A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 (AMP-514) in Combination With Durvalumab Versus Nivolumab Monotherapy in Subjects With Select Advanced Malignancies
Phase: PHASE1
Conditions: Select Advanced Malignancies, Kidney Cancer, Clear Cell Renal Cell Carcinoma
Sponsor: MedImmune LLC

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A Phase 1/2, Open-label Study to Evaluate the Safety and 
Antitumor Activity of MEDI0680 (AMP-514) in Combination 
with Durvalumab versus Nivolumab Monotherapy in 
Subjects with Select Advanced Malignancies 
Sponsor Protocol Number: D6020C00001 
Application Number: 
IND 122076 
EudraCT number: 2016-000323-43 
NCT number: NCT02118337 
Investigational Product: 
MEDI0680 and Durvalumab (MEDI4736) 
Sponsor:  
 
 
 
 
MedImmune, LLC, a wholly-owned subsidiary of 
 
 
 
 
 
 
 
 
AstraZeneca PLC, 
 
 
 
 
 
 
 
 
One MedImmune Way, Gaithersburg, MD 20878, USA 
Medical Monitor: 
, 
, 
 
 
, 
, MedImmune 
 
Phone: 
; Fax: 
 
 
, 
 
, 
, MedImmune 
Phone: 
; Fax: 
 
Contract Research  
Organization: 
 
 
 
inVentiv Health Clinical 
Protocol History, Date 
Original Protocol, 11Mar2014 
Amendment 1, 16Apr2014 
Amendment 2, 01Oct2014 
Protocol Administrative Change 1, 05Feb2015 
Amendment 3, 11Feb2016 
Amendment 4, 27May2016 
Amendment 5, 29Mar2017 
 

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PROTOCOL SYNOPSIS 
TITLE  
A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 (AMP-514) in 
Combination with Durvalumab versus Nivolumab Monotherapy in Subjects with Select Advanced 
Malignancies 
HYPOTHESES   
Primary hypotheses:  
Dose-escalation:  
MEDI0680 in combination with durvalumab (MEDI4736) will be adequately tolerated in subjects with select 
advanced malignancies. 
Dose-expansion:  
MEDI0680 in combination with durvalumab will have a higher response rate than nivolumab monotherapy in 
subjects with advanced or metastatic clear cell renal cell carcinoma (ccRCC) 
Secondary hypotheses:  
Dose-escalation:  
MEDI0680 in combination with durvalumab will have antitumor activity in subjects with select advanced 
malignancies  
Dose-expansion:  
MEDI0680 in combination with durvalumab will be adequately tolerated in subjects with advanced or 
metastatic ccRCC 
OBJECTIVES  
Primary objectives: 
Dose-escalation:  
To determine the maximum tolerated dose (MTD) or the highest protocol-defined dose in the absence of 
exceeding the MTD for MEDI0680 in combination with durvalumab and the safety profile of MEDI0680 in 
combination with durvalumab in subjects with advanced malignancies 
Dose-expansion:  
To evaluate the antitumor activity of MEDI0680 in combination with durvalumab versus nivolumab 
monotherapy in immunotherapy-naïve subjects with advanced or metastatic ccRCC as based on investigator 
assessed response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Secondary objectives: 
Dose-escalation:  
To evaluate the antitumor activity of MEDI0680 in combination with durvalumab in subjects with advanced 
malignancies as based on the investigator assessed response using modified RECIST v1.1  
Dose-expansion:  
To describe the safety and tolerability of MEDI0680 in combination with durvalumab or nivolumab 
monotherapy in immunotherapy-naïve subjects with advanced or metastatic ccRCC 
To evaluate the antitumor activity of MEDI0680 in combination with durvalumab versus nivolumab 
monotherapy in immunotherapy-naïve subjects with advanced or metastatic ccRCC as based on blinded 
independent central review (BICR) assessed response using RECIST v1.1  
Dose-escalation and Dose-expansion: 
1. To describe the pharmacokinetics (PK) of MEDI0680 in combination with durvalumab  
2. To describe the PK of durvalumab in combination with MEDI0680 
3. To determine the immunogenicity of MEDI0680 in combination with durvalumab  
4. To determine the immunogenicity of durvalumab in combination with MEDI0680 
5. To determine whether PD-L1 is a predictive biomarker for response to therapy with MEDI0680 in 
combination with durvalumab 

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Exploratory objectives: 
1. To identify biomarkers that are predictive of antitumor response to MEDI0680 in combination with 
durvalumab 
2. To profile gene expression changes that may correlate with antitumor response to MEDI0680 in 
combination with durvalumab 
3. To evaluate additional biomarkers that may correlate with antitumor activity of MEDI0680 in combination 
with durvalumab compared with nivolumab monotherapy 
4. To evaluate the pharmacodynamic activity of MEDI0680 in combination with durvalumab versus 
nivolumab monotherapy in the periphery. 
5. To compare the pharmacodynamic changes resulting from complete PD-1/PD-L1 pathway blockade versus 
treatment with nivolumab monotherapy 
6. To evaluate the antitumor activity of MEDI0680 in combination with durvalumab versus nivolumab 
monotherapy in subjects with advanced or metastatic ccRCC as assessed by immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) 
STUDY ENDPOINTS 
Primary objectives endpoints: 
Dose-escalation:  
The primary endpoints for safety assessment include adverse events (AEs) and serious adverse events (SAEs), 
as well as changes from baseline in laboratory evaluations, vital signs, physical examinations, and 
electrocardiogram (ECG) results. 
Dose-expansion:  
The primary endpoint is objective response (OR) of MEDI0680 in combination with durvalumab versus 
nivolumab monotherapy. Secondary endpoints include best overall response (BOR), disease control (DC), time 
to response (TTR), duration of response (DR), progression free survival (PFS), change from baseline in tumor 
size and overall survival (OS).  Efficacy endpoints except OS are based on an application of RECIST v1.1 to 
investigator-assessed tumor measurements. 
Secondary objectives endpoints: 
Dose-escalation:  
The endpoints for assessment of antitumor activity include BOR, OR, DC, TTR, DR, PFS, OS, and change 
from baseline in tumor size. Antitumor activity analyses except OS will be based on investigator-assessed 
response using modified RECIST v1.1. 
Dose-expansion:  
The endpoints for assessment of safety include the presence of AEs and SAEs, as well as changes from baseline 
in laboratory parameters, vital signs, physical examination, and ECG results. 
The endpoints for assessment of antitumor activity include BOR, OR, DC, TTR, DR, PFS, and change from 
baseline in tumor size as based on BICR-assessed response using RECIST v1.1.  
Dose-escalation and Dose-expansion:  
x 
The endpoints for assessment of PK include individual MEDI0680 and durvalumab concentrations in 
serum. PK parameters include peak concentration (Cmax) and trough concentration (Cmin) 
x 
The endpoints for assessment of immunogenicity of MEDI0680 and durvalumab include the presence of 
detectable anti-drug antibodies (ADAs). 
x 
PD-L1 expression / localization on tumor membrane and tumor-infiltrating immune cells within the tumor 
microenvironment 
Exploratory endpoints: 
1. The endpoints related to candidate predictive and/or prognostic biomarkers in dose-expansion will focus on 
tissue-based, protein or gene expression measures and peripheral gene signatures including, but not limited 
to immunohistochemistry (IHC) measures of markers associated with infiltrating immune cells (eg, cluster 
of differentiation 80) 

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2. Gene expression signatures associated with response to therapy will include expression of messenger 
ribonucleic acid in blood and tumor samples before and after treatment to examine gene expression 
patterns at baseline and changes in response to treatment. Analysis may also include but is not limited to: 
evaluation of key oncogenic mutations and/or mutations in immune-related molecules. 
3. Levels of circulating free DNA and/or circulating soluble factors which may include cytokines, 
chemokines, growth factors, soluble receptors, and antibodies against tumor and self-antigens, may be 
evaluated before and after treatment to evaluate response to treatment with MEDI0680 and durvalumab 
compared with nivolumab monotherapy 
4. Pharmacodynamic assessments of MEDI0680 and durvalumab combination in the periphery include: 
a. 
Flow cytometric assessment of cell populations such as T cells and B cells before and after treatment 
to evaluate their association with drug exposure and response to treatment; analysis may include 
characterization of phenotype, expression of activation markers, proliferation, and production of 
cytokines and effector molecules 
b. Dose escalation only: Serum soluble PD-L1 levels before and after treatment may be measured to 
evaluate their association with drug exposure and response to treatment with MEDI0680 and 
durvalumab  
c. 
Dose escalation only: MEDI0680 receptor occupancy on peripheral blood T cells before and after 
treatment may be measured to evaluate associations with drug exposure and response to treatment with 
MEDI0680 and durvalumab  
5. Expression and localization of key molecules such as PD-L1, PD-L2, and PD-1 within the tumor 
microenvironment, as well as the frequency, localization, and phenotype of tumor-infiltrating lymphocytes, 
may be examined in biopsy specimens by IHC, immunofluorescence, and/or flow cytometry and correlated 
with response to treatment 
6. Antitumor activity, including OR, DR, DC, and PFS, may be assessed by irRECIST 
STUDY DESIGN  
This is a multicenter, open-label, Phase 1/2 study to evaluate the safety, tolerability, PK, immunogenicity, and 
antitumor activity of MEDI0680 in combination with durvalumab or nivolumab monotherapy in adult 
immunotherapy-naïve subjects with selected advanced malignancies. The study will be conducted at 
approximately 50 study centers globally.  
The study includes 2 phases, dose-escalation and dose-expansion. In the dose-escalation phase, subjects with 
selected solid tumors will receive MEDI0680/durvalumab combination therapy. In the dose-expansion phase, 
subjects with ccRCC will receive either MEDI0680/durvalumab combination therapy or nivolumab 
monotherapy.  
In the dose-escalation phase, subjects may receive treatment for up to 12 months; in the dose expansion phase, 
subjects may remain on treatment until unacceptable toxicity, confirmed progressive disease (PD), or 
development of other reason for treatment discontinuation. Subjects in dose expansion may receive study 
drug(s) for a maximum of 2 years. At the conclusion of the study, subjects who continue to demonstrate clinical 
benefit will be eligible to receive study drug(s).  Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of the sponsor.  The sponsor reserves the right to terminate access to study drug if 
any of the following occur:  a) the marketing application is rejected by responsible health authority; b) the study 
is terminated due to safety concerns; c) the subject can obtain medication from a government sponsored or 
private health program; or d) therapeutic alternatives become available in the local market. All subjects will be 
evaluated regularly. Clinical status will be classified according to modified RECIST v1.1 for subjects in the 
dose-escalation phase and by RECIST v1.1 for subjects in the dose expansion phase, and other disease-specific 
assessments. All subjects will be followed for survival until the end of study. Adverse events and SAEs will be 
followed. 
In the dose-escalation phase, sequential cohorts of 3 to 6 subjects will be enrolled in 1 of 6 dose-level cohorts: 
0.1 mg/kg MEDI0680 Q2W with 3 mg/kg durvalumab Q2W, and increasing dose levels of MEDI0680 Q2W 
(0.1, 0.5, 2.5, 10, and 20 mg/kg) with 10 mg/kg durvalumab Q2W. The dose-escalation phase will initially 
include immunotherapy-naïve subjects with solid tumors. As of Protocol Amendment 2, only subjects with 
non-small cell lung cancer NSCLC, squamous cell carcinoma of the head and neck (SCCHN), microsatellite 
instability-high (MSI high) colorectal cancer (CRC), bladder cancer, ovarian cancer, esophageal cancer, gastric 

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cancer, or renal cell carcinoma (RCC) will be enrolled.  
The dose-escalation phase will be executed according to a 3 + 3 design. If ≥ 2 of 6 subjects experience a dose 
limiting toxicity (DLT), a dose level from the intermediate zone-based cohort(s) that does not exceed the MTD 
or the highest protocol defined dose for each investigational product in the absence of exceeding the MTD may 
be explored. Based on emerging safety, PK, pharmacodynamic, and clinical activity data for the MEDI0680 
Q2W treatment schedule, the dosing interval for MEDI0680 could have been increased to every 4 weeks 
(Q4W). 
Any dose-level cohort in the dose-escalation phase that did not exceed the MTD can be expanded up to a 
maximum of 18 subjects for further evaluation of safety, PK, pharmacodynamics, and antitumor activity. 
Based on 6 dose-level cohorts in the main 3 + 3 dose-escalation design on a Q2W treatment schedule, up to 
36 subjects may be enrolled. Additional subjects could be required if dose de-escalation occurs, intermediate 
dosing using the modified zone-based design is explored or any dose-level cohort is expanded beyond 
6 subjects.  
As of Protocol Amendment 3, the dose-escalation phase completed enrollment. Subjects were treated through 
the highest planned dose-level cohort of 20 mg/kg MEDI0680 Q2W in combination with durvalumab Q2W and 
the MTD was not reached. 
The dose-expansion phase will begin after the dose-escalation phase. As of Amendment 5, immunotherapy-
naïve subjects with ccRCC will be randomized in a 2:1 ratio to 1 of 2 treatment arms: (1) 
MEDI0680/durvalumab combination therapy or (2) nivolumab monotherapy. Stratification factors will include 
the Memorial Sloan Kettering Cancer Center (MSKCC) risk group (0 = favorable risk; 1 or 2 = intermediate 
risk; 3 = poor risk) and PD-L1 expression status (≤ 1% and > 1%). Up to 40 subjects may be randomized in to 
the MEDI0680/durvalumab combination therapy arm and up to 20 subjects in the nivolumab monotherapy arm 
based on evaluation of emerging safety and efficacy parameters in the current study as well as other ongoing 
studies. An interim futility analyses will be performed for the MEDI0680/durvalumab combination therapy arm 
in the dose-expansion phase after 20 subjects have been randomized and have reached their second 
post-baseline disease assessment or have completed study.  
An evaluation of a possible correlation between clinical activity of MEDI0680 in combination with durvalumab 
or nivolumab and potential biomarkers (eg, PD-L1 expression on tumor) will be ongoing throughout the study. 
Randomization into the dose expansion phase may be discontinued at the discretion of the sponsor should 
emerging clinical or pre-clinical data suggest that continued treatment may not be beneficial. 
TARGET SUBJECT POPULATION  
For the dose-escalation phase, subjects will be immunotherapy-naïve adults with selected solid tumors who are 
refractory or intolerant to standard therapy or for which no standard therapy exists. As of Protocol 
Amendment 2, only subjects with NSCLC, SCCHN, MSI-high CRC, bladder cancer, ovarian cancer, 
esophageal cancer, gastric cancer, or RCC will be enrolled. No more than 3 prior lines of systemic therapy in 
the recurrent or metastatic setting, including standard and investigational agents, will be allowed. 
For the dose-expansion phase, subjects will be immunotherapy-naïve adults with advanced or metastatic RCC 
with a clear cell component who have received and experienced disease progression after at least 1 and no more 
than 2 prior anti-angiogenic therapy regimens (including, but not limited to, sunitinib, sorafenib, pazopanib, 
axitinib, tivozanib, and bevacizumab) in the advanced or metastatic setting; must have received no more than 
3 total prior systemic treatment regimens in the advanced or metastatic setting (prior mammalian target of 
rapamycin [mTOR] regimens are not allowed); and must have evidence of radiographic progression on or after 
the last treatment regimen received within 6 months prior to study enrollment.  
Subjects in the dose-expansion phase will be required to provide formalin fixed paraffin embedded archival or 
fresh tumor tissue deemed to be evaluable for PD-L1 expression status in order to be randomized to study 
treatment. Subjects will not be excluded based on PD-L1 status. Subjects with non-evaluable PD L1 status will 
be excluded. 
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION 
Subjects will be treated in either the dose-escalation or dose-expansion phase. Both MEDI0680 and durvalumab 
will be administered via IV infusion. Nivolumab will be administered per the dosing information in the package 
insert. In the dose-escalation phase, sequential cohorts of subjects will receive 1 of 6 MEDI0680/durvalumab 
combination dose levels: 0.1 mg/kg MEDI0680 Q2W with 3 mg/kg durvalumab Q2W, or increasing dose levels 
of MEDI0680 Q2W (0.1, 0.5, 2.5, 10, and 20 mg/kg) with 10 mg/kg durvalumab Q2W. Subjects will remain on 

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treatment for up to 12 months. Subjects in the dose-escalation phase who achieve and maintain DC (ie, CR, PR, 
or stable disease SD) through the end of the 12-month treatment period will enter follow-up. During the first 
12 months of follow-up, if the subject has PD, the subject may be re-administered MEDI0680 and durvalumab 
for up to another 12 months with the same treatment guidelines followed during the initial 12-month period if 
the subject fulfills the criteria for retreatment in the setting of PD, has not received other anticancer treatments 
for their disease, and does not meet any of the investigational product discontinuation criteria. Only 1 round of 
retreatment will be allowed. 
In the dose-expansion phase, subjects will receive either 20 mg/kg MEDI0680 in combination with 750 mg 
(fixed dose) durvalumab Q2W or nivolumab Q2W monotherapy. Subjects in the dose-expansion phase will 
remain on treatment until unacceptable toxicity, confirmed PD, or development of other reason for treatment 
discontinuation. 
Prior to the removal of a MEDI0680 monotherapy arm in this protocol amendment, some subjects were 
randomized and began receiving MEDI0680 monotherapy. These subjects are to continue receiving 20 mg/kg 
MEDI0680 Q2W monotherapy until unacceptable toxicity, confirmed progressive disease (PD), or development 
of other reason for treatment discontinuation and will follow the schedule of study procedures for 
MEDI0680/durvalumab combination therapy.  
In the event of an initial assessment of PD (based on RECIST v1.1) in either the dose-escalation or 
dose-expansion phases, a subject may continue to receive the assigned study treatment until confirmation of PD 
if the subject fulfills the criteria for treatment in the setting of PD and does not meet any of the investigational 
product discontinuation criteria. If the lesions included in the tumor burden subsequently regress to the extent 
that the criteria for PD are no longer met, then treatment may continue according to the treatment schedule. 
Initial observation of PD must be confirmed by a subsequent scan no earlier than 4 weeks from the initial scan. 
Subjects with confirmed PD must discontinue treatment. 
STATISTICAL ANALYSIS PLAN  
Sample Size 
Initially, a total of approximately 96 subjects could be required for both dose-escalation and dose-expansion 
phases of the study. 
For dose-escalation (enrollment completed), the number of subjects will depend upon the toxicities observed as 
the study progresses. Up to approximately 36 evaluable subjects could be required by the 3 + 3 design with 
6 dose cohorts in the main dose escalation design. Additional subjects could be required if dose de-escalation 
occurs, intermediate dosing using the modified zone-based design is explored, the dosing interval of MEDI0680 
is changed, or expansion of a dose-escalation cohort occurs. Subjects in the dose escalation phase are 
considered evaluable if they receive the protocol-assigned doses of both durvalumab and MEDI0680, and 
complete the DLT-evaluation period or experience a DLT during the DLT-evaluation period. Non-evaluable 
subjects will be replaced. The table below provides the probability of dose-escalation to the next higher level 
for each underlying true DLT rate. For example, for a common toxicity that occurs in 10% of subjects, there is a 
greater than 90% probability of escalating to the next higher dose level. Conversely, for a toxicity that occurs 
with a rate of 60%, the probability of escalating to the next higher dose level is less than 10%. 
Probability of Escalating Dose for Different True Underlying Dose-limiting Toxicity Rate at Given Dose 
Level 
True Underlying DLT Rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of escalating dose 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.009 
0.001 
 
For dose-expansion, up to approximately 60 subjects (40 subjects in the MEDI0680/durvalumab combination 
therapy arm and 20 subjects in the nivolumab monotherapy arm) may be randomized at the selected 
combination dose (ie, MTD or highest protocol-defined dose for each agent in the absence of exceeding the 
MTD) in a 2:1 ratio. The primary objective of the dose-expansion phase is to evaluate the antitumor activity 
based on objective response rate (ORR) of MEDI0680 in combination with durvalumab versus nivolumab 
monotherapy in immunotherapy-naïve subjects with advanced or metastatic ccRCC based on an application of 
RECIST v1.1 to investigator-assessed tumor measurements. Assuming an ORR for nivolumab monotherapy of 
21.5%, the sample size is chosen to detect a difference in ORR of 26.0% (ie, ORR = 47.5%) with 76% power at 
a 1-sided significance level of 0.10. The 95% confidence interval of a 47.5% ORR (19 responders / 40 subjects) 

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is 31.5%, 63.9%).  
Safety 
The MTD evaluation will be based on the DLT-evaluable Population (Q2W schedule) which includes all 
subjects enrolled in the dose-escalation phase who receive 2 protocol-assigned doses of durvalumab and 
MEDI0680 and complete the safety follow-up through the end of the DLT-evaluation period, or experience a 
DLT during the DLT-evaluation period (defined as the time period starting with the first dose of study drugs 
until the planned administration of the third dose of durvalumab and MEDI0680).  
The safety evaluation will be based on the As-treated Population and will include AEs, SAEs, laboratory 
evaluations, vital signs, and physical examinations. Summary statistics will be provided for AEs, SAEs, and 
AE grade, severity, and relationship to investigational product, reported from the start of treatment with 
durvalumab and MEDI0680 or nivolumab. Adverse events will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 and described by system 
organ class using the Medical Dictionary for Regulatory Activities preferred term. Laboratory abnormalities 
with toxicity grades according to the NCI CTCAE v4.03 will be derived and summarized. Safety analyses will 
be descriptive in nature and no formal statistical comparison will be made. 
Efficacy 
For the dose-escalation phase, efficacy analyses will be based on an application of modified RECIST v1.1 to 
investigator-assessed tumor measurements. RECIST v1.1 has been modified to require confirmation of PD. A 
confirmed PD will be a PD confirmed by a consecutive repeat assessment no fewer than 4 weeks later. A PD 
that occurs without follow-up scans to provide confirmation or only non-evaluable follow-up scans will also be 
considered a confirmed PD. The efficacy analysis will be based on the As-treated Population. 
For the dose-expansion phase, efficacy analyses will be based on an application of RECIST v1.1 to 
investigator-assessed tumor measurements and BICR. The efficacy analysis will be based on the As-treated 
Population. 
The following efficacy endpoints will be analyzed. More details will be provided in the statistical analysis plan. 
x 
ORR is defined as the proportion of subjects with a BOR of confirmed CR or confirmed PR. ORR will be 
estimated with a 95% CI using the exact probability method. For the dose-expansion phase, comparison of 
arms will be obtained from Fisher’s exact test. 
x 
DCR16 is defined as the proportion of subjects with a BOR of confirmed CR, confirmed PR, or SD 
(maintained for ≥ 16 weeks). A similar definition applies to DCR24. DCR16 and DCR24 will be estimated 
with a 95% CI using the exact probability method.  
x 
TTR is defined as the time from the first dose of treatment until the first documentation of a subsequently 
confirmed objective response. Only subjects who have achieved OR will be evaluated for TTR. The 
median TTR and its 95% CI will be assessed using the Kaplan-Meier method. 
x 
DR is defined as the time from the first documentation of a subsequently confirmed objective response 
until the first documentation of a disease progression (subsequently confirmed for dose escalation phase) or 
death due to any cause, whichever occurs first. Only subjects who have achieved OR will be evaluated for 
DR. The median DR and its 95% CI will be estimated using the Kaplan-Meier method. 
x 
PFS is defined as the time from the first dose of treatment until the first documentation of a disease 
progression (subsequently confirmed for dose escalation phase) or death due to any cause, whichever 
occurs first. The median PFS and its 95% CI will be estimated using the Kaplan-Meier method. 
The Kaplan-Meier method will be used to estimate the PFS curve and the PFS rate at time points of 
interest.  
x 
OS is defined as the time from the first dose of treatment with durvalumab and MEDI0680 or nivolumab 
until death due to any cause. The median OS and its 95% CI will be estimated using the Kaplan-Meier 
method. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time points of 
interest. 
Immunogenicity 
Only subjects who receive at least one dose of both durvalumab and MEDI0680 and provide at least one 
posttreatment sample will be evaluated. Immunogenicity results will be analyzed descriptively by summarizing 
the number and percentage of subjects who develop detectable anti-durvalumab or anti-MEDI0680 antibodies. 
The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-durvalumab 
or anti-MEDI0680 antibodies. The impact of ADAs on PK and pharmacodynamics will also be assessed if data 

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allow. Samples will be collected and banked for evaluating neutralizing capacity of ADAs in the future. 
Pharmacokinetics 
Only subjects who receive at least one dose of investigational product and provide at least one posttreatment 
sample will be evaluated. Individual durvalumab and MEDI0680 concentrations will be tabulated by dose 
cohort along with descriptive statistics. The PK of durvalumab and MEDI0680 will be assessed using 
parameters including Cmax and Cmin after the first dose. Durvalumab and MEDI0680 steady-state PK 
parameters including concentrations at peak concentration at steady state (Cmax,ss) and trough concentration at 
steady state (Cmin,ss) will be estimated. Accumulation to steady state will be assessed as the ratio of 
Cmax,ss:Cmax and Cmin,ss:Cmin. All PK parameters will be estimated by non-compartmental analysis. 
Descriptive statistics of non-compartmental PK parameters will be provided. 
Exploratory Analyses 
Descriptive statistics will be the primary methods for the exploratory analyses. Depending on the nature of the 
data, geometric mean and other appropriate statistical summaries might be used as well. Tumor responses by 
irRECIST, immune-related complete response, immune-related partial response, immune-related stable disease, 
and immune-related progressive disease will be summarized and analyzed descriptively. Tumor response by 
irRECIST will be compared with that by RECIST v1.1. The irRECIST is similar to RECIST v1.1 except that 
measurements of the new lesions are included in the sum of the measurements of all target lesions and do not 
automatically constitute progressive disease under irRECIST, whereas new lesions are not measured and 
automatically constitute progressive disease under RECIST v1.1. 
Interim Analysis 
An interim futility analyses will be performed for the MEDI0680/durvalumab combination therapy arm in the 
dose-expansion phase after 20 subjects have been randomized and have reached their second post-baseline 
disease assessment or have completed study. Subject accrual may be paused in both cohorts to evaluate the 
MEDI0680/durvalumab combination therapy arm for futility. Continued randomization of subjects in both arms 
will be terminated if 2 (10%) or fewer responses within the MEDI0680/durvalumab combination arm are 
observed. For the futility analysis, a response is defined as either a confirmed or unconfirmed CR or PR as per 
RECIST v1.1. 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS...........................................................................................................2 
LIST OF ABBREVIATIONS ..................................................................................................15 
1 
INTRODUCTION .........................................................................................................18 
1.1 
Immunotherapy ...................................................................................................18 
1.2 
MEDI0680 and Durvalumab (MEDI4736) Background ....................................18 
1.2.1MEDI0680 Background ..............................................................................18 
1.2.2Durvalumab Background ............................................................................19 
1.3 
Summary of Nonclinical Experience ..................................................................19 
1.3.1MEDI0680 Nonclinical Experience ............................................................20 
1.3.2Durvalumab Nonclinical Experience ..........................................................20 
1.4 
Summary of Clinical Experience ........................................................................21 
1.4.1MEDI0680 Clinical Experience ..................................................................22 
1.4.2Durvalumab Clinical Experience ................................................................24 
1.5 
Rationale for Conducting the Study....................................................................28 
1.6 
Research Hypotheses ..........................................................................................31 
1.6.1Primary Hypotheses ....................................................................................31 
1.6.2Secondary Hypotheses ................................................................................32 
2 
OBJECTIVES AND ENDPOINTS...............................................................................32 
2.1 
Primary Objectives and Endpoints .....................................................................32 
2.2 
Secondary Objectives and Endpoints .................................................................32 
2.3 
Exploratory Objectives and Endpoints ...............................................................33 
3 
STUDY DESIGN ..........................................................................................................35 
3.1 
Description of the Study .....................................................................................35 
3.1.1Overview………. ........................................................................................35 
3.1.1.1 
Dose-escalation Phase ...............................................................36 
3.1.1.2 
Dose-expansion Phase ..............................................................37 
3.1.2Treatment Regimen.....................................................................................38 
3.1.2.1 
Treatment Beyond Progression .................................................39 
3.1.2.2 
Dosing Schedule .......................................................................40 
3.1.3Dose-escalation Phase: Dose-escalation and Modified Zone-based 
Design .......................................................................................41 
3.1.3.1 
Dose-escalation .........................................................................41 
3.1.3.2 
Modified Zone-based Design ....................................................43 
3.1.3.3 
Dose-limiting Toxicity ..............................................................44 
3.1.3.4 
Maximum Tolerated Dose ........................................................45 
3.1.4Dose-expansion Phase ................................................................................46 
3.1.5Management of Study Medication Related Toxicities ...............................46 

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3.1.5.1 
Dose Modifications of Durvalumab and MEDI0680 ...............46 
3.1.5.2 
Dose Modifications of Nivolumab ...........................................47 
3.2 
Study Design and Dose Rationale ......................................................................47 
3.2.1Dose Rationale (MEDI0680 and Durvalumab) ..........................................47 
3.2.1.1 
Dose-escalation Phase ...............................................................47 
3.2.1.2 
Dose-expansion Phase ..............................................................48 
3.2.2Rationale for Study Population ...................................................................49 
3.2.3Rationale for Endpoints ..............................................................................50 
4 
MATERIALS AND METHODS ..................................................................................54 
4.1 
Subjects ...............................................................................................................54 
4.1.1Number of Subjects ....................................................................................54 
4.1.2Inclusion Criteria ........................................................................................54 
4.1.3Exclusion Criteria .......................................................................................57 
4.1.4Subject Enrollment .....................................................................................58 
4.1.5Withdrawal from the Study.........................................................................59 
4.1.5.1 
Withdrawal of Consent .............................................................59 
4.1.5.2 
Withdrawal from Treatment .....................................................59 
4.1.5.3 
Lost to Follow-up ......................................................................60 
4.1.6Discontinuation of Investigational Product ................................................60 
4.1.7Replacement of Subjects .............................................................................61 
4.1.8Withdrawal of Informed Consent for Data and Biological Samples ..........61 
4.2 
Schedule of Study Procedures ............................................................................62 
4.2.1Enrollment/Screening Period ......................................................................62 
4.2.2Treatment Period.........................................................................................63 
4.2.3Follow-up Period ........................................................................................73 
4.3 
Description of Study Procedures ........................................................................75 
4.3.1Efficacy………. ..........................................................................................75 
4.3.1.1 
Solid Tumors .............................................................................75 
4.3.2Archival Tumor Samples, Bone Marrow Biopsies, and Tumor Biopsies ..76 
4.3.2.1 
Archival Tumor Samples ..........................................................76 
4.3.2.2 
Tumor Biopsies .........................................................................76 
4.3.3Medical History and Physical Examination................................................77 
4.3.4Clinical Laboratory Tests............................................................................78 
4.3.5Pharmacokinetic Evaluation and Methods .................................................80 
4.3.6Immunogenicity Evaluation and Methods ..................................................80 
4.3.7Biomarker Evaluation and Methods ...........................................................81 
4.3.8Estimate of Volume of Blood to Be Collected ...........................................82 
4.4 
Study Suspension or Termination .......................................................................82 

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4.5 
Investigational Products ......................................................................................83 
4.5.1Identity of Investigational Products ............................................................83 
4.5.1.1 
Durvalumab ..............................................................................84 
4.5.1.2 
MEDI0680 ................................................................................87 
4.5.1.3 
Nivolumab ................................................................................91 
4.5.1.4 
Monitoring of Dose Administration .........................................92 
4.5.1.5 
Reporting Product Complaints ..................................................92 
4.5.2Additional Study Medications ....................................................................93 
4.5.3Labeling……………. .................................................................................93 
4.5.4Storage………. ...........................................................................................93 
4.5.5Treatment Compliance ................................................................................93 
4.5.6Accountability .............................................................................................94 
4.6 
Treatment Assignment and Blinding ..................................................................94 
4.6.1Methods for Assigning Treatment Groups .................................................94 
4.6.2Methods for Ensuring Blinding ..................................................................94 
4.7 
Restrictions During the Study and Concomitant Treatment(s) ...........................94 
4.7.1Permitted Concomitant Medications ..........................................................95 
4.7.2Prohibited Concomitant Medications .........................................................95 
4.8 
Statistical Evaluation ..........................................................................................95 
4.8.1General Considerations ...............................................................................95 
4.8.2Sample Size and Power Calculations..........................................................96 
4.8.3Safety Analyses...........................................................................................97 
4.8.3.1 
Maximum Tolerated Dose Evaluation (Every 2-week 
Dosing Schedule) .......................................................97 
4.8.3.2 
Analyses of Safety Endpoints ...................................................97 
4.8.4Efficacy Analyses .......................................................................................97 
4.8.4.1 
Analysis of Efficacy Endpoints ................................................97 
4.8.5Pharmacodynamic Analyses .......................................................................98 
4.8.6Analyses of Immunogenicity and Pharmacokinetics ..................................99 
4.8.6.1 
Immunogenicity ........................................................................99 
4.8.6.2 
Pharmacokinetics ....................................................................100 
4.8.7Exploratory Analyses ................................................................................100 
4.8.7.1 
Immune-related Response Criteria .........................................100 
4.8.8Interim Analyses .......................................................................................100 
5 
ASSESSMENT OF SAFETY .....................................................................................101 
5.1 
Definition of Adverse Events ...........................................................................101 
5.2 
Definition of Serious Adverse Events ..............................................................102 
5.3 
Definition of Adverse Events of Special Interest .............................................103 

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5.3.1Immune-mediated Adverse Events ...........................................................103 
5.3.2Hepatic Function Abnormality (Hy’s Law) ..............................................104 
5.3.3Infusion Reactions ....................................................................................104 
5.3.4Hypersensitivity (Including Anaphylaxis) Reactions ...............................104 
5.4 
Recording of Adverse Events ...........................................................................105 
5.4.1Time Period for Collection of Adverse Events .........................................105 
5.4.2Follow-up of Unresolved Adverse Events ................................................106 
5.4.3Deaths………. ..........................................................................................106 
5.5 
Reporting of Serious Adverse Events ...............................................................106 
5.6 
Other Events Requiring Immediate Reporting .................................................107 
5.6.1Overdose……………… ...........................................................................107 
5.6.2Pregnancy……………..............................................................................108 
5.6.2.1 
Maternal Exposure ..................................................................108 
5.6.2.2 
Paternal Exposure ...................................................................108 
6 
STUDY AND DATA MANAGEMENT ....................................................................109 
6.1 
Training of Study Site Personnel ......................................................................109 
6.2 
Monitoring of the Study ....................................................................................109 
6.2.1Source Data ...............................................................................................109 
6.2.2Study Agreements .....................................................................................110 
6.2.3Archiving of Study Documents ................................................................110 
6.3 
Study Timetable and End of Study ...................................................................110 
6.4 
Data Management .............................................................................................111 
6.5 
Medical Monitor Coverage ...............................................................................111 
7 
ETHICAL AND REGULATORY REQUIREMENTS ..............................................111 
7.1 
Ethical Conduct of the Study ............................................................................111 
7.2 
Subject Data Protection ....................................................................................111 
7.3 
Ethics and Regulatory Review ..........................................................................112 
7.4 
Informed Consent .............................................................................................113 
7.5 
Changes to the Protocol and Informed Consent Form ......................................113 
7.6 
Audits and Inspections ......................................................................................114 
8 
REFERENCES ............................................................................................................115 
9 
SUMMARY OF CHANGES TO THE PROTOCOL .................................................123 
9.1 
Protocol Amendment 5, 29Mar2017 ................................................................123 
9.2 
Protocol Amendment 4, 27May2016 ................................................................131 
9.3 
Protocol Amendment 3, 11Feb2016 .................................................................132 
9.4 
Protocol Administrative Change 1, 05Feb2015 ................................................137 
9.5 
Protocol Amendment 2, 01Oct2014 .................................................................137 
9.6 
Protocol Amendment 1, 16Apr2014 .................................................................140 

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APPENDICES .......................................................................................................................142 
 
LIST OF IN-TEXT TABLES 
Table 2.1-1 
Primary Objectives and Associated Endpoints ....................................32 
Table 2.2-1 
Secondary Objectives and Associated Endpoints ................................32 
Table 2.3-1 
Exploratory Objectives and Associated Endpoints ..............................34 
Table 4.1.2-1 
Effective Methods of Contraception ....................................................57 
Table 4.2.1-1 
Schedule of Screening Procedures Following Protocol Amendment 
5............................................................................................................62 
Table 4.2.2-1 
Schedule of Study Procedures for Primary Q2W Treatment Period: 
Cycles 1-6 Following Protocol Amendment 5.....................................65 
Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: 
Cycles 7 to “n” Following Protocol Amendment 5 .............................68 
Table 4.2.3-1 
Schedule of Study Procedures: End of Treatment and Posttreatment 
Laboratory Follow-Up Following Protocol Amendment 5 .................73 
Table 4.5.1-1 
Identification of Investigational Products ............................................84 
Table 4.5.1.2-1 
Preparation of 20 mg/kg dose for IV infusion .....................................90 
Table 4.5.1.2-2 
Investigational Product Solution Volume by Treatment Group ..........91 
Table 4.8.2-1 
Probability of Escalating Dose for Different True Underlying Dose-
limiting Toxicity Rate at Given Dose Level ........................................96 
Table A5-1 
Evaluation of Overall Response .........................................................154 
Table A6-1 
Immune-mediated reactions ...............................................................157 
Table A6-2 
Infusion-related reactions ...................................................................176 
Table A6-3 
Non-immune-mediated reactions .......................................................177 
Table A7-1 
Determination of MSKCC Prognostic Score in Previously Treated 
Subjects ..............................................................................................178 
Table A7-2 
Risk Group Based on MSKCC Prognostic Score ..............................178 
 

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LIST OF IN-TEXT FIGURES 
Figure 3.1.1-1 
Study Flow Diagram ............................................................................38 
Figure 3.1.2.2-1 
Study Flow for Primary MEDI0680 Schedule (Every 2-week 
Dosing) .................................................................................................40 
Figure 3.1.3.1-1 
Primary (Every 2-week Dosing of MEDI0680) Dose-escalation 
Design ..................................................................................................43 
Figure 3.1.3.2-1 
Dose-escalation (Zone-based) for Primary Q2W Schedule .................44 
 
LIST OF APPENDICES 
Appendix 1 
Signatures ...........................................................................................143 
Appendix 2 
Additional Safety Guidance ...............................................................146 
Appendix 3 
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .....149 
Appendix 4 
Smoking Questionnaire ......................................................................150 
Appendix 5 
Solid Tumor Efficacy .........................................................................151 
Appendix 6 
Durvalumab and MEDI0680 Dose Modifications for Toxicity 
Management .......................................................................................156 
Appendix 7 
Memorial Sloan Kettering Cancer Center Prognostic Score (Renal Cell 
Carcinoma) .........................................................................................178 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialized Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
BICR 
blinded independent central review 
BOR 
best overall response 
BP 
blood pressure 
ccRCC 
clear-cell renal cell carcinoma 
CD80 
cluster of differentiation 80 
CI 
confidence interval 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response and remission 
CRC 
colorectal cancer 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen 4 
DC 
disease control 
DCR 
disease control rate 
DEHP 
di(2-ethylhexyl) phthalate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOI 
end of infusion 
EOT 
end of treatment 
EU 
European Union 
FAAN 
Food Allergy and Anaphylaxis Network 
FACT-G 
Functional Assessment of Cancer Therapy General 

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Abbreviation or 
Specialized Term 
Definition 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IF 
immunofluorescence 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG 
immunoglobulin G 
IHC 
immunohistochemistry  
IL 
interleukin 
imAE 
immune-mediated adverse event 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous(ly) 
IVBP 
intravenous bag protectant 
IXRS 
interactive voice response system/interactive web response system (collectively) 
KRAS 
Kirsten rat sarcoma oncogene homolog 
mAb 
monoclonal antibody 
MDS 
myelodysplastic syndrome 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MSI-high 
microsatellite instability-high 
MSKCC 
Memorial Sloan Kettering cancer center 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamyacin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NIAID 
National Institute of Allergy and Infectious Diseases 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NRAS 
neuroblastoma RAS viral oncogene homologue 
NSCLC 
non-small cell lung cancer 
OR 
objective response 

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Abbreviation or 
Specialized Term 
Definition 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PEF 
peak expiratory flow 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time 
PTPN11 
Protein tyrosine kinase phosphatase non-receptor Type 1l 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
RANKL 
receptor activator of nuclear factor kappa-B ligand 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SHP2 
Src homology domain containing phosphatase 2 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
TKI 
tyrosine kinase inhibitor 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
US or USA 
United States 
USP 
US Pharmacopeia 
WFI 
water for injection 
WT 
weight 
w/v 
weight per volume 
 

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1 
INTRODUCTION 
1.1 
Immunotherapy 
In the United States (US), cancer is the second most common cause of death after heart 
disease, accounting for nearly 1 in every 4 deaths (Siegel et al, 2013). There has been a 
20% lower death risk rate from cancer in 2009 in comparison to 1991, likely 
reflecting progress in diagnosing certain cancers earlier and improvements in treatment 
(Siegel et al, 2013). Unfortunately, despite this progress, there continues to be an unmet 
medical need for more effective and less toxic therapies, especially for patients with 
advanced refractory disease. 
Recent advances in immunotherapy offer promise for improving clinical outcomes in patients 
with advanced malignancies. It is increasingly appreciated that cancers are recognized by the 
immune system, and under some circumstances, the immune system may control or even 
eliminate tumors (Dunn et al, 2004). Studies in mouse models of transplantable tumors have 
demonstrated that manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell 
responses against tumors (Peggs et al, 2009). This may be accomplished by blocking 
co-inhibitory molecules such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or 
programmed cell death 1 (PD-1) from binding with their ligands, B7 or B7-H1 (programmed 
cell death ligand 1 [PD-L1]).  
The human CTLA-4 blocking antibody ipilimumab has demonstrated an overall 
survival (OS) benefit in two Phase 3 studies (Hodi et al, 2010; Robert et al, 2011). Based on 
these data, ipilimumab was approved in 2011 by the US Food and Drug Administration and 
the European Medicines Agency for the treatment of advanced (unresectable or metastatic) 
melanoma. Ipilimumab, in a sequenced combination with carboplatin and paclitaxel, 
improved clinical outcomes in non-small cell lung cancer (NSCLC) compared to carboplatin 
and paclitaxel alone (Lynch et al, 2012). Additionally, clinical activity across a range of 
tumor types, including NSCLC, for PD-1 blocking and PD-L1 blocking antibodies have been 
reported from Phase 1 studies (Brahmer et al, 2010; Brahmer et al, 2012; Topalian et al, 
2012; Hamid et al, 2013).
1.2 
MEDI0680 and Durvalumab (MEDI4736) Background 
1.2.1 
MEDI0680 Background 
MEDI0680 is a humanized modified IgG4 kappa monoclonal antibody (mAb) specific for 
human PD-1. MEDI0680 may help to promote an effective anti-tumor immune response by 
two mechanisms. Like other anti-PD-1 antibodies in clinical development, MEDI0680 blocks 

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the interactions between PD-1 and its ligands (PD-L1 and programmed cell death ligand 2 
[PD-L2]), thereby relieving inhibitory signaling downstream of PD-1. In addition, 
MEDI0680 improves the intrinsic functionality of T cells by triggering internalization of 
PD-1, thereby reducing levels of cell-surface PD-1 and membrane proximal Src homology 
domain containing phosphatase 2 (SHP2), also known as protein tyrosine phosphatase 
non-receptor type 11 (PTPN11). This mechanism has not been described for other PD-1 
targeted agents and may be unique to MEDI0680 (AMP 514). 
1.2.2 
Durvalumab Background 
Durvalumab is a human immunoglobulin G (IgG) 1 kappa mAb directed against human 
PD-L1. Durvalumab selectively binds human PD-L1 with high affinity and blocks its ability 
to bind to PD-1 and cluster of differentiation 80 (CD80). The fragment crystallizable (Fc) 
domain of durvalumab contains a triple mutation in the constant domain of the IgG1 
heavy chain that reduces binding to the complement component C1q and the Fcγ receptors 
responsible for mediating antibody-dependent cell-mediated cytotoxicity (Oganesyan et al, 2008). 
1.3 
Summary of Nonclinical Experience 
Programmed cell death 1 (CD279) is a member of the immunoglobulin superfamily of 
molecules involved in regulation of T-cell activation. Programmed cell death 1 expression is 
induced in activated T cells and is strongly upregulated following chronic antigen stimulation 
in the context of chronic infections and cancer. Programmed cell death 1 is also expressed on 
activated B cells and can be induced on natural killer (NK) cells, dendritic cells, and 
monocytes. Programmed cell death 1 binds to 2 ligands, PD-L1 (CD274) and PD-L2 
(CD273). Programmed cell death ligand 1 binds to two receptors, PD-1 and CD80 (B7-1), 
while PD-1 is the only known receptor for PD-L2 apart from RGMb. Programmed cell death 
ligand 1 is widely expressed and can be induced in many hematopoietic and non-
hematopoietic cells in response to inflammatory stimuli, especially interferon (IFN)-γ. It is 
expressed in a variety of normal tissues and in both solid and hematologic tumors. It has also 
been described on peripheral tissues including cardiac endothelium, lung, small intestine, 
keratinocytes, islet cells of the pancreas, and syncytiotrophoblasts in the placenta as well as 
a variety of tumor cell types (Hamanishi et al, 2007; Inman et al, 2007; Ishida et al, 2002; 
Keir et al, 2008; Latchman et al, 2001; Liu et al, 2007; Nakanishi et al, 2007; Ohigashi et al, 
2005; Parsa et al, 2007; Schreiner et al, 2004; Thompson et al, 2004; Yamazaki et al, 2002). 
Programmed cell death ligand 2 expression is more limited; it is largely restricted to subsets 
of B cells, monocytes, dendritic cells, and macrophages, where it is induced by T-helper 
cell 2 cytokines such as interleukin (IL)-4. Programmed cell death ligand 2 expression has 
also been reported in the lung, certain cancers, and cancer-associated fibroblasts. CD80 is 

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primarily expressed by professional antigen-presenting cells (APC), including B cells, 
dendritic cells, and monocytes, and can also be expressed on T cells. CD80 expression is 
generally low in the tumor microenvironment; however CD80 is present on APC in the 
draining lymph nodes (Blank, 2014; Hamid and Carvajal, 2013; Kamphorst and Ahmed, 
2013; Maj et al, 2013; Quezada and Peggs, 2013). 
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 (Bennett et al, 2003; Carter et al, 2002; Fife and Bluestone, 2008; 
Freeman et al, 2000; Nurieva et al, 2006; Saunders et al, 2005). 
1.3.1 
MEDI0680 Nonclinical Experience 
The pharmacology of MEDI0680 has been studied in a variety of in vitro and in vivo systems 
to support its use as an investigational drug in oncology. MEDI0680 binds to human PD-1 
with an affinity of 2.4 nM, determined using flow cytometry saturation binding experiments. 
MEDI0680 blocks the interactions between PD-1 and its ligands, PD-L1 and PD-L2; the half 
maximal inhibitory concentrations are 2.6 and 3.6 nM, respectively. MEDI0680 is 
internalized following binding to PD-1, while appreciable internalization was not observed 
with comparator anti PD-1 antibodies. Both blocking and internalization may contribute to 
the functional activity of MEDI0680. 
In the single-dose and repeat-dose toxicology studies of MEDI0680 performed in 
cynomolgus monkeys, there were no test-article effects on mortality, clinical observations, 
body weights, food consumption, ophthalmology, cardiovascular profiling, 
electrocardiography, hematology, urinalysis, gross pathology or organ weights. The most 
notable finding was a test article-related increase in prothrombin time (PT), which was 
observed on Study Day 3, Study Day 31, and Study Day 100 in males and females given 
≥ 1 mg/kg MEDI0680. This finding was considered non-adverse, as values remained within 
the historical control range and there were no correlating findings. The increase in PT was 
partially reversible. 
Please refer to the current Edition of the Investigator’s Brochure for additional information. 
1.3.2 
Durvalumab Nonclinical Experience 
Durvalumab has shown the following activity as an anti-PD-L1 molecule: 
• Durvalumab binds to PD-L1 and blocks its interaction with PD-1 and CD80 
• Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro 

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• Durvalumab inhibits human tumor growth in a xenograft model via a T-cell dependent 
mechanism 
• A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic 
tumor model as monotherapy and resulted in complete tumor regression in > 50% of 
treated mice when given in combination with chemotherapy 
 
In general, there were no durvalumab-related adverse effects in toxicology studies conducted 
in cynomolgus monkeys with durvalumab that were of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) pharmacokinetic 
(PK)/pharmacodynamic and dose range-finding study (4 doses over 5 weeks), and a GLP 
4-week repeat-dose toxicity study were consistent with anti-drug antibody (ADA)-associated 
morbidity and mortality in individual animals. The spectrum of findings, especially the 
microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose study was also 
consistent with ADA immune complex deposition, and ADA:durvalumab immune 
complexes were identified in a subsequent non-GLP, investigative immunohistochemistry 
study. Similar effects have been observed by MedImmune in cynomolgus monkeys 
administered human mAbs unrelated to durvalumab. Given that immunogenicity of human 
mAbs in nonclinical species is not generally predictive of responses in humans, the 
ADA-associated morbidity and mortality were not taken into consideration for the 
determination of the no-observed-adverse-effect level (NOAEL) of durvalumab. In the GLP 
13-week IV repeat-dose toxicity study, treatment with durvalumab was not associated with 
any adverse effects. Therefore, the NOAEL of durvalumab in all the general toxicity studies 
was considered to be 200 mg/kg loading dose followed by 4 or 13 weekly doses of 
100 mg/kg, respectively, the highest dose tested in these studies. In addition to the in vivo 
toxicology data, no unexpected membrane binding of durvalumab to human or cynomolgus 
monkey tissues was observed in GLP tissue cross-reactivity studies using normal human and 
cynomolgus monkey tissues. In vitro cytokine release studies showed that durvalumab did 
not induce cytokine release in blood from any donor. Additionally, an enhanced pre- and 
postnatal development study in cynomolgus monkeys showed that treatment with 
durvalumab from confirmation of pregnancy until natural delivery was not associated with 
maternal toxicity, effects on pregnancy outcome, embryofetal development, or effects on 
infant growth and development during the 6 month postnatal phase. 
1.4 
Summary of Clinical Experience 
Clinical experience with durvalumab and MEDI0680 is briefly described below. Refer to the 
current Investigator’s Brochures for details. 

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1.4.1 
MEDI0680 Clinical Experience 
Study D6020C00001 
In Study D6020C00001, the dose-escalation phase for immunotherapy-naïve subjects is 
complete. All dose-level cohorts were enrolled and 30 subjects were exposed to MEDI0680 
in combination with durvalumab. Dose levels included 0.1 mg/kg MEDI0680 Q2W with 
3 mg/kg durvalumab Q2W, and increasing doses of MEDI0680 Q2W (0.1, 0.5, 2.5, 10, and 
20 mg/kg) with 10 mg/kg durvalumab Q2W. The maximum tolerated dose (MTD) was not 
identified and the highest combination dose level administered was 20 mg/kg MEDI0680 
Q2W with 10 mg/kg durvalumab Q2W. The study is ongoing and data are included as of the 
data cut-off date of 30Nov2016. One subject received MEDI0680 20 mg/kg Q2W in 
combination with durvalumab 750 mg Q2W in dose expansion. Two subjects received 
MEDI0680 20 mg/kg monotherapy in dose expansion.  
The mean (range) exposure to MEDI0680 in combination with durvalumab as of the data 
cut-off date was 23.9 (2 to 52) weeks.  
Across all cohorts of subjects receiving MEDI0680 in combination with durvalumab, the 
most frequently reported AEs (≥ 5 subjects), regardless of causality, were anemia, arthralgia, 
back pain, constipation, cough, decreased appetite, diarrhea, dyspnea, edema peripheral, 
fatigue, nausea, pruritus, pyrexia, rash, upper respiratory tract infection, and vomiting. There 
was no trend towards a dose relationship in incidence of AEs. 
A total of 18 (58.1%) subjects receiving MEDI0680 in combination with durvalumab in the 
As-treated Population had at least 1 AE ≥ Grade 3 in severity (regardless of causality). All of 
these events were Grade 3.  
AEs ≥ Grade 3 considered related to MEDI0680 or durvalumab according to the investigator 
were reported in 6 (19.4%) subjects receiving MEDI0680 in combination with durvalumab in 
the As-treated Population. These included: increased lipase (0.1 mg/kg MEDI0680 Q2W + 
3 mg/kg durvalumab Q2W and 10 mg/kg MEDI0680 Q2W + durvalumab 10 mg/kg Q2W); 
prolonged ECG QT (0.5 mg/kg MEDI0680 Q2W + 10 mg/kg durvalumab Q2W); and 
increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), atrial 
fibrillation, increased γ-glutamyltransferase, and nausea (10 mg/kg MEDI0680 Q2W + 
10 mg/kg durvalumab Q2W). 
A dose limiting toxicity (DLT) was reported in 1 subject (10 mg/kg MEDI0680 Q2W + 
10 mg/kg durvalumab Q2W). The subject had Grade 3 increased ALT and Grade 3 increased 
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treatment was discontinued and the events resolved. Dose escalation continued to the highest 
protocol defined dose.  The MTD was not identified. 
Overall, 10 (32.3%) subjects receiving MEDI0680 in combination with durvalumab died 
during the study; 9 died due to disease under study and 1 due to “other” reason. 
Twelve subjects experienced treatment emergent serious adverse events (SAEs), of whom 
3 subjects had events considered related to MEDI0680 and durvalumab by the investigator. A 
total of 7 (22.6%) subjects receiving MEDI0680 in combination with durvalumab 
permanently discontinued investigational product as a result of an AE. No AEs leading to 
discontinuation were reported in more than 1 subject across cohorts. AEs included: ALT 
increased, AST increased, blood alkaline phosphatase increased, dyspnea, ECG QT 
prolonged, headache, intracranial mass, and pleural effusion.  
As of the data cut-off date across all cohorts in subjects receiving MEDI0680 in combination 
with durvalumab, 1 (3.2%) subject had a confirmed complete response (CR) and 8 (25.8%) 
subjects had a confirmed partial response (PR). The objective response rate (ORR) was 
29.0% (95% CI 14.2%, 48.0%). The rate of disease control (DC; CR + PR + stable disease 
for ≥ 8 weeks) was 48.4% (15 subjects; 95% CI 30.2%, 66.9%). 
Study D6020C00002 
As of 30Nov2016, 58 subjects received MEDI0680 monotherapy. All cohorts except dose 
de-escalation 3 mg/kg Q2W were enrolled. Dose levels included 0.1, 0.5, 2.5, 10, and 
20 mg/kg Q3W, 10 and 20 mg/kg Q2W, 20 mg/kg QW × 2 and 20 mg/kg QW × 4. 
Enrollment was completed in August 2015 and the study is ongoing. Overall, mean (range) 
exposure as of the data cut-off date was 23.1 (2 to 105) weeks. 
Across all cohorts, the most frequently reported AEs (≥ 10 subjects; regardless of causality) 
were arthralgia, anemia, asthenia, constipation, decreased appetite, dyspnea exertional, 
fatigue, nausea, pyrexia and vomiting. A total of 35 (60.3%) subjects in the As-treated 
Population had at least 1 AE ≥ Grade 3 in severity regardless of causality. The majority of 
these events were Grade 3. Six subjects experienced Grade 4 AEs: hyperbilirubinemia 
(0.5 mg/kg MEDI0680 Q3W), lacunar infarction (0.5 mg/kg MEDI0680 Q3W), atrial 
fibrillation (10 mg/kg MEDI0680 Q3W), myositis and blood creatinine phosphokinase 
increased (both events in the same subject; 20 mg/kg MEDI0680 Q2W), sepsis and 
respiratory distress (both events in the same subject; 20 mg/kg MEDI0680 Q2W) and 
pulmonary embolism (20 mg/kg MEDI0680 QW x 4). 

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The database includes 2 subjects with a Grade 5 AE. One subject died from superior vena 
cava syndrome (0.1 mg/kg MEDI0680 Q3W), and 1 subject died from respiratory failure 
(20 mg/kg MEDI0680 Q2W). Neither AE was considered related to MEDI0680. Overall, 
18 (31.0%) subjects died during the study; the additional 16 subjects died due to disease 
under study. Twenty-nine (50.0%) subjects experienced treatment emergent SAEs, of whom 
8 had events considered related to MEDI0680 by the investigator. 
AEs ≥ Grade 3 considered related to MEDI0680 according to the investigator were reported 
in 12 (20.7%) subjects in the As-treated Population. These included: anemia, autoimmune 
hepatitis, fatigue, increased ALT, increased AST, and increased blood alkaline phosphatase 
(0.5 mg/kg MEDI0680 Q3W); anemia, asthenia, dehydration, fatigue, hypercalcemia, and 
increased lipase (20 mg/kg MEDI0680 Q3W); abdominal pain, anemia, arthralgia, blood 
creatinine phosphokinase increased, increased AST, diarrhea, hyperkalemia, hypertension, 
myasthenia gravis, myositis and urinary tract infection (20 mg/kg MEDI0680 Q2W); and 
anemia (20 mg/kg MEDI0680 QW × 4).  
An MTD was not identified and the highest dose administered was MEDI0680 20 mg/kg 
Q2W. 
A total of 13 (22.4%) subjects permanently discontinued MEDI0680 as a result of an AE, 
with no apparent relationship to MEDI0680 dose level. Events reported in more than 
1 subject across cohorts included increased blood creatinine and fatigue (2 subjects each). 
Assessment of antitumor response was based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 (Eisenhauer et al, 2009). Across all cohorts, 1 (1.7%) subject had a 
confirmed CR, 8 (13.8%) subjects had a confirmed PR, and 1 (1.7%) subject had an 
unconfirmed PR. For these 10 subjects, the ORR was 17.2% (95% confidence interval [CI] 
8.6%, 29.4%). The ORR with confirmed CR and confirmed PR was 15.5% (9 subjects; 95% 
CI 7.3%, 27.4%). The rate of DC (CR + PR + stable disease for ≥ 8 weeks) was 39.7% 
(23 subjects; 95% CI 27.0%, 53.4%).  
1.4.2 
Durvalumab Clinical Experience 
As of the data cut-off date of 12Jul2016 reported in the current durvalumab (MEDI4736) 
Investigator’s Brochure, an estimated 5,225 subjects have been exposed to one or more doses 
of durvalumab in AstraZeneca or MedImmune sponsored studies, either as monotherapy or 
in combination, including 2,878 subjects in open-label trials, and 2,347 subjects as an 
estimate based on the randomization scheme in studies where the treatment arm is blinded. 
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durvalumab in externally sponsored/investigator-initiated clinical trials. Of the 2,878 subjects 
exposed to durvalumab in ongoing AstraZeneca- or MedImmune-sponsored open-label 
studies, 1,744 received durvalumab monotherapy, 808 received durvalumab in combination 
with tremelimumab, 140 received durvalumab in combination with other investigational 
products and 186 received durvalumab in combination with approved products. No study has 
been terminated prematurely due to toxicity.  
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune 
checkpoint inhibitor class. No tumor types appeared to be associated with unique AEs. Most 
adverse drug reactions seen with the immune checkpoint inhibitor class of agents are thought 
to be due to the effects of inflammatory cells on specific tissues. These immune-mediated 
risks seen with immune checkpoint inhibitors such as durvalumab can include 
gastrointestinal AEs such as colitis and diarrhea, pancreatitis, pneumonitis/interstitial lung 
disease, renal AEs such as nephritis and increases in serum creatinine, hepatic AEs such as 
hepatitis and liver enzyme elevations, dermatitis/rash, endocrinopathies such as hypo- and 
hyper-thyroidism, hypophysitis, adrenal insufficiency and type I diabetes mellitus, and 
neurotoxicities such as myasthenia gravis and Guillain Barre syndrome. These events are 
manageable by available/established treatment guidelines as described in the toxicity 
management guidelines contained in each of the study protocols. 
Data from Study CD-ON-MEDI4736-1108 (durvalumab monotherapy) is presented below. 
Please refer to the durvalumab Investigator’s Brochure for data from all studies. 
Study CD-ON-MEDI4736-1108 
Study CD-ON-MEDI4736-1108 is a Phase 1/2, first-time-in-human (FTIH), multicenter, 
open-label, dose-exploration, dose-escalation, and dose-expansion study to determine the 
maximum tolerated dose (MTD) or optimal biologic dose, safety, PK, pharmacodynamics, 
immunogenicity, and antitumor activity of durvalumab in adult subjects with advanced solid 
tumors refractory to standard therapy or for which no standard therapy exists. A total of 
1,012 subjects with advanced solid tumors have been treated in 
Study CD-ON-MEDI4736-1108 as of 24Jul2016. Of these subjects, 970 have received 
durvalumab at 10 mg/kg every 2 weeks (Q2W), either in the dose-escalation or dose-
expansion phase of the study. The 10 mg/kg Q2W cohort comprises subjects with NSCLC, 
urothelial carcinoma, squamous cell carcinoma of head and neck (SCCHN), microsatellite 
instability high, gastroesophageal cancer, ovarian cancer, hepatocellular carcinoma (HCC), 
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human papilloma virus (positive) , advanced cutaneous melanoma, small cell lung cancer, 
glioblastoma multiforme, soft tissue sarcoma, and nasopharyngeal carcinoma. Subjects in the 
10 mg/kg Q2W dose cohort were exposed to a median of 6 doses of durvalumab (range, 1–
27). 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune 
checkpoint inhibitor class. The safety profile of durvalumab monotherapy in the 970 subjects 
with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108 was 
manageable and generally consistent with the known safety profile of the anti-PD-L1/PD-1 
drug class. Immune-mediated AEs were manageable and generally reversible by delaying or 
interrupting the durvalumab dose, treating with immunosuppression and/or endocrine therapy 
per the toxicity management guidelines, or, infrequently, by permanently discontinuing 
durvalumab treatment.  
As of 24Jul2016, among the 970 subjects treated with durvalumab 10 mg/kg Q2W in 
Study CD-ON-MEDI4736-1108, a total of 554 subjects (57.1%) experienced a 
treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue 
(18.7%), nausea (7.9%), diarrhea (7.6%), pruritus (6.8%), decreased appetite (6.7%), 
hypothyroidism (6.3%) and rash (6.0%). The majority of the treatment-related AEs were 
Grade 1 or Grade 2 in severity with Grade 3 or higher AEs reported in 88 subjects (9.4%). 
Treatment-related ≥ Grade 3 or 4 events reported in ≥ 2 subjects were fatigue (1.6%), 
increased AST (1.0%), increased ALT (0.8%), increased γ glutamyl transferase (0.7%), 
hyponatraemia and diarrhea (0.5% each), colitis (0.4%), decreased appetite and vomiting 
(0.3% each), and increased ALP, anemia, arthralgia, autoimmune hepatitis, increased blood 
bilirubin, dyspnea, hyperglycemia, infusion related reaction, leukopenia, nausea, neutropenia, 
nervous system disorder, maculo-papular rash, thrombocytopenia, transaminases increased 
and weight decreased (0.2% each). Four subjects had a treatment-related Grade 5 event 
(autoimmune hepatitis, immune thrombocytopenic purpura, pneumonia, and pneumonitis). 
Treatment related SAEs that occurred in ≥ 2 subjects were colitis and pneumonitis (4 subjects 
each); nervous system disorder (3 subjects); and acute kidney injury, AST increased, and 
diarrhea (2 subjects each). The majority of the treatment-related SAEs were ≥ Grade 3 in 
severity and resolved with or without sequelae. Treatment-related AEs that resulted in 
permanent discontinuation were seen in 24 subjects (2.5%) with colitis being the most 
frequent (3 subjects). Approximately half of the treatment-related AEs resulting in 
discontinuation were ≥ Grade 3 in severity and the majority of these resolved with or without 
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Tumor assessments were based on RECIST v1.1. There are different data cut-offs for 
efficacy data from the different cohorts in the study. 
• NSCLC: As of 29Apr2016, 304 NSCLC subjects had received durvalumab monotherapy, 
144 (47%) subjects with non-squamous and 160 (53%) subjects with squamous histology. 
Subjects with tumors defined as PD-L1 high (defined as tumor tissue samples that had 
≥ 25% of tumor cells with membrane staining for PD-L1 [tumor cells ≥ 25%]) had 
improved ORR and OS. The ORR was 25% and 6% in subjects with PD-L1 high and 
low/negative (defined as tumor cells < 25%) tumors, respectively and 18% in the overall 
population, regardless of PD-L1 expression. The ORR in first-line subjects was 29%, 
11%, and 27% for PD-L1 high, PD-L1 low/negative, and the overall population, 
respectively. In the second-line setting ORR was 26%, 4%, and 19% and in the third-line 
plus setting it was 22%, 6% and 13% for PD L1 high, PD-L1 low/negative and the 
overall population, respectively. The 12-month OS rate was 71% and 44% in subjects 
with PD-L1 high and low/negative tumors, respectively, in the first-line setting. In the 
second-line setting the 12-month OS rate was 56% and 39% and in the third-line plus 
setting it was 51% and 37%, in subjects with PD L1 high and low/negative tumors, 
respectively. 
• SCCHN: As of 29Apr2016, 62 subjects with recurrent/metastatic squamous cell 
carcinoma of the head and neck had received durvalumab monotherapy. ORR was 11% 
across all subjects, 18% in subjects with PD-L1 high tumors (tumor cells ≥ 25%) and 8% 
in subjects with PD-L1 low/negative tumors (< 25%). Among the 7 responders (all 
subjects), 6 subjects had a duration of response (DoR) of ≥ 12 months, with the longest 
DoR being 19.8 months. Six- and 12-month OS were 62% and 42%, respectively, for the 
all treated subject population and 53% and 45%, respectively, for the subjects with 
PD-L1 high tumors, and 66% and 41%, respectively, for the subjects with PD-L1 
low/negative tumors. 
• Urothelial Carcinoma: As of 20Nov2015, 61 subjects had been enrolled into the 
urothelial cell cohort. Forty-two subjects who initiated study therapy ≥ 12 weeks prior to 
data cut-off were evaluable for response. Confirmed ORR was 46% in the PD-L1 high 
subgroup compared to 0% in the PD-L1 low/negative subgroup. ORR in the entire 
response evaluable population was 31% (13/42 subjects).  
• Other indications: In PD-L1 unselected subjects, the ORR, based on investigator 
assessment per RECIST v1.1, ranged from 0% in uveal melanoma to 17.4% in advanced 
cutaneous melanoma, and disease control rate (DCR) at 24 weeks (DCR24) ranged from 
4.2% in triple negative breast cancer to 39.1% in advanced cutaneous melanoma. Across 
the PD-L1 high tumors, ORR was > 10% for advanced cutaneous melanoma and HCC 
(33.3% each). In the PD-L1 high subset, DCR24 was > 10% in advanced cutaneous 
melanoma (66.7%) and HCC (33.3%). 
 
As of 24Jul2016, PK data were available for 977 subjects in the dose-escalation and 
dose-expansion phases of Study CD-ON-MEDI4736-1108 following treatment with 
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4 weeks (Q4W). The peak concentration (Cmax) increased in an approximately dose-
proportional manner over the dose range examined. The area under the concentration curve 
from zero to 14 hours increased dose-proportionally at doses of 3 to 20 mg/kg and more than 
dose-proportionally at doses of < 3 mg/kg, likely due to saturable target-mediated clearance. 
The steady state was achieved at approximately Week 16. Accumulation of durvalumab was 
observed following repeated dosing. Mean accumulation ratio ranged from 0.64 to 1.87 and 
3.15 to 4.93 for Cmax and trough concentration, respectively. Near complete target saturation 
(soluble PD-L1 [sPD-L1] and membrane bound) is expected with durvalumab ≥ 3 mg/kg 
Q2W. As of 24Jul2016, a total of 790 subjects provided evaluable samples for ADA analysis. 
Overall, 25 of 790 subjects (3.2%) tested positive for treatment emergent ADAs in the ADA 
evaluable population; 19 (2.4%) subjects were persistently positive for the presence of ADA. 
Three subjects (0.4%) were neutralising ADA positive. Based on population PK covariate 
analysis, ADA positive status was not associated with a clinically relevant reduction of 
exposure to durvalumab. There was no apparent effect of immunogenicity on the PK profile. 
At the 10 mg/kg Q2W dose, sPD-L1 suppression in ADA positive subjects was similar to 
that observed in ADA negative subjects. 
1.5 
Rationale for Conducting the Study 
There is sound rationale for evaluating the combination of durvalumab and MEDI0680 for 
the treatment of advanced malignancies. Both anti-PD-1 and anti-PD-L1 agents have shown 
clinical activity across a number of tumor types, such as melanoma, NSCLC, and renal cell 
carcinoma (RCC) (Weber et al, 2012; Topalian et al, 2012; Brahmer et al, 2010; Brahmer et 
al, 2012; Hamid et al, 2013; Motzer et al 2015). Previous studies have shown that PD-L1 
expression is associated with a poor prognosis in RCC, presumably because of its 
immunosuppressive function (Thompson et al, 2006). In a recent Phase 3 study involving 
subjects with advanced RCC who received previous treatment, an improvement in median 
OS was shown for patients that received nivolumab compared to patients that received 
everolimus. The ORR was greater with the anti-PD-1 checkpoint inhibitor than with the 
mammalian target of rapamycin (mTOR) inhibitor (based on independent review, 
21.5% [95% CI: 17.6%, 25.8%] vs 3.9% [95% CI: 2.2%, 6.2%]; 
Opdivo [nivolumab] Package Insert, 2015).  
The mechanisms of action of anti-PD-1 and anti-PD-L1 antibodies are distinct: while both 
inhibit the interaction between PD-1 and PD-L1, only anti-PD-1 blocks PD-1/PD-L2 and 
only anti-PD-L1 blocks PD-L1/CD80. All three interactions may contribute to 
immunosuppression in the tumor and tumor-draining lymph nodes. The interaction between 
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The blockade of PD-1 can lead to increased release of the pro-inflammatory cytokine IFN-γ 
at the tumor site (Peng et al, 2012). Interferon-γ enhances the expression of PD-L1 in a range 
of cell types (Lee et al, 2006) and so PD-1 blockade may result in increased PD-L1 mediated 
blockade of co-stimulatory CD80 within the tumor microenvironment. Similarly, 
PD-1/PD-L2 signaling may be more pronounced in the context of PD-L1 
blockade. Further support for the combination strategy is provided by mouse models of 
cancer (Curran et al, 2010). This includes significantly enhanced activity of a PD-1/PD-L1 
combination relative to maximally efficacious doses of PD-1 or PD-L1 monotherapies in a 
murine syngeneic sarcoma model as described in the current edition of the MEDI0680 
Investigator’s Brochure. Based upon these observations, the complex feedback between 
pathways and differences in pathway blockade between agents, combination therapy with 
durvalumab and MEDI0680 may generate superior antitumor activity compared to either 
monotherapy. This may translate into high rates of response in tumors known to respond to 
immunotherapies or increased likelihood of activity in tumors that have previously not shown 
high levels of responsiveness to immunotherapy. However, the combination of these two 
agents may increase the frequency or severity of toxicities, and thus a dose-escalation study 
in the appropriate setting to explore this combination is indicated.  
In the dose-expansion phase of the study, nivolumab is included as a comparator as it is now 
the standard of care in the metastatic RCC setting in some markets. 
Benefit-risk Evaluation 
Potential Benefits 
Emerging data with both durvalumab and MEDI0680 in a monotherapy setting across a 
range of tumor types demonstrate encouraging clinical activity with a manageable safety 
profile (Sections 1.4.1, Section 1.4.2). In Study D6020C00002, MEDI0680 monotherapy 
showed an ORR of 24.1% among 29 subjects with advanced RCC. Of the 14 RCC subjects 
who received MEDI0680 at the 20 mg/kg dose level, 4 (28.6%) subjects had an objective 
response (OR). 
Anti-PD-1 monoclonal antibodies such as MEDI0680 block the interaction of PD-1 with its 
ligands PD-L1 and PD-L2, but leave the interaction between PD-L1 and CD80 intact. PD-L1 
targeting strategies, such as the anti-human PD-L1 mAb durvalumab, block the interaction 
between PD-L1 and CD80 as well as between PD-L1 and PD-1, but do not block the 
interaction between PD-L2 and PD-1. The combination of durvalumab with MEDI0680 in 
nonclinical models that have shown superior antitumor activity of combination therapy over 
monotherapy. These observations suggest that a complete pathway blockade with 

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combination therapy may generate superior antitumor activity compared to monotherapy, 
which may yield more complete and more durable antitumor activity. The results from this 
study will inform the design of future studies of the combination of durvalumab and 
MEDI0680. The rationale for the study design and starting doses is described in Section 3.2. 
Summary of Risks 
As of 30Nov2016, 58 subjects have received MEDI0680 monotherapy in Study 
D6020C00002 and 31 subjects have received MEDI0680 in combination with durvalumab in 
Study D6020C00001. One DLT was observed in Study D6020C00001 and none in Study 
D6020C00002.  
Most frequently reported AEs (≥ 10 subjects) in subjects receiving MEDI0680 monotherapy 
in Study D6020C00002 were fatigue, decreased appetite, anemia, constipation, nausea, 
arthralgia, asthenia, dyspnea exertional, vomiting and pyrexia. Twenty-nine subjects in 
Study D6020C00002 (MEDI0680 monotherapy) had at least 1 SAE. SAEs reported in more 
than 1 subject across cohorts included pneumonia (5 subjects), fatigue and hypotension 
(4 subjects), pyrexia (3 subjects), abdominal pain, cellulitis, diarrhea, disease progression, 
pleural effusion, and vomiting (2 subjects).  
Most frequently reported AEs (≥ 5 subjects) for MEDI0680 in combination with durvalumab 
(Study D6020C00001) were anemia, arthralgia, back pain, constipation, cough, decreased 
appetite, diarrhea, dyspnea, fatigue, nausea, edema peripheral, pruritus, pyrexia, rash, upper 
respiratory tract infection, and vomiting. Twelve subjects in Study D6020C00001 receiving 
MEDI0680 in combination with durvalumab had at least 1 SAE. The only SAE reported in 
more than 1 subject across cohorts was pleural effusion (2 subjects). One subject in Study 
D6020C00001 received MEDI0680 monotherapy in expansion and had an SAE of abdominal 
pain.  
Immune-mediated reactions/immune-mediated adverse events (imAEs) are considered to be 
AEs of special interest (AESIs). ImAEs are important risks of immune checkpoint inhibitors, 
and are being closely monitored in clinical studies with durvalumab and MEDI0680 
monotherapy and combination therapy. See Section 5.3 for a summary of AESIs. 
The proposed combination of durvalumab with MEDI0680 has the potential to increase the 
frequency or severity of toxicities of monotherapy with either agent. 

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Overall Benefit-risk and Ethical Assessment  
There continues to be a high unmet need for new treatment options in advanced solid 
malignancies. An estimated 338,000 new cases of RCC are diagnosed worldwide, 
approximately 30% of patients present with metastatic disease at the time of diagnosis 
(Ferlay et al, 2015; Fisher et al, 2013; Motzer 2015). Recent approval of a check-point 
inhibitor monotherapy has afforded RCC patients an increased number of treatment options. 
However, there is an unmet need for additional treatment strategies for patients that do not 
respond or have limited clinical response to current therapeutic options. The study design 
aims to minimize potential risks by incorporating intensive monitoring. Early safety 
assessment is in place for risks deemed most likely based on prior experience with 
durvalumab and MEDI0680. 
Based upon the available nonclinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy 
due to malignant disease, and the strength of the scientific hypotheses under evaluation, 
combination therapy with MEDI0680 and durvalumab proposed for evaluation in this study 
may provide meaningful clinical benefit with a manageable safety and tolerability profile by 
generating durable and improved rate of clinical responses, as compared with monotherapy. 
Therefore, the investigation of the potential therapeutic efficacy of the combination of 
MEDI0680 with durvalumab in patients with selected solid tumors, including RCC is 
acceptable, and the overall benefit/risk assessment supports the proposed study design. 
1.6 
Research Hypotheses 
1.6.1 
Primary Hypotheses 
Dose-escalation: 
MEDI0680 in combination with durvalumab will be adequately tolerated in subjects with 
select advanced malignancies. 
Dose-expansion:  
MEDI0680 in combination with durvalumab will have a higher response rate than nivolumab 
monotherapy in subjects with advanced or metastatic clear-cell renal cell carcinoma 
(ccRCC). 

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1.6.2 
Secondary Hypotheses 
Dose-escalation: MEDI0680 in combination with durvalumab will have antitumor activity in 
subjects with select advanced malignancies.  
Dose-expansion: MEDI0680 in combination with durvalumab will be adequately tolerated in 
subjects with advanced or metastatic ccRCC. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives and Endpoints 
Table 2.1-1 
Primary Objectives and Associated Endpoints 
Type 
Objectives 
Endpoints 
Dose escalation 
Safety 
1. To determine the MTD or the highest 
protocol-defined dose in the absence of 
exceeding the MTD for MEDI0680 in 
combination with durvalumab, and the 
safety profile of MEDI0680 in 
combination with durvalumab in subjects 
with advanced malignancies 
1.1. Presence of AEs and SAEs, as well as 
changes from baseline in laboratory 
evaluations, vital signs, physical 
examinations, and ECG results 
Dose expansion 
Efficacy 
2. To evaluate the antitumor activity of 
MEDI0680 in combination with 
durvalumab versus nivolumab 
monotherapy in immunotherapy-naïve 
subjects with advanced or metastatic 
ccRCC as based on investigator assessed 
response using RECIST v1.1 
(Eisenhauer et al, 2009) 
2.1. Primary endpoint: OR of MEDI0680 
in combination with durvalumab 
versus nivolumab monotherapy. 
Secondary endpoints include BOR, 
DC, TTR, DR, PFS change from 
baseline in tumor size and OS. 
Efficacy endpoints except OS are 
based on an application of RECIST 
v1.1 to investigator-assessed tumor 
measurements.  
AE = adverse event; BOR = best overall response; ccRCC = clear-cell renal cell carcinoma; DC = disease control; DR = 
duration of response; ECG = electrocardiogram; MTD = maximum tolerated dose; OR = objective response; OS = overall 
survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse 
event; TTR = time to response. 
 
2.2 
Secondary Objectives and Endpoints 
Table 2.2-1 
Secondary Objectives and Associated Endpoints 
Type 
Objectives 
Endpoints 
Dose escalation 
Efficacy 
1. To evaluate the antitumor activity of 
MEDI0680 in combination with 
durvalumab in subjects with advanced 
malignancies as determined by the 
1.1 BOR, OR, DC, TTR, DR, PFS, OS, and 
change from baseline in tumor size. 
Antitumor activity analyses except OS 

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Table 2.2-1 
Secondary Objectives and Associated Endpoints 
Type 
Objectives 
Endpoints 
investigator based on modified 
RECIST v1.1 
will be based on investigator-assessed 
response using modified RECIST v1.1 
Dose expansion 
Safety 
2. To describe the safety and tolerability of 
MEDI0680 in combination with 
durvalumab or nivolumab monotherapy 
in immunotherapy-naïve subjects with 
advanced or metastatic ccRCC 
2.1 Presence of AEs and SAEs, as well as 
changes from baseline in laboratory 
parameters, vital signs, physical 
examination, and ECG results   
Efficacy 
3. To evaluate the antitumor activity of 
MEDI0680 in combination with 
durvalumab versus nivolumab 
monotherapy in immunotherapy-naïve 
subjects with advanced or metastatic 
ccRCC as based on BICR assessed 
response using RECIST v1.1 
3.1 BOR, OR, DC, TTR, DR, PFS, and 
change from baseline in tumor size as 
based on BICR-assessed response using 
RECIST v1.1. 
Dose escalation and dose expansion 
PK 
4. To describe the PK of MEDI0680 in 
combination with durvalumab  
5. To describe the PK of durvalumab in 
combination with MEDI0680 
4.1 and 5.1 The endpoints for assessment of 
PK include individual 
MEDI0680 and durvalumab 
concentrations in serum. PK 
parameters include Cmax and 
Cmin. 
Immunogenicity 
6. To determine the immunogenicity of 
MEDI0680 in combination with 
durvalumab  
7. To determine the immunogenicity of 
durvalumab in combination with 
MEDI0680 
6.1 and 7.1 Presence of detectable ADAs to 
MEDI0680 and durvalumab. 
Pharmaco-
dynamics 
8. To determine whether PD-L1 is a 
predictive biomarker for response to 
therapy with MEDI0680 in combination 
with durvalumab 
8.1 PD-L1 expression / localization on 
tumor membrane and tumor-infiltrating 
immune cells within the tumor 
microenvironment 
ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central; review; BOR = best overall response; 
Cmax =  peak concentration; Cmin = trough concentration; ccRCC = clear-cell renal cell carcinoma; DC = disease control; DR 
= duration of response; ECG = electrocardiogram; MTD = maximum tolerated dose; OR = objective response; OS = overall 
survival; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; PK = pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TTR = time to response. 
 
2.3 
Exploratory Objectives and Endpoints 
Exploratory assessments will be performed to examine the relationship between a subject’s 
health and immune status prior to treatment and clinical outcome, as well as to characterize 
any changes in immune status which may occur during and/or following treatment relative to 
clinical outcome. 

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Table 2.3-1 
Exploratory Objectives and Associated Endpoints 
Type 
Objectives 
Endpoints 
PD 
1. To identify biomarkers that are 
predictive of antitumor response to 
MEDI0680 in combination with 
durvalumab 
1.1 The endpoints related to candidate 
predictive and/or prognostic biomarkers 
in dose-expansion will focus on tissue-
based, protein or gene expression 
measures and peripheral gene signatures 
including, but not limited to IHC 
measures of markers associated with 
infiltrating immune cells (eg, CD80) 
PD 
2. To profile gene expression changes that 
may correlate with antitumor response to 
MEDI0680 in combination with 
durvalumab 
2.1 Gene expression signatures associated 
with response to therapy will include 
expression of messenger ribonucleic 
acid in blood and tumor samples before 
and after treatment to examine gene 
expression patterns at baseline and 
changes in response to treatment. 
Analysis may also include but is not 
limited to: evaluation of key oncogenic 
mutations and/or mutations in immune-
related molecules. 
PD 
3. To evaluate additional biomarkers that 
may correlate with antitumor activity of 
MEDI0680 in combination with 
durvalumab compared with nivolumab 
monotherapy  
3.1 Levels of circulating free DNA and/or 
circulating soluble factors which may 
include cytokines, chemokines, growth 
factors, soluble receptors, and 
antibodies against tumor and self-
antigens, may be evaluated before and 
after treatment to evaluate response to 
treatment with MEDI0680 and 
durvalumab compared with nivolumab 
monotherapy. 
PD 
4. To evaluate the pharmacodynamic 
activity of MEDI0680 in combination 
with durvalumab versus nivolumab 
monotherapy in the periphery. 
4.1 Pharmacodynamic assessments of 
MEDI0680 and durvalumab 
combination in the periphery include: 
a. Flow cytometric assessment of cell 
populations such as T cells and B cells 
before and after treatment to evaluate 
their association with drug exposure and 
response to treatment; analysis may 
include characterization of phenotype, 
expression of activation markers, 
proliferation, and production of 
cytokines and effector molecules 
b. Dose escalation only: Serum soluble 
PD-L1 levels before and after treatment 
may be measured to evaluate their 
association with drug exposure and 
response to treatment with MEDI0680 
and durvalumab  
c. Dose escalation only: MEDI0680 
receptor occupancy on peripheral blood 
T cells before and after treatment may 

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Table 2.3-1 
Exploratory Objectives and Associated Endpoints 
Type 
Objectives 
Endpoints 
be measured to evaluate associations 
with drug exposure and response to 
treatment with MEDI0680 and 
durvalumab 
PD 
5. To compare the pharmacodynamic 
changes resulting from complete 
PD-1/PD-L1 pathway blockade versus 
treatment with nivolumab monotherapy 
5.1 Expression and localization of key 
molecules such as PD-L1, PD-L2, and 
PD-1 within the tumor 
microenvironment, as well as the 
frequency, localization, and phenotype 
of tumor-infiltrating lymphocytes, may 
be examined in biopsy specimens by 
immunohistochemistry, 
immunofluorescence, and/or flow 
cytometry and correlated with response 
to treatment  
Efficacy 
6. To evaluate the antitumor activity of 
MEDI0680 in combination with 
durvalumab versus nivolumab 
monotherapy in subjects with advanced 
or metastatic ccRCC as assessed by 
irRECIST 
6.1 Antitumor activity, including OR, DR, 
DC, and PFS, may be assessed by 
irRECIST (Nishino et al, 2013). 
ccRCC = clear-cell renal cell carcinoma; CD80 = cluster of differentiation 80; DC = disease control; DR = duration of 
response; IHC = immunohistochemistry; irRECIST = immunerelated Response Evaluation Criteria in Solid Tumors; 
OR = objective response; PD-1 = programmed cell death 1; PD-L1 = programmed cell death ligand 1; PD-L2 – programmed 
cell death ligand 2. 
 
3 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 
Overview
 
This is a multicenter, open-label, Phase 1/2 study to evaluate the safety, tolerability, PK, 
immunogenicity, and antitumor activity of MEDI0680 in combination with durvalumab 
versus nivolumab monotherapy in adult immunotherapy naïve subjects with select advanced 
malignancies. The study will be conducted at approximately 50 study centers globally.  
The study includes 2 phases, dose-escalation and dose-expansion. In the dose-escalation 
phase, subjects with selected solid tumors will receive MEDI0680/durvalumab combination 
therapy. In the dose-expansion phase, subjects with ccRCC will receive either 
MEDI0680/durvalumab combination therapy or nivolumab monotherapy. Changes initiated 
to the dose-escalation and dose-expansion phases as of Protocol Amendment 5 are described 
in Section 9.1.  

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In the dose-escalation phase, subjects may receive treatment for up to 12 months; in the 
dose-expansion phase, subjects may remain on treatment until unacceptable toxicity, 
confirmed PD, or development of other reason for treatment discontinuation. All subjects 
will be evaluated regularly. Clinical status will be classified according to modified 
RECIST v1.1 (Eisenhauer et al, 2009) for subjects in the dose-escalation phase and by 
RECIST v1.1 for subjects in the dose-expansion phase, and other disease-specific 
assessments (see Appendix 4). All subjects will be followed for survival until the end of 
study (see Section 6.3). Adverse events and SAEs will be followed as per Section 5. 
3.1.1.1 
 Dose-escalation Phase  
In the dose-escalation phase, sequential cohorts of 3 to 6 subjects will be enrolled in 1 of 
6 dose-level cohorts: 0.1 mg/kg MEDI0680 Q2W with 3 mg/kg durvalumab Q2W, and 
increasing dose levels of MEDI0680 Q2W (0.1, 0.5, 2.5, 10, and 20 mg/kg) with 10 mg/kg 
durvalumab Q2W. The dose-escalation phase will include immunotherapy-naïve (defined in 
Section 4.1.2) with solid tumors. As of Protocol Amendment 2, only subjects with NSCLC, 
squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-high 
(MSI-high) colorectal cancer (CRC), bladder cancer, ovarian cancer, esophageal cancer, 
gastric cancer, or RCC will be enrolled.  
The dose-escalation phase will be executed according to a 3 + 3 design. If ≥ 2 of 6 subjects 
experience a DLT, a dose level from the intermediate zone-based cohort(s) that does not 
exceed the MTD or the highest protocol-defined dose for each investigational product in the 
absence of exceeding the MTD may be explored (see Section 3.1.3.2 for description of 
modified zone-based dose-escalation). Based on emerging safety, PK, pharmacodynamic, 
and clinical activity data for the MEDI0680 Q2W treatment schedule, the dosing interval for 
MEDI0680 could have been increased to every 4 weeks (Q4W; however, as of Protocol 
Amendment 3, this dosing schedule will not be implemented since dose-escalation is 
considered complete, see earlier versions of the protocol for more information on this dosing 
schedule). 
Any dose-level cohort in the dose-escalation phase that did not exceed the MTD can be 
expanded up to a maximum of 18 subjects for further evaluation of safety, PK, 
pharmacodynamics, and antitumor activity. 
Based on 6 dose-level cohorts in the main 3 + 3 dose-escalation design on a Q2W treatment 
schedule, up to 36 subjects may be enrolled. Additional subjects could be required if dose 
de-escalation occurs, intermediate dosing using the modified zone-based design is explored, 
or any dose-level cohort is expanded beyond 6 subjects. 

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As of Protocol Amendment 3, the dose-escalation phase completed enrollment. Subjects 
were treated through the highest planned dose-level cohort of 20 mg/kg MEDI0680 Q2W in 
combination with durvalumab Q2W and the MTD was not reached (See Section 1.4.1 for the 
number of subjects enrolled as of this amendment). 
3.1.1.2 
Dose-expansion Phase 
The dose-expansion phase will begin after the dose-escalation phase. Immunotherapy-naïve 
subjects (defined in Section 4.1.2) with ccRCC will be randomized in a 2:1 ratio to 1 of 
2 treatment arms: (1) MEDI0680/durvalumab combination therapy or (2) nivolumab 
monotherapy. Stratification factors will include the Memorial Sloan Kettering Cancer 
Center (MSKCC) risk group (0 = favorable risk; 1 or 2 = intermediate risk; 3 = poor risk; 
Motzer et al, 2002; see Appendix 7), and PD-L1 expression status (≤ 1% and > 1%). Up to 
40 subjects may be randomized in the MEDI0680/durvalumab combination therapy arm and 
up to 20 subjects may be randomized in the nivolumab monotherapy arm based on evaluation 
of emerging safety and efficacy parameters in the current study as well as other ongoing 
studies. An interim futility analyses will be performed for the MEDI0680/durvalumab 
combination therapy arm in the dose-expansion phase after 20 subjects have been 
randomized and have reached their second post-baseline disease assessment or have 
completed study. Randomization into the dose-expansion phase may be discontinued at the 
discretion of the sponsor should emerging clinical or pre-clinical data suggest that continued 
treatment may not be beneficial.  
The endpoints to be measured in this study are described in Section 2. 

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Figure 3.1.1-1 
Study Flow Diagram 
ccRCC = clear-cell RCC; CRC = colorectal cancer; MSI = microsatellite instability; MTD = maximum 
tolerated dose; NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma; SCCHN = squamous cell 
carcinoma of head and neck. 
a 
Up to a total of 60 subjects with ccRCC will be randomized in a 2:1 ratio to receive either 
MEDI0680/durvalumab combination therapy or nivolumab monotherapy.   
 
3.1.2 
Treatment Regimen 
Subjects will be treated in either the dose-escalation or dose-expansion phase. MEDI0680, 
durvalumab and nivolumab will be administered via IV infusion. In dose-escalation phase, 
subjects will remain on treatment for up to 12 months. In the dose-expansion phase, subjects 
will remain on treatment until unacceptable toxicity, confirmed PD, or development of other 
reason for treatment discontinuation. 
For subjects receiving MEDI0680 in combination with durvalumab, durvalumab will be 
administered first. The IV infusion of durvalumab will be approximately 1 hour in duration. 
MEDI0680 infusion will start approximately 30 minutes after the end of durvalumab 
infusion. MEDI0680 will be administered by IV infusion over a minimum of 30 minutes at 
dose levels of 0.1, 0.5, and 2.5 mg/kg, over a minimum of 60 minutes at dose levels of 
> 2.5 mg/kg up to a total dose of 1200 mg, and over a minimum of 90 minutes at total doses 
> 1200 mg. In the dose-escalation phase only, subjects who achieve and maintain DC (ie, 
Dose-escalation Phase
MEDI0680 and durvalumab combination therapy
Immunotherapy-naïve subjects
Tumor types – NSCLC, SCCHN, MSI-high CRC, bladder cancer, ovarian cancer, esophageal
cancer, gastric cancer or RCC
Dose(s) that could be used in expansion:
1.
MTD or highest protocol-defined dose for each agent in the absence of exceeding the 
MTD and/or
2. Intermediate dosing based on Modified Zone design
Dose-expansion Phase a
Immunotherapy-naïve subjects
Tumor type - ccRCC
MEDI0680 in combination with 
durvalumab
Nivolumab
Monotherapy

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CR, PR, or stable disease [SD]) through the end of the 12-month treatment period will enter 
follow-up. During the first 12 months of follow-up, if the subject has PD, the subject may be 
re-administered MEDI0680 and durvalumab for up to another 12 months with the same 
treatment guidelines followed during the initial 12-month period if the subject fulfills the 
criteria for retreatment in the setting of PD, has not received other anticancer treatments for 
their disease, and does not meet any of the investigational product discontinuation criteria 
(Section 4.1.6). Only 1 round of retreatment will be allowed.   
Nivolumab will be administered according to the package insert guidelines. 
3.1.2.1 
Treatment Beyond Progression 
For subjects treated with MEDI0680 monotherapy or in combination with durvalumab, in the 
event of an initial assessment of PD (based on an application of RECIST v1.1 to investigator-
assessed tumor measurements), a subject may continue to receive the assigned study 
treatment as long as none of the criteria listed below are met. 
• Confirmed PD: The assessment of PD by RECIST v1.1 (baseline PD assessment) will be 
confirmed by a repeat evaluation at the next tumor assessment time point, but no sooner 
than 4 weeks later. If any subsequent tumor assessment time point shows ≥ 20% increase 
in the overall tumor burden (the sum of diameters of target lesions and new lesions), 
when compared to the baseline PD assessment (the sum of diameters of target lesions and 
new lesions), the subject would be deemed as having confirmed PD and must be 
discontinued.  
• Meets any of the investigational product discontinuation criteria (Section 4.1.6). 
• Clinical symptoms or signs indicating significant PD such as the benefit-risk ratio of 
continuing therapy is no longer justified. 
• Decline in Eastern Cooperative Oncology Group (ECOG) performance status. 
• Threat to vital organs/critical anatomical sites (eg, spinal cord compression) requiring 
urgent alternative medical intervention, and continuation of study therapy would prevent 
institution of such intervention. 
 
Subjects will be made aware of the potential benefits and risks of continuing the study 
regimens in the setting of PD by providing separate written informed consent.  
Nivolumab will be administered according to the package insert guidelines. 

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3.1.2.2 
Dosing Schedule 
In the dose-escalation phase, durvalumab will be administered Q2W for 12 months and 
MEDI0680 will be administered Q2W for 12 months (Figure 3.1.2.2-1). In the 
dose-expansion phase, MEDI0680 in combination with durvalumab (depending on assigned 
treatment arm) will be administered Q2W until unacceptable toxicity, documentation of 
confirmed PD, or development of other reason for treatment discontinuation. 
In the dose expansion phase, nivolumab (depending on assigned treatment arm) will be 
administered Q2W as per the local (country-specific) package insert (or similar) until 
unacceptable toxicity, documentation of confirmed PD, or development of other reason for 
treatment discontinuation, according to the local (country-specific) package insert (or 
similar). 
 
Figure 3.1.2.2-1 
Study Flow for Primary MEDI0680 Schedule (Every 2-week 
Dosing) 
Q2W = every 2 weeks. 
 
Dose Escalation Phase
Screening Period
Durvalumab and 
MEDI0680: Q2W for 26 
doses
Survival Follow up
Progressive Disease 
after 12 month 
treatment period
Follow Retreatment 
Criteria and Rules
Dose Expansion Phase
Screening Period
MEDI0680 in combination with durvalumab Q2W
or
Nivolumab monotherapy Q2W until:
•
unacceptable toxicity
•
documentation of confirmed disease progression
•
development of other reasons for treatment 
discontinuation

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3.1.3 
Dose-escalation Phase: Dose-escalation and Modified Zone-based 
Design 
3.1.3.1 
Dose-escalation 
As of Protocol Amendment 3, enrollment in the dose-escalation phase is complete. 
Rules for dose-escalation and de-escalation are as follows: 
1. A minimum of 3 subjects will be enrolled in each dose cohort. 
2. The administration of durvalumab and MEDI0680 to the first and second subjects of each 
cohort will be separated by at least 24 hours.  
3. All safety data will be reviewed by a study-specific dose-escalation committee before 
proceeding with an escalation or de-escalation decision. 
4. A 3 + 3 dose-escalation design will be followed as summarized below: 
a. If 0 out of the 3 subjects in a dose cohort experience a DLT during the 
DLT-evaluation period, dose-escalation may proceed to the next planned cohort(s) 
with approval of the dose-escalation committee.  
b. If 1 of the 3 subjects in any dose cohort experiences a DLT during the 
DLT-evaluation period, that dose cohort will be expanded to a total of 6 subjects. If 
no more than 1 of 6 subjects in the dose cohort experiences a DLT, dose-escalation 
may proceed to the next planned dose cohort(s) with the approval of the 
dose-escalation committee. 
c. If 2 or more subjects in a dose cohort experience a DLT during the DLT-evaluation 
period, the MTD will have been exceeded and no further subjects will be enrolled 
into that dose cohort. The following options could be evaluated: 
◦ 
In the Primary Q2W schedule (see Figure 3.1.3.2-1): 
▪ 
A previous lower dose cohort or an intermediate dose cohort  
▪ 
A switch to Q4W dosing for MEDI0680 
▪ 
An intermediate dose using the modified zone-based design 
◦ 
In the Alternative Q4W schedule: 
▪ 
A previous lower dose cohort or an intermediate dose cohort  
▪ 
An intermediate dose using the modified zone-based design 
5. Intermediate doses may be explored based on a zone-based design (Huang et al, 2007). 
The modified zone-based design takes the initial dose-escalation along a predefined path 
(ie, main dose-escalation) until the MTD is exceeded or the highest protocol-defined 
doses for each agent in the absence of exceeding the MTD are reached. Lower zones or 
doses in the same zone as the MTD or the highest protocol-defined doses for each agent 
in the absence of exceeding the MTD may be explored simultaneously with the 
dose-expansion cohort (Section 3.1.3.2) 
6. If the MTD is exceeded for Cohort 1 (starting dose level):  
a. Based on ongoing review of emerging data from the current study as well as ongoing 
clinical studies with durvalumab and MEDI0680 (MEDI0680; monotherapy and 

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combination therapy), the dosing interval of MEDI0680 may be changed in which 
longer dosing intervals may be evaluated in combination with durvalumab. For 
example, if the emerging safety profile of the combination precludes the Q2W dosing 
interval for MEDI0680, a longer dosing interval for MEDI0680 (MEDI0680; ie, 
Q4W) may offer the possibility of better tolerability for the combination. There can 
be escalation to explore higher dose cohorts based on a 3 + 3 escalation design 
(see Figure 3.1.3.2-1) 
b. Dependent on emerging subject data, including safety, PK, pharmacodynamics, 
biomarker, and response among subjects on the Q4W dosing regimen, higher doses of 
MEDI0680 may be explored. 
7. If the MTD is not exceeded for Cohort 1, then higher cohorts will be explored using the 
3 + 3 escalation design.  
a. A switch to Q4W dosing for MEDI0680 could potentially permit additional time for 
recovery from any observed toxicities.  
b. The dose that would be used for the Q4W schedule would be the highest dose 
evaluated on the Q2W schedule that did not exceed the MTD or a lower dose based 
on evaluation of emerging PK, pharmacodynamics, safety, and efficacy parameters in 
the current study and other ongoing studies. 
8. Any dose-escalation cohort that has not exceeded the MTD can be expanded up to a 
maximum of 18 subjects for further evaluation of safety, PK, pharmacodynamics, and 
efficacy 
 

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Figure 3.1.3.2-1 
Dose-escalation (Zone-based) for Primary Q2W Schedule 
MEDI4736 = durvalumab; Q2W = every 2 weeks. 
 
3.1.3.3 
Dose-limiting Toxicity  
Dose-limiting toxicities will be evaluated during the dose-escalation phase. Non-evaluable 
subjects will be replaced in the same dose cohort (see Section 4.1.7). Grading of DLTs will 
be according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.03. 
A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs during 
the DLT-evaluation period, including but not limited to: 
• Any Grade 4 imAE regardless of duration 
• Any ≥ Grade 3 colitis regardless of duration 
• Any Grade 3 or Grade 4 non-infectious pneumonitis irrespective of duration 
• Any Grade 3 imAE, excluding colitis and pneumonitis, that does not downgrade to 
≤ Grade 2 within 3 days after onset of the event despite maximal supportive care 
including systemic corticosteroids or downgrade to ≤ Grade 1 or baseline within 14 days  
• Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care 
• Liver transaminase elevation higher than 8 × upper limit of normal (ULN) or total 
bilirubin higher than 5 × ULN 
• Grade 4 neutropenia and thrombocytopenia that does not resolve to ≤ Grade 3 within 
≤ 7 days and Grade 3 thrombocytopenia associated with any clinically important bleeding 

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• Any other toxicity that is greater than baseline grade, is clinically significant and/or 
unacceptable, and is judged to be a DLT by the dose-escalation review committee 
 
The definition excludes the following conditions:  
• Grade 3 endocrinopathy, that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy, and the subject is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) that resolves to ≤ Grade 1 within 
30 days 
• Concurrent vitiligo or alopecia of any AE grade 
 
Immune-mediated AEs are defined as AEs of immune nature (ie, 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 the rules for adjudicating DLTs in the context of dose-escalation are specified above, 
an AE not listed above may be defined as a DLT after a consultation with the sponsor and 
investigators, based on the emerging safety profile. 
Primary Escalation (Every 2-week Dosing of MEDI0680) Dose-limiting Toxicity 
Period 
The period for evaluating DLTs is the time period starting with the first dose of study drugs 
until the planned administration of the third dose of durvalumab and MEDI0680 during Q2W 
dosing. Subjects are considered evaluable for assessment of DLT if they receive the 
protocol-assigned doses of both durvalumab and MEDI0680 (ie, 2 doses of both durvalumab 
Q2W and MEDI0680 Q2W) and complete the safety follow-up through the end of the 
DLT-evaluation period, or experience a DLT during the DLT-evaluation period. 
3.1.3.4 
Maximum Tolerated Dose 
The MTD is defined as the highest dose within a dose-escalation cohort where no more than 
1 of 6 subjects experiences a DLT.  
Dose-escalation is complete (see Section 1.4.1). An MTD was not identified and the highest 
combination dose administered was 20 mg/kg MEDI0680 Q2W with 10 mg/kg durvalumab 
Q2W. 

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3.1.4 
Dose-expansion Phase  
Dose-expansion will be initiated following completion of the dose-escalation phase. 
Immunotherapy-naïve subjects with ccRCC will be randomized in a 2:1 ratio to receive 
either 20 mg/kg MEDI0680 in combination with 750 mg durvalumab Q2W or nivolumab 
Q2W. Dose levels of MEDI0680 and durvalumab were selected based on data from the 
dose-escalation phase of this study, the ongoing FTIH MEDI0680 Study D6020C00002, and 
ongoing durvalumab studies and analyses (see Section 3.2.1). The dose level of nivolumab is 
the recommended dose for treatment of patients with advanced RCC.  
Prior to the removal of a MEDI0680 monotherapy arm in this protocol amendment, some 
subjects were randomized and began receiving MEDI0680 monotherapy. These subjects are 
to continue receiving 20 mg/kg MEDI0680 Q2W monotherapy until unacceptable toxicity, 
confirmed PD, or development of other reason for treatment discontinuation, and will follow 
the study procedures outlined in Section 4.2 for MEDI0680/durvalumab combination therapy 
(with the exception of durvalumab specific procedures). 
During the dose-expansion phase, subjects will be monitored for safety according to the same 
criteria employed during dose-escalation. If during the treatment period, ≥ 33% of subjects in 
the MEDI0680/durvalumab combination arm experience safety events meeting DLT criteria 
(even if outside of the DLT-evaluation period [see Section 3.1.3.2]), randomization may be 
paused and study data will be reviewed to determine whether additional monitoring or 
alternate dose levels or treatment schedules should be evaluated prior to further 
randomization. 
3.1.5 
Management of Study Medication Related Toxicities 
3.1.5.1 
Dose Modifications of Durvalumab and MEDI0680 
Based on the mechanism of action of durvalumab and MEDI0680 leading to T-cell activation 
and proliferation, there is the possibility of observing imAEs during the conduct of this study. 
Potential imAEs may be similar to those seen with the use of ipilimumab, BMS-936558, and 
BMS-936559 and may include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies (Hodi et al, 2010; Brahmer et al, 2012; Topalian et al, 2012). Subjects 
should be monitored for signs and symptoms of imAEs. In the absence of an alternate 
etiology (eg, infection or PD), an immune-mediated etiology should be considered for signs 
or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy. Subjects should be 
evaluated to identify any alternative etiology 

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1. In the absence of clear alternative etiology, all events of an inflammatory nature should 
be considered to be immune-mediated 
1. Symptomatic and topical therapy should be considered for low-grade events 
2. Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event  
3. More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab, mycophenolate, etc) 
 
If the investigator has any question in regards to an AE being an imAE, the investigator 
should immediately contact the medical monitor. Dose modifications may not be required for 
AEs that are clearly not attributed to durvalumab or MEDI0680 (such as an accident) or for 
laboratory abnormalities that are deemed asymptomatic, not deemed to be clinically 
significant, require no intervention, and are documented in the medical records. Laboratory 
abnormalities that are felt to meet these criteria must be discussed and agreed on by the 
medical monitor before treatment can be continued. Dose reductions of durvalumab and 
MEDI0680 are not permitted. 
Treatment modifications of MEDI0680/durvalumab may be required in the event of 
treatment-related toxicity. General treatment modification and toxicity management 
guidelines are provided in Appendix 6. Additionally, management guidelines for adverse 
events of special interest (AESIs) are detailed in Section 5.3. All toxicities will be graded 
according to NCI CTCAE V4.03. In case of doubt the investigator should consult with the 
medical monitor. 
3.1.5.2 
Dose Modifications of Nivolumab 
The investigator should follow the recommendations in the local (country-specific) package 
insert (or similar). 
3.2 
Study Design and Dose Rationale 
3.2.1 
Dose Rationale (MEDI0680 and Durvalumab) 
3.2.1.1 
Dose-escalation Phase 
MEDI0680 
MEDI0680 monotherapy Study D6020C00002 (AMP-514-01), the ongoing FTIH study, will 
evaluate MEDI0680 doses of 0.1, 0.5, 2.5, 10, and 20 mg/kg Q3W; and 10 and 20 mg/kg 
Q2W. Provided the MTD is not exceeded at 20 mg/kg Q3W or Q2W, higher doses may be 
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exceed double the maximum dose. Based on available data from Study D6020C00002, the 
proposed starting dose of MEDI0680 in the current study will be given Q2W in order to align 
with the durvalumab schedule, and will be the lowest dose on a Q3W dosing schedule in the 
ongoing FTIH study. The MEDI0680 starting dose will be 0.1 mg/kg administered by IV on 
Day 1 and then Q2W (± 3 days) for 12 months. As of 02Nov2015, 58 subjects received 
MEDI0680 monotherapy (see Section 1.4.1). Dose levels included 0.1, 0.5, 2.5, 10, and 
20 mg/kg Q3W, 10 and 20 mg/kg Q2W, 20 mg/kg QW × 2 and 20 mg/kg QW × 4. One DLT 
was reported.  
Durvalumab 
Durvalumab dose levels were selected based on data from the FTIH Study 
CD-ON-MEDI4736-1108. The dose selected for further evaluation in the dose-expansion 
phase of Study CD-ON-MEDI4736-1108 is 10 mg/kg administered Q2W. This was based on 
evaluation of the current PK data in the subjects enrolled in Study CD-ON-MEDI4736-1108 
where doses of 0.1, 0.3, 1.0, 3.0, and 10 mg/kg Q2W were evaluated. Durvalumab exhibited 
nonlinear (dose-dependent) PK consistent with target-mediated drug disposition. Linear PK 
was observed at doses of 3.0 mg/kg and above and is consistent with near complete target 
suppression, which is supported by sPD-L1 suppression data. Further, the 10 mg/kg Q2W 
dose was not associated with any DLTs in the dose-escalation phase and was, therefore, 
selected for further evaluation in the dose-expansion phase of Study CD-ON-MEDI4736-
1108. For the current study, the starting dose of durvalumab was 3 mg/kg, one dose level 
below the 10 mg/kg referenced above. 
Durvalumab will be administered by IV on Day 1 and then Q2W (± 3 days) for 12 months. 
3.2.1.2 
Dose-expansion Phase 
MEDI0680/Durvalumab Combination Therapy 
The dose-escalation phase of this study (D6020C00001) was completed as of the date of this 
amendment with the highest MEDI0680/durvalumab combination dose level administered 
being 20 mg/kg MEDI0680 Q2W with 10 mg/kg durvalumab Q2W. A dose limiting toxicity 
(DLT) was reported in 1 subject. An MTD was not identified and no significant AE trends 
were observed across the dose levels evaluated.  
Following IV infusion of MEDI0680 in combination with durvalumab, mean Cmax, trough 
concentration, and AUCτ values of MEDI0680 increased approximately dose proportionally 
from 0.1 to 20 mg/kg. Co-administration of durvalumab did not affect MEDI0680 PK 

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compared to MEDI0680 monotherapy. Preliminary data from MEDI0680/durvalumab 
combination therapy in the dose-escalation phase of this study suggest that target receptor 
occupancy is achieved at both the 10 + 10 mg/kg and 20 + 10 mg/kg dose levels of 
MEDI0680 in combination with durvalumab in early assessments (first cycle). MEDI0680 
PK was linear with dose-proportional increases in serum concentrations from 0.1 to 20 mg/kg 
in combination with 10 mg/kg durvalumab administered Q2W.  
Durvalumab Weight-based Dosing to Fixed Dosing 
A population PK model was developed for durvalumab using monotherapy data from Study 
CD-ON-MEDI4736-1108 (solid tumors; N = 292; doses = 0.1 to 10 mg/kg Q2W or 15 mg/kg 
every 3 weeks). Population PK analysis indicated only minor impact of body weight (WT) on 
PK of durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) 
and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median and 95th percentiles) using the population PK 
model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median 
body WT of approximately 75 kg). A total of 1000 subjects were simulated using body WT 
distribution of 40 to 120 kg. Simulation results demonstrate that body WT-based and fixed-
dosing regimens yield similar median steady state PK concentrations with slightly less 
overall between-subject variability with fixed dosing regimen. Thus, a fixed dosing of 
durvalumab 750 mg will be explored in the dose-expansion phase of this study. The dose of 
20 mg/kg MEDI0680 Q2W with 750 mg durvalumab (fixed dose) Q2W was selected for the 
dose-expansion phase to maximize the likelihood of observing robust efficacy with tolerable 
safety profiles based on available PK, PD, and clinical response data.  
3.2.2 
Rationale for Study Population 
Despite considerable advancements made during the last decade, patients with advanced 
solid tumors have poor outcomes with currently available therapies. Although many of the 
solid tumor types have approved first-line treatments, further therapeutic options are limited 
with second- and third-line treatments generally providing short OS. 
Tumors that have historically shown responsiveness to immunotherapy (IMT) may benefit 
from complete pathway blockade. Solid tumors such as melanoma (MEL), RCC and NSCLC 
are known to respond to IMT (Brahmer et al, 2012; Hodi et al, 2010; Motzer et al, 2015; 
Topalian et al, 2012). 
Rationale for RCC Population 

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An estimated 338,000 new cases of RCC are diagnosed worldwide, with approximately 
30% of patients presenting with metastatic disease (Ferlay et al, 2015; Fisher et al, 2013; 
Motzer et al, 2015). A number of targeted therapies have been approved for the treatment of 
patients with advanced or metastatic RCC, however, these treatments are associated with 
limited OS (< 2 years). A PD-1-targeting agent, nivolumab, recently received approval for 
the treatment of patients with advanced RCC with its Phase 3 study stopped early after it was 
determined that nivolumab improved OS versus everolimus in subjects with advanced RCC 
(Motzer et al, 2015). The confirmed ORR (95% CI) in this Phase 3 study was 21.5% 
(17.6, 25.8) based on independent review, suggesting that some RCC patients are primarily 
nonresponsive or are only minimally responsive to nivolumab monotherapy (Opdivo 
[nivolumab] Package insert, 2015). Thus, exploration of new therapies in patients who are 
candidates for nivolumab monotherapy is warranted. Following Protocol Amendment 5, 
nivolumab monotherapy was added as a comparator arm in the dose expansion phase to 
enable comparison of MEDI0680/durvalumab activity with the current standard of care.  
The mechanisms of action of anti-PD-1 and anti-PD-L1 antibodies are distinct: while both 
inhibit the interaction between PD-1 and PD L1, only anti-PD-1 blocks PD-1/PD-L2 and 
only anti-PD-L1 blocks PD-L1/CD80 and support for the combination strategy is provided 
by mouse models of cancer (Curran et al, 2010). Based upon these observations, the complex 
feedback between pathways and differences in pathway blockade between agents, 
combination therapy with durvalumab and MEDI0680 may generate superior antitumor 
activity compared to either monotherapy. This may translate into high rates of response in 
tumors known to respond to therapeutic agents that target PD-1 or increased likelihood of 
activity in tumors that have previously not shown high levels of responsiveness to PD-1 
targeting agents. 
3.2.3 
Rationale for Endpoints 
Primary Endpoints 
The primary endpoints for this study are to determine the MTD or highest protocol-defined 
dose for each agent in the absence of exceeding the MTD for MEDI0680 in combination 
with durvalumab and to determine the safety of this combination. Ensuring the safety of the 
combination, and defining a dose for dose-expansion, is important prior to progressing to the 
next stage of clinical development. Standard safety parameters, and enhanced monitoring for 
imAEs, will be employed to assess the safety profiles of MEDI0680 in combination with 
durvalumab or nivolumab monotherapy.  

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The primary efficacy endpoint for the dose-expansion phase is a standard measure used to 
assess efficacy in oncology studies.  
Secondary Endpoints 
The secondary endpoints for this study include antitumor activity, PK, and immunogenicity. 
Antitumor activity is being examined to determine the effect of MEDI0680 in combination 
with durvalumab versus nivolumab monotherapy treatment on tumor burden which will help 
to further explore the benefit-risk profile for the combination. The PK of durvalumab and 
MEDI0680 are being examined to determine the effect of MEDI0680 on durvalumab PK 
parameters and the effect of durvalumab on MEDI0680 PK parameters. Immunogenicity will 
be examined to assess its impact on safety and efficacy. Expression and localization of 
PD-L1 will be examined to determine if it is a predictive biomarker for response to therapy. 
The endpoints chosen to assess secondary objectives are commonly used in oncology studies. 
Pharmacodynamic and Predictive Exploratory Endpoints 
The goals of exploratory assessments are to identify predictive markers (measures of a 
subject’s health or immune status prior to treatment that correlate with clinical response) and 
to characterize the pharmacodynamic effects of MEDI0680 and durvalumab (changes in a 
subject’s immune status following treatment and correlations with drug exposure and clinical 
response). The rationale for the exploratory endpoints is based on ongoing studies of 
MEDI0680 and durvalumab, as well as knowledge gained in clinical studies with other 
cancer immunotherapies. The collections are being synchronized in the monotherapy and 
combination treatment studies to enable comparisons of the pharmacodynamic markers and 
predictive markers among the two monotherapies and the combination treatment. 
Collection of tumor biopsy specimens, as well as whole blood, and plasma specimens, are 
needed to assess the requested pharmacodynamic and predictive markers. Peripheral blood 
mononuclear cells (PBMC) were also analyzed in dose escalation but were removed for dose 
expansion as of Amendment 5. Tumor biopsy specimens provide critical information about 
the status of the antitumor immune response, at the site of disease. Since the antitumor 
immune response can evolve with time and in response to different therapies, fresh pre-
treatment biopsies, when clinically feasible, provide more relevant information than archival 
biopsies. During dose-expansion, optional posttreatment biopsies will be collected at 
approximately Day 57 and end of treatment (EOT). If available, the pretreatment and Day 57 
biopsies will be compared to assess changes in the tumor microenvironment after one cycle 
of treatment, at a time when active tumor regression has occurred in subjects receiving 
durvalumab monotherapy treatment. The EOT biopsy specimens will be evaluated to 

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understand potential mechanisms of resistance in tumors that remain following treatment. 
Peripheral specimens (whole blood, PBMC, and plasma) indicate a subject’s overall immune 
status and can provide insight into the antitumor immune response. 
Pharmacodynamic Markers 
Receptor targeting and occupancy is being evaluated using the sPD-L1 assay (durvalumab) 
and the PD-1 flow cytometry assay (MEDI0680). These assays are especially useful during 
dose-escalation and may help to inform dose selection for the dose-expansion phase; these 
assays will not be conducted in the dose-expansion phase as of Protocol Amendment 5. 
The functional consequences of complete pathway blockade will be evaluated by assessing 
immune responses in the tumor microenvironment and periphery. Similar evaluations are 
being conducted in conjunction with monotherapy studies, to understand the functional 
consequences of each agent alone.  
Changes in the immune response in the tumor microenvironment will be assessed using 
multiple approaches. Expression and localization of key molecules such as PD-L1, PD-L2, 
and PD-1 within the tumor microenvironment may be examined by immunohistochemistry 
(IHC). Biopsy specimens may also be evaluated for changes in the frequency, phenotype, 
and/or localization of infiltrating T cells and APC. Gene expression profiling will be used to 
evaluate a broader panel of markers that indicate the level of inflammation within the tumor 
microenvironment and the balance between markers of immune suppression versus action in 
T cells and APC.  
Changes in the immune responses in the periphery are also being evaluated using multiple 
approaches. Flow cytometry assays may be used to evaluate factors such as phenotype, 
expression of activation markers, proliferation, and production of cytokines and effector 
molecules, by cell populations such as T cells, B cells, and myeloid-derived suppressor cell 
(MDSC). Gene expression analysis (evaluation of messenger ribonucleic acid [mRNA] 
and/or micro ribonucleic acid [miRNA]) of peripheral blood specimens and/or cryopreserved 
PBMC may also be conducted. Plasma specimens will also be collected prior to treatment 
and at several posttreatment time points to enable evaluation of circulating soluble factors 
indicative of immune response (eg chemokines, cytokines, soluble receptors, and antibodies 
to self-antigens and tumor antigens), cancer biomarkers, and tumor DNA.  
Other pharmacodynamic markers may be evaluated as determined by additional data. 

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Predictive Markers 
Candidate biomarkers for subject selection will be assessed to determine whether these 
markers predict which subjects are most likely to respond to treatment with durvalumab and 
MEDI0680. Similar evaluations are being conducted in conjunction with monotherapy 
studies for both agents. 
Tumors can express PD-L1 as a mechanism of adaptive resistance to an activated immune 
response within the tumor microenvironment. Fresh and/or archival pre-treatment biopsies 
will be collected from all subjects and analyzed by IHC to evaluate whether the expression of 
PD-L1 may be a predictive marker for response to treatment with durvalumab and 
MEDI0680. 
The combination of durvalumab and MEDI0680 may be especially beneficial in cases where 
PD-1, PD-L1, PD-L2, and CD80 are all expressed in the tumor microenvironment. 
Expression of PD-1, PD-L2, and CD80 may be evaluated using IHC and/or other methods, to 
determine whether expression of multiple pathway molecules may be a predictive marker for 
response to treatment with durvalumab and MEDI0680. 
Expression of additional immune-related markers in the tumor microenvironment may also 
be conducted by IHC and/or other methods. Gene expression analysis of pre-treatment 
biopsy specimens may also be conducted to determine whether certain baseline patterns of 
mRNA/miRNA expression, such as markers of an inflammatory tumor microenvironment, 
correlate with response. Results of these exploratory studies may suggest predictive markers 
for response to the combination treatment.  
Pre-treatment biopsy specimens may be analyzed for the presence of key mutations; these 
may include but are not limited to epidermal growth factor receptor, Kirsten rat sarcoma 
oncogene homolog (K-ras), neuroblastoma RAS viral oncogene (N-ras), APC, B catenin, 
anaplastic lymphoma kinase, and C-MNNG HOS transforming gene, as mutational status 
may impact tumor immunogenicity and mechanisms of tumor immune evasion. Correlations 
between key mutations and response to the durvalumab and MEDI0680 treatment 
combinations may be evaluated.  
The general status of the immune system may also affect responsiveness to immunotherapies, 
including MEDI0680 and durvalumab. Pre-treatment numbers of total T cells, CD4 T cells, 
CD8 T cells, B cells, and NK cells per mL of peripheral blood, the relative populations of 
these lymphocyte subsets, and the relative frequency of proliferating, naïve, effector, and 
memory T cells, will be evaluated by flow cytometry to determine whether baseline 

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characteristics of peripheral leukocytes may be a predictive marker for response to treatment 
with durvalumab and MEDI0680. 
Other predictive biomarkers may be evaluated as determined by additional data. 
4 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 
Number of Subjects 
A total of approximately 96 subjects could be enrolled at approximately 50 study centers 
globally. 
4.1.2 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Age ≥ 18 years at the time of screening 
2. ECOG performance status of 0 - 1 
3. For dose escalation: 
a. Histologically confirmed metastatic or recurrent NSCLC, SCCHN, MSI-high CRC, 
bladder cancer, ovarian cancer, esophageal cancer, gastric cancer, or RCC that are 
refractory or intolerant to standard therapy or for which no standard therapy exists 
b. No more than 3 prior lines of systemic therapy in the recurrent or metastatic setting, 
including standard and investigational agents (additional criteria apply for NSCLC, 
see item 3e) 
c. Subjects with at least one measurable lesion according to RECIST v1.1  
d. Immunotherapy naïve: Subjects must have no prior exposure to immunotherapy 
including but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies 
e. For NSCLC subjects: 
i. NSCLC subjects with metastatic or recurrent disease must have received no more 
than 3 prior lines of therapy, or either failed to respond, relapsed, or were unable 
to tolerate standard treatment 
ii. Subjects with EGFR-activating mutations must have received an EGFR tyrosine 
kinase inhibitor (TKI) and subjects with anaplastic lymphoma receptor tyrosine 
kinase (ALK) rearrangement positive tumors must have received an ALK TKI 
iii. Subjects with wild-type EGFR and ALK mutation must have failed a platinum-
based regimen. NOTE: Maintenance therapy following platinum doublet-based 
chemotherapy is not considered a separate line of therapy. Prior platinum-
containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for 
locally advanced disease is considered first line therapy only if recurrent (local or 
metastatic) disease developed within 6 months of completing therapy. Subjects 

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with recurrent disease > 6 months must also have progressed after a subsequent 
platinum-based chemotherapy regimen given to treat the recurrence 
4. For dose-expansion: 
a. Histological confirmation of advanced or metastatic RCC with a clear-cell component 
b. Must have received at least 1 and no more than 2 prior anti-angiogenic therapy 
regimens (including, but not limited to, sunitinib, sorafenib, pazopanib, axitinib, 
tivozanib, and bevacizumab) in the advanced or metastatic setting. 
c. Must have received no more than 3 total prior systemic treatment regimens in the 
advanced or metastatic setting, and must have evidence of radiographic progression 
on or after the last treatment regimen received and within 6 months prior to study 
enrollment. 
d. No prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways 
e. No prior treatment with an mammalian target of rapamycin (mTOR) inhibitor 
(including, but not limited to everolimus, temsirolimus, sirolimus, and ridaforolimus) 
f. Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed. 
g. Subjects must have at least 1 measurable lesion according to RECIST v1.1. A 
previously irradiated lesion cannot be considered a target lesion. Radiographic 
disease assessment can be performed up to 28 days prior to the first dose  
5. Biopsy requirements: 
a. For dose escalation, subjects must consent to provide archival tumor tissue (initial 
and subsequent tumor biopsy samples, if possible) for correlative biomarker studies if 
available 
b. Able and willing to give valid written consent for fresh tumor samples if required. 
Fresh tumor biopsies should be preferentially obtained from tumor tissues that are 
safely accessible as determined by the investigator and achieved via non-significant 
risk procedures (refer to Section 4.3.2.1). Sites are encouraged to confirm adequacy 
of tumor biopsy material at the time of the procedure. Fine-needle aspirate specimens 
are not acceptable.  
c. For dose-expansion: 
i.  Tumor tissue (formalin fixed paraffin embedded [FFPE] archival or fresh tumor 
tissue) must be received by the central vendor (block or unstained slides) and 
evaluable for PD-L1 expression status in order to randomize a subject to study 
treatment.  
ii. All subjects are encouraged to consent to and provide both pre-treatment and on-
treatment fresh tumor biopsies; however, on-treatment biopsies are optional  
6. For dose-escalation and dose-expansion: (If evaluations performed as part of standard of 
care for other purposes prior to obtaining informed consent are suitable for screening and 
occurred within 7 days prior to starting treatment, those evaluations do not need to be 
repeated if the subject consents to their use): 
a. Adequate organ and marrow function, as defined below: 
i. Hemoglobin ≥ 9 g/dL 

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ii. Absolute neutrophil count ≥ 1,500/mm3 
iii. Platelet count ≥ 100,000/mm3 
iv. Total bilirubin ≤ 1.5 × ULN except subjects with documented Gilbert’s syndrome 
(> 3 × ULN) or liver metastasis, who must have a baseline total bilirubin 
≤ 3.0 mg/dL 
v. Alanine aminotransferase (ALT) and AST ≤ 2.5 × ULN; for subjects with hepatic 
metastases, ALT and AST ≤ 5 × ULN 
vi. Calculated creatinine clearance or 24-hour urine creatinine clearance ≥ 40mL/min 
determined by the Cockcroft-Gault formula (using actual body weight) 
7. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the US, European Union [EU] Data Privacy 
Directive in the EU) obtained from the subject/legal representative prior to performing 
any protocol-related procedures, including screening evaluations) 
8. Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use at least one highly effective method of contraception from 
screening and must agree to continue using such precautions for 120 days after the 
subject’s last dose of MEDI0680 or durvalumab or 150 days after the subject’s last dose 
of nivolumab. It is strongly recommended for the male partner of a female subject to also 
use male condom plus spermicide throughout this period. Cessation of contraception after 
this point should be discussed with a responsible physician. Effective methods (including 
highly effective methods) of contraception are described in Table 4.1.2-1. Not engaging 
in sexual activity for the total duration of the study is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Female subjects should refrain from egg cell donation and 
breastfeeding throughout this period.  
a. Females of childbearing potential are defined as those who are not surgically sterile 
(ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or who are not post-menopausal 
i. Females < 50 years of age will be considered postmenopausal 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 postmenopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
ii. Females ≥ 50 years of age will be considered postmenopausal 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).  
b. A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. Note that 
some contraception methods are not considered highly effective.  
9. Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use male condom plus spermicide from Day 1 through 120 days after the 

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subject’s last dose of MEDI0680 or durvalumab or 150 days after the subject’s last dose 
of nivolumab. It is highly recommended for a female partner of childbearing potential of 
a male subject to use a highly effective method of contraception throughout this period, 
as described in Table 4.1.2-1. In addition, male subjects must refrain from fathering a 
child or donating sperm while on study and for 120 days after the subject’s last dose of 
MEDI0680 or durvalumab or 150 days after the subject’s last dose of nivolumab. 
 
Table 4.1.2-1 
Effective Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Male or female condom with or without 
spermicide a, b 
• 
Cap, diaphragm, or sponge with 
spermicide  a, b 
• 
Copper T intrauterine device d 
• 
Levonorgesterel-releasing intrauterine 
system) (eg, Mirena®) c, d 
• 
Implants d 
• 
Hormone shot or injection d 
• 
Combined pill d 
• 
Minipill a 
• 
Patch d 
Note: A highly effective method of contraception has a failure rate of < 1% per year.  
a 
Not highly effective (failure rate of ≥ 1% per year) 
b 
A male condom plus cap, diaphragm, or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods 
c 
Also considered a hormonal method. 
d 
Highly effective (failure rate of < 1% per year). 
 
4.1.3 
Exclusion Criteria 
Any of the following would exclude the subject from participation in the study: 
1. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an 
observational study 
2. Central nervous system (CNS) metastatic disease and leptomeningeal disease are 
excluded.  (Note: spinal cord compression which has been stabilized is allowed).  
3. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for 
diabetes and hormone replacement therapy) is acceptable 
(NOTE: Local treatment of isolated lesions for palliative intent is acceptable [eg, by local 
surgery or radiotherapy]) 
4. Any investigational anticancer therapy received within 28 days prior to the first dose of 
durvalumab and MEDI0680 or nivolumab 
5. Major surgical procedure (as defined by the investigator) within 28 days prior to the first 
dose of durvalumab and MEDI0680 or nivolumab or still recovering from prior surgery 
6. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values 
listed per the inclusion criteria. Subjects with prior endocrine toxicities 
(eg, hypothyroidism) who are stable on replacement therapy are not excluded. Subjects 

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with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab 
and MEDI0680 or nivolumab may be included (eg, hearing loss)  
7. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab and MEDI0680 or nivolumab with the exceptions of intranasal and 
inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 
10 mg/day of prednisone or equivalent 
8. Active or prior documented autoimmune or inflammatory disease (including 
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac 
disease, irritable bowel disease; Wegener’s granulomatosis; Hashimoto syndrome) within 
the past 3 years. Subjects with vitiligo, alopecia, Grave’s disease, or psoriasis not 
requiring systemic treatment (within the past 3 years) are not excluded 
9. History of primary immunodeficiency or tuberculosis  
10. Test results indicating active infection with human immunodeficiency virus (HIV), or 
hepatitis A, B, or C 
11. Receipt of live, attenuated vaccine within 28 days prior to the first dose of durvalumab 
and MEDI0680 or nivolumab. NOTE: Subjects, if enrolled, should not receive live 
vaccine during the study and 90 days after the last dose of durvalumab and MEDI0680 or 
nivolumab 
12. Females who are pregnant, lactating, or intend to become pregnant during the 
participation to the study 
13. Uncontrolled inter-current illness including, but not limited to, ongoing or active 
infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or 
psychiatric illness/social situations that would limit compliance with study requirement 
substantially increase risk of incurring AEs from durvalumab or MEDI0680 or 
nivolumab, or compromise the ability of the subject to give written informed consent 
14. Diagnosis of a second malignancy within the last 2 years prior to Cycle 1, Day 1, with the 
exception of those with a negligible risk of metastasis or death, treated with expected 
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated surgically with curative 
intent, ductal carcinoma in situ treated surgically with curative intent) 
15. Known allergy or hypersensitivity to study drug formulations 
16. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results 
17. Subjects with advanced NSCLC with tumors harboring anaplastic lymphoma kinase gene 
rearrangements or epidermal growth-factor receptor-sensitizing mutations who have not 
received appropriate TKI therapy. These subjects can be enrolled after documented 
progression or intolerance to appropriate TKIs 
 
4.1.4 
Subject Enrollment 
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice response system/interactive web 
response system [IXRS]) and the screening evaluations may begin to assess study eligibility 

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(inclusion/exclusion) criteria. The SID number will be used to identify the subject during the 
screening process and throughout study participation, if applicable.  
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screening failure. 
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
receive investigational product. There can be no exceptions to this rule. Subjects who are 
screening failures should be withdrawn from the study. 
4.1.5 
Withdrawal from the Study 
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will 
be seen and assessed by an investigator. Adverse events will be followed. If a subject 
withdraws from further participation in the study, then no further study visits or data 
collection should take place. 
4.1.5.1 
Withdrawal of Consent 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation. Note that the subject may be offered additional tests or tapering of 
treatment to withdraw safely. 
4.1.5.2 
Withdrawal from Treatment 
Subjects who are permanently discontinued from further receipt of investigational product 
(see Section 4.1.6) regardless of the reason (withdrawal of consent from further treatment, 
due to an AE, other), will be identified as having permanently discontinued treatment.  
Subjects who are permanently discontinued from treatment in the absence of disease 
progression will be asked to come in for every protocol-specified visit and will follow all 
protocol procedures with the exception of dosing. For subjects refusing to return to the site, 
they should be contacted every 3 months by phone to assess for survival unless consent is 
withdrawn. The time period for recording toxicity can be found in Section 5.4. 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 4.1.6, including the collection of any protocol-specified 
blood, or urine specimens, unless consent is withdrawn, the subject is lost to follow-up, starts 

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alternative treatment, or is enrolled in another clinical study. All subjects will be followed for 
survival until the end of the study. Subjects who decline to return to the site for evaluations 
should be contacted by phone every 3 months as an alternative. 
4.1.5.3 
Lost to Follow-up 
Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (as defined in Section 6.3) such that there is insufficient 
information to determine the subject’s status at that time. 
• Subjects who refuse continuing participation in the study including phone contact should 
be documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators 
should document attempts to re-establish contact with missing subjects throughout the 
study period. If contact with a missing subject is re-established, the subject should not be 
considered lost to follow-up and any evaluations should resume according to the 
protocol. 
 
4.1.6 
Discontinuation of Investigational Product 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1. Withdrawal of consent from further participation in study-related assessments and 
follow-up 
2. Withdrawal of consent from further treatment with investigational product 
3. Lost to follow-up  
4. An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing  
5. Any AE that meets criteria for discontinuation as defined in Section 3.1.5.1 
6. Dose-limiting toxicity (see Section 3.1.3.3 for definition of DLT) 
7. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk  
8. Pregnancy or intent to become pregnant  
9. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits) 
10. Initiation of alternative anticancer therapy, including another investigational agent 
11. Confirmed PD (solid tumors) and retreatment criteria in setting of PD are not fulfilled see 
Section 3.1.2) 
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent 

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is withdrawn specifically from further study participation (Section 4.1.5.1), the subject is lost 
to follow-up, the subject starts alternative treatment, or the subject is enrolled in another 
clinical study. 
4.1.7 
Replacement of Subjects 
Subjects in the Phase 1/dose-escalation cohorts are considered evaluable if they receive the 
protocol-assigned dose(s) of both durvalumab and MEDI0680 (ie, 2 doses of durvalumab 
Q2W and 2 doses of MEDI0680 Q2W) and complete the safety follow-up through the end of 
the DLT-evaluation period or they experience a DLT during the DLT-evaluation period. 
Non-evaluable subjects in the dose-escalation cohorts will be replaced in the same dose 
cohort. No subjects will be replaced in the dose-expansion phase. 
4.1.8 
Withdrawal of Informed Consent for Data and Biological Samples 
Biological Samples Obtained for the Main Study 
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject. 
Samples Obtained for Genetic Research or Future Research 
Samples obtained for genetic research or future research will be labeled with a sample 
identification number but will not be labeled with personal identifiers such as the subject’s 
name. If the subject withdraws consent for participating in the future research, this link will 
allow the sponsor to locate the subject’s sample and destroy it. The coding of samples and 
results is to ensure that these research results are kept confidential by keeping the subject’s 
identity and these results separate.  
If the subject consents to have his/her samples used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) including any specimens of extracted DNA will be 
stored by the sponsor with similar samples from other subjects at a secure central laboratory. 
The subject’s samples will not be kept for more than 25 years after the end of the study in 
which they were collected. If the subject chooses not to allow his/her study samples to be 

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used for genetic research or future research, the samples will be destroyed by the sponsor 
once they are no longer required for the main study. 
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s sample(s) have 
already been used for research, the sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed. 
4.2 
Schedule of Study Procedures 
4.2.1 
Enrollment/Screening Period 
Table 4.2.1-1 shows all procedures to be conducted at the screening visit. Assessments 
should be performed in the order shown in the table. 
Whenever vital signs, 12-lead electrocardiograms (ECGs), and blood draws are scheduled for 
the same nominal time, the assessments should occur in the following order: 12-lead ECG, 
vital signs, and then blood draws.  
Table 4.2.1-1 
Schedule of Screening Procedures Following Protocol 
Amendment 5 
Study Period 
Screening 
Visit Number 
V1 
Procedure / Study Day 
Day -28 to Day -1 
Written informed consent/ assignment of SID number  
X 
Medical history 
X 
Physical examination (full), weight, height 
X 
ECOG performance status 
X 
Smoking questionnaire (Appendix 4; dose-escalation only)  
X 
ECG a 
X 
MRI brain (solid tumors) c 
X 
Disease assessment c 
X 
Vital signs, including pulse oximetry 
X 
Serum chemistry  
X 

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Table 4.2.1-1 
Schedule of Screening Procedures Following Protocol 
Amendment 5 
Study Period 
Screening 
Visit Number 
V1 
Procedure / Study Day 
Day -28 to Day -1 
Hematology 
X 
Urinalysis 
X 
Pregnancy test 
X 
Hepatitis A, B, C; HIV-1 
X 
TSH, free T4,  free T3 
X 
Flow cytometry 
X 
Circulating soluble factors  
X 
mRNA/miRNA 
X 
Archival/fresh tumor biopsy b 
X 
Assessment of AEs/SAEs 
X 
Concomitant medications 
X 
Verify eligibility criteria 
X 
AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HIV = human 
immunodeficiency virus; miRNA = micro ribonucleic acid; MRI = magnetic resonance imaging; mRNA = 
messenger ribonucleic acid; SAE = serious adverse event; SID = subject identification; T3 = thyroxine 3; T4 = 
thyroxine 4; TSH = thyroid stimulating hormone; V = Visit. 
a 
At screening, ECGs will be obtained in triplicate (all 3 within a 5-minute time period, at least 1 minute 
apart). 
b 
For all subjects, if an archival tumor biopsy is available then fresh tumor biopsy is not required at 
screening. If a subject is unable to verify availability of archival tumor samples or where the tumor samples 
are unsuitable for use, then baseline fresh tumor biopsies will need to be obtained prior to administration of 
the first dose of study drugs for subjects in the dose-escalation phase or prior to randomization for subjects 
in the dose-expansion phase. 
c 
A computed tomography or MRI scan performed as part of standard of care prior to written informed 
consent may be used for this assessment if performed within 42 days prior to Day 1 (ie, Day -42 to Day -1).  
 
4.2.2 
Treatment Period 
Study procedures to be conducted during the primary Q2W dose-escalation treatment period 
and the dose-expansion treatment period are presented in Table 4.2.2-1 for Cycles 1 
through 6 and in Table 4.2.2-2 for Cycles 7 through 13, as well as beyond Cycle 13 for 
subjects who continue treatment. Assessments should be performed in the order shown in the 
table when possible. 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 

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blood draws. The timing of the first two assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the exact nominal time. 
Subjects who are assigned to MEDI0680 monotherapy should follow procedures outlined for 
the combination arm, except where it is a durvalumab specific procedure (eg. durvalumab PK 
collection). 
 

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Table 4.2.2-1 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 1-6 Following 
Protocol Amendment 5 
Procedure 
Treatment 
Cycle 1  
Cycle 2  
Cycle 3  
Cycle 4  
Cycle 5  
Cycle 6  
D1 
D15  
± 1 
D29 
± 3 
D43 
  ± 3 
D57 
±  3 
D71   
± 3 
D85   
± 3 
D99 
   ± 3 
D113 
 ± 3 
D127 
 ± 3 
D141 
± 3 
D155 
± 3 
Study procedures and examinations 
Abbreviated physical exam (including weight) 
X a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG b 
X  
 
X  
 
X  
 
 
 
X 
 
 
 
Vital signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of AEs/SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labs 
Hematology  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Serum chemistry 
X 
X 
X 
X  
X 
X  
X 
 
X 
 
X 
 
TSH, free T4,  free T3 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood or urine pregnancy test (females of child 
bearing potential)c 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pharmacokinetics  
Durvalumab PK (Combination arm only) 
X d 
 
X d 
 
 
 
 
 
X 
 
 
 
MEDI0680 PK (Combination arm only) e  
X f 
 
X f 
 
 
 
 
 
X 
 
 
 

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Table 4.2.2-1 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 1-6 Following 
Protocol Amendment 5 
Procedure 
Treatment 
Cycle 1  
Cycle 2  
Cycle 3  
Cycle 4  
Cycle 5  
Cycle 6  
D1 
D15  
± 1 
D29 
± 3 
D43 
  ± 3 
D57 
±  3 
D71   
± 3 
D85   
± 3 
D99 
   ± 3 
D113 
 ± 3 
D127 
 ± 3 
D141 
± 3 
D155 
± 3 
Other labs and assays 
Immunogenicity durvalumab (Combination arm 
only) 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Immunogenicity MEDI0680 (Combination arm 
only) 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Flow cytometry  
X g 
X 
 
 
X 
 
 
 
 
 
 
 
Circulating soluble factors  
X 
 
X 
 
X 
 
 
 
 
 
 
 
miRNA/mRNA 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsy (dose escalation and dose 
expansion) h 
 
 
 
 
X 
 
 
 
 
 
 
 
Disease assessment (Q8W) i 
 
 
 
 
X 
 (-7 to -1) 
 
 
 
X  
(-7 to -1) 
 
 
 
Durvalumab administration (Combination arm 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MEDI0680 administration j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nivolumab administration (Dose expansion 
monotherapy arm only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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AE = adverse event; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; miRNA = micro ribonucleic acid; mRNA = 
messenger ribonucleic acid; PK = pharmacokinetic; Q2W = every 2 weeks; Q8W = every 8 weeks; SAE = serious adverse event; T3 = thyroxine 3; T4 = 
thyroxine 4; TSH = thyroid stimulating hormone. 
Note: Evaluations and sample collections should be conducted prior to administration of MEDI0680 and durvalumab or nivolumab unless otherwise indicated. 
Cycles are 28 days in length and dosing is Q2W. 
a 
If physical exam was performed within 3 days prior to Dose 1, it does not need to be repeated.  Abbreviated physical exam includes disease specific 
examination or if clinically indicated.  
b 
On Cycle 1 Day 1 single ECGs will be obtained within 60 minutes prior to start of infusion of durvalumab or nivolumab, and within 10 minutes post-EOI 
of MEDI0680, and within 10 minutes post-EOI of nivolumab. At all other timepoints, single ECGs will be obtained within 60 minutes prior to start of 
infusion of each durvalumab or nivolumab and as clinically indicated.  If an ECG result is abnormal, collect in triplicate at that time (all within a 5 
minutes period, at least 1 minute apart). If clinically indicated, ECGs will be collected in triplicate (all within a 5 minute period, at least 1 minute apart) 
until resolved 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and MEDI0680 or nivolumab treatment days. 
On Cycle 1 Day 1 in the durvalumab and MEDI0680 combination arm, vital signs will be measured within 30 minutes prior to the start of durvalumab 
administration (± 30 minutes), 15 minutes (± 5 minutes) post-EOI of durvalumab, and for the first cycle at 10 minutes (± 5 minutes) and 60 minutes 
(± 5 minutes) post-EOI of MEDI0680. For all other combination dose days, vital signs will be measured 30 minutes (± 30 minutes) prior to durvalumab 
administration, 15 minutes (± 5 minutes) post durvalumab EOI, and 10 minutes (± 5 minutes) and 30 minutes (± 5 minutes) post MEDI0680 EOI. In the 
nivolumab arm, on Cycle 1 Day 1 vital signs will be measured within 30 minutes prior to the start nivolumab (± 30 minutes), and at 10 minutes 
(± 5 minutes) and 60 minutes (± 5 minutes) post-EOI of nivolumab.  All other nivolumab dose days will measure vital signs 30 minutes (± 30 minutes) 
prior to infusion and 10 minutes (± 5 minutes) post EOI. 
c 
Should be performed within 7 days prior to dosing 
d 
Predose and EOI (± 10 minutes) for durvalumab. 
e 
For subjects in the escalation phase who will switch from the 60 mg/mL formulation to the 50 mg/mL formulation, predose and EOI (± 10 minutes) 
MEDI0680 PK samples will be collected for the first 2 doses of MEDI0680 using the new formulation. 
f 
Predose and EOI (± 10 minutes) for MEDI0680. 
g 
Predose for flow cytometry 
h 
Subjects who are in the dose-expansion cohorts are encouraged to provide an optional on-treatment fresh tumor biopsy on Day 57 (could be performed up 
to 7 days prior to investigational treatment administration, but must not be performed after dosing of investigational treatment) if clinically feasible (ie, 
repeat biopsy does not pose unacceptable medical risk to a subject as determined by the investigator).  
i 
Disease assessments will be performed Q8W (± 3 days) during the treatment period or as indicated by signs/symptoms. Disease assessments should occur 
within 7 days prior to the planned administration of the scheduled investigational treatment.  
j 
MEDI0680 will be administered in the combination arm and to the subjects randomized to the MEDI0680 monotherapy arm prior to Protocol 
Amendment 5. Subjects who are assigned to MEDI0680 monotherapy should follow the procedures listed for the combination arm, with the exception of 
durvalumab specific procedures (eg, durvalumab PK) 

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Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 to “n” Following 
Protocol Amendment 5 
Procedures 
Treatment 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Cycle 13  
Cycle n 
D169 
± 3 
D183 
± 3 
D197 
± 3 
D211 
± 3 
D225 
± 3 
D239 
± 3 
D253 
± 3 
D267 
± 3 
D281 
± 3 
D295 
± 3 
D309 
± 3 
D323 
± 3 
D337 
± 3 
D351 
± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D365 ± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D379 ± 3 
Study procedures and examinations 
Disease assessment 
(Q8W) a 
X (-7 
to -1 
 
 
 
X (-7 
to -1) 
 
 
 
X (-7 
to -1) 
 
 
 
X (-7 
to -1) 
 
Q8W 
starting 
D393 (7 
to -1) 
 
Abbreviated 
physical exam 
(including weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X b 
X b 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 to “n” Following 
Protocol Amendment 5 
Procedures 
Treatment 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Cycle 13  
Cycle n 
D169 
± 3 
D183 
± 3 
D197 
± 3 
D211 
± 3 
D225 
± 3 
D239 
± 3 
D253 
± 3 
D267 
± 3 
D281 
± 3 
D295 
± 3 
D309 
± 3 
D323 
± 3 
D337 
± 3 
D351 
± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D365 ± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D379 ± 3 
ECG c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X c 
 
Q12W 
starting 
D421 d 
 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
AEs/SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labs 
Hematology  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X f 
 
Chemistry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X f 
 
TSH, free T4, free 
T3 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Q8W f 
 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Q8W f 
 
Blood or urine 
pregnancy test 
(females of child 
bearing potential) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X f 
 
Pharmacokinetics 
Durvalumab PK 
(combo arm only) 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
 
 
 
MEDI0680 PK 
(combo arm only) g 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
 
 
 

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Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 to “n” Following 
Protocol Amendment 5 
Procedures 
Treatment 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Cycle 13  
Cycle n 
D169 
± 3 
D183 
± 3 
D197 
± 3 
D211 
± 3 
D225 
± 3 
D239 
± 3 
D253 
± 3 
D267 
± 3 
D281 
± 3 
D295 
± 3 
D309 
± 3 
D323 
± 3 
D337 
± 3 
D351 
± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D365 ± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D379 ± 3 
Other labs and assays 
 
Durvalumab 
immunogenicity 
(combo arm only) 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
 
 
 
MEDI0680 
immunogenicity 
(combo arm only) 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
 
 
 
Durvalumab 
administration 
(combo arm only) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MEDI0680 
administration 
(combo arm only) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 to “n” Following 
Protocol Amendment 5 
Procedures 
Treatment 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Cycle 13  
Cycle n 
D169 
± 3 
D183 
± 3 
D197 
± 3 
D211 
± 3 
D225 
± 3 
D239 
± 3 
D253 
± 3 
D267 
± 3 
D281 
± 3 
D295 
± 3 
D309 
± 3 
D323 
± 3 
D337 
± 3 
D351 
± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D365 ± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D379 ± 3 
Nivolumab 
administration 
(Dose expansion 
monotherapy arm 
only) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; D = Day; ECG = electrocardiogram;; ECOG = Eastern Cooperative Oncology Group;; PK = pharmacokinetic; Q2W = every 2 weeks; 
Q4W = every 4 weeks; Q8W = every 8 weeks; SAE = serious adverse event; T3 = thyroxine 3; T4 = thyroxine 4; TSH = thyroid stimulating hormone. 
Note: Evaluations and sample collections should be conducted prior to administration of MEDI0680 durvalumab, or nivolumab unless otherwise indicated. 
Cycles are 28 days in length and dosing is Q2W. 
a 
Disease assessments will be performed Q8W (± 3 days) during the treatment period or as indicated by signs/symptoms. Disease assessments should occur 
within 7 days prior to the planned administration of the scheduled investigational treatment. 
b 
From the D365 visit, weight will be collected for dosing information but physical exams (disease focused) are only required  on Day 1 of each cycle, or if 
clinically indicated  
c 
A single ECG will be obtained within 60 minutes prior to start of infusion of each investigational product and as clinically indicated.  If clinically 
indicated, ECGs will be collected in triplicate (all within a 5 minute period, at least 1 minute apart) until resolved. If an ECG result is abnormal, collect in 
triplicate at that time (all within a 5 minutes period, at least 1 minute apart).  
d 
To be performed on Day 1 of every third cycle, ie, Cycle 16, Cycle 19, etc. 
e 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on durvalumab and MEDI0680 or nivolumab treatment days. 
Vital signs will be measured 30 min (± 30 min) prior to durvalumab administration, 15 min (± 5 min) post durvalumab EOI, and 10 min (± 5 min) and 
30 min (± 5 min) post MEDI0680 EOI.  In the nivolumab arm, vital signs 30 min (± 30 min) prior to infusion and 10 min (± 5 min) post EOI. 
f 
From the D365 visit, samples for analysis of hematology, clinical chemistry, and pregnancy tests are only required on Day 1 of every cycle unless 
clinically indicated. TSH, free T4, free T3 and urine will be collected every other month beginning on Day 365. 

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Table 4.2.2-2 
Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 to “n” Following 
Protocol Amendment 5 
Procedures 
Treatment 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Cycle 13  
Cycle n 
D169 
± 3 
D183 
± 3 
D197 
± 3 
D211 
± 3 
D225 
± 3 
D239 
± 3 
D253 
± 3 
D267 
± 3 
D281 
± 3 
D295 
± 3 
D309 
± 3 
D323 
± 3 
D337 
± 3 
D351 
± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D365 ± 3 
Q4W 
(unless 
noted 
otherwise) 
starting on 
D379 ± 3 
g 
For subjects in the escalation phase who will switch from the 60 mg/mL formulation to the 50 mg/mL formulation, predose and EOI (± 10 minutes) 
MEDI0680 PK samples will be collected for the first 2 doses of MEDI0680 using the new formulation. 
h 
For subjects enrolled in the dose-escalation phase, MEDI0680 and durvalumab may be administered up to 12 months. Subjects randomized in the 
dose-expansion phase will receive either MEDI0680 Q2W in combination with durvalumab Q2W or nivolumab monotherapy until progressive disease, or 
other reason for treatment discontinuation. 
 

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4.2.3 
Follow-up Period 
Table 4.2.3-1 shows all procedures to be conducted during the end of treatment visit and 
during the follow-up period. Assessments should be performed in the order shown in the 
table. 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, it is preferred that assessments are performed in the following order: 12-lead ECG, vital 
signs, and then blood draws. The timing of the first two assessments should be such that it 
allows the blood draw (eg, PK blood sample) to occur at the exact nominal time. 
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study. Subjects who decline to return to the site for 
evaluations should be contacted by phone every 3 months for 12 months and then every 
6 months. Subjects who are permanently discontinued from treatment because of toxicity in 
the absence of disease progression will be asked to come in for every protocol-specified visit 
and will follow all protocol procedures with the exception of dosing. 
Table 4.2.3-1 
Schedule of Study Procedures: End of Treatment and 
Posttreatment Laboratory Follow-Up Following Protocol 
Amendment 5 
Procedure 
End of 
Treatment 
Posttreatment 
Laboratory Follow-up 
After End of Treatment 
visit 
Long-term Follow-up 
30 Days 
(± 3 Days) 
60 and 90 
Days 
( ± 7 Days) 
Every 3 
Months 
(± 1 Week) 
for 12 
Months 
12 Months 
Since Last 
Dose and Then 
Every  
6 Months  
(± 2 Weeks) 
Tumor and disease assessments 
Disease assessment (Q8W only 
until disease progression) a 
X b 
 
 
 
 
Study procedures and examinations 
Physical exam (including 
weight);full at EOT 
X 
X b 
X b 
 
 
ECOG performance status 
X 
 
 
 
 
ECG d 
X 
 
X e 
 
 
Vital signs (temperature, BP, 
pulse rate, and respiratory rate) 
X 
X 
X 
 
 
Concomitant medications  
X 
X 
X 
 
 
Assessment of AEs/SAEs 
X 
X 
X 
 
 

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Table 4.2.3-1 
Schedule of Study Procedures: End of Treatment and 
Posttreatment Laboratory Follow-Up Following Protocol 
Amendment 5 
Procedure 
End of 
Treatment 
Posttreatment 
Laboratory Follow-up 
After End of Treatment 
visit 
Long-term Follow-up 
30 Days 
(± 3 Days) 
60 and 90 
Days 
( ± 7 Days) 
Every 3 
Months 
(± 1 Week) 
for 12 
Months 
12 Months 
Since Last 
Dose and Then 
Every  
6 Months  
(± 2 Weeks) 
Labs and assays 
Hematology  
X 
X 
X 
 
 
Chemistry 
X 
X 
X 
 
 
TSH, free T4, free T3 
X 
X 
X 
 
 
Blood or urine pregnancy test 
(females of childbearing 
potential)  
X  
 
X e 
X f 
 
Pharmacokinetics 
Durvalumab PK (combination 
arm only) 
 
 
X e 
X g 
 
MEDI0680 PK (combination 
arm only) 
 
 
X e 
X g 
 
Other labs and assays 
Immunogenicity (combination 
arm only) 
 
 
X e 
X g 
 
Circulating soluble factors  
X h 
 
 
 
 
miRNA/mRNA analysis 
X i 
 
 
 
 
Tumor biopsy 
X j 
 
 
 
 
Subsequent anticancer therapy 
 
 
 
X 
X 
Survival follow-up phone 
contact every 3 months 
 
 
 
X 
X 

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Table 4.2.3-1 
Schedule of Study Procedures: End of Treatment and 
Posttreatment Laboratory Follow-Up Following Protocol 
Amendment 5 
Procedure 
End of 
Treatment 
Posttreatment 
Laboratory Follow-up 
After End of Treatment 
visit 
Long-term Follow-up 
30 Days 
(± 3 Days) 
60 and 90 
Days 
( ± 7 Days) 
Every 3 
Months 
(± 1 Week) 
for 12 
Months 
12 Months 
Since Last 
Dose and Then 
Every  
6 Months  
(± 2 Weeks) 
Survival follow-up phone 
contact with subjects who 
refuse to return for evaluations 
and agree to be contacted 
 
 
X 
X 
X 
AE = adverse event; BP = blood pressure; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; miRNA = micro ribonucleic acid; mRNA = messenger ribonucleic acid; PK = 
pharmacokinetic; Q8W = every 8 weeks; SAE = serious adverse event; T3 = thyroxine 3; T4 = thyroxine 4; 
TSH = thyroid stimulating hormone. 
a 
Subjects discontinued from treatment for a reason other than radiologic disease progression should continue 
to have disease assessments on a Q8W schedule until radiologic disease progression is observed. 
b 
Abbreviated symptom-directed physical examination. 
c 
End of treatment disease assessment will not need to be repeated if it was performed ≤ 4 weeks from EOT 
visit. 
d 
A single ECG will be obtained at the specified timepoints. Unless clinically indicated at which time it will 
be collected in triplicate (all within a 5 minute period, at least 1 minute apart). 
e 
Collected on 90-day visit only. 
f 
Collected on 120-day visit only. Note that subjects should not become pregnant up to 150 days after the 
subject’s last dose of nivolumab. 
g 
Collected on 180-day visit only. 
h 
Circulating soluble factors to be collected at time of progression only; delay collection until progression if 
subject discontinues due to AE or other reasons. 
i 
mRNA to be collected at end of treatment and at time of progression if subject discontinues due to AE or 
other reasons 
j 
Optional tumor biopsy upon confirmed progressive disease, providing it is clinically feasible. 
 
4.3 
Description of Study Procedures 
4.3.1 
Efficacy
 
4.3.1.1 
Solid Tumors 
See Appendix 5. 

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4.3.2 
Archival Tumor Samples, Bone Marrow Biopsies, and Tumor Biopsies 
4.3.2.1 
Archival Tumor Samples 
Archival tumor samples are required for all subjects (dose-escalation and dose-expansion 
phases) and must be deemed available during the screening period. FFPE tumor samples will 
be collected for IHC and additional correlative markers (eg, tumor mutation analysis, 
ribonucleic acid analysis, and immunodiversity). If a tumor block cannot be provided for this 
study, then only freshly cut sections should be provided as described in the Laboratory 
Manual. 
4.3.2.2 
Tumor Biopsies 
If the subjects are unable to verify availability of archival tumor samples, as mentioned in 
Section 4.3.2.1, then baseline fresh tumor biopsies will need to be obtained prior to 
administration of the first dose of study drugs for the dose-escalation phase or prior to 
randomization for the dose-expansion phase.  
Subjects in the dose-expansion phase are encouraged to provide on-treatment fresh tumor 
biopsies on Day 57 (could be performed up to 7 days prior to investigational treatment 
administration, but must not be performed after dosing of investigational treatment) if 
clinically feasible (ie, repeat biopsy does not pose unacceptable medical risk to a subject as 
determined by the investigator). In addition, biopsies may be performed if clinically 
indicated, at the time of progression and at the end of treatment. For subjects who require 
serial image-guided core needle tumor biopsy, it will be performed according to institutional 
practice. These post-treatment biopsies are optional. Tumor lesions used for biopsy should 
not be lesions used as RECIST target lesions. 
An evaluation of a possible correlation between clinical activity of durvalumab and 
MEDI0680 and potential biomarkers (eg, PD-L1 expression on tumor) will be ongoing 
throughout the study. For the dose-escalation phase, tumoral PD-L1 expression will be 
assessed on screening samples after enrollment on an ongoing basis. For the dose-expansion 
phase, tumor tissue (FFPE archival or fresh tumor tissue) must be received by the central 
vendor (block or unstained slides) and evaluable for PD-L1 expression status in order to 
randomize a subject to study treatment.  
Tumor lesions used for biopsy should not be lesions used as RECIST target lesions, unless 
there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy the 
lesion must be ≥ 2 cm in longest diameter. Additional tumor biopsies are permitted as 
clinically indicated (eg, for mixed responses or upon PD). If clinically practical, at each time 

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point, subjects will undergo 4 core biopsies at each protocol-specified time point for tumor 
biopsy, 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 (fourth biopsy, if available) will be immediately frozen in liquid nitrogen and then 
stored at -80°C. 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). 
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by 
MedImmune. Core biopsies may be used for biomarker and pharmacodynamic studies using 
methods such as IHC, IF, tumor mutation analysis, and gene expression analysis. Additional 
details for sample collection, processing, storage, and shipment will be provided in the 
Laboratory Manual. 
4.3.3 
Medical History and Physical Examination 
Physical examinations will be performed on study days noted in Section 4.2. A full physical 
examination will include assessments of the head, eyes, ears, nose, and throat, respiratory, 
cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, psychiatric, 
dermatological, hematologic/lymphatic, and endocrine systems; weight; and height (at 
screening only). A smoking questionnaire will be administered at screening (dose-escalation 
only). Abbreviated symptom-directed physical examinations will be conducted post-
screening, except for a full physical examination at the end of treatment and end of study. 
Vital signs (temperature, blood pressure, pulse rate, pulse oximetry [at screening only], and 
respiratory rate) will be measured on study days noted in Section 4.2. On Cycle 1 Day 1 in 
the durvalumab and MEDI0680 combination arm, vital signs will be measured within 
30 minutes prior to the start of durvalumab administration (± 30 minutes), 15 minutes 
(± 5 minutes) post-end of infusion (EOI) of durvalumab, and at 10 minutes (± 5 minutes) and 
60 minutes (± 5 minutes) post-EOI of MEDI0680. For all other combination dose days, vital 
signs will be measured 30 minutes (± 30 minutes) prior to durvalumab administration, 
15 minutes (± 5 minutes) post durvalumab EOI, and 10 minutes (± 5 minutes) and 
30 minutes (± 5 minutes) post MEDI0680 EOI. 
In the nivolumab arm, on Cycle 1 Day 1 vital signs will be measured within 30 minutes prior 
to the start of nivolumab (± 30 minutes), and at 10 minutes (± 5 minutes) and 60 minutes 
(± 5 minutes) post-EOI of nivolumab.  All other nivolumab dose days will measure vital 
signs 30 minutes (± 30 minutes) prior to infusion and 10 minutes (± 5 minutes) post EOI. 

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Electrocardiograms will be recorded on study days as noted in Section 4.2. 
Electrocardiograms recorded at screening will be obtained in triplicate (all 3 within a 
5-minute time period, at least 1 minute apart). On Cycle 1 Day 1 single ECGs will be 
obtained within 60 minutes prior to start of infusion of durvalumab or nivolumab, and within 
10 minutes post-EOI of MEDI0680, and within 10 minutes post-EOI of nivolumab. At all 
other timepoints, single ECGs will be obtained within 60 minutes prior to infusion of each 
investigational product or nivolumab and as clinically indicated. For abnormal ECGs or if 
clinically indicated ECGs are required, they should be obtained in triplicate (all 3 within a 
5-minute time period, at least 1 minute apart). In case of clinically significant ECG 
abnormalities, including an ECG that demonstrates a QTcF value > 500 milliseconds, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) and the 
average of all 3 ECGs should be used to confirm prolongation.  
Findings from medical history (obtained at screening) and physical examination shall be 
given a baseline grade according to the procedure for AEs. Increases in severity of 
pre-existing conditions during the study will be considered AEs, with resolution occurring 
when the grade returns to the pre-study grade or below. 
4.3.4 
Clinical Laboratory Tests 
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. If the subject has completed any safety 
laboratory tests within 72 hours before Day 1, they will not need to be repeated. 
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Clinically significant abnormal laboratory results should be repeated 
as soon as possible (preferably within 24 to 48 hours).  
The following clinical laboratory tests will be performed according to the schedules of 
procedures in Section 4.2: 
Serum Chemistry 
x 
Calcium 
x 
Gamma glutamyl transferase  
x 
Chloride 
x 
Lactic dehydrogenase 
x 
Magnesium 
x 
Creatinine 
x 
Potassium 
x 
Blood urea nitrogen 
x 
Sodium 
x 
Glucose 

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x 
Bicarbonate 
x 
Albumin 
x 
Aspartate transaminase (AST) 
x 
Total protein 
x 
Alanine transaminase (ALT) 
x 
Triglycerides 
x 
Alkaline phosphatase (ALP) 
x 
Cholesterol 
x 
Total bilirubin 
x 
Amylase 
x 
Direct Bilirubin 
 
x 
Thyroid stimulating hormone (TSH), free 
thyroxine 4 (T4), free thyroxine 3 (T3) 
 
x 
Lipase 
 
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently. 
 
Hematology 
x 
White blood cell count with differential (to include 
absolute neutrophil count) 
x 
Platelet count 
x 
Hemoglobin  
x 
Fibrinogen 
x 
Prothrombin time/partial thromboplastin time 
 
x 
Hematocrit 
 
 

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Urinalysis 
x 
Color 
x 
Glucose 
x 
Appearance 
x 
Ketones 
x 
Specific gravity 
x 
Blood 
x 
pH 
x 
Bilirubin 
x 
Protein 
 
 
Pregnancy Test (females of childbearing potential only) 
• Urine human chorionic gonadotropin (hCG) or serum beta-hCG 
 
Other Safety Tests 
• Hepatitis A IgM antibody, hepatitis B surface antigen, hepatitis C antibody 
• HIV-1 antibody 
 
4.3.5 
Pharmacokinetic Evaluation and Methods 
Measurement of durvalumab and MEDI0680 concentrations in serum will be performed 
using validated immunoassays.  
Details for collection, aliquoting, storage, and shipment of serum samples for PK evaluations 
are presented in a separate Laboratory Manual. 
Blood samples for measurement of durvalumab and MEDI0680 concentrations in 
serum will be collected in samples taken according to the schedules of procedures 
presented in Section 4.2. For subjects in the escalation phase who will switch from the 
60 mg/mL formulation to the 50 mg/mL formulation, predose and EOI (± 10 minutes) 
MEDI0680 PK samples will be collected for the first 2 doses of MEDI0680 using the new 
formulation. 
4.3.6 
Immunogenicity Evaluation and Methods 
Validated electrochemiluminescence assays using a Meso Scale Discovery platform will be 
used for the determination of anti-durvalumab antibodies in human serum and for 
determination of anti-MEDI0680 antibodies in human serum. 
Details for collection, aliquoting, storage, and shipment of serum samples for ADA 
evaluations are presented in a separate Laboratory Manual. 

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Blood samples for measurement of durvalumab and MEDI0680 ADA concentrations in 
serum will be collected in samples taken according to the schedules of procedures presented 
in Section 4.2. 
4.3.7 
Biomarker Evaluation and Methods 
Blood samples will be collected and analyzed to evaluate protein, nucleic acid and 
cellular biomarkers according to the schedules presented in Section 4.2. 
The numbers of T cells, B cells, and NK cells as well as subsets of T cells may be evaluated 
in whole blood by flow cytometry. Additional flow cytometric assessment of immune-cell 
phenotypes and function will be conducted; these may include evaluating phenotype, 
expression of activation markers, proliferation, and production of cytokines and effector 
molecules, by cell populations such as T cells, B cells, and myeloid-derived suppressor cells.  
Blood samples will be collected for analysis of circulating soluble factors in relation to T-cell 
activation. They may include but are not limited to soluble CTLA-4, soluble B7-1/B7-2, 
soluble IL-6R, vascular endothelial growth factor, fibroblast growth factor, IL-1 IL-2, IL-4, 
IL-6, IL-8, IL-10, granzyme B, IFN, C-X-C motif chemokine 10, suppressor of cytokine 
signaling 3, a proliferation inducing ligand, B-cell activating factor, insulin-like growth 
factor (IGF)-1, IGF-2, the presence of IFN-γ, tumor necrosis factor alpha (TNF-α), IL-2, 
IL-6, IL-10, IL-8, and IL-12 as well as antibodies against tumor, self, or viral antigens and 
autoantibodies to host and tumor antigens and explore their association with treatment and 
clinical outcome. Additionally, levels of circulating tumor DNA may be evaluated in 
response to treatment and relationship with clinical outcome.  
In the dose escalation phase, peripheral blood mononuclear cells will be isolated from whole 
blood, preserved, and stored for flow cytometry of additional cell types such as immune 
regulatory populations which may include myeloid-derived suppressor cells, subsequent 
functional analysis or assessment of the diversity of the immune cell repertoire, its 
relationship to clinical responses, and changes in response to treatment with durvalumab and 
MEDI0680. Peripheral blood mononuclear cells may also be used for gene expression 
analysis. 
Whole blood samples will be collected in PAXgene tubes and stored frozen at -80°C for 
miRNA and/or mRNA sample preparation. Ribonucleic acid may be used in the analyses of 
transcript and/or miRNA expression and stored for future analyses. Ribonucleic acid analyses 
may be conducted to generate hypotheses associated with the mechanisms of action of 

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durvalumab and MEDI0680 as well as to identify subsets of subjects responsive to the 
durvalumab plus MEDI0680 treatment combinations evaluated in this protocol. 
For dose-expansion randomization, all subjects’ tumor tissue will be tested for expression of 
PD-L1 through a central vendor, as determined by the Ventana (SP263) IHC assay. Subjects 
with advanced or metastatic ccRCC who are naïve to immunotherapy will be randomized 2:1 
into one of two arms with either MEDI0680 in combination with durvalumab or nivolumab 
monotherapy. Subjects will be stratified by MSKCC risk group (0 = favorable risk; 1 or 
2 = intermediate risk; 3 = poor risk; see Appendix 7), and PD-L1 expression status (≤ 1% and 
> 1%; Motzer, et al 2002). 
Tumor biomarkers, including but not limited to the expression level and localization of 
PD-L1 protein on tumor cells (by IHC analysis) and the T-cell number and phenotype in 
tumor tissues will be evaluated in archived and fresh tumor samples for any relationship with 
subject response to treatment.  
Archived material and/or fresh biopsies may be analyzed for the presence of key mutations 
which may include but are not limited to: EGFR, KRAS, NRAS, APC, B catenin, ALK, and 
C-MNNG HOS transforming gene to evaluate their potential relevance and correlations with 
response to the treatment combinations used in this protocol. Analysis of mRNA and/or 
miRNA in archived and/or fresh tumor tissue may be performed to identify a predictive or 
posttreatment signature of response. 
Other biomarkers may be evaluated as determined by additional data. Details for sample 
collection, processing, storage, and shipment will be provided in the Laboratory Manual. 
4.3.8 
Estimate of Volume of Blood to Be Collected 
Following Protocol Amendment 5, a total of approximately 29 mL will be required for all 
screening tests, which may be conducted over 1 to 28 days during screening. No more than 
35 mL of blood will be drawn on any visit day after screening. Approximately 35 mL of 
blood will be collected at all visits related to the first dose. The total volume to be collected 
will depend on the number of doses administered and the length of follow-up.  
4.4 
Study Suspension or Termination 
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
to the following:  

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1. Any events that, in the judgment of the medical monitor, are deemed serious enough to 
warrant immediate review by the data safety monitoring committee. This may include 
any symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, colitis, 
dermatitis, or hepatitis or any symptomatic treatment-related related Grade ≥ 3 
neurological toxicity or uveitis 
2. Subject enrollment is unsatisfactory 
3. Non-compliance that might significantly jeopardize the validity or integrity of the study  
4. Sponsor decision to terminate development 
5. Sponsor decision to terminate the study  
 
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action. 
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study. 
4.5 
Investigational Products 
4.5.1 
Identity of Investigational Products 
MedImmune will provide the investigators with MEDI0680 and durvalumab (Table 4.5.1-1) 
using designated distribution centers.  
Nivolumab will be obtained from commercial supply and is formulated, administered and 
labelled according to locally approved prescribing information and guidance. 

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Table 4.5.1-1 
Identification of Investigational Products  
Investigational Product 
Manufacturer 
Concentration and Formulation as Supplied 
Durvalumab 
MedImmune 
Supplied as a lyophilized powder containing 200 mg 
(nominal) durvalumab. When reconstituted with 4.0 mL 
of WFI, the solution contains:  
50 mg/mL durvalumab, 26 mM histidine/histidine-HCl, 
275 mM trehalose dihydrate, 0.02% (w/v) 
polysorbate 80, at  
pH 6.0. 
MEDI0680 
MedImmune 
Supplied as frozen liquid containing 250mg MEDI0680 
in 10 mL vial filled with nominal 5 mL at a 
concentration of 50mg/mL, containing 20 mM sodium 
phosphate monobasic/dibasic phosphate, 
230 mM sucrose, and 0.01% (w/v) polysorbate 80, 
pH 6.9  
IV Bag Protectant for MEDI0680  
MedImmune 
Supplied as 3cc vials filled with a nominal 1.0 mL 
containing 3.1 mM citric acid, 21.9 mM sodium citrate 
dihydrate, 0.65% (w/v) polysorbate 80, pH 6.0 
HCl = hydrochloride; IV = intravenous; WFI = water for injection; w/v = weight per volume;  
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially available 
water for injection (WFI) and 0.9% (weight per volume [w/v]) saline will be supplied by 
each site. Upon completion of the study, copies of investigational product accountability 
records will be returned to MedImmune. All unused investigational product will be returned 
to a MedImmune-authorized depot or disposed of upon authorization by MedImmune 
according to the investigational site policy. Investigational products should be kept in a 
secure area. 
4.5.1.1 
Durvalumab  
Durvalumab Dose Preparation 
Each vial selected for dose preparation should be inspected. 
Durvalumab is supplied as a vial containing 200 mg (nominal) durvalumab as a lyophilized 
powder. Durvalumab must be stored at 2°C to 8°C (36°F to 46°F) in a secure area with 
restricted access. When reconstituted with 4.0 mL of WFI, the solution contains 50 mg/mL 
durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, 
0.02% (w/v) polysorbate 80, at pH 6.0. Each carton contains 4 single-dose vials. White labels 
will be applied to cartons and vials containing durvalumab. 

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Investigational product will be supplied to the site in vials in coded kits. Each kit has a 
unique number that is printed on all labels within the kit (ie, the outer carton label and the 
label of each vial within the carton).  
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.5) for further instructions. 
Durvalumab Dose Calculation 
Dose-escalation Phase 
The dose will be calculated using the following formula: 
By weight:  Dose (mL) = [subject weight (kg) × durvalumab dose level (mg/kg)] 
 
 
 
 
 
 
 
 
 
 
 
 
50 mg/mL 
where 50 mg/mL is durvalumab concentration after reconstitution. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL 
(0.1 mL). Dose adjustments for each cycle are only needed for greater than 10% change in 
baseline weight. 
Dose-expansion Phase 
A fixed dose of 750 mg (ie, 15 mL) durvalumab will be administered for all subjects 
randomized into the MEDI0680/durvalumab combination arm.  
Durvalumab Dose Preparation Steps 
No incompatibilities between durvalumab and polyethylene, polypropylene, 
polyvinylchloride, or polyolefin copolymers have been observed. Durvalumab does not 
contain preservatives and any unused portion must be discarded. Preparation of durvalumab 
and preparation of the IV bag are to be performed aseptically. Total in-use storage time from 
needle puncture of durvalumab to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If storage time exceeds these limits, a 
new dose must be prepared from new vials. 
Durvalumab requires reconstitution prior to use. The reconstitution should be performed with 
4.0 mL sterile WFI for each vial with the liquid added gently to the side of the vial to 
minimize product foaming. Commercially available sterile WFI will be supplied by the sites. 

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The vial should be gently rotated or swirled until dissolution is complete. The vial should not 
be shaken or vigorously agitated. Reconstituted durvalumab 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. 
Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline and 
delivered through an IV administration set with a 0.22 or 0.2-μm in-line filter. To prepare the 
durvalumab saline IV admixture, a volume of 0.9% (w/v) saline equal to the calculated 
volume of durvalumab to be added to the IV bag must be removed from the IV bag prior to 
addition of durvalumab. The calculated volume of durvalumab is then added to the IV bag, 
and the bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag. 
Following preparation of the dose, the entire contents of the IV bag should be administered 
as an IV infusion for approximately 1 hour. Flush the IV line with a volume of normal saline 
equal to the priming volume of the infusion set used after the contents of the IV bag are fully 
administered, or complete the infusion according to institutional policy to ensure the full dose 
is administered and document if the line was not flushed. Durvalumab infusion must be 
completed before MEDI0680 is dosed for subjects assigned to receive both products. 
MEDI0680 infusion will start approximately 30 minutes after the end of durvalumab 
infusion. 
Durvalumab solution should not be infused through an IV line in which other solutions or 
medications are being administered. The date, start time, interruption, and completion time of 
durvalumab administration must be recorded in the source documents. 
Durvalumab Administration Guidelines 
Each dose of durvalumab should be administered using the following guidelines: 
1. Investigational product must be administered at room temperature by controlled infusion 
via an infusion pump into a peripheral vein. 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. 
2. A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. Investigational product must not be 
administered via IV push or bolus but as a slow IV infusion. The entire content of each 
IV bag will be infused using an infusion pump. 
3. The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration will need to be equipped with 0.22- or 0.2μm in-line filters. 

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4. Some investigational product may remain in the IV line after the infusion is complete. 
15 to 30 mL of 0.9% sodium chloride IV solution should be added to the infusion bag 
after the investigational product has been administered to flush the line (infusion rate 
should not be changed) or complete the infusion according to institutional policy to 
ensure the full dose is administered and document if the line was not flushed.. 
The duration of the investigational product administration will be recorded. 
4.5.1.2 
MEDI0680 
Each vial selected for dose preparation should be carefully inspected. MEDI0680 is supplied 
as a sterile frozen liquid dosage form filled in a glass vial configuration. The product will be 
supplied to sites in separate multi-subject cartons and must be stored at -15°C to -50°C until 
ready to use.  
MEDI0680 Drug Product is filled in a 10 mL vial with 20 mm opening US Pharmacopeia 
(USP) Type I Clear Borosilicate glass vial. The 20 mm serum stopper is Teflon coated. The 
20 mm aluminum seal has a matte white flip off style top. The label is white. 
The IV Bag Protectant (IVBP) is filled in a 3 mL USP Type I Clear Borosilicate glass vial. 
The 13 mm serum stopper is Teflon coated. The 13 mm aluminum seal has a matte blue flip 
off style top. Investigational product will be supplied to the site in vials in coded kits. Each 
kit has a unique number that is printed on all labels within the kit (ie, the outer carton label 
and the label of each vial within the carton). 
Each carton contains 12 single-dose vials. White labels will be applied to cartons and vials 
containing MEDI0680. No other coding will be included. 
Each vial selected for dose preparation should be inspected after thawing. If there are any 
defects noted with the investigational product, the investigator and site monitor should be 
notified immediately. Refer to the Product Complaint section (Section 4.5.1.5) for further 
instructions.  
Preparation of MEDI0680 and preparation of the infusion bag are to be performed using 
aseptic technique. MEDI0680 does not contain preservative and hence any unused portion 
must be discarded. Total in-use storage time from needle puncture of the first vial of 
MEDI0680 for investigational product preparation to start of administration should not 
exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If storage time 
exceeds these limits, a new dose must be prepared from new vials and the study monitor 
must be notified immediately. 

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MEDI0680 Dose Preparation 
Thawing techniques include 3 options: 
• Option 1 (preferable) – Remove from carton the vial(s) required for the subject’s dose 
and place in a secure refrigerator approximately 3 to 4 hours prior to use. This technique 
allows MEDI0680 to thaw slowly while still being refrigerated. 
• Option 2 – Remove from carton the vial(s) required for the subject’s dose and place on a 
countertop in a secure location and thaw at room temperature. This technique will 
take approximately 1 to 1.5 hours to thaw MEDI0680. 
• Option 3 – Remove from carton the vial(s) required for the subject’s dose and place on 
the counter within a laminar flow hood and thaw via circulating airflow. This technique 
will take approximately 30 minutes to 1 hour to thaw MEDI0680. 
 
IMPORTANT: Do not remove vial cap until fully thawed and removed from the 
laminar flow hood. 
Mixing - Ensure that the contents of the vial are completely thawed before drawing the 
subject’s dose. Gently swirl the solution to completely mix the contents. Do not shake the 
vial. Do not foam the vial contents. 
Infusion of MEDI0680 should begin within 4 hours of completion of thaw. 
MEDI0680 Preparation of Intravenous Dose 
The IVBP is required for intravenous dose preparation of MEDI0680.  
For the 20 mg/kg dose level, the dose will be prepared directly using the investigational 
product. Calculate MEDI0680 dose using the following formula: 
ͳǣ
ܦ݋ݏ݁ሺ݉ܮሻൌ
ܵݑܾ݆݁ܿݐݓ݄݁݅݃ݐሺ݇݃ሻכ ݀݋ݏ݁݈݁ݒ݈݁ሺ݉݃
݇݃ሻ
ܿ݋݊ܿ݁݊ݐݎܽݐ݅݋݊݋݂݅݊ݒ݁ݏݐ݅݃ܽݐ݅݋݈݊ܽ݌ݎ݋݀ݑܿݐሺ݉݃
݉ܮሻ
 
 
Example of dose calculation with 50mg/mL Investigational Product, assuming a body 
weight of 40kg and dose level of 20 mg/kg. 
 
ܦ݋ݏ݁ሺ݉ܮሻൌ
ͶͲሺ݇݃ሻכ ʹͲሺ݉݃
݇݃ሻ
ͷͲሺ݉݃
݉ܮሻ
 

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
ൌͳ͸ǤͲ݉ܮ݋݂ͷͲ ݉݃
݉ܮܫ݊ݒ݁ݏݐ݅݃ܽݐ݅݋݈݊ܽܲݎ݋݀ݑܿݐ 
 
Example calculation for number of vials needed for this dose 
͓݋݂ܸ݈݅ܽݏሺݎ݋ݑ݊݀݁݀ݑ݌ݐ݋ݐ݄݁݊݁ܽݎ݁ݏݐݓ݄݋݈݁ݒ݈݅ܽሻൌܥ݈ܽܿݑ݈ܽݐ݁݀݀݋ݏ݁ݒ݋݈ݑ݉݁ሺ݉ܮሻ
݊݋݈݉݅݊ܽ݂݈݈݅ݒ݋݈ݑ݉݁ሺ݉ܮሻ
 
 
ܧݔܽ݉݌݈݁ǣ ͓݋݂ܸ݈݅ܽݏൌͳ͸ǤͲሺ݉ܮሻ
ͷǤͲሺ݉ܮሻൌሺ͵ǤʹሻͶݒ݈݅ܽݏ 
MEDI0680 Dose Preparation Steps 
The dose of MEDI0680 for administration must be prepared by the investigational product 
manager or other qualified professional using aseptic technique. Only remove the required 
MEDI0680 and the IVBP vials required for subject dosing from storage. 
No incompatibility between MEDI0680 and plastics (polyolefin, polyethylene and polyvinyl 
chloride) has been observed when used along with IVBP. IV bags must be free of latex and 
di(2-ethylhexyl) phthalate (DEHP). Polypropylene and polycarbonate syringes should be 
used for dose preparation. Infusion line should contain a 0.22 or 0.2 μm in-line filter. 
Follow the guidelines of the IV bag manufacturer for maximum number of allowable 
punctures through the injection port; if needed, use an intermittent adaptor on the injection 
port for dose preparation. 
For all dose levels, IVBP must be used to precondition the IV bag prior to addition of 
MEDI0680 (specific instructions below). 
Preparation of 20 mg/kg dose for IV infusion: 
• Add the calculated volume of 0.9% saline (described below) in an empty IV bag to 
achieve 60 mL dose delivery volume using following equation: 
◦ 
Equation 2: Volume of 0.9% saline required to add in IV bag = 60 mL – 
(Investigational Product + 1 mL IVBP)  
• To this bag, add 1 mL of IVBP, gently mix the bag, and then add the calculated volume 
of Investigational Product as described below (Table 4.5.1.2-1).  
 

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Table 4.5.1.2-1 
Preparation of 20 mg/kg dose for IV infusion 
Dose level 
(mg/kg) 
Investigational Product to 
be added(mL) 
A 
IVBP to be added 
to IV bag (mL) 
B 
0.9% Saline 
added (mL) 
C 
Total Delivery Volume 
(mL) 
A + B + C 
20 
Add as per Equation 1 
1.0 
Add as per 
Equation 2 
60 
IV = intravenous; IVBP = intravenous bag protectant. 
 
Dose preparation steps common for all dose levels are as follows: 
1. Select the IXRS-assigned number of vials of investigational product required to prepare 
the subject’s dose. 
2. After thawing, all investigational product vials should be equilibrated to room 
temperature for 30 minutes prior to dose preparation. 
3. To prepare investigational product, the investigational product manager should remove 
the tab portion of the vial cap and clean the rubber stopper with 70% ethanol or 
equivalent and allow to air dry. To avoid foaming, the vial should not be shaken. 
4. For ease of preparation, a 1.5-inch 19-gauge withdrawal needle is recommended. Use a 
new needle for withdrawing investigational product from each vial.  
5. Gently mix the contents of the infusion bag. The resulting mixture should be inspected to 
ensure that the solution is clear. 
 
MEDI0680 Administration Guidelines 
The day of dosing with investigational product is considered Day 1. 
Each dose of MEDI0680 should be administered using the following guidelines: 
1. Investigational product must be administered at room temperature by controlled infusion 
via an infusion pump into a peripheral vein. 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. 
2. A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. Investigational product must not be 
administered via IV push or bolus but as a slow IV infusion as per Table 4.5.1.2-2. The 
entire content of each IV bag will be infused using an infusion pump. 
3. The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration will need to be equipped with 0.22- or 0.2-μm in-line filters. 
4. Some investigational product may remain in the IV line after the infusion is completed. 
15 to 30 mL of 0.9% sodium chloride IV solution should be added to the infusion bag 
after the investigational product has been administered to flush the line (infusion rate 

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should not be changed) or complete the infusion according to institutional policy to 
ensure the full dose is administered and document if the line was not flushed. 
 
The duration of the investigational product administration will be recorded. 
Table 4.5.1.2-2 
Investigational Product Solution Volume by Treatment 
Group 
Dose level (mg/kg) 
Total Investigational Product Solution Volume Per Bag (mL) 
20 
60 
 
MEDI0680 will be administered by IV infusion over a minimum of 30 minutes at dose levels 
of 0.1, 0.5, and 2.5 mg/kg, over a minimum of 60 minutes at dose levels of > 2.5 mg/kg up to 
a total dose of 1200 mg, and over a minimum of 90 minutes at total doses > 1200 mg.  
During preparation of the investigational product infusion, the capacity of the tubing should 
be calculated in order to adjust the volume of investigational product solution needed to 
prime the IV tubing (see example below). This step is necessary because the same volume of 
saline will be needed at completion of the infusion to flush the IV tubing in order to deliver 
the complete volume of investigational product solution. Because the IV tubing contains 
investigational product solution, the flush must be infused using the same infusion rate as 
that used for the investigational product solution in the infusion bag. 
Example: 
If the IV tubing capacity is 15 mL, the IV tubing should be primed with 15 mL of 
investigational product solution from the investigational product infusion bag before 
initiating the investigational product infusion. Once the investigational product infusion bag 
is empty, the IV tubing should be flushed with at least 15 mL of 0.9% normal saline via 
infusion pump at the same rate as dosing. 
The start time of the investigational product infusion will be the time the infusion of the 
investigational product solution from the infusion bag (with IV tubing already primed with 
investigational product solution) is started. The stop time of the infusion should be the time 
the IV tubing has been flushed to administer the residual investigational product solution. 
4.5.1.3 
Nivolumab 
For information on nivolumab, refer to the local (country-specific) package insert (or 
similar). 

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4.5.1.4 
Monitoring of Dose Administration 
Subjects will be monitored during and after infusion of durvalumab, MEDI0680, or 
nivolumab (see Section 4.3.3).  
In the event of Grade ≤ 2 infusion-related reaction, the infusion rate of durvalumab or 
MEDI0680 may be decreased by 50% or temporarily interrupted until resolution of the event 
(up to 4 hours) and re-initiated at 50% of the initial rate until completion of the infusion.  
Refer to the local (country-specific) package insert (or similar) for guidance on dose 
administration and modification for subjects in the nivolumab arm. 
Primary prophylaxis against infusion-related reactions is not permitted during this study in 
order to avoid obscuring potential safety signal and enable a future assessment regarding 
whether pre-medications should be required for all subjects in future studies. However, at the 
discretion of the investigator, secondary prophylaxis (ie, prevention of infusion-related 
reaction following initial episode) is appropriate and will be permitted. Acetaminophen 
and/or an antihistamine (eg, diphenhydramine) or equivalent medications may be 
administered per institutional standard as secondary at the discretion of the investigator. If 
the infusion-related reaction is Grade 3 or higher in severity, treatment with durvalumab and 
MEDI0680 will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
4.5.1.5 
Reporting Product Complaints 
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed. 

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MedImmune contact information for reporting product complaints: 
Email: 
 
 
Phone: 
 
 
 
 
 
 
Fax: 
 
 
Mail: MedImmune, LLC 
 
 
Attn: Product Complaint Department 
 
 
One MedImmune Way 
 
 
Gaithersburg, MD 20878 USA 
 
4.5.2 
Additional Study Medications 
No other study medications are specified for use in this clinical protocol. 
4.5.3 
Labeling
 
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required. 
4.5.4 
Storage
 
Store durvalumab at 2°C to 8°C (36°F to 46°F). Do not freeze. 
Store MEDI0680 at -15°C to -50°C (5°F to -58°F) and store IVBP at 2°C to 8°C (36°F to 
46°F). Do not freeze the IVBP.  
For storage of nivolumab, refer to the local (country-specific) package insert (or similar). 
4.5.5 
Treatment Compliance 
Investigational product is administered by qualified study site personnel, who will monitor 
compliance. 

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4.5.6 
Accountability 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a 
MedImmune-authorized depot or disposed of upon authorization by MedImmune. 
4.6 
Treatment Assignment and Blinding 
4.6.1 
Methods for Assigning Treatment Groups 
During the dose-escalation phase, each subject who meets the eligibility criteria will be 
assigned open-label investigational product(s). A subject is considered entered into the study 
when the investigator notifies the IXRS that the subject meets eligibility criteria and is 
enrolled into the study. 
During the dose-expansion phase, subjects will be randomized 2:1 to 1 of 2 arms to either 
receive MEDI0680 in combination with durvalumab, or nivolumab monotherapy. Subjects 
are considered randomized into the study when the site confirms eligibility and enters the 
subject into the IXRS and are assigned unblinded investigational product(s). Subjects will be 
stratified by MSKCC risk group (0 = favorable risk; 1 or 2 = intermediate risk; 3 = poor risk; 
see Appendix 7), and PD-L1 expression status (≤ 1% and > 1%; Motzer, et al 2002). 
At that time the IXRS will provide the assignment of unblinded investigational product kit 
numbers to the subject. 
The investigational products must be administered or dispensed within 2 days after 
randomization.  If there is a delay in the administration of investigational product such that it 
will not be administered within the specified timeframe, the study monitor must be notified 
immediately. 
4.6.2 
Methods for Ensuring Blinding 
This study is not blinded. 
4.7 
Restrictions During the Study and Concomitant Treatment(s) 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until 90 days after the last dose of durvalumab, MEDI0680 or nivolumab. 

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Any concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the electronic case report form (eCRF). 
4.7.1 
Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate supportive care except for those 
medications identified as “excluded” as listed in Section 4.7.2. Specifically, subjects should 
receive full supportive care during the study, including transfusions of blood and blood 
products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, and 
other care as deemed appropriate, and in accordance with their institutional guidelines. 
4.7.2 
Prohibited Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study. The sponsor must 
be notified if a subject receives any of these during the study. 
1. Any investigational anticancer therapy 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable 
3. Any growth factor support except during hospitalization for neutropenic fevers 
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period of 
steroids could be allowed for different indications (eg, chronic obstructive pulmonary 
disease, radiation, nausea, etc) after discussion with the sponsor.  
5. Live attenuated vaccines during the study and 30 days after the last dose  
6. Herbal and natural remedies should be avoided 
 
4.8 
Statistical Evaluation 
4.8.1 
General Considerations 
Tabular summaries will be presented by cohorts. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. All analyses will be based on the As-treated Population, 

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which includes all subjects who receive any dose of investigational product analyzed 
according to the treatment they actually receive. Additional details of statistical analyses will 
be described in the statistical analysis plan. 
4.8.2 
Sample Size and Power Calculations 
A total of approximately 96 subjects could be required for both the dose-escalation and 
dose-expansion phases. For dose-escalation, the number of subjects will depend upon the 
toxicities observed as the study progresses. Up to approximately 36 evaluable subjects could 
be required by the 3 + 3 design with 6 dose cohorts in the main dose-escalation design. 
Additional subjects could be required if dose de-escalation occurs, intermediate dosing using 
the modified zone-based design is explored, the dosing interval of MEDI0680 is changed, or 
expansion of a dose-escalation cohort occurs. Subjects in the dose-escalation phase are 
considered evaluable if they receive the protocol-assigned doses of both durvalumab and 
MEDI0680, and complete the DLT-evaluation period or experience a DLT during the 
DLT-evaluation period. Non-evaluable subjects will be replaced. The table below provides 
the probability of dose-escalation to the next higher level for each underlying true DLT rate. 
For example, for a common toxicity that occurs in 10% of subjects, there is a greater than 
90% probability of escalating to the next higher dose level. Conversely, for a toxicity that 
occurs with a rate of 60%, the probability of escalating to the next higher dose level is less 
than 10%. 
Table 4.8.2-1 
Probability of Escalating Dose for Different True 
Underlying Dose-limiting Toxicity Rate at Given Dose 
Level 
True 
Underlying 
DLT Rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
escalating dose 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.009 
0.001 
DLT = dose-limiting toxicity. 
 
For the dose-expansion phase, up to approximately 60 subjects (40 subjects in the 
MEDI0680/durvalumab combination therapy arm and 20 subjects in the nivolumab 
monotherapy arm) may be randomized at the selected combination dose (ie, MTD or highest 
protocol-defined dose for each agent in the absence of exceeding the MTD) in a 2:1 ratio. 
The primary objective is to evaluate the antitumor activity as based on ORR of MEDI0680 in 
combination with durvalumab versus nivolumab monotherapy in immunotherapy-naïve 
subjects with advanced or metastatic ccRCC based on an application of RECIST v1.1 
(Eisenhauer et al, 2009) to investigator-assessed tumor measurements. Assuming an ORR for 

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nivolumab monotherapy of 21.5%, the sample size is chosen to detect a difference in ORR of 
26.0% (ie, ORR = 47.5%) with 76% power at a 1-sided significance level of 0.10. The 95% 
CI of a 47.5% ORR (19 responders / 40 subjects) based on the exact probability method is 
31.5%, 63.9%. The assumption of a nivolumab monotherapy ORR of 21.5% is based on the 
data from the nivolumab package insert (see Section 1.5). 
4.8.3 
Safety Analyses 
4.8.3.1 
Maximum Tolerated Dose Evaluation (Every 2-week Dosing Schedule) 
The MTD evaluation will be based on the DLT-evaluable Population which includes all 
subjects enrolled in the dose-escalation phase who receive 2 protocol-assigned doses of 
durvalumab and MEDI0680 and complete the safety follow-up through the end of the 
DLT-evaluation period, or experience a DLT during the DLT-evaluation period.  
4.8.3.2 
Analyses of Safety Endpoints 
The safety evaluation will be based on the As-treated Population and will include AEs, 
SAEs, laboratory evaluations, vital signs, and physical examinations. Summary statistics will 
be provided for AEs, SAEs, and AE grade, and relationship to investigational product, 
reported from start of treatment with durvalumab and MEDI0680 or nivolumab alone. 
Adverse events will be graded according to the NCI CTCAE v4.03 and described by system 
organ class using the Medical Dictionary for Regulatory Activities preferred term. 
Laboratory abnormalities with toxicity grades according to the NCI CTCAE v4.03 will be 
derived and summarized. Safety analyses will be descriptive in nature and no formal 
statistical comparison will be made. 
4.8.4 
Efficacy Analyses 
4.8.4.1 
Analysis of Efficacy Endpoints 
For the dose-escalation phase, efficacy analyses will be based on an application of modified 
RECIST v1.1 to investigator-assessed tumor measurements. RECIST v1.1 has been modified 
to require confirmation of PD. A confirmed PD will be a PD confirmed by a consecutive 
repeat assessment no fewer than 4 weeks later. A PD that occurs without follow-up scans to 
provide confirmation or only non-evaluable follow-up scans will also be considered a 
confirmed PD. The efficacy analysis will be based on the As-treated Population. 
For the dose-expansion phase, efficacy analyses will be based on an application of RECIST 
v1.1 to investigator-assessed tumor measurements and blinded independent central review 
(BICR). The efficacy analysis will be based on the As-treated Population.  

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The following efficacy endpoints will be analyzed. More details will be provided in the 
statistical analysis plan. 
ORR (primary endpoint) is defined as the proportion of subjects with a Best Overall 
Response (BOR) of confirmed CR or confirmed PR. ORR will be estimated with a 95% CI 
using the exact probability method. For the dose-expansion phase, comparison of arms will 
be obtained from Fisher’s exact test. 
DCR at 16 weeks (DCR16) is defined as the proportion of subjects with a BOR of confirmed 
CR, confirmed PR, or SD (maintained for ≥ 16 weeks). A similar definition applies to 
DCR24. DCR16 and DCR24 will be estimated with a 95% CI using the exact probability 
method.  
Time to response (TTR) is defined as the time from the first dose of treatment until the first 
documentation of a subsequently confirmed OR. Only subjects who have achieved OR will 
be evaluated for TTR. The median TTR and its 95% CI will be assessed using the Kaplan-
Meier method. 
Duration of response (DR) is defined as the time from the first documentation of a 
subsequently confirmed OR until the first documentation of a disease progression 
(subsequently confirmed for dose escalation phase) or death due to any cause, whichever 
occurs first. Only subjects who have achieved OR will be evaluated for DR. The median DR 
and its 95% CI will be estimated using the Kaplan-Meier method. 
Progression-free survival (PFS) is defined as the time from the first dose of treatment until 
the first documentation of a disease progression (subsequently confirmed for dose escalation 
phase) or death due to any cause, whichever occurs first. The median PFS and its 95% CI 
will be estimated using the Kaplan-Meier method. The Kaplan-Meier method will be used to 
estimate the PFS curve and the PFS rate at time points of interest.  
Overall survival (OS) is defined as the time from the first dose of treatment with durvalumab 
and MEDI0680 or nivolumab until death due to any cause. The median OS and its 95% CI 
will be estimated using the Kaplan-Meier method. The Kaplan-Meier method will be used to 
estimate the OS curve and the OS rate at time points of interest. 
4.8.5 
Pharmacodynamic Analyses 
Exploratory pharmacodynamic analyses may include but are not limited to: 

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1. Dose escalation only: Serum sPD-L1 levels will be measured to evaluate their association 
with drug exposure, and response to treatment with durvalumab and MEDI0680 or 
MEDI0680 alone 
2. Dose escalation only: Levels of PD-1 expression and MEDI0680 receptor occupancy on 
peripheral blood T cells before and after treatment may be measured to evaluate 
associations with drug exposure, response to treatment with durvalumab and MEDI0680 
3. Flow cytometric assessment of cell populations such as T cells, B cells, and 
myeloid-derived suppressor cell (MDSC) will be performed before and after treatment to 
evaluate its association with drug exposure and response to treatment with durvalumab 
and MEDI0680; analysis may include characterization of phenotype, expression of 
activation markers, proliferation, and production of cytokines and effector molecules  
4. Levels of circulating soluble factors, which may include cytokines, chemokines, growth 
factors, soluble receptors, and antibodies against tumor and self-antigens, will be 
evaluated before and after treatment may be examined in relation to treatment with 
durvalumab and MEDI0680 compared with nivolumab monotherapy 
5. Expression and localization of key molecules such as PD-L1, PD-L2, and PD-1 within 
the tumor microenvironment, as well as the frequency, localization, and phenotype of 
tumor-infiltrating lymphocytes, may be examined in biopsy specimens by IHC, IF, and/or 
flow cytometry and correlated with response to treatment  
6. Expression of miRNA/mRNA in blood and/or tumor samples may be performed before 
and after treatment to examine gene expression patterns at baseline and changes in 
response to treatment and to try to identify a gene signature predictive of response to 
treatment 
7. Genetic profiling of pre-treatment and posttreatment biopsy specimens may be performed 
to identify potential genetic predictors of response or resistance. This may include 
evaluation of key oncogenic mutations, and/or mutations in immune-related molecules. 
 
4.8.6 
Analyses of Immunogenicity and Pharmacokinetics 
4.8.6.1 
Immunogenicity 
Only subjects who receive at least one dose of both durvalumab and MEDI0680 (if 
assigned), and provide at least one posttreatment sample will be evaluated. Immunogenicity 
results will be analyzed descriptively by summarizing the number and percentage of subjects 
who develop detectable anti-durvalumab or anti-MEDI0680 antibodies. The immunogenicity 
titer will be reported for samples confirmed positive for the presence of anti-durvalumab or 
anti-MEDI0680 antibodies. The impact of ADAs on PK and pharmacodynamics will also be 
assessed if data allow. Samples will be collected and banked for evaluating neutralizing 
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4.8.6.2 
Pharmacokinetics 
Only subjects who receive at least one dose of durvalumab and MEDI0680 (if assigned) and 
provide at least one posttreatment sample will be evaluated. Individual durvalumab and 
MEDI0680 concentrations will be tabulated by dose cohort along with descriptive statistics. 
The PK of durvalumab and MEDI0680 will be assessed using parameters including Cmax and 
minimum concentration (Cmin) after the first dose. Durvalumab and MEDI0680 steady-state 
PK parameters including concentrations at peak concentration at steady state (Cmax,ss) and 
trough concentration at steady state (Cmin,ss) will be estimated. Accumulation to steady state 
will be assessed as the ratio of Cmax,ss:Cmax and Cmin,ss:Cmin. All PK parameters will be 
estimated by non-compartmental analysis. Descriptive statistics of non-compartmental PK 
parameters will be provided. 
4.8.7 
Exploratory Analyses 
Descriptive statistics will be the primary methods for the exploratory analyses. Depending on 
the nature of the data, geometric mean and other appropriate statistical summaries might be 
used as well. 
4.8.7.1 
Immune-related Response Criteria 
In order to more fully assess the efficacy of these immunotherapies, efficacy analyses will 
also be based on an application of immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST) (modified from Nishino et al, 2013) to investigator-assessed tumor 
measurements. Endpoints to be summarized include: BOR, OR, DC, TTR, DR, and 
PFS.Tumor response by irRECIST will be compared with that by RECIST v1.1. The 
irRECIST is similar to RECIST v1.1 (Appendix 5) except for the following: 
• The measurements of the new lesions are included in the sum of the measurements of all 
target lesions and do not automatically constitute PD under irRECIST, whereas new 
lesions are not measured and automatically constitute PD under RECIST v1.1. 
 
4.8.8 
Interim Analyses 
An interim futility analyses will be performed for the MEDI0680/durvalumab combination 
therapy arm in the dose-expansion phase after 20 subjects have been randomized and have 
reached their second post-baseline disease assessment or have completed study. Subject 
accrual may be paused in both cohorts to evaluate the MEDI0680/durvalumab combination 
therapy arm for futility. However, an accrual pause may not be necessary if existing data upon 
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predefined futility stopping criteria. The purpose of the interim futility analysis will be for 
evaluation of key efficacy data for internal program decision as to whether to continue 
randomization of subjects. Continued randomization of subjects in both arms will be 
terminated if 2 (10%) or fewer responses within the MEDI0680/durvalumab combination 
arm are observed. For the futility analysis, a response is defined as either a confirmed or 
unconfirmed CR or PR as per RECIST v1.1. 
Futility stopping criteria is defined as having a non-small probability (10%) to be greater than 
or equal to a target response rate of 25.1%.  If the true response rate is ≥ 25.1% there is a 
9.0% probability that the study will be stopped early erroneously (false negative). The target 
response rate was set so as to demonstrate an ORR at least as large as that of nivolumab 
based on investigator assessments, in a similar RCC population (ORR = 25.1 [95% 
CI: 21.0%, 29.6%]; Motzer et al, 2015). 
 
5 
ASSESSMENT OF SAFETY 
5.1 
Definition of Adverse Events 
The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 
 
Any untoward medical occurrence in a patient or clinical investigation subject 
 
administered a pharmaceutical product and which does not necessarily have a causal 
 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
 
associated with the use of a medicinal product, whether or not considered related to the 
 
medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. The term disease progression should not be reported as an AE or 
SAE, however, medically significant individual events and/or laboratory abnormalities 
associated with disease progression (see definition of disease progression below) that fulfill 
the AE or SAE definition should be reported. An abnormal laboratory finding (including 
ECG finding) that requires medical intervention by the investigator, or a finding judged by 
the investigator as medically significant should be reported as an AE. If clinical sequelae are 
associated with a laboratory abnormality, the diagnosis or medical condition should be 
reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, 

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urine red blood cells increased). Abnormal laboratory values that are not, in the investigator’s 
opinion, medically significant and do not require intervention should not be reported as AEs. 
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product.  
Elective or preplanned treatment or surgery (that was scheduled prior to the subject being 
enrolled into the study) for a documented pre-existing condition that did not worsen from 
baseline is not considered an AE (serious or nonserious). An untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should 
be recorded as an AE or SAE. 
Adverse Events Associated with Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. Death clearly resulting from disease 
progression should not be reported as an SAE (see reporting guidelines in Section 5.4.3). 
New Cancers 
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should not be reported as a new cancer. 
5.2 
Definition of Serious Adverse Events 
An SAE is any AE that: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect in offspring of the subject 

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• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse. 
5.3 
Definition of Adverse Events of Special Interest 
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 
5.3.1 
Immune-mediated Adverse Events 
Adverse events of special interest for durvalumab or MEDI0680 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 also being closely monitored in 
clinical studies with durvalumab monotherapy and combination therapy. An imAE is defined 
as an AE that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the imAE.  
If the investigator has any questions in regards to an AE being an imAE, the investigator 
should promptly contact the study physician. 
Potential imAEs include the following: 
• Colitis, enterocolitis, and other corresponding gastrointestinal disorders  
• Pneumonitis 
• Hepatitis and hepatotoxicity, including ALT/AST increases 

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• Neuropathy and neuromuscular toxicity (ie, events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (ie, events of hypophysitis, hypopituitarism (including diabetes 
insipidus), adrenal insufficiency, hyper- and hypothyroidism, type 1 diabetes mellitus) 
• Rash including dermatitis 
• Nephritis and increased creatinine 
• Pancreatitis (or laboratory tests suggestive of pancreatitis - increased serum lipase , 
increased serum amylase) 
 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and MEDI0680 Investigator’s Brochures. More specific 
guidelines for evaluation and treatment of these risks are described in detail in Appendix 6. 
5.3.2 
Hepatic Function Abnormality (Hy’s Law) 
Hepatic function abnormality meeting the definition of Hy’s law (ie, any increase in ALT or 
AST to greater than 3 × ULN and concurrent increase in total bilirubin to be greater than 
2 × ULN) is considered an AESI. Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other. Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to determine 
whether the findings are reproducible and/or whether there is objective evidence that clearly 
supports causation by a disease (eg, cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the investigational product. See Appendix 6 for the 
definition and reporting of AESIs of hepatic function abnormality 
5.3.3 
Infusion Reactions 
Adverse events of infusion reactions (also termed infusion-related reactions) are of special 
interest to the sponsor and are defined, for the purpose of this protocol, as all AEs occurring 
from the start of the study treatment infusion up to 48 hours after the infusion start time. 
Guidelines for management of subjects with infusion-related reactions are outlined in 
Appendix 6. For all infusion reactions, the eCRF should be completed as instructed in 
Section 5.4, and all SAEs should be reported to MedImmune Patient Safety as described in 
Section 5.5. 
5.3.4 
Hypersensitivity (Including Anaphylaxis) Reactions  
Hypersensitivity reactions (including anaphylaxis) been reported with anti-PD-L1 and 
anti-PD-1 therapy (Brahmer et al, 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of mAbs can be caused by 

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various mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and 
anaphylactoid reactions against the mAb, and serum sickness, etc. 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. 
5.4 
Recording of Adverse Events 
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to MedImmune 
Patient Safety. See Section 5.2 for the definition of SAEs and Appendix 2 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form. 
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic monoclonal antibodies delivered 
through IV infusion. These reactions are less common following subsequent exposures. 
Unlike infusion related reactions, anaphylaxis is a rare event, usually occurring after 
subsequent exposure to an antigen, and it is most commonly accompanied by severe systemic 
skin and or mucosal reactions. The investigator is advised to carefully examine symptoms of 
adverse reactions observed during or shortly after exposure to MEDI0680 and durvalumab or 
nivolumab, and consider the above mentioned facts prior to making a final diagnosis. 
Reactions occurring at the time of or shortly after subsequent infusions of investigational 
product are to be judged by the investigator at his/her own discretion. For the investigator’s 
convenience and in order to facilitate consistency in judgments a copy of the National 
Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network (FAAN) guidance for anaphylaxis diagnosis is provided in Appendix 3. 
5.4.1 
Time Period for Collection of Adverse Events 
Adverse events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period of 90 days after the last dose of 
durvalumab and MEDI0680 or nivolumab. Serious adverse events will be recorded from the 

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time of informed consent signature through 90 days after the last dose of durvalumab and 
MEDI0680 or nivolumab. 
5.4.2 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. After 90 days, only subjects with investigational product-related SAEs will 
continue to be followed for safety. 
5.4.3 
Deaths
 
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows: 
• Death clearly the result of disease progression should be reported and documented in the 
eCRF but should not be reported as an SAE. 
• Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death. 
• Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 
of the post-mortem results should be forwarded to MedImmune Patient Safety or 
designee within the usual timeframes. 
 
5.5 
Reporting of Serious Adverse Events 
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and fax it to MedImmune Patient Safety. 

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MedImmune contact information:  
Patient Safety  
MedImmune 
One MedImmune Way 
Gaithersburg, MD 20878, USA 
 
Global Fax: 
 
North America Fax number: 
 
The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH guidelines and/or local regulatory requirements. The sponsor may be 
required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit additional 
information requested by the sponsor as soon as it becomes available. 
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, investigators should submit a follow-up SAE Report Form 
(separate from the initial report form) with the new information. Any follow-up information 
to an SAE also needs to be provided to MedImmune Patient Safety within 24 hours of 
learning of the new information.  
5.6 
Other Events Requiring Immediate Reporting 
5.6.1 
Overdose
 
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochures, unless otherwise specified in this protocol. 
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 5.5 for 
contact information). If the overdose results in an AE, the AE must also be recorded on the 
AE eCRF (see Section 5.4). 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 reported as an SAE (see Section 5.4 and Section 5.5). MedImmune does 
not recommend specific treatment for an overdose. The investigator will use clinical 
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5.6.2 
Pregnancy
 
All pregnancies and outcomes of pregnancy should be reported to the sponsor. 
5.6.2.1 
Maternal Exposure 
If a subject becomes pregnant during the course of the study investigational product should 
be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of 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 during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 day, ie, immediately 
but no later than 24 hours after becoming aware of the event. 
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 5.5) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy. 
5.6.2.2 
Paternal Exposure 
Pregnancy of the subject’s partner(s) 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 120 days after 
the final dose of MEDI0680 or durvalumab or 150 days after the subject’s last dose of 
nivolumab should, if possible, be followed up and documented. 

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6 
STUDY AND DATA MANAGEMENT 
6.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized. 
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
6.2 
Monitoring of the Study 
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
• Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts) 
• Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
 
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
6.2.1 
Source Data 
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6.2.2 
Study Agreements 
The principal investigator at each study center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of 
any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, 
the terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and 
the treatment of subjects and in all other respects, not relating to study conduct or treatment 
of subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between MedImmune (or designee) and the principal investigator must be in 
place before any study-related procedures can take place, or subjects are enrolled. 
6.2.3 
Archiving of Study Documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 
6.3 
Study Timetable and End of Study 
An individual subject will be considered to have met the minimum criteria for study 
completion if the subject was followed through the DLT-evaluation period or experienced a 
DLT during the DLT-evaluation period (for subjects in the dose-escalation phase) or the 
subject completed at least 1 on-treatment disease evaluation (for subjects in dose-expansion 
phase) regardless of the number of doses of investigational product that was received. 
Subjects should continue treatment with investigational product beyond these minimum 
completion criteria unless criteria for discontinuation are met (Section 4.1.6), and all 
subsequent protocol-specified assessments will be performed as detailed in Section 4.2.2 and 
Section 4.2.3. 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study, 2 years after 
the last subject is enrolled, or the date the study is closed by the sponsor, whichever occurs 
first. Subjects may receive study drug(s) for a maximum of 2 years. At the conclusion of the 
study, subjects who continue to demonstrate clinical benefit will be eligible to receive study 
drug. Study drug will be provided via an extension of the study, a rollover study requiring 
approval by responsible health authority and ethics committee or through another mechanism 
at the discretion of the sponsor. The sponsor reserves the right to terminate access to study 
drug if any of the following occur: a) the study is terminated due to safety concerns; b) the 
subject can obtain medication from a government sponsored or private health program; or c) 
therapeutic alternatives become available in the local market. 

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6.4 
Data Management  
Data management will be performed according to the Data Management Plan. 
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
6.5 
Medical Monitor Coverage 
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the principal investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor. 
7 
ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements. 
7.2 
Subject Data Protection 
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 

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MedImmune will not provide individual genotype results to subjects, any insurance 
company, any employer, their family members, general physician or any other third party, 
unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject. For example, in the 
case of a medical emergency, a MedImmune medical monitor or an investigator might know 
a subject’s identity and also have access to his or her genetic data. Also regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate. 
7.3 
Ethics and Regulatory Review 
An IRB/IEC should approve the final study protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff. 
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrolment of any subject into the study.  
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually. 
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities. 
MedImmune will provide regulatory authorities, IRB/IEC and principal investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions, where relevant. 

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Each principal investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational products. MedImmune will provide this information to the principal 
investigator so that he/she can meet these reporting requirements. 
7.4 
Informed Consent 
The principal investigator(s) at each center will: 
• Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
• Ensure each subject is notified that they are free to discontinue from the study at any time 
• Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the investigator’s study file 
• Ensure a copy of the signed ICF is given to the subject 
• Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC 
 
7.5 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the coordinating 
investigator and MedImmune. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol. 
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols. 
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each principal investigator(s). For distribution to IRB/IEC see Section 7.3. 
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used.  

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If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC. 
7.6 
Audits and Inspections 
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The investigator will contact 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site. 

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8 
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HMAs. 54th ASH Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. 
Abstract 3810. 
 
 
 

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9 
SUMMARY OF CHANGES TO THE PROTOCOL 
9.1 
Protocol Amendment 5, 29Mar2017 
The purpose of this amendment was to remove the MEDI0680 monotherapy arm from the 
dose-expansion phase and replace with a nivolumab monotherapy arm. Nivolumab 
monotherapy was added as a comparator arm in the dose expansion phase as it is the current 
standard of care in the metastatic RCC setting in some markets. The investigational product 
MEDI4736 has been renamed durvalumab throughout the document. Text revisions resulting 
from this amendment are incorporated in the body of Protocol Amendment 5. Major changes 
to the protocol are summarized below. 
1. Title page: The following changes were made: 
◦ 
Updated title to remove MEDI0680 monotherapy arm, add nivolumab monotherapy 
arm and replace MEDI4736 by durvalumab. 
◦ 
Added nivolumab as a comparator product 
◦ 
Added the NCT number 
◦ 
Corrected the Primary Medical Monitor’s phone number 
◦ 
Changed the Secondary Medical Monitor. 
2. Protocol synopsis: The synopsis was updated to align with the body of the protocol. 
3. Section 1.2 (MEDI0680 and Durvalumab [MEDI4736] Background), Section 1.3.2 
(Durvalumab Nonclinical Experience), and Section 1.4 (Summary of Clinical 
Experience): Updated to align with information in the current MEDI0680 and 
durvalumab Investigator’s Brochures. 
4. Section 1.5 (Rationale for Conducting the Study): Clarified that the ORR value was based 
on independent review.  
5. Section 1.5 (Rationale for Conducting the Study) and Section 3.2.2 (Rationale for Study 
Population): Included the rationale for addition of the nivolumab monotherapy arm as a 
comparator. 
6. Section 1.5 (Rationale for Conducting the Study), Section 3.1.3.3 (Dose-limiting 
Toxicity), Section 3.1.5.1 (Dose Modification of Durvalumab and MEDI0680), 
Section 3.2.3 (Rationale for Endpoints), Section 4.1.3 (Exclusion Criteria) and Table A6-
1 (Immune Mediated Reactions): Replaced the abbreviation irAE with imAE to align 
with updated information on patient safety guidelines. 
7. Section 1.5 (Rationale for Conducting the Study): Changed the wording of this section to 
clarify that imAEs are considered AESIs but the terms imAE and AESI are not 
interchangeable. Updated to align with information in the current MEDI0680 
Investigator’s Brochures. 
8. Section 1.6, Section 2.1 and Section 2.3: Revised safety and efficacy hypotheses and 
objectives to replace MEDI0680 monotherapy with nivolumab monotherapy. Removed 
MEDI0680 monotherapy from PK, immunogenicity and biomarker objectives. 

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9. Section 2.1 and 2.2: Presented objectives and endpoints together to enable clearer 
mapping. Clarified endpoint for primary objective in dose escalation 
10. Section 2.1, Section 2.2 and Section 4.8.4: Clarified that OR is the primary endpoint in 
dose expansion and clarified OS as a secondary endpoint. 
11. Section 2.1 and Section 2.2: Clarified safety endpoint and immunogenicity endpoint. 
12. Section 2.3.2 (Exploratory Endpoints): The following changes were made to this section: 
◦ 
This section was updated to account for the removed of the MEDI0680 monotherapy 
arm and addition of the nivolumab monotherapy arm. 
◦ 
Removed the potential for analysis of total mutational load, gene conformational 
changes or epigenetics and T-cell reception (TCR) diversity  
◦ 
Removed the specification that biopsies were to be pre-treatment and posttreatment 
for IHC, IF and/or flow cytometry analysis for expression and localization of key 
molecules to reduce the burden for patients. 
◦ 
Clarified that sPD-L1 levels and receptor occupancy will only be measured in the 
dose-escalation phase as the data previously collected in the study are sufficient for 
analysis. 
13. Section 3.1.1 (Overview) and Section 4.1.1 (Number of Subjects): Changed the number 
of study centers from 80 to 50 as fewer subjects are required following the change in 
study design. 
14. Section 3.1.1 (Overview), Figure 3.1.1-1 (Study Flow Diagram), Figure 3.1.2.2-1 (Study 
Flow for Primary MEDI0680 Schedule (Every 2-week Dosing), Section 3.1.4 (Dose-
expansion Phase), Section 3.2.3 (Rationale for Endpoints), Section 4.3.7 (Biomarker 
Evaluation and Methods), Section 4.6.1 (Methods for Assigning Treatment Groups), 
Section 4.8.2 (Sample Size and Power Calculations), Section 4.8.3.2 (Analyses of Safety 
Endpoints), and Appendix 5 (Solid Tumor Efficacy): Removed the MEDI0680 
monotherapy arm and replaced with nivolumab monotherapy arm. 
15. Section 3.1.1.1 (Dose escalation Phase), Section 3.1.2.3 (Alternative MEDI0680 
Schedule [Every 4-week Dosing]), Figure 3.1.3.1-1 (Primary [Every 2-week Dosing of 
MEDI0680] Dose escalation Design), Figure 3.1.3.1-2 (Alternative [Every 4-week 
Dosing of MEDI0680] Dose escalation Design), Figure 3.1.3.2-2 (Dose escalation [Zone 
based] for Alternative Q4W Schedule), Section 3.1.3.3 (Dose limiting Toxicity), Section 
3.2.1.1 (Dose escalation Phase), Section 4.1.7 (Replacement of Subjects), Section 4.2.2 
(Treatment Period), Section 4.8.3.2 (Maximum Tolerated Dose Evaluation [Every 4 week 
Dose Schedule), Appendix 6 (Alternate Q4W Dosing Schedule): Removed the alternative 
Q4W dosing schedule as dose-escalation has completed and this schedule has not been 
used in this study. 
16. Section 3.1.1.2 (Dose-expansion Phase): The following changes were made to this 
section: 
◦ 
Added that an interim futility analyses will be performed for the 
MEDI0680/durvalumab combination therapy arm in the dose-expansion phase after 
20 subjects have been randomized and have reached their second post-baseline 
disease assessment or have completed study. 

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17. Section 3.1.1.2 (Dose-expansion Phase), Section 4.1.1 (Number of Subjects), and 
Section 4.8.2 (Sample Size and Power Calculations): Changed the planned number of 
subjects as follows as fewer subjects are required following the change in study design: 
◦ 
From 156 to approximately 96 subjects for both dose escalation and dose expansion.  
◦ 
The number of subjects in the dose-expansion phase was changed from 120 to 
approximately 60. 
18. Section 3.1.1 (Figure 3.1.1-1), Section 3.1.1.2 (Dose expansion Phase), Section 3.1.4 
(Dose expansion Phase), Section 4.3.7 (Biomarker Evaluation and Methods), Section 
4.6.1 (Methods for Assigning Treatment Groups, and Section 4.8.2 (Sample Size and 
Power Calculation): Changed the ratio for randomization of combination and 
monotherapy from 1:1 to 2:1. 
19. Section 3.1.1.2 (Dose-expansion Phase), Section 3.1.4 (Dose-expansion Phase), Table 
4.2.2-2 (Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 7 13 
Following Protocol Amendment 5), Section 4.3.7 (Biomarker Evaluation and Methods), 
and Section 4.5.1.1 (Durvalumab): Clarified that subjects were randomized into the dose-
expansion phase. 
20. Section 3.1.2 (Treatment Regimen), Section 4.1.3 (Exclusion Criteria), Section 4.3.3 
(Medical History and Physical Examination), Section 4.5.1.4 (Monitoring of Dose 
Administration), Section 4.7 (Restrictions During the Study and Concomitant 
Treatment[s]), Section 4.8.4.1 (Analysis of Efficacy Endpoints), Section 5.4 (Recording 
of Adverse Events) and Appendix 5 (Solid Tumor Efficacy): The nivolumab 
monotherapy arm was added to these sections. 
21. Section 3.1.2 (Treatment Regimen):  
◦ 
Clarified that in the dose-escalation phase subjects may be re administered 
MEDI0680 and durvalumab if they have PD only during the first 12 months of follow 
up. 
◦ 
And in Section 4.5.1.1: The time between the durvalumab infusion and MEDI0680 
infusion was reduced from 1 hour to 30 minutes for subject convenience because of 
increased experience with durvalumab 
22. Section 3.1.2 (Treatment Regimen), Section 3.1.5.2 (Dose Modifications of Nivolumab), 
Section 4.5.1.3 (Nivolumab), Section 4.5.1.4 (Monitoring of Dose Administration), and 
Section 4.5.4 (Storage): Added that for dosing and storage of nivolumab, the investigator 
should refer to the local (country-specific) package insert) (or similar). 
23. Section 3.1.2.1 (Treatment Beyond Progression): Clarified that the initial assessment of 
PD will be based on an application of RECIST v1.1 to investigator-assessed tumor 
measurements. 
24. Section 3.1.2.2 (Dosing Schedule): Added the frequency of dosing for the nivolumab 
monotherapy arm. 
25. Section 3.1.4 (Dose-expansion Phase): The following changes were made: 
◦ 
And in Section 4.2.2: Added that prior to this Protocol Amendment some subjects had 
been randomized to and began receiving treatment in the MEDI0680 monotherapy 
arm, which has now been removed. Outlined the dose of MEDI0680 monotherapy 
that these subjects should receive and that they are to follow the same study 
procedures as the combination therapy arm.  

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◦ 
Explained that the dose information for nivolumab is the recommended dose for 
treatment of patients with advanced RCC. 
26. Section 3.1.5 (Management of Study Medication Related Toxicities): The following 
changes were made: 
◦ 
The title of Section 3.1.5.1 was updated to clarify this relates to durvalumab and 
MEDI0680 only. 
◦ 
Section 3.1.5.2 (Dose Modification of Nivolumab) was added. 
27. Section 3.1.5.1 (Dose Modifications of Durvalumab and MEDI0680): Reduced the 
information about treatment modifications for AEs clearly not related to 
MEDI0680/durvalumab as the previous information was repetitive. 
28. Section 3.2.1.2 (Dose-expansion Phase) and Section 4.8.6 (Analyses of Immunogenicity 
and Pharmacokinetics): References to the MEDI0680 monotherapy arm were removed as 
this will no longer be performed. 
29. Section 3.2.3 (Rationale for Endpoints): The following changes were made as the data 
previously collected in the study are sufficient for analysis: 
◦ 
Clarified that PBMC would no longer be collected in the dose-expansion phase after 
Protocol Amendment 5.  
◦ 
Clarified that biopsies are optional. 
◦ 
Added that sPD-L1 and PD-1 analysis would no longer be collected in the 
dose-expansion phase after Protocol Amendment 5. 
◦ 
Removed the specification that immune response will be assessed using paired pre-
treatment and posttreatment biopsies. 
◦ 
Removed the assessment of TCR usage 
30. Section 4.1.2 (Inclusion Criteria): The following changes were made 
◦ 
Inclusion criterion 4b – Changed the number of prior systemic treatment regimens 
from only 1 to at least 1 and no more than 2 prior anti-angiogenic therapy regimens 
(including, but not limited to, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and 
bevacizumab) in the advanced or metastatic setting. This resulted in the addition of 
Criterion 4c, and thus re-lettering of subsequent criteria. Added that subjects must 
have received no more than 3 total prior systemic treatment regimens in the advanced 
or metastatic setting, and must have evidence of radiographic progression on or after 
the last treatment regimen received and within 6 months prior to study enrollment. 
◦ 
Inclusion criterion 5cii – Clarified that on-treatment biopsies are optional. 
◦ 
Inclusion criterion 5ciii – Removed this criterion as biopsies are now optional. “Once 
the initial 50 subjects have been enrolled and the futility analysis is completed, up to 
15 subjects enrolled subsequently into each treatment arm must consent to and 
provide both pre-treatment and on treatment tumor biopsies. Tumor lesions used for 
biopsy should not be lesions used as RECIST target lesions.”  
◦ 
Inclusion Criterion 6avi – Replaced serum creatinine cut-off with 24-hour urine 
creatinine clearance to align with clinical practice. 
◦ 
Inclusion Criterion 6b – Removed the inclusion of subjects with central nervous 
system metastases to enable clearer assessment of efficacy. 

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◦ 
Inclusion Criterion 8 – Updated this criterion relating to female subjects of 
childbearing potential to align with current protocol template language and guidance 
for nivolumab. This included adding that it is strongly recommended for the male 
partner of a female subject to also use male condom plus spermicide from screening 
until 120 days after the subject’s last dose of MEDI0680 or durvalumab or 150 days 
after the subject’s last dose of nivolumab and that female subjects should refrain from 
egg cell donation throughout this period. 
◦ 
Inclusion Criterion 9 – Increased the time period that nonsterilized males who are 
sexually active with a female partner of childbearing potential should use male 
condoms plus spermicide from 90 to 120 days after the last dose of MEDI0680 or 
durvalumab or 150 days after the subject’s last dose of nivolumab. The time period 
that they must refrain from fathering a child or donating sperm was also increased 
from 90 to 120 days to align with MEDI0680 requirements and the protocol schedule, 
and to 150 days for nivolumab. 
◦ 
Table 4.1.2 (Effective Methods of Contraception): The title was reworded to clarify 
that not all methods in the table are highly effective. The methods listed in the table 
were also updated to align with current protocol template language. 
31. Section 4.1.3 (Exclusion Criteria): The following change was made: 
◦ 
Exclusion Criterion 2 – Updated this criterion for clarity. 
◦ 
Removed Exclusion Criteria 5 about prior toxicities following immunotherapy as it is 
irrelevant in the population recruited as of Protocol Amendment 5. 
◦ 
Exclusion Criterion 15 – Clarified the time frame that second malignancies should not 
have occurred in and provided further examples of the second malignancies that are 
exempt from this criterion. 
32. Section 4.1.5.2 (Withdrawal from Treatment): Removed text that stated ‘Subjects who 
permanently discontinue treatment may either be considered to have completed the study 
or not to have completed the study’ as it was not meaningful. 
33. Table 4.2.1-1 (Schedule of Screening Procedures Following Protocol Amendment 5): The 
following changes were made to this table: 
◦ 
Added to the title “Following Protocol Amendment 5” to show that different 
screening procedures were carried out in earlier versions of the protocol. 
◦ 
Clarified that the physical examinations should be full physical examinations. 
◦ 
Removed receptor occupancy, sPD-L1, and PBMC as the data previously collected in 
the study are sufficient for analysis. 
34. Section 4.2.2: (Treatment Period): The following changes were made: 
◦ 
Clarified that the study procedures in Table 4.2.2-1 and Table 4.2.2-2 are also to be 
followed in the dose-expansion phase as this was inadvertently omitted. 
35. Table 4.2.2-1 (Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 
1-6 Following Protocol Amendment 5) and Table 4.2.2-2 (Schedule of Study Procedures 
for Primary Q2W Treatment Period: Cycles 7 13 Following Protocol Amendment 5): The 
following changes were made: 
◦ 
Added to the title “Following Protocol Amendment 5” to show that different 
procedures were carried out in earlier versions of the protocol. 

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◦ 
Reduced the number of physical examinations, ECGs, hematology, serum chemistry, 
TSH, free T4, free T3, and urinalysis measurements as there is now more clinical 
experience with the investigational products. 
◦ 
Changed some of the full physical examinations to abbreviated physical examinations 
as there is now more clinical experience with the investigational products. 
◦ 
Reduced the number of vital sign and ECG measurements required as there is now 
more clinical experience with the investigational products. 
◦ 
Clarified that MEDI0680 PK and MEDI0680 immunogenicity will be measured in 
the combination arm only as this information is not needed in the nivolumab 
monotherapy arm. 
◦ 
Removed sPD-L1, receptor occupancy, and PBMC collection as the data previously 
collected in the study are sufficient for analysis. 
◦ 
Clarified that disease assessments occur Q8W and should occur within 7 days prior to 
the planned administration of the scheduled treatment. 
◦ 
Added nivolumab administration for the nivolumab monotherapy arm. 
◦ 
Added a footnote to clarify that MEDI0680 will be administered in the combination 
arm and to those who were randomized and began receiving treatment with 
MEDI0680 monotherapy prior to Protocol Amendment 5. 
36. Table 4.2.2-1 (Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 
1-6 Following Protocol Amendment 5): The following changes were made: 
◦ 
Reduced the number of vital signs measurements and ECGs  on dosing days and 
removed monitoring on non-dosing days as there is now more clinical experience 
with the investigational products.  
◦ 
Amended table to clarify when disease assessments should be performed (identified 
as prior to subsequent dosing rather than included as a separate visit day). 
◦ 
Clarified that biopsies are optional and removed “Once the initial 50 subjects have 
been enrolled and the futility analysis is completed, up to 15 subjects enrolled 
subsequently into each treatment arm must consent to and provide both pre-treatment 
and on treatment tumor biopsies” as biopsies are optional. 
◦ 
miRNA/mRNA assessments removed from Cycle 1 Days 2 and 8 and added to Cycle 
1 Day 15.  
37. Table 4.2.2-2 (Schedule of Study Procedures for Primary Q2W Treatment Period: Cycles 
7 to13 Following Protocol Amendment 5):  
◦ 
Reduced the number of assessments for physical examinations and laboratory 
assessments following 1 year of treatment, unless clinically indicated.  
◦ 
Reduced the number of vital sign and ECG measurements required as there is now 
more clinical experience with the investigational products. 
◦ 
Revised Visit headers for clarity.  
◦ 
Removed flow cytometry, circulating soluble factors, miRNA/mRNA and tumor 
biopsies. 
38. Section 4.2.3 (Follow-up Period): Changed the wording of this section to clarify that it is 
preferred but not mandatory that assessments are performed in a certain order. Clarified 
which physical examinations should be full or abbreviated. 

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39. Table 4.2.3-1 (Schedule of Study Procedures: End of Treatment and Posttreatment 
Laboratory Follow-Up Following Protocol Amendment 5): The following changes were 
made: 
◦ 
Added to the title “Following Protocol Amendment 5” to show that different 
procedures were carried out in earlier versions of the protocol. 
◦ 
Clarified that MEDI0680 PK, and immunogenicity will be measured in the 
combination arm only as this information is not needed in the nivolumab 
monotherapy arm and clarification of the timings. 
◦ 
Removed sPD-L1, flow cytometry, receptor occupancyand PBMC collection as the 
data previously collected in the study are sufficient for analysis. 
◦ 
Removed physical examinations, vital signs and AE assessments in long-term follow 
up as not required. 
◦ 
Clarified that disease assessments are only required for subject discontinued from 
treatment for a reason other than radiologic disease progression and these should 
continue on a Q8W schedule until radiologic disease progression is observed. 
◦ 
Added blood or urine pregnancy test in the long-term follow up to match new 
protocol template language. 
◦ 
Added that circulating soluble factors and miRNA/mRNA will be performed in all 
treatment arms and added a footnotes to clarify time points 
◦ 
Added that tumor biopsies are optional. 
40. Section 4.3.2.2 (Tumor Biopsies): Clarified that posttreatment biopsies are optional and 
removed “Once the initial 50 subjects have been enrolled and the futility analysis is 
completed, up to 15 subjects enrolled subsequently into each treatment arm must consent 
to and provide both pre-treatment and on treatment tumor biopsies” as biopsies are now 
optional. 
41. Section 4.3.3 (Medical History and Physical Examination): The following changes were 
made to this section: 
◦ 
Reduced the number of vital signs measurements on dosing days and removed 
monitoring on non-dosing days as there is now more clinical experience with the 
investigational products. 
◦ 
Stated the time points for measuring vital signs and ECGs in the nivolumab 
monotherapy arm. 
◦ 
Added that abbreviated symptom-directed examinations will be conducted post-
screening, except for a full physical examination at the end of treatment. 
42. Section 4.3.4 (Clinical Laboratory Tests): Clarified that only clinically significant 
abnormal laboratory results should be repeated. 
43. Section 4.3.7 (Biomarker Evaluation and Methods): The following changes were made to 
this section as the data previously collected in the study are sufficient for analysis: 
◦ 
Removed the assessment of serum sPD-L1 levels. 
◦ 
Tumor DNA is referenced instead of nucleosomal DNA as a marker of apoptosis 
◦ 
Clarified that PBMC were only to be collected in the dose-escalation phase. 

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44. Section 4.3.7 (Biomarker Evaluation and Methods): Removed the specification that 
protein, nucleic acids and cellular biomarkers that are analyzed will be related to 
durvalumab or MEDI0680 to account for the addition of the nivolumab monotherapy 
arm. 
45. Section 4.3.8 (Estimate of Blood Volume to be collected): Estimates reduced due to 
streamlining of assessments. 
46. Section 4.5.1 (Identity of Investigational Products): The following changes were made to 
this section: 
◦ 
Added that nivolumab will be obtained from commercial supply and is formulated, 
administered and labelled according to locally approved prescribing information and 
guidance. 
47. Section 4.5.1, 4.5.1.2, 4.5.4 and Appendix 8: Removed reference to the initial MEDI0680 
60 mg/mL formulation and Amplimmune as the formulation is no longer in use. 
48.  Section 4.5.1.1 (Durvalumab): Clarified that the allowed storage time starts from needle 
puncture not reconstitution for the durvalumab dose preparation steps. Correction of 
infusion duration text. 
49. Section 4.5.1.4 (Monitoring of Dose Administration): Removed time points for 
monitoring vital signs and added a cross reference to Section 4.3.3 where they are first 
presented. 
50. Section 4.6.1 (Methods for Assigning Treatment Groups): text added to that the 
investigational products must be administered or dispensed within 2 days after 
randomization, to allow some flexibility in dosing from randomization.   
51. Section 4.8.2 (Sample Size and Power Calculations): The following changes were made 
to this section to account for the removal of the MEDI0680 monotherapy arm and the 
addition of the nivolumab monotherapy arm: 
◦ 
Updated the ORR, power, sample size and 95%CI. 
◦ 
Added that subjects are randomized in a 2:1 ratio. 
◦ 
Updated the primary objective to be consistent with Section 2.1. 
52. Section 4.8.4.1 (Analysis of Efficacy Endpoints): Clarified the definitions for duration of 
response and progression free survival. 
53. Section 4.8.5 (Pharmacodynamic Analyses): The following changes were made to this 
section: 
◦ 
Added that serum sPD-L1 levels and levels of PD-1 expression will only be measured 
in the dose-escalation phase as the data previously collected in the study are sufficient 
for analysis. 
◦ 
Removed the specification that biopsies were to be pre-treatment and posttreatment 
for IHC, IF and/or flow cytometry analysis for expression and localization of key 
molecules. 
54. Section 4.8.7.1 (Immune-related Response Criteria): Clarified the use of irRECIST and 
included the endpoints that will be summarized. 
55. Section 4.8.8 (Interim Analysis): This section was replaced with detailed information 
about the conduct of the interim futility analysis.  

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56. Section 5.3 (Definition of Adverse Events of Special Interest): The following changes 
were made to this section to align with updated information on patient safety guidelines: 
◦ 
Replaced the abbreviation irAEs with imAEs. 
◦ 
Reworded the list of irAEs for clarity. 
◦ 
Removed neurotoxicity and autonomic neuropathy from the list of irAEs. 
◦ 
Removed Section 5.3.2 (pneumonitis) and Section 5.3.4 (Gastrointestinal Disorders). 
57. Section 5.5: FAX numbers for reporting of SAEs were updated to be current. 
58. Section 5.6.2.2 (Paternal Exposure): Changed that the outcome of all pregnancies should 
be followed-up from 90 days after the final dose of combination or monotherapy to 
120 days. 
59. Section 6.3 and Appendix 5: One of the criteria for the definition of the end of study was 
revised from 3 years to 2 years after the last subject was enrolled. Possible treatment 
options for subjects still receiving treatment at the end of study added. 
60. Appendix 6 (Durvalumab and MEDI0680 Dose Modifications for Toxicity 
Management): The guidelines for durvalumab and MEDI0680 toxicity management were 
updated according to the 31Aug2016 version. 
 
9.2 
Protocol Amendment 4, 27May2016 
Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 4. Major changes to the protocol are summarized below. 
1. Title page: Added Protocol Administrative Change 1, 05Feb2015, which was 
inadvertently omitted.  
2. Section 1.5 (Rationale for Conducting the Study): Updated to align with information in 
the current MEDI0680 Investigator’s Brochure. 
3. Section 2.2.3 (Exploratory Endpoints): Clarified exploratory endpoint 5 to align with the 
treatment arms.  
4. Section 3.2.3 (Rationale for Endpoints), Predictive Markers: Included CD80 among the 
candidate biomarkers for evaluation. 
5. Section 4.1.2 (Inclusion Criteria): Inclusion criterion 9 - Revised requirement for a 
female partner of childbearing potential of a male subject to use a highly effective 
method of contraception from mandatory to highly recommended, to align with current 
protocol template language. The clarification encourages safe contraceptive practices for 
individuals who are not study participants.  
6. Section 4.1.3 (Exclusion Criteria): Added exception to permit enrollment of subjects with 
prior endocrine toxicities who are stable on replacement therapy since TKI-induced 
thyroid dysfunction is common, however, exact mechanisms are unclear. Symptomatic 
treatment of TKI-induced hypothyroidism improves the patient’s quality of life and 
allows continuation of the anti-cancer therapy. Per original protocol, endocrine function 
tests will be monitored throughout study participation and guidelines for management of 
endocrinopathy are also included. 

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7. Table 4.2.1-1 (Schedule of Screening Procedures): Clarified that procedure for TSH 
includes assessment for TSH, free T4, and free T3, consistent with presentation in 
Table 4.2.2-1 and Table 4.2.2-2. 
8. Table 4.2.2-1 (Schedule of Study Procedures for Primary Q2W Treatment Period: 
Cycles 1-6): Revised visits for disease assessment to begin on Day 56 and occur every 
8 weeks (Q8W; ie, Days 50, 106, and 162 were revised to Days 56, 112, and 168); and 
added footnote “k” to clarify that results must be available prior to the planned 
administration of the scheduled investigational treatment.  
9. Table 4.2.2-2 (Schedule of Study Procedures for Primary Q2W Treatment Period: 
Cycles 7-13): (1) Revised visits for disease assessment to continue on the Q8W schedule 
(ie, Day 218, Day 274, and Q8W starting on Day 330 were revised to Day 224, Day 280, 
and Q8W starting on Day 336), and added footnote “a” to clarify that results must be 
available prior to the planned administration of the scheduled investigational treatment; 
and (2) footnote “f” – clarified to indicate that MEDI0680 and durvalumab will be 
administered on a Q2W schedule. Consistent with edits in Protocol Amendment 3, 
assessments beginning in Cycle 12 Day 330 through end of treatment will be conducted 
Q8W, however, MEDI0680 and durvalumab will continue on a Q2W treatment schedule.  
10. Section 9.3 (Protocol Amendment 3): Items 38 and 39 - Clarified changes to the 
appendices resulting from Protocol Amendment 3. 
11. Section 9.4 (Protocol Administrative Change 1): Added this protocol administrative 
change, which was inadvertently omitted, to provide a complete history of protocol 
changes.    
9.3 
Protocol Amendment 3, 11Feb2016 
The purpose of this amendment was to update the dose-expansion phase of the study to enroll 
PD-L1 positive immunotherapy naïve subjects who have RCC to either receive MEDI0680 
monotherapy or in combination with durvalumab.  
1. Title page: The title of the study was changed to “A Phase 1/2, Open-label Study to 
Evaluate the Safety and Antitumor Activity of MEDI0680 (AMP-514) Monotherapy and 
in Combination with MEDI4736 in Subjects with Select Advanced Malignancies” 
a. The EudraCT number was added 
b. The Primary Medical Monitor was changed to 
 and the Secondary 
Medical monitor was changed to 
.  
2. Protocol Synopsis: The synopsis was updated to align with the body of the protocol. 
3. Section 1.2 (Durvalumab [MEDI4736] and MEDI0680 Background): The background for 
durvalumab and MEDI0680 was updated, the sections were reorganized for clarity. 
4. Section 1.3 (Summary of Nonclinical Experience): This section was updated to provide a 
more concise summary of the relevant studies. 
5. Section 1.4 (Summary of Clinical experience): This section was updated and reorganized. 
The safety and efficacy information for studies in the MEDI0680 and durvalumab 
development program were updated based on current data. 

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6. Section 1.5 (Rationale for conduct of the study) was updated with rationale for including 
subjects with RCC.  
7. Section 1.6 (Research Hypotheses): This section was updated to include primary and 
secondary hypotheses for the dose-expansion phase. 
8. Section 2.1.1 (Primary Objectives): The objective for the dose expansion phase was 
changed to “To evaluate the antitumor activity of MEDI0680 monotherapy and in 
combination with durvalumab in immunotherapy-naïve subjects with advanced or 
metastatic ccRCC as based on investigator assessed response using RECIST v1.1,” in 
order to provide a measure of efficacy for dose-expansion phase. 
9. Section 2.1.2 (Secondary Objectives): The following changes were made.  
a. A secondary objective for the dose-expansion phase, “To describe the safety and 
tolerability of MEDI0680 monotherapy and in combination with durvalumab in 
immunotherapy-naïve subjects with advanced or metastatic ccRCC” was updated 
according to the new study design. 
b. A secondary objective for the dose expansion phase, “To evaluate the antitumor 
activity of MEDI0680 monotherapy and in combination with durvalumab in 
immunotherapy-naïve subjects with advanced or metastatic ccRCC as based on BICR 
assessed response using RECIST v1.1” was added. 
c. The wording for objectives applicable to both the dose-escalation and dose-expansion 
phase was updated for clarity. 
10. Section 2.1.3 (Exploratory Objectives) 
a. The exploratory objective on patient-reported outcomes was removed. 
11. Section 2.2.1 (Primary Endpoints): 
a. The primary endpoint “The primary endpoint is determination of the MTD, which is 
the highest dose within a cohort where no more than 1 out of 6 subjects experience 
DLTs, or the highest protocol-defined dose for each agent in the absence of exceeding 
the MTD” was removed. 
b. The primary endpoint for the dose-expansion phase “The primary endpoints to assess 
antitumor activity include best overall response (BOR), DC, time to response (TTR), 
duration of response (DR), progression-free survival (PFS) and change from baseline 
in tumor size as based on investigator assessed response using RECIST v1.1” was 
added to correspond with the updated study design. 
12. Section 2.2.2 (Study Endpoints): 
a. The endpoint specific for the dose-escalation phase was updated to “the endpoints for 
assessment of antitumor activity include BOR, OR, DC, TTR, DR, PFS, OS, and 
change from baseline in tumor size. Antitumor activity analyses will be as determined 
by the investigator based on modified RECIST v1.1” in order to match the new study 
design 
b. In the dose-expansion phase the endpoint was updated to “The endpoints for 
assessment of safety include the presence of AEs, SAEs, laboratory parameters, vital 
signs, physical examination, and ECG results” in order to match the study design. 
c. The endpoint specifically for the dose-expansion phase was updated to “The 
endpoints for assessment of antitumor activity include BOR, DC, TTR, DR, PFS, and 

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change from baseline in tumor size as based on BICR assessed response using 
RECIST v1.1; and OS” in order to match the study design. 
d. The endpoint “PD-L1 expression / localization on tumor membrane and 
tumor-infiltrating immune cells within the tumor microenvironment” was added to 
support the updated study design. 
13. Section 2.2.3 (Exploratory Endpoints): 
a. The order of the endpoints was changed to match the order presented for the 
exploratory objectives 
b. The endpoint to measure quality of life was removed. 
14. Section 3.1.1 (Overview) was updated. The dose-expansion phases for MDS subjects and 
immunotherapy pretreated subjects was removed. The dose-expansion phase for 
immunotherapy naïve RCC subjects was added. 
15. Section 3.1.2.1 (Treatment Beyond Progression): This section was updated to correspond 
with new language applicable to MedImmune protocols. 
16. Section 3.1.4 (Dose-expansion phase): An overview of the study design for the 
dose-expansion phase was added. 
17. Section 3.1.5 (Management of Study Medication Related Toxicities): This section was 
updated to correspond with Medimmune Patient Safety guidelines 
a. The Dose modification table was replaced with toxicity management guidelines in 
Appendix 7 in order to correspond with MedImmune Patient Safety guidelines. 
18. Section 3.2.1 (Dose Rationale [MEDI0680 and Durvalumab]): The dose rationale for 
MEDI0680 monotherapy and combination therapy with durvalumab was updated based 
on current study information. 
19. Section 3.2.2 (Rationale for Study Population): The rationale for including the RCC 
subjects in the study population was added to support the new study design 
20. Section 3.2.3 (Rationale for endpoints): The following sentence was updated “The EOT 
biopsy specimens will be evaluated to understand potential mechanisms of resistance in 
tumors that remain following 9 months of treatment.” The text “9 months” of treatment 
was removed from the sentence in order to avoid language that restricts when tumor 
samples will be evaluated. 
21. Section 4.1.1 (Number of Subjects): The total number of subjects was updated to 156 and 
the number of study centers was increased to 80. 
22. Section 4.1.2 (Inclusion criteria): This following changes were included in this section:  
a. Inclusion criteria specific for MDS subjects (previously criterion 4 in Amendment 2) 
in the dose-expansion phase was removed because subjects with MDS will not be 
included in the dose-expansion phase. 
b. The following inclusion criteria for the RCC subjects to be included in the 
dose-expansion phase were added. 
i. Histological confirmation of advanced or metastatic RCC with a clear-cell 
component 
ii. Must have received only 1 total prior systemic treatment regimen in the solid 
tumor groups (advanced or metastatic setting and the prior treatment must be an 
approved anti-angiogenic therapy regimen (including, but not limited to, sunitinib, 

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sorafenib, pazopanib, axitinib, tivozanib, and bevacizumab), and must have 
evidence of progression 
iii. No prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell 
co stimulation or checkpoint pathways 
iv. No prior treatment with an mammalian target of rapamycin (mTOR) inhibitor 
(including, but not limited to everolimus, temsirolimus, sirolimus, and 
ridaforolimus) 
v. Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed. 
vi. Subjects must have at least 1 measurable lesion according to RECIST v1.1. A 
previously irradiated lesion cannot be considered a target lesion. Radiographic 
disease assessment can be performed up to 28 days prior to the first dose  
c. Contraception language (criteria 8 and 9) was updated according to current 
MedImmune patient safety guidelines.  
i. Male condom with spermicide was removed from the list of highly effective 
contraceptive methods in order to align with health authority feedback. 
ii. The list of highly effective hormonal methods of contraception was updated to 
align with recent health authority feedback. 
d. The following biopsy requirements were added to support the new study design: 
For dose-escalation  
i. Subjects must consent to provide archival tumor tissue (initial and subsequent 
tumor biopsy samples, if possible) for correlative biomarker studies if available 
ii. Able and willing to give valid written consent for fresh tumor samples if required. 
Fresh tumor biopsies should be preferentially obtained from tumor tissues that are 
safely accessible as determined by the investigator and achieved via non-
significant risk procedures (refer to Section 4.3.2.1 and dose-expansion). Sites are 
encouraged to confirm adequacy of tumor biopsy material at the time of the 
procedure. Fine-needle aspirate specimens are not acceptable.  
For dose-expansion: 
iii.  Tumor tissue (formalin fixed paraffin embedded [FFPE] archival or fresh tumor 
tissue) must be received by the central vendor (block or unstained slides) and 
evaluable for PD-L1 expression status in order to randomize a subject to study 
treatment.  
iv. All subjects are encouraged to consent to and provide both pretreatment and on-
treatment fresh tumor biopsies  
v. Once the initial 50 subjects have been enrolled and the futility analysis is 
completed, up to 15 subjects enrolled into each treatment arm must consent to and 
provide both pre-treatment and on treatment tumor biopsies. Tumor lesions used 
for biopsy should not be lesions used as RECIST target lesions 
vi. For dose-escalation and dose-expansion: (If evaluations performed as part of 
standard of care for other purposes prior to obtaining informed consent are 
suitable for screening and occurred within 7 days prior to starting treatment, those 
evaluations do not need to be repeated if the subject consents to their use): 

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23. Exclusion criteria specific to MDS subjects were removed. 
24. Exclusion Criteria 12 was updated such that patients should not receive live attenuated 
vaccination 90 days after administration of MEDI0680 monotherapy or combination 
therapy durvalumab. 
25. Section 4.1.7 (Replacement of Subjects): The text was updated to indicate that no 
subjects will be replaced in the dose-expansion phase in order to match the new study 
design. 
26. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples): The 
sentence “A file linking this sample identification number with the SID number will be 
kept in a secure place at the sponsor with restricted access” was removed. It is not 
applicable to the study. 
27. Schedule of screening procedures was updated to remove bone marrow biopsy, archival 
bone marrow sample and cytogenics from bone marrow sample. A screening for receptor 
occupancy was added to support endpoints for the new study design. 
28. The following changes were made to Schedule of Study Procedure Primary Q2W Cycles 
1-6 and 7-13: 
a. The pain questionnaire, quality of life questionnaire and FACT-Leu were removed. 
b. For Cycles 7-13 the Day 197 tumor biopsy was removed and replaced with EOT 
tumor biopsy. 
29. The following changes were made to serum chemistry labs; measurement for total protein 
was added and measurements for beta 2 microglobulin was removed. 
30. The following changes were made to the hematology labs; the lab test for mean 
corpuscular Hgb concentration was removed and the lab test for hematocrit was added. 
31. Section 4.3.8 (Estimate of Blood Volume to Be Collected): The estimated amount of 
blood to be collected was increased to facilitate completion of planned analysis. “A total 
of approximately 75 mL will be required for all screening tests, which may be conducted 
over 1 to 28 days during screening. No more than 90 mL of blood will be drawn on any 
visit day after screening. Approximately 90 mL of blood will be collected at all visits 
related to the first dose.” 
32. Section 4.5 (Investigational Product): The following information was updated. 
a. Details for preparation of MEDI680 60 mg/mL was moved to Appendix 8. 
b. Details for preparation of the MEDI0680 50 mg/mL drug product was added to the 
main body. 
c. For durvalumab dose preparation steps, the instruction for the duration to swirl the 
vail was removed and replaced with clear language.  
d. The following instructions for the time interval for between combination therapy with 
MEDI0680 and durvalumab was added “for subjects assigned to receive both 
products. MEDI0680 infusion will start approximately 1 hour after the end of 
durvalumab infusion.”   
e. Section 4.5.1.2 (MEDI0680): Guidance that dose-escalation subjects receiving the 
60 mg/ml drug product will be transitioned to the 50 mg/mL drug product was added. 
f. Section 4.5.4 (Storage): Information for storing the MEDI0680 (50 mg/mL) 
investigational product was added.  

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33. Section 4.7.1 (Prohibited Concomitant Medications): Biphosphonate and RANKL 
inhibitors was removed 
34. Section 4.8 (Statistical Evaluation) was updated. The total amount of subjects to be 
enrolled was changed to 156.  
35. Section 4.8.2 Sample Size and Power Calculations. The sample size and power 
calculations were updated to correspond with the new study design. 
a. For the dose expansion phase up to 120 subjects will be included (60 subjects per 
arm) 
36. Section 4.8.8 (Interim analysis): A futility gate for the combination and monotherapy arm 
in the dose-expansion phase was added. The information will be used to support internal 
company decisions. 
37. Section 5 Assessment of Safety was updated to correspond with MedImmune Safety 
guidelines 
38. Appendices 5 (Pain Questionnaire), 6 (Patient-reported Outcome Questionnaire EORTC 
QLT-C30), and 7 (Patient-reported Outcome Questionnaire EORTC QLWQ-LC13): 
Deleted in alignment with removal of exploratory endpoint for patient-reported 
outcomes.  
39. Appendices 7, 8, and 9 were added.  
a. Appendix 7 (Durvalumab and MEDI0680 Dose Modifications for Toxicity 
Management): Added to correspond with changes to Section 3.1.5 and to support the 
current MedImmune Patient Safety guidelines. 
b. Appendix 8 (Preparation of MEDI0680 60 mg/mL): Details for preparation of this 
dose level were removed from Section 4.5 and placed here since 50 mg/kg 
MEDI0680 is the new Drug Product presentation.  
c. Appendix 9 (Memorial Sloan Kettering Cancer Center Prognostic Score [Renal Cell 
Carcinoma]): Added to support inclusion of RCC patient population. 
 
9.4 
Protocol Administrative Change 1, 05Feb2015 
The purpose of this administrative change was to correct typographical errors in 
Appendix 11, Schedule of Study Procedures for Alternative Q4W Treatment Period. 
9.5 
Protocol Amendment 2, 01Oct2014 
The purpose of this amendment was to limit the tumor types in dose escalation to NCSLC, 
SCCHN, MSI-high CRC, bladder cancer, ovarian cancer, esophageal cancer, gastric cancer, 
and RCC, and to add a 20 mg/kg MEDI0680 (AMP-514) cohort to the Q2W dose-escalation 
schedule. Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 2. Major changes to the protocol are summarized below. 
1. Protocol Synopsis: The synopsis was updated to align with the body of the protocol. 

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2. Section 1.4 (Summary of Clinical Experience): Updated this section with more recent 
clinical data for both durvalumab (Section 1.4.1) and MEDI0680 (AMP-514; 
Section 1.4.2). 
3. Section 3.1.1 (Overview): The following changes were made to this section: 
◦ 
Limited the tumor types in dose escalation to NCSLC, SCCHN, MSI-high CRC, 
bladder cancer, ovarian cancer, esophageal cancer, gastric cancer, and RCC.  
◦ 
Increased the number of subjects in dose escalation from 30 to 36. 
◦ 
Allowed for any dose-escalation cohort that has not exceeded the MTD to be 
expanded by up to a maximum of 18 subjects for further evaluation of safety, PK, 
pharmacodynamics, and efficacy. 
4. Section 3.1.1.1 (Dose-escalation Phase): Indicated that as of Amendment 2, only subjects 
with NCSLC, SCCHN, MSI-high CRC, bladder cancer, ovarian cancer, esophageal 
cancer, gastric cancer, or RCC will be enrolled in the dose-escalation phase. 
5. Section 3.1.2 (Treatment Regimen): Revised the MEDI0680 (AMP-514) administration 
duration for doses > 2.5 mg to the following: MEDI0680 (AMP-514) will be 
administered over a minimum of 60 minutes at doses > 2.5 mg/kg up to a total dose of 
1200 mg, and over a minimum of 90 minutes at total doses > 1200 mg. 
6. Section 3.1.3.1 (Dose Escalation): The following changes were made: 
◦ 
Allowed for any dose-escalation cohort that has not exceeded the MTD to be 
expanded by up to a maximum of 18 subjects for further evaluation of safety, PK, 
pharmacodynamics, and efficacy. 
◦ 
Figure 3.1.3.1-1 (Primary [Every 2-week Dosing of MEDI0680 (AMP-514)] 
Dose-escalation Design): Added a 20 mg/kg MEDI0680 (AMP-514) plus 10 mg/kg 
durvalumab cohort (Cohort 6) to the Q2W dose-escalation schedule. 
7. Section 3.1.3.2 (Modified Zone-based Design): Modified the zone-based design 
(Figure 3.1.3.2-1) to reflect the addition of dose-escalation Cohort 6. 
8. Section 3.2.1.2 (MEDI0680 [AMP-514]): Revised the dosing information for Study 
D6020C00002 (AMP-514-01) to be consistent with the most recent amendment 
(Amendment 3). 
9. Section 4.1.2 (Inclusion Criteria): The following changes were made: 
◦ 
Criterion #2: Revised to reflect the solid tumors types that will be allowed in the 
dose-escalation phase (NSCLC, SCCHN, MSI-high CRC, bladder cancer, ovarian 
cancer, esophageal cancer, gastric cancer, and RCC). In addition, indicated that no 
more than 3 prior lines of systemic therapy will be allowed in the recurrent or 
metastatic setting. 
◦ 
Criterion #2f: Added the following specific inclusion criteria for NSCLC subjects in 
dose escalation and dose expansion: 
▪ 
NSCLC subjects must have received no more than 3 prior lines of therapy, or 
either failed to respond, relapsed or were unable to tolerate standard treatment. 
▪ 
Subjects with EGFR-activating mutations must have received an EGFR TKI and 
subjects with ALK rearrangement positive tumors must have received an ALK 
TKI. 

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▪ 
Subjects with wild-type EGFR and ALK mutation must have failed a 
platinum-based regimen. NOTE: Maintenance therapy following platinum 
doublet-based chemotherapy is not considered a separate line of therapy. Prior 
platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy 
given for locally advanced disease is considered first line therapy only if recurrent 
(local or metastatic) disease developed within 6 months of completing therapy. 
Subjects with recurrent disease > 6 months must also have progressed after a 
subsequent platinum-based chemotherapy regimen given to treat the recurrence. 
◦ 
Criterion #3b: Added that subjects with previously treated CNS metastases must be 
radiographically and neurologically stable for at least 6 weeks. 
10. Section 4.1.3 (Exclusion Criteria): The following changes were made: 
◦ 
Criterion #13: Added that subjects, if enrolled, should not receive live vaccine during 
the study and 30 days after the last dose of durvalumab and MEDI0680. 
◦ 
Criterion #20: Revised to indicate that subjects who have been on bisphosphonates or 
RANKL inhibitors within the past 28 days prior to the first dose of both agents will 
be excluded. 
11. Section 4.2.2 (Treatment Period): The following changes were made: 
◦ 
Indicated that ECGs will be obtained in triplicate for the first dose only and single 
ECGs will be obtained prior to infusion of investigational products at all other 
timepoints and as clinically indicated. 
◦ 
Added a cross-reference to the study procedures for the alternative Q4W 
dose-escalation treatment period in Appendix 11. 
12. Section 4.3.2.2 (Tumor Biopsies): Indicated that fresh tumor biopsies will be obtained at 
baseline from subjects who are in the expanded dose-escalation cohorts or 
dose-expansion cohorts for the malignancies specified. 
13. Section 4.3.4 (Medical History and Physical Examination): Indicated that ECGs will be 
obtained in triplicate for screening and the first dose only and single ECGs will be 
obtained prior to infusion of investigational products at all other timepoints and as 
clinically indicated. 
14. Section 4.5.1.1 (Investigational Product Dose Preparation): The following changes were 
made: 
◦ 
In Table 4.5.1.1-1 (MEDI0680 [AMP-514] Total Deliverable Volume), a row was 
added to show that the total deliverable volume for the 20 mg/kg dose level is 60 mL. 
◦ 
Revised the MEDI0680 (AMP-514) administration duration for doses > 2.5 mg to the 
following: MEDI0680 (AMP-514) will be administered over a minimum of 
60 minutes at doses > 2.5 mg/kg up to a total dose of 1200 mg, and over a minimum 
of 90 minutes at total doses > 1200 mg. 
15. Section 4.5.1.2 (Treatment Administration): Revised the MEDI0680 (AMP-514) 
administration duration for doses > 2.5 mg to the following: MEDI0680 (AMP-514) will 
be administered over a minimum of 60 minutes at doses > 2.5 mg/kg up to a total dose of 
1200 mg, and over a minimum of 90 minutes at total doses > 1200 mg. 
16. Section 4.7.2 (Prohibited Concomitant Medications): Replaced “denosumab” with 
“bisphosphonates and RANKL inhibitors.” 

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17. Section 4.8.2 (Sample Size and Power Calculations): Changed the planned number of 
subjects as follows: 
◦ 
From 190 to 196 subjects for both dose escalation and dose expansion. 
◦ 
The maximum number of subjects that could be enrolled was increased from 510 to 
516. 
◦ 
The number of subjects in the dose-escalation phase was changed from 30 to 36. 
◦ 
The number of dose cohorts to be evaluated in the dose-escalation phase was changed 
from 5 to 6.  
18. Section 5.3 (Definition of Adverse Events of Special Interest): To be consistent with 
other MedImmune immunotherapy protocols, revised the language for Section 5.3.1 
(Hepatic Function Abnormality) and Section 5.3.2 (Pneumonitis), and added language to 
Section 5.3.3 (Infusion Reactions), Section 5.3.4 (Hypersensitivity Reactions), and 
Section 5.3.5 (Gastrointestinal Disorders). 
 
9.6 
Protocol Amendment 1, 16Apr2014 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Major changes to the protocol are summarized below. 
1. All relevant sections: Given regulatory approval of the new drug name, “AMP-514” was 
replaced with “MEDI0680.”  
2. Title page and headers: The protocol number “D.6020.C00001” was changed to 
“D6020C00001.” 
3. Synopsis: The synopsis was updated to align with the body of the protocol. 
4. Section 2.2.2 (Secondary Endpoints): A reference (Cheson et al, 2006) was added for the 
IWG 2006 MDS response criteria. 
5. Section 3.1.1 (Overview) and Section 3.1.1.2 (Dose-expansion Phase): Text was added to 
clarify that immunotherapy-naïve subjects will be enrolled in up to 8 hematologic and 
solid tumor cohorts, and to indicate that the immunotherapy-naïve cohort could enroll an 
additional 60 subjects based on emerging efficacy and safety data from the current study 
and ongoing studies. In addition, text was added to specify that each hematologic cohort, 
including MDS, will only be expanded after submission of a formal protocol amendment. 
Identical language was added for the immunotherapy-pretreated cohort. 
6. Section 4.1.2 (Inclusion Criteria): The following sub-bullet “b” was added under 
inclusion criterion #4: “Must have failed to respond or relapsed following platinum-
containing doublet chemotherapy.” 
7. Section 4.2.1 (Enrollment/Screening Period): In Table 4.2.1-1, the cross-reference to the 
Smoking Questionnaire was corrected (changed from “Appendix 5” to “Appendix 4”). 
8. Section 4.3.3.1 (Pain Questionnaire): The cross-reference to the Pain Questionnaire was 
corrected (changed from “Appendix 4” to “Appendix 5”). 
9. Section 4.7.2 (Prohibited Concomitant Medications): The following statement was 
removed from the exclusionary medications list: “If steroids are permitted, there must be 

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a 14 days delay between stopping of steroids and the next dose of durvalumab and 
AMP-514.” 
10. Section 8 (References): The Cheson et al, 2006 reference was added to the list. 
11. Appendix 4 (Smoking Questionnaire): The questionnaire was revised to correct typos, 
number the questions, and add notes to indicate that questions can be skipped as needed. 
 

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APPENDICES 
 

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Appendix 1 
Signatures 

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Sponsor Signature(s) 
A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 
(AMP-514) in Combination with Durvalumab versus Nivolumab Monotherapy in Subjects 
with Select Advanced Malignancies 
I agree to the terms of this protocol. 
 
Signature and date:  Electronic signature appended 
 
, MD, 
, 
, 
 
One MedImmune Way, Gaithersburg MD, 20878, USA  
Telephone number: 
 
 
 
 
 
 
 
 
 
 
 

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Signature of Principal Investigator 
A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 
(AMP-514) in Combination with Durvalumab versus Nivolumab Monotherapy in Subjects 
with Select Advanced Malignancies. I, the undersigned, have reviewed this protocol, and I 
agree to conduct this protocol in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with the International Conference for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP), any applicable laws and 
requirements, and any conditions required by a regulatory authority and/or Institutional 
Review Board/Independent Ethics Committee (IRB/IEC).  
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt. 
Signature and date:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name and title:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address including postal code:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone number:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site/Center Number (if available): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision. 
 

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Appendix 2 
Additional Safety Guidance 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03 as provided 
below. The determination of severity for all other events not listed in the NCI CTCAE should 
be made by the investigator based upon medical judgment and the severity categories of 
Grade 1 to 5 as defined below. 
Grade 1 (mild) 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living. 
Grade 2 (moderate) 
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject. 
Grade 4 (life threatening) 
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc). 
Grade 5 (fatal)  
 
 
 
Death (loss of life) as a result of an event. 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE. 
 

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Assessment of Relationship 
Relationship to Investigational Product 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. 
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met: 
• An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related) 
• A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident) 
• A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
 
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met.  
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation). 
Relationship to Protocol Procedures 
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, washout of an existing medication). The 
following guidelines should be used by investigators to assess the relationship of SAEs to the 
protocol: 

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Protocol related: 
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record. 
Not protocol related: 
The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative 
etiology must be documented in the study subject’s medical 
record). 

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Appendix 3 
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report -- 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7. 
The NIAID and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset 
and may cause death. They recognize 3 categories of anaphylaxis, with criteria designated to 
capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 
3 categories).  
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
 
 

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Appendix 4 
Smoking Questionnaire 
Question 
Answer 
1. Have you ever smoked? 
Yes          
No  
(If no, skip to Question 9) 
2. Do you currently smoke? 
Yes          
No  
(If yes, skip to Question 4) 
3. If you do not currently smoke, specify number of  
    years since cessation 
___________ years (number) 
4. Smoking duration 
___________ years (number) 
5. Average number of cigars/day 
___________ per day (number) 
6. Average number of pipes/day 
___________ per day (number) 
7. Average number of packs/day (20 cigarettes per  
    pack) 
___________ per day (number) 
8. Number of pack-years 
___________ years (number) 
9. Have you ever used smokeless tobacco (chewing  
    tobacco or snuff) 
Yes          
No  
(If no, skip the questions below) 
10. Do you currently use smokeless tobacco? 
Yes          
No  
(If yes, skip to Question 12) 
11. If you do not currently use smokeless tobacco,  
      specify the number of years since cessation 
___________ years (number) 
12. Smokeless tobacco duration 
___________ years (number) 
13. Average packages (cans or pouches) of 
smokeless  
      tobacco per day 
___________ per day (number) 
 
 
 
 

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Appendix 5 
Solid Tumor Efficacy 
Tumor assessments will be based on RECIST v1.1 (Eisenhauer et al, 2009) and will be 
performed according to the schedule presented in Section 4.2. All images will be collected 
and stored for possible future central re-analysis. All subjects will be followed for survival 
every 3 months (± 1 week) until 12 months post last dose, and then every 6 months 
(± 2 weeks) until the end of the study (defined as 2 years after the last subject is enrolled or 
the sponsor stops the study). 
In the dose-escalation phase, RECIST will be modified so that PD must be confirmed at least 
4 weeks after the initial assessment of PD in the absence of clinical deterioration (ie, rapid 
disease progression or threat to vital organs/critical anatomical sites requiring urgent 
alternative medical intervention, decline in ECOG performance status, or symptoms or signs 
indicating clinically significant progressive disease). Treatment with investigational products 
(MEDI0680 and durvalumab) will continue between the initial assessment of progression and 
confirmation of progression (see Section 3.1.2.1 for treatment beyond progression). In the 
absence of clinical deterioration, RECIST with this modification may discourage the early 
discontinuation of the investigational products and provide a more complete evaluation of its 
antitumor activity than would be seen with conventional response criteria. 
Tumor assessments should include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable) and CT or magnetic resonance 
imaging (MRI) scans. Computed tomography or MRI scan of the chest, abdomen, and pelvis 
will be performed at screening and for response assessment in all subjects. Computed 
tomography or MRI scan of the head and neck is only required for subjects with SCCHN or 
for subjects with metastatic disease in the head or neck not involving the CNS. Computed 
tomography or MRI scan of the brain will be performed at screening for subjects with known 
CNS metastatic disease or if the subject is neurologically symptomatic during the course of 
the study. The preferred method of disease assessment is CT with contrast. If CT with 
contrast is contraindicated, CT without contrast is preferred over MRI. The same method is 
preferred for all subsequent tumor assessments. 
Physical examination 
• Lesions detected by physical examination will only be considered measurable if 
superficial, eg, skin nodules and palpable lymph nodes. Documentation by color 
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CT scan  
• CT (contrast preferred) scans should be performed with contiguous cuts in slice thickness 
of 5 mm or less. Spiral CT should be performed using a 5-mm contiguous reconstruction 
algorithm. 
 
MRI scan 
• MRI scan should use the same anatomical plane for serial assessments.  
• In case of MRI, measurements will be preferably performed in the axial (transverse) 
plane on contrast-enhanced T1-weighted images. However, there are no specific 
sequence recommendations. 
 
Measurability of Tumor Lesions  
Tumor lesions will be categorized as follows: 
• Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:  
 
◦ 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm)  
◦ 
10-mm caliper measurement by clinical exam (when superficial) 
◦ 
For malignant lymph nodes to be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm) 
• Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm in short axis). Lesions considered truly 
nonmeasurable include the following: leptomeningeal disease, ascites, pleural/pericardial 
effusion, and inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that are not 
measurable by reproducible imaging techniques. 
• Target Lesions – At baseline, all lesions up to a maximum of 5 lesions total (and a 
maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
• Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case report form (eg, “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
• New Lesions - If measurable, new lesions will be measured and included as target lesions 
in order to facilitate the exploratory irRECIST analysis. Using irRECIST, up to 

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5 additional new lesions (maximum of 2 additional lesions per organ) may be included in 
the tumor burden at each post-baseline assessment. Other new lesions will be followed as 
non-target lesions. 
 
RECIST v1.1 Response Criteria 
Evaluation of Target Lesions 
• Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes).  
• Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more 
new lesions is also considered progression.) 
• Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
Evaluation of Non-target Lesions 
• Complete Response - Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm in short 
axis).  
• Non-complete Response/Non-progressive Disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
• Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in nonmeasurable disease comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from “trace” to “large,” or an increase in lymphangitic disease from localized to 
widespread. 
 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v1.1. Considering the 
unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 

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continue to receive MEDI0680/durvalumab combination therapy or nivolumab monotherapy 
if investigators consider that subjects continue to benefit from treatment (see Section 3.1.2.1). 
Evaluation of Overall Response 
Confirmation of CR, PR is required by a repeat assessment no fewer than 4 weeks from the 
date of first documentation.  
For the dose-escalation phase, efficacy analyses will be based on an application of modified 
RECIST v1.1 to investigator-assessed tumor measurements. RECIST v1.1 has been modified 
to require confirmation of PD. A confirmed PD will be a PD confirmed by a consecutive 
repeat assessment no fewer than 4 weeks later. A PD that occurs without follow-up scans to 
provide confirmation or only non-evaluable follow-up scans will also be considered a 
confirmed PD. The efficacy analysis will be based on the As-treated Population. 
For the dose-expansion phase, efficacy analyses will be based on an application of 
RECIST v1.1 to investigator-assessed tumor measurements and BICR. The efficacy analysis 
will be based on the As-treated Population. 
Overall responses for all possible combinations of tumor responses in target and non-target 
lesions with or without the appearance of new lesions are shown below. 
Table A5-1 
Evaluation of Overall Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response or  
No non-target lesion 
No 
Complete response 
Complete response 
Non-complete response / 
Non-progressive disease or  
Non-evaluable b 
No (or NE) 
Partial response 
Partial response 
Complete response or  
Non-complete response / 
Non-progressive disease or  
Non-evaluable b 
No (or NE) 
Partial response 
Stable disease 
Complete response or  
Non-complete response / 
Non-progressive disease or  
Non-evaluable b 
No (or NE) 
Stable disease 
Progressive disease 
Any 
Yes or No 
Progressive disease 
Any 
Progressive disease 
Yes or No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
Non-evaluable 
Complete response or  
Non-complete response / 
No 
Non-evaluable 

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Table A5-1 
Evaluation of Overall Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Non-progressive disease or  
Non-evaluable b 
No target lesion a  
Complete response 
No 
Complete response 
No target lesion a 
Non-complete response / 
Non-progressive disease 
No 
Non-complete response / 
Non-progressive disease 
No target lesion a 
Not all evaluated 
No 
Not evaluable 
No target lesion a 
Complete response or  
Non-complete response / 
Non-progressive disease 
Yes 
Non-complete response / 
Non-progressive disease 
a 
Defined as no target or non-target lesion at baseline. 
b 
Non-evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment or when lesion intervention occurs that directly affects a target lesion.  If progressive disease 
criteria is met despite these events, progressive disease should be defined. 
 
 
 
 
 

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Appendix 6 
Durvalumab and MEDI0680 Dose Modifications for 
Toxicity Management 
Table A6-1 Immune-mediated reactions 
Table A6-2 Infusion-related reactions 
Table A6-3 Non-immune mediated reactions 
 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Immune-
mediated 
adverse events 
(overall 
management for 
toxicities not 
noted below) 
 
Drug administration modifications of 
study drug/study regimen will be made to 
manage potential immune-mediated AEs 
based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
• 
In addition to the criteria for 
permanent discontinuation of 
study drug/regimen based on CTC 
grade/severity (table below) , 
permanently discontinue study 
drug/study regimen for the 
following conditions: Inability to 
reduce corticosteroid to a dose of 
≤ 10 mg of prednisone per day (or 
equivalent) within 12 weeks after 
last dose of study drug/regimen 
• 
Recurrence of a previously 
experienced Grade 3 treatment-
related AE following resumption 
of dosing. 
It is recommended that management of imAEs follow the guidelines 
presented in this table 
- 
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, concomitant 
medications, infections, etc) 
- 
In the absence of a clear alternative etiology, all events 
should be considered potentially immune mediated. 
- 
Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events  
- 
For persistent (greater than 3 to 5 days) low-grade (Grade 2) 
or severe (Grade ≥ 3) events promptly start prednisone PO 
1-2 mg/kg/day or IV equivalent  
- 
If symptoms recur or worsen during corticosteroid tapering 
28 days of taper), increase the corticosteroid dose (prednisone 
dose [eg, up to 2-4 mg/kg/day or IV equivalent]) until 
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (> 28 days of taper) 
- 
More potent immunosuppressives such as TNF inhibitors (eg, 
infliximab) – (also refer to the individual sections of the 
immune mediated adverse event for specific type of 
immunosuppressive) should be considered for events not 
responding to systemic steroids.  
- 
Discontinuation of study drug is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumour 
response (eg, inflammatory reaction at sites of metastatic 
disease, lymph nodes etc). Continuation of study drug in this 
situation should be based upon a benefit/risk analysis for that 
subject.  
Grade 1 
No dose modification 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 2 
Hold study drug/study regimen dose until 
grade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 
3 or Grade 4 
• If toxicity improves to baseline then 
treat at next scheduled treatment date 
Study drug/study treatment can be 
resumed at the next scheduled dose once 
event stabilizes to Grade ≤ 1 and 5-7 
days have passed after completion of 
steroid taper 
Subjects with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 1) the event stabilizes and is 
controlled, 2) the subject is clinically 
stable as per Investigator or treating 
physician’s clinical judgement, and 3) 
doses of prednisone are at less than or 
equal to 10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, 
may permanently discontinue study 
drug/study regimen. Please refer to 
guidelines below 
Grade 4 
Permanently discontinue study 
drug/study regimen  
Note: For Grade 3 and above asymptomatic amylase or lipase levels hold study drug/regimen and if complete work up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ILD 
Grade of 
pneumonitis 
(CTCAE version 
4.03)  
Any Grade 
- 
Monitor subjects for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Subjects should be evaluated with imaging and pulmonary 
function tests including other diagnostic procedures as 
described below 
- 
Initial work-up may include clinical evaluation, monitoring 
of oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT scan.  
Grade 1  
(asymptomatic, 
clinical or 
diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. However, 
consider holding study drug/study 
regimen dosing as clinically appropriate 
and during diagnostic work-up for other 
etiologies 
• 
For Grade 1 (radiographic changes only) 
- 
Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated 
- 
Consider pulmonary and infectious disease consult 
Grade 2  
(symptomatic, 
medical intervention 
indicated, limiting 
instrumental ADL)  
• 
Hold study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4  
• 
Study drug/study treatment can be 
resumed based upon treating 
physician’s clinical judgment at the 
next scheduled dose once event 
stabilizes to Grade ≤ 1 or baseline 
and 5-7 days have passed after 
completion of steroid taper  
• 
For Grade 2 (mild to moderate new symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (eg, prednisone 
1-2 mg/kg/day or IV equivalent) 
- 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started  
- 
If still no improvement within 3-5 days despite IV 
methylprednisone at 2-4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors (eg, 
infliximab at 5 mg/kg every 2 weeks). Caution: Important to 
rule out sepsis and refer to infliximab label for general 
guidance before using infliximab  

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
- 
Once improving, gradually taper steroids over ≥ 4 weeks and 
consider prophylactic antibiotics, antifungal or anti PCP 
treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections (Category 2B recommendation)1 
- 
Consider pulmonary and infectious disease consult 
- 
Consider as necessary discussing with study physician 
Grade 3 or 4  
(Grade 3: severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention 
indicated [eg, 
tracheostomy or 
intubation])  
Permanently discontinue study 
drug/study regimen 
• 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life threatening  
- 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent  
- 
Obtain pulmonary and infectious disease consult 
- 
Hospitalize the subject 
- 
Supportive Care (oxygen, etc) 
- 
If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors (eg, 
infliximab at 5 mg/kg every 2 weeks dose) started. Caution: 
rule out sepsis and refer to infliximab label for general 
guidance before using infliximab  
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and in 
particular, anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation) 2 
Diarrhea/ 
enterocolitis 
Grade of diarrhea 
(CTCAE version 
4.03) 
Any grade 
- 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 
                                                 
1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”  
2 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”  

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs and ileus) 
- 
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, infections including testing for clostridium 
difficile toxin, etc) 
- 
Steroids should be considered in the absence of clear 
alternative etiology, even for low grade events, in order to 
prevent potential progression to higher grade event 
- 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis 
Grade 1 diarrhea 
(stool frequency of 
< 4 over baseline 
per day)  
No dose modification 
• 
For Grade 1 diarrhea :  
- Close monitoring for worsening symptoms 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical judgment. 
Grade 2 diarrhea 
(stool frequency of 
4-6 over baseline 
per day)  
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to baseline 
then treat at next scheduled 
treatment date will be based upon 
treating physician’s clinical 
judgment. 
• 
Study drug/study treatment can be 
resumed based upon treating 
physician’s clinical judgment at 
the next scheduled dose once 
• 
For Grade 2 diarrhea:  
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide  
- 
Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, GI consult 
should be obtained for consideration of further workup such 
as imaging and/or colonoscopy to confirm colitis and rule out 
perforation, and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started.  
If still no improvement within 3-5 days despite 2-4 mg/kg IV 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
event stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have passed 
after completion of steroid taper 
methylprednisolone, promptly start 
immunosuppressives - such as (infliximab at 5 mg/kg once 
every 2 weeks3). Caution: important to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab  
- 
Consult study physician if no resolution to ≤ Grade 1 in  
3-4 days 
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 
Grade 3 or 4 
diarrhea  
 
(Grade 3: stool 
frequency of ≥ 7 
over baseline per 
day;  
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen 
• 
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent  
- 
Monitor stool frequency and volume and maintain hydration  
- 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate 
- 
If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg, infliximab at 5 mg/kg 
once every 2 weeks).  
- 
Caution: ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before using 
infliximab.  
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
                                                 
3 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects  

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
treatment of cancer-related infections [Category 2B 
recommendation]) 
Hepatitis 
(elevated LFTs) 
Infliximab 
should not be 
used for 
management of 
immune 
mediated 
hepatitis 
Grade of liver 
function test 
elevation (CTCAE 
version 4.03) 
Any grade 
  
- 
Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin  
- 
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications)  
Grade 1  
(AST or ALT > 
ULN to 3 times 
ULN and/or TB > 
ULN to 1.5 times 
ULN) 
No dose modification 
If it worsens, treat as Grade 2 event 
• 
For Grade 1 AST or ALT and/or TB elevation  
•  - Continue LFT monitoring per protocol  
Grade 2  
(AST or ALT > 3 to 
5 times ULN and/or 
TB > 1.5-3.0 times 
ULN) 
• Hold Study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 
3 or Grade 4 
• Study drug/study treatment can be 
resumed based upon treating 
physician’s clinical judgment at the 
next scheduled dose once event 
stabilizes to Grade ≤ 1 or baseline 
and 5-7 days have passed after 
completion of steroid taper 
• 
For Grade 2 AST or ALT and or TB elevation :  
- 
Regular and frequent checking of LFTs (eg, every 1-2 days) 
until elevations of these are improving or resolved.  
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with study 
physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1-2 mg/kg/day or IV equivalent.  
- 
If still no improvement within 3-5 days despite 
1-2 mg/kg/day of prednisone or IV equivalent, consider 
additional workup and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started. 
- If still no improvement within 3-5 days despite 2-
4 mg/kg/day of IV methylprednisolone, promptly start 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
immunosuppressives (mycophenolate mofetil-)4 . Discuss 
with study physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used. 
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals, and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 
Grade 3 
(AST or ALT 
> 5-20 times ULN 
and/or TB > 
3.0-10 times ULN 
• For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 × 
ULN  
• 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 or 
baseline  
• Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade ≤ Grade 
1 or baseline   
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to ≤ Grade 1  
• For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 × 
ULN, discontinue study drug/study 
regimen  
• Permanently discontinue study 
drug/study regimen for any case 
• 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent  
- 
If still no improvement within 3-5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
- 
Hepatology consult, abdominal workup, and imaging as 
appropriate. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals, and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 
                                                 
4 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by Michael Postow MD 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
meeting Hy’s law criteria (ALT > 3 × 
ULN + bilirubin > 2 × ULN without 
initial findings of cholestasis (i.e. 
elevated alkaline P04) and in the 
absence of any alternative cause5 
Grade 4  
(AST or ALT > 
20 times ULN 
and/or TB > 
10 times ULN)  
Permanently discontinue study 
drug/study regimen  
 
Nephritis or 
renal 
dysfunction 
(elevated serum 
creatinine)  
Grade of elevated 
serum creatinine 
(CTCAE version 
4.03) 
 
Any grade  
-- 
 
 
 
- 
Consult with nephrologist 
- 
Monitor for signs and symptoms that may be related to 
changes in renal function (eg, 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 (eg, disease progression, infections etc.) 
- 
Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 2), in 
order to prevent potential progression to higher grade event 
Grade 1 [serum 
creatinine > 1-1.5 × 
baseline; > ULN to 
1.5 × ULN]  
No dose modification 
• 
For Grade 1 elevated creatinine:  
• Monitor serum creatinine weekly and any accompanying 
symptom 
x 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
x 
If it worsens, depending on the severity , treat as 
                                                 
5 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 or Grade 3 or 4  
• Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc. 
Grade 2 [serum 
creatinine > 1.5-3.0 
× baseline; > 1.5 × 
3.0 × ULN] 
• 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
Study drug/study treatment can be 
resumed based upon treating 
physician’s clinical judgment at the 
next scheduled dose once event 
stabilizes to Grade ≤ 1 or baseline 
and 5-7 days have passed after 
completion of steroid taper 
• 
For Grade 2 elevated creatinine:  
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc.  
- 
Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted 
- 
Consult nephrologist and consider renal biopsy if clinically 
indicated 
- 
If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2-4 mg/kg/day started.  
- 
Once improving gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals, and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).  
- 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4  
(Grade 3: serum 
creatinine > 3.0 × 
baseline; > 3.0-6.0 × 
ULN 
Permanently discontinue study 
drug/study regimen 
- 
Carefully monitor serum creatinine on daily basis 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- 
Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent  

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 4: serum 
creatinine > 6.0 × 
ULN)  
- 
If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started.  
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals, and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]  
Rash (excluding 
bullous skin 
formations) 
Grade of skin rash  
(please refer to NCI 
CTCAE version 
4.03 for definition 
of severity/grade 
depending on type 
of skin rash)  
Any grade 
• 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus)  
• 
**IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED AND 
STUDY DRUG DISCONTINUED** 
Grade 1  
No dose modification 
• 
For Grade 1: 
- 
Consider symptomatic treatment including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream) 
Grade 2 
• 
For persistent (> 1-2 weeks) 
Grade 2 events, hold scheduled 
study drug/study regimen until 
resolution to ≤ Grade 1 or baseline  
- 
If toxicity worsens then treat as 
Grade 3  
- 
If toxicity improves then resume 
administration at next scheduled 
• 
For Grade 2: 
- 
Obtain dermatology consult  
- 
Consider symptomatic treatment including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream) 
- 
Consider moderate-strength topical steroid  
- 
If no improvement of rash/skin lesions occurs within 3-5 days 
or is worsening despite symptomatic treatment and/or use of 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
dose 
- 
Study drug/study regimen can 
be resumed at the next 
scheduled dose once event 
stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have 
passed after completion of 
steroid taper  
moderate strength topical steroid, discuss with study 
physician and promptly start systemic steroids prednisone  
1-2 mg/kg/day or IV equivalent  
- 
Consider skin biopsy if persistent for > 1-2 weeks or recurs 
Grade 3 
• Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
• Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade ≤ Grade 
1 or baseline  
• 
For Grade 3 or 4: 
- 
Consult dermatology  
- 
 Promptly initiate empiric IV methylprednisolone 1 to  
4 mg/kg/day or equivalent  
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
- 
Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 
- 
Discuss with study physician 
Grade 4 
Permanently discontinue study 
drug/study regimen  

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Endocrinopathy 
(eg, 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc) 
Any grade  
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining the 
CTC grade/severity)  
 
- 
Consult Endocrinologist 
- 
Monitor subjects for signs and symptoms of 
endocrinopathies. Non-specific symptoms include headache, 
fatigue, behavior changes, changed mental status, vertigo, 
abdominal pain, unusual bowel habits, hypotension and 
weakness. 
- 
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy.  
- 
If a subject experiences an AE that is thought to be possibly 
of autoimmune nature (eg, thyroiditis, pancreatitis, 
hypophysitis, diabetes insipidus), the investigator should send 
a blood sample for appropriate autoimmune antibody testing  
Grade 1 
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining the 
CTC grade 1) 
No dose modification 
• 
For Grade 1: (including those with asymptomatic TSH 
elevation) 
- 
Monitor subject with appropriate endocrine function tests 
- 
If TSH < 0.5 × LLN, or TSH > 2 × ULN or consistently out 
of range in 2 subsequent measurements, include FT4 at 
subsequent cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2  
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
• For Grade 2 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until subject 
is clinically stable 
• If toxicity worsens then treat as Grade 
3 or Grade 4  
• 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
4.03 for defining the 
CTC grade/severity 
2) 
• If toxicity improves to baseline then 
treat at next scheduled treatment date 
• Study drug/study regimen can be 
resumed at the next scheduled dose 
once event stabilizes to Grade ≤ 1 and 
5-7 days have passed after completion 
of steroid taper 
• Subjects with endocrinopathies who 
may require prolonged or continued 
steroid replacement can be retreated 
with study drug/study regimen on the 
following conditions: 1) the event 
stabilizes and is controlled, 2) the 
subject is clinically stable as per 
Investigator or treating physician’s 
clinical judgement, and 3) doses of 
prednisone are at less than or equal to 
10 mg/day or equivalent. 
- 
Initiate hormone replacement as needed for management 
- Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan 
- For subjects with abnormal endocrine work up, except for 
those with isolated hypothyroidism, consider short-term, 
corticosteroids (eg, 1-2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with relevant 
hormone replacement (eg, Levothyroxine, hydrocortisone, or 
sex hormones). 
- Once improving, gradually taper steroids over ≥ 28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]) 
- For subjects with normal endocrine work up (lab or MRI 
scans), repeat labs/MRI as clinically indicated. 
Grade 3 or 4 
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining the 
CTC grade/severity 
3 or 4)  
• For Grade 3 or 4 endocrinopathy 
other than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled 
• Resume study drug/study regimen 
administration if controlled at the next 
scheduled dose 
• Study drug/study treatment can be 
resumed based upon treating 
physician’s clinical judgment at the 
next scheduled dose once event 
stabilizes to Grade ≤ 1 or baseline and 
• 
For Grade 3 or 4: 
- 
Consult endocrinologist 
- 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids 
- 
Promptly initiate empiric IV methylprednisolone 1 to  
2 mg/kg/day or equivalent 
- 
Administer hormone replacement therapy as necessary. 
- 
For adrenal crisis, severe dehydration, hypotension, or shock: 
immediately initiate IV corticosteroids with 
mineralocorticoid activity 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
5-7 days have passed after completion 
of steroid taper 
- 
Once improving, gradually taper immunosuppressive steroids 
over ≥ 4 weeks and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
- 
Discuss with study physician 
Immune 
mediated  
neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
myasthenia 
gravis and 
Guillain-Barre)  
 
Grade of 
neurotoxicity  
Depending on the 
type of 
neurotoxicity, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 
 
Any grade  
 
 
 
 
 
 
 
- 
Subjects should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes and medications, etc)  
- 
Monitor subject for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness) 
- 
Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations) 
- 
Symptomatic treatment with neurological consult as 
appropriate 
 
Grade 1 
No dose modifications 
• 
See “Any Grade” recommendations above. 
Grade 2 
• 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
- 
Discuss with the study physician  
- 
Obtain Neurology Consult  

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Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
regimen dose until resolution to 
≤ Grade 1 
• 
For sensory neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose until 
resolution to ≤ Grade 1. 
- 
If toxicity worsens then treat as 
Grade 3 or Grade 4  
- 
If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
• 
Study drug/study regimen can be 
resumed at the next scheduled dose 
once event stabilizes to Grade ≤ 1 
and 5-7 days have passed after 
completion of steroid taper  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin, duloxetine, etc) 
- 
Promptly start systemic steroids prednisone 1-2 mg/kg/day or 
IV equivalent  
- 
If no improvement within 3-5 days despite 1-2 mg/kg/day 
prednisone or IV equivalent consider additional workup and 
promptly treat with additional immunosuppressive therapy 
(eg, IVIG)  
 
Grade 3 
• 
Hold Study drug/study regimen dose 
until resolution to ≤ Grade 1 
• 
Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade ≤ 
Grade 1 or baseline. 
• 
For Grade 3 or 4: 
- 
Discuss with study physician 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent  
- 
If no improvement within 3-5 days despite IV corticosteroids, 
consider additional workup and promptly treat with 
additional immunosuppressants (eg, IVIG)  
- 
Once stable, gradually taper steroids over ≥ 4 weeks 
Grade 4 
• 
Permanently discontinue study 
drug/study regimen 
Immune-
mediated 
peripheral 
 
Any Grade 
- 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain subjects 
may unpredictably experience acute decompensations which 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
neuromotor 
syndromes, such 
as Guillain-Barre 
and myasthenia 
gravis 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
which may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability 
- 
Subjects should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes and medications, etc). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in subjects with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological 
consult 
- 
Neurophysiologic diagnostic testing (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” 
if myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated by 
means of a neurology consultation  
• 
Important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Subjects requiring treatment should be 
started with IVIG and followed by plasmapheresis if not 
responsive to IVIG  
Grade 1 
No dose modification 
- 
Discuss with the study physician 
- 
Care should be taken to monitor subjects for sentinel 
symptoms of a potential decompensation as described above 
- 
Obtain a neurology consult unless the symptoms are very 
minor and stable 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 
• Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
• Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade ≤ Grade 
1 or baseline 
• 
Grade 2  
- 
Discuss with the study physician  
- 
Care should be taken to monitor subjects for sentinel 
symptoms of a potential decompensation as described above 
- 
Obtain a Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin, duloxetine, etc) 
◦ 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat 
Myasthenia Gravis. Important to consider that 
steroid therapy (especially with high doses) may 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IVIG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each subject. 
o 
If Myasthenia Gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
◦ 
GUILLAIN-BARRE:  
o 
Important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not 
typically considered effective. Subjects requiring 
treatment should be started with IVIG and followed 
by plasmapheresis if not responsive to IVIG. 

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Table A6-1 
Immune-mediated reactions 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 
• Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
• Resume study drug/study regimen 
administration at the next scheduled 
dose if elevations downgrade ≤ Grade 
1 or baseline 
• 
For severe or life threatening (Grade 3 or 4) events:  
- 
Discuss with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
◦ 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat 
Myasthenia Gravis. It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IVIG. 
o 
If Myasthenia Gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
◦ 
GUILLAIN-BARRE:  
◦ 
Important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not 
typically considered effective. Subjects requiring 
treatment should be started with IVIG and followed 
by plasmapheresis if not responsive to IVIG 
Grade 4 
Permanently discontinue study 
drug/study regimen  
AChE = acetylcholine esterase; ADL = activities of daily living; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; CT = computed tomography; CTC = Common Terminology Criteria; FT4 = free thyroxine; GI = 
gastrointestinal; ILD = interstitial lung disease; imAE = immune-mediated adverse event; IV = intravenous; IVIG = intravenous immunoglobulin; LFT = liver 
function test; LLN = lower limit of normal; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events; PCP = pneumocystis pneumonia; PO = oral; TB = total bilirubin; TNF = tumor necrosis 
factor; TSH = thyroid-stimulating hormone; ULN = upper limit of normal. 
 

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Table A6-2 
Infusion-related reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any grade 
 
- 
Management per institutional standard at the discretion of investigator 
- 
Monitor subjects for signs and symptoms of infusion-related reactions 
(eg, fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
etc) and anaphylaxis (eg, generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia, etc) 
Grade 1 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator  
- 
Consider premedication per institutional standard prior to subsequent 
doses 
Grade 2 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until 
resolution of the event  
Subsequent infusions may be given at 50% of the initial 
infusion rate 
Grade 3/4 
Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions per institutional standards (eg, 
IM epinephrine, followed by IV diphenhydramine and ranitidine, and IV 
glucocorticoid) 
IM = intramuscular; IV = intravenous. 
 

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Table A6-3 
Non-immune-mediated reactions 
CTC Grade/Severity 
Dose Modification 
Toxicity Management 
Any grade 
Note: dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly as per 
institutional standard 
1 
No dose adjustment  
Treat accordingly as per 
institutional standard 
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per 
institutional standard 
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline, resume 
study drug/study regimen administration at next scheduled dose based upon treating physician’s 
clinical judgment . Otherwise, discontinue study drug/study regimen 
Treat accordingly as per 
institutional standard 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with the sponsor)  
Treat accordingly as per 
institutional standard 
AE = adverse event; CTC = Common Terminology Criteria. 
 
 

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Appendix 7 
Memorial Sloan Kettering Cancer Center Prognostic 
Score (Renal Cell Carcinoma) 
Table A7-1 
Determination of MSKCC Prognostic Score in Previously 
Treated Subjects 
Parameter 
Risk Factor 
Criteria Value 
Subject 
Value 
If subject value meets 
criteria value, enter 1 
KPS 
Low KPS 
< 80% 
 
 
Corrected calciuma 
High corrected 
calcium 
 
t 10 mg/dL 
 
 
 
Hemoglobin 
Low hemoglobin 
Males: d 13 g/dL 
Females: d 11.5 g/dL 
 
 
 
Sum total of above = 
MSKCC Prognostic 
Score 
Adapted from Motzer et al, 2015 
KPS = Karnofsky performance score; MSKCC = Memorial Sloan Kettering Cancer Center. 
a 
Corrected calcium = ([4 - serum albumin in g/dL] × 0.8) + serum calcium 
 
Table A7-2 
Risk Group Based on MSKCC Prognostic Score 
Risk Group 
MSKCC Prognostic Score 
Favorable-risk 
0 
Intermediate-risk 
1 or 2 
Poor-risk 
3 
MSKCC = Memorial Sloan Kettering Cancer Center. 
Prognostic risk groups are based on the presence of 0 (favorable), 1 or 2 (intermediate), or 3 (poor) of the 
following prognostic factors: anemia, hypercalcemia, and poor Karnofsky performance status