Conditions: Glioblastoma
Keywords: Glioblastoma Immunotherapy T Cell PD-L1 MEDI4736 Radiation Radiotherapy GBM
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: no

Brief summary:
This is an ongoing Phase 2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with glioblastoma (GBM) enrolled into 5 non-comparative cohorts. Primary study objectives, which vary by cohort due to differences in subject populations, include evaluation of the clinical efficacy as measured by the overall survival (OS) rate at 12 months (Cohort A), progression-free survival (PFS) at 6 months (Cohorts B, B2, and B3), and OS at 6 months (Cohort C). For all cohorts, secondary objectives include evaluation of the safety/tolerability and clinical efficacy of study treatment, and exploratory objectives include evaluation of the neurologic function and correlative biomarkers.

Detailed description:
Eligible subjects are enrolled in parallel into one of the following 5 cohorts as described below. In each cohort, the first study drug administration for the first subject and the second subject are separated by at least 1 week.

* Cohort A: Subjects with newly diagnosed unmethylated O\^6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) GBM receive durvalumab (10 mg/kg every 2 weeks \[Q2W\]) + standard radiotherapy. The first 6 subjects are evaluated for dose-limiting toxicity (DLT) for 10 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg.
* Cohort B: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy.
* Cohort B2: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W).
* Cohort B3: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W).
* Cohort C: Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). The first 6 subjects are evaluated for DLTs for 6 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg.

The Core Study lasts for up to 12 months; optional extension treatment may be offered to subjects who complete 51 weeks of treatment on the Core Study with stable disease or better and upon agreement between the subject, Investigator, and Sponsor.

Subjects are followed on study for 90 days after the last drug administration and off study every 6 months for 3 years from the date of the first dose of study treatment.

The primary study endpoints have been met, although some subjects remain in treatment and/or follow-up and data collection is ongoing.

Arms:
arm 1: Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy. arm 2: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy. arm 3: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W). arm 4: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). arm 5: Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W).

Interventions: intervention 1: Durvalumab intervention 2: Standard radiotherapy intervention 3: Bevacizumab
Intervention descriptions: intervention 1: Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W. intervention 2: Focal radiotherapy is administered at 2 Gy given daily 5 days per week for a total of 60 Gy over 30 fractions per local institutional guidelines or local prescribing information. On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab. intervention 3: Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.

Protocol document:
Prot_SAP_000.pdf: 
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Study Protocol 
LUD2013-006 
US-IND# 118511 
Amendment 5 
Final 
14-APR-2017 
 
Protocol Title 
Phase 2 study to Evaluate the Clinical Efficacy and Safety of MEDI4736 in Patients with 
Glioblastoma (GBM) 
 
Objectives and Synopsis 
This is an open-label, non-randomized, multicenter Phase 2 study of MEDI4736 with three 
non-comparative cohorts:  
Cohort A:  37 Subjects with newly diagnosed unmethylated MGMT GBM will receive 
MEDI4736 every 2 weeks (Q2W) for up to 12 months in combination with standard 
radiotherapy.  The cohort will be started on 10 mg/kg intravenous (IV), which was the current 
recommended Phase 2 dose (RP2D) based on previous Phase 1 monotherapy data.  Since 
there are no safety data available for this combination, the first 6 subjects will be evaluated 
for DLTs for 10 weeks to determine if the dose for this cohort should be lowered to 3 mg/kg 
or 1 mg/kg, which may add up to 12 subjects, for a total of 49 subjects.  The Primary 
Objective is to evaluate the clinical efficacy as measured by the Overall Survival (OS) rate at 
12 months. 
Cohort B:  30 bevacizumab-naïve subjects with recurrent GBM receive MEDI4736 Q2W for up 
to 12 months as monotherapy at 10 mg/kg IV infusion, which is the current RP2D based on 
previous Phase 1 monotherapy data.  The Primary Objective is to evaluate the clinical efficacy 
as measured by progression-free survival rate at six months (PFS-6). 
Per Protocol Amendment 2, two additional cohorts will be added to the study.  The 2 
additional cohorts will have the same study population criteria as Cohort B but will receive 
the following treatments: 
• 
Cohort B2 (n=32): MEDI4736 (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W) 
• 
Cohort B3 (n=32): MEDI4736 (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). 
Cohort C:  17 bevacizumab-refractory subjects with recurrent GBM receive MEDI4736 Q2W 
for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W.  
MEDI4736 will be administered prior to bevacizumab and start at 10 mg/kg IV, the current 
RP2D based on previous Phase 1 monotherapy data.  Since there is no safety data for this 
combination, the first 6 subjects will be evaluated for DLTs for 6 weeks to determine if the 
MEDI4736 dose for this cohort should be lowered to 3 mg/kg or 1 mg/kg, which may add up 
to 12 subjects, for a total of 29 subjects.  The Primary Objective is to evaluate the clinical 
efficacy as measured by the Overall Survival (OS) rate at 6 months (OS-6). 
In all Cohorts, the Secondary Objectives are the evaluation of safety/tolerability and clinical 
efficacy as measured by median progression-free survival, median overall survival and 
radiographic response, and quality of life (QoL) by the European Organization for Research 
and Treatment of Cancer quality of life questionnaire with a brain cancer module (EORTC 
QLQ-C30/BN20).  The Exploratory Objectives are the evaluation of subject neurologic 
function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as the 
correlative biomarkers. 


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Per Amendment 3, optional treatment extension beyond the 1-year study (Core Study) is 
available for subjects who complete 51 weeks of treatment on Core Study with Stable Disease 
or better; the optional treatment extension will be permitted upon agreement with subject, 
Sponsor and Investigator.  See Appendix 8.8 for details. 
Per Amendment 4, the collection of samples for MEDI4736 PK, ADA, sPD-L1, and circulating 
soluble factors was removed.  
 
Sponsor:  Ludwig Institute for Cancer 
Research, Ltd.  
Study Chair:  David A. Reardon, MD; 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
Sponsor Representative Signature & Date 
 
 
 
 
 
 
 
 
 
Study Chair Signature & Date 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s).  The information cannot be used, or divulged to any third party or published without the written consent of the 
Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom 
study medication may be administered.  Any misappropriation of this information is prohibited by law. 
 
 


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Table of Contents 
1 
Background.............................................................................................................................. 7 
1.1 
Glioblastoma .................................................................................................................... 7 
1.1.1 
Unmethylated MGMT Glioblastoma ........................................................................ 7 
1.2 
PD-1 and PD-L1 ................................................................................................................ 7 
1.3 
MEDI4736 ......................................................................................................................... 8 
1.3.1 
Summary of MEDI4736 Nonclinical Experience ....................................................... 9 
1.3.2 
Summary of MEDI4736 Clinical Experience ............................................................. 9 
1.4 
Temozolomide Chemoradiotherapy for Newly Diagnosed GBM................................... 10 
1.5 
Therapy for Recurrent GBM ........................................................................................... 11 
2 
Study Rationale ..................................................................................................................... 14 
2.1 
Rationale for Amendment 2........................................................................................... 15 
3 
Experimental Plan ................................................................................................................. 18 
3.1 
Study Design ................................................................................................................... 18 
3.1.1 
Study Phase ............................................................................................................ 18 
3.1.2 
Enrollment/Randomization .................................................................................... 18 
3.1.3 
Blinding/Unblinding ............................................................................................... 18 
3.1.4 
Subject Population ................................................................................................. 18 
3.1.5 
Number of Sites/Subjects ...................................................................................... 18 
3.1.6 
Sample Size Considerations ................................................................................... 19 
3.1.6.1 
Cohort A ......................................................................................................... 19 
3.1.6.2 
Cohort B ......................................................................................................... 19 
3.1.6.3 
Cohort C ......................................................................................................... 20 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 20 
3.1.8 
Dosing Adjustments, Delays and Discontinuations ................................................ 22 
3.1.8.1 
Radiotherapy (Cohort A only) ........................................................................ 22 
3.1.8.2 
MEDI4736 (Cohorts A, B, B2, B3 and C) ......................................................... 23 
3.1.8.3 
Bevacizumab (Cohorts B2, B3 and C) ............................................................. 23 
3.1.9 
DLT and MTD .......................................................................................................... 23 
3.1.10 
Subject Withdrawal from Treatment or from Study .............................................. 24 
3.1.11 
Subject Evaluability and Replacement ................................................................... 25 
3.1.12 
Optional Study Treatment Extension ..................................................................... 26 
3.1.13 
Interim Analysis ...................................................................................................... 26 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 26 
3.1.15 
Duration of Study ................................................................................................... 27 
3.1.16 
On Study and Post Study Follow-up ....................................................................... 27 
3.1.16.1 
End of Study Visit ........................................................................................... 28 
3.2 
Study Flowchart ............................................................................................................. 29 
4 
Study Objectives & Endpoints ............................................................................................... 32 
4.1 
Clinical Efficacy ............................................................................................................... 32 
4.1.1 
Endpoints and Assessment Methods ..................................................................... 32 


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4.1.1.1 
Overall Survival (OS) ....................................................................................... 32 
4.1.1.2 
Overall Radiographic Response Rate (ORR) ................................................... 33 
4.1.1.3 
Progression-free Survival (PFS) ...................................................................... 33 
4.1.2 
Subject Evaluation & Statistics ............................................................................... 33 
4.2 
Safety and Tolerability ................................................................................................... 34 
4.2.1 
Endpoints & Assessment Methods ........................................................................ 34 
4.2.2 
Subject Evaluation & Statistics ............................................................................... 34 
4.3 
Health Related Quality of Life ........................................................................................ 34 
4.3.1 
Endpoints & Assessment Methods ........................................................................ 34 
4.3.2 
Subject Evaluation & Statistics ............................................................................... 34 
4.4 
Neurologic Function ....................................................................................................... 35 
4.4.1 
Endpoint and Assessment Method ........................................................................ 35 
4.4.2 
Subject Evaluation and Statistics ........................................................................... 35 
4.5 
Biological activity of MEDI4736 ..................................................................................... 35 
4.5.1 
Endpoints & Assessment Methods ........................................................................ 36 
4.5.2 
Subject Evaluation & Statistics ............................................................................... 36 
4.6 
Exploratory Review and Analysis of Radiological Scans and Data ................................. 36 
4.7 
Exploratory Analysis of Mutational Load ....................................................................... 36 
5 
Subject Eligibility ................................................................................................................... 37 
5.1 
Inclusion Criteria ............................................................................................................ 37 
5.2 
Exclusion Criteria ............................................................................................................ 39 
5.3 
Restrictions on Concomitant Therapies ......................................................................... 41 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................. 41 
5.3.2 
Permitted Concomitant Therapies ......................................................................... 41 
5.4 
Special Requirements for Contraception ....................................................................... 42 
6 
Study Drug Preparation and Administration ......................................................................... 44 
6.1 
MEDI4736 (Durvalumab) ............................................................................................... 44 
6.1.1 
Study Drug Information ......................................................................................... 44 
6.1.2 
Investigational Product Inspection ........................................................................ 44 
6.1.3 
Preparation ............................................................................................................ 44 
6.1.4 
Administration ....................................................................................................... 45 
6.1.4.1 
MEDI4736 Administration .............................................................................. 45 
6.1.4.2 
Cohort A and Cohorts B2, B3 and C Administration ...................................... 46 
6.1.5 
Monitoring of MEDI4736 Dose Administration ..................................................... 46 
6.2 
Estimated Study Requirements...................................................................................... 47 
6.3 
Drug Overdose Management ......................................................................................... 47 
7 
Administrative, Legal & Ethical Requirements ...................................................................... 48 
7.1 
Documentation and Reporting of Adverse Events......................................................... 48 
7.1.1 
Definitions .............................................................................................................. 48 
7.1.2 
Additional Expedited Reporting Requirements for this Study ............................... 49 
7.1.2.1 
Pregnancy ....................................................................................................... 49 
7.1.2.2 
Overdose ........................................................................................................ 50 
7.1.2.3 
Hepatic Function Abnormality ....................................................................... 50 


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7.1.3 
Severity of an Adverse Event ................................................................................. 50 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 50 
7.1.5 
General Reporting Requirements .......................................................................... 51 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ......................... 51 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 52 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................. 52 
7.2 
Administrative Sponsor Requirements .......................................................................... 54 
7.2.1 
Pre-Study Requirements ........................................................................................ 54 
7.2.2 
Study Master Files .................................................................................................. 55 
7.2.3 
Case Report Form Data Collection ......................................................................... 55 
7.2.4 
Language ................................................................................................................ 55 
7.2.5 
Monitoring ............................................................................................................. 55 
7.2.6 
Protocol Amendments ........................................................................................... 56 
7.2.7 
Premature Subject Withdrawal ............................................................................. 56 
7.2.8 
Early Trial Termination ........................................................................................... 56 
7.2.9 
Study Drug Shipments & Accountability ................................................................ 56 
7.3 
Regulatory, Legal & Ethical Requirements ..................................................................... 57 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations .............................................. 57 
7.3.2 
Informed Consent .................................................................................................. 57 
7.3.3 
Institutional Review Board ..................................................................................... 57 
7.3.4 
Subject Confidentiality ........................................................................................... 58 
7.3.5 
Inclusion of Women and Minorities....................................................................... 58 
8 
Appendices ............................................................................................................................ 59 
8.1 
Protocol Version History ................................................................................................ 59 
8.2 
Participating Study Sites, Investigators, Staff and Laboratories .................................... 72 
8.3 
Sponsor Information ...................................................................................................... 73 
8.4 
Tumor Response by Modified RANO ............................................................................. 74 
8.4.1 
Evaluable for Objective Response .......................................................................... 74 
8.4.2 
Measurable disease ............................................................................................... 74 
8.4.3 
Non-measurable Evaluable Disease ....................................................................... 74 
8.4.4 
Response/Progression Categories ......................................................................... 74 
8.4.5 
Progressive Disease: Assessment Based on Contrast Enhancing Tumor 
Measurement ........................................................................................................................ 76 
8.4.6 
Study Continuation Beyond Initial Progressive Disease ........................................ 76 
8.4.6.1 
Modified RANO Response Criteria to Assess Response ................................. 77 
8.4.7 
Methods for Evaluation of Measurable Disease .................................................... 77 
8.4.8 
Evaluation of Best Response .................................................................................. 77 
8.5 
Neurologic Function and Health Related Quality of Life Questionnaires ...................... 78 
8.5.1 
Neurologic Function in Neuro-Oncology (NANO) Scale ......................................... 79 
8.5.2 
Health Related Quality of Life Questionnaire EORTC QLQ - C30 ........................... 81 
8.5.3 
Health Related Quality of Life Questionnaire EORTC QLQ - BN20 ......................... 83 
8.6 
MEDI4736 Toxicity Management and Dose Adjustments ............................................. 84 
8.6.1 
Dose Modifications Due to Toxicity of MEDI4736 ................................................. 84 


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8.6.1.1 
Immune-related Adverse Events (irAEs) ........................................................ 85 
8.6.1.2 
Infusion-related Reactions ............................................................................. 86 
8.6.1.3 
All other Adverse Events ................................................................................ 86 
8.6.1.4 
Cerebral Edema .............................................................................................. 87 
8.6.2 
MEDI4736 Dose Modification Not Due to Treatment-related Toxicities .............. 87 
8.7 
Laboratory procedures................................................................................................... 88 
8.7.1 
MEDI4736 Pharmacokinetics and Immunogenicity for Anti-drug antibodies (ADA) .  
 
................................................................................................................................ 88 
8.7.2 
sPD-L1..................................................................................................................... 88 
8.7.3 
Flow Cytometry ...................................................................................................... 88 
8.7.4 
PBMC Banking ........................................................................................................ 88 
8.7.5 
Circulating soluble factors ...................................................................................... 89 
8.7.6 
Myeloid derived suppressor cells (MDSC) ............................................................. 89 
8.7.7 
Archival Tumor Samples and Tumor Biopsies ........................................................ 89 
8.7.7.1 
Archival Tumor Samples ................................................................................. 89 
8.7.7.2 
Tumor Biopsies ............................................................................................... 89 
8.7.8 
Additional Translational and Exploratory Studies .................................................. 90 
8.7.9 
Exploratory Review and Analysis of Radiological Scans and Data ......................... 90 
8.7.10 
Exploratory Analysis of Mutational Load ............................................................... 90 
8.8 
Additional Details for Subjects who Continue Treatment after 1-Year Core Study....... 91 
8.8.1 
Preparation of Fixed Dose of 1500 mg for MEDI4736 ........................................... 91 
8.8.2 
Study Flowchart for Subjects who Continue Study Treatment after 1-Year Core 
Study 
................................................................................................................................ 93 
8.9 
List of Abbreviations ...................................................................................................... 94 
9 
References ............................................................................................................................. 97 
 
 


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1 Background 
1.1 Glioblastoma 
Glioblastoma (GBM), the most common primary malignant CNS tumor, remains a major unmet 
oncologic need.  Current standard therapy including aggressive surgery, brain irradiation and 
temozolomide chemotherapy, yields a 15-month median overall survival while exposing patients 
to significant potential neurologic morbidity and detrimental impact on quality of life.(1)  
Following progression, no therapy has been identified that durably prolongs survival.  Clinical 
studies evaluating targeted molecular inhibitors have consistently yielded disappointing results 
(2) while bevacizumab, a monoclonal antibody targeting VEGF, improves progression-free 
survival and radiographic response rate, but has not been shown to meaningfully improve 
survival. (3, 4)  Furthermore, all patients ultimately progress on bevacizumab, and then typically 
succumb to progressive disease within a few months.  No therapeutic approach has had any 
impact on outcome for bevacizumab-resistant, glioblastoma patients (5) although bevacizumab 
continuation beyond initial progression appears to be associated with minimal benefit.(6)  
Innovative treatment strategies that improve outcome while preserving neurologic integrity for 
glioblastoma patients are desperately needed.  
1.1.1 Unmethylated MGMT Glioblastoma 
Approximately 2/3 of GBM patients have tumors that express significant levels of methylguanine 
methyltransferase (MGMT) due to lack of methylation of the promoter.(7)  MGMT is a 
ubiquitous DNA repair enzyme whose expression is enhanced in some cancers, including the 
majority of GBM patients.  These patients have been shown to derive minimal benefit from the 
addition of temozolomide to standard radiation therapy.  Specifically in a Phase 3 study, subjects 
with unmethylated MGMT tumors who received radiation alone had median progression-free 
and overall survivals of 4.4 months and 11.8 months compared to 5.3 months and 12.7 months 
for those who received temozolomide and radiation.(8)  The addition of temozolomide 
increased both PFS and OS for these subjects by less than one month, and was also associated 
with more adverse events including neutropenia, thrombocytopenia and infections.  
Nonetheless, unmethylated MGMT GBM patients are routinely offered standard of care 
treatment with temozolomide due to lack of more effective treatment options, and because 
their outcome is otherwise so poor.  There is a clear need to develop new treatment approaches 
for unmethylated MGMT GBM patients. 
1.2 PD-1 and PD-L1 
Programmed Death-1 (PD-1, CD279) is a member of the immunoglobulin superfamily (IGSF) of 
molecules involved in regulation of T cell activation.  PD-1 acquired its name ‘programmed 
death’ when it was identified in 1992 as a gene upregulated in T cell hybridoma undergoing cell 
death.(9)  The structure of PD-1 is composed of one IGSF domain, a transmembrane domain, 
and an intracellular domain containing an immunoreceptor tyrosine-based inhibitory motif 
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).(10-12)  PD-1 has two binding 
partners: PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), distant relatives of the B7-1 and B7-2 
molecules.  PD-L1, discovered in 1999, is expressed quite broadly, on both hematopoietic and 
non-hematopoietic lineages.(13-15)  It is found on T cells, B cells, macrophages, NK cells, DCs, 
and mast cells.(16)  It has also been described on peripheral tissues including cardiac 


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endothelium, lung, small intestine, keratinocytes, islet cells of the pancreas, and 
syncytiotrophoblasts in the placenta as well as a variety of tumor cell types including GBM.(15-
32)  PD-L1 is constitutively expressed on many hematopoietic cells, but may be upregulated in 
hematopoietic and non-hematopoietic cells.(33)  Regulation of PD-L1 is mediated, in part, by 
type I and type II interferons.  PD-L2 was identified in 2001.(34, 35)  Its expression is far more 
restricted and is confined to hematopoietic cells.(36) 
Engagement of PD-1 on T cells inhibits activation with downstream effects on cytokine 
production, proliferation, cell survival, and transcription factors associated with effector T cell 
function.(13, 37-41)  Inhibitory signaling by PD-1 is thought to depend upon the cytosolic ITSM 
domain, which associates with phosphatases SHP-1 and SHP-2.(42, 43)  While CTLA-4 and PD-1 
are both inhibitory receptors, they fulfill distinct roles and mediate their effects through distinct 
mechanisms.(44)  For example, PD-1 inhibits activation of the serine threonine kinase Akt via its 
effect on the phosphoinositide 3-kinase (PI3K) pathway, whereas CTLA-4 inhibits Akt in a PI3K 
independent manner.(38, 42, 45)  Studies of PD-1 -/- knockout and PD-L -/- knockout mice 
support a unique role for PD-1: PD-L interaction in mediating peripheral tolerance and 
preventing autoimmunity.(28)  The phenotype of the PD-1-/- knockout mouse depends upon the 
genetic background, but manifestations of spontaneous autoimmunity have been reported, 
including dilated cardiomyopathy and glomerulonephritis.(46, 47) 
Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, has demonstrated promising anti-
tumor activity among some advanced solid tumor cancer subjects (6, 48, 49) and growing data 
implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in 
glioblastoma.  PD-1 is expressed by many glioblastoma infiltrating lymphocytes (29) while PD-L1 
is expressed by 61-100% of glioblastoma tumors.(17, 19, 20, 23)  PD-L1 expression in a formalin-
fixed, paraffin-embedded tissue microarray of 83 glioblastoma tumors revealed that 85% 
express PD-L1 in over 80% of the tumor cells (D. Reardon, M.D., personal communication).  
Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, 
leads to increased transcription and expression of PD-L1 in glioblastoma.(23)  Inhibition of PD-1 
in an immunocompetent, orthotopic preclinical GBM model was recently demonstrated to 
improve survival when administered with radiotherapy.(50)  Additional preclinical experiments 
involving an immunocompetent, orthotopic murine glioblastoma model revealed that 25% of 
animals treated with a murine anti-PD-L1 monoclonal antibody remained alive for over 140 days 
with no evidence of tumor (control mice uniformly died within 30 days) (D. Reardon, M.D., 
unpublished data).  These aggregate findings indicate that PD-1/PD-L1 is an attractive and 
important therapeutic target in glioblastoma. 
1.3 MEDI4736 
MEDI4736 is briefly described in this section.  Refer to the current Investigator’s Brochure for 
complete and current information. 
MEDI4736 is a human immunoglobulin G1 kappa monoclonal antibody (MAb) directed against 
human PD-L1.  MEDI4736 has an overall molecular weight of approximately 149 kDa, including 
N-linked oligosaccharides.  The antibody is composed of 2 identical heavy chains of 
approximately 49,670 Da each, and 2 identical light chains of approximately 23,390 Da each.  
The fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant 
domain of the IgG1 heavy chain that reduces binding to the complement component C1q and 


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the Fcm receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity 
(ADCC). (51)  Subsequent to this triple mutation, the anticipated lack of MEDI4736-mediated 
ADCC and complement dependent cytotoxicity were confirmed using cell based functional 
assays.  MEDI4736 is selective for recombinant PD-L1 and blocks the binding of recombinant PD-
L1 to the PD-1 and cluster of differentiation (CD) 80 receptors. 
1.3.1 Summary of MEDI4736 Nonclinical Experience 
Nonclinical data with MEDI4736 suggest that targeting PD-L1 with a biologic agent could be an 
effective antitumor therapy.  MEDI4736 is a human monoclonal antibody that selectively binds 
human PD-L1 with high affinity and blocks its ability to bind to PD-1 and CD80.  PD-L1 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 by delivering 
inhibitory signals to T cells through the PD-1 and CD80 receptors.  Blockade of PD-L1 with 
MEDI4736 relieved PD-L1-mediated suppression of human T-cell activation in vitro.  In a 
xenograft model, MEDI4736 inhibited human tumor growth via a 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. 
1.3.2 Summary of MEDI4736 Clinical Experience 
The first-time-in-human (FTIH) trial, study CD-ON-MEDI4736-1108 (NCT01693562), currently 
being conducted by MedImmune, is a multicenter, open-label study to evaluate the safety, 
tolerability, and pharmacokinetics of MEDI4736 in subjects with advanced solid tumors.  The 
study includes a standard 3+3 dose-escalation phase followed by an expansion phase in 
melanoma, CRC, and NSCLC.  Dose escalation began enrollment at 0.1 mg/kg administered by 
intravenous infusion every 2 weeks.  Escalation continued at dose levels of 0.3, 1, 3, and 10 
mg/kg or until a maximum tolerated dose (MTD) or optimal biologic dose (OBD) was 
determined.  Once an MTD or OBD was determined, subjects were enrolled in each expansion 
cohort to further evaluate the safety and preliminary antitumor activity of MEDI4736.  
According to the Investigator’s Brochure (Edition 6.0, Issue date: 28Mar2014), a total of 
198 subjects have been treated with at least one dose of MEDI4736 (ranging from 1 to 27 doses) 
in study CD-ON-MEDI4736-1108.  Twenty-one subjects have been enrolled in the following 
dose-escalation cohorts: 4 subjects in each of the 0.1, 0.3, and 1 mg/kg every 2 weeks (Q2W) 
cohorts; 3 subjects in the 3 mg/kg Q2W cohort, and 6 subjects in the 15 mg/kg Q3W cohort.  A 
total of 177 subjects have received MEDI4736 10 mg/kg Q2W which has been selected for 
further evaluation in the dose expansion phase and is the current recommended Phase 2 dose 
(RP2D).  This includes subjects receiving 10 mg/kg Q2W from both the dose escalation and dose 
expansion phases.  Among the 177 subjects, the most frequently reported (≥ 10% of subjects) 
treatment-emergent adverse events (TEAEs) regardless of grade or causality were fatigue, 
dyspnea, nausea, constipation, and decreased appetite.  The majority of TEAEs were Grades 1 to 
2 in severity and manageable by the general treatment guidelines as described in the current 
MEDI4736 study protocol and Appendix 8.6.  The Grade 3 or higher TEAEs occurring in 2 or more 
subjects included dyspnea, dehydration, abdominal pain, fatigue, sepsis, increased aspartate 
aminotransferase, increased gamma-glutamyltransferase, hyperbilirubinemia, back pain, 
pulmonary embolism, respiratory failure, hypotension, and “progression of disease” (verbatim 
term).  Treatment-related TEAEs (all grades) occurring in 2 or more subjects were fatigue, 


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nausea, dyspnea, diarrhea, vomiting, pyrexia, myalgia, hypothyroidism, decreased appetite, 
dizziness, cough, pruritus, rash, abdominal pain, increased aspartate aminotransferase, 
arthralgia, asthenia, influenza-like illness, edema peripheral, increased alanine 
aminotransferase, headache, and dry skin.   
The SAEs reported for 3 or more subjects were dyspnea, dehydration, abdominal pain, and 
sepsis.  Four subjects had treatment-related SAEs: arthralgia (1 subject); pleural effusion and 
pneumonitis (both in the same subject); muscular weakness and “rule out cord compression” 
(verbatim term) (both in the same subject); and ataxia (1 subject).  For the entire study 
population, none of the deaths or TEAEs resulting in discontinuation of MEDI4736 were 
considered related to MEDI4736.  No dose-limiting toxicities (DLTs) have been reported.  
Partial efficacy data is also available for this FTIH trial, study CD-ON-MEDI4736-1108 
(NCT01693562).  Tumor assessments were based on Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 guidelines (52) with modifications for subjects in the dose-
expansion phase.  Of the 177 subjects treated with MEDI4736 10 mg/kg Q2W, 77 have had at 
least one post-baseline disease assessment as of 18Feb2014.  Four subjects (5.2%) had a best 
response of PR (unconfirmed).  In addition, 36 subjects (46.8%) had stable disease, 20 subjects 
(26.0%) had confirmed progressive disease (PD), 14 subjects (18.2%) had unconfirmed PD, and 
3 subjects (3.9%) were not evaluable.   
There are 4 additional ongoing clinical studies of MEDI4736 (1 with MEDI4736 as monotherapy 
and 3 as combination therapy), with limited safety data available.  Of the available safety data, 
there have been no DLTs or deaths reported among 8 additional subjects treated with 
MEDI4736 monotherapy.  As of May 13, 2014, safety data from subjects treated with MEDI4736 
and tremelimumab combination include 1 DLT of Grade 3 colitis and 1 death due to myasthenia 
gravis, both with a causal relationship to the treatment combination.  
Updated safety data for MEDI4736 will be made available to the Investigators prior to starting 
this study.  It is expected that the clinical experience with MEDI4736 from other clinical trials will 
increase rapidly and frequently during the course of this study.  Hence, relevant safety data will 
be communicated to the Investigators via IB updates and safety reports, while this section 
(Section 1.3.2) will not, or less frequently, be amended. 
1.4 Temozolomide Chemoradiotherapy for Newly Diagnosed GBM 
Temozolomide (TMZ) is an alkylating agent that induces autophagy, apoptosis and senescence in 
GBM cells.(53)  A meta-analysis of studies evaluating adjuvant nitrosourea therapy for GBM 
several years ago initially demonstrated the benefit of alkylator chemotherapy for GBM as 
reflected by a modest survival benefit among treated subjects (6% to 10% increase in 1-year 
survival). (54, 55)  In a large, randomized Phase 3 study conducted by the European Organization 
for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada 
(NCIC) among newly diagnosed GBM subjects, the role of radiotherapy (RT) alone (60 Gy over 6 
weeks) was compared to RT and concomitant daily temozolomide 75 mg/m2/day, followed by 
adjuvant temozolomide 150 to 200 mg/m2/day for 5 consecutive days out of every 28-day cycle, 
for 6 cycles.  The results of this study demonstrated that the addition of temozolomide 
chemotherapy to radiation therapy prolonged median overall survival from 12.1 to 14.6 months 
for newly-diagnosed GBM subjects.(56)  In addition, the proportion of surviving subjects in the 


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temozolomide group at 2 years was 26.5% compared to only 10.4% among subjects treated with 
RT-alone group.  Longer term follow-up of this study confirmed persistent survival benefit 
associated with temozolomide administration including a median survival of 9.8% at 5 years for 
the temozolomide group, compared to only 1.9% among the RT recipients [hazard ratio 0.6; 95% 
confidence interval: 0.5-0.7; P < .0001].(1)  Based on these results, the addition of temozolomide 
to RT was approved by the US FDA for newly diagnosed GBM patients in 2005.  Although the 
approved dosing for temozolomide specifies up to 6 cycles (28-day cycle) of adjuvant therapy 
following the concomitant phase, standard of care treatment in some regions has evolved to 
include temozolomide treatment for 12 adjuvant cycles or longer. 
In a companion study, an analysis of the methylation status of the O-6-methylguanine-DNA 
methyltransferase (MGMT) gene promoter among tumor specimens from subjects of the 
EORTC/NCIC study were evaluated.  This retrospective analysis confirmed that subjects with a 
methylated MGMT promoter achieved a significantly improved outcome compared to those 
with an unmethylated MGMT promoter.  Specifically, subjects with MGMT methylated tumors 
who received temozolomide had a median survival was 21.7 months and 2-year survival rate of 
46%; in contrast, subjects with unmethylated MGMT tumors who received temozolomide had a 
median survival of 12.7 months and a 2-year survival rate of 13.8%. (8)  Among subjects who 
had an unmethylated MGMT promoter, the addition of temozolomide was associated with a 
nominal 0.8 month increase in median overall survival compared to radiation therapy.(1)  
Importantly, methylation of the MGMT promoter occurs only in 30-45% of newly diagnosed 
GBM patients.(7, 8)  The prognostic value of tumor MGMT promoter methylation status was 
recently confirmed in RTOG 0525, a large prospective study that randomized newly diagnosed 
GBM subjects to standard 5-day adjuvant temozolomide versus dose dense adjuvant 
temozolomide administered for 21 days of each 28 day cycle.  In this study, which required 
prospective determination of tumor MGMT status for eligibility, there was no difference in 
overall survival or progression-free survival between the study arms, but subjects who had a 
methylated MGMT promoter had significantly better outcome.  Specifically, MGMT methylation 
was associated with improved median overall survival (21.2 vs 14.0 months; HR 1.74; p<0.001) 
and median progression-free survival (8.7 vs 5.7 months; HR, 1.63; p<0.001).(57)  
Although temozolomide provides a modest benefit for newly diagnosed glioblastoma subjects, 
its value is particularly limited among subjects with unmethylation of the MGMT tumor 
promoter.  Nonetheless, due to lack of better available therapies, temozolomide with radiation, 
followed by adjuvant temozolomide remains the standard of care for newly diagnosed GBM 
patients, regardless of tumor MGMT promoter status. 
TMZ is marketed by Merck under the name Temodar® Details of clinical studies and the safety 
profile of temozolomide are documented in the Temodar® prescribing information. 
1.5 Therapy for Recurrent GBM 
Progression among newly diagnosed GBM patients treated with current standard therapy is 
essentially inevitable, and the median progression-free survival associated with temozolomide 
chemoradiotherapy is only 5.5 months among those with MGMT unmethylated tumors.(57)  
Conventional chemotherapy for recurrent GBM patients has had limited benefit.  Phase 2 trials 
of temozolomide for recurrent GBM treated initially with radiotherapy alone demonstrate ORR 
rates of only 5%, stable disease in 40% of subjects, and a 6-month PFS rate of approximately 


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21%. (58-60)  Administration of protracted, daily temozolomide schedule has also demonstrated 
poor outcome among subjects who have progressed after standard 5-day temozolomide.(61)  
Other agents such as carmustine, lomustine, carboplatin, etoposide, irinotecan, and 
procarbazine used in chemotherapy combinations produce low response rates and no significant 
survival benefit.(62)  
Significant insight into the molecular pathogenesis of GBM has been achieved in recent 
years,(63-68) and these findings have stimulated significant interest in evaluating therapeutics 
aimed at blocking key mediators of dysregulated cell signaling pathways in clinical trials.(2, 69, 
70)  Nonetheless, despite multiple trials incorporating a wide array of targeted inhibitors, results 
of these efforts have been consistently unsuccessful.(71)  A variety of factors have been 
implicated in the poor response of salvage therapies for recurrent GBM patients, including 
reduced drug delivery as a result of the blood-brain barrier, intrinsic resistance to cytotoxic 
chemotherapy, complex and redundant mechanisms of dysregulated cell signaling, 
heterogeneity within and across tumors, tumor hypoxia, pharmacokinetic interactions with anti-
convulsant therapies that diminish chemotherapy exposure, and a relatively low tumor cell 
growth fraction. 
Glioblastoma is one of the most angiogenic of cancers and the role of angiogenic factors such as 
vascular endothelial growth factor (VEGF) has been well established.(72-74)  Bevacizumab, a 
VEGF inhibitor, has been evaluated as a single agent in subjects with recurrent GBM.  Among 
recurrent GBM subjects, bevacizumab has been associated with durable radiographic responses.  
Specifically, a randomized, multi-center Phase 2 study noted a 4.2 month median duration of 
response,(3) while a single arm study conducted at the National Cancer Institute observed an 
objective response rate of 19.6% and a 3.9 month median duration of response.(4)  Based on 
these studies, bevacizumab was approved in the US for treatment of patients with recurrent 
GBM,(75) but approval was not achieved in other countries.(76)  Nonetheless, essentially all 
recurrent patients ultimately progress following bevacizumab salvage therapy and to date, no 
effective therapy has been identified after progression on bevacizumab.(77) 
Reardon et al. retrospectively analyzed the outcomes of subjects who received subsequent 
therapy after progression to evaluate the efficacy of bevacizumab regimens against recurrent 
GBM in five clinical trials with similar eligibility, treatment, and assessment criteria.(78)  The 
results of this pooled analysis suggested bevacizumab continuation beyond initial progression 
modestly improves median overall survival and overall survival at 6 months, compared with a 
non-bevacizumab regimen (5.9 months and 49.2% vs 4 months and 29.5%).  Bevacizumab 
continuation was identified as independent predictor of improved overall survival (HR = 0.64; 
p = 0.04). 
Bevacizumab continuation beyond progression in GBM may be necessary to prevent increased 
tumor-associated cerebral edema or rapid tumor re-growth, reported as a “rebound” 
phenomenon by Zuniga et al.(79)  In their retrospective review of 40 subjects refractory to 
bevacizumab therapy, 27.5% exhibited rebound progression with a median overall survival of 
only 6.8 weeks.  Of 3 subjects who were restarted on bevacizumab treatment after rebound 
progression, 2 exhibited a partial response, and the OS was extended to 21.3 weeks.  The study 
suggests abrupt discontinuation of bevacizumab after progression often leads to a dramatic 
rebound phenomenon and rapid clinical decline.  


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Based on data from Reardon et al.(78) and Zuniga et al.,(79) evaluating bevacizumab 
continuation in combination with new agents in subjects progressing on bevacizumab warrants 
further prospective investigation.   
Importantly, the toxicity profiles of bevacizumab and immune checkpoint inhibiting therapeutics 
are non-overlapping; thus the combination of bevacizumab continuation and MEDI-4736 is 
expected to be well tolerated.  In support of this expectation, preliminary data demonstrate that 
the combination of bevacizumab plus ipilimumab among advanced melanoma subjects has been 
well tolerated and without unexpected toxicity or increased toxicity compared to that noted 
with administration of either agent alone.(80)   
 


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2 Study Rationale 
Outcome among both newly diagnosed as well as recurrent GBM patients remains poor and 
novel therapeutic approaches are clearly needed.  Targeting Programmed Death-1 (PD-1) and its 
ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid 
tumors,(6, 81) and growing data implicate PD-1/PD-L1 signaling as a significant contributor to 
immunosuppression in glioblastoma.  PD-1 is expressed by many glioblastoma infiltrating 
lymphocytes (29) while PD-L1 is expressed by 61-100% of glioblastoma tumors.(17, 19, 20)  
PD-L1 expression in a formalin-fixed, paraffin-embedded tissue microarray of 83 glioblastoma 
tumors revealed that 85% express PD-L1 in over 80% of the tumor cells (D. Reardon, M.D., 
personal communication).  Furthermore, loss of the PTEN tumor suppressor gene, which occurs 
in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in 
glioblastoma.(23)  Inhibition of PD-1 in an immunocompetent, orthotopic preclinical GBM model 
was recently demonstrated to improve survival when administered with radiotherapy.(50)  
Additional preclinical experiments involving an immunocompetent, orthotopic murine 
glioblastoma model revealed that 25% of animals treated with a murine anti-PD-L1 monoclonal 
antibody remained alive for over 140 days with no evidence of tumor (control mice uniformly 
died within 30 days) (D. Reardon, M.D., unpublished data).  These aggregate findings indicate 
that PD-1/PD-L1 is an attractive and important therapeutic target in GBM. 
The current study is thus designed to evaluate the immunogenicity, safety and clinical efficacy of 
MEDI4736 among both newly diagnosed and recurrent glioblastoma subject subsets. The results 
of this study will provide important insight to optimally guide development of MEDI4736 for this 
indication.  
As discussed in Section 1.3.2, 10 mg/kg is the RP2D of MEDI4736 for other cancer indications 
based upon completed dose escalation and expansion portions of the FTIH Phase 1 study.  It is 
anticipated that this dose will be suitable for all three cohorts, however, as there are no safety 
data for MEDI4736 in combination with radiation or bevacizumab, the option for dose 
de-escalations to 3 mg/kg and 1 mg/kg is included for Cohorts A and C.  In all cohorts, the first 
study drug administration for the first subject and the second subject will be separated by at 
least 1 week. 
In Cohort A, which consists of newly diagnosed glioblastoma subjects with MGMT unmethylated 
tumors, we will evaluate MEDI4736 when administered with standard radiotherapy after 
maximum safe resection.  The rationale for this approach is that radiation induces cell death 
with release of tumor antigens that could potentiate the immune-mediated anti-tumor activity 
of MEDI4736.(82)   
The standard combination of temozolomide with radiotherapy will not be administered to 
subjects in Cohort A because MGMT unmethylated glioblastoma subjects experience no survival 
benefit and increased systemic toxicity as previously discussed, and because temozolomide may 
limit anti-tumor immune responses following anti-PD-L1 therapy.  
The toxicities reported with MEDI4736 do not appear to overlap with those associated with 
standard radiotherapy for newly diagnosed glioblastoma subjects.  Thus, it is anticipated that a 
dose of 10 mg/kg will be well tolerated when combined with standard radiotherapy.  Toxicity 
management and dose adjustments will be followed according to local approved radiotherapy 


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guidelines and Appendix 8.6 for MEDI4736.  Although bevacizumab received FDA accelerated 
approval for recurrent glioblastoma patients based on radiologic response,(75) clinical benefit to 
support full approval has not been demonstrated.  In addition, bevacizumab failed to improve 
overall survival in two placebo-controlled, randomized Phase 3 studies among newly diagnosed 
glioblastoma subjects.(83, 84)  Furthermore, all subjects progress following bevacizumab 
therapy and then typically succumb within a few months from fulminate, progressive disease, 
regardless of whether bevacizumab is continued.  Despite many attempts, no therapies have 
been of benefit following the emergence of bevacizumab resistance.(77, 78, 85)  Thus, the 
identification of active agents for recurrent glioblastoma patients remains a major unmet need 
in oncology today.   
This study will evaluate two cohorts of subjects with recurrent glioblastoma; MEDI4736 as 
monotherapy in bevacizumab naïve subjects (Cohort B) and MEDI4736 combined with 
bevacizumab continuation in bevacizumab refractory subjects (Cohort C).  As described in 
Section 1.5, the continuation of bevacizumab following progression may alleviate tumor-
associated rebound edema and mass effect thereby potentiating anti-tumor immune response 
from MEDI4736.  Due to limited safety data on bevacizumab and anti-PD-L1 combination 
treatment, Cohort C will begin with a 3+3 subject safety run-in observing subjects in sequential 
groups of 3 to evaluate DLTs.  De-escalations to 3 mg/kg and 1 mg/kg of MEDI4736 will be made 
as necessary.  Toxicity management and dose adjustments will be followed according to local 
approved bevacizumab regulatory prescribing information and Appendix 8.6 for MEDI4736.  As 
discussed in Section 1.5, the toxicity profiles of bevacizumab and immune checkpoint inhibiting 
therapeutics are non-overlapping; thus the combination of bevacizumab continuation and 
MEDI4736 is expected to be well tolerated. 
Evidence of anti-tumor activity in the current study for MEDI4736 among bevacizumab naive or 
bevacizumab resistant, recurrent glioblastoma subjects, would provide a justification for 
randomized, definitive clinical trials of MEDI4736 for these subjects. 
2.1 Rationale for Amendment 2 
Per Protocol Amendment 2, two additional cohorts will be added to the study.  The 2 additional 
cohorts will have the same study population criteria as Cohort B, which is defined as subjects 
with refractory GBM (first or second recurrence) who have not previously been treated with 
bevacizumab.  The treatments for the 2 additional cohorts will be as follows: 
• 
Cohort B2 - MEDI4736 (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W) on the same 
treatment days for 13 four-week cycles  
• 
Cohort B3 - MEDI4736 (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W) on the same 
treatment days for 13 four-week cycles  
The hypothesis is that the anti-tumor activity of MEDI4736 will be enhanced when administered 
with bevacizumab among recurrent GBM subjects. Furthermore, we anticipate that the 
combination of MEDI4736 plus bevacizumab will be well tolerated among recurrent GBM 
subjects because the toxicity profiles of MEDI4736 and bevacizumab do not overlap indicating 
that these two agents are expected to be well tolerated when co-administered.  In addition, per 
Protocol Amendment 2, dosing for Cohort B2 will be the same as that of Cohort C (MEDI4736 10 


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mg/kg Q2W + bevacizumab 10 mg/kg Q2W).  At this time, 5 of the 6 subjects in the safety run-in 
for Cohort C have completed the DLT observation period without experiencing a DLT.  
Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor 
(VEGF), is currently approved in the US and Australia for recurrent GBM. Despite durable 
radiographic responses, bevacizumab fails to improve overall survival.(3, 83, 84, 86)  Growing 
data suggest that VEGF inhibition may enhance the anti-tumor benefit of immunotherapies by 
several potential mechanisms. First, VEGF is known to significantly contribute to the 
immunosuppressive microenvironment of tumors.(87-89)  Specifically, VEGF can inhibit 
dendritic cell (DC) maturation and antigen presentation, induce apoptosis of CD8+ T cells, 
enhance Treg activity and diminish infiltration of T cells across tumor endothelium.(90-93)  
Second, preclinical studies demonstrate that immunotherapeutics may be combined with VEGF 
inhibitors to generate enhanced anti-tumor benefit.(88-99)  Specifically, VEGF blockade can 
decrease tumor immunosuppression(90-93, 97-99) and enhance the anti-tumor activity of co-
administered immunotherapies.(94, 96-99)  Third, preclinical strategies to normalize tumor 
vasculature, including administration of anti-VEGF therapy, can shift tumor-associated 
macrophages from an M2 immune-inhibitory phenotype to an immune-stimulatory M1-
phenotype, as well as increase tumor infiltrating CD8+ T cells and enhance survival following 
whole tumor cell vaccination.(95) Fourth, VEGF has been shown to induce FasL expression by 
tumor endothelial cells which selectively kills effector CD8+ T cells but not Tregs; VEGF blockade 
can thereby lead to increased influx of tumor-rejecting CD8+ over FoxP3+ T cells.(100) With 
regard to clinical application, limited data from studies evaluating anti-VEGF therapy plus 
immune checkpoint blockade have been published, but results from a recent Phase 1 study 
among subjects with metastatic melanoma reveal that administration of bevacizumab with 
ipilimumab, an inhibitor of the CTLA-4 immune checkpoint, led to improved overall survival as 
well as increased immune cell trafficking into tumor sites.(80)  
In addition to the potential immune-enhancing features of anti-VEGF therapy, another 
important benefit is that co-administration of bevacizumab leads to decreased dexamethasone 
requirement for subjects with GBM.(3, 83, 101)  Dexamethasone is routinely administered to 
treat symptomatic cerebral edema among GBM patients; however, systemic corticosteroid use 
has been shown to diminish the anti-tumor benefit associated with immune checkpoint 
blockade among patients with brain melanoma metastases.(102) 
According to Amendment 2, the study will evaluate MEDI4736 combined with bevacizumab 
administered using either a standard (10 mg/kg biweekly; Cohort B2) or a reduced (3 mg/kg 
biweekly; Cohort B3) dosing schedule. Although the hypothesis is that VEGF blockade will 
enhance the anti-tumor activity of anti-PD-1/PD-L1 therapy, a currently unanswered critical 
question is whether there is an optimized dosing schedule of bevacizumab to do so. Standard 
bevacizumab dosing, administered as single agent therapy, represents the approved schedule 
for recurrent GBM based on durable radiographic responses.(75)  In fact, as a monotherapeutic, 
a higher dosing schedule of bevacizumab may be required to achieve a sufficient anti-angiogenic 
effect to translate into anti-tumor benefit. However, higher (standard) dosing has also been 
shown to significantly decrease perfusion and tumor vasculature permeability, leading to 
intratumoral hypoxia which may in turn drive GBM invasion and infiltration.(103-107)  In 
contrast, a lower dosing schedule has been shown to normalize rather than eradicate tumor 
vasculature, leading to improved blood flow, less hypoxia and enhanced delivery of co-
administered anti-tumor agents in preclinical cancer models including GBM.(108, 109) 


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Normalized vasculature has also been associated with enhanced survival among cancer patients 
including those with GBM treated with anti-VEGF therapy.(110, 111)  Furthermore, additional 
preclinical studies demonstrate that normalized tumor vasculature following reduced anti-VEGF 
therapy also leads to enhanced intratumoral immune cell infiltration.(95, 112)  Finally, a recently 
published preclinical study evaluating lower versus higher doses of anti-VEGF therapy showed 
that only lower anti-VEGF therapy dosing led to enhanced immune infiltrate and improved 
survival following co-administration with an anti-tumor immunotherapeutic.(95)  
A prospective evaluation of standard versus reduced bevacizumab dosing has not been 
conducted for subjects with GBM. A retrospective review of 219 subjects treated with 
bevacizumab showed that subjects treated with lower dose intensity (< 5 mg/kg per week) of 
bevacizumab had longer PFS and OS when compared with those treated with the standard 10 
mg/kg biweekly dosing. (113)   
 


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3 Experimental Plan 
3.1 Study Design 
3.1.1 Study Phase 
Phase 2 
3.1.2 Enrollment/Randomization 
Subjects will be enrolled in parallel and independently in all cohorts in a non-randomized, 
sequential manner, with competitive enrollment between study sites.  Enrollment will be under 
ongoing review by an internal data safety monitoring panel (see Section 3.1.14, Safety 
Monitoring and Study Stopping Rules).  For each cohort, the first study drug administration for 
the first subject and the second subject will be separated by at least 1 week (see Section 3.1.7, 
Treatment Arms and Treatment Schema).  Eligible subjects have to be registered centrally with 
the Sponsor before enrollment.  
Per Protocol Amendment 2, two cohorts (B2 and B3) will be added to the study as described in 
Section 2.1.  Subjects in Cohorts B2 and B3 will be enrolled in a concurrent randomized manner. 
3.1.3 Blinding/Unblinding 
Open label. 
3.1.4 Subject Population 
Cohort A:  Subjects with newly diagnosed unmethylated MGMT glioblastoma scheduled for 
standard radiotherapy. 
Cohorts B, B2 and B3:  Bevacizumab-naïve subjects with recurrent glioblastoma. 
Cohort C:  Bevacizumab-refractory subjects with recurrent glioblastoma. 
For complete Subject Eligibility details, see Section 5. 
3.1.5 Number of Sites/Subjects 
Up to 172 subjects in 7 sites will participate as follows: 
Cohort A:  37 subjects, including the first 6 subjects who will be evaluated for DLTs to confirm 
the suitability of the MEDI4736 dose in combination with standard radiotherapy.  Up to 12 
additional subjects may be required if the dose needs to be reduced (see Section 3.1.6.1). 
Cohort B:  30 subjects 
Cohort B2: 32 subjects 
Cohort B3: 32 subjects 
Cohort C:  17 subjects, including the first 6 subjects who will be evaluated for DLTs to confirm 
the suitability of the MEDI4736 dose in combination with bevacizumab.  Up to 12 additional 
subjects may be required if the dose needs to be reduced (see Section 3.1.6.3). 


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Additional subjects may be enrolled in accordance with the subject replacement criteria in 
Section 3.1.11. 
3.1.6 Sample Size Considerations 
3.1.6.1 Cohort A 
Overall survival at 12 months of newly diagnosed unmethylated MGMT GBM subjects treated 
with standard radiotherapy is 50%, based on the Phase 3 EORTC 26981-22981/NCIC CE3 
study.(1)  As discussed in Section 1.4, the addition of temozolomide in this subject population 
provides negligible survival benefit at the expense of increased toxicities. 
An increase of the overall survival rate at 12-months from 50% to 70% is considered clinically 
relevant and justifies further investigation of MEDI4736 in this subject population.  With 80% 
power and 0.05 significance level, using a one-sided exact binomial, to test a null hypothesis of 
50% in historical controls against a one-sided alternative of 70% requires 24 of 37 subjects to be 
alive at 12 months. 
The DLT evaluation of the first 6 subjects to confirm the suitability of the initial 10 mg/kg RP2D 
follows the principles of standard 3+3 dose escalation studies, i.e., if ≤1 of 3 subjects develops 
DLT, expand to 6, and if >1 of 3 or >1 of 6 subjects develop DLT, de-escalate to the next lower 
dose level.  If at any of the three defined dose levels (10, 3, or 1 mg/kg) ≤1 of 6 subjects 
develops DLT, this dose level will be expanded to the full 37 subjects sample size.  This process 
may require up to 18 subjects, of which 6 will be part of the expanded cohort.  If at the lowest 
dose level >1 subject develops DLT, this cohort will be discontinued. 
3.1.6.2 Cohort B 
Three large meta-analyses of clinical trials performed among recurrent glioblastoma subjects in 
the modern, pre-bevacizumab era, reveal that only 10% of subjects remain progression-free for 
six months (PFS-6) or longer with salvage therapy.(114-116)  The current study will therefore 
incorporate a PFS-6 of 10% as the comparative historical benchmark.  If the true PFS-6 rate on 
the current study were 30% or higher, there would be interest in further investigation of this 
treatment regimen, and if the PFS-6 rate were ≤ 10%, there would be limited interest.  
Therefore, the study will be used to differentiate between a 10% and 30% rate of PFS-6, testing 
the hypothesis H0: p≤0.1 versus H1: p≥0.3, with p being the proportion of subjects remaining 
progression free for at least six months.  Enrollment of 30 subjects will yield 80% power to 
detect a 20% difference in PFS-6 at an alpha level of 0.05 (one-sided).  If at least seven subjects 
achieve PFS-6, the null hypothesis will be rejected in favor of the alternative hypothesis.  
3.1.6.2.1 Cohorts B2 and B3 
Outcome for subjects enrolled in Cohorts B2 or B3 will be separately compared to established 
historical benchmarks of bevacizumab for recurrent GBM. Among 85 subjects with GBM at first 
or second recurrence, PFS-6 was 42.6% (97.5 CI, 29.6% to 55.5%) following bevacizumab 
monotherapy in the BRAIN study.(3)  This result coupled with an objective response rate of 28% 
was the basis for accelerated approval of bevacizumab for recurrent GBM patients in the United 
States.(75)  In a recently reported Phase 2 study (BELOB), PFS-6 was also 42% (95% CI, 29-55) for 
GBM subjects at first recurrence randomized to receive bevacizumab plus lomustine.(117)  The 
current study will therefore incorporate a PFS-6 of 42% as the comparative historical benchmark 


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of bevacizumab for recurrent GBM subjects as achieved in the BRAIN and BELOB studies, 
respectively. If the true PFS-6 rate for Cohorts B2 or B3 for the current study were 62% or 
higher, there would be interest in further investigation of this treatment regimen, and if the PFS-
6 rate were ≤ 42%, there would be limited interest. Therefore, the study will be used to 
differentiate between a 42% and 62% rate of PFS-6, testing the hypothesis H0: p≤0.42 versus H1: 
p≥0.62, with p being the proportion of subjects remaining progression free for at least six 
months. Enrollment of 32 subjects to each cohort will yield 80% power to detect a 20% 
difference in PFS-6 at an alpha level of 0.1 (one-sided).  If at least 18 subjects per cohort achieve 
PFS-6, the null hypothesis will be rejected in favor of the alternative hypothesis for that cohort.  
3.1.6.3 Cohort C 
The outcome for recurrent GBM subjects who progress on bevacizumab and continue with 
further salvage therapy that includes bevacizumab is dismal.  Quant (n=35), Torcuator (n=23), 
Reardon (n=23) and Lu-Emerson (n=14) reported median survivals of only 2.9 months, 3.3 
months, 4.1 months and 2.8 months, respectively.(118-121)  Thus, the rate of OS at 6 months 
for these subjects is expected to be approximately 25-35%, based on the broad experience 
established to date.  Reardon et al reported that the median OS among subjects who received a 
second bevacizumab containing regimen after failing initial bevacizumab treatment was 5.9 
months (95% CI: 4.4, 7.6) and the OS at 6 months was 49.2% (95% CI: 35.2, 61.8).(78)  For the 
current study, if the true 6 month OS rate is 65% or higher, there will be interest in further 
investigation of this treatment regimen.  However, if the OS-6 rate is ≤ 35%, there would be 
limited interest in pursuing the development of this treatment regimen in this subject 
population.  Therefore, the study will be used to differentiate between a 35% and 65% rate of 
OS-6.  Statistically, the hypothesis that will be tested is (p = proportion of subjects who are alive 
at 6 months):  H0: p<0.35 versus H1: p>0.65 OS-6 for cohort C will be compared to the historical 
benchmark set by Reardon.  Enrollment of 17 subjects will yield 90% power to detect an OS-6 
rate of 65% at an alpha level of 0.1 (one-sided).  If at least 9 subjects are alive by 6 months, the 
null hypothesis will be rejected in favor of the alternative hypothesis.  
The DLT evaluation of the first 6 subjects to confirm the suitability of the 10 mg/kg RP2D of 
MEDI4736 combined with bevacizumab follows the principles of standard 3+3 dose escalation 
studies, i.e., if ≤1 of 3 subjects develops DLT, expand to 6, and if >1 of 3 or >1 of 6 subjects 
develop DLT, de-escalate to the next lower dose level.  If at any of the three defined dose levels 
(10, 3, or 1 mg/kg) ≤1 of 6 subjects develops DLT, this dose level will be expanded to the full 17 
subjects sample size.  This process may require up to 18 subjects, of which 6 will be part of the 
expanded cohort.  If at the lowest dose level >1 subject develops DLT, this cohort will be 
discontinued. 
3.1.7 Treatment Arms and Treatment Schema 
In all Cohorts, MEDI4736 will be administered intravenously in 0.9% sodium chloride or 5% (w/v) 
dextrose over 60 minutes (± 5 minutes) according to Section 6.1.4.  Each subject will receive up 
to 26 administrations at 10 mg/kg body weight (or at a reduced dose level as specified below for 
Cohorts A and C) two weeks apart over 52 weeks as shown in Figure 1.  Individual dosing 
adjustments per subject due to toxicity will be allowed, as described in Section 3.1.8.2.  Subjects 
will be followed on study for 90 days after the last drug administration and off-study every 6 
months for three years from the date of first dose of study treatment (see Section 3.1.16). 


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In Cohort A, treatment will start on Day 1 of the Standard Radiotherapy after maximum safe 
resection.  Standard Radiotherapy is defined as focal radiotherapy administered at 2 Gy given 
daily 5 days per week for a total of 60 Gy over 30 fractions per local institutional guidelines or 
local prescribing information. 
Cohort A will be started on MEDI4736 at 10 mg/kg body weight, which is the current RP2D 
based on previous Phase 1 monotherapy data.  As there are no safety data available for this 
combination, the first 6 subjects will be observed in sequential groups of 3+3 for DLTs for a DLT 
evaluation period of 10 weeks (see DLT definitions in Section 3.1.9), and any necessary dose de-
escalations to 3 mg/kg and 1 mg/kg will be made as follows: 
• 
If ≤1 of the first 3 subjects develop DLT, 3 more subjects will be enrolled. 
• 
If >1 of the first 3 subjects or >1 of the first 6 subjects develop DLT, cohort enrollment 
will be stopped immediately, and re-started from the beginning with 3+3 subjects 
enrolled at the next lower dose level. 
• 
If at any of the 3 dose levels (10, 3, or 1 mg/kg) ≤1 of 6 subjects develop DLT, this dose 
level will be expanded to the full 37 subjects sample size. 
• 
If at the lowest dose level >1 of the first 6 subjects develops DLT, Cohort A will be 
discontinued. 
In Cohorts B, B2 and B3, the Day 1 treatment start must fall within 14 days of the last baseline 
magnetic resonance imaging (MRI) confirmation of first or second recurrence of GBM by 
diagnostic biopsy or contrast enhanced MRI per modified RANO criteria.(122)   
No safety run-in will be performed for Cohort B as it uses MEDI4736 as monotherapy. 
Per Protocol Amendment 2, Cohort B2 dosing will be the same as that of Cohort C (MEDI4736 10 
mg/kg Q2W + bevacizumab 10 mg/kg Q2W).  At this time, 5 of the 6 subjects in the safety run-in 
for Cohort C have completed the DLT observation period without experiencing a DLT; therefore, 
a safety run-in period for Cohort B2 will not be required.  As Cohort B3 will have a lower dose 
bevacizumab along with the MEDI4736, a safety run-in period will not be required as well. 
In Cohort C, the Day 1 treatment start must fall within 14 days of the last baseline MRI 
confirmation of first recurrence of GBM following initial bevacizumab therapy as defined by 
diagnostic biopsy or contrast enhanced MRI per modified RANO criteria.(122)  Subjects will 
continue receiving bevacizumab at 10 mg/kg intravenous (IV) every 2 weeks.  On each treatment 
day, MEDI4736 will be administered first followed by a one-hour observation period, after 
which, bevacizumab will be infused.  
Cohort C will be started on MEDI4736 at 10 mg/kg body weight, which is the current RP2D based 
on previous Phase 1 monotherapy data.  Since there is no safety data available for this 
combination, the first 6 subjects will be observed in groups of 3+3 for DLTs for a DLT evaluation 
period of 6 weeks (see DLT definitions in Section 3.1.9), and any necessary dose de-escalations 
to 3 mg/kg and 1 mg/kg will be made as follows: 
• 
If ≤1 of the first 3 subjects develop DLT, 3 more subjects will be enrolled. 
• 
If >1 of the first 3 subjects or >1 of the first 6 subjects develop DLT, cohort enrollment 
will be stopped immediately, and re-started from the beginning with 3+3 subjects 
enrolled at the next lower dose level. 


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• 
If at any of the 3 dose levels (10, 3, or 1 mg/kg) ≤1 of 6 subjects develop DLT, this dose 
level will be expanded to the full 17 subjects sample size. 
• 
If at the lowest dose level >1 of the first 6 subjects develops DLT, Cohort C will be 
discontinued. 
 
Cohort A (n=37): Newly Diagnosed GBM, MGMT Unmethylated Promoter
Cohort B (n=30): Recurrent GBM, Avastin naive
Cohort C (n=17): Recurrent GBM, Avastin refractory
Cohorts B2 and B3 (n=32 for each): Recurrent GBM, Avastin naive
 
Figure 1 
See Section 3.2, for complete treatment and assessment details for the cohorts. 
3.1.8 Dosing Adjustments, Delays and Discontinuations 
3.1.8.1 Radiotherapy (Cohort A only) 
Dosing adjustment, delays and discontinuations of radiotherapy should be managed in 
accordance with institutional guidelines or local approved regulatory prescribing information.   


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3.1.8.2 MEDI4736 (Cohorts A, B, B2, B3 and C) 
Dosing adjustment, delays and discontinuations for MEDI4736 should be managed in 
accordance with the instructions given in Appendix 8.6. 
3.1.8.3 Bevacizumab (Cohorts B2, B3 and C) 
Dosing delays and discontinuations of bevacizumab should be managed in accordance with 
institutional guidelines or local approved regulatory prescribing information.   
3.1.9 DLT and MTD 
DLTs will be observed over a DLT evaluation period of 10 weeks for Cohort A and 6 weeks for 
Cohort C; Cohorts B, B2, and B3 have no DLT evaluation period (see Section 3.1.11 for DLT 
evaluability). The decisions for dose de-escalations will primarily be based on the number of 
subjects with DLTs occurring during the DLT evaluation period.  DLTs occurring outside the DLT 
evaluation period will also be evaluated and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of MEDI4736 alone and/or the respective combination of MEDI4736 with 
radiotherapy or bevacizumab, and fulfill any of the following criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event or uveitis. 
2. Any Grade 2 pneumonitis, neurological event or uveitis with the following exception: 
• 
Grade 2 pneumonitis neurological event or uveitis that downgrades to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade 3 irAEs (see definition below) that downgrade to Grade ≤ 2 within 3 days, or 
to Grade ≤ 1 or baseline within 14 days after onset, whereby maximal supportive 
care, including systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times the upper limit of normal (ULN) that 
downgrades to Grade ≤ 2 (≤ 5 times ULN) within 7 days after onset, whereby 
maximal supportive care, including systemic corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 or Grade 4 lymphopenia. 


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• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days. 
• 
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but where 
the increment of deterioration is considered not clinically significant by both 
Investigator and Sponsor. 
 
In Cohort A, if the planned radiotherapy dose cannot be reached or needs to be substantially 
interrupted (defined as either administration of less than 75% of planned XRT dose or XRT 
dosing is interrupted for more than two consecutive weeks) due to toxicity that is at least 
“possibly” related to the administration of MEDI4736, this should be counted as DLT. 
In Cohort C, if the planned bevacizumab administration needs to be discontinued or 
substantially interrupted as per Prescribing Information due to toxicity that is at least “possibly” 
related to the administration of MEDI4736, this should be counted as DLT. 
Immune-related AEs (irAEs) are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a DLT. 
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as DLT after consultation with the Sponsor and Investigators, based 
on the emerging safety profiles of MEDI4736 alone and/or the respective combination of 
MEDI4736 with radiotherapy or bevacizumab.  Likewise, subjects who become not evaluable for 
DLT, because they discontinued from the study or interrupted treatment due to toxicities other 
than DLTs, may be counted as DLT subjects, if the toxicities cannot be managed in accordance 
with the dosing modifications described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study therapy and will enter the On 
Study Follow-up period, followed by the Post Study Follow-up period (see Section 3.2).  
However, if it is in the best interest of the subject, the Investigator and Sponsor may agree to 
continue treatment, possibly at a lower dose level.  
The MTD of MEDI4736 will not be determined in this study. 
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment. 
2. Pregnancy or intent to become pregnant. 
3. Dose-limiting toxicity of MEDI4736 at any time (see Section 3.1.9 for definition of DLT 
and permitted continuation). 
4. Confirmation of progressive disease by modified RANO criteria requiring alternative 
treatment. 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal. 


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6. Development of intercurrent, non-cancer related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 
A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator. 
2. Initiation of alternative anti-cancer therapy (marketed or investigational). 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If applicable, subjects who are withdrawn from study treatment should undergo 
the planned On Study Follow-up procedures (see Study Flowchart, Section 3.2), followed by the 
Post Study follow-up period (see Section 3.1.16).   
Subjects who begin other anti-cancer therapy should immediately be considered as being off 
study and proceed to Post Study Follow-up. 
NOTE: Subjects in Cohorts B2, B3, and C who are taken off treatment but continue bevacizumab 
alone should not be considered as having started new treatment.  These subjects should 
continue into the On Study Follow-up visits, unless they are off study for other reasons. 
General subject withdrawal criteria are outlined in the Administrative, Legal and Ethical 
Requirements section of the protocol (see Section 7.2.7). 
See also Appendix 8.6 for subject withdrawal from treatment due to necessary dosing 
interruptions or discontinuations. 
3.1.11 Subject Evaluability and Replacement  
In Cohort A, subjects who are not fully evaluable per protocol for the primary objective of 
clinical efficacy per Section 4.1.2 may be replaced. 
In the Safety Run-in portion of Cohort A, subjects who are not evaluable for DLTs during the DLT 
evaluation period as defined in Sections 3.1.7 and 3.1.9, will be replaced. 
Subjects are evaluable for DLTs if: 
a. they experienced a DLT as per Section 3.1.9, or 
b. in the absence of a DLT, if they received at least 75% of the scheduled radiotherapy dose 
without dosing disruption for more than 2 consecutive weeks, and at least 4 of the 5 
scheduled MEDI4736 doses over the first 8 weeks (Study Day 57), as well as, respective 
safety assessments, without major protocol violations, over the entire DLT evaluation 
period. 
In Cohorts B, B2, and B3, subjects who are not fully evaluable per protocol for the primary 
objective of clinical efficacy per Section 4.1.2 may be replaced. 


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In Cohort C, subjects who are not fully evaluable per protocol for the primary objective of 
clinical efficacy per Section 4.1.2 may be replaced. 
In the Safety Run-in portion of Cohort C, subjects who are not evaluable for DLTs during the DLT 
evaluation period, as defined in Sections 3.1.7 and 3.1.9, will replaced. 
Subjects are evaluable for DLTs if: 
(1) they experienced a DLT as per Section 3.1.9, or 
(2) in the absence of a DLT, if they received at least 2 of the 3 scheduled bevacizumab doses 
and at least 2 of the 3 scheduled MEDI4736 doses over the first 4 weeks (Study Day 29), 
as well as, respective safety assessments, without major protocol violations, over the 
entire DLT evaluation period. 
In all Cohorts, subjects who are being replaced may continue on study, unless another reason 
for discontinuation as defined in Section 3.1.10 occurs. 
3.1.12 Optional Study Treatment Extension 
Optional treatment extension beyond the 1-year study (Core Study) is available for subjects who 
complete 51 weeks of treatment on Core Study with Stable Disease or better; the optional 
treatment extension will be permitted upon agreement with subject, Sponsor and Investigator.  
See Appendix 8.8 for details. 
3.1.13 Interim Analysis 
Interim safety reviews will be performed to assess DLTs in context of the safety run-in for 
Cohorts A and C (see Section 3.1.7).  Interim analyses may be performed to analyze the 
endpoints of progression free survival at 6 months and overall survival at 6 or 12 month for the 
applicable cohorts as specified in the statistical analysis plan. 
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and co-investigators as needed), the Sponsor Medical 
Monitor, and drug safety personnel from MedImmune, the provider of the study drug.  
Additional Investigators and staff, or additional Sponsor personnel and consultants, shall 
participate in reviews as indicated.  An Independent Data Monitoring Board will not be utilized 
for this open label study. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to MEDI4736, or to the 
combination of radiotherapy or bevacizumab and MEDI4736. 
2. Severe anaphylactic reaction to MEDI4736 (i.e., with respiratory and cardiovascular 
failure). 
3. Any events that, in the judgment of the Medical Monitor, are at least probably related 
to MEDI4736 and are deemed serious enough to warrant immediate review by the 
internal data safety monitoring panel.  This may include any symptomatic and/or 


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irreversible treatment-related grade 4 pneumonitis, colitis, dermatitis, or hepatitis or 
any symptomatic treatment-related related grade ≥ 3 neurological toxicity or uveitis.  
4. Any other safety finding assessed as related to MEDI4736 or its respective combinations 
with radiotherapy or bevacizumab that, in the opinion of the internal data safety 
monitoring panel, contraindicates further dosing of study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
Study stopping rules may be applied to individual cohorts, if the internal data safety monitoring 
panel concludes that the identified risk to one cohort does not carry over to another cohort. 
General criteria for premature trial termination are outlined in the Administrative, Legal and 
Ethical Requirements section of the protocol (Section 7). 
3.1.15 Duration of Study 
Enrollment Period: 
15 months 
Duration of Treatment & Follow-up  
15 months  
See Section 3.1.12 for optional treatment extension. 
Length of Study: 
27 months 
Post Study Follow-up: 
36 months 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue study treatment 
prematurely, or prematurely withdraw from the study as per Sections 3.1.10 and 7.2.7, will be 
followed as per institutional guidelines in accordance with the usual standard of care principles.   
For all subjects who complete study treatment or discontinue treatment prematurely, there will 
be an On Study Follow-up for 90 days after the last MEDI4736 treatment, which will include 
collection of AE data (see Section 3.1.10 for subjects who begin other anti-cancer treatment and 
Section 7.1.5 for details on collection of AEs).   
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On-Study Follow-up Period (which is 14 days after the last dose of study 
treatment), any assessments required in the 14 day On Study Follow-up visit that are not 
covered as part of the last on-treatment visit (usually correlative labs) should be done as soon as 
possible.  If these assessments cannot be done on the same day, the subject should be brought 
back in at the earliest opportunity.  Any assessments or correlative samples required by both the 
last on-treatment visit and the 14 day On Study Follow-up visit should not be repeated. 
Following the On Study Follow-up, there will be a Post Study Follow-up, where clinical outcomes 
data will be collected at least every 6 months for up to 3 years from the initiation of the 
treatment.  Clinical outcomes data may include the following: 
• 
First date of progression/relapse (for subjects who did not already progress while on 
study) 
• 
First new anti-cancer treatment after the subject comes off study 
• 
Survival data (including date/reason for death). 
 


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The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug. 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician.  
See Section 3.1.12 for optional study treatment extension. 
3.1.16.1 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End 
of Study visit must be conducted at the time of withdrawal. For subjects not yet in On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For 
subjects already in On Study Follow-up, this End of Study visit will be the next planned visit of 
the On Study Follow-up. However, any procedures/assessments that were done within 7 days of 
the End of Study visit need not be repeated. All subjects of childbearing potential who withdraw 
from study must have a serum pregnancy test done at the End of Study visit unless it was done 
within 7 days prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up). 


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3.2 Study Flowchart 
 
Study Flowchart (1 of 3)
Screening / 
Baseline
Treatment  weeks
-4 to 0 
Week 1 Week 2 Week 3 Week 4 Week 5
Week 6
Week 7
Week 9
Week 11
Week 13
Treatment days
-28 to 0 
1
8±1
15±1
22±1
29±3
36±3
43±3
57±3
71±3
85±3
Treatment (Cohort A)
MEDI4736
x
x
x
x
x
x
x
Radiotherapy (Day 1-5) for 6 weeks
x
x
x
x
x
x
Treatment (Cohort B)
MEDI4736
x
x
x
x
x
x
x
Treatment (Cohort B2)
MEDI4736
x
x
x
x
x
x
x
Bevacizumab (10mg/kg)
x
x
x
x
x
x
x
Treatment (Cohort B3)
MEDI4736
x
x
x
x
x
x
x
Bevacizumab (3mg/kg)
x
x
x
x
x
x
x
Treatment (Cohort C)
MEDI4736
x
x
x
x
x
x
x
Bevacizumab
x
x
x
x
x
x
x
Tumor & Disease Assessments 
Disease Staging (1st diagnosis & at study entry)
x
Disease Assessment by modified RANO (including 
appropriate imaging) 
x5
X
Study Procedures & Examinations
Eligibility Assessment3,5
x
Demographics (incl. DoB; sex; height; race; ethnicity)
x
Medical history and Pre-Existing Symptoms
x
Physical Exam (incl. weight and ECOG Perf Status)  
x
x
x
x
x
x
12-Lead ECG
x
Vital Signs (T, HR, BP, RR). See Section 6.1.5 for assessment 
before/during/after MEDI4736 dose
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medications and Procedures
-7 to 0
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after consent) 6
x
x
x
x
x
x
x
x
x
x
x
Quality of Life (EORTC QLQ-C30/BN20)
x
x
Neurologic Assessment in Neuro-Oncology (NANO)
x
x
Laboratory Assessments
Blood Hematology (CBC, differential, platelets)
-7 to 0
x1
x
x1
x
x1
x
x1
x1
x1
x1
Chemistry (gluc., BUN, creat., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
-7 to 0
x1
x
x1
x
x1
x
x1
x1
x1
x1
Chemistry cont. (Amylase, lipase)
-7 to 0
x1
x
x1
x
x1
x
x1
x1
x1
x1
Urinalysis (Cohorts B2, B3, and C only) 
x2
x2
x2
x2
x2
x2
x2
Serum pregnancy test (urine test only on Day 1)
-7 to 0
x1
x1
MGMT expression (by standard, commercially available 
assay as per institutional guidelines)7
x
IDH mutation (by standard, commercially available 
assay as per institutional guidelines)7
x
Tumor Biopsy (PD-L1 expression)
x (archival)
MDSC   
x4
x1
Flow Cytometry 
x4
x
x1
x1
x1
PBMC 
x4
x
x1
x1
x1
Long-Term Follow-up
Post Study Follow-up as described in Section 3.1.16
1 - pre MEDI4736 dose  on same day as infusion . Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing
2 -  pre bevacizumab dose; if urine protein dipstick is 2+ or greater, manage according to bevacizumab package insert
3 - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
4- Samples may be collected up to 28 days prior to Day 1; if collected on Day 1, collection must be pre MEDI4736 dose.
5 - For Cohorts B, B2, B3 and C, the last baseline MRI confirmation of first or second recurrence of GBM per modified RANO criteria must occur  within 14 days of Day 1 of treatment.
6 -  See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
7 - Archival results >28 days prior to the start of treatment are acceptable.  If archival results are not available, this testing should be done within 28 days of start of treatment.
x  (at time of progression: optional)
Treatment


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Study Flowchart  (2 of 3)
Treatment  weeks
Week 15
Week 17
Week 19
Week 21
Week 23
Week 25
Week 27
Week 29
Week 31
Week 33
Week 35
Treatment days
99±3
113±3
127±3
141±3
155±3
169±3
183±3
197±3
211±3
225±3
239±3
Treatment (Cohort A)
MEDI4736
x
x
x
x
x
x
x
x
x
x
x
Radiotherapy (Day 1-5) for 6 weeks
Treatment (Cohort B)
MEDI4736
x
x
x
x
x
x
x
x
x
x
x
Treatment (Cohort B2)
MEDI4736
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab (10mg/kg)
x
x
x
x
x
x
x
x
x
x
x
Treatment (Cohort B3)
MEDI4736
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab (3mg/kg)
x
x
x
x
x
x
x
x
x
x
x
Treatment (Cohort C)
MEDI4736
x
x
x
x
x
x
x
x
x
x
x
Bevacizumab
x
x
x
x
x
x
x
x
x
x
x
Tumor & Disease Assessments 
Disease Staging (1st diagnosis & at study entry)
Disease Assessment by modified RANO (including 
appropriate imaging) 
X
X
X
Study Procedures & Examinations
Eligibility Assessment3,5
Demographics (incl. DoB; sex; height; race; ethnicity)
Medical history and Pre-Existing Symptoms
Physical Exam (incl. weight and ECOG Perf Status)  
x
x
x
x
x
12-Lead ECG
Vital Signs (T, HR, BP, RR). See Section 6.1.5 for assessment 
before/during/after MEDI4736 dose
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medications and Procedures
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after consent) 6
x
x
x
x
x
x
x
x
x
x
x
Quality of Life (EORTC QLQ-C30/BN20)
x
x
X
Neurologic Assessment in Neuro-Oncology (NANO)
x
x
X
Laboratory Assessments
Blood Hematology (CBC, differential, platelets)
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
Chemistry (gluc., BUN, creat., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
Chemistry cont. (Amylase, lipase)
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
Urinalysis (Cohorts B2, B3, and C only) 
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
Serum pregnancy test (urine test only on Day 1)
x1
x1
x1
MGMT expression (by standard, commercially available 
assay as per institutional guidelines)7
IDH mutation (by standard, commercially available 
assay as per institutional guidelines)7
Tumor Biopsy (PD-L1 expression)
MDSC   
x1
Flow Cytometry 
PBMC 
x1
Long-Term Follow-up
Post Study Follow-up as described in Section 3.1.16
1 - pre MEDI4736 dose  on same day as infusion . Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing
2 -  pre bevacizumab dose; if urine protein dipstick is 2+ or greater, manage according to bevacizumab package insert
3 - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
4- Samples may be collected up to 28 days prior to Day 1; if collected on Day 1, collection must be pre MEDI4736 dose.
5 - For Cohorts B, B2, B3 and C, the last baseline MRI confirmation of first or second recurrence of GBM per modified RANO criteria must occur  within 14 days of Day 1 of treatment.
6 -  See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
7 - Archival results >28 days prior to the start of treatment are acceptable.  If archival results are not available, this testing should be done within 28 days of start of treatment.
x  (at time of progression: optional)
Treatment


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Study Flowchart (3 of 3)
Treatment  weeks
Week 37
Week 39
Week 41
Week 43
Week 45
Week 47
Week 49
Week 51
Week 53
Week 57
Week 64
(End of 
Study)
Treatment days
253±3
267±3
281±3
295±3
309±3
323±3
337±3
351±3
365±3
393±7
442±7
Treatment (Cohort A)
MEDI4736
x
x
x
x
x
x
x
x
Radiotherapy (Day 1-5) for 6 weeks
Treatment (Cohort B)
MEDI4736
x
x
x
x
x
x
x
x
Treatment (Cohort B2)
MEDI4736
x
x
x
x
x
x
x
x
Bevacizumab (10mg/kg)
x
x
x
x
x
x
x
x
Treatment (Cohort B3)
MEDI4736
x
x
x
x
x
x
x
x
Bevacizumab (3mg/kg)
x
x
x
x
x
x
x
x
Treatment (Cohort C)
MEDI4736
x
x
x
x
x
x
x
x
Bevacizumab
x
x
x
x
x
x
x
x
Tumor & Disease Assessments 
Disease Staging (1st diagnosis & at study entry)
Disease Assessment by modified RANO (including 
appropriate imaging) 
X
X
Study Procedures & Examinations
Eligibility Assessment3,5
Demographics (incl. DoB; sex; height; race; ethnicity)
Medical history and Pre-Existing Symptoms
Physical Exam (incl. weight and ECOG Perf Status)  
x
x
x
x
x
x
x
12-Lead ECG
Vital Signs (T, HR, BP, RR). See Section 6.1.5 for assessment 
before/during/after MEDI4736 dose
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medications and Procedures
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after consent) 6
x
x
x
x
x
x
x
x
x
x
x
Quality of Life (EORTC QLQ-C30/BN20)
X
X
Neurologic Assessment in Neuro-Oncology (NANO)
X
X
Laboratory Assessments
Blood Hematology (CBC, differential, platelets)
x1
x1
x1
x1
x1
x1
x1
x1
x
x
x
Chemistry (gluc., BUN, creat., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x1
x1
x1
x1
x1
x1
x1
x1
x
x
x
Chemistry cont. (Amylase, lipase)
x1
x1
x1
x1
x1
x1
x1
x1
x
x
x
Urinalysis (Cohorts B2, B3, and C only) 
x2
x2
x2
x2
x2
x2
x2
x2
Serum pregnancy test (urine test only on Day 1)
x1
x1
x
x
MGMT expression (by standard, commercially available 
assay as per institutional guidelines)7
IDH mutation (by standard, commercially available 
assay as per institutional guidelines)7
Tumor Biopsy (PD-L1 expression)
MDSC   
Flow Cytometry 
x
PBMC 
x1
x
Long-Term Follow-up
Post Study Follow-up as described in Section 3.1.16
x
1 - pre MEDI4736 dose  on same day as infusion . Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing
2 -  pre bevacizumab dose; if urine protein dipstick is 2+ or greater, manage according to bevacizumab package insert
3 - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
4- Samples may be collected up to 28 days prior to Day 1; if collected on Day 1, collection must be pre MEDI4736 dose.
5 - For Cohorts B, B2, B3 and C, the last baseline MRI confirmation of first or second recurrence of GBM per modified RANO criteria must occur  within 14 days of Day 1 of treatment.
6 -  See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
7 - Archival results >28 days prior to the start of treatment are acceptable.  If archival results are not available, this testing should be done within 28 days of start of treatment.
Post Study 
Follow-up 
(Done at least 
every 6 months 
for up to 3 
years from 
start of 
treatment)
On-Study Follow-up6
x  (at time of progression: optional)
Every 8 weeks starting 8 weeks 
after last disease assessment
Treatment
Last Study 
Drug Admin 
+90 ± 7 days 
(End of Study)
Last Study 
Drug Admin 
+42 ± 5 days
Last Study 
Drug Admin 
+14 ± 3 days


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4 Study Objectives & Endpoints 
Primary 
Objectives 
Evaluation of Clinical Efficacy. 
 
Cohort A (newly diagnosed subjects with unmethylated MGMT GBM): 
Primary Endpoint: Overall Survival (OS) Rate at 12 months. 
Cohort B, B2, B3 (bevacizumab-naïve subjects with recurrent GBM): 
Primary Endpoint: Progression-free survival rate at 6 months (PFS-6). 
Cohort C (bevacizumab-refractory subjects with recurrent GBM): 
Primary Endpoint: Overall Survival (OS) Rate at 6 months. 
Secondary 
Objectives 
Cohorts A, B, B2, B3 and C: 
1. Evaluation of Safety and Tolerability. 
2. Evaluation of Clinical Efficacy by median Progression-Free Survival, 
and Overall Survival as well as overall response rate (ORR). 
3. Quality of Life (EORTC QLQ-30/BN20). 
Exploratory 
Objectives 
Cohorts A, B, B2, B3 and C: 
1. Evaluation of subject neurologic function (NANO scale). 
2. Evaluation of MEDI4736 biological activity. 
Per Amendment 4, the collection of samples for MEDI4736 PK, ADA, sPD-L1, and circulating 
soluble factors was removed. 
4.1 Clinical Efficacy  
The assessment of Clinical Efficacy is the primary objective of the study for all cohorts.  
However, the primary endpoints differ by cohort due to the difference in subject populations. 
4.1.1 Endpoints and Assessment Methods 
In Cohort A, the primary endpoint is the Overall Survival (OS) rate at 12 months. 
In Cohorts B, B2 and B3, the primary endpoint is the percentage of subjects who remain 
progression free at 6 months (PFS-6) 
In Cohort C, the primary endpoint is the Overall Survival (OS) rate at 6 months. 
In all cohorts, secondary efficacy endpoints are a) median progression-free survival, b) median 
overall survival, and c) overall response rate (ORR). 
4.1.1.1 Overall Survival (OS)  
For Cohort A, Overall Survival (OS) will be measured for each subject with time origin at the time 
of diagnosis until recorded date of death or last follow-up.  For Cohorts B, B2, B3, and C, OS will 
be measured for each subject with time origin at the date of Study Day 1 until recorded date of 
death or last follow-up.  If a subject is still alive, they will be censored on the date of last follow-
up.  Every effort will be made to follow subjects for overall survival after they discontinue the 
study. 


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4.1.1.2  Overall Radiographic Response Rate (ORR) 
Overall response rate (ORR) will be assessed by modified RANO criteria (122) (see Appendix 8.4).  
ORR is defined as the percentage of subjects meeting criteria of CR or PR over a period of at 
least 4 weeks.  Every attempt should be made to use whichever imaging technique(s) and test(s) 
are used initially for repeat evaluations throughout the study.  End of study tumor assessment 
will be at least 4 weeks from prior assessment, at the Investigator’s discretion, and in 
accordance with the proposed modified RANO criteria.  
Radiographic assessment of response will be performed as outlined in the Study Flowchart 
(Section 3.2) while subjects are receiving study therapy.  Following completion of study therapy, 
radiographic assessment of response will continue at regular intervals for subjects who have not 
withdrawn from the study.  Guidelines for ongoing response assessment for such subjects 
include MRI evaluation every 2 months during the first year after completing study therapy, 
every 3 months during the second year, every 4 months during the third year, and every six 
months thereafter.  For subjects who achieve a radiographic response, follow-up imaging four 
weeks later is encouraged if feasible in order to confirm the response. 
4.1.1.3 Progression-free Survival (PFS) 
Progression-free survival will be defined as the number of days from the date of first dose to the 
date of earliest disease progression based on modified RANO criteria or to the date of death, if 
disease progression does not occur.  All disease progression will be included regardless of 
whether the event occurred while subject was taking the study drug or had previously 
discontinued the study. 
4.1.2 Subject Evaluation & Statistics 
The analysis of the primary endpoint will be based on both the intent-to-treat (ITT) and the per-
protocol (PP) populations.  Subjects who received any dose of MEDI4736 and at least baseline 
and one post-baseline assessment will be included in the ITT population.  Subjects who received 
at least 75% of the planned radiotherapy doses (Cohort A only), at least 75% of the planned 
bevacizumab doses (Cohort B2, B3 and C only), and at least 75% of the planned MEDI4736 
doses, as well as, respective disease assessments, without major protocol violations, are 
considered fully evaluable and will be included in the PP population. 
In each analysis population, the rate of Overall Survival for the primary endpoints will be 
calculated using the Kaplan-Meier method at month 12 for Cohort A subjects and month 6 for 
Cohort C subjects.   
For Cohorts B, B2 and B3, the rate of progression-free survival at 6 months (PFS-6) will be 
calculated using a Kaplan-Meier Estimate and the corresponding 90% confidence intervals 
(CI).  A one-sided binomial test will be used as a sensitivity analysis method to estimate PFS-
6 and its 90% CIs.   
Tumor Response as defined by the modified RANO criteria will be summarized and analyzed 
descriptively for each cohort among subjects with measurable disease at baseline.  Ninety-five 
percent confidence intervals (95% CI) based on binomial distribution will be constructed for the 
estimated ORR. 


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The secondary endpoints of median PFS, and median OS will be calculated for the ITT population 
and PP population using the Kaplan-Meier method.  In addition, survival curves will be 
generated on the basis of these estimates. 
The analysis of PFS and OS will be updated based on data collected during the Post Study 
Follow-up (Section 3.1.16). 
4.2 Safety and Tolerability 
Assessment of overall safety and tolerability will be performed by the internal data safety 
monitoring panel on an ongoing basis, based on data review and regular conference calls with 
the Investigators. 
4.2.1 Endpoints & Assessment Methods 
Clinical laboratory tests, vital sign and weight measurements, physical exams, performance 
status evaluation, MRI scans and any other medically indicated assessments including subject 
interviews, will be performed to detect new abnormalities and deteriorations of any pre-existing 
conditions.  The Investigator will evaluate any laboratory abnormalities for clinical significance, 
and clinically significant abnormalities will be recorded as adverse events.  All “treatment-
emergent” clinically significant abnormalities and deteriorations from time of signing of 
informed consent to the end of study visit should be recorded in the Case Report Forms as 
adverse events and graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03.  See further adverse event documentation and 
reporting requirements in Section 7.1. 
4.2.2 Subject Evaluation & Statistics 
All subjects who receive any dose of MEDI4736 will be evaluated for safety and tolerability.  
Appropriate summaries of AEs, laboratory data and vital sign data will be presented.  AEs will be 
listed individually per subject according to CTCAE version 4.03, and the number of subjects 
experiencing each AE will be summarized using descriptive statistics. 
4.3 Health Related Quality of Life 
4.3.1 Endpoints & Assessment Methods 
Health related quality of life (HRQoL) will be self-reported and measured with the use of the 
validated core quality of life questionnaire (QLQ-C30) and a quality of life questionnaire 
specifically for subjects with brain tumors (BN-20) of the European Organization for Research 
and Treatment of Cancer (123-125) in each treatment cohort (see Appendix 8.5).  The 
questionnaires can be completed by the subject or with the assistance of the examiner at 
baseline prior to initiation of study therapy, and then at study visits that include an MRI 
assessment while on study therapy (approximately every two months) according to the schedule 
in Section 3.2.  The questionnaires should be completed prior to discussing treatment response 
at each specified visit whenever possible. 
4.3.2 Subject Evaluation & Statistics 
The evaluation of HRQoL will be measured by mean changes from baseline in the EORTC-QLQ-30 
global health status/QoL composite scale and by mean changes from baseline in the remaining 


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EORTC QLQ-C30 and BN-20 scales.  All scales and single items are scored on a categorical scale 
and linearly transformed to 0-to-100 scales with 1) higher scores for a functional scale 
representing higher levels of functioning, 2) higher scores for the global health status/quality of 
life representing higher levels of global health status/quality of life, 3) and higher scores for a 
symptom scale representing higher level of symptoms.   
4.4 Neurologic Function 
4.4.1  Endpoint and Assessment Method 
Neurologic function of subjects in each treatment cohort will be assessed using The Neurologic 
Assessment in Neuro-Oncology (NANO) Scale: A Tool To Assess Neurologic Function for 
Integration in the Radiologic Assessment in Neuro-Oncology (RANO) Criteria (126) (see 
Appendix 8.5).  The NANO scale is an objective and quantifiable metric of neurologic function 
that incorporates direct observation/testing of eight relevant neurologic domains designed to be 
evaluated quickly during a routine clinic visit.  The NANO scale is designed to complement 
subjective, subject-reported outcomes such as health-related quality of life questionnaires.  
Level of function scores for each neurologic domain will be evaluated by a physician, physician 
assistant or nurse practitioner at baseline prior to initiation of study therapy, and then at study 
visits that include an MRI assessment while on study therapy (approximately every two months) 
according to the schedule in Section 3.2.  
4.4.2 Subject Evaluation and Statistics 
For this study, the NANO scale will not be used to define clinical progression.  Changes in level of 
function scores for each neurologic domain defined by the NANO scale will be descriptively 
summarized on an individual subject basis over time.  For each cohort, the median survival of 
subjects with and without significant neurologic decline as defined by the NANO scale (a ≥ 2 
point decline in one or more neurologic domains attributable to underlying tumor and not due 
to co-morbid event or change in concurrent medication) will be estimated. 
4.5 Biological activity of MEDI4736 
Samples for exploratory pharmacodynamic assessments will be collected according to the 
schedule presented in Section 3.2. 


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4.5.1 Endpoints & Assessment Methods 
Assessments may include but not be limited to: 
• 
MEDI4736 PK and Anti-drug antibodies (ADA)  
• 
Serum sPD-L1 levels  
• 
Flow cytometry (immune monitoring) 
• 
Peripheral blood mononuclear cells (PBMCs) will be collected and banked to potentially 
assess immune cell phenotypes and function as well as immune diversity. 
• 
Levels of Circulating soluble factors (cytokine profiling) 
• 
Levels of circulating myeloid derived suppressor cells (MDSC) 
• 
PD-L1 tumor expression in archived tumor and fresh tumor, if available. 
 
Per Amendment 4, the collection of samples for MEDI4736 PK, ADA, sPD-L1, and circulating 
soluble factors was removed. 
4.5.2 Subject Evaluation & Statistics 
Subjects who received at least one dose of MEDI4736, and provide baseline and at least one 
post-treatment sample (if applicable), will be evaluated.  Results from these assessments will be 
evaluated in relation to outcome.  Descriptive statistics will be used to summarize these 
measurements.  
4.6 Exploratory Review and Analysis of Radiological Scans and Data 
An exploratory review and analysis of radiological scans and other appropriate data will be 
conducted. See Appendix 8.7.9 for additional details. 
4.7 Exploratory Analysis of Mutational Load  
An exploratory analysis of mutational load will be conducted. See Appendix 8.7.10 for additional 
details. 
 


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5 Subject Eligibility 
Note: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
Cohort A: 
1. 
Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible 
for standard radiation therapy; 
Cohorts B, B2, B3 and C: 
2. 
First or second recurrence of GBM by diagnostic biopsy or contrast enhanced MRI per 
modified RANO criteria (122), with last baseline MRI confirmation within 14 days prior 
to Study Day 1; 
[NOTE: Recurrence is defined as progression following therapy (i.e., chemotherapy; radiation).  If 
the subject had a surgical resection for relapsed disease and no anti-tumor therapy was 
administered for up to 12 weeks, and the subject has further evidence of tumor growth or 
undergoes another resection, this will be considered as one episode of recurrence.] 
3. 
On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease 
outside of the radiation field or histopathologic confirmation of unequivocal tumor); 
4. 
Cohort B, B2, B3: No prior VEGF/VEGFR targeted therapy; 
Cohort C: No more than one prior bevacizumab regimen; 
5. 
Recovery from any prior treatment clinically significant, related adverse events to grade 
≤ 1 or pretreatment baseline with the exception of alopecia and laboratory values listed 
per inclusion criteria; 
Cohorts A, B, B2, B3 and C: 
6. 
Subjects with measurable or non-measurable disease 
7. 
Histopathologic confirmation of glioblastoma; 
8. 
At the time of Study Day 1, subjects must be at least 4 weeks since major surgical 
procedure, open biopsy, or significant traumatic injury; there should be no anticipation 
of need for major surgical procedure during the course of the study. 
 
There should be no core biopsy or other minor surgical procedure, excluding placement 
of a vascular access device, within 7 days prior to Study Day 1. 
9. 
Subjects who have previously been treated with the Optune™ device are eligible for the 
study as long as toxicity related to the treatment has resolved to ≤ Grade 1 or baseline 
10. 
ECOG ≤ 1 or Karnofsky performance status of ≥70; 
11. 
Adequate hematologic, renal and hepatic function, as defined below: 
• 
Absolute Neutrophil Count ≥ 1000/mm3 
• 
Platelet count ≥ 100,000/mm3 
• 
Total bilirubin ≤ 1.5 x ULN; or if subject has Gilbert syndrome, then total bilirubin 
≤ 3 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN  
• 
Creatinine ≤ 1.5x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the 
Cockcroft-Gault formula): 


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o Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum creatinine in 
mg/dL 
o Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in 
mg/dL 
Cohorts B2, B3 and C 
• 
Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on dipstick, 
unless quantitative protein is < 1000 mg in a 24 hour urine sample 
12. 
Age ≥ 18 years at date of consent 
13. 
Written informed consent and any locally required authorization (e.g., Health Insurance 
Portability and Accountability Act [HIPAA] in the USA) obtained from the subject/legal 
representative prior to performing any protocol-related procedures, including screening 
evaluations; 
 
 


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5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
All Cohorts  
1. 
Primary tumors localized to the brainstem or spinal cord; 
2. 
Locally directed therapies including but not limited to stereotactic radiosurgery, re-
irradiation, Gliadel, and therapeutics administered by direct injection or convection-
enhanced delivery within 6 months of start of study treatment; 
3. 
Prior exposure to MEDI4736 or other anti-PD-1, anti-PD-L1, anti-CTLA4 antibodies; 
4. 
Presence of diffuse leptomeningeal disease or extracranial disease; 
5. 
Active, suspected or prior documented autoimmune disease (including inflammatory 
bowel disease, celiac disease, irritable bowel syndrome, Wegner’s granulomatosis and 
Hashimoto’s thyroiditis).  Subjects with vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll; 
6. 
Known primary immunodeficiency or active HIV; 
7. 
Known active or chronic viral hepatitis or history of any type of hepatitis within the last 
6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or 
hepatitis C virus ribonucleic acid (HCV antibody); 
8. 
History of organ transplant requiring use of immunosuppressive medication; 
9. 
History of active tuberculosis; 
10. 
Significant active systemic illness including infections requiring intravenous antibiotics; 
11. 
Current pneumonitis or interstitial lung disease; 
12. 
Other invasive malignancy within 2 years prior to entry into the study, except for those 
treated with surgical therapy only; 
13. 
History of severe allergic reactions to any unknown allergens or any components of the 
study drugs; 
14. 
Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-
refractory irAE; 
15. 
Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study; 
16. 
Lack of availability for follow-up assessments; 
17. 
Lack of availability for Post Study Follow-up contacts to determine relapse and survival; 
18. 
Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG); 
19. 
Women of childbearing potential not using a medically acceptable means of 
contraception for the duration of the study and unsterilized males not willing to abide 
by requirements for contraception as stated in Section 5.4; 
20. 
If a subject previously received another investigational treatment, the last dose of 
investigational treatment was administered within 4 weeks of Day 1 of the study; 
21. 
Any condition that, in the clinical judgment of the treating physician, is likely to prevent 
the subject from complying with any aspect of the protocol or that may put the subject 
at unacceptable risk. 


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22. 
Cohorts B2, B3 and C: 
• 
Evidence of hemorrhage on the baseline MRI or CT scan other than those that 
are ≤ grade 1 and either post-operative or stable on at least two consecutive 
scans 
• 
Current use of warfarin sodium or any other Coumadin-derivative 
anticoagulant. Participant must be off Coumadin-derivative anticoagulants for 
at least seven days prior to starting study drug.  Low molecular weight heparin 
and Factor Xa antagonists are allowed 
• 
History of clinically significant bleeding within 6 months of enrollment 
• 
History of arterial thromboembolism within 12 months prior to enrollment 
• 
Inadequately controlled hypertension (defined as systolic blood pressure >150 
and/or diastolic blood pressure > 90 mmHg on antihypertensive medications) 
• 
Any prior history of hypertensive crisis or hypertensive encephalopathy 
• 
Clinically significant cardiovascular disease within 12 months prior to 
enrollment (or randomization), including myocardial infarction, unstable 
angina, grade 2 or greater peripheral vascular disease, cerebrovascular 
accident, transient ischemic attack, congestive heart failure, or arrhythmias not 
controlled by outpatient medication, percutaneous transluminal coronary 
angioplasty/stent  
• 
Evidence of bleeding diathesis or coagulopathy 
• 
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 6 months prior to study enrollment 
• 
Serious, non-healing wound, ulcer, or bone fracture 
23. 
Subjects must not donate blood while on study and for at least 90 days following the 
last MED4736 treatment. 
 
 
 


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5.3 Restrictions on Concomitant Therapies 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study.  Any concomitant medication(s), including herbal 
preparations taken during the study will be recorded. 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care as described in Section 5.3.2, #8. 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with high dose corticosteroids or other immunosuppressive treatments 
(e.g. dexamethasone > 4mg/day or bioequivalent for at least 3 days within 1 week of Study 
Day 1, methotrexate, chloroquine, azathioprine).  See Section 5.3.2 for exceptions. 
Wash-out period: 4 weeks prior to Study Day 1 or as stated. 
2. 
Other cancer therapy (chemotherapy, radiation or immunotherapy).  
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Study Day 1 (6 
weeks for nitrosoureas). 
3. 
Live attenuated vaccines within 30 days before first and after last dose of MEDI4736. 
5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
For subjects in Cohort C, bevacizumab may continue to be administered up to the start of 
study treatment if the subject is currently receiving it.  A washout period for bevacizumab is 
not required. 
2. 
Systemic high dose (>4 mg/day) dexamethasone or bioequivalent corticosteroids to treat 
cerebral edema and for supportive postoperative management. 
3. 
Intranasal, inhaled or oral corticosteroids for treating mild to moderate asthma or allergies, 
or topical steroids for localized (< 5% of body surface area) dermatitis, not to exceed 
10mg/day prednisone or bioequivalent corticosteroid. 
4. 
Physiologic replacement of glucocorticoids as maintenance therapy for adrenal 
insufficiency.  Standard doses of hydrocortisone for maintenance therapy are up to 10–20 
mg/m2/day divided 2–4 times per day.  For a subject with a body surface area (BSA) of 1.73 
m2, this translates to a total dose of up to 34.6 mg of hydrocortisone per day.  The 
equivalent dose of dexamethasone is up to 1.2 mg per day.  Some subjects may additionally 
receive mineralocorticoid-replacement maintenance therapy with fludrocortisone.  The 
maintenance dose of fludrocortisone for this indication is 0.05–0.1 mg/day. 
5. 
NSAIDs, acetylsalicylic acid and specific COX-2 inhibitors. 
6. 
Antihistamines and other non-steroidal anti-allergy medication. 
7. 
Hormone or hormone-related anti-cancer therapy. 
8. 
At the discretion of the Investigator, any drug or non-drug therapy necessary to treat any 
condition arising during the study, including high dose corticosteroids to treat MEDI4736 
related immune-mediated adverse reactions.  Subjects should receive full supportive care, 
including transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheal, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.  Use of anticoagulants such as warfarin is 


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permitted however, caution should be exercised in subjects receiving bevacizumab (Cohorts 
B2, B3 and C) and additional International Normalized Ratio (INR) monitoring is 
recommended. 
All prescription and nonprescription drugs must be recorded, listing generic (preferably) or brand 
name, indication, dose, route and dates of administration.  All non-drug therapies must also be 
recorded. 
5.4 Special Requirements for Contraception  
Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least one highly effective method of contraception (see table below) from 
the time of screening and must agree to continue using such precautions for 90 days after the 
last dose of MED4736. Non-sterilized male partners of a female subject must use male condoms 
plus spermicide throughout this period. Cessation of birth control after this point should be 
discussed with a responsible physician. Not engaging in sexual activity for the total duration of 
the trial and the drug washout period is an acceptable practice; however, periodic abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of contraception.  
Female subjects should also refrain from breastfeeding throughout the period described above. 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
Females will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:  
• 
Females <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
• 
Females ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy.  
Non-sterilized male subjects who are sexually active with a female partner of childbearing 
potential must use male condoms plus spermicide from screening through 90 days after last 
dose of MEDI4736. Female partners (of childbearing potential) of a male subject must use a 
highly effective method of contraception (see table below) throughout this period. Cessation of 
birth control after this point should be discussed with a responsible physician. Not engaging in 
sexual activity for the total duration of the trial and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  
Male subjects should refrain from sperm donation throughout the period described above.  


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Highly effective methods of contraception are described in the table below. A highly effective 
method of contraception is defined as one that results in a low failure rate (i.e. less than 1% per 
year) when used consistently and correctly. Note that some contraception methods are not 
considered highly effective (e.g. male or female condom with or without spermicide; female 
cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine 
device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not 
the primary mode of action [excluding Cerazette/desogestrel which is considered highly 
effective]; and triphasic combined oral contraceptive pills). 
Acceptable highly effective methods of contraception are described in the following table: 
Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)b 
• 
“Implants”: Etonogestrel-releasing 
implants: e.g., Implanon® or Norplan®  
• 
“Intravaginal Devices”: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g., NuvaRing®   
• 
“Injection”: Medroxyprogesterone 
injection: e.g., Depo-Provera®   
• 
“Combined Pill”: Normal and low dose 
combined oral contraceptive pill 
• 
“Patch”: Norelgestromin / ethinylestradiol-
releasing transdermal system: e.g., Ortho 
Evra®    
• 
“Minipillc”: Progesterone based oral 
contraceptive pill using desogestrel: e.g., 
Cerazette®  
a 
Highly effective (i.e. failure rate of <1% per year)  
b 
This is also considered a hormonal method 
c 
 Cerazette® is currently the only highly effective progesterone based pill 
 
 
 


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6 Study Drug Preparation and Administration 
6.1 MEDI4736 (Durvalumab) 
MEDI4736 is supplied by the Sponsor.  Commercially available water for injection (WFI) and 
0.9% (w/v) saline or 5% (w/v) dextrose will be supplied by each site.  Please see Section 7.2.9, 
Study Drug Shipments & Accountability, for additional details. 
6.1.1 Study Drug Information 
 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification or in the in the QA 
Disposition of Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: 
Single use vial  
Material: 
 
Size: 
 
Formulation 
Lyophilized powder containing 200 mg MEDI4736. When 
reconstituted with 4 mL of WFI, the solution contains 50 
mg/mL MEDI4736, 26 mM histidine/histidine-HCl, 275 mM 
trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 
80, at pH 6.0. 
Active Ingredient Content 
Mass/Weight: 
200 mg 
Volume: 
n/a 
Concentration: 
n/a 
Storage Conditions 
+2°C to +8°C 
Stability after 
reconstitution 
24h at 2 to 8°C and 4h at 25°C/ambient 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
 
6.1.2 Investigational Product Inspection 
Each vial of MEDI4736 selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product, the Investigator, Site Monitor, and Sponsor 
should be notified immediately. 
6.1.3 Preparation  
Preparation of MEDI4736 and preparation of the intravenous bag are to be performed 
aseptically by the IP Manager or designated personnel. No incompatibilities between MEDI4736 
and polyvinylchloride or polyolefin copolymers have been observed. 
MEDI4736 requires reconstitution prior to use.  The reconstitution should be performed with 
4 mL sterile WFI for each vial with the liquid added gently to the side of the vial to minimize 
product foaming.  The vial should be gently rotated or swirled for 5 minutes or until dissolution 
is complete.  The vial should not be shaken or vigorously agitated.  Reconstituted MEDI4736 
should stand undisturbed at room temperature for a minimum of 5 minutes or until the solution 


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clarifies.  The reconstituted solution should appear clear or slightly opalescent.  A thin layer of 
bubbles on the liquid surface is considered normal. 
Doses will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter.  The 
volume of reconstituted MEDI4736 to add to the IV bag is calculated as follows: 
Volume of 
MEDI4736 (mL)  
= 
Dose 
(mg/kg) 
X 
Subject Weight 
(kg) 
÷ 
MEDI4736 
Concentration 
(nominal 50 mg/mL) 
 
 
A volume of 0.9% (w/v) saline or 5% (w/v) dextrose equal to the calculated volume of MEDI4736 
to be added to the IV bag must be removed from the bag prior to addition of MEDI4736.  The 
calculated volume of MEDI4736 is then added to the IV bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag.   
Example: For a subject weighing 80 kg and dosed at 10 mg/kg, 16 mL [10 mg/kg x 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted in a 250 mL IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose.  First, 16.0 mL of diluent is removed from the IV bag, and then 16 mL of 
MEDI4736 is added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity of 
the dose in the bag and the diluted MEDI4736 is administered as described below.  
6.1.4 Administration 
6.1.4.1 MEDI4736 Administration 
The first day of dosing will be considered Day 1.  Following preparation of the dose, the entire 
contents of the IV bag should be administered as an IV infusion over 60 (± 5) minutes, using a 
0.2- or 0.22-μm in-line filter.  An infusion of less than 55 minutes is considered a deviation.   
After the contents of the IV bag are fully administered, the IV line will be flushed with a volume 
of IV diluent equal to the priming volume of the infusion set used (unless prohibited by 
institutional practice). Alternatively, the infusion will be completed according to institutional 
policy to ensure the full dose is administered. If the line was not flushed, documentation is 
required.    
See Appendix 8.6.1.2 for details regarding infusion-related reactions. 
Each dose of investigational product should be administered using the following guidelines: 
A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of investigational product(s). Fully functional resuscitation facilities 
should be available.  
Investigational product(s) must not be administered via IV push or bolus but as an IV infusion. 
Investigational product(s) must be administered at room temperature by controlled infusion 
into a peripheral vein or central line.  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. 


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The total time between reconstitution of MEDI4736 to start of administration should not exceed 
4 hours at room temperature or 24 hours at 2 to 8 °C (36°F to 46°F). Standard infusion time is 60 
± 5 minutes. An infusion of less than 55 minutes is considered a deviation. However, if there are 
interruptions during infusion, the total allowed infusion time should not exceed 8 hours at room 
temperature.  If either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials.   
MEDI4736 does not contain preservatives and any unused portion must be discarded. 
MEDI4736 solution should not be infused with other solutions or medications. 
The date, start time, interruption, and completion time of MEDI4736 administration must be 
recorded in the source documents. 
Subjects will be monitored before, during and after infusion with assessment of vital signs 
according to Section 6.1.5. 
6.1.4.2 Cohort A and Cohorts B2, B3 and C Administration 
In Cohort A, focal radiotherapy will be administered at 2 Gy daily for a total of 60 Gy over 30 
fractions per local institutional guidelines or local prescribing information.  Treatment with 
MEDI4736 will start on Day 1 of radiotherapy.  On days when radiotherapy and MEDI4736 
overlap, radiotherapy will first be administered followed by MEDI4736.  Subjects will be 
monitored during and after MEDI4736 infusion as indicated in Section 6.1.5. 
In Cohorts B2, B3 and C, subjects will first be administered MEDI4736 and monitored according 
to Section 6.1.5.  Following, the observation period, bevacizumab will be infused, according to 
prescribing information. 
6.1.5 Monitoring of MEDI4736 Dose Administration 
Subjects will be monitored before, during and after infusion with assessment of vital signs 
according to the table below: 
Vital Signs Assessment on 
Study Drug Administration 
Days 
Pre-
dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
Post infusion  
+ 30 minutes  
(± 5 minutes) 
Post Infusion  
+ 60 minutes  
(± 5minutes) 
MEDI4736 Vital Signs 
X 
every 15 minutes  
(± 5 minutes) 
X 
X 
x 
 
If a subject tolerates treatment well for the first 4 doses of MEDI4736 (i.e., no infusion 
reactions), subsequent infusions in that subject can be monitored according to the following 
schedule.  A longer duration of observation after the end of infusion can be used if the 
Investigator deems it clinically necessary. 
 


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Vital Signs Assessment on Study 
Drug Administration Days (after 
week 8 [after first 4 doses]) 
Pre-dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
Post infusion + 15 
minutes (± 5 minutes) 
MEDI4736 Vital Signs 
X 
every 30 minutes 
(± 5 minutes) 
X 
X 
 
6.2 Estimated Study Requirements 
Drug 
Required Quantity 
MEDI4736 
12500 vials 
Additional MEDI4736 for optional study 
treatment extension per Section 3.1.12 
 
2000 vials 
Radiotherapy 
Provided by the sites as standard of care 
Bevacizumab 
Provided by the sites as standard of care  
 
6.3 Drug Overdose Management 
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in this protocol by >10%.  There are no known antidotes available for 
MEDI4736.  Any overdoses with this drug should be managed symptomatically and reported, 
with or without associated AEs/SAEs, according to Sections 7.1.2.2, 7.1.5, and 7.1.6.  
 
 


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7 Administrative, Legal & Ethical Requirements 
7.1 Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the 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 (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of LICR studies to include any events, intercurrent diseases and accidents observed 
while the subject is on study, i.e., during the actual treatment period, as well as during drug-
free, pre- and post-treatment periods, under placebo or in a reference group receiving drug or 
non-drug therapy or no treatment. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient or subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient/subject or may require intervention to 
prevent one of the outcomes listed in the definition above.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
patient/subject/event outcome or action criteria usually associated with events that pose a 
threat to patient’s or subject’s life or vital functions.  Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. 


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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (see Section 8.3 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.3) 
3. Hepatic Function Abnormality (as defined in Section 7.1.8). 
7.1.2.1 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of MEDI4736. 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see Section 7.1.6). Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, the Investigator or other site personnel 
should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when 
he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of MEDI4736. 
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last drug 
dose should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use. 


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7.1.2.2 Overdose 
Any overdose (as defined in Section 6.3) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor. If the 
overdose results in an AE, the AE must also be recorded as an AE according to Section 7.1.5. 
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 according to Section 7.1.6. There is currently no specific treatment in the 
event of an overdose of the study drugs. The Investigator will use clinical judgment to treat any 
overdose. See Section 6.3 for additional details. 
7.1.2.3 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the Investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 


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relationship.  Information provided in the IB and/or in the “Background” of this protocol may 
support these evaluations. 
7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship. The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4.  This documentation is required for 
all AEs that occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (See Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE as per Sections 7.1.1 and 7.1.2, irrespective of suspected 
causation, must be reported by the Investigator to the Sponsor’s Drug Safety Contact 
(primarily) or, alternatively, to the Primary Sponsor Contact, within 24 hours of becoming 
aware of the event.  This should be done using the “Initial Serious Adverse Event Report 
Form,” provided by the Sponsor, or, if Medidata RAVE data capture is utilized, using the 
respective Adverse Event and Safety Case Summary eCRFs.  This includes any deaths that 
occur after the off-study date, but within 30 days of last study drug administration.  
(Pregnancy, overdose, and hepatic function abnormality will be handled according to Section 
7.1.2.)  Note: If an SAE cannot be reported through the “Initial Serious Adverse Event Report 
Form” or through Medidata RAVE within 24 hours of becoming aware of the event, the 
Sponsor’s Drug Safety Contact (primarily) or, alternatively, the Primary Sponsor Contact, must 
be contacted by phone or email within 24 hours of becoming aware of the event. In this case, 
the phone or email notification can then be followed up by an “Initial Serious Adverse Event 
Report Form” or through Medidata RAVE within one working day of the event. 
The expedited reports should be directed by fax or e-mail to the Drug Safety Contact (primarily) 
or, alternatively, the Primary Sponsor Contact, as specified in “Sponsor Information,” 
Appendix 8.3.  Studies utilizing the Medidata “Safety Gateway”, built into the eCRF, and 
respective SAE reporting procedures, do not require reporting by fax or email.  Questions 
related to “Safety Gateway” procedures should be directed to the Drug Safety Contact or 
Primary Sponsor Contact. 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Serious adverse events must also be reported by the Principal Investigator to the respective 
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Sponsor.  Institutional Review Boards may have specific rules on which Adverse Events need to 
be reported expeditiously, as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory authorities and 
other Investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered.  In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available, using the “SAE 
Follow-up Report Form”, provided by the Sponsor, or, if Medidata RAVE data capture is utilized, 
using the respective Adverse Event and Safety Case Summary eCRFs. 
7.1.8 Adverse Events of Special Interest (AESIs) 
MEDI4736, as an anti-PD-L1 antibody that binds with high affinity and specificity to PD-L1 and 
blocks its binding to PD-1 and CD80, promotes anti-tumor immunity and tumor cell killing.  Its 
potential risks are based on this mechanism of action and include immune-mediated reactions, 
such as enterocolitis, dermatitis, hepatotoxicity or hepatitis, endocrinopathy, neurotoxicity and 
pneumonitis.  Immune checkpoint antibodies, such as anti-PD-1 or anti-CTLA-4, can have a wide 
spectrum of immune-mediated reactions of inflammatory nature and can affect any organ of 
the body. 
An AESI is an event of scientific and medical interest specific to understanding of the 
investigational product(s) and may require close monitoring and rapid communication by the 
Investigator to the Sponsor.  An AESI may be serious or non-serious.  The rapid recording of all 
AEs including AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of the investigational product(s).   
AESIs for MEDI4736 include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with MEDI4736 monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
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If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with MEDI4736 and those considered AESIs for the purpose of this study are 
listed below.  Further information on these AESIs (e.g. presenting symptoms) can be found in 
the current version of the MEDI4736 Investigator’s Brochure. Guidelines for the management of 
subjects experiencing these toxicities can be found in Appendices 8.6 and 8.6.1 and in the 
following Medimmune guideline: “Medimmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune- mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 (durvalumab) Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab monotherapy).” 
• 
Colitis 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs following 
dosing with MEDI4736.  In rare cases colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome, if not properly managed. 
• 
Pneumonitis 
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-
L1antibodies.(6) (48)  Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatotoxicty, Hepatitis) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies.(6)  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated 
with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of 
ipilimumab-treated subjects included general weakness, fatigue, nausea and/or mild fever 
and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total 
bilirubin. Hepatic function abnormality is defined as any increase in ALT or AST to greater 
than 3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN.  
Concurrent findings are those that derive from a single blood draw or from separate 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 
concurrent or pre-existing disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product. Cases where a 
subject shows an AST or ALT ≥ 3 x ULN or total bilirubin ≥ 2 x 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. 
• 
Neurotoxicity (Neuropathy/Neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 


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• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators 
should obtain an endocrinology consult and institute appropriate management which may 
include the administration of insulin. 
• 
Dermatitis  
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines. 
• 
Nephritis 
Consult with Nephrologist should be done as well as monitoring for signs and symptoms 
that may be related to changes in renal function (e.g., routine urinalysis, elevated serum 
BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in 
urine output, proteinuria, etc.). Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections, etc.). Steroids should be 
considered in the absence of clear alternative etiology even for low grade events (Grade 2), 
in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis); increased serum lipase, increased serum amylase). 
• 
Infusion Reactions  
Adverse events of infusion reactions (also termed infusion-related reactions) are defined as 
all AEs occurring from the start of the study treatment infusion up to 48 hours after the 
infusion start time. 
• 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy.(6)  As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of monoclonal antibodies 
(MAbs) can be caused by various mechanisms, including acute anaphylactic (IgE-mediated) 
and anaphylactoid reactions against the MAb, and serum sickness.  Acute allergic reactions 
may occur, may be severe, and may result in death.  Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
 
7.2 Administrative Sponsor Requirements 
7.2.1 Pre-Study Requirements 
The following is required before study drug can be shipped to the study site: 
• 
Satisfactory Site Validation (conducted by Sponsor, if applicable) 
• 
Signed Statement of Investigator 
• 
Regulatory Approval (e.g., active IND or equivalent) 


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• 
Institutional Review Board approval of Protocol and Informed Consent Form 
• 
Executed Clinical Trial Agreement (if applicable) 
 
7.2.2 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.3 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data 
entry, query management and sign-off.  Systems used for electronic data capture will be 
compliant with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local 
regulatory agency guidelines (whichever provides the greatest protection to the integrity of the 
data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections.  This signature will indicate a 
thorough inspection of the data in the CRF and will certify its content. 
7.2.4 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.5 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
validation, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or other 
Sponsor staff will meet with the Investigator staff and require direct access to source 
data/documents.  Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits.  Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and Sponsor’s proprietary information will be 
exercised. 
It is the Clinical Monitor’s responsibility to inspect the case report forms at regular intervals 
throughout the trial to verify adherence to the protocol, the completeness, accuracy and 


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consistency of the data, and adherence to Good Clinical Practice guidelines.  The Clinical 
Monitor should have access to subject charts, laboratory reports and other subject records 
needed to verify the entries on the case report forms (“source data verification”). 
7.2.6 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals.  However, in this case, approval must be obtained as soon as possible after 
implementation.  Implementation of administrative amendments that do not affect the safety of 
the subjects do usually not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor if circumstances permit, to discuss the 
planned course of action.  Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.7 Premature Subject Withdrawal 
A subject may withdraw from treatment or from the study at any time for any reason without 
prejudice to his/her future medical care by the physician or at the study site.  Likewise, the 
Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw, all efforts will be made to 
complete the required study procedures and report the treatment observations as thoroughly 
as possible. 
A complete final evaluation should be made at the time of the subject’s withdrawal from 
treatment or from study.  The appropriate section in the case report form should be completed 
with an explanation of why the subject is withdrawing, and an attempt should be made to 
perform a follow-up evaluation. 
7.2.8 Early Trial Termination 
Sponsor and Investigator have the right to terminate the study early.  Specific study stopping 
rules are listed in Section 3.1.14.  In such case, one party must notify the other in advance in 
writing about the intent of and the reasons for the termination.  The Investigator must also 
notify the appropriate Institutional Review Board accordingly. 
7.2.9 Study Drug Shipments & Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably, the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the Investigator/pharmacy (if applicable) 


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• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The 
Investigator is responsible for seeing to it that all used and unused trial supplies are accounted 
for.  At the end of the study, the Clinical Monitor will also collect the original study drug 
dispensing records. 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal & Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The Investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 
7.3.2 Informed Consent 
The Investigator must obtain witnessed (if applicable) written informed consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study 
procedures are performed.  The subject should be given a copy of the informed consent 
documentation.  The original signed and dated informed consent form must be retained in the 
study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Institutional Review Board 
The Investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and informed consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The Investigator must report Serious Adverse Events (SAEs) to the appropriate Institutional 
Review Board in accordance with the Institutional Review Board’s rules and guidelines (see also 
Section 7.1). 
The Investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study.  If so 
required by the Institutional Review Board, the Investigator must provide study reports on an 
annual basis and upon completion of the study. 


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All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the case report forms or other 
documents submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., 
signed informed consent form) should be kept in a strictly confidential section of the study file 
by the Investigator. 
The Investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As 
part of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
7.3.5 Inclusion of Women and Minorities 
Both men and women and members of all ethnic groups are eligible for this trial.  The expected 
distribution of men and women enrolled is based on the experience with other clinical trials at 
the study sites included in this study.  The anticipated study population will be about 50% male 
and 50% female. 
 
 


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8 Appendices 
8.1 Protocol Version History 
Version 000 (Original)  
Issue Date: 23-July-2014 
Summary of Changes: Original Issue 
 
Version 001 (Amendment 1) 
Issue Date: 02-April-2015 
Summary of Changes: 
 
Based on updated information from MedImmune and to provide clarifications for the protocol, 
updates for this amendment are outlined below.  Due to the extent of changes made in this 
amendment, a separate document (LUD2013-006 Amendment 1 Summary of Changes) was 
generated.  The outline of changes is as follows: 
• 
Synopsis: The duration of the DLT evaluation period was corrected from 10 weeks to 
6 weeks for Cohort C. 
• 
Section 2 (Study Rationale): Language was updated to clarify that subjects in Cohort A will 
not receive standard first line therapy of temozolomide + radiotherapy. 
• 
Section 3.1.5 (Number of Sites/Subjects): The number of subjects was changed from 96 to 
108, and the number of sites was changed from 6 to 7. 
• 
Section 3.1.6.1 (Cohort A, Sample Size Considerations): In paragraph 2, the following 
sentence was changed (26 was changed to 24) “With 80% power and 0.05 significance 
level, using a one-sided exact binomial, to test a null hypothesis of 50% in historical 
controls against a one-sided alternative of 70% requires 24 of 37 subjects to be alive at 12 
months.” 
• 
Section 3.1.6.2 (Cohort B, Sample Size Considerations): In the next to last sentence, ORR 
was changed to PFS-6. 
• 
Section 3.1.6.3 (Cohort C, Sample Size Considerations): Additional background information 
and some wording corrections were added to provide support to the selection of the null 
hypothesis.  A clear statement regarding the number of subjects necessary to be alive at 6 
months in order to accept the alternative hypothesis was also added. 
• 
Section 3.1.7 (Treatment Arms and Treatment Schema): For Cohorts B and C, it was 
clarified that the last baseline MRI confirmation of first or second recurrence of GBM must 
occur within 14 days of Day 1 of treatment.  Clarification was also provided to indicate 
that the Post Study Follow-up will continue for 3 years from initial treatment. 
• 
Section 3.1.9 (DLT and MTD): Additional DLT exclusions have been added, and the entire 
section was updated and restructured to be consistent with current MedImmune 
recommendations. Duration of DLT evaluation periods was added for the cohorts, and 
clarification of the DLT definition and permitted continuation was provided. 
• 
Section 3.1.10 (Subject Withdrawal):  
o Point 2 was clarified to indicate that subjects who experience DLTs of MEDI4736 at 
any time will be withdrawn from treatment and proceed to the On Study Follow-up 
period.  
o Death was added as a reason (#9) for withdrawal. 


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o The language has also been updated to clarify that subjects who are withdrawn from 
the study will proceed to the 90 day On Study Follow-up period, with the exception of 
subjects who start other anti-cancer therapy who should immediately proceed to Post 
Study Follow-up. 
• 
Section 3.1.11 (Subject Evaluability and Replacement): The duration of the DLT evaluation 
periods for Cohorts A and C were deleted, and the DLT evaluability was clarified based on 
changes to Section 3.1.9. 
• 
Section 3.1.14 (Safety Monitoring and Study Stopping Rules): Point 2 was changed to 
indicate that anaphylactic reaction refers to severe reactions such as those associated 
with respiratory and cardiovascular failure. 
• 
Section 3.1.16 (Post Study Follow-up): Clarification was added to indicate that, for all 
subjects, there will be an On Study Follow-up for 90 days after the last MEDI4736 
treatment, which will include collection of AE data.  Following the On Study Follow-up, 
there will be a Post Study Follow-up.  
• 
Section 3.2 (Study Flowchart): 
o The timing of Day 8 MEDI4736 PK and sPD-L1 samples for Cohort C was changed to 
single sampling only. 
o T3 and T4 have been clarified to indicate that Free T3 and Free T4 should be collected. 
o The Week 4 and Week 6 Physical exams and ECOG assessments have been moved to 
Week 3 and Week 5, respectively.   
o The End of Study Period was renamed as the On Study Follow-up.  A footnote was 
added to indicate that during the On Study Follow-up, subjects who complete the 
study and those who discontinue treatment or are prematurely withdrawn from the 
study will be followed for 90 days post last day of treatment, and all AE s will be 
collected during the 90 day On Study Follow-up. 
o The flowchart was updated to clarify that there is a Post Study Follow-up schedule 
that is separate from the 90 day On Study Follow-up.   
o A footnote was added to indicate that, for Cohorts B and C, the last baseline MRI 
confirmation of first or second recurrence of GBM recurrence must occur within 14 
days of Day 1 of treatment. 
o For the footnotes for pre dose samples, timeframes were added for the correlative 
samples (i.e., up to 15 minutes prior to start of infusion); for post infusion, a 
timeframe of up to +10 minutes was added. 
• 
Section 4.1.1.1 (Overall Survival (OS): This section was modified to define OS as the time 
from original diagnosis to death or last follow-up for Cohort A.  For Cohorts B and C, OS 
will be measured for each subject with time origin at the date of Study Day 1 until 
recorded date of death or last follow-up. 
• 
Section 5.1 (Inclusion Criteria): 
o Inclusion criterion #2 was updated to clarify that, for Cohorts B and C, the last 
baseline MRI confirmation of first or second recurrence of GBM must occur within 14 
days prior to Study Day 1.  
o The inclusion criterion originally numbered as #3 (“Patients with measurable or non-
measurable disease,“ under the section for Cohorts B and C) was moved to the 
inclusion criteria for all cohorts and was re numbered as #6.  Other criteria were re-
numbered as appropriate. 


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o Inclusion criterion #10 was amended to more clearly indicate that subjects with 
Gilbert’s syndrome have a higher threshold for elevated bilirubin. 
• 
Section 5.2 (Exclusion Criteria): Exclusion criterion #2 was modified to exclude the listed 
therapies only if administered within the past 6 months prior to start of study treatment. 
• 
Section 5.3.2 (Permitted Concomitant Therapies): A new item #1 has been added to clarify 
that subjects who are planning to enroll in Cohort C do NOT need to have a washout 
period for bevacizumab as this is a standard of care treatment and will be continued in 
combination with MEDI4736 on study.  Other items were re-numbered as appropriate. 
• 
Section 6.1.5 (Monitoring of MEDI4736 Dose Administration): The change indicates that a 
full 60 minutes of monitoring post end of MEDI4736 infusion may only be required for the 
first 4 doses of MEDI4736 treatment for a particular subject.  If treatment is well tolerated 
for a particular subject, the post infusion observation period may be reduced to 15 
minutes for the fifth dose, starting in Week 9.  In addition, the observation frequency 
during the infusion may also be changed from every 15 minutes to every 30 minutes. 
• 
Section 6.3 (Drug Overdose Management): Overdose was more specifically defined as 
administration in excess of that mandated by the protocol by >10%. 
• 
Section 7.1.2 (Additional SAE Definitions for this Study): A new section was added as 
Section 7.1.2, Additional SAE Definitions for this Study: Pregnancy and Overdose.  Other 
sections in Section 7.1 were renumbered as appropriate. 
• 
Section 7.1.5 (General Reporting Requirements): This section was renumbered from 7.1.4 
to 7.1.5 and language was clarified to indicate how AEs should be collected during the On 
Study Follow-up for subjects who have completed the study and for those who 
discontinue treatment or are withdrawn from the study.  
• 
Section 7.1.6 (Expedited SAE Reporting Requirements): Additional detail was provided for 
SAE reporting requirements 
• 
Section 7.1.7 (SAE Follow-up Requirements): Instructions were added to provide 
clarification if Medidata RAVE data capture is used. 
• 
Section 7.1.8 (Adverse Events of Special Interest):  The AESI descriptions have been moved 
from their original position in Appendix 8.6.2 and inserted as Section 7.1.8.  The 
descriptions and definitions of the AESIs have also been updated according to 
MedImmune current information.  
• 
Section 7.2.7 (Premature Subject Withdrawal):  The second paragraph was changed to 
remove the specific name of the form to be used for recording subject withdrawal.  In 
addition, the list of reasons for subject withdrawal was deleted as it is redundant with the 
list in Section 3.1.10. 
• 
Appendix 8.1 (Protocol Version History): The format of the table was changed to allow 
more space for recording the Summary of Changes. 
• 
Appendix 8.3 (Sponsor Information): The Clinical Project Manager was changed to Andrew 
J Park, PharmD. 
• 
Appendix 8.4.1 (Evaluable for Objective Response): The Note section (“Participants who 
exhibit objective disease progression or die prior to the end of Cycle 1 will also be 
considered evaluable”) was deleted.  
• 
Appendix 8.4.4 (Response/Progression Categories): The Note for Complete Response and 
Partial Response was clarified to indicate that the content of the note applies to subjects 


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who have only non-measurable disease.  The Progressive Disease criteria language was 
modified for greater clarity to indicate that any one of the listed criteria must be met.   
• 
Appendix 8.4.6 (Study Continuation Beyond Initial Progressive Disease): The requirements 
under which subjects can continue treatment beyond initial progression have been 
modified to allow subjects to remain on study after confirmed objective progression as 
long as the subject continues to experience clinical benefit.  The change was also made to 
the footnote in Appendix 8.4.6.1. 
• 
Appendix 8.5: Health Related Quality of Life questionnaires were added to the protocol. 
Sections were re-numbered, as appropriate. 
• 
Appendix 8.6 (MEDI4736 Toxicity Management and Dose Adjustments):  
o Two additional references (package inserts for nivolumab and pembrolizumab) were 
provided for the management of irAEs.  
o The sentence regarding continuation of dosing despite concurrent vitiligo and 
alopecia was deleted as it is included in the table in Appendix 8.6.1 
o The guideline from MedImmune for management of toxicity due to MEDI4736 was 
referenced in Appendix 8.6.   
o The table in Appendix 8.6.1 (Dose Modifications Due to Toxicity of MEDI4736) was 
modified and replaced with an updated table based on the most recent 
recommendations from MedImmune.  
• 
Appendix 8.7.7.2 (Tumor Biopsies): The option to take samples from surgically resected 
tumors was added. 
• 
Administrative changes: 
o The terms “patient(s)” and “participant(s)” were changed to “subject(s)” throughout 
the document, where appropriate (i.e., when referring to a study). 
o Study phase numbers were changed from Roman to Arabic numerals 
o General spelling and capitalization changes, as needed. 
 
Amendment 2 
Issue Date: 02-NOV-2015 
Summary of Changes: 
 
In order to add Cohorts B2 and B3 and to provide clarifications to the protocol, the following 
changes were made: 
• 
Synopsis, Section 2.1: Modifications and rationale were provided for the addition of 2 
cohorts. The additional cohorts will have the same study population criteria as Cohort B 
but will receive the following treatments: 
o Cohort B2 (n=32): MEDI4736 (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W) 
o Cohort B3 (n=32): MEDI4736 (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W) 
• 
Section 3.1.2: The following was added: Subjects in Cohorts B2 and B3 will be enrolled 
in a concurrent randomized manner.  
• 
Sections 3.1.4 and 3.1.5: Cohorts B2 and B3 were added and number of subjects in the 
study was updated. 
• 
Section 3.1.6: section 3.1.6.2.1 was added for Cohorts B2 and B3 sample size 
consideration. 


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• 
Section 3.1.7: Cohorts B2 and B3 were added.  The following was added: Per Protocol 
Amendment 2, Cohort B2 dosing will be the same as that of Cohort C (MEDI4736 10 
mg/kg Q2W + bevacizumab 10 mg/kg Q2W).  At this time, 5 of the 6 subjects in the 
safety run-in for Cohort C have completed the DLT observation period without 
experiencing a DLT; therefore, a safety run-in for Cohort B2 will not be required.  As 
Cohort B3 will have a lower dose bevacizumab along with the MEDI4736, a safety run-in 
will not be required as well. 
• 
Figure 1 was updated to include Cohorts B2 and B3 
• 
Sections 3.1.8.2, 3.1.8.3, 3.1.9, and 3.1.11: Cohorts B2 and B3 were added as 
appropriate. 
• 
Section 3.1.9:  
o neurological event and uveitis were added to #1, #2, and bullet for #2  
o For #3, bullet 2: “Grade 3 asymptomatic endocrinopathy” was changed to 
“Grade 3 endocrinopathy that becomes asymptomatic …” 
• 
Section 3.1.10:  
o Section was clarified to indicate reasons for withdrawal from treatment vs. 
withdrawal from study. 
o Note was added to indicate that Subjects in Cohorts B2, B3, and C who are 
taken off treatment but continue bevacizumab alone should not be considered 
as having started new treatment.  These subjects should continue into the On 
Study Follow-up visits. 
• 
Section 3.1.15: enrollment period duration was updated. 
• 
Section 3.1.16:  
o Clarification was provided for On Study Follow-up versus Post Study Follow-up. 
o Clarification was provided to indicate that If the determination is made to 
remove a subject from treatment at a visit that coincides with the first visit of 
the On-Study Follow-up Period (which is 14 days after the last dose of study 
treatment), any assessments required in the 14 day post-last treatment visit 
that are not covered as part of the on-treatment visit (usually correlative labs) 
should be done as soon as possible.  If these assessments cannot be done on 
the same day, the subject should be brought back in at the earliest opportunity.  
Any assessments or correlative samples required by both the protocol visit and 
14 day post-last treatment visit should not be repeated. 
• 
Section 3.2, Flowchart: 
o Added Cohorts B2 and B3 to study treatments and other 
assessments/footnotes as appropriate. 
o 12-lead ECG was added to the Screening Visit; previously omitted 
o Pregnancy test was added to the On Study Follow-up (Day +14 and Day +90 
post last study drug); previously omitted. 
o Footnote 1 - Note was added indicating that blood chemistry, hematology, 
urinalysis and pregnancy test do NOT need to be done within 15 minutes prior 
to start of infusion as long as the sample is taken before the infusion and on the 
same day as the planned infusion) 
o Footnote 2 - Clarification was added to indicate if urine protein dipstick is 2+ or 
greater, manage according to bevacizumab package insert. 
o Footnote 6 - Clarification was added to indicate that During the On Study 
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prematurely (but are not withdrawn from study) will be followed for 90 days 
post last day of treatment; all AEs will be collected during this period. See 
Section 3.1.16 for details. 
o Footnote 7 was added indicating that the 28 day window for screening samples 
does not apply to MGMT and IDH testing; archival results are acceptable. If 
archival results are not available, this testing should be done within 28 days of 
start of treatment. 
• 
Section 4: Cohorts B2 and B3 were added as appropriate 
• 
Section 5.1 (Inclusion Criteria):  
o Added Cohorts B2 and B3 as appropriate 
o # 8 - updated language to read as follows: At the time of Study Day 1, subjects 
must be at least 4 weeks (changed from 3 weeks) since major surgical 
procedure, open biopsy, or significant traumatic injury; there should be no 
anticipation of need for major surgical procedure during the course of the 
study.  There should be no core biopsy or other minor surgical procedure, 
excluding placement of a vascular access device, within 7 days prior to Study 
Day 1. 
o #9: language was added to indicate: Subjects who have previously been treated 
with the Optune™ device are eligible for the study as long as toxicity related to 
the treatment has resolved to ≤ Grade 1 or baseline. 
o other inclusion criteria were re-numbered as appropriate 
o #11: The following was added for adequate renal function: Cohorts B2, B3 and C 
- Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on 
dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample. 
• 
Section 5.2 (Exclusion Criteria): 
o #20 was clarified to indicate: If a subject previously received another 
investigational treatment, the last dose of investigational treatment was 
administered within 4 weeks of Day 1 of the study 
o #22 was added. The following exclusion criteria were added for Cohorts B2, B3, 
and C: 
 
Evidence of hemorrhage on the baseline MRI or CT scan other than 
those that are ≤ grade 1 and either post-operative or stable on at least 
two consecutive scans 
 
Current use of warfarin sodium or any other Coumadin-derivative 
anticoagulant. Participant must be off Coumadin-derivative 
anticoagulants for at least seven days prior to starting study drug.  Low 
molecular weight heparin and Factor Xa antagonists are allowed 
 
History of clinically significant bleeding within 6 months of enrollment 
 
History of arterial thromboembolism within 12 months prior to 
enrollment 
 
Inadequately controlled hypertension (defined as systolic blood 
pressure >150 and/or diastolic blood pressure > 90 mmHg on 
antihypertensive medications) 
 
Any prior history of hypertensive crisis or hypertensive encephalopathy 
 
Clinically significant cardiovascular disease within 12 months prior to 
enrollment (or randomization), including myocardial infarction, 
unstable angina, grade 2 or greater peripheral vascular disease, 


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cerebrovascular accident, transient ischemic attack, congestive heart 
failure, or arrhythmias not controlled by outpatient medication, 
percutaneous transluminal coronary angioplasty/stent  
 
Evidence of bleeding diathesis or coagulopathy 
 
History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 6 months prior to study enrollment 
 
Serious, non-healing wound, ulcer, or bone fracture 
• 
Section 5.3.2: clarification was added to #8 to indicate that Use of anticoagulants such 
as warfarin is permitted; however, caution should be exercised in subjects receiving 
bevacizumab (Cohorts B2, B3 and C) and additional International Normalized Ratio (INR) 
monitoring is recommended. 
• 
Section 6.1.4.2:  Added Cohorts B2 and B3 to section describing order of administration 
for MEDI4736 and bevacizumab 
• 
Section 6.2: updated drug requirements for MEDI4736 
• 
Section 7.1.5: Clarification was provided for collection of AEs during the On Study 
Follow-up based on clarifications provided in Sections 3.1.10 and 3.1.16.  
• 
Section 7.1.6: additional detail and clarification were added regarding reporting of SAEs 
to the Sponsor within 24 hours. 
• 
Section 7.1.8:  clarification was added regarding recording of AESIs. Expedited reporting 
by the Investigator to the Sponsor within 24 hours is not required  
• 
Section 7.1.8.6, Uveitis, was added. 
• 
Section 7.2.7:  Section was updated to be aligned with Section 3.1.10. 
• 
Appendix 8.3: Primary Sponsor Contact was changed from Linda Pan to Andrew Park, 
who was already listed in this section as the Clinical Project Manager 
• 
Appendix 8.6: all sections were updated based on the most recent dose modification 
guidelines from Medimmune 
• 
Appendix 8.6.2:  MEDI4736 Dose Modification Not Due to Toxicities was added 
• 
Administrative Changes: 
o Updated formatting and logo in protocol to be consistent with new protocol 
format (SOP-C01 TMP 3 v3).  
o Spelling and grammar changes, as needed. 
 
Amendment 3 
Issue Date: 13-APR-2016 
Summary of Changes: 
 
• 
Synopsis: The following statement was added: “Per Amendment 3, optional treatment 
extension beyond the 1-year study (Core Study) is available for subjects who complete 
51 weeks of treatment on Core Study with Stable Disease or better; the optional 
treatment extension will be permitted upon agreement with subject, Sponsor and 
Investigator.  See Appendix 8.8 for details.”  
• 
Section 3.1.10:  
o Treatment withdrawal criterion #6 “Initiation of alternative anti-cancer therapy 
including another investigational agent” was moved to Study withdrawal 
criterion #2 and changed to “Initiation of alternative anti-cancer therapy 
(marketed or investigational).” 


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o The following phrase was removed form Study withdrawal criterion #1: “e.g., 
start of new treatment.” 
• 
Section 3.1.12 was updated to indicate that optional treatment extension beyond 
1-year Core Study is permitted.  The following statement was added: “Optional 
treatment extension beyond the 1-year study (Core Study) is available for subjects who 
complete 51 weeks of treatment on Core Study with Stable Disease or better; the 
optional treatment extension will be permitted upon agreement with subject, Sponsor 
and Investigator.  See Appendix 8.8 for details. 
• 
Section 3.1.13: section was updated to include the possibility of interim analyses; 
changes in bold.  “No formal interim analysis will be performed.  Analyses Interim 
safety reviews will be performed to assess DLTs in context of the safety run-in for 
Cohorts A and C (see Section 3.1.7).  Interim analyses may be performed to analyze the 
endpoints of progression free survival at 6 months and overall survival at 6 or 12 
month for the applicable cohorts as specified in the statistical analysis plan.” 
• 
Section 3.1.15 and Section 3.1.16: reference was provided to Section 3.1.12 regarding 
optional study treatment extension. 
• 
Section 3.1.16:  
o Paragraph 4 was changed FROM: “Following the On Study Follow-up, there will 
be a Post Study Follow-up, where clinical outcomes data (dates of 
progression/relapse and survival) will be collected at least every 6 months for 
up to 3 years from the initiation of the treatment.” TO: “Following the On Study 
Follow-up, there will be a Post Study Follow-up, where clinical outcomes data 
will be collected at least every 6 months for up to 3 years from the initiation of 
the treatment.  Clinical outcomes data may include the following:  
 
First date of progression/relapse (for subjects who did not already 
progress while on study) 
 
First new anti-cancer treatment after the subject comes off study 
 
Survival data (including date/reason for death).” 
o The following statement was added: “The Post Study Follow-up will include a 
query to determine if there were any immune-related adverse events (irAEs) 
during the 90 days since the last administration of study drug.” 
• 
Section 3.2, Study Flowchart: 
o Amylase and lipase assessments were added. 
o The following was added to the Vital Signs assessment line: “See Section 6.1.5 
for assessment before/during/after MEDI4736 dose.” 
o Footnote 1 was changed FROM: “pre MEDI4736 dose (15 to 0 min. Note: Blood 
chemistry, hematology, urinalysis and pregnancy test do NOT need to be done 
within 15 minutes prior to start of infusion as long as the sample is taken before 
the infusion and on the same day as the planned infusion)” 
TO: “pre MEDI4736 on same day as infusion.” 
o Footnote 3 was changed FROM: “pre dose (-15 to 0 minutes) and post infusion 
(up to +10 minutes” TO: “pre MEDI4736 dose (on same day as infusion) and 
post MEDI4736 infusion (up to +10 minutes).” 
o Footnote 6 was changed: FROM “During the On Study Follow-up, subjects who 
complete study treatment or discontinue treatment prematurely (but are not 
withdrawn from study) will be followed for 90 days post last day of treatment; 
all AEs will be collected during this period. See Section 3.1.16 for details.”       


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TO: “See section 7.1.5 for details regarding collection of AEs for 90 days after 
last study drug administration.” 
o Footnote 8 was added: “Standard of Care procedures may be used for eligibility 
assessments provided they meet the criteria specified in either the inclusion 
criteria or flowchart.” 
o Screening/baseline sample collections for circulating soluble factors, flow 
cytometry, and PBMC were deleted. MDSC collection was moved from 
baseline/screening visit to Day 1. 
o Footnote 9 (“Samples may be collected up to 28 days prior to Day 1; if collected 
on Day 1, collection must be pre MEDI4736 dose.”) was added for Day 1 
collections of ADA, circulating soluble factors, MDSC, flow cytometry, and 
PBMC.  This was done to allow sites to have flexibility for collecting the baseline 
samples. 
o For Long-Term Follow-up: 2 lines were combined into one and changed to “Post 
Study Follow-up as described in Section 3.1.16.” 
o Blood volume collected at each visit was deleted, as this is provided in the Lab 
Manual. 
• 
Section 4.1.2:  
o Paragraph 2: For Overall Survival (Cohorts A and C), one-sided Binomial test was 
changed to the Kaplan-Meier method.  
o Paragraph 3: For Cohorts B, B2, and B3, one-sided binomial test for PFS-6 was 
changed to: “Kaplan-Meier Estimate and the corresponding 90% confidence 
intervals (CI).” The following statement was added: “A one-sided binomial test 
will be used as a sensitivity analysis method to estimate PFS-6 and its 90% 
CIs.” 
• 
Section 5, Subject Eligibility: The following note was added: “Note: Standard of Care 
procedures may be used for eligibility assessments provided they meet the criteria 
specified in either the inclusion criteria or flowchart.” 
• 
Section 6.1, MEDI4736 
o Section 6.1.3, “Investigational Product Inspection,” was moved to the position 
before “Preparation,” and sections were re-numbered accordingly. 
o MEDI4736 Preparation and Administration sections were re-organized to 
remove redundancy and to improve clarity. 
o The following statements were added:  
 
Each dose of investigational product should be administered using the 
following guidelines: 
 
A physician must be present at the site or immediately available to 
respond to emergencies during all administrations of investigational 
product(s). Fully functional resuscitation facilities should be available. 
Investigational product(s) must not be administered via IV push or bolus 
but as an IV infusion. 
 
Investigational product(s) must be administered at room temperature 
by controlled infusion via an infusion pump into a peripheral vein or 
central line.  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. 


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o Infusion window was changed from ±10 minutes to ± 5 minutes, and the 
following statement was added: “An infusion of less than 55 minutes is 
considered a deviation.”  Infusion time window was also updated in Section 
3.1.7. 
• 
Section 6.2: Additional estimated MEDI4736 requirements (2000 vials) for optional 
study treatment extension was added. 
• 
Section 7.1.5: language for reporting AEs was changed  
FROM: “Documentation of serious and non-serious adverse events includes: dates of 
onset and resolution, severity, seriousness, study drug intervention, treatment and 
outcome, as well as, the causal relationship between the event and the study drug in 
accordance with Section 7.1.4.  All serious and non-serious adverse events occurring 
between the date of signing the informed consent and the off-study date (which 
includes the 90 day On Study Follow-up period) must be documented in the source 
records and on the respective section of the CRF, regardless of severity or the 
assumption of a causal relationship.  During the On Study Follow-up period, all AEs must 
be documented for 90 days after the last dose of study drug for subjects who complete 
the study as well as those subjects who discontinue study treatment prematurely (see 
Section 3.1.10 for subjects who begin other anti-cancer treatment).” 
TO: “All serious and non-serious adverse events must be documented in the source 
records and on the respective section of the CRF, regardless of severity or the 
assumption of a causal relationship.  The documentation includes: dates of onset and 
resolution, severity, seriousness, study drug intervention, treatment and outcome, as 
well as, the causal relationship between the event and the study drug in accordance 
with Section 7.1.4.  This documentation is required for all AEs that occur: a) from the 
date of signing the informed consent, and b) until the off-study date or 90 day after the 
last administration of study drug, whichever is longer, or until a new treatment is 
initiated (see Section 3.1.10 for subjects who begin other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed 
consent through 90 days after the last dose of the last study treatment (regardless of 
initiation of another therapy). 
• 
Section 7.2.3: the following statement was added: “All subjects who sign an informed 
consent form, regardless of study procedures performed, will be assigned a screening 
number and have their data entered into the eCRF.” 
• 
Appendix 8.6: The statement, which referenced guidelines for ipilimumab, nivolumab, 
and pembrolizumab was deleted. 
• 
Appendix 8.6.1 MEDI4736 Dose Modifications due to toxicity were updated according 
to current recommendations from MedImmune/AstraZeneca (Dated 02-OCT-2015). 
• 
Appendix 8.6.2: 
o For Point 2, “7 days or less” was changed to “≤ half the planned dosing 
interval.” 
o For Point 3, “7 days“ was changed to “half the planned dosing interval.” 
• 
Appendix 8.8 was added to provide additional details and flowchart for subjects who 
continue treatment after the 1-year Core Study. 
• 
Administrative:  
o Spelling, grammar and typographical errors were corrected; formatting changes 
were implemented, as applicable. 


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o Monitor and Study Monitor were standardized as “Clinical Monitor” in Sections 
7.25 and 7.2.9. 
 
Amendment 4 
Issue Date: 31-OCT-2016 
Summary of Changes: 
• 
Synopsis and Sections 4.0, 4.5, 4.5.1, 8.7.1, 8.7.2, and 8.7.5:  The following statement 
was added as appropriate: “Per Amendment 4, the collection of samples for MEDI4736 
PK, ADA, sPD-L1, and circulating soluble factors was removed.” 
• 
Synopsis and Section 4.0: MEDI4736 PK and immunogenicity were deleted from 
objectives, as appropriate. 
• 
Section 3.1.16.1, End of Study Visit, was added. 
• 
Section 3.2, Flowchart: 
o Deleted sampling for MED4736 PK, ADA, sPD-L1 and circulating soluble factors. 
o For Weeks 5 and 6, changed dosing window from ±1 to ±3 days 
o For Footnote 1, the following note was added: “Note: It is strongly 
recommended that hematology, chemistry and pregnancy test (when 
applicable) results are reviewed before dosing.” 
o Deleted footnotes 3 and 4 
o Re-numbered footnotes 8 and 9 as footnotes 3 and 4, respectively. 
o Added ECOG Perf Status to Physical exam 
o Added Physical exam to On Study Follow-up visits 
o Changed Disease assessment during On Study Follow-up to be ”Every 8 weeks 
starting 8 weeks after last disease assessment” 
• 
Sections 4.6 and 8.7.9, Exploratory Review and Analysis of Radiological Scans and Data, 
were added. 
• 
Section 5.4, Special Requirements for Contraception: updated entire section for 
agreement with current Medimmune guidelines. 
• 
Sections 6.0 and 8.8: dextrose was added as an optional diluent (in addition to saline) 
for MEDI4736. 
• 
Section 6.1.4.1, MEDI4736 Administration:  
o The following statement was added:  See Appendix 8.6.1.2 for details regarding 
infusion-related reactions. 
o The following change (in bold) was made): Investigational product(s) must be 
administered at room temperature by controlled infusion via an infusion pump 
into a peripheral vein or central line. 
o The following statement was changed FROM: “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.”  TO: “MEDI4736 solution should not be 
infused with other solutions or medications.” 
• 
Section 7.1.2, Additional SAE Definitions for this Study: 
o Section was renamed as Additional Expedited Reporting Requirements for this 
Study 
o Hepatic function abnormality was added to pregnancy and overdose 


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o Additional detail was added for each item according to updated Medimmune 
guidelines. 
• 
Section 7.1.6, Expedited SAE Reporting:  
o The following sentence was changed FROM: ”This includes any deaths that 
occur after the off-study date, but within 30 days of last study drug 
administration, and pregnancy, or overdose as defined in Section 6.3.”  TO: 
“This includes any deaths that occur after the off-study date, but within 30 days 
of last study drug administration.  (Pregnancy, overdose, and hepatic function 
abnormality will be handled according to Section 7.1.2.)” 
o The following statement was added: “Serious adverse event reporting to 
AstraZeneca/Medimmune is described in a separate agreement.” 
• 
Section 7.1.8, AESIs: additional details were added for AESIs to correspond with current 
Medimmune/AZ guidelines. Uveitis was deleted from the list, as it is not in the current 
recommendations. 
• 
Appendix 8.6.1, MEDI4736 Toxicity Management Guidelines: Section was updated to 
correspond with current Medimmune/AZ guidelines (19August2016). 
• 
Appendix 8.6.2, MEDI4736 Dose Modification Not Due to Treatment-related Toxicities: 
Section was changed  
FROM: MEDI4736 administration may be modified or discontinued as a result of events 
other than toxicity, e.g., intercurrent illness or logistical/administrative reasons, 
whereby the following rules should apply: 1. If the subject misses 2 consecutive planned 
doses, the subject should be discontinued from treatment; 2. If the dosing interruption 
is ≤ half the planned dosing interval, the originally planned drug administration should 
be given.  Any respective protocol deviation should be documented, if applicable; 3. If 
the dosing interruption is greater than half the planned dosing interval, the dosing 
should be skipped and the next scheduled drug administration should be performed.  
The respective protocol deviation should be documented. 
TO: MEDI4736 administration may be modified or discontinued as a result of events 
other than toxicity, e.g., intercurrent illness or logistical/administrative reasons, 
whereby the following rules should apply: 1. The originally planned visit/treatment 
schedule should be maintained in general, i.e., dosing interruptions should not reset the 
original treatment schedule. Exceptions may be made only for individual dosing days, 
whereby the interval between any two doses shall be no less than 10 days. All resulting 
protocol deviations should be documented. NOTE: For subjects who continue treatment 
beyond the 1-year core study, the interval between any two doses shall be no less than 
21 days.; 2. If the dosing interruption causes 2 consecutive planned doses to be missed, 
the treatment should be discontinued; 3. If the dosing interruption is ≤ half the planned 
dosing interval, the originally planned dose should be given and the next dose(s) should 
be adjusted in accordance with #1, if necessary; 4. If the dosing interruption is greater 
than half the planned dosing interval, the dose should be skipped and the next dose(s) 
should be adjusted in accordance with #1, if necessary. 
• 
Appendix 8.8.1, Preparation of Fixed Dose of 1500 mg for MEDI4736: 
o The following sentence was changed FROM: “Subjects will receive a fixed dose 
of MEDI4736, regardless of weight.”  TO: Subjects will receive a fixed dose of 
MEDI4736: 1500 mg Q4W for subjects > 30 kg.  If a subject’s body weight drops 
to ≤ 30 kg while on the study, the subject will be dosed at 600 mg Q4W for 
MEDI4736 as long as the body weight remains ≤ 30 kg.” 


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o Dextrose was added as an optional diluent for MEDI4736 (in addition to saline). 
• 
Appendix 8.8.2, Appendix Flowchart: 
o Added ECOG Perf Status to Physical exam 
o Added Physical exam to On Study Follow-up visits 
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
 
Amendment 5 
Issue Date: 14-APR-2017 
Summary of Changes: 
1. Sections 4.7 and 8.7.10 (Exploratory Analysis of Mutational Load) were added to provide 
clarification of testing that is defined in the agreement with Dana Farber Cancer Institute.  
2. Section 5.2, Exclusion Criteria: #23 was added; “Subjects must not donate blood while on 
study and for at least 90 days following the last MED4736 treatment.” 
3. Section 6.1.1 (Study Drug Information) and Sections 6.1.3 and 6.1.4 (Preparation and 
Administration of MEDI4736): Clarifications and additional details were provided based on 
current recommendations from Medimmune; added concentration of dextrose - 5% (w/v). 
Dextrose was also added to Section 3.1.7.For interruptions during infusion, total allowed 
time was changed from 4 to 8 hours 
4. Section 7.1.8, AESIs: Additional detail was provided for the description of endocrine 
disorders (added Type 1 DM) and dermatitis. 
5. Section 8.6.1.2 (Infusion related reactions): for Grades 1 and 2 : deleted “total infusion time 
not to exceed 4 hours” 
6. Section 8.8 (Additional Details for Subjects who Continue treatment beyond core study): 
Clarificatiosn were provided to indicate that fixed dosing of 15000 mg Q4W if for subjects 
>30 kg 
7. Section 8.8.1, Preparation of fixed dose of 1500 mg for MEDI4736:  
a. added concentration of dextrose - 5% (w/v). 
b. Paragraph 5 was changed to clarify that if a subject’s weight drops to ≤ 30 kg, weight 
based dosing will be used (changes in bold): “Subjects will receive a fixed dose of 
MEDI4736: 1500 mg Q4W for subjects > 30 kg.  If a subject’s body weight drops to ≤ 30 
kg while on the study, the subject will be dosed at 600 mg Q4W for MEDI4736 as long 
as the body weight remains ≤ 30 kg receive weight-based dosing equivalent to 20 
mg/kg of MEDI4736 as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject 
would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  
When the weight improves to >30 kg, the subject may return to fixed dosing of 
MEDI4736 1500 mg. 
 
 
 
 


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8.2 Participating Study Sites, Investigators, Staff and Laboratories 
Study team roster will be maintained by the Sponsor. 
 
 


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8.3 Sponsor Information 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel:  212-450-1500 
 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@licr.org  
 
Primary Sponsor Contact: 
Andrew J Park, PharmD 
Senior Clinical Project Manager 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel: 212-450-1587 
Fax: 212-450-1535 
apark@licr.org 
Clinical Monitoring: 
Alison Nortman 
Clinical Research Associate 
The Ludwig Institute for Cancer Research  
666 Third Avenue, 28th Floor 
New York, NY 10017 
Tel: 212-450-1536 
Mobile: 646-409-5642 
Fax: 212-450-1535 
anortman@licr.org  
 
 


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8.4 Tumor Response by Modified RANO 
Tumor Response will be assessed by the by modified RANO criteria as outlined below and 
published by Wen et al.(122)   
8.4.1 Evaluable for Objective Response 
Only those subjects who have measurable disease as defined by modified RANO criteria (122) 
present at baseline (Cycle 1, Day 1 scan) and have received at least one dose of therapy will be 
considered evaluable for response.  These subjects will have their response classified according 
to the definitions stated below.  
8.4.2 Measurable disease 
Measurable disease is defined as bi-dimensionally contrast-enhancing lesions with clearly 
defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, visible 
on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip.  
Enhancement around cysts or surgical cavities is in general considered non-measurable unless 
there is a nodular component measuring ≥ 10 mm in diameter.  The cyst or surgical cavity should 
not be measured in determining response.  
8.4.3 Non-measurable Evaluable Disease 
Non-measurable disease is defined as either unidimensionally measurable lesions, masses with 
margins not clearly defined, or lesions with maximal perpendicular diameter < 1 cm. 
8.4.4 Response/Progression Categories 
Modified RANO criteria, as described below, will serve to define response classification for this 
protocol.  As discussed in detail below, RANO criteria modifications to be used to assess 
response in this study address two relevant considerations for immune based therapies among 
GBM subjects including:  
1) use of contrast enhancing changes to define progressive disease; and  
2) allowance of specified subjects to continue study therapy following initial determination of 
progressive disease for up to 8 weeks in order to confirm progression. 
Complete response (CR): All of the following criteria must be met: 
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks.  In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease. 
b. No new lesions. 
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
d. Subjects must be on no steroids or on physiologic replacement doses only. 
e. Stable or improved non-enhancing (T2/FLAIR) lesions. 
f. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
NOTE: Subjects with only non-measurable disease cannot have a complete response.  The best 
response possible is stable disease. 


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Partial response (PR): All of the following criteria must be met: 
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks.  
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b. No progression of non-measurable disease. 
c. No new lesions. 
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically. 
NOTE: Subjects with only non-measurable disease cannot have a partial response.  The best 
response possible is stable disease. 
Stable disease (SD): All of the following criteria must be met: 
a. Does not qualify for CR, PR, or progression. 
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
c. Stable clinically. 
Unknown response status 
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed. 
Progressive disease (PD): Any one of the following criteria must be met: 
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids  
b. Any new lesion 
c. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.).  The definition of clinical deterioration is left to the discretion of the 
Investigator but may include a decline in the Karnofsky Performance Score (KPS) from 100 or 
90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a decline in KPS from any 
baseline to 50 or less, for at least 7 days, unless attributable to co-morbid events or changes 
in concurrently administered medications. 
d. Failure to return for evaluation due to death or deteriorating condition. 


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8.4.5 Progressive Disease: Assessment Based on Contrast Enhancing Tumor 
Measurement  
Immune based therapies are expected to be associated with inflammatory changes that may 
include edema.  RANO expanded radiologic criteria to define progressive disease to include the 
development of “significantly” increased T2 or FLAIR abnormality because such changes can be a 
major component defining radiographic progression following therapeutic use of VEGF/VEGFR-
targeting therapeutics which are known to elicit potent anti-permeability changes that limit 
contrast uptake.  Our study will define radiographic progressive disease by assessment of 
enhancing tumor burden and will not incorporate assessment of T2 or FLAIR changes as outlined 
in RANO because:  
1) there is no expectation that immunotherapy agents will falsely diminish enhancing tumor 
burden as has been noted with anti-angiogenic therapies; and 
2) immune based therapies may be associated with increased edema and associated T2/FLAIR 
changes which may inaccurately be interpreted to represent tumor progression (i.e. 
pseudoprogression). 
8.4.6 Study Continuation Beyond Initial Progressive Disease 
Accumulating evidence indicates that some subjects treated with immunotherapeutics may 
develop apparent progression of disease (by conventional response criteria) before 
demonstrating objective responses and/or stable disease.(127)  This phenomenon was observed 
in approximately 10% of subjects in the Phase 1 study of nivolumab, (48) a humanized 
monoclonal antibody against PD-1, and has also been reported for ipilimumab 
monotherapy.(127)  In order to minimize premature discontinuation of study medication and 
distinguish pseudoprogression from progressive disease (PD), this protocol will include a 
modification of the standard RANO criteria for assessing GBM progression.  The purpose of this 
modification is to permit continued study therapy at least until confirmation of PD.  Specifically, 
subjects meeting criteria for progressive disease (Appendix 8.4.4) will be permitted to continue 
study medication at least until confirmation of progression with an MRI performed 8 weeks 
after suspected progression as long as the following criteria are met: 
1) The subject is believed to demonstrate clinical benefit as determined by the treating 
physician; 
2) The subject is tolerating study medication. 
Assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.  
If progression is confirmed on follow-up imaging, defined as a 25% (±10%) increase from 
baseline or best response, then the date of disease progression will be the first date the subject 
met criteria for progression.  Subjects who have confirmed disease progression will discontinue 
study medication if they are no longer experiencing clinical benefit and enter the 
follow-up/survival period of the study. 
The modified RANO response criteria employed in this study to assess response are summarized 
in Appendix 8.4.6.1: 
 


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8.4.6.1 Modified RANO Response Criteria to Assess Response 
 
CR 
PR 
SD 
PD1 
T1+Gad 
None 
≥ 50% decrease 
< 50% decrease 
but < 25% 
increase 
≥ 25% increase 
T2/FLAIR 
Stable or 
decreased 
Stable or 
decreased 
Stable or 
decreased 
NA 
New lesion 
None 
None 
None 
Present 
Corticosteroids 
None 
Stable or 
decreased 
Stable or 
decreased 
NA 
Clinical Status 
Stable or 
improved 
Stable or 
improved 
Stable or 
improved 
Decreased 
Requirement for 
Response 
All 
All 
All 
Any 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NA=not 
applicable (increase in corticosteroid dosing or increase in T2/FLAIR changes without clinical decline or 
increased enhancing tumor are not sufficient to define PD for this study). 
1PD - Subjects who are benefiting from study therapy and tolerating it are permitted to continue study 
therapy following initial documentation of PD for at least up to 8 weeks in order to confirm underlying 
tumor progression (Appendix 8.4.4-8.4.6). 
8.4.7 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 14 days before beginning of treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
8.4.8 Evaluation of Best Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response.  If the response is sustained, i.e. still 
present on the subsequent MRI at least four weeks later, it will be recorded as a sustained 
response, lasting until the time of tumor progression.  Subjects without measurable disease may 
only achieve SD or PD as their best “response.” 
 
 


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8.5 Neurologic Function and Health Related Quality of Life 
Questionnaires 
 
 


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8.5.1 Neurologic Function in Neuro-Oncology (NANO) Scale 
Scoring assessment is based on direct observation and testing performed during clinical 
evaluation and is not based on historical information or reported symptoms. 
Domain Levels of Function 
Please check 1 answer for each domain 
 
Domains                                                                               
Key Considerations 
Gait 
0 
   Normal 
1 
   Abnormal but walks without assistance 
2 
   Abnormal and requires assistance  
(companion, cane, walker, etc.) 
3 
   Unable to walk 
   
   Not assessed 
   
   Not evaluable 
 
Strength 
0 
   Normal 
1 
   Movement present but decreased 
 against resistance 
2 
   Movement present but none against resistance 
3 
   No movement 
   
   Not assessed 
   
   Not evaluable 
 
 
 
Ataxia (upper extremity) 
0 
   Able to finger to nose touch without difficulty 
1 
   Able to finger to nose touch but difficult 
2 
   Unable to finger to nose touch 
   
   Not assessed 
   
   Not evaluable 
 
 
Sensation 
0 
   Normal 
1 
   Decreased but aware of sensory modality 
2 
   Unaware of sensory modality 
   
   Not assessed 
   
   Not evaluable 
 
 
 
 
• 
Walking is ideally assessed by at least 10 
steps 
• 
Test each limb separately 
• 
Recommend assess proximal (above knee or 
elbow) and distal (below knee or elbow) 
major muscle groups 
• 
Score should reflect worst performing area 
• 
Patients with baseline level 3 function in 
one major muscle group/limb can be scored 
based on assessment of other major muscle 
groups/limb 
• 
Non-evaluable if strength is compromised  
• 
Trunk/lower extremities assessed by gait 
domain  
• 
Particularly important for patients with 
brainstem and cerebellar tumors  
• 
 Score based on best response of at least 3 
• 
Recommend evaluating major body areas 
separately (face, limbs and trunk)  
• 
Score should reflect worst performing area 
• 
Sensory modality includes but not limited to 
light touch, pinprick, temperature and 
proprioception 
• 
 Patients with baseline level 2 function in 
one major body area can be scored based on 
assessment of other major body areas 


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Visual Fields 
0 
   Normal 
1 
   Inconsistent or equivocal partial hemianopsia  
(≥quadrantopsia) 
2 
   Consistent or unequivocal partial hemianopsia  
(≥quadrantopsia) 
3 
   Complete hemianopsia 
   
   Not assessed 
   
   Not evaluable 
 
Facial Strength 
0 
   Normal 
1 
   Mild/moderate weakness 
2 
   Severe facial weakness 
   
   Not assessed 
   
   Not evaluable 
 
Language 
0 
   Normal 
1 
   Abnormal but easily conveys meaning to examiner 
2 
   Abnormal and difficulty conveying meaning to examiner 
3 
   Abnormal.  If verbal, unable to convey meaning  
to examiner OR non-verbal (mute/global aphasia) 
   
   Not assessed 
   
   Not evaluable 
 
Level of Consciousness 
0 
   Normal 
1 
   Drowsy (easily arousable) 
2 
   Somnolent (difficult to arouse) 
3 
   Unarousable/coma  
   
   Not assessed 
   
   Not evaluable 
 
Behavior 
0 
   Normal 
1 
   Mild/moderate alteration 
2 
   Severe alteration 
   
   Not assessed 
   
   Not evaluable 
 
 
• 
Patients who require corrective lenses should 
be evaluated while wearing corrective lenses  
• 
Each eye should be evaluated and score 
should reflect the worst performing eye  
• 
Particularly important for brainstem tumors 
• 
Weakness includes nasolabial fold flattening, 
asymmetric smile and difficulty elevating 
• 
Assess based on spoken speech. Non-verbal 
cues or writing should not be included. 
• 
Level 1: Includes word finding difficulty; few 
paraphasic errors/neologisms/word 
substitutions; but able to form sentences 
(full/broken) 
• 
Level 2: Includes inability to form sentences 
(<4 words per phrase/sentence); limited word 
output; fluent but “empty” speech. 
•
None
• 
Particularly important for frontal lobe 
tumors 
• 
Alteration includes but is not limited to 
apathy, disinhibition and confusion 
• 
Consider subclinical seizures for significant 


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8.5.2 Health Related Quality of Life Questionnaire EORTC QLQ - C30 
ENGLISH 
 
EORTC QLQ - C30 (version 3)  
We are interested in some things about you and your health. Please answer all of the questions yourself 
by circling the number that best applies to you. There are no "right" or "wrong" answers. The information 
that you provide will remain strictly confidential.  
Please fill in your initials:  
 
___  ___  ___  ___ 
Your birthdate (Day, Month, Year):  
___  ___    ___  ___    ___  ___  ___  ___ 
Today's date (Day, Month, Year):  31 
___  ___    ___  ___    ___  ___  ___  ___ 
 
 
Not at  
All 
A  
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk 
outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the 
day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at  
All 
A  
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or 
other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
Please go on to the next page  


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ENGLISH  
During the past week: 
Not at  
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhoea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best 
applies to you  
29. How would you rate your overall health during the past week?  
1 
2 
3 
4 
5 
6  
7  
Very poor  
 
 
 
 
 
Excellent  
 
30. How would you rate your overall quality of life during the past week?  
1 
2 
3 
4 
5 
6  
7  
Very poor  
 
 
 
 
 
Excellent 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0    
 


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8.5.3 Health Related Quality of Life Questionnaire EORTC QLQ - BN20 
ENGLISH  
 
EORTC QLQ - BN20  
Patients sometimes report that they have the following symptoms. Please indicate the extent to 
which you have experienced these symptoms or problems during the past week.  
During the past week: 
Not at 
All 
A  
Little 
Quite  
a Bit 
Very 
Much 
31. Did you feel uncertain about the future? 
1 
2 
3 
4 
32. Did you feel you had setbacks in your condition? 
1 
2 
3 
4 
33. Were you concerned about disruption of family 
life? 
1 
2 
3 
4 
34. Did you have headaches? 
1 
2 
3 
4 
35. Did your outlook on the future worsen? 
1 
2 
3 
4 
36. Did you have double vision? 
1 
2 
3 
4 
37. Was your vision blurred? 
1 
2 
3 
4 
38. Did you have difficulty reading because of your 
vision? 
1 
2 
3 
4 
39. Did you have seizures? 
1 
2 
3 
4 
40. Did you have weakness on one side of your body? 
1 
2 
3 
4 
41. Did you have trouble finding the right words to 
express yourself? 
1 
2 
3 
4 
42. Did you have difficulty speaking? 
1 
2 
3 
4 
43. Did you have trouble communicating your 
thoughts? 
1 
2 
3 
4 
44. Did you feel drowsy during the daytime? 
1 
2 
3 
4 
45. Did you have trouble with your coordination? 
1 
2 
3 
4 
46. Did hair loss bother you? 
1 
2 
3 
4 
47. Did itching of your skin bother you? 
1 
2 
3 
4 
48. Did you have weakness of both legs? 
1 
2 
3 
4 
49. Did you feel unsteady on your feet? 
1 
2 
3 
4 
50. Did you have trouble controlling your bladder? 
1 
2 
3 
4 
 
© Copyright 1994 EORTC Quality of Life Group  
 


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8.6 MEDI4736 Toxicity Management and Dose Adjustments 
Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, 
there is the possibility of observing immune related adverse events (irAE)s during the conduct of 
this study.  IrAEs are defined as AEs of immune nature (i.e., inflammatory) in the absence of a 
clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory testing will 
be conducted to confirm significant laboratory findings prior to designation as a DLT.  Potential 
irAEs may be similar to those seen with the use of ipilimumab and may include immune-
mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies.(6, 48, 81, 128)  Subjects 
should be monitored for signs and symptoms of irAEs.  In the absence of an alternate etiology 
(e.g., infection or PD), an immune-mediated etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy.   
In general, the following are recommended: 
1. Subjects should be evaluated to identify any alternative etiology 
2. In the absence of clear alternative etiology, all events of an inflammatory nature 
should be considered to be immune-related 
3. Symptomatic and topical therapy should be considered for low-grade events 
4. Systemic corticosteroids should be considered for a persistent low-grade event or 
for a severe event 
5. More potent immunosuppressives should be considered for events not responding 
to systemic steroids (e.g., infliximab, mycophenolate, etc.). 
 
MEDI4736 may be modified or discontinued as a result of toxicities as described in the table in 
Appendix 8.6.1.  Dose modifications will not be required for AEs that are clearly not attributed 
to MEDI4736 (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant.   
In addition, management guidelines for AEs of special interest (AESIs) are detailed in 
Section 7.1.8.  All toxicities will be graded according to NCI CTCAE v4.03.  In case of doubt, the 
Investigator should consult with the Medical Monitor. 
Additional information and guidance regarding dose modification due to toxicity are provided 
from MedImmune in the following guideline:   
“MedImmune’s 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).” 
8.6.1 Dose Modifications Due to Toxicity of MEDI4736 
Note: If MEDI4736 dosing is held temporarily until resolution of the event as per instructions 
below, treatment(s) should be skipped and resume at the next scheduled treatment date (and 
not at the date of resolution).   


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8.6.1.1 Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in the 
absence of a clear alternative etiology. Maximum supportive care, including immunosuppressive 
medications, such as high dose steroids, is allowed to induce resolution of the event.  However, 
infliximab should not be used for management of immune-related hepatitis. 
In addition to the criteria for permanent discontinuation of MEDI4736 depicted below, 
permanently discontinue MEDI4736 also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
Management of irAEs may require administration of immunosuppressive medications (and/or 
hormone replacement therapy for endocrinopathies).  Resolution of irAEs managed in this 
manner in the timeframes specified is acceptable. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease, consider holding MEDI4736 dosing as clinically 
appropriate and during diagnostic work-up for other etiologies. 
Grade 2 
• 
In general, hold MEDI4736 until resolution to ≤ Grade 1 and after the end of any steroid 
taper, and discontinue MEDI4736 permanently if such resolution does not occur within 
60 days (30 days for neurotoxicities).  Criteria for temporary hold or permanent 
discontinuation of MEDI4736 may differ by event as detailed below. 
• 
For pneumonitis/interstitial lung disease, the decision to reinitiate MEDI4736 upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event 
does not meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, 
follow general instructions above, but always discontinue MEDI4736 permanently if 
there are signs of respiratory insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism, follow general instructions 
above, but patients may be retreated if the endocrinopathy is controlled and the patient 
is clinically stable while requiring steroid doses of ≤ 10 mg/day prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, and for 
sensory neuropathy/neuropathic pain, holding MEDI4736 is at the discretion of the 
Investigator. 
• 
For elevated creatinine or rash, MEDI4736 should be held until resolution to ≤ Grade 1 or 
baseline. 
• 
For vitiligo, no dose modification required. 


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Grade 3 
• 
In general, hold MEDI4736 until resolution to ≤ Grade 1 and after the end of any steroid 
taper, and discontinue MEDI4736 permanently if such resolution does not occur within 
60 days (30 days for neurotoxicities and rash).  Criteria for permanent discontinuation of 
MEDI4736 may differ by event as detailed below. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), 
apply respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For pneumonitis/interstitial lung disease, diarrhea/enterocolitis, and elevated serum 
creatinine (e.g., nephritis or renal dysfunction) always discontinue MEDI4736 
permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold MEDI4736, and if complete 
work up shows no evidence of pancreatitis, MEDi4736 may be continued 
• 
For hepatitis, discontinue MEDI4736 permanently for (1) transaminases or bilirubin not 
resolving to ≤ Grade 1 or baseline within 14 days, (2) transaminases > 8 × the upper limit 
of normal (ULN) or bilirubin > 5 × ULN, or (3) any case meeting Hy’s law criteria (as 
defined in FDA Guidance Document “Drug-Induced Liver Injury”). 
• 
For rash, MEDI4736 should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue MEDI4736 permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold MEDI4736, and if complete 
work up shows no evidence of pancreatitis, MEDI4736 may be continued. 
8.6.1.2 Infusion-related Reactions 
Grade 1 
• 
The infusion rate of MEDI4736 may be decreased 50% or temporarily interrupted until 
resolution of the event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards 
at the discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions. 
Grade 2 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion 
rate. 
Grade 3-4 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM 
epinephrine, followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
8.6.1.3 All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2 
• 
Hold MEDI4736 until resolution to ≤ Grade 1 or baseline, and discontinue MEDI4736 
permanently if such resolution does not occur within 60 days. 
Grade 3 
• 
Hold MEDI4736. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume MEDI4736 administration at next scheduled dose. 
Otherwise, discontinue MEDI4736 permanently 
Grade 4 
• 
In general, discontinue MEDI4736 permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment and in consultation with the 
Sponsor. 


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8.6.1.4 Cerebral Edema 
Due to the immunologic nature of MEDI4736, cerebral edema could theoretically result as a 
consequence of MEDI4736 administration due to immune infiltration of the brain.  Symptoms 
related to cerebral edema may include headache or neurologic deficit that is either new or 
worsened.  Subjects with any signs or symptoms of cerebral edema should be treated as 
clinically appropriate including initiation or increased systemic corticosteroid dosing, treatment 
with an osmotic diuretic or surgical decompression.  Subsequent MEDI4736 dosing should be 
immediately interrupted if significant clinical symptoms attributable to cerebral edema develop.  
Treatment with additional MEDI4736 doses may only be re-initiated if clinically significant 
symptoms attributable to cerebral edema have resolved to grade ≤ 1 or pre-treatment baseline.  
Subjects who develop CTCAE 4.0 grade 4 cerebral edema attributable to MEDI4736 
administration should not receive any further MEDI4736 doses and should discontinue study 
therapy. 
8.6.2 MEDI4736 Dose Modification Not Due to Treatment-related Toxicities 
MEDI4736 administration may be modified or discontinued as a result of events other than 
toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby the following 
rules should apply: 
1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 10 days. All resulting protocol deviations should be documented.  
NOTE: For subjects who continue treatment beyond the 1-year Core study, the interval 
between any two doses shall be no less than 21 days. 
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
4. If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
 
 


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8.7 Laboratory procedures 
8.7.1 MEDI4736 Pharmacokinetics and Immunogenicity for Anti-drug antibodies 
(ADA) 
Samples will be collected for analyses at time points designated in the study flowchart 
(Section 3.2). 
A validated electrochemiluminescence assay (ECLA) using a Meso Scale Discovery (MSD) 
platform will be used for the quantitative determination of MEDI4736 concentrations in serum.   
Anti-MEDI4736 antibodies in human serum will be detected using a validated MSD 
electrochemiluminescence assay. 
Per Amendment 4, the collection of samples for MEDI4736 PK and ADA was removed. 
8.7.2 sPD-L1   
Samples to assess serum sPD-L1 levels before and after treatment will be collected for analyses 
at time points designated in the study flowchart (Section 3.2).  Its association with response to 
treatment and clinical outcome will be evaluated. 
Per Amendment 4, the collection of samples for sPD-L1 was removed. 
8.7.3 Flow Cytometry 
Samples will be collected for analyses at time points designated in the study flowchart 
(Section 3.2) 
Peripheral blood populations before and after treatment, including absolute lymphocyte counts, 
numbers of T cells, T-cell subsets, NK cells, and B cells as well as their cellular phenotypes will be 
assessed by flow cytometry to evaluate the association with treatment and subject responses. 
8.7.4 PBMC Banking 
Peripheral Blood Mononuclear Cells (PBMCs) will be isolated and banked as described below at 
time points designated in the study flowchart (Section 3.2) 
These samples may be used to address several key questions: 
- 
The diversity of the immune cell repertoire may be assessed in PBMCs based on VDJ 
coding region analysis to determine if clinical responses are correlated with 
immunodiversity and if repertoire changes occur in response to treatment.   
- 
Functional assays such as ELISPOT or tetramer staining or intracellular cytokine analysis 
may be employed to assess the activation state or antigen specificity of immune cell 
populations in the periphery.  
- 
Flow cytometric analyses to examine additional markers not included in the primary 
panel may be performed on banked samples to supplement our understanding of a 
subject’s immune status.   


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8.7.5 Circulating soluble factors 
Blood samples at baseline and following treatment with MEDI4736 will be collected for analyses 
of circulating levels of soluble factors such as cytokines and chemokines.  They may include but 
are not limited to VEGF, FGF, TGF, IL-1 IL-2, IL-4, IL-6, IL-8, IL-10, IFN, G-CSF, TNF, and explore their 
association with treatment and clinical outcome. 
Per Amendment 4, the collection of samples for circulating soluble factors was removed. 
8.7.6 Myeloid derived suppressor cells (MDSC) 
MDSCs constitute a heterogeneous population of immature myeloid cells with various immune 
suppressive functions including suppression of T-cell proliferation, inducement of T-cell 
apoptosis and disruption of T-cell signaling pathways.  Levels of circulating MDSCs are 
increasingly recognized as important in determining clinical responses to novel drugs for cancer 
and autoimmune disease.  Samples will be collected for analyses at time points designated in 
the study flowchart (Section 3.2). 
MDSCs are defined as events that are:  
Lineageneg, CD14pos, HLA-‐DRlow/neg 
Each sample is analyzed using well-established flow cytometry techniques for the presence of 
MDSCs.  For each sample a single data point will be delivered, being the mean of values for the 
percentage of Lineage neg, CD14pos events that are HLA-‐DRlow/neg to study the effects of MEDI4736 
therapy on levels of MDSCs in GBM subjects. 
8.7.7 Archival Tumor Samples and Tumor Biopsies 
8.7.7.1 Archival Tumor Samples 
Archival tumor samples are required for all subjects.  Formalin fixed paraffin embedded (FFPE) 
tumor samples will be collected for immunohistochemistry (IHC) and additional correlative 
markers (e.g., tumor mutation analysis, RNA analysis, and immunodiversity).  If a tumor block 
cannot be provided for this study, then only freshly prepared unstained sections should be 
provided as described in the Laboratory Manual. 
8.7.7.2 Tumor Biopsies 
Tumor biopsy may be obtained during the study as an optional procedure according to 
Section 3.2.   
Image-guided core needle tumor biopsy will be performed according to institutional practice.  If 
clinically practical, at each time point, subjects will undergo 4 core biopsies, but a minimum of at 
least 3 core biopsies are required.  The first and third core biopsies will be placed in formalin and 
processed for FFPE, while the second and fourth core biopsies (4th biopsy, if available) will be 
immediately frozen in liquid nitrogen or equivalent method and then stored at -60°C or below.  
In exceptional cases, excisional or punch biopsies are permitted and may be substituted for the 
required minimum of 3 core biopsies if sufficiently large (4 mm or greater in diameter).  
 


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Alternatively, equivalent samples can be taken from resected tumor in the case that a subject 
needs to have the tumor surgically removed at the time of progression as part of standard of 
care. 
 
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by LICR.  Core 
biopsies may be used for correlative studies such as IHC, tumor mutation analysis, RNA analysis, 
proteomic analysis, and immunodiversity.  Additional details for sample collection, processing, 
storage, and shipment will be provided in the Laboratory Manual.  
8.7.8 Additional Translational and Exploratory Studies 
Optional research studies may only be performed for subjects who voluntarily gave their 
consent for additional correlative research on the informed consent document.  Subjects who 
declined consent to participate in additional translational studies will have their samples 
destroyed at the end of the study.  Refusal to participate in this optional research will involve no 
penalty or loss of benefits to which the subject would otherwise be entitled.  Based on the data 
generated during the study and/or in other studies, not all samples from subjects consenting to 
this optional research may be utilized. 
8.7.9 Exploratory Review and Analysis of Radiological Scans and Data 
This exploratory review and analysis of radiological scans and other appropriate data will be 
conducted to examine the time course and variability of imaging changes associated with 
treatment based on both conventional and advanced magnetic resonance imaging (MRI) 
sequences. The exploratory analysis will also examine the accuracy of available advanced 
imaging modalities acquired at the time of suspected tumor progression in predicting 
subsequent true progression as well as overall survival. This review and analysis will be confined 
to scans that were obtained from subjects while on study; scans obtained after subjects have 
completed the study are not part of the scope of this imaging analysis. 
There are 2 objectives for the exploratory review and analysis: 
• 
Objective 1: To determine the frequency, time of onset, and duration of 
pseudoprogression for subjects enrolled in the trial.  
• 
Objective 2: To determine the diagnostic value of advanced imaging techniques for 
pseudoprogression.   
In this study, the Investigator assessments will be used for efficacy analyses and subject 
treatment decisions. The exploratory review and analysis will not be used for efficacy 
determinations or to determine the correlation of these results with the efficacy evaluations 
as assessed by the study Investigators. 
8.7.10 Exploratory Analysis of Mutational Load 
Mutational load analysis using formalin-fixed, paraffin-embedded (FFPE) tissue samples for a 
subset of subjects will be conducted by Dana Farber Cancer Institute. The purpose of this study 
is to perform Whole Exome Sequencing (WES) on FFPE tissue slides derived from a subset of 
patients. The mutational pattern of FFPE-derived tumor DNA is revealed by comparison to 
matched normal DNA from peripheral blood. The study will be divided into 2 phases, a Pilot 
phase that also assesses the feasibility of the proposed experimental setup and subsequently a 
Small-Scale Study, which includes WES from FFPE-tissue and PBMCs from subjects.  
 


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8.8 Additional Details for Subjects who Continue Treatment after 
1-Year Core Study 
According to Section 3.1.12, optional treatment extension beyond 1-year Core Study is available 
for subjects who complete 51 weeks of treatment on Core Study with Stable Disease or better; 
the optional treatment extension will be permitted upon agreement with subject, Sponsor and 
Investigator.   
Optional treatment extension will continue according to the dosing defined for the respective 
subject in the Core Study, with the exception that MEDI4736 will be administered according to 
the currently recommended fixed dose of 1500 mg every 4 weeks (Q4W) for subjects > 30 kg, 
which is equivalent to 10 mg/kg Q2W or 20 mg/kg Q4W.   
The following procedures will be implemented for subjects who continue study treatment 
beyond the Core Study: 
1. Preparation of fixed dose of 1500 mg for MEDI4736 will be used; details are provided in 
Appendix 8.8.1. 
2. The flowchart for optional treatment extension, which is provided in Appendix 8.8.2, 
will be followed. 
 
For Cohorts B2, B3 and C, bevacizumab treatments may continue Q2W as defined for the Core 
Study.  All data from the respective study visit (dosing, AEs, concomitant 
medications/procedures, lab results and urinalysis) should be recorded on the CRF. 
8.8.1 Preparation of Fixed Dose of 1500 mg for MEDI4736  
Each vial of MEDI4736 selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product, the Investigator and Site Monitor Sponsor 
should be notified immediately.   
Preparation of MEDI4736 and preparation of the intravenous bag are to be performed 
aseptically.  
MEDI4736 requires reconstitution prior to use.  Each vial contains 200 mg MEDI4736; after 
reconstitution, a 50 mg/mL solution is obtained. 
The reconstitution should be performed with 4 mL sterile WFI for each vial with the liquid added 
gently to the side of the vial to minimize product foaming.  The vial should be gently rotated or 
swirled for 5 minutes or until dissolution is complete.  The vial should not be shaken or 
vigorously agitated.  Reconstituted MEDI4736 should stand undisturbed at room temperature 
for a minimum of 5 minutes or until the solution clarifies.  The reconstituted solution should 
appear clear or slightly opalescent.  A thin layer of bubbles on the liquid surface is considered 
normal.   
Subjects will receive a fixed dose of MEDI4736: 1500 mg Q4W for subjects > 30 kg.  If a subject’s 
body weight drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 20 mg/kg of MEDI4736 as long as the body weight remains ≤ 30 kg (e.g., a 30 kg 


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subject would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  When 
the weight improves to >30 kg, the subject may return to fixed dosing of MEDI4736 1500 mg. 
MEDI4736 will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose.   
For a 1500 mg dose, 30 mL of reconstituted MEDI4736 is to be diluted in a 250 mL IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose.  (NOTE: 8 vials, 32 mL, of reconstituted 
MEDI4736 are required in order to be able to measure 30 mL for the dilution.)  
First, 30 mL of diluent is removed from the IV bag, and then 30 mL of MEDI4736 is added to the 
bag.  The bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag. 
Administration of MEDI4736 will proceed according to Section 6.1.4.  Subjects will be monitored 
by assessment of vital signs before, during and after each MEDI4736 dose administration 
according to Section 6.1.5.  
 
 


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8.8.2 Study Flowchart for Subjects who Continue Study Treatment after 1-Year Core 
Study 
 
MEDI4736 (1500 mg) 
Q4W (±3days)
starting on Week 53 
MEDI4736 (1500 mg) 
Q4W (±3days)
starting on Week 53 
Bevacizumab (10 mg/kg)3 
Q2W (±3days)
starting on Week 53
MEDI4736 (1500 mg) 
Q4W (±3days)
starting on Week 53 
Bevacizumab (3 mg/kg)3 
Q2W (±3days)
starting on Week 53
MEDI4736 (1500 mg) 
Q4W (±3days)
starting on Week 53 
Bevacizumab (10 mg/kg)3  
Q2W (±3days)
starting on Week 53
Disease Assessment by modified RANO (including appropriate 
imaging) 
SOC 
starting on Week 57
SOC
SOC
SOC
Physical Exam (incl. weight and ECOG Perf Status) 
Q4W (±3days)
starting on Week 53 
X
X
X
Vital Signs (T, HR, BP, RR)6  
Q2W (±3days)
starting on Week 53
X
X
X
Concomitant Medications and Procedures 
Q2W (±3days)
starting on Week 53
X
X
X
Adverse Events (starting or worsening after consent)5  
Q2W (±3days)
starting on Week 53
X
X
X
Quality of Life (EORTC QLQ-C30/BN20) 
Q8W (±3days)
starting on Week 57
Neurologic Assessment in Neuro-Oncology (NANO) 
Q8W (±3days)
starting on Week 57
Blood Hematology (CBC, differential, platelets)1 
Q4W (±3days)
starting on Week 53 
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., alb., bili., 
AST, ALT, LDH, ALP, Free T3, Free T4, TSH)1
Q4W (±3days)
starting on Week 53 
X
X
X
Chemistry cont. (Amylase and lipase)1
Q4W (±3days)
starting on Week 53 
X
X
X
Urinalysis (Cohorts B2, B3, and C only)2,3 
Q2W (±3days)
starting on Week 53
Serum pregnancy test1   
Q8W (±3days)
starting on Week 57
X
X
PBMC1   
Week 53 (±3days)
x4
Post Study Follow-up as described in Section 3.1.16
x
1 - pre administration of drug(s), if applicable - Note: hematology, chemistry and pregnancy test (when applicable) results must be available and reviewed before infusion.
2 - pre bevacizumab dose; if urine protein dipstick is 2+ or greater, manage according to bevacizumab package insert
3 - For Cohorts B2, B3 and C, bevacizumab treatments may continue every 2 weeks (Q2W) as defined for Year 1 Core Study.  All data from the respective study visit (dosing, 
      AEs, concomitant medications/procedures, lab results and urinalysis) should be recorded on the CRF.
4 - Samples may be collected at the last study visit when the subject is discontinued from treatment.
5 - See Section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
6 - See Section 6.1.5 for assessment of vital signs before, during and after MEDI4736 dose administration. Pre bevacizumab dose on days when no MEDI4736 dose is given
Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; SOC = Standard of Care.
Study Procedures & Examinations
Laboratory Assessments
Long-Term Follow-up
Treatment (Cohort B3)
Treatment (Cohort C)
Tumor & Disease Assessments 
Treatment (Cohort B2)
Last Study Drug 
Administration 
+28 (± 3) days
Last Study Drug 
Administration 
+56 (± 5) days
Last Study Drug 
Administration 
+91 (± 7) days 
Optional 
Study Treatment Extension
Study Flowchart for Subjects who Continue 
Study Treatment after 1-Year Core Study 
Post Study 
Follow-up 
(Done at least 
every 6 months for 
up to 3 years from 
start of treatment)
On Study Follow-up5
Treatment (Cohorts A and B)


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8.9 List of Abbreviations 
Abbreviation or Specialized Term  
Definition 
ADA  
anti-drug antibody 
ADCC   
antibody-dependent cell-mediated cytotoxicity 
AE  
adverse event 
AESI  
adverse event of special interest 
ALT  
alanine transaminase 
APC  
antigen presenting cell 
AST  
aspartate transaminase 
AUC  
area under the concentration time curve 
BID 
twice daily 
CD  
cluster of differentiation 
CL  
clearance 
CL/F  
apparent systemic clearance 
Cmax  
peak concentration 
CNS  
central nervous system 
CRO  
contract research organization 
CT  
computed tomography 
CTC  
circulating tumor cell 
CTLA-4  
cytotoxic T-lymphocyte antigen 4 
DC  
dendritic cell 
DCR  
disease control rate 
DLT  
dose-limiting toxicity 
DMC  
Data Monitoring Committee 
DoR  
duration of response 
DTIC  
dacarbazine 
ECG  
electrocardiogram 
ECHO  
echocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
electronic case report form 
EMA  
European Medicines Agency 
EORTC  
European Organization for Research and Treatment of 
Cancer 
EU  
European Union 
FAAN  
Food and Allergy Anaphylaxis Network 
Fc  
fragment crystallizable 
GBM  
glioblastoma 
GLP  
Good Laboratory Practice 
GMP  
Good Manufacturing Practice 
Gy 
Grey 
HDPE  
high density polyethylene 
HIPAA  
Health Insurance Portability and Accountability Act 
HR  
hazard ratio 
IB  
Investigator’s Brochure 


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ICF  
informed consent form 
ICH  
International Conference on Harmonisation 
IEC  
Independent Ethics Committee 
IL  
interleukin 
ILD  
interstitial lung disease 
INR  
International Normalized Ratio 
IRB  
Institutional Review Board 
irAE  
immune-related adverse event 
irRC  
immune-related response criteria 
IV  
intravenous 
IXRS  
interactive voice/web response system 
KA  
keratoacanthoma 
LVEF  
left-ventricular-ejection-fraction 
MAb  
monoclonal antibody 
MAPK  
mitogen-activated protein kinase 
MDSC  
myeloid derived suppressor cells 
MedDRA  
Medical Dictionary for Regulatory Activities 
MGMT  
methylguanine methyltransferase 
miRNA  
microRNA 
mPFS  
median progression-free survival 
MTD  
maximum tolerated dose 
MRI  
magnetic resonance imaging 
MUGA  
multiple gated acquisition 
NCIC  
National Cancer Institute of Canada 
NCI CTCAE  
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NIAID  
National Institute of Allergy and Infectious Disease 
NSCLC  
non-small cell lung cancer 
OCT  
ocular coherence tomography 
OR  
objective response 
ORR  
objective response rate 
OS  
overall survival 
PBMC  
peripheral blood mononuclear cell 
PD  
progressive disease 
PD-1  
programmed death 1 
PD-L1  
programmed death ligand 1 
PFS  
progression-free survival 
PK  
pharmacokinetic 
PPES  
Palmar-Plantar Erythrodysesthaesia Syndrome 
PRO  
patient-reported outcome 
PT  
prothrombin time 
Q2W  
every 2 weeks 
Q4W 
every 4 weeks 
QD  
once daily 
QoL  
quality of life 
QTc  
time between start of Q wave and end of T wave 
corrected for heart rate  


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RECIST  
Response Evaluation Criteria in Solid Tumors 
RNA  
ribonucleic acid 
RP2D 
recommended phase 2 dose 
RPED  
retinal pigment epithelial detachment 
RT  
radiation therapy 
RTOG   
Radiation Therapy Oncology Group 
RVO  
retinal vein occlusion 
SAE  
serious adverse event 
SID  
subject identification 
sPD-L1  
soluble programmed death ligand 1 
SUSAR  
suspected unexpected serious adverse reactions 
tu  
half-life 
ULN  
upper limit of normal 
US FDA  
United States Food and Drug Administration 
USA  
United States of America 
V  
valine 
Vc/F  
Apparent volume of distribution 
VDJ  
variable, diverse, and joining gene segments 
WFI  
water for injection 
WT  
wild-type 
 
 


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Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab 
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Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene 
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Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of 
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Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, et al. The human PD-1 
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Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal 
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