have undergone 
surgery with pre-surgical 
blood sampling, and are 
able to continue to post- 
operative drug treatment 
with blood sampling prior 
to the first post-surgical 
dose will be evaluable for 
this endpoint.”
For increased clarity.
Section 6.4
Table showing
comparison of RANO and 
iRANO criteria
Malignant glioma and 
low-grade glioma were 
listed together under one 
column heading.
Low grade glioma has 
been deleted and is paced 
correctly in the next 
column.
Correction of error
Throughout
Previous information
Some minor 
administrative updates 
have been made and 
references to sections and 
appendices have been 
corrected.
For clarity and 
consistency.
Section 10.3 and Study
Summary
Previous statistical 
language.
Timepoints were stated as 
“Immunologic measures 
will be summarized over 
the three or more time 
points (pre-treatment, 
treatment, post- 
treatment).”
Language has been 
updated to align with the 
new accrual numbers as 
stated above.
The time points have 
been reworded as 
“Immunologic measures 
will be summarized over 
the three or more time 
points (pre-treatment, 
following first 
treatment/pre-surgery, 
post-surgery.” for better 
clarity.
For consistency and 
accuracy.
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Section 11
Previous language
Janssen Scientific Affairs 
was listed as funding 
sponsor
Language updated to 
align with current CTO 
template and policy.
Updated to
AstraZeneca/MedImmune
Administrative. 
Correction of error.
Appendix B
Effective methods of 
contraception
Previous list
List has been updated and 
formatted.
For clarity.
Amendment 6
8.29.18
Section(s) Affected
Prior Version
Amendment 4 changes
Rationale
Title page 
Dr.Orin Bloch is 
listed as the 
Principal 
Investigator
PI name updated to 
Dr.Karan Dixit with 
contact information.
Dr Orin Bloch is leaving 
Northwestern University 
and  has handed over the 
study to Dr.Karan Dixit as 
the new Principal 
Investigator.
Section 4.4
Toxicity management and 
Dose delays/Modifications
Previous table
(version November 
2017)
CTCAE v.4.03
Updated:

Management of 
immune-
mediated 
hepatitis

Regarding 
Cardiac toxicities
the major 
modification is: 
drug is to be 
discontinued 
permanently 
upon diagnosis, 
regardless of 
biopsy as 
opposed to 
previous 
requirement of 
proof of biopsy.
Based on Durvalumab 
Action letter dated 
8.6.18.
(Note: The modifications 
align with the CTCAEv5.0
as stated in the action letter]
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