Conditions: Advanced and/or Metastatic Sarcoma
Keywords: Malignant neoplasms of bone and articular cartilage Multiple sarcoma subtypes Advanced and/or metastatic sarcoma Adipocytic tumors Vascular tumors Leiomyosarcoma Angiosarcoma Epithelioid hemangioendothelioma Undifferentiated pleomorphic sarcoma Synovial sarcoma Osteosarcoma Other sarcoma histologies Durvalumab Tremelimumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 57
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if the combination of durvalumab and tremelimumab can help to control sarcoma. The safety of this drug combination will also be studied.

This is an investigational study. Durvalumab and tremelimumab are not FDA approved or commercially available. They are currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work.

Up to 150 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive tremelimumab and durvalumab by vein, over about 1 hour each, every 4 weeks for up to 16 weeks (4 doses). After Week 16, you may continue to receive durvalumab alone by vein over about 1 hour for an additional 32 weeks (8 doses).

If you have a side effect related to the combination of durvalumab and tremelimumab during the first 16 weeks of the study, you may be able to switch over to receive durvalumab alone sooner than expected. This will be discussed with you.

Study Visits:

On Day 1 of Week 0:

* You will have a physical exam.
* You will have 3 EKGs in a row.
* Blood (about 1 tablespoon) and urine will be collected for routine tests. If you can become pregnant, part of this routine blood and urine sample will be used for a pregnancy test.
* Blood (about 2½ tablespoons) will be drawn for biomarker and genetic testing. Biomarkers are found in the blood and may be related to your reaction to the study drug. The type of genetic testing in this study will be performed to learn how your DNA (genetic material) may change how you respond to the study drugs.

On Day 1 of Weeks 2 and 6, blood (about 3½ tablespoons) will be drawn for routine, genetic, and biomarker testing.

On Day 1 of Week 4 and then every 4 weeks after that (Weeks 8, 12, 16, and so on) until Week 44:

* You will have a physical exam.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* You will have imaging scans. You will not have these scans at Weeks 16 and 24.

On Day 1 of Weeks 10 and 14, blood (about 1 tablespoon) will be drawn for routine tests.

Length of Study:

You may receive up to 4 doses of durvalumab in combination with tremelimumab and up to an additional 8 doses of durvalumab alone. You will no longer be able to take the study drug(s) if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

If you complete 12 months of therapy but the disease appears to get worse, you may be able to re-start treatment. The study doctor will discuss this with you.

It is expected that your participation in this study may last up to 15 months. Your participation on the study will be over after the follow-up visits.

End-of-Treatment Visit:

As soon as possible after your last dose of study drug(s):

* You will have a physical exam.
* You will have an MRI, CT, or PET/CT scan.
* Blood (about 1 tablespoon) and urine will be collected for routine tests.
* Blood (about 1 tablespoon) will be drawn for biomarker and genetic testing.

Follow-Up Visit:

About 30 days after your last dose of study drug(s):

You will have a physical exam. Blood (about 1 tablespoon) will be drawn for routine tests.

Long-Term Follow-Up

Every 3 months:

* You will have an MRI, CT, or PET/CT scan.
* You may be called to learn how you are doing and if you have started any anti-cancer treatments. If you are called, it should take about 5-10 minutes.

Arms:
arm 1: Adipocytic Tumors Group consists of well-diff/de-differentiated, pleomorphic and myxoid LPS.

Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab 1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses. arm 2: Vascular Tumors Group consists of leiomyosarcomas, angiosarcomas, epithelioid hemangioendotheliomas, and hemangiopericytomas.

Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by Durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses. arm 3: Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab 1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by Durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses. arm 4: Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab 1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which Durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses. arm 5: Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab 1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which Durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses. arm 6: Age group ≥12 and \<18: Dosages of study drugs to be determined (TBD).

Age group ≥ 18: Durvalumab 1500 mg and Tremelimumab 75 mg every 4 weeks for 4 cycles followed by durvalumab 1500 mg every 4 weeks for up to 8 additional cycles.

Combination of both agents administered every 4 weeks for a maximum of 4 doses, after which Durvalumab continues as a single agent every 4 weeks till progression or unacceptable toxicity for a maximum of 8 additional doses.

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: Age group ≥ 18: Durvalumab 1500 mg by vein every 4 weeks for 4 cycles. After Week 16, participant may continue to receive durvalumab alone by vein for an additional 32 weeks (8 doses). intervention 2: Age group ≥ 18: Tremelimumab 75 mg every 4 weeks for 4 cycles.

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 1 
Clinical Study Protocol 
Study Code: 2015-1071 
Edition Number: Version 2 
Date: 10 Sep 2019 
<< A Phase II multi-arm study to test the efficacy of immunotherapeutic agents in 
multiple sarcoma subtypes >> 
Sponsor: 
MD Anderson IND office 
Proprietary Information of M.D. Anderson


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 2 
 
 
 
PROTOCOL SYNOPSIS 
 
 
<< A Phase II multi-arm study to test the efficacy of immunotherapeutic 
agents in multiple sarcoma subtypes >> 
 
 
 
Principal Investigator 
Neeta Somaiah M.D., 
 
Co-Principal Investigator 
Anthony Conley M.D. 
Sarcoma Medical Oncology 
1515 Holcombe Blvd. 
Unit 0450 
Houston, TX 77030 
 
 
Study site(s) and number of subjects planned 
Single site: University of Texas M D Anderson Cancer Center 
Total number of subjects: ≤ 150 
Study period 
Phase of development 
Estimated date of first subject enrolled 
July 2016 
Phase II 
Estimated date of last subject completed 
December 2017 
Phase II 
 
Hypothesis 
 
Novel immunotherapeutic agents (including the combination of durvalumab and 
tremelimumab) will be safe, adequately tolerated, and will demonstrate clinical activity in 
Proprietary Information of MD Anderson


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 3 
 
 
 
subjects with select sarcoma subtypes. 
 
Study design 
 
This study is a single-center phase II multi-arm study. This study will include patients (age ≥18 
years) with recurrent/metastatic sarcoma, who have received at least one prior systemic therapy 
(if a standard therapy exists for the subtype), divided into the following categories/subtypes: 
 
a. Adipocytic tumors (Well-differentiated/dedifferentiated liposarcoma, 
myxoid liposarcoma, pleomorphic liposarcoma) 
b. Vascular tumors (leiomyosarcoma, angiosarcoma) 
c. Undifferentiated pleomorphic sarcoma 
d. Synovial sarcoma 
e. Osteosarcoma 
f. Other sarcomas. 
 
Objectives 
 
Primary Objective: 
Outcome Measure: 
To determine the progression-free survival 
(PFS) rate at 12 weeks after the initiation of 
the treatment in patients with 
relapsed/refractory sarcoma receiving novel 
immunotherapeutic agents 
PFS at 12 weeks as defined by RECIST 1.1 
 
 
Secondary Objective: 
Outcome Measure : 
To estimate the tumor response (irRC and 
RECIST) in patients with 
relapsed/refractory sarcoma receiving novel 
immunotherapeutic agents 
irRC and RECIST response rate 
To evaluate the safety and tolerability of 
receiving novel immunotherapeutic agents 
in patients with relapsed/refractory sarcoma 
Toxicity rate (persistent grade 3 and/or 4 toxicity 
despite therapy) per treatment cohort 
To estimate the PFS and overall survival 
(OS) in patients with relapsed/refractory 
sarcoma receiving novel 
immunotherapeutic agents 
PFS and OS 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 4 
 
 
 
 
 
 
Exploratory Objective: 
Outcome Measure : 
To determine expression of biomarkers 
(including but not limited to PD-1 and PD- 
L1) in pre & post tx samples. 
Biomarker (PD-1/PD-L1) expression analysis 
(pre & post tx samples) 
Quantification and characterization of the 
immune infiltrate (and other histologic and 
immunohistologic changes) from tissue 
samples prior to treatment initiation and 
post (treatment biopsy at week 6). 
Tumor infiltrating lymphocytes (TILs) (pre & 
post tx samples) 
Identification/quantification of 
immunologic changes (CD4+, CD8+, Teff, 
and Treg cells) in peripheral blood. 
Determining an immunoscore based on 
baseline tumor sample (identification of 
molecular response/resistance 
patterns/future therapy options) 
 
 
Target subject population 
This study will include patients (age ≥18 years) with recurrent/metastatic sarcoma of the 
following subtypes, who have received at least one prior systemic therapy (if a standard 
therapy exists for the subtype). Patients with low-grade tumors are eligible if there is definite 
evidence of metastasis or progression (defined as 10% increase within a 3 month period). 
 
Cohort 1: Adipocytic sarcomas-Well-diff/De-differentiated, Pleomorphic and Myxoid 
LPS 
Cohort 2: Vascular sarcomas-Leiomyosarcomas, Angiosarcomas 
Cohort 3: Undifferentiated Pleomorphic sarcomas (UPS) 
Cohort 4: Synovial sarcomas 
Cohort 5: Osteosarcoma 
Cohort 6: Other sarcoma subtypes 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 5 
 
 
Duration of treatment 
The expected duration of a patient’s participation in the trial is up to 15 months, including 
screening, treatment period (maximum of 12 months), and a follow-up visit at 1 month after last 
treatment and every 3 months after end of treatment (± 28 days) thereafter until progression or 
death. Patients who progress after completing 12 months of therapy in the observation period 
can be re-treated. 
 
Investigational product dosage and mode of administration 
Regimen 1 Dose: 
Durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for 4 cycles followed by 
Durvalumab 1500 mg every 4 weeks for up to 8 additional cycles. 
Mode of administration: Both agents will be administered by intravenous (IV) infusion. 
Tremelimumab will be administered first, and the infusion duration will be approximately 1 
hour. The durvalumab (MEDI4736) infusion will start approximately 1 hour after the end of the 
tremelimumab infusion, and the infusion will be administered over approximately 1 hour. The 
combination of both agents shall be administered at Q4 week intervals for a maximum of 4 
doses, after which the durvalumab will continue as a single agent at Q4 week intervals till 
progression or unacceptable toxicity for a maximum of 8 additional doses. If toxicity was noted 
with the combination, investigator can decide to continue durvalumab alone in case patient is 
having clinical benefit (SD or better). 
Subjects enrolled who achieve and maintain disease control through the end of the treatment 
period will enter follow-up. During the first 12 months of follow-up, if the subject has 
progressive disease (PD), the subject may be re-administered durvalumab/tremelimumab for up 
to another 12 months with the same treatment guidelines followed during the initial 12-month 
period provided the subject does not meet any of the investigational product discontinuation 
criteria and fulfills the criteria for retreatment in the setting of PD, which include absence of 
clinical symptoms or signs indicating clinically significant disease progression; no decline in 
Eastern Cooperative Oncology Group (ECOG) performance status compared to baseline; and 
absence of rapid disease progression or threat to vital organs/critical anatomical sites (eg, spinal 
cord compression) requiring urgent alternative medical intervention. 
 
This study will not only allow us to evaluate the efficacy and safety of durvalumab and 
tremelimumab but provide the translational science to guide further development of novel 
immunotherapeutic agents in sarcomas. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 6 
 
 
 
Statistical methods 
 
Sample Size: The planned sample size includes a maximum of 25 subjects in each cohort and 
less than or equal to 150 evaluable subjects in total for the combination of durvalumab and 
tremelimumab. 
 
Design: The primary efficacy endpoint will be progression-free survival (PFS) at 12 weeks 
(PFS12 weeks). 12-week PFS is defined as evidence of stable disease or better 12 weeks after the 
initiation of therapy. In the meanwhile, we will also monitor the toxicity of the agent (Thall, 
1996). Toxicity will be assessed within the first two cycles of the treatment (56 days). If there 
is a high probability that the PFS12 weeks is unlikely to be at least 40% or that the unacceptable 
toxicity rate is likely to be greater than 30%, the drug would not be considered of interest for 
further study. Formally if Pr(PFR12 weeks < 0.40 | Data) > 0.90 or Pr(toxicity rate > 0.30 | Data) 
> 0.90, the corresponding cohort will be stopped. The assumed prior distribution for PFS12 weeks 
is Beta (0.4, 0.6) and for toxicity is Beta (0.3, 0.7). The resulting prior means are 0.40 and 0.3 
for PFS12 weeks and toxicity rate, respectively, with one patient worth of information. Each of the 
disease cohorts will be monitored separately in cohorts of 5 patients after a minimum of 5 
patients have been enrolled. For cohort 1, 2 and 6, since these include more than distinct 
subtypes, in order to assess anti-tumor activity of the treatment regimen within each histologic 
subtype, we will open enrollment simultaneously for each of the histologic subtypes but keep 
the maximum number of patients at 25 in each of these cohorts. Patients who are not evaluable 
for response to the treatment by 12 weeks post initiation of treatment will be considered a 
treatment failure. 
 
Analysis plan: 
 
Efficacy: If a cohort is stopped early, this drug will not be considered of interest for future study 
for this cohort of patients. If all 25 patients are accrued, we will estimate the PFS12 weeks and the 
corresponding 95% posterior credible interval. We will also apply a Bayesian hierarchical 
statistical model (Wathen, 2008) to analyze the data from all six cohorts to borrow information 
from each other. Response rate will be estimated along with 95% confidence interval. PFS and 
overall survival (OS) will be estimated using the Kaplan-Meier method (Kaplan,1958). Log- 
rank test (Mantel, 1966) will be performed to test the difference in survival between groups. 
Regression analyses of survival data based on the Cox proportional hazards model (Cox, 1972) 
will be conducted on PFS or OS. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 7 
 
 
Safety: Toxicity data will be summarized by frequency tables. For the toxicity endpoint, per- 
treated analysis will be used to include any patient who received the treatment regardless of the 
eligibility nor the duration or dose of the treatment received. Toxicity rate will be estimated with 
95% credible interval. 
 
Correlatives: Exploratory data analysis and graphical methods will be applied to examine the 
distribution of the biomarker data, error checking, and outlier identification. T-test/ANOVA or 
their nonparametric countparts, Wilcoxon rank-sum test/Kruskal-Wallis test will be used to 
detect differences of the biomarkers between groups (1) Linear mixed effect models for repeated 
measures analysis (Liang, 1986) will be employed to assess the change of the biomarkers over 
time with multi-covariates including disease characteristics (tumor stage, site, pathology), and 
other prognostic factors. Appropriate transformation of the outcome assessment values will be 
used to satisfy the normality assumption of linear mixed effect model. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 8 
 
 
 
Figure 1 
Schema 
 
 
 
 
Population: Advanced/metastatic sarcoma 
1. Adipocytic tumors 
2. Vascular tumors 
3. Undifferentiated pleomorphic sarcoma 
4. Synovial sarcoma 
5. Osteosarcoma 
6. Others 
Required: Pre-treatment blood draw and tumor biopsy. Archived sample is 
acceptable if it is within 6 months with no intervening therapy or if repeat biopsy 
is considered harmful for the patient) 
Treatment (28 days per cycles) by age group: 
≥18: Durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for 4 cycles 
followed by durvalumab 1500 mg every 4 weeks alone. If toxicity was noted with the 
combination, investigator can decide to continue durvalumab alone in case patient is having 
clinical benefit (SD or better). 
Disease Assessment 
- Follow up with restaging at 8 weeks (+/- 1 week) with a confirmatory scan at 12 weeks 
(+/- 1 weeks). Every 8 weeks after the 12th week scan. 
- Blood draw at 2 and 6 weeks (+/- 1week) 
-Optional tumor biopsy at 6 weeks (+/- 1week) –plan to obtain on at least 10 patients in each 
cohort (Those patients who undergo a fresh biopsy prior to the start of the treatment will be encouraged to get the 
on-treatment biopsy to ensure availability of matched fresh tumor specimens). 
- Blood draw and optional tumor biopsy at confirmed progression (in previously 
responding patients) 
Continue treatment until: 
Disease progression (unless pseudoprogression suspected with clinical stability per 
investigator) 
Unacceptable toxicity Patient preference 
Completion of 12 months of therapy 
Follow up 
-End of treatment assessment at 90 days (+/- 2 weeks) for resolution of side effects 
-Follow-up every 3 months (+/- 28 days) for study related toxicities and survival 
-Re-treatment will be considered for patients who progress during the off therapy phase and did not 
experience unacceptable toxicities while on treatment. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 9 
 
Table of Contents 
TITLE PAGE ............................................................................................................................ 1 
PROTOCOL SYNOPSIS ......................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 13 
INTRODUCTION ............................................................................................................ 14 
Background and rationale for conducting this study ..................................................... 14 
Durvalumab and Tremelimumab Background .............................................................. 16 
Durvalumab Background ............................................................................................ 16 
Tremelimumab Background ...................................................................................... 16 
Summary of Nonclinical Experience ............................................................................. 17 
Durvalumab Nonclinical Experience .......................................................................... 17 
Tremelimumab Nonclinical Experience ..................................................................... 19 
Summary of Clinical Experience ................................................................................... 21 
Durvalumab Clinical Experience ................................................................................ 21 
Tremelimumab Clinical Experience ........................................................................... 31 
Rationale for study design and dosing ........................................................................... 33 
Rationale for study design ........................................................................................... 33 
Rationale for endpoints............................................................................................... 33 
Rationale for pre-treatment and on treatment biopsy ......................................................... 34 
Rationale for dosing of durvalumab and Tremelimumab .................................................. 34 
STUDY OBJECTIVES ..................................................................................................... 35 
Primary objective ........................................................................................................... 35 
Secondary objectives ..................................................................................................... 35 
Exploratory objectives ................................................................................................... 36 
STUDY DESIGN .............................................................................................................. 36 
Description of the Study ................................................................................................ 36 
Treatment Regimen .................................................................................................... 37 
Management of study related toxicities ...................................................................... 37 
Cohort enrollment ......................................................................................................... 43 
Describe Bayesian design and monitoring of patients ....................................................... 43 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 10 
 
Unacceptable toxicity ................................................................................................. 43 
SUBJECT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL .................................................... 44 
Number of Subjects ........................................................................................................ 44 
Inclusion criteria ............................................................................................................ 44 
Exclusion criteria ........................................................................................................... 46 
4.3.1. 
Prior therapy with anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody ......................... 46 
4.3.2. 
Active or prior documented autoimmune disease (including inflammatory 
bowel disease, celiac disease, Wegener syndrome) within the past 2 years. 
Subjects with childhood atopy or asthma, vitiligo, alopecia, Hashimoto 
syndrome, Grave’s disease, or psoriasis not requiring systemic treatment 
(within the past 2 years) are not excluded. ............................................................. 46 
Subject enrollment ......................................................................................................... 49 
Withdrawal from the Study ........................................................................................... 49 
Withdrawal from Treatment ....................................................................................... 50 
Withdrawal of Consent ............................................................................................... 50 
Lost to Follow-up ....................................................................................................... 50 
Discontinuation of investigational product ................................................................... 50 
Replacements of subjects ............................................................................................ 51 
Withdrawal of consent for data and biological samples ..................................................... 51 
SCHEDULE OF STUDY PROCEDURES ..................................................................... 51 
Enrollment/screening period (Day-30 to Day 1): ....................................................... 53 
Treatment period ........................................................................................................... 54 
Follow-up period ........................................................................................................... 56 
Efficacy assessments ..................................................................................................... 58 
Efficacy ....................................................................................................................... 58 
Measurability of Tumor Lesions ................................................................................ 59 
Evaluation of Tumor Response by irRC ...................................................................... 60 
Safety assessments ......................................................................................................... 64 
Laboratory Safety Variables ....................................................................................... 64 
Physical examination .................................................................................................. 65 
ECG ............................................................................................................................ 65 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 11 
 
     Vital signs ........................................................................................................................................ 65 
     Other assessments ........................................................................................................................... 65 
     Biomarker analysis .......................................................................................................................... 65 
Storage, re-use and destruction of biological samples 
68 
Withdrawal of Informed Consent for donated biological samples .......................................... 68 
     SAFETY REPORTING AND MEDICAL MANAGEMENT ........................................................ 68 
6.1 
Definition of Adverse Event ...................................................................................................... 68 
     Unexpected Adverse Event ............................................................................................................. 68 
     Serious Adverse Event (SAE) ......................................................................................................... 69 
Definition of Adverse Events of Special Interest 
70 
6.2 Adverse Event Severity ................................................................................................................. 71 
     Relationship to Investigational Drug ................................................................................................. 72 
     Adverse Event Collection Period .................................................................................................... 73 
     Adverse Event Reporting ................................................................................................................ 73 
     Serious Adverse Event Reporting ................................................................................................... 73 
     Pregnancy ....................................................................................................................................... 74 
     Overdose ......................................................................................................................................... 75 
     Protocol Deviations ......................................................................................................................... 75 
     INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .............................................. 76 
     Identity of investigational product(s) .............................................................................................. 76 
     Durvalumab .................................................................................................................................... 76 
     Tremelimumab ................................................................................................................................ 76 
     Summary ................................................................................................................................. 77 
 Dose and treatment regimens ............................................................................................................. 77 
     Labelling ......................................................................................................................................... 77 
     Durvalumab .................................................................................................................................... 77 
     Tremelimumab ........................................................................................................................ 77 
     Storage ............................................................................................................................................ 78 
     Compliance ..................................................................................................................................... 78 
    Accountability ................................................................................................................................. 78 
     Concomitant and other treatments ................................................................................................... 78 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 12 
 
 
 
Permitted Concomitant Medications .......................................................................... 78 
Prohibited Concomitant Medications ......................................................................... 79 
STATISTICAL ANALYSES .......................................................................................... 79 
Statistical considerations ............................................................................................ 79 
Sample size estimate ...................................................................................................... 82 
Definitions of analysis sets ............................................................................................ 82 
Efficacy analysis set .................................................................................................... 82 
Safety analysis set ....................................................................................................... 82 
Outcome measures for analyses ..................................................................................... 83 
Methods for statistical analyses ..................................................................................... 83 
Analysis of the primary variable(s) ............................................................................. 83 
Analysis of the secondary variable(s) ......................................................................... 83 
STUDY AND DATA MANAGEMENT ........................................................................ 84 
Training of study site personnel ..................................................................................... 84 
Data and Safety Monitoring .......................................................................................... 84 
Data Collection and storage ........................................................................................... 85 
Study timetable and end of study................................................................................... 85 
ETHICAL AND REGULATORY REQUIREMENTS ................................................. 85 
Ethical conduct of the study ......................................................................................... 85 
Subject data protection ................................................................................................ 85 
Ethics and regulatory review ....................................................................................... 86 
Informed consent ......................................................................................................... 86 
Changes to the protocol and informed consent form ......................................................... 87 
Recruitment procedure ................................................................................................ 87 
LIST OF REFERENCES ............................................................................................... 87 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 12 
 
LIST OF TABLES 
Table 1 
Treatment-related Adverse Events Summary, As-treated 
Population, Study D4190C00006 ............................................................. 26 
Table 2 
Treatment-related Serious Adverse Events in Subjects Treated 
with Durvalumab Q4W/Tremelimumab Q4W, As-treated 
Population, Study D4190C00006 ............................................................. 27 
Table 3 
Durvalumab and Tremelimumab Treatment Modification Due ............... 38 
Table 4 
All procedures to be conducted at the screening visit ............................... 53 
Table 5 
Schedule of Treatment Period Study Procedures Weeks 1 to 25 .............. 54 
Table 6 
Schedule of Follow-up Procedures ........................................................... 56 
Table 7 
Immune-related Response Evaluation Criteria in Solid Tumors: 
Overall Response ...................................................................................... 61 
Table 8 
Adverse Event Severity Assessment ......................................................... 71 
Table 9 
Assessment of Relationship ...................................................................... 72 
Table 10 
Stopping boundaries for PFS12 weeks futility monitoring or for 
excessive toxicity monitoring within each cohort ..................................... 80 
Table 11 
Operating characteristics for the stopping rules for PFS12 weeks 
futility monitoring or for excessive toxicity monitoring in the 
expansion phase ........................................................................................ 81 
 
 
LIST OF FIGURES 
Figure 1 
Schema ........................................................................................................ 8 
Figure 2 
1A - U293 cell line (negative control); 1B - placenta (positive 
control); 1C - UPS; 1D - synovial sarcoma .............................................. 16 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 13 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
<<>> 
 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
Abbreviation 
or 
special term 
Explanation 
AE 
Adverse event 
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LSLV 
Last Subject Last Visit 
OAE 
Other Significant Adverse Event 
PGx 
Pharmacogenetic research 
PI 
Principal Investigator 
SAE 
Serious adverse event 
WBDC 
Web Based Data Capture 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 14 
 
 
 
INTRODUCTION 
Background and rationale for conducting this study 
Sarcomas are a rare collection of mesenchymal tumors with around 11,000 new cases diagnosed 
each year in the United States (2). While low-grade, localized disease may be amenable to 
surgical resection, patients with unresectable disease or metastasis have a high mortality rate. 
Currently, cytotoxic chemotherapy is the primary treatment modality for patients with 
unresectable/metastatic disease, and the most common front-line regimens include doxorubicin. 
While time to progression on doxorubicin-containing combinations has repeatedly been shown 
to be superior to that of doxorubicin alone, overall survival is not different in the same 
randomized studies (3). Furthermore, previous studies have shown an estimated median survival 
for these patients to be approximately 8 to 13 months from the start of first-line anthracycline-
based chemotherapy, (4-7). Gemcitabine-docetaxel is most commonly used in the second line 
with specific activity against leiomyosarcomas and undifferentiated pleomorphic sarcoma. 
Recently, pazopanib, a multi-tyrosine kinase receptor inhibitor, received an FDA indication for 
use in soft tissue sarcomas on the basis of a 4.6-month progression-free survival (PFS), a 3-
month improvement compared to placebo. Despite some of these advances there are still sub-
types such as epithelioid sarcoma, clear cell sarcoma or well-differentiated liposarcomas for 
which we have no effective regimens beyond surgical resection. 
 
In several solid tumor types, there are data to suggest that an antigen-specific adaptive immune 
response to cancer naturally exists in patients. In the tumor microenvironment, antigen 
presenting cells acquire and process peptides released from cell turnover during tumor growth. 
The most potent antigen presenting cells are dendritic cells (DCs). DCs then migrate to the 
draining lymph nodes where they sensitize and activate T cells against these peptide antigens. 
T cells, in particular antigen-specific, cytotoxic CD8 T cells, are then capable of eliminating 
antigen-expressing tumor cells found in the peripheral tissues. This process is restricted by the 
display of the antigen on the tumor cell surface in the context of an appropriate, matched major 
histocompatibility complex (MHC; e.g. human leukocyte antigen or HLA) molecule. 
 
Multiple inhibitory mechanisms, however, may be responsible for the inability of the immune 
system to eliminate tumor cells. Inappropriate antigen presentation or lack of appropriate 
activation signals from DCs can result in the opposite effect, tolerance of T cells to the target 
antigen. Immunosuppressive cytokines (TGF-beta, IL-10) and alternate immune cell types 
(myeloid derived suppressor cells, regulatory T cells, tumor-associated macrophages) present 
at the tumor microenvironment may directly inhibit the anti-tumor immune response. Tumor 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 15 
 
 
 
cells may lose expression of the target antigen and thus avoid detection. Activated T cells also 
express inhibitory signals known as immune checkpoint molecules, which arise naturally and 
dampen the immune response, to the advantage of tumor cells. Among the most extensively 
studied immune checkpoint molecules are CTLA4 and PD-1. 
 
Immune-based therapies, offer the possibility of significant response and even durable complete 
responses for patients with cancers that are considered “incurable” (8, 9), but remain largely 
unexplored in sarcoma. Anti-CTLA-4 activity via ipilumumab has demonstrated survival 
benefits in melanoma and agents that target programmed death-1 (PD-1) have shown responses 
and potential survival benefits in various malignancies such as melanoma, non-small cell lung 
carcinoma, and renal cell carcinoma (9, 10). The presence of TILs and more importantly PD- 
L1 expression in the tumor have been correlated with objective response to the anti-PD-1 agent, 
nivolumab (9, 11). 
 
High expression of PD-1/PD-L1 has also been reported in various subtypes of sarcoma and has 
been shown to be a negative prognostic marker for OS (12-14). Recent data also shows blockade 
of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs 
in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 
mouse model of metastatic osteosarcoma (15). Combination immunotherapy with α-CTLA-4 
and α-PD-L1 antibody blockade in the K7M2 mouse model of metastatic osteosarcoma resulted 
in complete control of tumors in a majority of mice as well as immunity to further tumor 
inoculation (16). Our preliminary clinical data also confirms the presence of PD-L1 expression 
in multiple sarcoma subtypes tested at MD Anderson (alveolar soft part sarcomas, 
chondrosarcomas, leiomyosarcomas, liposarcomas, undifferentiated pleomorphic sarcomas, 
osteosarcomas, and synovial sarcomas to name a few) (Figure 1). A majority of sarcomas also 
have a defined immunologic target (e.g. chromosomal fusion protein, cancer testis antigen, or 
mutation) and there is indeed a naturally-occuring immune infiltrate in multiple sarcomas. 
Previous studies, including one from our group has demonstrated the presence of TILs in certain 
sarcoma subtypes (17-19). The presence of a naturally-occurring immune infiltrate in many 
subtypes of sarcomas is encouraging and suggests that immunotherapy may potentially be 
beneficial in these patients. Interestingly, one of the earliest examples of immunotherapy from 
the late 19th century (Coley’s toxin) was in fact, motivated by a sarcoma patient with tumor 
regression after clearance of a bacterial infection. 
 
We believe checkpoint inhibitors will lead to clinical benefit in at least some of these sarcoma 
subtypes and lead to a survival benefit. This study will help us evaluate the clinical benefit in 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 16 
 
 
 
multiple common sarcoma subtypes (selected on the basis of their higher mutation load, 
presence of TILs, and/or PD-L1 staining). This study will help us identify the immune markers 
of response or resistance in these sarcomas that will inform the future development of 
immunotherapy options for these patients. As part of this investigator-initiated study we intend 
to analyze blood and tissue specimens to help us select the next novel immunotherapeutic agent 
from the Medimmune pipeline that is likely to benefit these patients. 
 
1A 
1B 
1C 
1D 
Figure 2 1A - U293 cell line (negative control); 1B - placenta (positive control); 1C - UPS; 
1D - synovial sarcoma 
 
Durvalumab and Tremelimumab Background 
Durvalumab (MEDI4736) and tremelimumab are briefly described below. Refer to the current 
Investigator’s Brochures for details. 
 
Durvalumab Background 
Durvalumab is a human immunoglobulin G (IgG)1 kappa mAb directed against human PD-L1. 
Durvalumab is expressed in Chinese hamster ovary cells and has an overall molecular weight of 
approximately 149 kDa. Durvalumab selectively binds human PD-L1 with high affinity and 
blocks its ability to bind to PD-1 and cluster of differentiation (CD)80. 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 Fc gamma 
receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (20). 
 
Tremelimumab Background 
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb being investigated as a cancer 
immunotherapeutic agent. Tremelimumab is expressed in NS0 (murine myeloma) cells and has 
an overall molecular weight of approximately 149 kDa. Tremelimumab is specific for human 
CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks the 
inhibitory effect of CTLA-4, and therefore enhances T-cell activation. Tremelimumab shows 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 17 
 
 
 
minimal specific binding to Fc receptors, does not induce natural killer (NK) ADCC activity, 
and does not deliver inhibitory signals following plate-bound aggregation. 
 
Summary of Nonclinical Experience 
Nonclinical experience with durvalumab and tremelimumab are briefly described below. Refer 
to the current Investigator’s Brochures for details. 
 
Durvalumab Nonclinical Experience 
Programmed cell death 1 (CD279) is a member of the immunoglobulin superfamily of 
molecules involved in regulation of T-cell activation. It is found on T cells, B cells, 
macrophages, NK cells, dendritic cells, and mast cells. 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 (21- 
32). 
 
Programmed cell death ligand 1 (CD274, B7-H1) is constitutively expressed on many 
hematopoietic cells, but may be upregulated in hematopoietic and non-hematopoietic cells. 
Regulation of PD-L1 is mediated, in part, by type I and type II interferon (IFN). Programmed 
cell death ligand 2 (PD-L2; B7-DC) was identified in 2001 (25, 33). Its expression is far more 
restricted and is confined to hematopoietic cells. 
 
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 (34-39); ). 
 
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. 
• 
Durvalumab inhibits tumor growth in a xenograft model via a T-cell-dependent 
mechanism. 
• 
A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic tumor 
model as monotherapy and resulted in complete tumor regression in > 50% of treated mice when 
given in combination with chemotherapy. 
• 
In the same study, anti-mouse PD-L1 antibody-treated mice were completely tumor free 3 
months after tumor implantation and demonstrated long-term immunity during 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 18 
 
 
 
re-challenge. 
• 
In a subsequent study in the same syngeneic model, the combination of an anti-mouse PD- 
L1 antibody and anti-CTLA-4 antibody resulted in complete tumor regression in all mice 
treated. 
• 
Prevalence of PD-L1 expression on the surface of human tumors, ranging from 
approximately 0% to 35%, was demonstrated in a broad survey of samples derived from tumor 
types of interest. 
 
The cynomolgus monkey is considered to be the only relevant nonclinical species for evaluation 
of local and systemic toxicities of durvalumab. In addition, in vivo in cynomolgus monkeys, 
durvalumab suppresses soluble programmed cell death ligand 1 (sPD-L1) in serum and fully 
occupies membrane PD-L1 on various leukocyte subsets at doses equal to or more than 0.1 
mg/kg (lowest dose tested) with a dose-related duration of suppression and occupancy. 
 
In general, there were no 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 antidrug antibody (ADA)-associated morbidity and mortality in individual 
animals. The spectrum of findings, especially the clinical signs and microscopic pathology, in a 
single animal in the GLP, 4-week, repeat-dose study was also consistent with ADA immune 
complex deposition, and ADA:durvalumab immune complexes were identified in a subsequent 
non-GLP, investigative immunohistochemistry (IHC) study. Similar observations have been 
reported 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. Interim audited data from the dosing phase of the pivotal 3-month GLP toxicity 
study with durvalumab in cynomolgus monkeys showed that subchronic dosing of durvalumab 
was not associated with any adverse effects. Therefore, the NOAEL of durvalumab in all the 
general toxicity studies was considered to be 100 mg/kg, the highest dose tested in these studies. 
In addition to the in vivo toxicology data, no unexpected membrane binding of durvalumab to 
human or cynomolgus monkey tissues was observed in GLP tissue cross-reactivity studies using 
normal human and cynomolgus monkey tissues. Finally, in vitro cytokine release studies 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 19 
 
 
 
showed that durvalumab and tremelimumab, either alone or in combination, did not induce 
cytokine release in blood from any donor. 
 
Tremelimumab Nonclinical Experience 
Cytotoxic T-lymphocyte-associated antigen 4 (CD152) is a cell-surface receptor expressed 
primarily on activated T cells. Cytotoxic T-lymphocyte-associated antigen 4 engagement on 
activated T cells inhibits cytokine synthesis and restricts cell proliferation (40-44) . Upon T-cell 
activation, CTLA-4 expression is upregulated and acts to dampen immune responses, 
modulating and eventually switching off T-cell activation. The natural ligands for CTLA-4 are 
CD80 and CD86, which are present on antigen-presenting cells (APCs). Binding of these 
ligands to CTLA-4 delivers a negative regulatory signal to T cells. 
 
Tremelimumab selectively binds to human CTLA-4 and blocks binding of CD80 and CD86 and 
has been shown to enhance human T-cell cytokine release in response to stimulation. 
 
Both in vitro and in vivo preclinical data suggest that a range of anti-CTLA-4 mAb exposures 
has the potential to be efficacious, the lower end of the potentially efficacious range being a 
plasma concentration of approximately 10 μg/mL and the target plasma concentration being 30 
μg/mL. The toxicology program conducted for tremelimumab consisted of in vivo general 
toxicology studies in cynomolgus monkeys for up to 6 months duration, an embryo-fetal 
development study in monkeys, tissue cross-reactivity studies in both monkey and human 
tissues, and blood compatibility studies. Overall, tremelimumab toxicities were consistent with 
inhibition of CTLA-4 and with clinical safety findings, and indicated that chronic clinical use of 
tremelimumab may lead to adverse effects on the gastrointestinal tract, skin, lymphoid organs, 
thyroid tissues, and hematologic systems. Clinical dose-limiting toxicity (DLT; eg, 
gastrointestinal effects) and non-DLT (eg, skin rash) were appropriately identified in a chronic 
toxicity study in monkeys. Most toxicities were reversible or showed a trend towards 
reversibility. 
 
An embryo-fetal development study was conducted in pregnant cynomolgus monkeys during 
the period of organogenesis. Tremelimumab administered intravenously (IV) once weekly from 
Days 20 to 50 of gestation at doses of 0, 5, 15, or 30 mg/kg did not elicit maternal toxicity, 
developmental toxicity, or teratogenicity. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 21 
 
 
 
Summary of Clinical Experience 
Clinical experience with durvalumab and tremelimumab are briefly described below. Refer to 
the current Investigator’s Brochures for details. 
 
Durvalumab Clinical Experience 
MEDI4736 has been administered to subjects in 5 ongoing clinical studies (2 investigating 
MEDI4736 as monotherapy and 3 as combination therapy). 
 
Monotherapy Studies 
Study CD-ON-MEDI4736-1108: 
Study CD-ON-MEDI4736-1108 is a Phase 1, first-time-in-human, multicenter, open-label, 
dose-escalation, and dose-expansion study to determine the maximum tolerated dose (MTD) or 
optimal biologic dose, safety, PK, 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 414 subjects with advanced solid tumors have been treated in 
Study CD-ON-MEDI4736-1108, where 393 of these subjects have received durvalumab at 10 
mg/kg Q2W (either in the dose-escalation or dose-expansion phase of the study). In addition, 21 
subjects have been enrolled in the following dose-escalation cohorts: 4 subjects in each of the 
0.1, 0.3, and 1.0 mg/kg Q2W cohorts, 3 subjects in the 3.0 mg/kg Q2W cohort, and 6 subjects in 
the 15 mg/kg every 3 weeks (Q3W) cohort. 
Of the 393 subjects treated with 10 mg/kg Q2W, 331 subjects (84.2%) had at least 1 AE 
(regardless of causality; Table 5.3.1.3-1). Overall, the most frequently reported (≥ 10% of 
subjects) AEs (all grades) were fatigue, nausea, dyspnea, decreased appetite, constipation, 
diarrhea, vomiting, cough, pyrexia, back pain, and rash. Approximately half (48.1%) of these 
AEs were Grade 1 to 2 in severity and manageable by general treatment guidelines as described 
in the current durvalumab study protocols. Grade 3 or higher AEs were noted in 141 of 393 
subjects (35.9%). These events occurring in more than 1% of subjects were dyspnea (5.1%); 
increased gamma-glutamyltransferase (3.3%); fatigue, general physical health deterioration, 
increased aspartate aminotransferase, and back pain (2.3% each); anemia and dehydration (1.8% 
each); and abdominal pain, vomiting, sepsis, syncope, sepsis, and hypotension (1.3% each). 
 
Treatment-related AEs were reported for 162 of 393 subjects (41.2%). The most frequently 
reported (≥ 2% of subjects) treatment-related AEs (all grades) were fatigue (13.5%); nausea 
(8.4%); diarrhea, decreased appetite, and rash (5.3% each); vomiting (4.8%); pruritus (4.1%); 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 22 
 
 
 
dyspnea (3.8%); pyrexia (3.1%); hypothyroidism (2.8%); increased alanine aminotransferase, 
increased aspartate aminotransferase, and cough (2.5% each); myalgia (2.3%); and abdominal 
pain and dizziness (2.0% each). Treatment-related Grade 3 events that occurred in 2 or more 
subjects were fatigue (4 subjects), increased gamma-glutamyltransferase (3 subjects), and 
vomiting, increased alanine aminotransferase, increased aspartate aminotransferase, and 
arthralgia (2 subjects each). There were 2 subjects with treatment-related Grade 4 events 
(hypercalcemia, fatigue) and 1 subject with a treatment-related Grade 5 event (progression of 
disease [verbatim term]). However, the causality of the Grade 5 AE was changed to “not related” 
after the data cutoff date of 14Jul2014. According to the patient safety database, 1 subject in 
this study died due to treatment-related angiopathy (entry into the clinical database is pending). 
 
A total of 229 SAEs (regardless of causality) have been reported in 123 of 393 subjects (31.3%) 
treated with 10 mg/kg MEDI4736 Q2W. The SAEs reported for 5 or more subjects were 
dyspnea, general physical health deterioration, pyrexia, abdominal pain, back pain, dehydration, 
pleural effusion, and sepsis. Eleven subjects (2.8%) had SAEs considered related to durvalumab 
by the investigator. A majority of these events were Grade 3 or higher in severity and recovered 
with or without sequelae. 
 
Three subjects with treatment-related SAEs died. Two deaths due to progression of disease; 
pneumonitis was ongoing at the time of one of the subject’s death but pleural effusion had 
resolved. The third death was due to treatment-related angiopathy. 
 
Of the 414 subjects treated with durvalumab (all dose levels), 169 subjects were evaluable for 
response analysis, which included subjects who had at least 24 weeks of follow-up as of 
14Jul2014 and had either at least 1 post-baseline tumor assessment or experienced clinical PD 
or death. Nineteen subjects (11.2%) had a best overall response of CR/PR (confirmed and 
unconfirmed). The DCR (CR + PR + SD ≥ 12 weeks) was 32% (54 of 169 subjects). 
Programmed cell death ligand 1 status (based on Ventana/MedImmune assay) was known for 
143 of 169 evaluable subjects, of whom 30 were PD-L1 positive. A best overall response of 
CR/PR (confirmed and unconfirmed) was observed in 7 of 30 (23.3%) PD-L1-positive subjects 
and in 6 of 113 (5.3%) PD-L1-negative subjects. 
 
Study D4190C00002 (Phase 1 Dose Escalation and Dose Expansion in Japanese Subjects 
with Advanced Solid Tumors) 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 23 
 
 
 
Overall, 12 of 18 Japanese subjects (66.7%) who have been treated in Study D4190C00002 had 
at least 1 AE (Table 5.3.1.3-2). Treatment-related AEs were reported for 9 of 18 subjects 
(50.0%). The most frequent (≥ 2 subjects) treatment-related AEs (all grades) were constipation, 
stomatitis, fatigue, pyrexia, and pruritus (2 subjects each). In the majority of the subjects, the 
maximum severity of AEs was Grade 1 (6 of 12 subjects) or Grade 2 (5 of 12 subjects). These 
events were manageable by general treatment guidelines as described in the study protocol. 
Grade 3 or higher AEs were reported in 1 subject in the 10 mg/kg MEDI4736 Q2W cohort. The 
event for this subject was a Grade 3 treatment-related SAE of decreased free tri-iodothyronine. 
The SAE was ongoing at the time of the subject’s death due to disease progression. 
 
Limited efficacy data are available for Study D4190C00002. Twelve of 18 subjects had at least 
1 post-baseline tumor assessment. One subject had a best overall response of PR (unconfirmed) 
and 6 subjects had SD as assessed by RECIST guidelines v1.1 (45). 
 
Study D4191C00003 (ATLANTIC; Phase 2 Open Label in Subjects with NSCLC) 
Fourteen subjects have been treated in Study D4191C00003. Subjects have received 1 to 4 doses 
of durvalumab (10 mg/kg Q2W). Only SAE data (from the patient safety database) are 
available. One of 6 subjects reported SAEs. The events were Grade 3 abnormal 
 
liver function test, thrombotic stroke (severity unknown), Grade 3 asthenia, and Grade 3 
ischemic cerebral infarction. The subject died due to asthenia and ischemic cerebral infarction. 
None of the SAEs were considered related to investigational product. 
 
Study D4190C00007 (Phase 1 Dose Escalation and Dose Expansion in Subjects with 
Myelodysplastic Syndrome [MDS]) 
Two subjects have been treated in Study D4190C00007. Subjects have received 2 to 3 doses of 
durvalumab (10 mg/kg Q2W) and both subjects reported AEs. All of these events were Grade 
1 or 2 in severity, with 3 events considered to be related to durvalumab. Nearly half of the events 
resolved. No DLTs have been reported. 
 
Study D4191C00001 (PACIFIC; Phase 3 Randomized in Subjects with NSCLC) 
One subject has been treated in Study D4191C00001. The subject received 6 doses of 
investigational product. The subject had events of Grade 1 dehydration and sinus tachycardia, 
Grade 3 shortness of breath, and Grade 3 hypotension (downgraded to Grade 2). The event of 
dehydration was considered related to investigational product. All of the events resolved, except 
for sinus tachycardia that was reported as ongoing. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 24 
 
 
 
Durvalumab and Tremelimumab Combination Study Experience 
 
Study D4190C00006 
Study D4190C00006 is a multicenter, open-label, dose-escalation, and dose-expansion study of 
durvalumab in combination with tremelimumab to evaluate the safety, tolerability, PK, 
immunogenicity, and antitumor activity of durvalumab and tremelimumab in adult subjects with 
advanced NSCLC. In the dose-escalation phase up 102 patients were enrolled and received 
treatment. (46) Median follow up was 18.8 weeks (IQR 11 – 33). The maximum tolerated dose 
was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 
3 mg/kg. 
 
Overall, 82 of the 102 subjects (80%) reported a treatment-related AE (all grades,). See table 1 
for details. The most common of these AEs included diarrhea in 33 patients (32%), fatigue in 
24 patients (24%), and pruritus in 21 patients (21%). There was no dose dependency of the AEs 
noted in subjects with fixed dose of tremelimumab 1 mg/kg. Most of the Grade 1 and 2 AEs 
were manageable. Fifty-six subjects (55%) required treatment with immunosuppressants 
(corticosteroids, adalimumab, or infliximab) from all cohorts (102 patients). There were 15 
(35%) of 43 patients that received one or more doses of the study regimen after the initiation of 
the first grade 3 or grade 4 treatment-related adverse event. 
 
Forty-three of 102 subjects (42%) experienced grade 3/grade 4 treatment-related AEs. Thirty- 
seven of 102 subjects (36%) experienced a treatment-related SAE. See Table 2 for details. 
Twenty-nine of the 102 subjects (28%) discontinued the study as a result of treatment. 
 
For the cohort of durvalumab 10 – 20 mg/kg every 2 weeks or 4 weeks plus tremelimumab 1 
mg/kg, the most common treatment-related hematologic grade 3/grade 4 toxicity was anemia in 
3 subjects (5%). The most common treatment-related, non-hematologic grade 3/grade 4 toxicity 
was diarrhea in 4 subjects (7%). The most treatment-related, grade 3/4 laboratory abnormality 
was increased lipase in 5 subjects (9%). 
 
There were 3 deaths (3%) related to treatment. One patient died from complications arising from 
myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg). Another 
patient died of complications related to a pericardial effusion (durvalumab 20 mg/kg every 4 
weeks plus tremelimumab 1 mg/kg). The last treatment-related death occurred due to  a 
neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). 
 
For the cohort of durvalumab 10 – 20 mg/kg every 2 weeks or 4 weeks plus tremelimumab 1 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 10 September 10, 2019 Page | 25 
 
 
 
mg/kg, 6 patients of 26 evaluable patients (23%) experienced an objective response and 9 of 26 
patients (35%) experienced disease control in patients with ≥ 24 weeks of follow up. PD-L1 
status did not appear to select out for response (Antonia reference). This data represents 
information from patients gathered between October 28, 2013 and June 1, 2015. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 26 
 
 
 
 
 
 
Table 1 
Treatment-related Adverse Events Summary, As-treated Population, Study D4190C00006 
 
D3 q4w D10 q4w D15 q4w D20 q4w D10 q2w D10 q4w D15 q4w D20 q4w D10 q2w D15 q4w All cohorts 
T1 
T1 
T1 
T1 
T1 
T3 
T3 
T3 
T3 
T10 
N=102 
n (%) 
n=3 
n=3 
n=18 
n=18 
n=17 
n=3 
n=14 
n=6 
n=11 
n=9 
Safety summary 
Any AE 
3 (100) 
3 (100) 18 (100) 18 (100) 
16 (94) 
3 (100) 
14 (100) 
6 (100) 
11 (100) 
9 (100) 
101 (99) 
Any Grade 3/4 AE 
0 (0) 
2 (67) 
13 (72) 
11 (61) 
9 (53) 
3 (100) 
11 (79) 
6 (100) 
9 (82) 
8 (89) 
72 (71) 
Any deaths 
0 (0) 
1 (33) 
6 (33) 
6 (33) 
2 (12) 
0 (0) 
3 (21) 
2 (33) 
1 (9) 
1 (11) 
22 (22) 
SAE 
1 (33) 
2 (67) 
13 (72) 
10 (56) 
6 (35) 
2 (67) 
10 (71) 
6 (100) 
8 (73) 
8 (89) 
66 (65) 
AE leading to D/C 
1 (33) 
1 (33) 
8 (44) 
4 (22) 
3 (18) 
2 (67) 
6 (43) 
5 (83) 
5 (45) 
5 (56) 
40 (39) 
Related AE 
1 (33) 
3 (100) 
13 (72) 
11 (61) 
14 (82) 
3 (100) 
13 (93) 
5 (83) 
11 (100) 
8 (89) 
82 (80) 
Related Grade 3/4 AE 
0 (0) 
2 (67) 
8 (44) 
3 (17) 
4 (24) 
2 (67) 
7 (50) 
5 (83) 
5 (45) 
7 (78) 
43 (42) 
Related deaths 
0 (0) 
1 (33)* 
0 (0) 
1 (6)† 
0 (0) 
0 (0) 
0 (0) 
1 (17)‡ 
0 (0) 
0 (0) 
3 (3) 
Related SAE 
0 (0) 
1 (33) 
5 (28) 
4 (22) 
2 (12) 
2 (67) 
6 (43) 
5 (83) 
5 (45) 
7 (78) 
37 (36) 
Related AE leading to 
0 (0) 
1 (33) 
3 (17) 
3 (17) 
2 (12) 
2 (67) 
4 (29) 
4 (67) 
5 (45) 
5 (56) 
29 (28) 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 27 
 
 
 
 
 
 
Table 2 
Treatment-related Serious Adverse Events in Subjects Treated with Durvalumab Q4W/Tremelimumab Q4W, 
As-treated Population, Study D4190C00006 
 
 
n (%) 
D3 q4w 
T1 
n=3 
D10 q4w 
T1 
n=3 
D15 q4w 
T1 
n=1 
8 
D20 q4w 
T1 
n=1 
8 
D10 q2w 
T1 
n=1 
7 
D10 q4w 
T3 
n=3 
D15 q4w 
T3 
n=1 
4 
D20 q4w 
T3 
n=6 
D10 q2w 
T3 
n=1 
1 
D15 q4w 
T10 
n=9 
All 
cohorts 
N=1
0 2 
Preferred term 
Any related SAE 
0 (0) 
1 (33) 
5 (28) 
4 (22) 
2 (12) 
2 (67) 
6 (43) 
5 (83) 
5 (45) 
7 (78) 
37 (36) 
Colitis 
0 (0) 
0 (0) 
1 (6) 
1 (6) 
0 (0) 
1 (33) 
2 (14) 
1 (17) 
3 (27) 
2 (22) 
11 (11) 
Diarrhoea 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
3 (50) 
1 (9) 
3 (33) 
8 
(8) 
Pneumonitis 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
2 (14) 
0 (0) 
1 (9) 
2 (22) 
5 
(5) 
AST increased 
0 (0) 
1 (33) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
3 
(3) 
ALT increased 
0 (0) 
1 (33) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
2 
(2) 
Fatigue 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (9) 
1 (11) 
2 
(2) 
Amylase increased 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
1 
(1) 
Asthenia 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
Blood alkaline phosphatase 
increased 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
Decreased appetite 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
Dehydration 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (7) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 28 
 
 
 
 
 
Depressed level of 
consciousness 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
Dyspnoea 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
Enteritis 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 
(1) 
 
 
 
GGT increased 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Headache 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Hypophysitis 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
1 (1) 
Hypotension 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (7) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Hypoxia 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (7) 
0 (0) 
1 (9) 
0 (0) 
2 (2) 
Lipase increased 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
1 (1) 
Myalgia 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (33) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Myasthenia gravis 
0 (0) 
1 (33) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Nausea 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
1 (1) 
Neck pain 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Neuromyopathy 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (17) 
0 (0) 
0 (0) 
1 (1) 
Pancreatitis 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Pericardial effusion 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Platelet count decreased 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Polymyositis 
0 (0) 
1 (33) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 29 
 
 
 
 
 
Purpura 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (11) 
1 (1) 
Rash maculo-papular 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (11) 
1 (1) 
Sepsis 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 
Thrombocytopenia 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (6) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (1) 


 
Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 30 
 
 
 
 
 
Study D4880C00010 
 
Study D4880C00010 is a Phase 1, multicenter, open-label, dose-escalation and combination 
phase study of tremelimumab to evaluate the safety, tolerability, PK, immunogenicity, and 
antitumor activity of tremelimumab monotherapy and tremelimumab in combination with 
durvalumab in adult Japanese subjects with advanced solid malignancies. As of the data cutoff 
date of 12Nov2014, a total of 11 subjects has been treated in the study with 8 subjects receiving 
tremelimumab monotherapy (4 subjects each at 3 and 10 mg/kg) and 3 subjects receiving 10 
mg/kg tremelimumab in combination with 15 mg/kg Q4W durvalumab. 
Eight (72.7%) of the 11 subjects had treatment-related AEs. The most frequently reported 
treatment-related AEs were: fatigue (4 subjects), diarrhea, decreased appetite, pruritus, maculo- 
papular rash (3 subjects each), and hypothyroidism (2 subjects). 
 
Serious adverse events were reported in 4 of 11 subjects (36.4%), of whom 3 subjects (27.3%) 
had events that were considered related to treatment. One female subject with advanced 
thymoma received tremelimumab 10 mg/kg and durvalumab 15 mg/kg. She developed Grade 3 
hypophysitis and Grade 4 muscular weakness after one dose. The subject developed worsening 
generalized muscle weakness requiring mechanical ventilation. The muscular weakness was 
eventually diagnosed as myasthenia gravis and considered related to treatment. The underlying 
diagnosis of thymoma likely increased the risk of developing myasthenia gravis. No treatment- 
related deaths have been reported in this study. 
 
Study D4190C00010 
 
Study D4190C00010 is a Phase 1, multicenter, open-label, dose-exploration, and dose- 
expansion study to evaluate the safety, tolerability, antitumor activity, PK, and immunogenicity 
of durvalumab in combination with tremelimumab in subjects with select advanced solid 
tumors. The study has enrolled 3 subjects in the dose exploration phase. Two subjects have been 
treated as of the data cutoff date of 12Nov2014. 
 
Study D4190C00011 
 
Study D4190C00011 is a multicenter, open-label, dose-exploration, and dose-expansion study 
to evaluate the safety, tolerability, antitumor activity, PK, and immunogenicity of durvalumab 
in combination with tremelimumab or tremelimumab alone in subjects with recurrent/metastatic 
SCCHN. As of the data cutoff date of 12Nov2014, 4 of 6 subjects who have been treated in this 
study reported at least 1 AE. With the exception of fatigue that was reported in 2 subjects, all 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 31 
 
 
 
 
other preferred terms were reported in 1 subject each. A majority of the events were considered 
mild or moderate in severity and not related to tremelimumab. 
 
Two of 6 subjects reported an SAE: systemic inflammatory response syndrome and worsening 
pleural effusion. The event of systemic inflammatory response syndrome was severe and 
considered related to initial treatment with tremelimumab. The subject died due to this event 
and only received tremelimumab therapy prior to developing the SAE. The event of worsening 
pleural effusion was considered to be moderate in severity and not related to tremelimumab. 
 
D4191C00004 
 
D4191C00004 is a Phase 3 open-label multi-center, global study in subjects with locally 
advanced or metastatic NSCLC (Stage IIIB-IV). The study will evaluate durvalumab used as 
monotherapy (10 mg/kg), tremelimumab (10 mg/kg) used as monotherapy and durvalumab used 
in combination with tremelimumab. This study was originally planned as a monotherapy study 
with durvalumab. The protocol was amended in August 2014 to include a tremelimumab 
combination arm as well as a tremelimumab monotherapy arm. No subjects have been enrolled 
in any portion of the study as of the data cutoff date of 12Nov2014. 
 
Tremelimumab Clinical Experience 
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cutoff 
date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of the 
tremelimumab clinical development program. Of these studies, 13 have been completed and 9 
are ongoing. Tremelimumab has been administered as monotherapy to 973 subjects (not 
including 497 subjects who have been treated in the blinded Phase 2b study, D4880C00003 
[DETERMINE]) participating in 10 of the 22 sponsored clinical studies, 2 of which are ongoing. 
Most of these subjects had melanoma and received the tremelimumab 15 mg/kg every 90 days 
dosing regimen. In addition, 208 subjects with a variety of tumor types have received 
tremelimumab in combination with other anticancer agents in 12 of the 22 sponsored clinical 
studies, 7 of which are ongoing. 
 
Across the clinical development program for tremelimumab a pattern of efficacy has emerged, 
also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to be consistent 
across tumor types for this class of agents. Response rates to anti-CTLA-4 antibodies are 
generally low, approximately 10%. However, in subjects who respond, the responses are 
generally durable, lasting months to years even in subjects with aggressive tumors, such as, 
refractory metastatic melanoma. Some subjects may have had progression of their disease early 
during treatment, with delayed tumor response or disease stabilization. Tremelimumab has been 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 32 
 
 
 
 
tested in a Phase 3 study for advanced melanoma. Although the study failed to demonstrate 
improved overall survival (OS; primary endpoint) following a prespecified interim futility 
analysis, the final analysis showed a median OS of 12.6 months in the tremelimumab arm and 
10.7 months in the dacarbazine/temozolomide arm. The ongoing Phase 2b study in recurrent 
pleural or peritoneal malignant mesothelioma is testing an alternative dosing schedule of 
tremelimumab with a dose of 10 mg/kg Q4W to maximize exposure to tremelimumab while 
managing safety according to the established anti-CTLA-4 AE management guidelines. The 10 
mg/kg Q4W regimen is also being tested in an ongoing Phase 2 investigator-sponsored study in 
malignant mesothelioma (NCT01655888). 
 
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following IV infusion. 
The estimate of clearance, volume of distribution at steady state, and terminal-phase half-life is 
1.132 mL/h/kg, 81.2 mL/kg, and 22.1 days, respectively. These values are consistent with those 
of natural IgG2. 
 
Overall, 944 of the 973 subjects (97.0%) treated with tremelimumab monotherapy experienced 
at least 1 AE. The events resulted in discontinuation of tremelimumab in 10.0% of subjects, 
were serious in 36.5%, were considered to be treatment related in 79.1% of subjects. The profile 
of AEs and the spectrum of event severity have remained stable across the tremelimumab 
clinical program and are consistent with the pharmacology of the target. To date, no tumor type 
or stage appears to be associated with unique AEs (except for vitiligo that seems to be confined 
to subjects with melanoma). Events reported in the tremelimumab monotherapy studies at a 
frequency > 5% and assessed by the investigator as treatment related were diarrhea (41.2%), 
rash (27.2%), pruritus (25.1%), fatigue (23.8%), nausea (21.9%), vomiting (13.5%), decreased 
appetite(11.3%), headache (7.2%), pyrexia (7.0%), abdominal pain (6.7%), and colitis (5.5%). 
The events of diarrhea, rash, and pruritus are considered as identified risks. Infusion-related side 
effects are rare. The incidence and/or severity of many of the AEs observed following 
administration of tremelimumab can be reduced by adherence to current immune-related 
toxicity management guidelines. 
 
As of the data cutoff date of 12Nov2014, 659 subjects (67.7%) who received tremelimumab 
monotherapy have died. Majority of the deaths were ascribed to the subject’s underlying 
malignant disease (61.8%), only 5 deaths were caused by AEs considered by the investigator as 
related to tremelimumab (0.5%), whereas the remaining causes included other or 
unknown/missing (7.1%). 
 
The frequency of any AEs and ≥ Grade 3 AEs was generally similar across the tremelimumab 
dose groups. However, a higher percentage of subjects in the 10 mg/kg Q28D and 15 mg/kg 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 33 
 
 
 
 
Q90D groups compared with the < 10 mg/kg group experienced treatment-related AEs, SAEs, 
AEs resulting in discontinuation of investigational product, and deaths. 
 
Rationale for study design and dosing 
Rationale for study design 
Sarcoma is a heterogeneous group of diseases that includes more than 50 subtypes. 
Traditionally, due to the rarity of sarcomas they have been lumped together in clinical trials 
even though response to treatment is quite variable among the different subtypes. This has 
slowed the progress in identifying novel effective therapies that might be relevant for specific 
sarcoma subtypes. Options for treatment for patients with advanced / recurrent or metastatic 
disease are quite limited. This study is designed to evaluate the efficacy of check-point inhibitors 
in the multiple sarcoma subtypes divided into cohorts that will be individually analysed. The 
first five cohorts were selected on the basis of their higher frequency, the mutational load and 
reported presence of PD-L1 positivity in prior studies. The 6th cohort will allow enrollment of 
subjects with other sarcoma subtypes not included in the first 5. The goal of this trial is not only 
to test the efficacy and safety of the check-point inhibitor combination farthest along in 
development (anti-PDL-1 and anti-CTLA4) but have the correlative studies to help guide us 
regarding the biomarkers for activity or lack thereof and inform us in prioritizing the novel 
immunotherapeutic agents for the next trial. 
 
Rationale for endpoints 
Response to systemic therapy in metastatic/refractory disease is low and is less meaningful if 
not correlated with improvement in survival. For this reason, PFS has become an acceptable 
metric in the measurement of efficacy in sarcomas with refractory disease or in sarcomas with 
primary resistance to anthracycline-based chemotherapies. The objective data to support use of 
PFS as a primary end point in sarcomas was derived from a review of the EORTC sarcoma 
database by van Glabbeke et al in 2002 (46). In the EORTC analysis, which involved 12 clinical 
trials, patients with no prior treatment received experimental agents were compared to those 
with prior systemic treatment who were received experimental agents. In a multivariate analysis, 
patients with prior therapy obtained an improved PFS with active agents compared to inactive 
agents. For previously treated patients, an active agent was associated with a PFS of at least 
39% and 14% at 3 months and 6 months, respectively. Inactive agents were associated with a 
PFS of 21% and 8% at 3 months and 6 months, respectively. 
 
Hence PFS has been used as the primary end-point to determine if the investigational agents 
being tested are active in the sarcoma subtypes. Secondary endpoints include safety, response 
rate by RECIST and irRC and OS. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 34 
 
 
 
 
Rationale for pre-treatment and on treatment biopsy 
In addition to evaluating the efficacy of these novel immunotherapeutic agents in sarcoma, the 
unique strength of this study is the translational science that can not only help us understand the 
rationale for response and resistance but also guide us with the selection of appropriate sarcoma 
subtypes and also the right combination of immunotherapeutic agents for the next planned 
studies. All patients will require to have baseline tissue available from a resection or biopsy 
(archived samples are acceptable if they are recent within 6 month with no intervening treatment 
including radiation to the biopsied lesion). Exceptions to the baseline biopsy will be made only 
on a case-to-case basis after discussion with the PI. For example, if a biopsy attempt was 
unsuccessful or if the risk was felt to be unduly high. On-treatment biopsy at 6 weeks will be 
optional but we hope to acquire at least 10 patient biopsies in each cohort. Patients who got 
baseline fresh biopsy will be encouraged to get an on-treatment biopsy so we can get paired 
samples in at least 10 patients in each cohort. The pre-treatment biopsy and on-treatment biopsy 
for 10 patients in each cohort is key in order to maximize the potential of this collaboration with 
Medimmune and strategically access their novel immunotherapeutics pipeline to benefit 
sarcoma patients. We will need to understand the immune-microenvironment of the tumors and 
the patient characteristics that lead to response or resistance. The biomarkers from tissue and 
blood acquired as part of this prospective trial will be analyzed in real-time by the correlative 
science team headed by Dr. Wistuba and Dr. Lazar, so the results can inform the next phase of 
the sarcoma immunotherapy studies. Blood for correlative testing including flow cytometry 
(under Dr. Bernatchez) will be obtained at baseline, 2 weeks, 6 weeks and at the time of 
confirmed progression. Patients who are part of this trial but do not experience benefit from the 
combination of durvalumab and tremelimumab might be eligible for future combinations based 
on their tumor immunoprofile. 
 
Rationale for dosing of durvalumab and Tremelimumab 
A population PK model was developed for durvalumab using monotherapy data from the Phase 
1 study, CD-ON-MEDI4736-1108 (N = 292; doses of 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; 
solid tumors). Population PK analysis indicated only minor impact of body weight on PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body weight-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 weight of ~75 kg). A 
total of 1000 subjects were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady-state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 35 
 
 
 
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N = 654; doses of 0.01 to 15 mg/kg Q4W or every 90 days; metastatic 
melanoma; (47). The population PK model indicated minor impact of body weight on PK of 
tremelimumab (coefficient of ≤ 0.5). The weight-based (1 mg/kg Q4W) and fixed dosing (75 
mg/kg Q4W; based on median body weight of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1,000 subjects with body weight distribution of 40 to 120 kg. Similar to 
durvalumab, simulations indicated that both body weight-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between- 
subject variability with fixed dosing regimen. 
 
Similar findings have been reported by others (48-51). Wang and colleagues investigated 12 
mAbs and found that fixed and body size-based dosing perform similarly, with fixed dosing 
being better for 7 of 12 antibodies (49). In addition, they investigated 18 therapeutic proteins 
and peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing 
the between-subject variability in PK/pharmacodynamics parameters (50). A fixed dosing 
approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar PK exposure and variability, we considered it feasible to 
switch to fixed dosing regimens. Based on an average body weight of 75 kg, a fixed dose of 750 
mg Q2W durvalumab is equivalent to 10 mg/kg Q2W, 1500 mg Q4W durvalumab is equivalent 
to 20 mg/kg Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W. 
 
STUDY OBJECTIVES 
Primary objective 
 
Primary Objective: 
Outcome Measure: 
To determine the progression free 
survival (PFS) rate at 12 weeks after the 
initiation of the treatment in patients with 
relapsed/refractory 
sarcoma 
receiving 
check-point inhibitors (anti-CTLA-4 and 
anti-PD-L1). 
PFS at 12 weeks as defined by RECIST 1.1 
Secondary objectives 
 
Secondary Objective: 
Outcome Measure: 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 36 
 
 
 
 
To estimate the tumor response (irRC and 
RECIST) 
in 
patients 
with 
relapsed/refractory 
sarcoma 
receiving 
receiving check-point inhibitors (anti- 
CTLA-4 and anti-PD-L1). 
irRC and RECIST response rate 
To evaluate the safety and tolerability of 
check-point inhibitors in patients with 
relapsed/refractory sarcoma 
Toxicity rate (persistent grade 3 and/or 4 toxicity 
despite therapy) per treatment cohort 
To estimate the PFS at 24 weeks and 
overall survival (OS) in patients with 
relapsed/refractory 
sarcoma 
receiving 
check-point inhibitors (anti-CTLA-4 and 
anti-PD-L1). 
PFS at 24 weeks and OS 
 
Exploratory objectives 
 
Exploratory Objective: 
Outcome Measure : 
To determine PD-1/PD-L1 expression 
analysis (pre & post tx samples). 
PD-1/PD-L1 expression analysis (pre & post tx 
samples) 
Quantification and characterization of 
immune infiltrate (and other histologic 
and immunohistologic changes) from 
tissue samples prior to treatment initiation 
and post treatment (biopsy at week 6). 
Tumor infiltrating lymphocytes (TILs) (pre & 
post tx samples) 
 
STUDY DESIGN 
Description of the Study 
This is a single center, open-label, phase II study to evaluate the antitumor activity, safety, 
tolerability and immunogenicity of durvalumab in combination with tremelimumab in subjects 
with advanced/metastatic sarcomas. This study will include patients (age ≥12 years) with 
recurrent/metastatic sarcoma, who have received at least one prior systemic therapy (if a 
standard therapy exists for the subtype), divided into the following categories/subtypes: 
 
1. Adipocytic tumors (Well-differentiated/dedifferentiated liposarcoma, 
myxoid liposarcoma, pleomorphic liposarcoma) 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 37 
 
 
 
 
2. Vascular tumors (leiomyosarcoma, angiosarcoma) 
3. Undifferentiated pleomorphic sarcoma 
4. Synovial sarcoma 
5. Osteosarcoma 
6. Other sarcomas 
 
A Bayesian design will be used to analyze data in each of the cohorts. 
 
Treatment Regimen 
Durvalumab 1500 mg IV and tremelimumab 75 mg IV every 4 weeks for 4 cycles followed by 
durvalumab 1500 mg every 4 weeks for up to 8 additional cycles. If toxicity was noted with the 
combination, investigator can decide to continue durvalumab alone in case patient is having 
clinical benefit (SD or better). 
 
Cycle duration: 28 days 
 
Mode of Administration: Tremelimumab will be administered first and the infusion duration 
will be approximately 1 hour. The durvalumab infusion will start approximately 1 hour after the 
end of the tremelimumab infusion and the infusion will be administered over approximately 1 
hour. Both agents will be administered by intravenous (IV) infusion Q4W for 4 doses, after 
which durvalumab will continue to be administered Q4W (up to 8 additional doses). 
 
Subjects enrolled who achieve and maintain disease control 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 
progressive disease (PD), the subject may be re-administered durvalumab/tremelimumab (4 
doses of combination followed by single agent durvalumab) and continue treatment as long as 
they do not meet any of the investigational product discontinuation criteria (Section 4.6). In the 
setting of PD, they need to meet criteria for continuation in the setting of PD; which include 
absence of clinical symptoms or signs indicating clinically significant disease progression; no 
decline in Eastern Cooperative Oncology Group (ECOG) performance status compared to 
baseline; absence of rapid disease progression or threat to vital organs/critical anatomical sites 
(eg, spinal cord compression) requiring urgent alternative medical intervention; and continuing 
benefit in the opinion of the investigator and PI. 
 
 
Management of study related toxicities 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation 
and proliferation, the occurrence of irAEs that are either overlapping or greater than each of 
these drugs when used as monotherapy is possible. Potential irAEs may be similar to those seen 
with the use of ipilimumab, nivolumab, or the combination thereof and may include immune- 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 38 
 
 
mediated enterocolitis, dermatitis, pneumonitis, hepatitis (hepatotoxicity), neuropathy, and 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 39 
 
 
 
 
endocrinopathies (8-10, 52). Subjects should be monitored for signs and symptoms of irAEs. In 
the absence of an alternate etiology (eg, infection or PD), an immune-related etiology should be 
considered for signs or symptoms of enterocolitis, pneumonitis, dermatitis, hepatitis, neuropathy, 
and endocrinopathy. In addition to the treatment modifications shown in Table 3.1.5-1, it is 
recommended that management of irAEs follow the guidelines outlined for ipilimumab (53). 
These guidelines recommend the following: 
1. Subjects should be evaluated to identify any alternative etiology. 
2. In the absence of a clear alternative etiology, all events of an inflammatorynature should 
be considered to be immune-related. 
3. Symptomatic and topical therapy should be considered for low-grade events. 
4. Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event. 
5. More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab, mycophenolate, etc). 
 
Treatment modifications will not be required for AEs that are clearly not attributed to 
durvalumab or tremelimumab (such as an accident) or for laboratory abnormalities that are not 
deemed to be clinically significant. Dose reductions of durvalumab or tremelimumab are not 
permitted. 
 
Treatment modifications may be required for durvalumab and tremelimumab in the event of 
treatment-related toxicity. General guidelines regarding treatment modification are provided in 
Table 3. All toxicities will be graded according to NCI CTCAE v4.03. If toxicity requires 
discontinuation of check-point inhibitor therapy and was experienced while receiving the 
combination, the investigator has the option to continue single agent durvalumab if safe and if 
clinical benefit is noted (SD or better). 
 
Table 3 
Immunotherapy (durvalumab and Tremelimumab) Treatment 
Modification Due to Toxicity and Supportive Care Guidelines for 
Immune-Related Adverse Events (irAEs) 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 40 
 
 
 
GRADE 1 - Immunotherapy Related Toxicities 
 
For endocrinopathy irAEs 
• 
Do not hold immunotherapy (Durvalumab and/or Tremelimumab) 
• 
Obtain labs pertinent to specific endocrinopathy 
 
For dermatologic irAEs 
• 
Do not hold immunotherapy (Durvalumab and/or Tremelimumab) 
• 
Start medium potency topical steroid Antihistamine 
• 
Reassess verbally in 72 hours 
• 
If responds continue same directions for 7 days then taper off 
• 
If no relief advance to wet dressings and consult dermatology. 
 
For gastrointestinal irAEs 
• 
Do not hold immunotherapy (Durvalumab and/or Tremelimumab) 
• 
Fluid replacement (2-3 liters/day) 
• 
If patient has lab abnormalities or dehydrated consider outpatient IV fluids with 
• 
electrolyte replacement for a total of 2-3 liters x 48 hours) 
• 
Anti-diarrheals 
• 
Reassess verbally in 24 hours 
• 
If responds, continue same directions for 72 hours then taper 
• 
If no relief, proceed to grade 2 management 
 
For hepatitis (ALT, AST and/or bilirubin) irAEs 
• 
Continue immunotherapy (Durvalumab and/or Tremelimumab) 
• 
Consider increased LFT monitoring 
 
For pneumonitis irAEs 
• 
Continue immunotherapy (Durvalumab and/or Tremelimumab) if clinically stable 
• 
Monitor symptoms every 2-3 days 
• 
Repeat Chest X-ray in 2 weeks 
 
For Uveitis/Episcleritis irAEs 
• 
Consider ophthalmology consultation 
• 
Topical steroids (1% prednisolone acetate suspension) 
 
For infusion-related reactions: 
• 
The infusion rate of Durvalumab or Tremelimumab may be decreased by 50% or temporarily interrupted until 
resolution of the event. In subjects experiencing Grade ≤ 2 infusion related reaction, subsequent infusions may be 
infused at 50% of the initial rate. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standard at the discretion of the 
investigator. 
• 
Consider premedication prior to subsequent doses. 
 
For all other irAEs: 
• 
No treatment adjustment is required. 
 
GRADE 2 - Immunotherapy Related Toxicities 
 
For endocrinopathy irAEs 
• 
Hold treatment (Durvalumab and Tremelimumab or Durvalumab alone) 
• 
When endocrinopathy is controlled, resume treatment (Durvalumab and Tremelimumab or Durvalumab alone) 
 
For dermatologic irAEs 
• 
Do not hold Tremelimumab and/or Durvalumab 
• 
Start medium potency topical steroid Antihistamine 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 41 
 
 
 
• 
Reassess verbally in 72 hours 
• 
If responds continue same directions for 7 days then taper off 
• 
If no relief advance to wet dressings and consult dermatology. 
 
For gastrointestinal irAEs 
• 
Hold immunotherapy (Tremelimumab and/or Durvalumab) 
• 
Fluid replacement (2-3 liters/day) 
• 
If patient has lab abnormalities or dehydrated consider outpatient IV fluids with electrolyte replacement for a total of 2-3 
liters x 48 hours 
• 
Anti-diarrheals 
• 
Reassess verbally in 24 hours 
• 
If responds, continue same directions for 72 hours then taper 
• 
If persists after 24 hours: 
• 
Hold immunotherapy until less than grade 1 
• 
Prednisone oral 1 mg/kg/day 
• 
Consult gastroenterology 
• 
Obtain CT scan of abdomen & pelvis +/- colonoscopy 
• 
If immune mediated colitis is confirmed by biopsy, proceed to grade 3/grade 4 management 
• 
If patient is benefiting from treatment per imaging then PI discretion on length of time study drugs can be held. 
• 
Allow time for steroid taper. 
 
For Pneumonitis irAEs 
• 
Hold immunotherapy (Tremelimumab and/or Durvalumab) until improvement to ≤ Grade 1 
• 
HospitalAdmission 
• 
Monitor symptomsdaily 
• 
Obtain chest imaging (CT chest is preferred) 
• 
Evaluate for disease progression 
• 
Pulmonary & Infectious Disease Consultations 
• 
Rule out other etiologies (infectious, autoimmune, etc.) 
• 
Prednisone PO 1 mg/kg/day 
• 
If no improvement, treat as grade 3/grade 4 pneumonitisirAE. 
 
For Hepatitis (ALT, AST and/or bilirubin)irAEs 
• 
Hold Tremelimumab and/or Durvalumab until less than grade 1 
• 
Monitor LFTs every 72 hours (3 days) 
• 
Evaluate for disease progression 
• 
If this does not improve, monitor LFTs daily, and initiate prednisone oral 1 mg/kg/day 
• 
If improvement to ≤ Grade 1 does not occur within 30 days, discontinue treatment. 
 
For Uveitis/EpiscleritisirAEs 
• 
Considerophthalmology consultation 
• 
Topical steroids (1% prednisolone acetatesuspension) 
 
For infusion-related reactions:  
• 
The infusion rate of Durvalumab or Tremelimumab may be decreased by 50% or temporarily interrupted until resolution 
of the event. In subjects experiencing Grade ≤ 2 infusion related reaction, subsequent infusions may be administered at 
50% of the initial rate. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standard at the discretion of the 
investigator. 
• 
Consider premedication prior to subsequent doses. 
 
For all other irAEs 
• 
Hold treatment (Durvalumab and Tremelimumab or Durvalumab alone) until improvement to ≤ Grade 1 or baseline. 
• 
If improvement to ≤ Grade 1 does not occur within 60 days, discontinue treatment (Tremelimumab and/or Durvalumab). 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 42 
 
 
 
Grade 3 - Immunotherapy Related Toxicities 
 
Forendocrinopathy irAEs 
• 
Hold treatment (Tremelimumab and/or Durvalumab) 
• 
Considerhospitaladmission 
• 
Monitor labs pertinent to endocrinopathy 
• 
Endocrinology consultation 
• 
Evaluate for disease progression 
• 
Initiate high-dose steroids (1 mg/kg/day) 
• 
Replace deficient hormones (hypophysitis) 
• 
When endocrinopathy is controlled, resume treatment (Tremelimumab and/or Durvalumab) administration at next 
scheduled dose. 
 
For Dermatologic irAEs 
• 
Hold treatment (Tremelimumab and/or Durvalumab) until improvement to ≤ Grade 1 or baseline 
• 
Dermatology consult 
• 
High potency topical steroids Prednisone oral 0.5-1 mg/kg/day Antihistamine 
• 
Reassess verbally in 72 hours 
• 
If responds continue same directions for 7 days and then taper off 
• 
If no relief, proceed to grade 4 management. 
• 
If improvement to ≤ Grade 1 or baseline does not occur within 30 days, discontinue treatment (Tremelimumab and/or 
Durvalumab) 
 
For Gastrointestinal irAEs 
• 
Discontinue immunotherapy (Tremelimumab and/or Durvalumab) 
• 
Hospital Admission Bowel Rest – NPO 
• 
Methylprednisolone IV 2 mg/kg/day 
• 
Gastroenterology consult 
• 
Obtain CT scan of abdomen & pelvis +/- colonoscopy to evaluate for immune- mediated colitis 
• 
Evaluate for perforation 
• 
If perforation is suspected, obtain a surgical consultation immediately and do not start anti-diarrheals, steroids, and 
Infliximab 
• 
Consider Infliximab IV 5 mg/kg; may repeat in 2 weeks (if no contraindication). 
• 
If resolution occurs, slow taper steroid over greater than 4 weeks. 
 
For Hepatitis (ALT, AST, and/or bilirubin) irAEs 
• 
Discontinue immunotherapy (Tremelimumab and/or Durvalumab) 
• 
Hospital Admission 
• 
Monitor LFTs daily and consult gastroenterology/hepatology 
• 
Initiate Methylprednisolone IV 2 mg/kg/day 
• 
If persistent, add immunosuppressant (tacrolimus, antithymocyte globulin) 
• 
For elevations in transaminases ≤ 8 times ULN, hold treatment (Tremelimumab and/or Durvalumab) until improvement to 
≤ Grade 1 or baseline. 
• 
If elevations downgrade to ≤ Grade 2 within 7 days or to ≤ Grade 1 or baseline within 28 days, resume treatment 
(Tremelimumab and/or Durvalumab administration at next scheduled dose. Otherwise, discontinue treatment 
(Tremelimumab and/or Durvalumab) 
• 
For elevations in transaminases > 8 times ULN, discontinue treatment (Tremelimumab and/or Durvalumab) 
• 
For elevations in total bilirubin ≤ 5 times ULN, hold treatment (Tremelimumab and/or Durvalumab) until improvement 
to ≤ Grade 1 or baseline. If elevations downgrade to ≤ Grade 2 (< 3 Å~ ULN) within 7 days or improve to ≤ Grade 1 or 
baseline within 28 days, resume treatment (Tremelimumab and/or Durvalumab) administration at  next  scheduled 
dose. Otherwise, discontinue treatment (Tremelimumab and/or Durvalumab) 
• 
For elevations in total bilirubin > 5 times ULN, discontinue treatment (Tremelimumab and/or Durvalumab) 
• 
If resolution occurs, slow taper systemic steroid over greater than 4 weeks. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 43 
 
 
 
 
For pneumonitis irAEs 
• 
Discontinue immunotherapy (Tremelimumab and/or Durvalumab) 
• 
HospitalAdmission 
• 
Monitor symptomsdaily 
• 
Methylprednisolone IV 2 mg/kg/day 
• 
Evaluate for disease progression 
• 
Pulmonary and Infectious Disease consultation 
• 
Bronchoscopy a n d B A L a n a l y s i s is stronglyrecommended. 
• 
If resolves, s low taper s tero ids over greater than 4 weeks. 
 
For Uveitis/EpiscleritisirAEs 
• 
Discontinue immunotherapy (Tremelimumab and/or Durvalumab) permanently 
• 
Ophthalmology consultation 
• 
Topical steroids 
(1% prednisolone acetatesuspension) 
• 
Consider oral prednisone 1 mg/kg/day with at least a 30-day taper. 
 
For hypersensitivity and infusion-related reactions 
• 
Discontinue treatment (Tremelimumab and/or Durvalumab) 
 
For all other irAEs 
• 
Hold treatment (Tremelimumab and/or Durvalumab) until improvement to ≤ Grade 1 or baseline. 
• 
For AEs that downgrade to ≤ Grade 2 within 7 days or improve to ≤ Grade 1 or baseline within 14 days, resume 
treatment (Tremelimumab and/or Durvalumab) administration at next scheduled dose. Otherwise, discontinue 
treatment (Tremelimumab and/or Durvalumab) 
 
Grade 4 - Immunotherapy Related Toxicities 
 
For endocrinopathy irAEs 
• 
Same as management for grade 3 endocrinopathy irAEs. 
 
For dermatologic irAEs 
• 
Discontinue immunotherapy (Tremelimumab and/or Durvalumab) 
• 
Hospital admission 
• 
IV hydration; especially if large BSA of denuded skin 
• 
Dermatology consult 
• 
Monitor closely for sepsis, respiratory symptoms 
• 
Prednisone IV 2 mg/kg/day 
• 
Oral care & eye care as indicated 
• 
If resolves, slow taper systemic steroid over at least 4 weeks to prevent recurrence. 
 
For gastrointestinal irAEs 
• 
Same as management for grade 3 gastrointestinal irAEs. 
 
For hepatitis irAEs 
• 
Same as management for grade 3 hepatitis irAEs. 
 
For pneumonitis irAEs 
• 
Same as management for grade 3 pneumonitis irAEs. 
 
For Uveitis/Episcleritis irAEs 
• 
Same as management for grade 3 episcleritis/uveitis. 
 
For all other irAEs 
• 
Discontinue treatment (Durvalumab and/or Tremelimumab). 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 44 
 
 
 
 
Cohort enrollment 
Describe Bayesian design and monitoring of patients 
Within each cohort, we will treat up to 25 patients. The primary efficacy endpoint will be 
progression-free survival at 12 weeks (PFS12 weeks). 12-week PFS is defined as evidence of stable 
disease or better 12 weeks after the initiation of therapy. In the meanwhile, we will also monitor 
the toxicity of the agent. Toxicity will be assessed within the first two cycles of the treatment. 
If there is a high probability that the PFS12 weeks is unlikely to be at least 40% or that the 
unacceptable toxicity rate (as described in section 3.2.2 below) is likely to be greater than 30%, 
the drug would not be considered of interest for further study. The cohort will be monitored in 
cohorts of 5 patients after a minimum of 5 patients have been enrolled. 
 
Unacceptable toxicity 
All toxicities will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.03. Toxicities will be managed per section 3.1.2. 
In each cohort if the unacceptable toxicity rate as described below is greater than 30%, then 
further enrollment in that cohort will stop. Patients already on therapy will continue on treatment 
as per protocol. 
 
Toxicity that is clearly and directly related to the primary disease or to another etiology is 
excluded from this definition. 
Any Grade 4 immune-related adverse event (irAE) 
 
Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care 
Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 
2 within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 
days 
Liver transaminase elevation > 8 × upper limit of normal (ULN) or total bilirubin 5 × ULN 
Any ≥ Grade 3 non-irAE 
The following will not be considered as unacceptable toxicity: 
• Grade 3 fatigue lasting ≤ 7 days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) 
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, 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 45 
 
 
 
 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc) 
• Concurrent vitiligo or alopecia of any AE grade 
• Grade 3 infusion-related reaction (first occurrence and in the absence 
of steroid prophylaxis) that resolves within 6 hours with appropriate 
clinical management 
• Grade 3 or 4 neutropenia that is not associated with fever or systemic infection 
that improves by at least 1 grade within 3 days. 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant 
bleeding that requires medical intervention, and improves by at least 1 grade 
within 3 days 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical 
signs or symptoms and are reversed with appropriate maximal medical 
intervention within 3 days 
 
Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings. 
 
SUBJECT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL 
Number of Subjects 
Approximately 5 to 25 subjects in each of the six cohorts and up to 150 subjects in total will be 
enrolled. All eligibility criteria should occur according to timeframes listed within Table 4, 
Section 5 of the protocol. 
Inclusion criteria 
4.2.1 
Age: >/= 18 years of age 
 
4.2.2 
Histologically or cytologically confirmed sarcoma that fall into one of the 
following categories Patients with low-grade tumors are eligible if there is 
definite evidence of metastasis or progression (defined as at least a 10% increase 
in the cumulative sum of the longest diameters within a 3 month period): 
 
1. Adipocytic tumors (Well-differentiated/dedifferentiated 
liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma) 
2. Vascular tumors (leiomyosarcoma, 
angiosarcoma) 
3. Undifferentiated pleomorphic sarcoma 
4. Synovial sarcoma 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 46 
 
 
 
 
5. Osteosarcoma 
6. Other sarcoma histologies 
 
4.2.3 
Must have received and have progressed, are refractory or intolerant to standard 
therapy appropriate for the specific sarcoma subtype, if there is a standard 
therapy for the subtype (i.e. Progressing well-differentiated liposarcoma, clear 
cell sarcoma etc do not require prior therapy). 
 
4.2.4 
Subjects must have at least 1 lesion that is measurable by irRECIST 
 
a. A previously irradiated lesion can be considered a target lesion if the 
lesion is well defined, measurable per irRECIST, and has clearly 
progressed. 
b. Subjects undergoing fresh tumor biopsies must have additional non- 
target lesions that can be biopsied at acceptable risk as judged by the 
investigator or if no other lesion suitable for biopsy, then an 
irRECIST target lesion used for biopsy must be ≥ 2 cm in longest 
diameter. 
 
4.2.5 
Subjects must consent to provide archived tumor specimens for correlative 
biomarker studies. Tumor tissue must be identified and availability confirmed 
prior to initiation of study therapy. In the setting where archival material is 
unavailable or unsuitable for use, or there have been multiple intervening 
therapies subjects must consent and undergo fresh tumor biopsy. A tumor lesion 
planned for biopsy must not be an irRECIST target lesion unless there are no 
other lesions suitable for biopsy and lesion used for biopsy is ≥ 2 cm in longest 
diameter. 
 
4.2.6 
ECOG performance status of 0 or 1 
 
4.2.7 
Adequate organ function as determined by (lymphocyte count): 
 
a. Hematological (without growth factor or transfusion support): 
3 
i. Absolute neutrophil count ≥ 1.5 x 109/L (1,500/mm ) 
9 
3 
ii. Platelet count ≥ 90 × 10 /L (100,000/mm ) 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 47 
 
 
 
iii. Hemoglobin ≥ 8.0 g/dL within first 2 weeks prior to first dose of 
investigational product 
 
b. Renal: 
i. Calculated creatinine clearance (CrCl) or 24-hour urine CrCl > 50 
mL/min Cockcroft-Gault formula (using actual body weight) will be used 
to calculate CrCl, except for pts with Osteosarcoma who will be allowed 
to participate with an estimated creatinine clearance (CrCl) of > 40 
mL/min, as calculated by the Cockroft-Gault equation. 
 
c. Hepatic: 
i. Total bilirubin ≤ 1.5 × ULN; for subjects with 
documented/suspected Gilbert's disease, bilirubin ≤ 3 × ULN 
ii. AST and ALT ≤ 2.5 × ULN; for subjects hepatic metastases, ALT 
and AST ≤ 5 × ULN 
 
4.2.8 
Females of childbearing potential who are sexually active with a nonsterilized 
male partner must use a highly effective method of contraception from the time 
of screening, and must agree to continue using such precautions for 90 days after 
the final dose of investigational product. 
 
4.2.9 
Life expectancy of at least 6 months. 
 
4.2.10 Ability to understand the purposes and risks of the study and has signed a written 
consent form approved by the investigator’s IRB/Ethics Committee. 
 
Exclusion criteria 
4.3.1. 
Prior therapy with anti-PD1, anti-PD-L1 or anti-CTLA-4 antibody 
 
4.3.2. 
Active or prior documented autoimmune disease (including inflammatory bowel 
disease, celiac disease, Wegener syndrome) within the past 2 years. Subjects with 
childhood atopy or asthma, vitiligo, alopecia, Hashimoto syndrome, Grave’s 
disease, or psoriasis not requiring systemic treatment (within the past 2 years) are 
not excluded. 
 
4.3.3. 
Untreated central nervous system metastatic disease, leptomeningeal disease, or 
cord compression. Subjects previously treated central nervous system metastases 
that are radiographically and neurologically stable for at least 6 weeks and do not 
require corticosteroids (of any dose) for symptomatic management for at least 14 
days prior to first dose of durvalumab and tremelimumab are permitted to enroll. 
 
4.3.4. 
Concurrent enrollment in another clinical study, unless it is an observational 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 48 
 
 
 
(non-interventional) clinical studyor the follow-up period of an interventional study. 
 
4.3.5. 
Receipt of any conventional or investigational anticancer therapy not otherwise 
specified above within 28 days o r 5 hal f - l i ves of t he agent prior to the first 
dose of durvalumab and tremelimumab. 
4.3.6. 
Any concurrent chemotherapy, IMT, or 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. In addition, local 
treatment (eg, by local surgery or radiotherapy) of isolated lesions for palliative 
intent is acceptable beyond the first cycle with prior consultation and in agreement 
with the PI. 
 
4.3.7. 
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 irreversible toxicity 
that is not reasonably expected to be exacerbated by any of the investigational 
products may be included (eg, hearing loss) after consultation with  the  study chair. 
 
4.3.8. 
Current or prior use of immunosuppressive medication within 14 days prior to 
the first dose of durvalumab or tremelimumab. The following are exceptions to this 
criterion: 
 
a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection). 
 
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent. 
 
c. Steroids as premedication for hypersensitivity reactions (eg, computed 
tomography [CT] scan premedication). 
 
4.3.9. 
History of primary immunodeficiency, solid organ transplantation, or previous 
clinical diagnosis of tuberculosis. 
 
4.3.10. True positive test results for human immunodeficiency virus (HIV) or hepatitis 
B or C. 
 
4.3.11. Receipt of live, attenuated vaccine within 28 days prior to the first dose of 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 49 
 
 
 
investigational products (NOTE: Subjects, if enrolled, should not receive live 
vaccine during the study and 180 days after the last dose of investigational products). 
 
 
4.3.12. Major surgery (as defined by the investigator) within 4 weeks or thoracotomy 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 50 
 
 
 
 
for pulmonary metastases within 2 weeks prior to first dose of treatment or if still 
recovering from prior surgery. Local surgery of isolated lesions for palliative intent 
is acceptable. 
 
4.3.13. Other invasive malignancy within 2 years except for noninvasive malignancies 
such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or 
ductal carcinoma in situ of the breast that has/have been surgically cured. 
 
4.3.14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or 
psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs from durvalumab or 
tremelimumab, or compromise the ability of the subject to give written informed 
consent. 
 
4.3.15. Any condition that, in the opinion of the investigator or sponsor, would interfere 
with evaluation of the investigational product or interpretation of subject safety or 
study results. 
 
4.3.16. Patients with a history of pneumonitis or interstitial lung disease. 
 
Subject enrollment 
Study participation begins (ie, a subject is “enrolled”) once written informed consent is obtained. 
Once informed consent is obtained, and the patient is enrolled an accession number will be 
assigned, and the screening evaluations may begin to assess study eligibility 
(inclusion/exclusion) criteria. The accession 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. 
 
Withdrawal from the Study 
Subjects are at any time free to withdraw from the study 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 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 51 
 
 
 
 
events will be followed up by the investigator for as long as medically indicated. 
 
Withdrawal from Treatment 
If a subject withdraws consent to further treatment, they will not receive any further 
investigational product(s), but may continue with further study observation. Subjects who 
decline to return to the site for evaluations will be offered follow-up by phone according to the 
schedule in Section 4.2.3 as an alternative. If a subject withdraws from further participation in 
the study, then no further study visits or data collection should take place. 
 
Withdrawal of Consent 
If consent is withdrawn, the subject will not receive any further investigational product(s) or 
further study observation. Note that the subject may be offered additional tests. 
 
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 such that there is insufficient information to determine the subject’s status 
at that time. Subjects, who refuse continued 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. 
 
Discontinuation of investigational product 
An individual subject will not receive any further investigational product (durvalumab and 
tremelimumab) if any of the following occur in the subject in question: 
 
1. Withdrawal of consent from further participation in study 
2. Lost to follow-up 
3. An AE that, in the opinion of the investigator or the sponsor, contraindicates further dosing. 
If toxicity was noted with the combination, investigator can decide to continue durvalumab 
alone in case patient is having clinical benefit (SD or better). 
4. Subject experienced unacceptable toxicity as defined in Section 3.2.2 
5. Subject is determined to have met one or more of the exclusion criteria for study participation 
at study entry and continuing investigational product dosing might constitute a safety risk 
7. Pregnancy or intent to become pregnant 
8. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits) 
9. Initiation of alternative anticancer therapy including another investigational agent 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 52 
 
 
 
 
10. Confirmation of PD and retreatment criteria in the setting of PD are not met (absence of 
clinical symptoms or signs indicating clinically significant disease progression; no decline in 
Eastern Cooperative Oncology Group (ECOG) performance status compared to baseline; and 
absence of rapid disease progression or threat to vital organs/critical anatomical sites (eg, spinal 
cord compression) requiring urgent alternative medical intervention. 
 
Replacements of subjects 
Nonevaluable subjects who withdraw consent prior to any study related treatment or are unable 
to begin treatment will be replaced. 
 
Withdrawal of consent for data and biological samples 
Study data are protected by the use of an accession number, which is a specific number for each 
subject. The investigators are in control of the information that is needed to connect a study 
sample to a subject. A subjects 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 used but no additional data or 
samples will be collected unless specifically required to monitor safety of a subject. 
 
SCHEDULE OF STUDY PROCEDURES 
All patients will have history/physical examinations & laboratory assessments during the 
screening phase (day -30 to day -1) and prior to each drug administration every four weeks. 
Laboratory assessments for toxicity will be every 2 weeks for the first four months then the 
frequency will change to every 4 weeks. Patients with grade 3 or 4 immune-related adverse 
events (irAEs) will receive immunosuppressive treatment with systemic corticosteroids as per 
protocol. 
 
Baseline imaging studies (CT-scans and/or MRI-scans) should be within 30 days prior to 
treatment initiation. The first restaging assessment will be performed at week 8 (+/- 1 week) 
with a confirmatory scan at 12 weeks (+/- 1 week). Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 and Immune Response Evaluation Criteria in Solid tumors (iRECIST) 
will be used to measure response to treatment. Thus, the patient will continue on treatment until 
confirmed disease progression, unacceptable toxicities, or unless the patient chooses to 
withdraw consent for study participation. 
 
Baseline biopsies will be obtained prior to treatment initiation (archived sample is acceptable if 
it is within 6 months with no intervening therapy including radiation to the biopsied lesion). In 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 53 
 
 
 
 
each cohort we hope to have at least 10 patients that undergo a repeat biopsy at 6 weeks (+/- 1 
week). Those patients who undergo a fresh biopsy prior to the start of the treatment will be 
encouraged to get the on-treatment biopsy to ensure availability of matched fresh tumor 
specimens for correlative analysis. Those patients with an increased risk from repeat biopsy as 
determined by the PI and the IR physician will be exempt. These biopsies would be obtained 
through interventional radiologic techniques with exception to superficial tumors that are 
accessible by punch biopsy. Blood work obtained for correlative studies would be performed at 
baseline, week 2, and week 6 (+/- 1 week for all time points). Blood draw for correlative 
biomarkers should coincide with the biopsy date when feasible. Optional biopsy and a blood 
draw for correlative studies will be performed at the time of confirmed progression in patients 
with prior evidence of response. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date17 May 2017 Page | 54 
Enrollment/screening period (Day-30 to Day 1): 
 
Table 4 
All procedures to be conducted at the screening visit. 
 
Procedure 
Screening/Baseline 
Days -30 to Day 1 
Written informed consent/assignment of an accession number 
X 
Verifyeligibility criteria 
X 
Tumor and disease assessments 
History of prior cancer treatment 
X 
Disease assessment by irRECIST (CT / MRI / (PET/CT), including evaluation for brain 
metastases 
X 
Study procedures and examinations 
Demographics (including date of birth, sex, race, ethnicity) 
X 
Medical history 
X 
Physical examination, height, weight 
X 
ECOG performance status 
X 
a 
12-lead ECG 
X 
Vital signs 
X 
Assessment of AEs/SAEs 
X 
Concomitant medications 
X 
Laboratory tests 
Serumchemistry 
X 
Hematology 
X 
Thyroid function tests (TSH, free T3, and free T4) 
X 
Urinalysis 
X 
Serum pregnancy test 
X 
Hepatitis B and C; HIVb 
X 
Other laboratory tests and assays 
Archival tumor sample (if one obtained within the past 6 months is available with no 
intervening treatment including radiation to the biopsied lesion) 
X 
Fresh tumor biopsy (if no recent archival sample available as above) 
X 
Correlative laboratory assays (5 purple-top tubes, 8-10 ml per tube) 
X 
AE = adverse event; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; HIV = human immunodeficiency virus; irRECIST = immune-related Response 
Evaluation Criteria in Solid Tumors; MRI = magnetic resonance imaging; PET= positron emission 
tomography; SAE = serious adverse event; SID = subject identification; TSH = thyroid-stimulating 
hormone. 
a 
At screening, ECGs will be obtained in triplicate (all 3 within a 5-minute time period, at least 1 
minute apart). 
 
b 
Do not need to be repeated if negative result obtained within the last 3 months with no intervening 
symptoms or exposures. 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 55 
 
 
 
 
 
Treatment period 
Procedures to be conducted during the treatment period are presented in Table 5 for Weeks 0 to 44 and in Table 6 for Week 45 through 
end of treatment. 
 
All samples are collected predose unless otherwise indicated. 
 
Table 5 
Schedule of Treatment Period Study Procedures Weeks 0 to 44 
 
Study Period 
Week/Day 
W0 
D1 
W 
2 
D1 
W4 
D1 
± 3D 
W6 
D1 
± 3D 
W 
8 
D1 
W1 
0 
D1 
W12 
D1 
± 3D 
W14 
D1 
± 3D 
W1 
6 
D1 
W20 
D1 
± 3D 
W2 
4 
D1 
W28,W32,W36 
, W40, W44 
D1 ± 3D 
Procedure/Study Day 
1 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
Durvalumabadministration 
(Q4W dosing schedule) 
X 
X 
X 
X 
X 
X 
X 
X 
Tremelimumabadministration 
(Q4W dosing schedule) 
X 
X 
X 
X 
Tumor and disease assessments 
Disease assessment by irRECIST 
(CT /(PET)CT/ MRI) a 
X 
X 
X 
X 
Fresh tumor biopsy 
X b 
± 7D 
Study procedures and examinations 
Physical examination, weightf 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Xc 
X 
X 
X 
X 
X 
X 
X 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG e 
X 
Assessment of AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 56 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests 
Serumchemistry g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests (TSH, free T3, 
free T4) 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
Urine or serum pregnancy test 
X 
Correlative laboratory assays (5 
purple-top tubes, 8-10 ml per tube) 
Flowcytometry 
X 
X 
PBMCcollection 
X 
X 
miRNA/mRNAcollection(whole 
blood PAXgene RNA tube) 
X 
X 
AE = adverse event; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; miRNA = micro ribonucleic acid; MRI = magnetic resonance imaging; mRNA = 
messenger ribonucleic acid; PBMC = peripheral blood mononuclear cell; Q4W = every 4 weeks; RNA = ribonucleic acid; SAE = serious adverse event; TSH = 
thyroid-stimulating hormone; W = week 
 
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of MEDI4736/tremelimumab unless otherwise indicated. Tremelimumab 
will be administered first and the infusion duration will be approximately 1 hour. The MEDI4736 infusion will start approximately 1 hour post EOI of tremelimumab and the 
infusion will be administered over approximately 1 hour. 
a. 
All Imaging time points have a window of +/- 1 week. After W12, restaging scans will be obtained every 8 weeks. 
b. 
Optional on-treatment biopsy at 6 weeks (+/- 1 week). We plan to biopsy at least 10 patients in each of the 6 cohorts on-treatment. Those patients who undergo a fresh 
biopsy prior to the start of the treatment will be encouraged to get the on-treatment biopsy to ensure availability of matched fresh tumor specimens. Those patients with an 
increased risk from repeat biopsy as determined by the PI and the IR physician will be exempt. 
c. 
If physical examination or safety laboratory tests are performed within 3 days prior to Dose 1, they do not need to be repeated. 
d. Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on MEDI4736/tremelimumab treatment days. Vital signs will be measured 
prior to the start of tremelimumab and durvalumab administration, during and at the end of infusion per institutional guidelines. For the first day of administration of 
investigational product, an additional 60 minutes (± 15 minutes) post MEDI4736 infusion period of observation will be required. 
e. 
On Day 1, ECGs will be obtained in triplicate (all 3 within a 5-minute time period) within 30 minutes prior to start of tremelimumab infusion. 
f. 
Weight and height will be assessed (at screening only) 
g. 
Week 2, 6, 10, and 14 labs window +/- 7 days 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 57 
 
 
Follow-up period 
Table 6 shows all procedures to be conducted during the end of treatment visit and follow-up period. For subjects who 12 months of therapy, 
the last dosing visit within the 12-month period is considered to be the end of treatment visit. Subjects who discontinue before 12 months 
will complete the end of treatment visit at the time the decision is made to discontinue treatment. Patient will complete all 12 cycles of 
treatment if meets all criteria per protocol even if greater than 12 months. 
 
All subjects are to complete the end of treatment visit, all follow-up visits and be contacted for survival status in accordance with the 
Schedule of Assessments. However, if a subject discontinues from treatment and moves onto alternative anticancer treatment, the follow-up 
visits will no longer be required; however, survival follow-up assessments would be required as indicated in the Schedule of Assessments 
unless the subject withdraws consent for further survival follow-up. Survival follow-up will continue until the end of study as defined in 
Section 5.4.1. 
 
Table 6 
Schedule of Follow-up Procedures 
 
Study Period 
Follow-up Period 
Procedure / Study Day or Month 
EOT a 
Day 30 ± 
2 Weeks 
Every 3 Months after end of treatment ± 28 
Days 
Disease assessments 
Disease assessment by irRECIST (CT, MRI, or PET/CT) b 
X 
X 
Fresh tumor biopsy 
X c 
Subsequent anticancer therapy 
X 
X 
Survival status 
X 
X 
Study procedures and examinations 
Physical examination, 
X 
X 
ECOG 
X 
X 
Vital signs 
X 
X 
Assessment of AEs/SAEs 
X 
X 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 58 
 
 
 
Concomitant medications 
X 
X 
Laboratory tests 
Serumchemistry 
X 
X 
Hematology 
X 
X 
Thyroid function tests (TSH, free T3, free T4) 
X 
Correlative laboratory assays (5 green-top tubes, 8-10 ml per tube) 
Flowcytometry 
Xd 
PBMCcollection 
Xd 
miRNA/mRNA collection (whole blood PAXgene RNA tube) 
Xd 
AE = adverse event; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; TSH = thyroid-stimulating hormone 
a 
For subjects who complete the 12-month treatment period, the last dosing visit within that period is considered to be the EOT visit. Subjects who discontinue 
before 12 months will complete the EOT visit at the time the decision is made to discontinue treatment. 
b 
If a subject discontinues treatment due to confirmed PD, only the EOT disease assessment is required. 
c 
Optional tumor biopsy collected once upon confirmed PD. 
d 
Blood for correlative markers will also be obtained at EOT 
 
 
After 90 days, subjects with investigational product-related SAEs will continue to be followed until resolution as determined by the treating 
physician for safety. 


Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 59 
 
 
Efficacy assessments 
Efficacy 
Tumor assessments will be based on irRC (54) and will be performed according to the schedule 
presented in Section 5. Investigators are required to assess the subjects based on irRC and 
irRECIST. Antitumor activity will a l s o be assessed by RECIST guidelines v1.1 during central 
review of scans. After end-of-treatment subjects will be followed for progression and survival 
every 3 months (± 28 days) thereafter (according to the schedule in Table 6) through the end 
of the study (defined as 5 years after the final subject is enrolled or when all data points to 
assess the end-points of this study have been collected). 
 
Tumor assessments may include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable); cross-sectional imaging using CT, 
positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) scan of the 
chest, abdomen, and pelvis, and CT or MRI scan of the brain. Computed tomography or MRI 
scan of the brain will be performed if the subject is neurologically symptomatic. The preferred 
method of disease assessment is CT with contrast. The same method is preferred for all 
subsequent tumor assessments. If PET/CT imaging is utilized, the metabolic changes 
(alterations in FDG avidity) will be noted, but these changes alone will not guide therapy 
unless the treating investigator deems it to be necessary and it is approved by the principal 
investigators. 
Physical examination 
Lesions detected by physical examination will only be considered measurable if superficial, 
eg, skin nodules and palpable lymph nodes. Documentation by color photography including 
ruler is recommended for estimating the size of skin lesion. 
 
Computed tomography scan with contrast of the chest, abdomen, 
and pelvis (optional scan of pelvis unless known pelvic disease is present 
at baseline) 
Computed tomography 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. 
 
Magnetic resonance imaging scans 
Magnetic resonance imaging of the chest, abdomen and pelvis is acceptable for measurement 
of lesions provided that the same anatomical plane is used for serial assessments. Computed 
tomography or MRI scan of the brain will be performed only at screening or if the subject is 
neurologically symptomatic. If possible, the same imaging modality should be used for serial 
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Date: 17 May 2017 Page | 60 
 
 
evaluations. In case of MRI, measurements will be preferably performed in the axial 
(transverse) plane on contrast-enhanced T1-weighted images. However, there are no specific 
sequence recommendations. 
 
Positron Emission Tomography – Computed Tomography 
At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with 
IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT introduces additional 
data, which may bias an investigator if it is not routinely or serially performed. 
 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG- 
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
Note: A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
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 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 61 
 
 
slice thickness and a minimum of 10 mm). 
◦ 
10 mm caliper measurement by clinical exam (when superficial). 
◦ 
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is 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 (eg, “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
• New Lesions - If measurable, new lesions will be measured and included as target 
lesions. Up to 3 additional target lesions (maximum of 2 additional lesions per organ) 
may be added in this way. Other new lesions will be included as non-target lesions. 
 
Evaluation of Tumor Response by irRC 
Tumor response will be assessed by the irRC and irRECIST (54). irRECIST and irRC are  a 
reconciliation of RECIST guidelines v1.1 with the original irRC (55). The latter standard 
incorporated principles important for assessment of IMT for cancer, but fundamentally 
differed from RECIST in using 2-dimensional tumor assessment. In contrast, irRECIST is 
based on 1- dimensional tumor measurement, but it differs from RECIST guidelines v1.1 in 
the following key ways: 
 
• Under RECIST guidelines v1.1, the appearance of new lesions indicates PD. Under 
irRECIST, new measurable lesions are incorporated in the tumor burden, which is used 
 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 62 
 
 
to determine immune-related progressive disease (irPD), immune-related partial 
response, and immune-related complete response (irCR). New nonmeasurable lesions 
preclude irCR. 
• Under RECIST guidelines v1.1, there is no confirmation for PD. In addition, responses 
and irPDs must be confirmed by consecutive scans at least 4 weeks apart, assuming no 
clinical deterioration. 
 
The following sub-sections describe irRECIST in more detail. 
 
Tumor Burden 
At baseline, the tumor burden is the sum of single diameters (short axis for nodal lesions, 
longest diameter for other lesions) for the target lesions. In subsequent scans, the diameters of 
new measurable lesions are added to the tumor burden. If a subject is retreated, then up to 5 
target lesions (perhaps different from the original lesions) will be selected and a new baseline 
tumor burden will be established. 
 
Overall Response at a Single Time Point 
Table 7 shows the disease response will be determined at a single assessment based on 
irRECIST. 
 
Table 7 
Immune-related Response Evaluation Criteria in Solid Tumors: Overall 
Response 
 
Tumor Burden 
(Baseline and New) 
Non-Target Lesions 
(Baseline and New) 
Response 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short axis) 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short axis) 
a 
irCR 
≥ 30% decrease from baseline 
Any 
a 
irPR 
≥ 20% increase from nadir and at least 5 mm 
Any 
a 
irPD 
Neither sufficient decrease to qualify for PR, 
nor sufficient increase to qualify for PD 
Any 
irSD 
Disappearance of all non-nodal lesions. All 
pathologic lymph nodes < 10 mm 
Any other than disappearance of all non-nodal 
lesions and reduction of pathologic lymph 
nodes < 10 mm 
a 
irPR 
b 
Not all evaluated 
Any 
irNE 
irCR = immune-related complete response; irPD = immune-related progressive disease; irPR = immune- 
related partial response; irNE = immune-related not evaluable; irSD = immune-related stable disease; PD = 
progressive disease; PR = partial response. 
 
a 
Selection as best overall response requires confirmation by 2 consecutive measurements at least 4 
weeks apart. 
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b 
If some lesions are measured, response may be inferred from available measurements. For example, 
growth in evaluated target lesions may be sufficient for irPD regardless of status of non-evaluated lesions. 
 
Safety assessments 
The following laboratory variables will be measured: 
 
Laboratory Safety Variables 
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 concerning 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 Sections 5.1, 5.2 and 5.3. 
 
Serum Chemistry 
• 
Calcium 
• 
Lipase 
• 
Chloride 
• 
Gamma glutamyl transferase 
• 
Magnesium 
• 
Lactic dehydrogenase 
• 
Potassium 
• 
Uric acid 
• 
Sodium 
• 
Creatinine 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Aspartate aminotransferase (AST) 
• 
Glucose 
• 
Alanine aminotransferase (ALT) 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Total protein 
• 
Total bilirubin 
• 
Indirectbilirubin – not required for week 10 or 14 
• 
Thyroid stimulating hormone (TSH), free T4, 
free T3 
• 
Amylase 
Note for serum chemistries: Tests for AST, ALT, ALP, indirect bilirubin and total bilirubin must be 
conducted concurrently and assessed concurrently. 
 
Hematology 
• 
White blood cell count with differential 
• 
Platelet count 
• 
Hemoglobin 
• 
Mean corpuscular volume 
• 
Prothrombin time/ International Normalized Ratio 
• 
Mean corpuscular hemoglobin concentration 
 
Urinalysis 
• 
Color 
• 
Glucose 
• 
Appearance 
• 
Ketones 
• 
Specific gravity 
• 
Blood 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 65 
 
 
• 
pH 
• 
Bilirubin 
• 
Protein 
 
Pregnancy Test (females of childbearing potential only) 
• 
Urine human chorionic gonadotropin 
• 
Serum beta-human chorionic gonadotropin (at screening only) 
 
Other Safety Tests 
• 
Hepatitis B surface antigen, hepatitis C antibody 
• 
Human immunodeficiency virus (HIV) antibodies 
 
Physical examination 
Physical examinations will be performed according to institutional guidelines on study days 
noted in Sections 5.1, 5.2 and 5.3, and weight and height will be assessed (at screening only). 
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 prestudy grade or below. 
 
ECG 
Electrocardiograms (12-lead) will be recorded on study days as noted in Sections 5.1 and 
5.2. Electrocardiograms recorded on Day 1 will be obtained in triplicate (all 3 within a 5- 
minute time period). In case of clinically significant ECG abnormalities, including an ECG 
that demonstrates a QT corrected using Fridericia’s formula (QTcF) value > 500 
millisecond, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 
minutes) to confirm prolongation. 
 
Vital signs 
Vital signs (temperature, blood pressure [BP], pulse rate, and respiratory rate) will be 
measured on study days noted in Sections 5.1, 5.2 and 5.3. 
 
Other assessments 
Biomarker analysis 
Sample collection and processing. Both diagnostic and research tissue collection activities will 
be performed by members of the MD Anderson Cancer Center Institutional Tissue Bank (ITB) 
supervised by specialized pathologists. Tissue, cell and blood specimens will be processed 
immediately after procurement in order to preserve the quality of tissue, cells and analytes. All 
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Date: 17 May 2017 Page | 66 
 
 
biospecimens will be collected using the Biorepository NCI Best Practices, and standard 
operating procedures (SOPs). All specimens and derivatives are given de-identified numbers. 
 
Translational studies to be performed on tissue and blood will be detailed in a separate manual. 
A brief description of each type of specimen collection and processing is included below: 
 
1) Core needle biopsy (CNB) samples: At least 5 cores will be obtained from the CNB 
procedure, and if possible, fine needle aspiration (FNA) specimens will be collected. Whenever 
possible additional passes to obtain fresh tissue for flow cytometry will be done. The CNB cores 
(~6-8 mm in length) will be processed as FFPE and fresh frozen specimens. The FNA samples 
will be placed on 4-6 smears and fixed in alcohol-based fixative immediately after collection, 
and if possible, a cell-block specimen will be prepared. The CNB and FNA specimens will be 
examined for quality control and pathological characterization before being utilized for 
immune-profiling, as well as for DNA, RNA, protein extractions and flow. These samples will 
be stored at -80°C. 
 
2) Tissue collection from surgically resected tumors (during or prior to start of therapy): Fresh 
frozen and formalin-fixed and paraffin-embedded (FFPE) specimens will be obtained. For fresh 
frozen and FFPE collections, at least two specimens, tumor and adjacent normal tissue will be 
removed from removed from the surgically resection immediately. The fresh specimens if 
obtained will be used for: a) fresh tissue for flow cytometry and other procedures that require 
fresh tissue samples; b) “snap” frozen in liquid nitrogen; c) RNA “later”; d) OCT embedded; 
and, e) fixation in formalin. Samples will be stored at -80°C for subsequent isolation of nucleic 
acids and protein. For all fresh tissue samples, corresponding FFPE tissues will be available, 
including tumor and normal tissue specimens. The tissue specimens will be examined for quality 
control and pathological characterization before being utilized for immune-profiling, as well as 
for DNA, RNA and protein extractions. 
 
3) Peripheral blood specimens: Blood will be collected at baseline, week 2, week 6 and at 
confirmed progression (5 green-top tubes, 8-10 ml per tube at each time point) per patient. Of 
those, plasma and peripheral blood mononuclear cells (PBMCs) will be immediately obtained, 
aliquoted and stored at -80°C. 
 
Pathological evaluation and quality control (QC). All tissue specimens collected will be 
reviewed by a reference pathologists. At least, three types of QC activities for specimens 
collected will be performed: a) histology/cytology examination of the tissues and cells; b) tissue 
quality assessment of fresh specimens for extraction of DNA, RNA and proteins, and to prepare 
histology specimens such as whole sections for immunohistochemistry and 
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immunofluorescence; and, c) quality assessment of DNA, RNA and protein extracted. All 
histology stained samples will be scanned and digital images will be available. 
 
Nucleic acids and protein extraction. All blood, tumor and corresponding normal tissue 
samples will be subjected to DNA, RNA and protein extraction using standard methods. DNA 
and RNA quantity and integrity will be assessed using NanoDrop 1000 spectrophotometer 
(Nanodrop technologies) and Pico-green analysis. Also, protein lysate will be extracted using 
standard methods. 
 
Immuno-profiling: Fresh frozen and FFPE tissues will be used for analysis of immune markers. 
For immunohistochemistry (IHC) and immunofluorescence (IF) analyses, histology sections 
obtained from both type of tissue specimens will be will be utilized. IHC and IF will be 
performed on autostainers or manually. All antibodies used will be optimized for IHC/IF by 
examination of positive and negative controls and testing of the antibodies standard methods, 
including Western blotting. All pathology slides will be scanned into a digital image scanner 
and analyzed using image analysis software, including among others the Aperio Image 
Toolbox™ (Leica Biosystems) and Inform™ (Perkin-Elmer). For quantification of immune 
markers (immune cells infiltrates, immune checkpoints and other proteins) whole tissue sections 
or five randomly selected one-mm square areas within the tumor region will be selected for 
analysis. In selected cases, peritumoral and intratumoral areas will be examined. The expression 
of markers in malignant cells will be evaluated using image analysis to determine the percentage 
of positive cells (0 to 100) and intensity (0 to 3+), with a total score ranging from 0 to 300 (H- 
score system). The expression of protein markers and inflammatory cells will be examined using 
an infiltrate density score established by the number of cells expressing a determined marker by 
tissue area. The data and digital images will be deposited in a central database for review of 
pathology collaborators. For muliplex IF analysis, we will use the specialized microscopes such 
as the Vectra system (Perkin-Elmer) which includes the Nuance software. Among other 
markers, we will study the expression of the following PD-L1, PD-1, FOXP3, CD3, CD4, CD8 
CD20, CD45Ro, CD57, CD68, and Granzyme B; additional markers will be selected according 
the results of the initial analysis. 
 
As additional exploratory analysis, we will consider to perform tumor DNA genotyping by next- 
generation sequencing and other methodologies to identify mutations, copy number variations 
and translocations, as well as to perform clonal analysis of T and B cells. Gene expression 
analysis of immune and other relevant signatures using RNA sequencing, microarray and other 
methodologies (e.g., RNA-sequencing, Nanostring™, HTG EdSeq™, in situ hybridization, etc.) 
will be also used as exploratory methodologies to identify expression of gene(s) associated to 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 68 
 
 
outcome of patients. Finally, protein analysis of tissues’ lysates may be performed applying 
protein arrays (e.g., RPPA, multiplex ELISA, etc.), mass spectrometry and other techniques to 
identify protein(s) correlated with patients’ outcome. 
 
Storage, re-use and destruction of biological samples 
If the patient agrees, the remaining biomarker samples (tumor, blood) may be stored for up to 
15 years and further analyzed to address scientific questions related to MEDI4736 and 
tremelimumab, findings related to the drug class or disease, as well as reagent and assay 
availability. 
 
Withdrawal of Informed Consent for donated biological samples 
Studydata are protected by the use of a SID number, which is a specific number for each subject. 
The investigators are in control of the information that is needed to connect a study sample to a 
subject. A subjects 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 used but no additional data or samples will 
be collected unless specifically required to monitor safety of a subject. 
 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
6.1 Definition of Adverse Event 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product, medical treatment or procedure and which 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product, 
medical treatment or procedure whether or not considered possibly, probably or definitely 
related to the medicinal product. 
 
Unexpected Adverse Event 
An AE is “unexpected” when its nature (specificity), severity, or frequency are not consistent 
with (a) the known or foreseeable risk of AE associated with the research procedures 
described in the protocol, informed consent form or the investigator brochure. 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 69 
 
 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
Death 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
 
 
When there is doubt regarding an AE meeting the criteria for an SAE, the investigator should 
default to reporting the AE as an SAE. 
 
There are special circumstances in which an SAE reporting form is used to communicate 
important clinical trial safety observations that may not constitute an SAE. 
 
1. Pregnancy: Although pregnancy is not considered an SAE and is instead a normal 
human experience, all pregnancies reported in the month before or month after last 
investigational treatment must be reported to sponsor. 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 70 
 
 
1. Overdose: An overdose is defined as the accidental or intentional administration of 
any dose of a product that is considered both excessive and medically important. 
For reporting purposes, an overdose will be considered, regardless of adverse 
outcome, as an important medical event. All cases of overdose must be reported 
immediately to the sponsor. 
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. 
• Diarrhea / Colitis and intestinal perforation 
• Pneumonitis / ILD 
• hepatitis / transaminase increases 
• Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• Rash / Dermatitis 
• Nephritis / Blood creatinine increases 
• Pancreatitis / serum lipase and amylase increases   
• Myocarditis 
• Myositis / Polymyositis 
• Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eyeskin, haematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis. 
• In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with 
a different underlying pharmacological aetiology are also considered AESIs. 
• Further information on these risks (e.g. presenting symptoms) can be found in the 
current version of the durvalumab Investigator’s Brochure. More specific guidelines 
for their evaluation and treatment are described in detail in the Dosing Modification 
and Toxicity Management Guidelines (please see Appendix 1). These guidelines have 
been prepared by the Sponsor to assist the Investigator in the exercise of his/her 
clinical judgment in treating these types of toxicities.  These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting 
investigator. 
Adverse Event Severity 
All 
AEs 
will 
be 
evaluated 
according 
to 
the 
NCI 
CTCAE 
v4.03 
(2010) 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 71 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
For AEs not listed in this reference scale, severity will be assessed by the investigator according 
to the criteria in Table 8. 
 
Table 8 
Adverse Event Severity Assessment 
 
Grade 1 (Mild) 
Requires minimal or no treatment and do not interfere with 
the patient’s daily activities. 
Grade 2 (Moderate) 
Results in a low level of inconvenience or concern and 
may interfere with the patient’s functioning. 
Grade 3 (Severe) 
Interrupts a patient’s usual daily activity, may be 
incapacitating and may require systemic drug therapy or 
other treatment. 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 72 
 
 
Grade 4 (Life 
threatening) 
Places the patient at immediate risk of death from the 
reaction as it occurred; it does not include a reaction that, 
had it occurred in a more severe form, might have caused 
death. 
Grade 5 (Death) 
Death 
 
 
Changes in the severity of an AE should be documented to enable an assessment of the duration 
of the event at each level of intensity. Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Relationship to Investigational Drug 
The relationship between an AE and the study treatment will be determined by the investigator 
on the basis of his or her clinical judgment and the definitions in Table 9. 
 
Table 9 
Assessment of Relationship 
 
Definitely related 
AEs clearly attributable to study treatment administration 
Probably related 
AEs for which there is a reasonable possibility of causal 
association to study treatment 
Possibly related 
AEs for which there is confounding by comorbidities, medications 
or other considerations but for which it is not unreasonable that the 
AE may have been caused by study treatment It is not appropriate 
to invoke 
“you can’t rule it out.” 
Not related 
AEs that are clearly not causally related to study treatment, or for 
which there is a clear alternative explanation 
AE = adverse event 
 
If there is any question whether or not an AE is possibly, probably or definitely related, the 
investigator should default to conservatism in categorization. Similarly, the investigator should 
default to conservatism by calling an AE an SAE if there is doubt regarding the serious nature 
of an AE. 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 73 
 
 
Adverse Event Collection Period 
All enrolled patients will have periodic assessment of clinical and laboratory AEs. Please see 
Section 6.5 for guidelines on AE Reporting. 
 
Adverse Event Reporting 
At each study visit (including unscheduled visits), the investigator, or designee, will determine 
whether any AEs have occurred. Any AE that is possibly, probably or definitely related to study 
drug (section 6.3) will be reported in the patient’s medical record and on the AE CRF page and 
each will be classified according to the criteria in Section 6.2 and 6.3. Any AEs that are grade 3 
and above (section 6.2) regardless of relationship, will be reported in the patient’s medical 
record and on the AE CRF page and each will be classified according to the criteria in Section 
6.2 and 6.3. If known, the diagnosis should be recorded, in preference to the listing of individual 
signs and symptoms. Adverse event reporting for each patient starts when the patient signs the 
ICF and continues at all subsequent visits through the end-of-treatment visit. Any pre-existing 
conditions that are detected as part of the initial screening procedures will need to be reported 
in the medical history and not as an AE. However, pre-existing conditions that worsen after 
enrollment should be reported as an AE. Adverse events will be reported to FDA in accordance 
with the requirements outlined in 21 CFR 312.32. AESI’s will be expedited to regulatory 
authorities, study investigators and DMC. 
 
Each AE will also be assessed for meeting the criteria for a serious adverse event. If the AE 
meets the criteria of a SAE, expedited reporting must occur. 
 
Serious Adverse Event Reporting 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
 
If a SAE occurs and is deemed related or possible related (expected and unexpected), 
Medimmune will be notified within 5 days of awareness of the event. In particular, if the SAE 
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is fatal, Medimmune must be notified within 24 hours, irrespective of the extent of available AE 
information. In the rare event that the investigator or designee does not become aware of the 
occurrence of a SAE immediately, the investigator or designee must report the event within 5 
days (non-fatal SAE’s) or 24 hours (fatal SAE’s) of their awareness and document the time of 
when his/her first awareness occurred. Institutional guidelines for SAE reporting will be 
followed in addition to the above. 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 90 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
Additionally, any serious adverse events that occur after the 90 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
Pregnancy 
Sexually active men and FCBP must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimized. Before enrolling FCBP in this 
clinical trial, all FCBP must be advised of the importance of avoiding pregnancy during trial 
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Date: 17 May 2017 Page | 75 
 
 
participation and the potential risk factors for an unintentional pregnancy. All patients (men and 
women) must sign an informed consent form documenting this discussion. 
 
All FCBP must have a negative pregnancy test within 3 days prior to the study treatment 
initiation. If the pregnancy test is positive, the subject must not be enrolled in the study. 
 
In addition, all FCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
If following initiation of study treatment, it is subsequently discovered that a trial subject is 
pregnant or may have been pregnant within one month before or after study treatments will be 
permanently discontinued and the patient will be followed as possible by the investigator or 
designated health care professional to determine pregnancy outcomes for both mother and baby. 
If a male patient enrolled in study has a female sexual partner who becomes pregnant after 
initiation of study, then the study subject should be asked permission for the investigator (or 
designated health care professional) to approach his partner for permission to follow-up with 
the pregnant partner to determine outcomes for both mother and baby. 
 
Overdose 
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochure, and as specified in this protocol. 
 
If the overdose results in an AE, the AE must also be recorded on the AE eCRF. 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. The 
investigator will use clinical judgment to treat any overdose. 
 
 
Protocol Deviations 
A protocol deviation is any change, divergence or departure from the study design or procedures 
defined in the protocol such as the accidental destruction of a tissue biopsy sample intended for 
phenotyping to characterize the subject's type of tumor in order to determine study eligibility, 
or an accidental misread of a laboratory value as being within the reference range when it 
actually is sufficiently abnormal to preclude study participation by the subject. 
 
Important protocol deviations are a subset of protocol deviations that might significantly affect 
the completeness, accuracy, and/or reliability of the study data or that might significantly affect 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 76 
 
 
a subject’s rights, safety or well being such as the PI prescribing or administering the wrong 
treatment, or the study subject being scheduled to return for follow-up intervention outside the 
protocol-dictated window as a convenience to the patient or study staff. 
 
The investigator is responsible for complying with and adhering to IRB procedures for reporting 
protocol deviations and violations. All protocol deviations should be documented and forwarded 
to Medimmune or its authorized representative on a yearly basis. All protocol violations will be 
reported as per MD Anderson’s institutional guidelines. 
 
Protocol deviations will be collected during the study, and reported to the IRBs yearly in the 
annual report. 
 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
Identity of investigational product(s) 
Durvalumab 
Investigational Product: Durvalumab is a human immunoglobulin (Ig)G1κ mAb directed against 
PD-L1, with reduced binding to C1q and the Fcγ receptors. Durvalumab is selective for human 
PD-L1 and blocks the binding of human PD-L1 to the human PD-1 and CD80 receptors. 
Medimmune is the manufacturer of durvalumab. 
 
Therapeutic Indication: Durvalumab is being developed for the treatment of patients with 
advanced sarcomas. 
 
Tremelimumab 
Investigational Product: Tremelimumab is a human immunoglobulin (Ig)G2 monoclonal 
antibody (mAb) specific for human cytotoxic T lymphocyte-associated 4 (CTLA-4; cluster of 
differentiation [CD] 152). Tremelimumab has no cross-reactivity to related human proteins, or 
to mouse, hamster, rat, or rabbit CTLA-4, but it does demonstrate cross-reactivity to 
cynomolgus monkey CTLA-4. Medimmune is the manufacturer of tremelimumab. 
 
Therapeutic Indication: Tremelimumab is being developed for the treatment of patients with 
advanced sarcomas. 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 77 
 
 
Summary 
 
 
 
 
 
< 
Dose and treatment regimens 
The dose of durvalumab will be 1500 mg every 4 weeks, and the dose of tremelimumab will be 
75 mg every 4 weeks. Both agents will be administered by intravenous (IV) infusion. 
Tremelimumab will be administered first, and the infusion duration will be approximately 1 
hour. The durvalumab infusion will start approximately 1 hour after the end of the 
tremelimumab infusion, and the infusion will be administered over approximately 1 hour. The 
combination of both agents shall be administered at Q4 week intervals for 4 doses, after which 
the durvalumab will continue to be at Q4 week intervals (up to 8 additional doses). If toxicity 
was noted with the combination, investigator can decide to continue durvalumab alone in case 
patient is having clinical benefit (SD or better). 
 
Labelling 
Durvalumab 
 
Liquid formulation: Durvalumab is formulated at 50 mg/mL. The investigational product is 
supplied as a vialed liquid solution in clear 10R glass vials closed with an elastomeric stopper 
and a flip-off cap overseal. Each vial contains 500 mg (nominal) of active investigational 
product at a concentration of 50 mg/mL. 
Mode of Administration: The reconstituted solution (for lyophilized product) or liquid product 
is to be diluted with 0.9% (w/v) saline for IV infusion. 
 
         Tremelimumab 
Tremelimumab will be supplied by AstraZeneca either as a 400-mg or a 25-mg vial solution for 
infusion after dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL.  The nominal fill 
volume is 20.0 mL for the 400-mg vial and 1.25 mL for the 25-mg vial.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
original container until use to prevent prolonged light exposure. 
Storage 
Durvalumab: Unopened vials of durvalumab lyophilized or liquid Drug Product must be stored 
at 2oC to 8oC (36oF to 46oF). 
Tremelimumab: Unopened vials of Tremelimumab must be stored at 2oC to 8oC (36oF to 46oF) 
and must not be frozen. This product should be protected from light when not in use. 
 
Compliance 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
1500 mg Q4 weeks 
MedImmune 
Tremelimumab 
75 mg Q4 weeks 
MedImmune 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 78 
 
Investigational product is administered by study site personnel, who will monitor compliance. 
 
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. 
Concomitant and other treatments 
The investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the treatment phase of the study (EOT visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
patient’s medical record. 
 
Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in Section 7.7.2. Best supportive care 
(including antibiotics, nutritional support, correction of metabolic disorders, optimal symptom 
control and pain management [including palliative radiotherapy, etc]) should be used when 
necessary for all subjects. Opioids can be used but with caution and under medical control after 
discussion with the study chair. 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 79 
 
 
Prohibited Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator to make sure they are permitted on the trial. The 
following medications are considered exclusionary during the study. 
1. Any investigational anticancer therapy 
2. Monoclonal antibodies against CTLA-4, PD-1, or PD-L1 through 90 days post last 
dose during the study 
3. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), IMT, 
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 
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, topical, and intranasal 
corticosteroids is permitted. Temporary uses of corticosteroids for concurrent 
illnesses (eg, food allergies, CT scan contrast hypersensitivity, etc) are acceptable 
upon discussion with the Principal Investigators 
5. Live attenuated vaccines during the study through 180 days after the last dose of 
investigational product 
6. Inactivated vaccinations ± 30 days around any dose of investigational product 
7. Herbal and natural remedies should be avoided 
 
STATISTICAL ANALYSES 
Statistical considerations 
Response to systemic therapy in metastatic/refractory disease is low and is less meaningful if 
not correlated with improvement in survival. For this reason, PFS has become an acceptable 
metric in the measurement of efficacy in sarcomas with refractory disease or in sarcomas with 
primary resistance to anthracycline-based chemotherapies. The objective data to support use of 
PFS as a primary end point in sarcomas was derived from a review of the EORTC sarcoma 
database by van Glabbeke et al in 2002 (46). In the EORTC analysis, which involved 12 clinical 
trials, patients with no prior treatment received experimental agents were compared to those 
with prior systemic treatment who were received experimental agents. In a multivariate analysis, 
patients with prior therapy obtained an improved PFS with active agents compared to inactive 
agents. For previously treated patients, an active agent was associated with a PFS of 
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Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 80 
 
 
at least 39% and 14% at 3 months and 6 months, respectively. Inactive agents were associated 
with a PFS of 21% and 8% at 3 months and 6 months, respectively. 
 
A concern with the use of PFS at 3 months as a primary endpoint for this study is whether 
response assessment at 3 months will fail to capture patients who may have delayed benefit from 
check-point inhibitors, however it has been shown that the majority of patients with response to 
anti-PD-1 therapy obtained response within 12 weeks of drug initiation (9). 
 
The goal of this trial is to assess the efficacy of MEDI4736 in combination with tremelimumab 
by evaluating progression-free rate at 12 weeks for each cohort. 
 
Design and sample size/power 
 
For cohort 3, 4 and 5, we will treat up to 25 patients within each cohort. The primary efficacy 
endpoint will be progression-free survival at 12 weeks (PFS12 weeks). 12-week PFS is defined as 
evidence of stable disease or better 12 weeks after the initiation of therapy. In the meanwhile, we 
will also monitor the toxicity  of  the  agent (56). Toxicity  will  be  assessed  within  the  first 
two cycles of the treatment. If there is a high probability that the PFS12 weeks is unlikely to be at 
least 40% or that the unacceptable toxicity rate (as described in section 3.2.2) is likely to be 
greater than 30%, the drug would not be considered of interest for further study. Formally if 
Pr(PFR12 weeks < 0.40 | Data) > 0.90 or Pr(toxicity rate > 0.30 | Data) > 0.90, the corresponding 
cohort will be stopped. The assumed prior distribution for PFS12 weeks is Beta (0.4, 0.6) and for 
toxicityis Beta (0.3, 0.7). The resulting prior means are 0.40 and 0.3 for PFS12 weeks and toxicity 
rate, respectively, with one patient worth of information. Each of the disease cohorts will be 
monitored separately in cohorts of 5 patients after a minimum of 5 patients have completed two 
cycles, a summary will be submitted to the IND Office Medical Monitor after each cohort of 5 
patients. All patients who receive at least one study related treatment will be included in the 
analysis. Patients who are not evaluable for response to the treatment by 12 weeks post 
treatment initiation will be considered treatment failure. Patients who withdraw consent or 
become ineligible prior to receiving any study related treatment (full or partial dose) will be 
replaced. Consideration will be given to stop the cohort according to the following stopping 
boundaries. 
 
 
 
 
 
Table 10 
Stopping boundaries for PFS12 weeks futility monitoring or for excessive 
toxicity monitoring within each cohort 
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Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 81 
 
 
# 
Patients 
(Inclusive) 
# 12-week PFS (Inclusive) 
# Toxicities (Inclusive) 
5 
0 
4-5 
10 
0-2 
6-10 
15 
0-3 
8-15 
20 
0-5 
9-20 
25 
Always stop with this many 
patients 
Always stop with this many 
patients 
 
 
 
Table 11 
Operating characteristics for the stopping rules for PFS12 weeks futility 
monitoring or for excessive toxicity monitoring in the expansion phase 
 
True 
Progression- 
Free Rate 
True 
toxicity 
Rate 
Probability 
Stop Early 
Average 
number of 
patients 
treated 
0.20 
0.15 
0.86 
11.8 
0.20 
0.30 
0.88 
11.4 
0.20 
0.45 
0.95 
10.0 
0.20 
0.50 
0.97 
9.3 
0.40 
0.15 
0.25 
21.3 
0.40 
0.30 
0.35 
20.1 
0.40 
0.45 
0.71 
15.7 
0.40 
0.50 
0.83 
13.8 
0.60 
0.15 
0.02 
24.6 
0.60 
0.30 
0.16 
23.1 
0.60 
0.45 
0.62 
17.5 
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Date: 17 May 2017 Page | 82 
 
 
0.60 
0.50 
0.77 
15.2 
 
For cohort 1, 2 and 6, since these include more than distinct subtypes, in order to assess anti- 
tumor activity of the treatment regimen within each histologic subtype, we will open enrollment 
simultaneously for each of the histologic subtypes but keep the maximum number of patients at 
25 in each of these cohorts. The stopping boundaries for PFS12 weeks futility monitoring or for 
excessive toxicity monitoring in Table 10 will be applied within each histologic subtype. For 
example, enrollment to vascular sarcomas-Leiomyosarcomas will be stopped if none of the first 
5 patients with vascular sarcomas-Leiomyosarcomas were progression-free at12 weeks or 4 or 
more patients had the unacceptable toxicity. With 5 patients enrolled within each histologic 
subtype, the probabilities of observing one or more patients with 12-week PFS are 67.2%, 92.2% 
and 99% if the true 12-week PFS are 20%, 40%, and 60% while the probabilities of observing 
four or more patients with toxicities are 0.2%, 3.1% and 18.8% if the true toxicity rate are 15%, 
30%, and 50%. If 10 patients with the same histologic subtype have been enrolled, the 
probabilities of observing three or more patients with 12-week PFS are 32.2%, 83.3% and 98.8% 
if the true 12-week PFS are 20%, 40%, and 60% while the probabilities of observing six or more 
patients with toxicities are 0.1%, 4.7% and 37.7% if the true toxicity rate are 15%, 30%, and 
50%. 
 
Sample size estimate 
The study consists of 6 cohorts arranged by histologic classifications. Within each cohort, a 
minimum of 5 patients (in cohorts 3, 4 and 5), 10 patients (cohort 2), 15 patients (cohort 1) and 
25 (cohort 6) will be enrolled. The maximum number of patients in all the cohorts will be 25 
patients. Therefore, the minimum patients to be enrolled onto this trial will 65 patients and the 
maximum is 150 patients. 
 
Definitions of analysis sets 
The analysis of data will be based on different subsets according to the purpose of the analysis. 
 
Efficacy analysis set 
All patients who have received at least one dose of treatment (durvalumab and/or 
tremelimumab) and have disease reassessed will be considered evaluable for response. Patients 
who drop out the study due to drug-related toxicity and/or death before the time of first response 
assessment will be included in the denominator for the estimation of PFS at 12 weeks and 
response rate. 
 
Safety analysis set 
All patients who received at least 1 full or partial dose of durvalumab in combination with 
tremelimumab. 
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Outcome measures for analyses 
Primary Endpoint is PFS at 12 weeks. 
 
Seondary endpoints include 1) response rate (CR,PR) assessed by irRC and RECIST; 2) 
toxicities; 3) PFS and OS. 
 
Correlative endpoints include PD-1/PD-L1, immune panels including AIC, CD4, CD8 et al 
measured in tumor as well as in blood samples over time. 
 
Methods for statistical analyses 
Analysis of the primary variable(s) 
If a cohort is stopped early, this drug will not be considered of interest for future study for this 
cohort of patients. If all 25 patients are accrued, we will estimate both the PFS at12 weeks and 
toxicity rate and the corresponding 95% posterior credible intervals. We will also apply a 
Bayesian hierarchical statistical model (57) to analyze the data from all six cohorts to borrow 
information from each other. 
 
Analysis of the secondary variable(s) 
PFS is defined as the time from treatment onset to either disease progression as defined by 
RECIST or death from any cause, whichever occurs first. OS is defined as the time from 
treatment onset to death. For events that have not occurred by the time of data analysis, times 
will be censored at the last contact at which the patient was known to be progression-free for 
PFS, or the last time the patient was known to be alive for OS. PFS and OS will be estimated 
using the Kaplan-Meier method (58). Log-rank test (59) will be performed to test the difference 
in survival between groups. Regression analyses of survival data based on the Cox proportional 
hazards model (60) will be conducted on PFS or OS. The proportional hazards assumption will 
be evaluated graphically and analytically, and regression diagnostics (e.g., martingale and 
Shoenfeld residuals) will be examined to ensure that the models are appropriate. 
 
Toxicity data will be summarized by frequency tables. For the toxicity endpoint, per-treated 
analysis will be used to include any patient who received the treatment regardless of the 
eligibility nor the duration or dose of the treatment received. Toxicity rate will be estimated with 
95% credible interval. 
 
Exploratory data analysis and graphical methods will be applied to examine the distribution of 
the biomarker data, error checking, and outlier identification. Range check and consistency 
check will be applied to ensure the data quality. Standard distribution plots such as the histogram 
and box-plot will be applied. A more versatile BLiP plot will be used to facilitate the plotting 
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of both discrete and continuous data. Since PD-1/PD-L1 IHC expression and the immune 
correlates will be measured at baseline and multiple post treatment time points. T-test/ANOVA 
or their nonparametric countparts, Wilcoxon rank-sum test/Kruskal-Wallis test will be used to 
detect differences of the biomarkers between groups (1) Linear mixed effect models for repeated 
measures analysis (61) will be employed to assess the change of the biomarkers over time with 
multi-covariates including disease characteristics (tumor stage, site, pathology), and other 
patient prognostic factors. Appropriate transformation of the outcome assessment values will be 
used to satisfy the normality assumption of linear mixed effect model. 
 
STUDY AND DATA MANAGEMENT 
Training of study site personnel 
Before the first subject is entered into the study, the Principal Investigator via site Initiation 
Meeting will review and discuss the requirements of the Clinical Study Protocol with 
investigational research staff. Also, Principal Investigator will train investigational research 
staff 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 Delegation of Authority log. 
 
Data and Safety Monitoring 
The Principal Investigators will be responsible for monitoring the safety and efficacy of the 
trial, and complying with all reporting requirements. This will be accomplished under the 
oversight of the IND office of MD Anderson Cancer Center (MDACC). 
 
The MDACC IND office is responsible for monitoring data quality and patient safety for all 
interventional investigator-initiated trials (IIT's). The MDACC IND office will have 
oversight of this protocol. Also, the IIT will be audited by the IND Clinical Research Quality 
Specialist at least once a year. 
 
The IND reviews all IRB reportable serious adverse events, monitoring/ auditing reports, and 
protocol deviations and has the authority to recommend closure and/or suspension for trials 
on which there are safety or trial conduct issues and may submit recommendations for 
corrective actions. All IRB reportable serious adverse events, monitoring/ auditing reports 
will be reviewed by the IND. The Sarcoma Clinical Trials Center will forward the SAE 
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event report to the IRB using the eSAE (electronic Serious Adverse Event ) reporting system 
and they will then be reviewed by the IND Office. 
 
Data Collection and storage 
Electronic and hard copy CRF’s will be provided for the recording of data. Will be using the 
REDCap database for data entry and tracking. With the exception of hard copy case report forms 
utilized for expedited reporting requirements as described in section 6.6 Reporting of SAE’s, 
the remainder of patient data will be collected and submitted via electronic CRFs. All data 
should be substantiated by clinical source documents organized within a patient research record. 
ICH Good Clinical Practices are to be followed. 
 
Federal law requires that an Investigator maintain all study records for two years after the 
investigation is discontinued. 
 
9.4 
Study Timetable and End of Treatment 
An individual subject will be considered to have completed the study if the subject was 
followed through the on-treatment evaluation period or the subject completed at least 1 
on-treatment disease evaluation regardless of the number of doses of investigational 
product that was received. 
 
The end of the treatment (“study completion”) is 5 years after the final subject is enrolled or 
the date the study is closed as all data-points have been collected, whichever occurs first. 
 
ETHICAL AND REGULATORY REQUIREMENTS 
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. 
 
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. 
 
In exceptional circumstances, however, certain individuals might see the personal identifiers 
of a subject. For example, in the case of a medical emergency, a medical monitor or an 
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investigator might know a subject’s identity and also have access to his or her medical 
information. 
 
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 enrollment of any subject into the study. 
 
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
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. 
 
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 
product. MedImmune will provide this information to the principal investigator so that he/she 
can meet these reporting requirements. 
 
Informed consent 
The principal investigator(s) 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 
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Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the MD Anderson 
Cancer Center Investigator(s) and MedImmune. 
 
If there are any substantial changes to the studyprotocol, 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 IRB/IEC and if applicable, before implementation. 
 
Recruitment procedure 
All patients referred to or seeking treatment for advanced stage soft tissue sarcoma and meet 
the eligibility criteria will be offered this trial. 
 
Women and men will be recruited, and are anticipated to be equally represented in the trial. 
Minority participation will be encouraged. 
 
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Clinical Study Protocol 
Drug Substance: Durvalumab 
Study Code: 2015-1071 Edition Number: 2 
Date: 17 May 2017 Page | 92 
 
 
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